In my role as the Director of The Johns Hopkins Sex and Gender Clinic, I have had the opportunity to provide care to 3 broad categories of patients: patients with sexual dysfunctions, patients experiencing gender dysphoria, and patients manifesting a paraphilic disorder. This article will not address sexual dysfunctions or gender dysphoria, but these terms are defined in the Box^1-3 to clearly distinguish them from paraphilic disorders.

Box

Persons with paraphilic disorders (predominantly males) experience recurrent atypical sexual fantasies and urges that cause clinically significant impairment or distress.¹ Those atypical fantasies and urges may be directed towards unacceptable partners such as animals or children, or towards unacceptable behaviors such as public exhibitionism. Table 1¹ lists the paraphilic disorders identified in DSM-5. This article focuses primarily, though not exclusively, upon pedophilic disorder, and its pharmacologic treatment. However, the rationale underlying such treatment is applicable across the paraphilic spectrum. Before providing such treatment, it is important for clinicians to have a clear conceptual understanding of paraphilic disorders.

When is a difference a disorder?

Cancer and respiration are 2 different biologic phenomenon. Cancer causes suffering and impairment, and as a consequence, we label it a disorder. We do so in the hope of learning more about it, and being able to successfully treat it. We do not classify respiration as a disorder because we do not consider it to be harmful.

The spectrum of human sexuality is quite broad, and psychiatry is generally not concerned with private sexual thoughts and behaviors involving consenting adults that do not cause suffering or impairment. When adults choose to engage in “kinky sex” that causes neither harm nor distress, so be it.

Some individuals may be privately aware of experiencing either an exclusive or nonexclusive sexual attraction to children. Some of these individuals may not be distressed by experiencing such attractions, and may be fully capable of resisting the temptation to enact them. In such an instance, even though an individual may be experiencing sexual attractions that are different from the norm, there may not be a sufficient basis for diagnosing pedophilic disorder. However, that difference in sexual phenomenology (ie, mental experience) could rise to the level of a diagnosable disorder if the individual in question expresses distress about experiencing such attractions, and/or if his capacity to resist acting upon them is impaired.⁴ Under such circumstances, treatment would be warranted.

Patients with paraphilic disorders deserve treatment

Prior to establishment of the Betty Ford Clinic in 1982, individuals who were drug- or alcohol-dependent were often portrayed in a negative light and referred to by derogatory pejoratives such as “bum” or “pothead.”⁵ Over time, society came to appreciate that good people, deserving of treatment, can become dependent upon substances, and in recent years there has been considerable support for related research initiatives and humane care. However, there has not been analogous support for individuals who manifest paraphilic disorders, especially those with pedophilic disorder. Instead, such individuals are often perceived as undeserving of mental health care and resources. This has been the case, even though successful treatment of a pedophilic disorder could help prevent the serious consequences of child molestation from occurring.

In contemporary society, the term pedophilia, which is a psychiatric specifier intended to guide research and treatment, has been hijacked by the nonmedical community and turned into a demeaning pejorative. In the collective consciousness of the public, the term pedophilia is routinely and mistakenly equated with the behavior of child molestation. Just as all alcoholics are not drunk drivers, all individuals with pedophilic disorder are not “child molesters.” Conversely, not all “child molesters” have pedophilic disorder.

Continue to: Individuals with other types...

Individuals with other types of paraphilic disorders are frequently similarly maligned and referred to as “perverts” or “deviants.” Public service announcements are frequently aired to reach out to individuals who are depressed, or drug- or alcohol-dependent, or suffering with other forms of mental disorders. When does one hear a public service announcement that encourages young people who may be experiencing disturbing or unacceptable sexual feelings to seek psychiatric treatment? There is a support group on the internet called Virtuous Pedophiles.⁶ That organization is unequivocally opposed to child molestation, while supporting efforts to improve the mental well-being of individuals who, through no fault of their own, experience unwanted pedophilic feelings.

Causes and noncauses

In attempting to elucidate etiology, researchers typically investigate nature (biology) and/or nurture (life experiences). In terms of the development of pedophilic disorder, there is evidence that both nature and nurture can play a role. Researchers have found that boys who are sexually abused are at increased risk for developing pedophilic disorder, and evidence of temporal lobe disturbances has also been documented in some instances.^7,8

From clinical, societal, and forensic perspectives, it may be equally important to identify noncausal factors. Paraphilic disorders, including pedophilic disorder, do not develop as a consequence of volitional choice.⁹ For example, none of us decide which category, or categories, of potential partners are going to attract us sexually. Rather, in maturing we discover the nature of our own sexuality. Children do not ponder their options, somehow deciding while growing up to be attracted to the opposite sex (heterosexuality), the same sex (homosexuality), or both sexes (bisexuality). Similarly, in maturing into adulthood, individuals do not decide to become sexually attracted to prepubescent children. Who would decide to do that? Instead, unlike most of us, some individuals discover this about themselves; this often is a deeply disturbing insight.

It is not an individual’s fault that he or she has a paraphilic disorder. It is, however, his or her responsibility to do something about it. This may require accessing appropriate psychiatric care.

Why treatment may be needed

Sex is a powerful, biologically based appetite that recurrently craves satiation. God or nature has put that drive into all of us to ensure the survival of humanity. Even when that powerful biologic drive becomes misdirected (for example, towards children, or towards a desire to engage in public exhibitionism), it still recurrently craves satisfaction. It does not require mental health expertise to appreciate what a problematic situation this could become.

Continue to: Some individuals need help...

Some individuals need help in overcoming cravings related to nonsexual appetites. For example, Americans spend millions of dollars each year trying to diet; they often require some form of assistance in order to succeed. Individuals who crave drugs or alcohol often require mental health interventions to abstain because they are unable to consistently resist through willpower alone the powerful biologic urges that drive their actions.

The fundamental mental characteristic of any paraphilic disorder is the presence of intense, recurrent, sexual urges of an atypical nature. In the case of a pedophilic disorder, those urges involve sexual feelings about children.² In the case of an exhibitionistic disorder, the afflicted individual experiences intense, recurrent sexual fantasies/urges related to exposing his genitals in public.¹ Clearly, most men do not have to recurrently fight off the urge to act in such a fashion. Given the driven nature of intense erotic cravings, individuals who experience such cravings will frequently require access to competent mental health care.

Pharmacologic treatment of paraphilic disorders

In the future, we may develop a scientifically based understanding of the biologic factors that underlie qualitative differences in sexuality. At that point, it may become possible to intervene pharmacologically, changing the qualitative nature of a sexual urge with pharmacologic interventions. This cannot yet be done. However, much is already known about the biology related to the quantitative (intensity) dimension of sexuality.

In 1939, a Nobel Prize in Chemistry was awarded for the identification and isolation of the hormone testosterone, which energizes sexual drive.¹⁰ If an individual is hungering sexually to expose himself, to view child pornography, or to engage in sexual acts with children, the intensity of such hungers can be significantly reduced by lowering testosterone, thereby enhancing the capacity for successful sexual self-control.

A large body of scientific data has documented a marked decrease in sexually motivated behaviors when testosterone levels are significantly diminished.¹¹ There is also evidence that recidivism rates of sexually motivated crimes can be significantly reduced when testosterone-lowering interventions are used.¹²

Continue to: Historically, removal of the testes...

Historically, removal of the testes (surgical castration) had been the only effective way to reliably lower testosterone. Today, this can be achieved pharmacologically. Use of a sex drive–lowering medication should be considered when either the clinician or the patient is concerned that a nonpharmacologic approach may be inadequate. In all instances, a patient with a paraphilic disorder should be informed that pharmacologic treatment is an option. A protocol for the pharmacologic treatment of paraphilic disorders that is based on my clinical experience is summarized in Table 2.

Leuprolide. A depot form of leuprolide is the most commonly employed agent to pharmacologically lower testosterone to treat a paraphilic disorder.¹³ When injected into muscle, leuprolide binds to it before gradually being released into the bloodstream. Previously, a depot medroxyprogesterone (a form of progesterone) had been used to treat paraphilic disorders.¹⁴ However, that had required weekly rather than monthly injections, and carried an increased risk of thrombotic emboli.

Prescribing leuprolide to treat a paraphilic disorder falls under FDA guidelines regarding the use of an approved drug for an “off-label” indication, and therefore is not considered investigational. For treating a paraphilic disorder, an effective dosage of leuprolide is 7.5 mg IM every 4 weeks. Long-term treatment is generally required, analogous to the management of diabetes. Because the initial injection of the series can cause a transient increase in testosterone (prior to its sustained decline), flutamide, a testosterone receptor blocking agent, is ordinarily prescribed for the first 14 days only, following initiation of treatment with depot leuprolide.¹⁵ Using flutamide in this fashion prevents the transient increase in testosterone from transiently increasing sexual drive. Flutamide should be discontinued after 14 days because long-term use can result in liver toxicity.

Some clinicians have been hesitant to prescribe leuprolide because of negative connotations associated with the term “chemical castration.” Unlike surgical castration, use of leuprolide is not a physically irreversible intervention, and does not result in sterility (although there may be an increase of atypical sperm and a decrease in total sperm production). The dosage can sometimes be titrated without a loss of efficacy.

In general, leuprolide’s safety protocol is well within the range associated with psychotropic medications.¹³ Low-risk adverse effects, such as hot flashes or cold sweats, may occur, especially during the period when hormone levels are in transition. There are no absolute contraindications to the use of leuprolide.

Continue to: Other medications

Other medications. Some researchers have suggested treating paraphilic disorders with psychotropic medications known to lower libido, such as selective serotonin reuptake inhibitors (SSRIs).¹⁶ However, leuprolide is far more reliable in consistently lowering testosterone and lowering the frequency and intensity of sexual urges. Although psychiatrists unfamiliar with treating paraphilic disorders may feel more comfortable initiating treatment with an SSRI, in my clinical experience, SSRIs have often proven inadequate for this purpose. When it comes to those paraphilic disorders in which treatment failure can result in significant harm (eg, pedophilic disorder), in my judgment, leuprolide should be the pharmacologic treatment of choice.

The opioid antagonist naltrexone has been used clinically to reduce cravings, primarily cravings for alcohol or drugs.¹⁷ However, I have not seen convincing evidence that it can be reliably beneficial in treating paraphilic disorders.

Tests to order before starting leuprolide

Long-term use of leuprolide can increase the risk of osteoporosis. Therefore, a baseline bone density scan should be performed before starting a patient on leuprolide. Baseline levels of testosterone, follicle-stimulating hormone, and luteinizing hormone also should be obtained. Patients should have yearly physical examinations, with accompanying laboratory testing. Hematocrit levels are often marginally low after beginning treatment, but not in a clinically significant way. Patients should also undergo routine monitoring for possible weight gain and the potential for associated hypertension. Treatment is predicated upon the known testosterone-suppressing effects of leuprolide, not upon routine monitoring of blood androgen levels.

Pharmacologic treatment of a paraphilic disorder should ordinarily occur in conjunction with nonpharmacologic modalities. One such modality would be group therapy, similar to the type frequently used to treat other craving disorders, such as drug or alcohol dependency.

In recent years, I have seen increasing numbers of patients presenting with a history of accessing and viewing child pornography. Once they have become more aware of the serious consequences of this behavior, most patients have been able to discontinue doing so without pharmacologic treatment. However, for patients in whom that behavior has seemed more driven (suggestive of a variant of voyeuristic disorder), prescription of leuprolide has been beneficial. Under such circumstances, I have diagnosed the patient’s condition as “other specified paraphilic disorder” with elements of pedophilia and voyeurism—the associated behaviors restricted to the voyeuristic viewing of child pornography.¹⁸

Continue to: Can treated patients still be sexual?

If pharmacologic treatment of a paraphilic disorder results in erectile dysfunction, prescription of a medication such as sildenafil can be considered for patients who are in a consenting adult relationship, generally with the knowledge of their partner. Sildenafil can facilitate erectile capacity without increasing sexual drive. It can be helpful to explain to a patient that the purpose of pharmacologic treatment is not to prevent the enjoyment of sexual feelings within the context of a healthy, consenting, adult relationship, but instead to lower the intensity of problematic sexual urges, thereby facilitating sexual self-control. Just as lowering the appetite for food can make it easier to diet but not impossible to eat, lowering sexual appetite can facilitate successful self-control without necessarily interfering with erotic feelings experienced during sexual intimacy.

Bottom Line

Paraphilic disorders are not manifestations of a character flaw, but manifestations of unchosen qualitative differences in the nature of one’s sexual cravings. Not enough is yet known about the biology of sex to be able to pharmacologically alter its qualitative nature. However, pharmacologically lowering the intensity of a patient’s sexual drive can facilitate successful sexual self-regulation.

Related Resources

• LeVay S. Gay, straight and the reason why: the science of sexual orientation. London, UK: Oxford University Press; 2011.
• Rosler A, Witztum E. Treatment of men with paraphilia with a long-acting analogue of gonadotropin-releasing hormone. N Engl J Med. 1998;338(7):416-422.
• Brown GR. Overview of paraphilic disorders (paraphilias). https://www.merckmanuals.com/professional/psychiatricdisorders/sexuality,-gender-dysphoria,-and-paraphilias/overview-of-paraphilic-disorders.

Drug Brand Names

Flutamide • Eulexin
Leuprolide injection •
Eligard, Lupron Depot
Medroxyprogesterone •
Provera
Naltrexone • Revia, Vivitrol
Progesterone • Prometrium
Sildenafil • Viagra

In my role as the Director of The Johns Hopkins Sex and Gender Clinic, I have had the opportunity to provide care to 3 broad categories of patients: patients with sexual dysfunctions, patients experiencing gender dysphoria, and patients manifesting a paraphilic disorder. This article will not address sexual dysfunctions or gender dysphoria, but these terms are defined in the Box^1-3 to clearly distinguish them from paraphilic disorders.

Box

Persons with paraphilic disorders (predominantly males) experience recurrent atypical sexual fantasies and urges that cause clinically significant impairment or distress.¹ Those atypical fantasies and urges may be directed towards unacceptable partners such as animals or children, or towards unacceptable behaviors such as public exhibitionism. Table 1¹ lists the paraphilic disorders identified in DSM-5. This article focuses primarily, though not exclusively, upon pedophilic disorder, and its pharmacologic treatment. However, the rationale underlying such treatment is applicable across the paraphilic spectrum. Before providing such treatment, it is important for clinicians to have a clear conceptual understanding of paraphilic disorders.

When is a difference a disorder?

Cancer and respiration are 2 different biologic phenomenon. Cancer causes suffering and impairment, and as a consequence, we label it a disorder. We do so in the hope of learning more about it, and being able to successfully treat it. We do not classify respiration as a disorder because we do not consider it to be harmful.

The spectrum of human sexuality is quite broad, and psychiatry is generally not concerned with private sexual thoughts and behaviors involving consenting adults that do not cause suffering or impairment. When adults choose to engage in “kinky sex” that causes neither harm nor distress, so be it.

Some individuals may be privately aware of experiencing either an exclusive or nonexclusive sexual attraction to children. Some of these individuals may not be distressed by experiencing such attractions, and may be fully capable of resisting the temptation to enact them. In such an instance, even though an individual may be experiencing sexual attractions that are different from the norm, there may not be a sufficient basis for diagnosing pedophilic disorder. However, that difference in sexual phenomenology (ie, mental experience) could rise to the level of a diagnosable disorder if the individual in question expresses distress about experiencing such attractions, and/or if his capacity to resist acting upon them is impaired.⁴ Under such circumstances, treatment would be warranted.

Patients with paraphilic disorders deserve treatment

Prior to establishment of the Betty Ford Clinic in 1982, individuals who were drug- or alcohol-dependent were often portrayed in a negative light and referred to by derogatory pejoratives such as “bum” or “pothead.”⁵ Over time, society came to appreciate that good people, deserving of treatment, can become dependent upon substances, and in recent years there has been considerable support for related research initiatives and humane care. However, there has not been analogous support for individuals who manifest paraphilic disorders, especially those with pedophilic disorder. Instead, such individuals are often perceived as undeserving of mental health care and resources. This has been the case, even though successful treatment of a pedophilic disorder could help prevent the serious consequences of child molestation from occurring.

In contemporary society, the term pedophilia, which is a psychiatric specifier intended to guide research and treatment, has been hijacked by the nonmedical community and turned into a demeaning pejorative. In the collective consciousness of the public, the term pedophilia is routinely and mistakenly equated with the behavior of child molestation. Just as all alcoholics are not drunk drivers, all individuals with pedophilic disorder are not “child molesters.” Conversely, not all “child molesters” have pedophilic disorder.

Continue to: Individuals with other types...

Individuals with other types of paraphilic disorders are frequently similarly maligned and referred to as “perverts” or “deviants.” Public service announcements are frequently aired to reach out to individuals who are depressed, or drug- or alcohol-dependent, or suffering with other forms of mental disorders. When does one hear a public service announcement that encourages young people who may be experiencing disturbing or unacceptable sexual feelings to seek psychiatric treatment? There is a support group on the internet called Virtuous Pedophiles.⁶ That organization is unequivocally opposed to child molestation, while supporting efforts to improve the mental well-being of individuals who, through no fault of their own, experience unwanted pedophilic feelings.

Causes and noncauses

In attempting to elucidate etiology, researchers typically investigate nature (biology) and/or nurture (life experiences). In terms of the development of pedophilic disorder, there is evidence that both nature and nurture can play a role. Researchers have found that boys who are sexually abused are at increased risk for developing pedophilic disorder, and evidence of temporal lobe disturbances has also been documented in some instances.^7,8

From clinical, societal, and forensic perspectives, it may be equally important to identify noncausal factors. Paraphilic disorders, including pedophilic disorder, do not develop as a consequence of volitional choice.⁹ For example, none of us decide which category, or categories, of potential partners are going to attract us sexually. Rather, in maturing we discover the nature of our own sexuality. Children do not ponder their options, somehow deciding while growing up to be attracted to the opposite sex (heterosexuality), the same sex (homosexuality), or both sexes (bisexuality). Similarly, in maturing into adulthood, individuals do not decide to become sexually attracted to prepubescent children. Who would decide to do that? Instead, unlike most of us, some individuals discover this about themselves; this often is a deeply disturbing insight.

It is not an individual’s fault that he or she has a paraphilic disorder. It is, however, his or her responsibility to do something about it. This may require accessing appropriate psychiatric care.

Why treatment may be needed

Sex is a powerful, biologically based appetite that recurrently craves satiation. God or nature has put that drive into all of us to ensure the survival of humanity. Even when that powerful biologic drive becomes misdirected (for example, towards children, or towards a desire to engage in public exhibitionism), it still recurrently craves satisfaction. It does not require mental health expertise to appreciate what a problematic situation this could become.

Continue to: Some individuals need help...

Some individuals need help in overcoming cravings related to nonsexual appetites. For example, Americans spend millions of dollars each year trying to diet; they often require some form of assistance in order to succeed. Individuals who crave drugs or alcohol often require mental health interventions to abstain because they are unable to consistently resist through willpower alone the powerful biologic urges that drive their actions.

The fundamental mental characteristic of any paraphilic disorder is the presence of intense, recurrent, sexual urges of an atypical nature. In the case of a pedophilic disorder, those urges involve sexual feelings about children.² In the case of an exhibitionistic disorder, the afflicted individual experiences intense, recurrent sexual fantasies/urges related to exposing his genitals in public.¹ Clearly, most men do not have to recurrently fight off the urge to act in such a fashion. Given the driven nature of intense erotic cravings, individuals who experience such cravings will frequently require access to competent mental health care.

Pharmacologic treatment of paraphilic disorders

In the future, we may develop a scientifically based understanding of the biologic factors that underlie qualitative differences in sexuality. At that point, it may become possible to intervene pharmacologically, changing the qualitative nature of a sexual urge with pharmacologic interventions. This cannot yet be done. However, much is already known about the biology related to the quantitative (intensity) dimension of sexuality.

In 1939, a Nobel Prize in Chemistry was awarded for the identification and isolation of the hormone testosterone, which energizes sexual drive.¹⁰ If an individual is hungering sexually to expose himself, to view child pornography, or to engage in sexual acts with children, the intensity of such hungers can be significantly reduced by lowering testosterone, thereby enhancing the capacity for successful sexual self-control.

A large body of scientific data has documented a marked decrease in sexually motivated behaviors when testosterone levels are significantly diminished.¹¹ There is also evidence that recidivism rates of sexually motivated crimes can be significantly reduced when testosterone-lowering interventions are used.¹²

Continue to: Historically, removal of the testes...

Historically, removal of the testes (surgical castration) had been the only effective way to reliably lower testosterone. Today, this can be achieved pharmacologically. Use of a sex drive–lowering medication should be considered when either the clinician or the patient is concerned that a nonpharmacologic approach may be inadequate. In all instances, a patient with a paraphilic disorder should be informed that pharmacologic treatment is an option. A protocol for the pharmacologic treatment of paraphilic disorders that is based on my clinical experience is summarized in Table 2.

Leuprolide. A depot form of leuprolide is the most commonly employed agent to pharmacologically lower testosterone to treat a paraphilic disorder.¹³ When injected into muscle, leuprolide binds to it before gradually being released into the bloodstream. Previously, a depot medroxyprogesterone (a form of progesterone) had been used to treat paraphilic disorders.¹⁴ However, that had required weekly rather than monthly injections, and carried an increased risk of thrombotic emboli.

Prescribing leuprolide to treat a paraphilic disorder falls under FDA guidelines regarding the use of an approved drug for an “off-label” indication, and therefore is not considered investigational. For treating a paraphilic disorder, an effective dosage of leuprolide is 7.5 mg IM every 4 weeks. Long-term treatment is generally required, analogous to the management of diabetes. Because the initial injection of the series can cause a transient increase in testosterone (prior to its sustained decline), flutamide, a testosterone receptor blocking agent, is ordinarily prescribed for the first 14 days only, following initiation of treatment with depot leuprolide.¹⁵ Using flutamide in this fashion prevents the transient increase in testosterone from transiently increasing sexual drive. Flutamide should be discontinued after 14 days because long-term use can result in liver toxicity.

Some clinicians have been hesitant to prescribe leuprolide because of negative connotations associated with the term “chemical castration.” Unlike surgical castration, use of leuprolide is not a physically irreversible intervention, and does not result in sterility (although there may be an increase of atypical sperm and a decrease in total sperm production). The dosage can sometimes be titrated without a loss of efficacy.

In general, leuprolide’s safety protocol is well within the range associated with psychotropic medications.¹³ Low-risk adverse effects, such as hot flashes or cold sweats, may occur, especially during the period when hormone levels are in transition. There are no absolute contraindications to the use of leuprolide.

Continue to: Other medications

Other medications. Some researchers have suggested treating paraphilic disorders with psychotropic medications known to lower libido, such as selective serotonin reuptake inhibitors (SSRIs).¹⁶ However, leuprolide is far more reliable in consistently lowering testosterone and lowering the frequency and intensity of sexual urges. Although psychiatrists unfamiliar with treating paraphilic disorders may feel more comfortable initiating treatment with an SSRI, in my clinical experience, SSRIs have often proven inadequate for this purpose. When it comes to those paraphilic disorders in which treatment failure can result in significant harm (eg, pedophilic disorder), in my judgment, leuprolide should be the pharmacologic treatment of choice.

The opioid antagonist naltrexone has been used clinically to reduce cravings, primarily cravings for alcohol or drugs.¹⁷ However, I have not seen convincing evidence that it can be reliably beneficial in treating paraphilic disorders.

Tests to order before starting leuprolide

Long-term use of leuprolide can increase the risk of osteoporosis. Therefore, a baseline bone density scan should be performed before starting a patient on leuprolide. Baseline levels of testosterone, follicle-stimulating hormone, and luteinizing hormone also should be obtained. Patients should have yearly physical examinations, with accompanying laboratory testing. Hematocrit levels are often marginally low after beginning treatment, but not in a clinically significant way. Patients should also undergo routine monitoring for possible weight gain and the potential for associated hypertension. Treatment is predicated upon the known testosterone-suppressing effects of leuprolide, not upon routine monitoring of blood androgen levels.

Pharmacologic treatment of a paraphilic disorder should ordinarily occur in conjunction with nonpharmacologic modalities. One such modality would be group therapy, similar to the type frequently used to treat other craving disorders, such as drug or alcohol dependency.

In recent years, I have seen increasing numbers of patients presenting with a history of accessing and viewing child pornography. Once they have become more aware of the serious consequences of this behavior, most patients have been able to discontinue doing so without pharmacologic treatment. However, for patients in whom that behavior has seemed more driven (suggestive of a variant of voyeuristic disorder), prescription of leuprolide has been beneficial. Under such circumstances, I have diagnosed the patient’s condition as “other specified paraphilic disorder” with elements of pedophilia and voyeurism—the associated behaviors restricted to the voyeuristic viewing of child pornography.¹⁸

Continue to: Can treated patients still be sexual?

If pharmacologic treatment of a paraphilic disorder results in erectile dysfunction, prescription of a medication such as sildenafil can be considered for patients who are in a consenting adult relationship, generally with the knowledge of their partner. Sildenafil can facilitate erectile capacity without increasing sexual drive. It can be helpful to explain to a patient that the purpose of pharmacologic treatment is not to prevent the enjoyment of sexual feelings within the context of a healthy, consenting, adult relationship, but instead to lower the intensity of problematic sexual urges, thereby facilitating sexual self-control. Just as lowering the appetite for food can make it easier to diet but not impossible to eat, lowering sexual appetite can facilitate successful self-control without necessarily interfering with erotic feelings experienced during sexual intimacy.

Bottom Line

Paraphilic disorders are not manifestations of a character flaw, but manifestations of unchosen qualitative differences in the nature of one’s sexual cravings. Not enough is yet known about the biology of sex to be able to pharmacologically alter its qualitative nature. However, pharmacologically lowering the intensity of a patient’s sexual drive can facilitate successful sexual self-regulation.

Related Resources

• LeVay S. Gay, straight and the reason why: the science of sexual orientation. London, UK: Oxford University Press; 2011.
• Rosler A, Witztum E. Treatment of men with paraphilia with a long-acting analogue of gonadotropin-releasing hormone. N Engl J Med. 1998;338(7):416-422.
• Brown GR. Overview of paraphilic disorders (paraphilias). https://www.merckmanuals.com/professional/psychiatricdisorders/sexuality,-gender-dysphoria,-and-paraphilias/overview-of-paraphilic-disorders.

Drug Brand Names

Flutamide • Eulexin
Leuprolide injection •
Eligard, Lupron Depot
Medroxyprogesterone •
Provera
Naltrexone • Revia, Vivitrol
Progesterone • Prometrium
Sildenafil • Viagra

In my role as the Director of The Johns Hopkins Sex and Gender Clinic, I have had the opportunity to provide care to 3 broad categories of patients: patients with sexual dysfunctions, patients experiencing gender dysphoria, and patients manifesting a paraphilic disorder. This article will not address sexual dysfunctions or gender dysphoria, but these terms are defined in the Box^1-3 to clearly distinguish them from paraphilic disorders.

Box

Persons with paraphilic disorders (predominantly males) experience recurrent atypical sexual fantasies and urges that cause clinically significant impairment or distress.¹ Those atypical fantasies and urges may be directed towards unacceptable partners such as animals or children, or towards unacceptable behaviors such as public exhibitionism. Table 1¹ lists the paraphilic disorders identified in DSM-5. This article focuses primarily, though not exclusively, upon pedophilic disorder, and its pharmacologic treatment. However, the rationale underlying such treatment is applicable across the paraphilic spectrum. Before providing such treatment, it is important for clinicians to have a clear conceptual understanding of paraphilic disorders.

When is a difference a disorder?

Cancer and respiration are 2 different biologic phenomenon. Cancer causes suffering and impairment, and as a consequence, we label it a disorder. We do so in the hope of learning more about it, and being able to successfully treat it. We do not classify respiration as a disorder because we do not consider it to be harmful.

The spectrum of human sexuality is quite broad, and psychiatry is generally not concerned with private sexual thoughts and behaviors involving consenting adults that do not cause suffering or impairment. When adults choose to engage in “kinky sex” that causes neither harm nor distress, so be it.

Some individuals may be privately aware of experiencing either an exclusive or nonexclusive sexual attraction to children. Some of these individuals may not be distressed by experiencing such attractions, and may be fully capable of resisting the temptation to enact them. In such an instance, even though an individual may be experiencing sexual attractions that are different from the norm, there may not be a sufficient basis for diagnosing pedophilic disorder. However, that difference in sexual phenomenology (ie, mental experience) could rise to the level of a diagnosable disorder if the individual in question expresses distress about experiencing such attractions, and/or if his capacity to resist acting upon them is impaired.⁴ Under such circumstances, treatment would be warranted.

Patients with paraphilic disorders deserve treatment

Prior to establishment of the Betty Ford Clinic in 1982, individuals who were drug- or alcohol-dependent were often portrayed in a negative light and referred to by derogatory pejoratives such as “bum” or “pothead.”⁵ Over time, society came to appreciate that good people, deserving of treatment, can become dependent upon substances, and in recent years there has been considerable support for related research initiatives and humane care. However, there has not been analogous support for individuals who manifest paraphilic disorders, especially those with pedophilic disorder. Instead, such individuals are often perceived as undeserving of mental health care and resources. This has been the case, even though successful treatment of a pedophilic disorder could help prevent the serious consequences of child molestation from occurring.

In contemporary society, the term pedophilia, which is a psychiatric specifier intended to guide research and treatment, has been hijacked by the nonmedical community and turned into a demeaning pejorative. In the collective consciousness of the public, the term pedophilia is routinely and mistakenly equated with the behavior of child molestation. Just as all alcoholics are not drunk drivers, all individuals with pedophilic disorder are not “child molesters.” Conversely, not all “child molesters” have pedophilic disorder.

Continue to: Individuals with other types...

Individuals with other types of paraphilic disorders are frequently similarly maligned and referred to as “perverts” or “deviants.” Public service announcements are frequently aired to reach out to individuals who are depressed, or drug- or alcohol-dependent, or suffering with other forms of mental disorders. When does one hear a public service announcement that encourages young people who may be experiencing disturbing or unacceptable sexual feelings to seek psychiatric treatment? There is a support group on the internet called Virtuous Pedophiles.⁶ That organization is unequivocally opposed to child molestation, while supporting efforts to improve the mental well-being of individuals who, through no fault of their own, experience unwanted pedophilic feelings.

Causes and noncauses

In attempting to elucidate etiology, researchers typically investigate nature (biology) and/or nurture (life experiences). In terms of the development of pedophilic disorder, there is evidence that both nature and nurture can play a role. Researchers have found that boys who are sexually abused are at increased risk for developing pedophilic disorder, and evidence of temporal lobe disturbances has also been documented in some instances.^7,8

From clinical, societal, and forensic perspectives, it may be equally important to identify noncausal factors. Paraphilic disorders, including pedophilic disorder, do not develop as a consequence of volitional choice.⁹ For example, none of us decide which category, or categories, of potential partners are going to attract us sexually. Rather, in maturing we discover the nature of our own sexuality. Children do not ponder their options, somehow deciding while growing up to be attracted to the opposite sex (heterosexuality), the same sex (homosexuality), or both sexes (bisexuality). Similarly, in maturing into adulthood, individuals do not decide to become sexually attracted to prepubescent children. Who would decide to do that? Instead, unlike most of us, some individuals discover this about themselves; this often is a deeply disturbing insight.

It is not an individual’s fault that he or she has a paraphilic disorder. It is, however, his or her responsibility to do something about it. This may require accessing appropriate psychiatric care.

Why treatment may be needed

Sex is a powerful, biologically based appetite that recurrently craves satiation. God or nature has put that drive into all of us to ensure the survival of humanity. Even when that powerful biologic drive becomes misdirected (for example, towards children, or towards a desire to engage in public exhibitionism), it still recurrently craves satisfaction. It does not require mental health expertise to appreciate what a problematic situation this could become.

Continue to: Some individuals need help...

Some individuals need help in overcoming cravings related to nonsexual appetites. For example, Americans spend millions of dollars each year trying to diet; they often require some form of assistance in order to succeed. Individuals who crave drugs or alcohol often require mental health interventions to abstain because they are unable to consistently resist through willpower alone the powerful biologic urges that drive their actions.

The fundamental mental characteristic of any paraphilic disorder is the presence of intense, recurrent, sexual urges of an atypical nature. In the case of a pedophilic disorder, those urges involve sexual feelings about children.² In the case of an exhibitionistic disorder, the afflicted individual experiences intense, recurrent sexual fantasies/urges related to exposing his genitals in public.¹ Clearly, most men do not have to recurrently fight off the urge to act in such a fashion. Given the driven nature of intense erotic cravings, individuals who experience such cravings will frequently require access to competent mental health care.

Pharmacologic treatment of paraphilic disorders

In the future, we may develop a scientifically based understanding of the biologic factors that underlie qualitative differences in sexuality. At that point, it may become possible to intervene pharmacologically, changing the qualitative nature of a sexual urge with pharmacologic interventions. This cannot yet be done. However, much is already known about the biology related to the quantitative (intensity) dimension of sexuality.

In 1939, a Nobel Prize in Chemistry was awarded for the identification and isolation of the hormone testosterone, which energizes sexual drive.¹⁰ If an individual is hungering sexually to expose himself, to view child pornography, or to engage in sexual acts with children, the intensity of such hungers can be significantly reduced by lowering testosterone, thereby enhancing the capacity for successful sexual self-control.

A large body of scientific data has documented a marked decrease in sexually motivated behaviors when testosterone levels are significantly diminished.¹¹ There is also evidence that recidivism rates of sexually motivated crimes can be significantly reduced when testosterone-lowering interventions are used.¹²

Continue to: Historically, removal of the testes...

Historically, removal of the testes (surgical castration) had been the only effective way to reliably lower testosterone. Today, this can be achieved pharmacologically. Use of a sex drive–lowering medication should be considered when either the clinician or the patient is concerned that a nonpharmacologic approach may be inadequate. In all instances, a patient with a paraphilic disorder should be informed that pharmacologic treatment is an option. A protocol for the pharmacologic treatment of paraphilic disorders that is based on my clinical experience is summarized in Table 2.

Leuprolide. A depot form of leuprolide is the most commonly employed agent to pharmacologically lower testosterone to treat a paraphilic disorder.¹³ When injected into muscle, leuprolide binds to it before gradually being released into the bloodstream. Previously, a depot medroxyprogesterone (a form of progesterone) had been used to treat paraphilic disorders.¹⁴ However, that had required weekly rather than monthly injections, and carried an increased risk of thrombotic emboli.

Prescribing leuprolide to treat a paraphilic disorder falls under FDA guidelines regarding the use of an approved drug for an “off-label” indication, and therefore is not considered investigational. For treating a paraphilic disorder, an effective dosage of leuprolide is 7.5 mg IM every 4 weeks. Long-term treatment is generally required, analogous to the management of diabetes. Because the initial injection of the series can cause a transient increase in testosterone (prior to its sustained decline), flutamide, a testosterone receptor blocking agent, is ordinarily prescribed for the first 14 days only, following initiation of treatment with depot leuprolide.¹⁵ Using flutamide in this fashion prevents the transient increase in testosterone from transiently increasing sexual drive. Flutamide should be discontinued after 14 days because long-term use can result in liver toxicity.

Some clinicians have been hesitant to prescribe leuprolide because of negative connotations associated with the term “chemical castration.” Unlike surgical castration, use of leuprolide is not a physically irreversible intervention, and does not result in sterility (although there may be an increase of atypical sperm and a decrease in total sperm production). The dosage can sometimes be titrated without a loss of efficacy.

In general, leuprolide’s safety protocol is well within the range associated with psychotropic medications.¹³ Low-risk adverse effects, such as hot flashes or cold sweats, may occur, especially during the period when hormone levels are in transition. There are no absolute contraindications to the use of leuprolide.

Continue to: Other medications

Other medications. Some researchers have suggested treating paraphilic disorders with psychotropic medications known to lower libido, such as selective serotonin reuptake inhibitors (SSRIs).¹⁶ However, leuprolide is far more reliable in consistently lowering testosterone and lowering the frequency and intensity of sexual urges. Although psychiatrists unfamiliar with treating paraphilic disorders may feel more comfortable initiating treatment with an SSRI, in my clinical experience, SSRIs have often proven inadequate for this purpose. When it comes to those paraphilic disorders in which treatment failure can result in significant harm (eg, pedophilic disorder), in my judgment, leuprolide should be the pharmacologic treatment of choice.

The opioid antagonist naltrexone has been used clinically to reduce cravings, primarily cravings for alcohol or drugs.¹⁷ However, I have not seen convincing evidence that it can be reliably beneficial in treating paraphilic disorders.

Tests to order before starting leuprolide

Long-term use of leuprolide can increase the risk of osteoporosis. Therefore, a baseline bone density scan should be performed before starting a patient on leuprolide. Baseline levels of testosterone, follicle-stimulating hormone, and luteinizing hormone also should be obtained. Patients should have yearly physical examinations, with accompanying laboratory testing. Hematocrit levels are often marginally low after beginning treatment, but not in a clinically significant way. Patients should also undergo routine monitoring for possible weight gain and the potential for associated hypertension. Treatment is predicated upon the known testosterone-suppressing effects of leuprolide, not upon routine monitoring of blood androgen levels.

Pharmacologic treatment of a paraphilic disorder should ordinarily occur in conjunction with nonpharmacologic modalities. One such modality would be group therapy, similar to the type frequently used to treat other craving disorders, such as drug or alcohol dependency.

In recent years, I have seen increasing numbers of patients presenting with a history of accessing and viewing child pornography. Once they have become more aware of the serious consequences of this behavior, most patients have been able to discontinue doing so without pharmacologic treatment. However, for patients in whom that behavior has seemed more driven (suggestive of a variant of voyeuristic disorder), prescription of leuprolide has been beneficial. Under such circumstances, I have diagnosed the patient’s condition as “other specified paraphilic disorder” with elements of pedophilia and voyeurism—the associated behaviors restricted to the voyeuristic viewing of child pornography.¹⁸

Continue to: Can treated patients still be sexual?

If pharmacologic treatment of a paraphilic disorder results in erectile dysfunction, prescription of a medication such as sildenafil can be considered for patients who are in a consenting adult relationship, generally with the knowledge of their partner. Sildenafil can facilitate erectile capacity without increasing sexual drive. It can be helpful to explain to a patient that the purpose of pharmacologic treatment is not to prevent the enjoyment of sexual feelings within the context of a healthy, consenting, adult relationship, but instead to lower the intensity of problematic sexual urges, thereby facilitating sexual self-control. Just as lowering the appetite for food can make it easier to diet but not impossible to eat, lowering sexual appetite can facilitate successful self-control without necessarily interfering with erotic feelings experienced during sexual intimacy.

Bottom Line

Paraphilic disorders are not manifestations of a character flaw, but manifestations of unchosen qualitative differences in the nature of one’s sexual cravings. Not enough is yet known about the biology of sex to be able to pharmacologically alter its qualitative nature. However, pharmacologically lowering the intensity of a patient’s sexual drive can facilitate successful sexual self-regulation.

Related Resources

• LeVay S. Gay, straight and the reason why: the science of sexual orientation. London, UK: Oxford University Press; 2011.
• Rosler A, Witztum E. Treatment of men with paraphilia with a long-acting analogue of gonadotropin-releasing hormone. N Engl J Med. 1998;338(7):416-422.
• Brown GR. Overview of paraphilic disorders (paraphilias). https://www.merckmanuals.com/professional/psychiatricdisorders/sexuality,-gender-dysphoria,-and-paraphilias/overview-of-paraphilic-disorders.

Drug Brand Names

Flutamide • Eulexin
Leuprolide injection •
Eligard, Lupron Depot
Medroxyprogesterone •
Provera
Naltrexone • Revia, Vivitrol
Progesterone • Prometrium
Sildenafil • Viagra

Click here to read the supplement.

What can be done to provide a cost-effective treatment option for von Willebrand Disease?

Topics include:

• Review of Key Clinical Studies and Surgical Procedures
• Pharmacokinetics Comparison
• Pharmacoeconomic Comparisons

Click here to read the supplement.

Click here to read the supplement.

What can be done to provide a cost-effective treatment option for von Willebrand Disease?

Topics include:

• Review of Key Clinical Studies and Surgical Procedures
• Pharmacokinetics Comparison
• Pharmacoeconomic Comparisons

Click here to read the supplement.

Click here to read the supplement.

What can be done to provide a cost-effective treatment option for von Willebrand Disease?

Topics include:

• Review of Key Clinical Studies and Surgical Procedures
• Pharmacokinetics Comparison
• Pharmacoeconomic Comparisons

Click here to read the supplement.

From the Geriatric Education and Research in Aging Sciences (GERAS) Centre for Aging Research, McMaster University, Hamilton, ON.

Abstract

• Objective. To summarize the literature on improving opportunities for physical activity for residents in long-term care (LTC).
• Method. Narrative review of the literature.
• Results. Residents in LTC spend much of their time in sedentary activities such as sitting or lying in bed. Physical activity is important to help decrease the negative effects of sedentary time, such as poor mood and increased risk of death, and to improve physical function. This review identifies several strategies for promoting physical activity for LTC residents: incorporating simple strategies into daily activities, participating in group activities (eg, exercise, dance, or music therapy), using motivational strategies to encourage staff to promote activity, leveraging the physical environment, reducing physical and chemical restraints, and using innovative solutions such as robots or interactive technology.
• Conclusion. While the quality of evidence to date is limited, preliminary work suggests that the strategies identified in this article could be included as part of a multifactorial approach to increasing physical activity in LTC.

Keywords: long-term care; nursing homes; physical activity; sedentary; mobility.

The United Nations estimates that between 2013 and 2050 the population aged 60 years or older will double.¹ Furthermore, the fastest growth rate will be seen in older adults over the age of 80 years.¹ With this demographic shift, a growing number of older adults will require supportive housing, such as long-term care (LTC). Indeed, it is projected that the number of older adults requiring LTC will double by 2036.²

Residents in LTC are often medically complex and experience multimorbidity, cognitive impairment, and functional decline,³ making it difficult for them to engage in physical activity. LTC residents spend approximately 75% of their waking time in sedentary activities (eg, sitting, lying down, watching TV), which amounts to more than 12 hours per day.^4-6 Residents with cognitive impairment are even more sedentary, spending as little as 1 minute per day in moderate physical activity and approximately 87% of their time in sedentary activities.⁷ Additionally, a high prevalence of use of psychotropic drugs and physical restraints contributes to high levels of physical inactivity for residents in LTC.⁸ Increased time spent in sedentary activities has been associated with adverse health outcomes, such as incidence of cardiovascular disease and type 2 diabetes, and mortality.^9-11 Moreover, bed and chair rest are associated with muscle disuse, which can lead to functional impairment.^12,13

Given the large amount of time LTC residents spend in sedentary activities and the negative consequences this has on their health, it is essential to find opportunities to engage residents in physical activity throughout the day. This article summarizes evidence about increasing opportunities for physical activity for LTC residents. Physical activity is defined as “any bodily movement produced by skeletal muscles that results in energy expenditure,” while exercise, which is a subset of physical activity, is purposefully planned, structured, and repetitive and has a goal of maintaining or improving physical fitness.¹⁴ Previous work has described exercise among LTC residents in detail,^8,15,16 and thus exercise is not addressed here. Also, as a narrative review, this article provides an overview of available interventions to improve physical activity for LTC residents and does not provide comments on efficacy or an exhaustive list of potential interventions. Rather, it provides a starting point for LTC homes to consider when providing opportunities to improve physical activity for their residents.

Guidelines for Increasing Physical Activity

There are currently no published evidence-based guidelines for increasing physical activity and reducing sedentary time for residents of LTC homes. However, an international task force of experts in geriatrics, exercise, and LTC research convened in 2015 and made recommendations on this matter.⁸ They emphasize the importance of considering the needs of residents, family members, health care professionals, LTC staff, and policy-makers when designing strategies to promote movement in LTC.⁸ This will ensure that the strategies to promote movement will be realistic and sustainable. Additionally, the task force identified motivation and pleasure as key to engaging residents in physical activities, and recommended that interests and preferences should be used to guide the selection of activities.⁸ The following sections describe example strategies to improve physical activity for residents in LTC that LTC homes can use to help facilitate movement for their residents.

Leveraging Daily Activities

One approach to promoting physical activity in LTC homes is to systematically use simple strategies embedded within routine care to engage residents in movement.⁸ Function-focused, or restorative care,¹⁷ is a philosophy of care that promotes increasing physical activity and maintaining functional abilities based on the resident’s abilities. Examples include walking with residents to the dining room rather than pushing them in a wheelchair where appropriate, inviting residents to events that require them to leave their room, improving independent wheelchair propulsion for residents who cannot walk, and increasing opportunities for sit-to-stand activities where possible. These activities are scaled to the resident’s underlying physical and cognitive capabilities. A systematic review of function-focused care revealed that it can help maintain functional skills for residents in LTC, and there is no significant risk associated with implementation.¹⁸ In a study by Slaughter et al¹⁹ that examined the effectiveness of techniques to encourage mobility by residents’ usual caregivers, health care aides prompted residents to perform the sit-to-stand activity 4 times per day, with the number of repetitions individualized based on resident ability, fatigue, and motivation. Residents who completed the sit-to-stand activity had smaller declines in mobility and functional outcomes (ie, less decline on the Functional Independence Measure).¹⁹ This study included residents with Alzheimer’s disease and dementia who could transfer independently or with the assistance of one person,²⁰ indicating that this type of intervention is feasible and appropriate for residents with cognitive impairment.

Group Activities

Group activities in LTC homes are another way of engaging residents in physical activity in a motivating and pleasant setting that also encourages social engagement among residents and LTC staff. Group exercise classes can be effective for improving mood and functional outcomes. For example, a systematic review of dance classes in LTC homes revealed an improvement in problematic behaviors, mood, cognition, communication, and socialization.²¹ Most studies included participants with dementia, and no adverse events were reported, supporting the feasibility and safety of implementing group dance activities for residents with cognitive impairment. Group exercise is the most common delivery method for exercise within LTC homes²² and has been demonstrated to have small positive effects on activities of daily living (ADL; ie, improvement in ADL independence equivalent to 1.3 points on the Barthel Index).²³ Other group activities, such as music therapy, have demonstrated improvements in depressive symptoms, emotional well-being, and anxiety for LTC residents with dementia.²⁴ Group activities also provide the opportunity for movement as residents leave their rooms, walk to a new location (if able), and return to their rooms when the activity is complete.

Barriers to Physical Activity and Strategies to Overcome Them

Caregiver-related Factors

LTC staff have limited time to spend promoting physical activity since residents often have complex health care needs and staffing levels are often constrained.²⁵ Indeed, having lower staffing levels has been associated with lower levels of physical activity for residents.^26,27 LTC staff have identified a lack of time to walk with residents^28,29 and having other tasks to do (eg, clean) as barriers to promoting movement.^28,29 However, asking residents to help staff with small household chores, such as folding laundry or clearing dishes, was a facilitator to promoting movement.³⁰ Activating residents by helping them transfer to a wheelchair for independent mobilization around the home or by assisting them to walk where appropriate were also facilitators.^30,31 Leveraging facilitators will help staff who have limited time to help residents engage in more physical activity.

Motivation of LTC staff can also be a barrier to encouraging physical activity for residents in LTC. Fear that increasing physical activity will cause adverse events like falls, illness, or exacerbation of symptoms often decreases motivation for staff to facilitate physical activity.^32,33 Another potential barrier is the conceptualization of the role of nursing in LTC as protecting residents from harm by encouraging them to engage in “risk-free” activities like staying in bed.^34-39 Strategies to increase staff motivation to engage LTC residents in physical activity that have been shown to be effective are verbal prompts, modelling behaviors, goal setting, and home champions to promote function-focused care.^17,33,40-43

The Physical Environment

Aspects of the physical environment of LTC homes may facilitate or limit residents’ ability to be physically active. A 2017 systematic review examined elements of the physical environment that acted as barriers and facilitators to physical activity for older adults living in LTC.³⁰ The authors found that the person-environment fit, security, accessibility, and comfort were key components of the physical environment that were associated with residents’ physical activity levels.³⁰ First, an appropriate fit between the residents’ abilities and the demands of the environment was related to improved activity as measured by actigraphy.⁴⁴ For example, having long hallways between residents’ rooms and common spaces discourages residents who can only walk short distances from walking to these locations. However, residents were more active in larger-scaled LTC homes with shorter distances between different areas (eg, resident rooms and dining rooms).⁴⁵ Clearly, there must be enough space to encourage walking between areas, but not so much space that walking is not feasible. Residents participating in a focus group identified accessibility and comfort features as being facilitators for walking in the corridor, such as wide corridors, sturdy handrails, carpet, chairs placed at short intervals for seated breaks, windows to look out, plants, and accessible activity rooms and restrooms.^45,46 On the other hand, limited things to see and do indoors and outdoors, along with restricted walking areas, were identified as barriers to corridor walking by residents.⁴⁶

One method for optimizing LTC home architecture to promote movement is to provide therapeutic outdoor spaces, such as gardens. Indeed, therapeutic gardens have been studied as a nonpharmacological method of engaging LTC residents with dementia and have been shown to benefit mood, pain, and fall prevention.⁴⁷ Secure therapeutic gardens or outdoor spaces provide opportunities for various activities to increase movement, including gardening, animal care, and walking.⁴⁸ However, there is a higher propensity for residents who use walkers or wheelchairs to slide off paths or become stuck in mud or mulch.⁴⁹ Residents with physical limitations may require additional supervision in garden spaces, and as such spaces should be designed with improved safety in mind (eg, barriers between paths and places where mud could accumulate). The number of available indoor (eg, a physical therapy gym) and outdoor (eg, gardens) spaces was also found to be positively related to residents’ physical activity levels.⁵⁰ However, these relationships were mediated by the number of activity programs available in the LTC homes.⁵⁰ Therefore, having staff available to facilitate activities is also important for promoting physical activity.

Chemical and Physical Restraints

Physical and chemical restraints (eg, antipsychotics and sedatives) are sometimes used to manage the behavioral and psychological symptoms of dementia,^51,52 which many residents in LTC experience.³ Though there has been an emphasis in North America to decrease their use, physical and chemical restraints are still used in LTC.⁵³ Physical restraint use is associated with a higher risk of functional and cognitive decline.^53,54 Residents who are both physically and chemically restrained through antipsychotic use are at even higher risk for these declines.⁵⁴ Thus, to improve opportunities for movement in LTC, physical restraint use should be minimized. The risks and benefits of using psychotropic medications that often decrease residents’ physical activity levels must be evaluated individually, and other nonpharmacological strategies should be used to manage the behavioral and psychological symptoms of dementia. These could include functional analysis-based interventions (ie, individualized interventions aimed at identifying unmet needs, causes, antecedents, and consequences of the behavior),⁵⁵ music therapy,⁵⁵ or other interventions described above.

Emerging Innovative Interventions

Robots are an emerging nonpharmacological intervention for improving the behavioral and psychological symptoms of dementia and facilitating physical activity in LTC. Robotic animal interventions, where LTC residents interact with robotic animals in an individual or group setting, have been shown to reduce negative behaviors and increase positive mood.⁵⁶ Additionally, robots are being used in rehabilitation to provide exercise post-stroke⁵⁷ and could easily be transitioned to do similar tasks in LTC. Robotic interventions are attractive for the LTC sector as they could help relieve the workload demands on an often overloaded sector, and, in the case of pet therapy, surmount regulations for bringing live animals into a LTC home. Though studies examining the use of robots in LTC have mainly focused on the effect of pet therapy on reducing behavioral symptoms, the use of robots to promote physical activity and exercise in LTC is a natural progression for the work that has been done in inpatient rehabilitation.⁵⁷ On a similar note, an interactive technology (similar to a Kinect system) used to promote 30-minute, twice-weekly physical activity sessions has demonstrated improvements in physical function (Short Physical Performance Battery [SPPB]) for pre-disabled (SPPB of 6 to 9) residents in LTC without dementia.⁵⁸ The role of technology to promote physical activity in LTC is an emerging area of interest, and future innovations in this area will continue to help facilitate movement.

Quality of Evidence

Most studies aimed at improving physical activity for LTC residents to date are small, have nonrandomized designs, and have limited generalizability and evidence to support the efficacy of the interventions. For example, most studies included in systematic reviews for function-focused care, dance, group exercise, and music therapy are small, observational, or quasi-experimental studies with methodological issues resulting in bias.^18,21,23,24 Likewise, the evidence surrounding nonpharmacological interventions for reducing behavioral and psychological symptoms of dementia is of very low to moderate quality.⁵⁵ Innovative interventions, such as robotics and interactive technology, to promote physical activity in LTC are in their infancy. There are no data syntheses available to date to summarize the available literature on this topic, and conclusions rely on small, nonrandomized designs or extrapolations of results from similar sectors (eg, inpatient rehabilitation). Thus, the studies described in this review can be used as preliminary evidence to support the implementation of interventions to improve physical activity, but discretion should be used when interpreting the efficacy of these interventions.

Discussion

This review identifies several strategies for promoting physical activity for LTC residents, including incorporating simple strategies into daily activities, participating in group activities (eg, exercise, dance, or music therapy), using motivational strategies to encourage staff to promote activity, leveraging the physical environment, reducing physical and chemical restraints, and using innovation solutions like robots or interactive technology. While the quality of evidence to date is limited, preliminary work suggests that strategies identified in this paper could be included as part of a multifactorial approach to increasing physical activity in LTC.

The current evidence does not suggest that any one strategy is more effective at improving physical activity, and it is likely that LTC homes will need to employ a combination of strategies to help residents move more. Additionally, residents’ preferences, goals, and capabilities should always be considered when designing an individualized physical activity plan. For example, if a resident does not like to be outdoors or gardening but enjoys dancing and music, then their physical activity plan should include group dance class and music therapy rather than gardening. LTC homes will need to have a menu of opportunities for movement that residents can choose from so that activities are pleasant and motivating, and therefore more likely to be completed.

Many of the interventions described in this review are safe and feasible to implement with residents who have physical or cognitive impairments. Function-focused care is scaled to the residents’ capabilities and did not increase the risk of falling, though LTC staff require the skills to scale physical activities appropriately.¹⁸ Likewise, group dance activities and music therapy were tested with residents with dementia, with no adverse events reported.^21,24 However, more work is needed to determine the feasibility of implementing emerging methods, such as robotics and interactive technology, for increasing physical activity for residents with physical and cognitive impairments. Most studies to date have included mobile residents or those with minimal cognitive impairment. Similarly, outdoor garden spaces may be less safe for residents who use walkers or wheelchairs if there is an opportunity for them to slip off paths or get stuck in mud or mulch. LTC homes implementing any of these interventions should evaluate the benefits and risks of each intervention, the resources available within the home to support them (eg, trained staff), and the target residents’ physical and cognitive capabilities.

While increasing physical activity is important, structured exercise is needed to see gains in components of physical fitness such as strength, aerobic capacity, and balance. Indeed, one major consideration highlighted by the aforementioned task force is that every resident who does not have contraindications must also have a personalized multicomponent exercise program as part of their care plan.⁸ The task force recommends moderate- to high-intensity strength, aerobic, and balance exercises 2 times per week for 35 to 45 minutes per session.⁸ There is an interrelationship between physical activity and structured exercise: structured exercise programs can certainly be part of a physical activity plan, but physical activity can include more than structured exercise. Physical activity also includes any activity that involves movement, such as walking in gardens or between home areas, or physically participating more in personal care activities (eg, assisting with bathing or dressing).¹⁴ Both structured exercise and physical activity are important for LTC residents. Structured exercise provides an opportunity to improve strength and cardiovascular fitness, which aim to decrease the negative effects of sarcopenia and cardiovascular disease, such as disability and death.^59,60 However, structured exercise should not be done daily for the same muscle groups.⁸ Rather, it is recommended for LTC residents to engage in structured exercise 2 times per week.⁸ Increasing physical activity is a daily goal, as daily physical activity decreases sedentary time, which has negative consequences such as decreased mood⁶¹ and increased mortality.⁶² LTC homes should incorporate strategies to both increase daily physical activity and promote individualized, structured exercise programs.

Conclusion

Residents in LTC spend much of their time in sedentary activities such as sitting or lying in bed. Physical activity is important to help decrease the negative effects of sedentary time, like poor mood and increased risk of death, and to improve physical function. This review describes several strategies to promote physical activity within LTC homes, such as leveraging daily activities and the physical environment, providing group activities, reducing physical and chemical restraint use, and using innovative technology such as robots. LTC homes can use the information in this review to plan strategies to promote physical activity.

Corresponding author: Caitlin McArthur, MScPT, PhD, Hamilton Health Sciences, St. Peter’s Hospital, 88 Maplewood Avenue, Hamilton, ON L8M 1W9; mcarthurc@hhsc.ca.

Financial disclosures: None.

From the Geriatric Education and Research in Aging Sciences (GERAS) Centre for Aging Research, McMaster University, Hamilton, ON.

Abstract

• Objective. To summarize the literature on improving opportunities for physical activity for residents in long-term care (LTC).
• Method. Narrative review of the literature.
• Results. Residents in LTC spend much of their time in sedentary activities such as sitting or lying in bed. Physical activity is important to help decrease the negative effects of sedentary time, such as poor mood and increased risk of death, and to improve physical function. This review identifies several strategies for promoting physical activity for LTC residents: incorporating simple strategies into daily activities, participating in group activities (eg, exercise, dance, or music therapy), using motivational strategies to encourage staff to promote activity, leveraging the physical environment, reducing physical and chemical restraints, and using innovative solutions such as robots or interactive technology.
• Conclusion. While the quality of evidence to date is limited, preliminary work suggests that the strategies identified in this article could be included as part of a multifactorial approach to increasing physical activity in LTC.

Keywords: long-term care; nursing homes; physical activity; sedentary; mobility.

The United Nations estimates that between 2013 and 2050 the population aged 60 years or older will double.¹ Furthermore, the fastest growth rate will be seen in older adults over the age of 80 years.¹ With this demographic shift, a growing number of older adults will require supportive housing, such as long-term care (LTC). Indeed, it is projected that the number of older adults requiring LTC will double by 2036.²

Residents in LTC are often medically complex and experience multimorbidity, cognitive impairment, and functional decline,³ making it difficult for them to engage in physical activity. LTC residents spend approximately 75% of their waking time in sedentary activities (eg, sitting, lying down, watching TV), which amounts to more than 12 hours per day.^4-6 Residents with cognitive impairment are even more sedentary, spending as little as 1 minute per day in moderate physical activity and approximately 87% of their time in sedentary activities.⁷ Additionally, a high prevalence of use of psychotropic drugs and physical restraints contributes to high levels of physical inactivity for residents in LTC.⁸ Increased time spent in sedentary activities has been associated with adverse health outcomes, such as incidence of cardiovascular disease and type 2 diabetes, and mortality.^9-11 Moreover, bed and chair rest are associated with muscle disuse, which can lead to functional impairment.^12,13

Given the large amount of time LTC residents spend in sedentary activities and the negative consequences this has on their health, it is essential to find opportunities to engage residents in physical activity throughout the day. This article summarizes evidence about increasing opportunities for physical activity for LTC residents. Physical activity is defined as “any bodily movement produced by skeletal muscles that results in energy expenditure,” while exercise, which is a subset of physical activity, is purposefully planned, structured, and repetitive and has a goal of maintaining or improving physical fitness.¹⁴ Previous work has described exercise among LTC residents in detail,^8,15,16 and thus exercise is not addressed here. Also, as a narrative review, this article provides an overview of available interventions to improve physical activity for LTC residents and does not provide comments on efficacy or an exhaustive list of potential interventions. Rather, it provides a starting point for LTC homes to consider when providing opportunities to improve physical activity for their residents.

Guidelines for Increasing Physical Activity

There are currently no published evidence-based guidelines for increasing physical activity and reducing sedentary time for residents of LTC homes. However, an international task force of experts in geriatrics, exercise, and LTC research convened in 2015 and made recommendations on this matter.⁸ They emphasize the importance of considering the needs of residents, family members, health care professionals, LTC staff, and policy-makers when designing strategies to promote movement in LTC.⁸ This will ensure that the strategies to promote movement will be realistic and sustainable. Additionally, the task force identified motivation and pleasure as key to engaging residents in physical activities, and recommended that interests and preferences should be used to guide the selection of activities.⁸ The following sections describe example strategies to improve physical activity for residents in LTC that LTC homes can use to help facilitate movement for their residents.

Leveraging Daily Activities

One approach to promoting physical activity in LTC homes is to systematically use simple strategies embedded within routine care to engage residents in movement.⁸ Function-focused, or restorative care,¹⁷ is a philosophy of care that promotes increasing physical activity and maintaining functional abilities based on the resident’s abilities. Examples include walking with residents to the dining room rather than pushing them in a wheelchair where appropriate, inviting residents to events that require them to leave their room, improving independent wheelchair propulsion for residents who cannot walk, and increasing opportunities for sit-to-stand activities where possible. These activities are scaled to the resident’s underlying physical and cognitive capabilities. A systematic review of function-focused care revealed that it can help maintain functional skills for residents in LTC, and there is no significant risk associated with implementation.¹⁸ In a study by Slaughter et al¹⁹ that examined the effectiveness of techniques to encourage mobility by residents’ usual caregivers, health care aides prompted residents to perform the sit-to-stand activity 4 times per day, with the number of repetitions individualized based on resident ability, fatigue, and motivation. Residents who completed the sit-to-stand activity had smaller declines in mobility and functional outcomes (ie, less decline on the Functional Independence Measure).¹⁹ This study included residents with Alzheimer’s disease and dementia who could transfer independently or with the assistance of one person,²⁰ indicating that this type of intervention is feasible and appropriate for residents with cognitive impairment.

Group Activities

Group activities in LTC homes are another way of engaging residents in physical activity in a motivating and pleasant setting that also encourages social engagement among residents and LTC staff. Group exercise classes can be effective for improving mood and functional outcomes. For example, a systematic review of dance classes in LTC homes revealed an improvement in problematic behaviors, mood, cognition, communication, and socialization.²¹ Most studies included participants with dementia, and no adverse events were reported, supporting the feasibility and safety of implementing group dance activities for residents with cognitive impairment. Group exercise is the most common delivery method for exercise within LTC homes²² and has been demonstrated to have small positive effects on activities of daily living (ADL; ie, improvement in ADL independence equivalent to 1.3 points on the Barthel Index).²³ Other group activities, such as music therapy, have demonstrated improvements in depressive symptoms, emotional well-being, and anxiety for LTC residents with dementia.²⁴ Group activities also provide the opportunity for movement as residents leave their rooms, walk to a new location (if able), and return to their rooms when the activity is complete.

Barriers to Physical Activity and Strategies to Overcome Them

Caregiver-related Factors

LTC staff have limited time to spend promoting physical activity since residents often have complex health care needs and staffing levels are often constrained.²⁵ Indeed, having lower staffing levels has been associated with lower levels of physical activity for residents.^26,27 LTC staff have identified a lack of time to walk with residents^28,29 and having other tasks to do (eg, clean) as barriers to promoting movement.^28,29 However, asking residents to help staff with small household chores, such as folding laundry or clearing dishes, was a facilitator to promoting movement.³⁰ Activating residents by helping them transfer to a wheelchair for independent mobilization around the home or by assisting them to walk where appropriate were also facilitators.^30,31 Leveraging facilitators will help staff who have limited time to help residents engage in more physical activity.

Motivation of LTC staff can also be a barrier to encouraging physical activity for residents in LTC. Fear that increasing physical activity will cause adverse events like falls, illness, or exacerbation of symptoms often decreases motivation for staff to facilitate physical activity.^32,33 Another potential barrier is the conceptualization of the role of nursing in LTC as protecting residents from harm by encouraging them to engage in “risk-free” activities like staying in bed.^34-39 Strategies to increase staff motivation to engage LTC residents in physical activity that have been shown to be effective are verbal prompts, modelling behaviors, goal setting, and home champions to promote function-focused care.^17,33,40-43

The Physical Environment

Aspects of the physical environment of LTC homes may facilitate or limit residents’ ability to be physically active. A 2017 systematic review examined elements of the physical environment that acted as barriers and facilitators to physical activity for older adults living in LTC.³⁰ The authors found that the person-environment fit, security, accessibility, and comfort were key components of the physical environment that were associated with residents’ physical activity levels.³⁰ First, an appropriate fit between the residents’ abilities and the demands of the environment was related to improved activity as measured by actigraphy.⁴⁴ For example, having long hallways between residents’ rooms and common spaces discourages residents who can only walk short distances from walking to these locations. However, residents were more active in larger-scaled LTC homes with shorter distances between different areas (eg, resident rooms and dining rooms).⁴⁵ Clearly, there must be enough space to encourage walking between areas, but not so much space that walking is not feasible. Residents participating in a focus group identified accessibility and comfort features as being facilitators for walking in the corridor, such as wide corridors, sturdy handrails, carpet, chairs placed at short intervals for seated breaks, windows to look out, plants, and accessible activity rooms and restrooms.^45,46 On the other hand, limited things to see and do indoors and outdoors, along with restricted walking areas, were identified as barriers to corridor walking by residents.⁴⁶

One method for optimizing LTC home architecture to promote movement is to provide therapeutic outdoor spaces, such as gardens. Indeed, therapeutic gardens have been studied as a nonpharmacological method of engaging LTC residents with dementia and have been shown to benefit mood, pain, and fall prevention.⁴⁷ Secure therapeutic gardens or outdoor spaces provide opportunities for various activities to increase movement, including gardening, animal care, and walking.⁴⁸ However, there is a higher propensity for residents who use walkers or wheelchairs to slide off paths or become stuck in mud or mulch.⁴⁹ Residents with physical limitations may require additional supervision in garden spaces, and as such spaces should be designed with improved safety in mind (eg, barriers between paths and places where mud could accumulate). The number of available indoor (eg, a physical therapy gym) and outdoor (eg, gardens) spaces was also found to be positively related to residents’ physical activity levels.⁵⁰ However, these relationships were mediated by the number of activity programs available in the LTC homes.⁵⁰ Therefore, having staff available to facilitate activities is also important for promoting physical activity.

Chemical and Physical Restraints

Physical and chemical restraints (eg, antipsychotics and sedatives) are sometimes used to manage the behavioral and psychological symptoms of dementia,^51,52 which many residents in LTC experience.³ Though there has been an emphasis in North America to decrease their use, physical and chemical restraints are still used in LTC.⁵³ Physical restraint use is associated with a higher risk of functional and cognitive decline.^53,54 Residents who are both physically and chemically restrained through antipsychotic use are at even higher risk for these declines.⁵⁴ Thus, to improve opportunities for movement in LTC, physical restraint use should be minimized. The risks and benefits of using psychotropic medications that often decrease residents’ physical activity levels must be evaluated individually, and other nonpharmacological strategies should be used to manage the behavioral and psychological symptoms of dementia. These could include functional analysis-based interventions (ie, individualized interventions aimed at identifying unmet needs, causes, antecedents, and consequences of the behavior),⁵⁵ music therapy,⁵⁵ or other interventions described above.

Emerging Innovative Interventions

Robots are an emerging nonpharmacological intervention for improving the behavioral and psychological symptoms of dementia and facilitating physical activity in LTC. Robotic animal interventions, where LTC residents interact with robotic animals in an individual or group setting, have been shown to reduce negative behaviors and increase positive mood.⁵⁶ Additionally, robots are being used in rehabilitation to provide exercise post-stroke⁵⁷ and could easily be transitioned to do similar tasks in LTC. Robotic interventions are attractive for the LTC sector as they could help relieve the workload demands on an often overloaded sector, and, in the case of pet therapy, surmount regulations for bringing live animals into a LTC home. Though studies examining the use of robots in LTC have mainly focused on the effect of pet therapy on reducing behavioral symptoms, the use of robots to promote physical activity and exercise in LTC is a natural progression for the work that has been done in inpatient rehabilitation.⁵⁷ On a similar note, an interactive technology (similar to a Kinect system) used to promote 30-minute, twice-weekly physical activity sessions has demonstrated improvements in physical function (Short Physical Performance Battery [SPPB]) for pre-disabled (SPPB of 6 to 9) residents in LTC without dementia.⁵⁸ The role of technology to promote physical activity in LTC is an emerging area of interest, and future innovations in this area will continue to help facilitate movement.

Quality of Evidence

Most studies aimed at improving physical activity for LTC residents to date are small, have nonrandomized designs, and have limited generalizability and evidence to support the efficacy of the interventions. For example, most studies included in systematic reviews for function-focused care, dance, group exercise, and music therapy are small, observational, or quasi-experimental studies with methodological issues resulting in bias.^18,21,23,24 Likewise, the evidence surrounding nonpharmacological interventions for reducing behavioral and psychological symptoms of dementia is of very low to moderate quality.⁵⁵ Innovative interventions, such as robotics and interactive technology, to promote physical activity in LTC are in their infancy. There are no data syntheses available to date to summarize the available literature on this topic, and conclusions rely on small, nonrandomized designs or extrapolations of results from similar sectors (eg, inpatient rehabilitation). Thus, the studies described in this review can be used as preliminary evidence to support the implementation of interventions to improve physical activity, but discretion should be used when interpreting the efficacy of these interventions.

Discussion

This review identifies several strategies for promoting physical activity for LTC residents, including incorporating simple strategies into daily activities, participating in group activities (eg, exercise, dance, or music therapy), using motivational strategies to encourage staff to promote activity, leveraging the physical environment, reducing physical and chemical restraints, and using innovation solutions like robots or interactive technology. While the quality of evidence to date is limited, preliminary work suggests that strategies identified in this paper could be included as part of a multifactorial approach to increasing physical activity in LTC.

The current evidence does not suggest that any one strategy is more effective at improving physical activity, and it is likely that LTC homes will need to employ a combination of strategies to help residents move more. Additionally, residents’ preferences, goals, and capabilities should always be considered when designing an individualized physical activity plan. For example, if a resident does not like to be outdoors or gardening but enjoys dancing and music, then their physical activity plan should include group dance class and music therapy rather than gardening. LTC homes will need to have a menu of opportunities for movement that residents can choose from so that activities are pleasant and motivating, and therefore more likely to be completed.

Many of the interventions described in this review are safe and feasible to implement with residents who have physical or cognitive impairments. Function-focused care is scaled to the residents’ capabilities and did not increase the risk of falling, though LTC staff require the skills to scale physical activities appropriately.¹⁸ Likewise, group dance activities and music therapy were tested with residents with dementia, with no adverse events reported.^21,24 However, more work is needed to determine the feasibility of implementing emerging methods, such as robotics and interactive technology, for increasing physical activity for residents with physical and cognitive impairments. Most studies to date have included mobile residents or those with minimal cognitive impairment. Similarly, outdoor garden spaces may be less safe for residents who use walkers or wheelchairs if there is an opportunity for them to slip off paths or get stuck in mud or mulch. LTC homes implementing any of these interventions should evaluate the benefits and risks of each intervention, the resources available within the home to support them (eg, trained staff), and the target residents’ physical and cognitive capabilities.

While increasing physical activity is important, structured exercise is needed to see gains in components of physical fitness such as strength, aerobic capacity, and balance. Indeed, one major consideration highlighted by the aforementioned task force is that every resident who does not have contraindications must also have a personalized multicomponent exercise program as part of their care plan.⁸ The task force recommends moderate- to high-intensity strength, aerobic, and balance exercises 2 times per week for 35 to 45 minutes per session.⁸ There is an interrelationship between physical activity and structured exercise: structured exercise programs can certainly be part of a physical activity plan, but physical activity can include more than structured exercise. Physical activity also includes any activity that involves movement, such as walking in gardens or between home areas, or physically participating more in personal care activities (eg, assisting with bathing or dressing).¹⁴ Both structured exercise and physical activity are important for LTC residents. Structured exercise provides an opportunity to improve strength and cardiovascular fitness, which aim to decrease the negative effects of sarcopenia and cardiovascular disease, such as disability and death.^59,60 However, structured exercise should not be done daily for the same muscle groups.⁸ Rather, it is recommended for LTC residents to engage in structured exercise 2 times per week.⁸ Increasing physical activity is a daily goal, as daily physical activity decreases sedentary time, which has negative consequences such as decreased mood⁶¹ and increased mortality.⁶² LTC homes should incorporate strategies to both increase daily physical activity and promote individualized, structured exercise programs.

Conclusion

Residents in LTC spend much of their time in sedentary activities such as sitting or lying in bed. Physical activity is important to help decrease the negative effects of sedentary time, like poor mood and increased risk of death, and to improve physical function. This review describes several strategies to promote physical activity within LTC homes, such as leveraging daily activities and the physical environment, providing group activities, reducing physical and chemical restraint use, and using innovative technology such as robots. LTC homes can use the information in this review to plan strategies to promote physical activity.

Corresponding author: Caitlin McArthur, MScPT, PhD, Hamilton Health Sciences, St. Peter’s Hospital, 88 Maplewood Avenue, Hamilton, ON L8M 1W9; mcarthurc@hhsc.ca.

Financial disclosures: None.

From the Geriatric Education and Research in Aging Sciences (GERAS) Centre for Aging Research, McMaster University, Hamilton, ON.

Abstract

• Objective. To summarize the literature on improving opportunities for physical activity for residents in long-term care (LTC).
• Method. Narrative review of the literature.
• Results. Residents in LTC spend much of their time in sedentary activities such as sitting or lying in bed. Physical activity is important to help decrease the negative effects of sedentary time, such as poor mood and increased risk of death, and to improve physical function. This review identifies several strategies for promoting physical activity for LTC residents: incorporating simple strategies into daily activities, participating in group activities (eg, exercise, dance, or music therapy), using motivational strategies to encourage staff to promote activity, leveraging the physical environment, reducing physical and chemical restraints, and using innovative solutions such as robots or interactive technology.
• Conclusion. While the quality of evidence to date is limited, preliminary work suggests that the strategies identified in this article could be included as part of a multifactorial approach to increasing physical activity in LTC.

Keywords: long-term care; nursing homes; physical activity; sedentary; mobility.

The United Nations estimates that between 2013 and 2050 the population aged 60 years or older will double.¹ Furthermore, the fastest growth rate will be seen in older adults over the age of 80 years.¹ With this demographic shift, a growing number of older adults will require supportive housing, such as long-term care (LTC). Indeed, it is projected that the number of older adults requiring LTC will double by 2036.²

Residents in LTC are often medically complex and experience multimorbidity, cognitive impairment, and functional decline,³ making it difficult for them to engage in physical activity. LTC residents spend approximately 75% of their waking time in sedentary activities (eg, sitting, lying down, watching TV), which amounts to more than 12 hours per day.^4-6 Residents with cognitive impairment are even more sedentary, spending as little as 1 minute per day in moderate physical activity and approximately 87% of their time in sedentary activities.⁷ Additionally, a high prevalence of use of psychotropic drugs and physical restraints contributes to high levels of physical inactivity for residents in LTC.⁸ Increased time spent in sedentary activities has been associated with adverse health outcomes, such as incidence of cardiovascular disease and type 2 diabetes, and mortality.^9-11 Moreover, bed and chair rest are associated with muscle disuse, which can lead to functional impairment.^12,13

Given the large amount of time LTC residents spend in sedentary activities and the negative consequences this has on their health, it is essential to find opportunities to engage residents in physical activity throughout the day. This article summarizes evidence about increasing opportunities for physical activity for LTC residents. Physical activity is defined as “any bodily movement produced by skeletal muscles that results in energy expenditure,” while exercise, which is a subset of physical activity, is purposefully planned, structured, and repetitive and has a goal of maintaining or improving physical fitness.¹⁴ Previous work has described exercise among LTC residents in detail,^8,15,16 and thus exercise is not addressed here. Also, as a narrative review, this article provides an overview of available interventions to improve physical activity for LTC residents and does not provide comments on efficacy or an exhaustive list of potential interventions. Rather, it provides a starting point for LTC homes to consider when providing opportunities to improve physical activity for their residents.

Guidelines for Increasing Physical Activity

There are currently no published evidence-based guidelines for increasing physical activity and reducing sedentary time for residents of LTC homes. However, an international task force of experts in geriatrics, exercise, and LTC research convened in 2015 and made recommendations on this matter.⁸ They emphasize the importance of considering the needs of residents, family members, health care professionals, LTC staff, and policy-makers when designing strategies to promote movement in LTC.⁸ This will ensure that the strategies to promote movement will be realistic and sustainable. Additionally, the task force identified motivation and pleasure as key to engaging residents in physical activities, and recommended that interests and preferences should be used to guide the selection of activities.⁸ The following sections describe example strategies to improve physical activity for residents in LTC that LTC homes can use to help facilitate movement for their residents.

Leveraging Daily Activities

One approach to promoting physical activity in LTC homes is to systematically use simple strategies embedded within routine care to engage residents in movement.⁸ Function-focused, or restorative care,¹⁷ is a philosophy of care that promotes increasing physical activity and maintaining functional abilities based on the resident’s abilities. Examples include walking with residents to the dining room rather than pushing them in a wheelchair where appropriate, inviting residents to events that require them to leave their room, improving independent wheelchair propulsion for residents who cannot walk, and increasing opportunities for sit-to-stand activities where possible. These activities are scaled to the resident’s underlying physical and cognitive capabilities. A systematic review of function-focused care revealed that it can help maintain functional skills for residents in LTC, and there is no significant risk associated with implementation.¹⁸ In a study by Slaughter et al¹⁹ that examined the effectiveness of techniques to encourage mobility by residents’ usual caregivers, health care aides prompted residents to perform the sit-to-stand activity 4 times per day, with the number of repetitions individualized based on resident ability, fatigue, and motivation. Residents who completed the sit-to-stand activity had smaller declines in mobility and functional outcomes (ie, less decline on the Functional Independence Measure).¹⁹ This study included residents with Alzheimer’s disease and dementia who could transfer independently or with the assistance of one person,²⁰ indicating that this type of intervention is feasible and appropriate for residents with cognitive impairment.

Group Activities

Group activities in LTC homes are another way of engaging residents in physical activity in a motivating and pleasant setting that also encourages social engagement among residents and LTC staff. Group exercise classes can be effective for improving mood and functional outcomes. For example, a systematic review of dance classes in LTC homes revealed an improvement in problematic behaviors, mood, cognition, communication, and socialization.²¹ Most studies included participants with dementia, and no adverse events were reported, supporting the feasibility and safety of implementing group dance activities for residents with cognitive impairment. Group exercise is the most common delivery method for exercise within LTC homes²² and has been demonstrated to have small positive effects on activities of daily living (ADL; ie, improvement in ADL independence equivalent to 1.3 points on the Barthel Index).²³ Other group activities, such as music therapy, have demonstrated improvements in depressive symptoms, emotional well-being, and anxiety for LTC residents with dementia.²⁴ Group activities also provide the opportunity for movement as residents leave their rooms, walk to a new location (if able), and return to their rooms when the activity is complete.

Barriers to Physical Activity and Strategies to Overcome Them

Caregiver-related Factors

LTC staff have limited time to spend promoting physical activity since residents often have complex health care needs and staffing levels are often constrained.²⁵ Indeed, having lower staffing levels has been associated with lower levels of physical activity for residents.^26,27 LTC staff have identified a lack of time to walk with residents^28,29 and having other tasks to do (eg, clean) as barriers to promoting movement.^28,29 However, asking residents to help staff with small household chores, such as folding laundry or clearing dishes, was a facilitator to promoting movement.³⁰ Activating residents by helping them transfer to a wheelchair for independent mobilization around the home or by assisting them to walk where appropriate were also facilitators.^30,31 Leveraging facilitators will help staff who have limited time to help residents engage in more physical activity.

Motivation of LTC staff can also be a barrier to encouraging physical activity for residents in LTC. Fear that increasing physical activity will cause adverse events like falls, illness, or exacerbation of symptoms often decreases motivation for staff to facilitate physical activity.^32,33 Another potential barrier is the conceptualization of the role of nursing in LTC as protecting residents from harm by encouraging them to engage in “risk-free” activities like staying in bed.^34-39 Strategies to increase staff motivation to engage LTC residents in physical activity that have been shown to be effective are verbal prompts, modelling behaviors, goal setting, and home champions to promote function-focused care.^17,33,40-43

The Physical Environment

Aspects of the physical environment of LTC homes may facilitate or limit residents’ ability to be physically active. A 2017 systematic review examined elements of the physical environment that acted as barriers and facilitators to physical activity for older adults living in LTC.³⁰ The authors found that the person-environment fit, security, accessibility, and comfort were key components of the physical environment that were associated with residents’ physical activity levels.³⁰ First, an appropriate fit between the residents’ abilities and the demands of the environment was related to improved activity as measured by actigraphy.⁴⁴ For example, having long hallways between residents’ rooms and common spaces discourages residents who can only walk short distances from walking to these locations. However, residents were more active in larger-scaled LTC homes with shorter distances between different areas (eg, resident rooms and dining rooms).⁴⁵ Clearly, there must be enough space to encourage walking between areas, but not so much space that walking is not feasible. Residents participating in a focus group identified accessibility and comfort features as being facilitators for walking in the corridor, such as wide corridors, sturdy handrails, carpet, chairs placed at short intervals for seated breaks, windows to look out, plants, and accessible activity rooms and restrooms.^45,46 On the other hand, limited things to see and do indoors and outdoors, along with restricted walking areas, were identified as barriers to corridor walking by residents.⁴⁶

One method for optimizing LTC home architecture to promote movement is to provide therapeutic outdoor spaces, such as gardens. Indeed, therapeutic gardens have been studied as a nonpharmacological method of engaging LTC residents with dementia and have been shown to benefit mood, pain, and fall prevention.⁴⁷ Secure therapeutic gardens or outdoor spaces provide opportunities for various activities to increase movement, including gardening, animal care, and walking.⁴⁸ However, there is a higher propensity for residents who use walkers or wheelchairs to slide off paths or become stuck in mud or mulch.⁴⁹ Residents with physical limitations may require additional supervision in garden spaces, and as such spaces should be designed with improved safety in mind (eg, barriers between paths and places where mud could accumulate). The number of available indoor (eg, a physical therapy gym) and outdoor (eg, gardens) spaces was also found to be positively related to residents’ physical activity levels.⁵⁰ However, these relationships were mediated by the number of activity programs available in the LTC homes.⁵⁰ Therefore, having staff available to facilitate activities is also important for promoting physical activity.

Chemical and Physical Restraints

Physical and chemical restraints (eg, antipsychotics and sedatives) are sometimes used to manage the behavioral and psychological symptoms of dementia,^51,52 which many residents in LTC experience.³ Though there has been an emphasis in North America to decrease their use, physical and chemical restraints are still used in LTC.⁵³ Physical restraint use is associated with a higher risk of functional and cognitive decline.^53,54 Residents who are both physically and chemically restrained through antipsychotic use are at even higher risk for these declines.⁵⁴ Thus, to improve opportunities for movement in LTC, physical restraint use should be minimized. The risks and benefits of using psychotropic medications that often decrease residents’ physical activity levels must be evaluated individually, and other nonpharmacological strategies should be used to manage the behavioral and psychological symptoms of dementia. These could include functional analysis-based interventions (ie, individualized interventions aimed at identifying unmet needs, causes, antecedents, and consequences of the behavior),⁵⁵ music therapy,⁵⁵ or other interventions described above.

Emerging Innovative Interventions

Robots are an emerging nonpharmacological intervention for improving the behavioral and psychological symptoms of dementia and facilitating physical activity in LTC. Robotic animal interventions, where LTC residents interact with robotic animals in an individual or group setting, have been shown to reduce negative behaviors and increase positive mood.⁵⁶ Additionally, robots are being used in rehabilitation to provide exercise post-stroke⁵⁷ and could easily be transitioned to do similar tasks in LTC. Robotic interventions are attractive for the LTC sector as they could help relieve the workload demands on an often overloaded sector, and, in the case of pet therapy, surmount regulations for bringing live animals into a LTC home. Though studies examining the use of robots in LTC have mainly focused on the effect of pet therapy on reducing behavioral symptoms, the use of robots to promote physical activity and exercise in LTC is a natural progression for the work that has been done in inpatient rehabilitation.⁵⁷ On a similar note, an interactive technology (similar to a Kinect system) used to promote 30-minute, twice-weekly physical activity sessions has demonstrated improvements in physical function (Short Physical Performance Battery [SPPB]) for pre-disabled (SPPB of 6 to 9) residents in LTC without dementia.⁵⁸ The role of technology to promote physical activity in LTC is an emerging area of interest, and future innovations in this area will continue to help facilitate movement.

Quality of Evidence

Most studies aimed at improving physical activity for LTC residents to date are small, have nonrandomized designs, and have limited generalizability and evidence to support the efficacy of the interventions. For example, most studies included in systematic reviews for function-focused care, dance, group exercise, and music therapy are small, observational, or quasi-experimental studies with methodological issues resulting in bias.^18,21,23,24 Likewise, the evidence surrounding nonpharmacological interventions for reducing behavioral and psychological symptoms of dementia is of very low to moderate quality.⁵⁵ Innovative interventions, such as robotics and interactive technology, to promote physical activity in LTC are in their infancy. There are no data syntheses available to date to summarize the available literature on this topic, and conclusions rely on small, nonrandomized designs or extrapolations of results from similar sectors (eg, inpatient rehabilitation). Thus, the studies described in this review can be used as preliminary evidence to support the implementation of interventions to improve physical activity, but discretion should be used when interpreting the efficacy of these interventions.

Discussion

This review identifies several strategies for promoting physical activity for LTC residents, including incorporating simple strategies into daily activities, participating in group activities (eg, exercise, dance, or music therapy), using motivational strategies to encourage staff to promote activity, leveraging the physical environment, reducing physical and chemical restraints, and using innovation solutions like robots or interactive technology. While the quality of evidence to date is limited, preliminary work suggests that strategies identified in this paper could be included as part of a multifactorial approach to increasing physical activity in LTC.

The current evidence does not suggest that any one strategy is more effective at improving physical activity, and it is likely that LTC homes will need to employ a combination of strategies to help residents move more. Additionally, residents’ preferences, goals, and capabilities should always be considered when designing an individualized physical activity plan. For example, if a resident does not like to be outdoors or gardening but enjoys dancing and music, then their physical activity plan should include group dance class and music therapy rather than gardening. LTC homes will need to have a menu of opportunities for movement that residents can choose from so that activities are pleasant and motivating, and therefore more likely to be completed.

Many of the interventions described in this review are safe and feasible to implement with residents who have physical or cognitive impairments. Function-focused care is scaled to the residents’ capabilities and did not increase the risk of falling, though LTC staff require the skills to scale physical activities appropriately.¹⁸ Likewise, group dance activities and music therapy were tested with residents with dementia, with no adverse events reported.^21,24 However, more work is needed to determine the feasibility of implementing emerging methods, such as robotics and interactive technology, for increasing physical activity for residents with physical and cognitive impairments. Most studies to date have included mobile residents or those with minimal cognitive impairment. Similarly, outdoor garden spaces may be less safe for residents who use walkers or wheelchairs if there is an opportunity for them to slip off paths or get stuck in mud or mulch. LTC homes implementing any of these interventions should evaluate the benefits and risks of each intervention, the resources available within the home to support them (eg, trained staff), and the target residents’ physical and cognitive capabilities.

While increasing physical activity is important, structured exercise is needed to see gains in components of physical fitness such as strength, aerobic capacity, and balance. Indeed, one major consideration highlighted by the aforementioned task force is that every resident who does not have contraindications must also have a personalized multicomponent exercise program as part of their care plan.⁸ The task force recommends moderate- to high-intensity strength, aerobic, and balance exercises 2 times per week for 35 to 45 minutes per session.⁸ There is an interrelationship between physical activity and structured exercise: structured exercise programs can certainly be part of a physical activity plan, but physical activity can include more than structured exercise. Physical activity also includes any activity that involves movement, such as walking in gardens or between home areas, or physically participating more in personal care activities (eg, assisting with bathing or dressing).¹⁴ Both structured exercise and physical activity are important for LTC residents. Structured exercise provides an opportunity to improve strength and cardiovascular fitness, which aim to decrease the negative effects of sarcopenia and cardiovascular disease, such as disability and death.^59,60 However, structured exercise should not be done daily for the same muscle groups.⁸ Rather, it is recommended for LTC residents to engage in structured exercise 2 times per week.⁸ Increasing physical activity is a daily goal, as daily physical activity decreases sedentary time, which has negative consequences such as decreased mood⁶¹ and increased mortality.⁶² LTC homes should incorporate strategies to both increase daily physical activity and promote individualized, structured exercise programs.

Conclusion

Residents in LTC spend much of their time in sedentary activities such as sitting or lying in bed. Physical activity is important to help decrease the negative effects of sedentary time, like poor mood and increased risk of death, and to improve physical function. This review describes several strategies to promote physical activity within LTC homes, such as leveraging daily activities and the physical environment, providing group activities, reducing physical and chemical restraint use, and using innovative technology such as robots. LTC homes can use the information in this review to plan strategies to promote physical activity.

Corresponding author: Caitlin McArthur, MScPT, PhD, Hamilton Health Sciences, St. Peter’s Hospital, 88 Maplewood Avenue, Hamilton, ON L8M 1W9; mcarthurc@hhsc.ca.

Financial disclosures: None.

From the Division of Rheumatology & Immunology, University of Nebraska Medical Center, and Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE.

Abstract

• Objective: To review the management of traditional and nontraditional CVD cardiovascular disease risk factors in rheumatoid arthritis (RA).
• Methods: Literature review of the management of CVD risk in RA.
• Results: Because of the increased risk of CVD events and CVD mortality among RA patients, aggressive management of CVD risk is essential. Providers should follow national guidelines for the management of traditional CVD risk factors, including dyslipidemia, hypertension, and diabetes mellitus. Similar efforts are needed in counseling on lifestyle modifications, including smoking cessation, regular exercise, and maintaining a healthy body weight. Because higher RA disease activity is also linked with CVD risk, aggressive treatment of RA to a target of low disease activity or remission is critical. Furthermore, the selection of potentially “cardioprotective” agents such as methotrexate and tumor necrosis factor inhibitors, while limiting use of nonsteroidal anti-inflammatory drugs and glucocorticoids, are strategies that could be employed by rheumatologists to help mitigate CVD risk in their patients with RA.
• Conclusion: Routine assessment of CVD risk, management of traditional CVD risk factors, counseling on healthy lifestyle habits, and aggressive treatment of RA are essential to minimize CVD risk in this population.

Keywords: rheumatoid arthritis; cardiovascular disease; cardiovascular risk assessment; cardiovascular risk management.

Editor’s note: This article is part 2 of a 2-part article. “Assessment of Cardiovascular Disease Risk in Rheumatoid Arthritis” was published in the January/February 2019 issue.

Rheumatoid arthritis (RA) is a systemic autoimmune condition that contributes to an increased risk for cardiovascular disease (CVD) among affected patients. In persons with RA, the risk of incident CVD and CVD mortality are increased by approximately 50% compared with the general population.^1,2 To minimize CVD risk in this population, providers must routinely assess for CVD risk factors³ and aggressively manage both traditional and nontraditional CVD risk factors.

Managing Traditional Risk Factors

As in the general population, identification and management of traditional CVD risk factors are crucial to minimize CVD risk in the RA population. A prospective study of 201 RA patients demonstrated that traditional CVD risk factors were in fact more predictive of endothelial dysfunction and carotid atherosclerosis than were disease-related inflammatory markers in RA.⁴ Management of traditional risk factors is detailed in the following sections, and recommendations for managing all traditional CVD risk factors are summarized in the Table.

Dyslipidemia

The role of dyslipidemia in atherogenesis is well established, and as a result, lipid levels are nearly universally included in CVD risk stratification tools. However, the interpretation of lipid levels in the context of RA is challenging because of the effects of systemic inflammation on their absolute values. Compared to the general population, patients with RA have lower total cholesterol (TC) and low-density lipoprotein (LDL) levels independent of lipid-lowering therapy.^5,6 Despite this, RA patients are at increased risk for CVD. There is even some evidence to suggest a “lipid paradox” in RA, whereby lower TC (< 4 mmol/L) and LDL levels suggest an increased risk of CVD.^7,8 In contrast to LDL, higher levels of high-density lipoprotein (HDL) are typically associated with reduced CVD risk, as in the general population.^8,9 Interestingly, in a cohort of 16,085 RA patients and 48,499 age- and sex-matched controls, there was no significant difference in the relationship between LDL and CVD risk, suggesting that quantitative lipid levels alone may not entirely explain the CVD mortality gap in RA.⁹ As such, there is substantial interest in lipoprotein function within the context of CVD risk in RA. Recent investigations have identified impaired HDL function, with reduced cholesterol efflux capacity and antioxidant properties, as well as increased scavenger receptor expression and foam cell formation, in patients with RA.^10,11 More research is needed to elucidate how these alterations affect CVD morbidity and mortality and how their measurement could be integrated into improved CVD risk assessment.

Meta-analyses of randomized controlled trials have estimated that lipid-lowering therapy with HMG-CoA reductase inhibitors (statins) reduces the risk of CVD by 25% to 30%; as such, statin therapy has become the standard of care for reduction of CVD risk in the general population.¹² Benefits for primary prevention of CVD in RA have also been observed; statin therapy was associated with a reduced risk of CVD events (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.20-0.98) and all-cause mortality (HR, 0.43; 95% CI, 0.20-0.92) in a population-based cohort study.¹³ Statins appear to have similar lipid-lowering effects and result in similar CVD risk reduction when used for primary or secondary prevention in RA patients compared to non-RA controls.^14-16 Additionally, anti-inflammatory properties of statins may act in synergy with disease-modifying antirheumatic drugs (DMARDs) to improve RA disease activity. In a small study of RA patients, statin therapy improved subjective and objective markers of RA disease activity in conjunction with methotrexate.¹⁷

While statins provide robust reduction in CVD risk, some individuals cannot tolerate statin therapy or do not achieve goal LDL levels with statin therapy. Select non-statin LDL-cholesterol-lowering agents have shown promise for reducing CVD events in the general population.¹⁸ Ezetimibe, which inhibits cholesterol absorption in the small intestine, very modestly reduced CVD events when added to atorvastatin (relative risk [RR], 0.94; 95% CI, 0.89-0.99) in a double-blind randomized controlled trial.¹⁹ Novel monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibit the internalization of surface LDL receptors, promoting LDL clearance. Two PCSK-9 inhibitors, alirocumab and evolocumab, were approved by the US Food and Drug Administration (FDA) after randomized controlled trials demonstrated their efficacy in lowering LDL by approximately 60% and reducing CVD events by approximately 15% in patients on maximum-tolerated statin therapy.^20-22 To date, non-statin LDL-cholesterol-lowering agents have been subject to limited study in RA.²³

Identification and management of dyslipidemia offers an opportunity for substantial CVD risk reduction at the RA population level. Unfortunately, current rates of lipid screening are inadequate in this high-risk group. In a study of 3298 Medicare patients with RA, less than half of RA patients with an indication underwent appropriate lipid screening.²⁴ Additionally, statins are often underutilized for both primary and secondary prevention in RA patients. Only 27% of RA patients meeting National Cholesterol Education Program Adult Treatment Panel III criteria were initiated on statin therapy in a population-based cohort study.²⁵ Among patients discharged after a first myocardial infarction (MI), the odds of receiving lipid-lowering therapy were 31% lower for RA patients (odds ratio [OR], 0.69; 95% CI, 0.58-0.82).²⁶ Similar to the general population, adherence to statins in RA patients appears to be poor.^27-30 This raises particular concern considering that a population-based cohort study of RA patients demonstrated a 67% increased risk of MI associated with statin discontinuation, regardless of prior MI status.²⁷ Providers—rheumatologists, primary care providers, and cardiologists alike—need to remain vigilant in efforts to assess CVD risk to identify patients who will benefit from lipid-lowering therapy and to emphasize the importance to patients of statin adherence. Novel models of health-care delivery, health technologies, and patient engagement in care may prove useful for improving lipid screening and management in RA.

Tobacco Use

Cigarette smoking is a shared risk factor for both CVD and RA. Large cohort studies have identified a dose-dependent increased risk of incident RA, particularly seropositive RA, among smokers.^31-34 Tobacco smoking has also been associated with increased levels of inflammation and RA disease activity.³⁵ The consequences of tobacco use in the general population are staggering. Among individuals over the age of 30 years, tobacco use is responsible for 12% of all deaths and 10% of all CVD deaths.³⁶ Similar findings are observed in RA; a recent meta-analysis estimated there is a 50% increased risk of CVD events in RA related to smoking tobacco.³⁷ In the general population, smoking cessation markedly lowers CVD risk, and over time CVD risk may approach that of nonsmokers.^38,39 Thus, regular counseling and interventions to facilitate smoking cessation are critical to reducing CVD risk in RA patients. RA-specific smoking cessation programs have been proposed, but have yet to outperform standard smoking cessation programs.⁴⁰

Diabetes Mellitus

It is estimated that almost 10% of the US population has diabetes mellitus (DM), which in isolation portends substantial CVD risk.⁴¹ There is an increased prevalence of DM in RA, perhaps owing to factors such as physical inactivity and chronic glucocorticoid use, though a higher level of RA disease activity itself has been associated with increased insulin resistance.^42-45 In a cohort of 100 RA patients who were neither obese nor diabetic, RA patients had significantly higher fasting blood glucose and insulin levels than age- and sex-matched controls. These findings were even more pronounced in RA patients with higher levels of disease activity.⁴⁴ Similar to the general population, DM is associated with poor CVD outcomes in RA.³⁷ Therefore, both appropriate management of diabetes and control of RA disease activity are vitally important to minimize CVD risk related to DM.

Though not a universal finding, there may be an increased prevalence of hypertension in RA patients.^31,46 Nonsteroidal anti-inflammatory drug (NSAID) and glucocorticoid use may play a role in the development of hypertension, while DMARDs appear to exert a less substantial effect on blood pressure.^47,48 At least one study found that DMARD initiation (particularly for methotrexate and hydroxychloroquine) was associated with significant, albeit small, declines in both systolic and diastolic blood pressure over the first 6 months of treatment.⁴⁹

Despite its potentially higher prevalence in this population, hypertension is both underdiagnosed and undertreated in RA patients.^24,50-52 This is an important deficiency to target because, as in the general population, hypertension is associated with an increased risk of MI (RR, 1.84; 95% CI, 1.38-2.46) and composite CVD outcomes (RR, 2.24; 95% CI, 1.42-3.06) in RA.³⁷ Thresholds for initiation and escalation of antihypertensive therapy are not specific to the RA population; thus, diagnosis and management of hypertension should be informed by the American College of Cardiology/American Heart Association guidelines, treating those with in-office blood pressures exceeding 140/90 mm Hg (> 130/80 mm Hg if aged > 65 years or with concomitant CVD, DM, chronic kidney disease, or 10-year atherosclerotic cardiovascular disease risk > 10%), typically with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, or thiazide diuretics as comorbidities may dictate or allow.⁵³ Also, the use of NSAIDs and glucocorticoids should be minimized, particularly in those with concomitant hypertension.

Physical Activity

Likely due to factors such as articular pain and stiffness, as well as physical limitations, RA patients are more sedentary than the general population.^54,55 In a study of objectively assessed sedentary behavior in RA patients, greater average sedentary time per day and greater number of sedentary bouts (> 20 min) were associated with increased 10-year risk of CVD as assessed by the QRISK2.⁵⁶ Conversely, the beneficial effects of exercise are well documented. Light to moderate physical activity has been associated with improved cardiovascular outcomes, greater physical function, higher levels of HDL, as well as reduced systemic inflammation and disease activity, and improved endothelial function in RA patients.^57-61 While there has been concern that physical activity may result in accelerated joint damage, even high-intensity exercise was shown to be safe without causing significant progression of joint damage.⁵⁸

Obesity, Weight Loss, and Diet

While obesity is clearly associated with CVD risk in the general population, this relationship is much more complex in RA, as underweight RA patients are also at higher risk for CVD and CVD-related mortality.^62-64 One potential explanation for this finding is that pathological weight loss resulting in an underweight body mass index (BMI) is an independent predictor of CVD. In a study of US Veterans with RA, higher rates of weight loss (> 3 kg/m²/year) were associated with increased CVD mortality (HR, 2.27; 95% CI, 1.61-3.19) independent of BMI.⁶⁵ Systemic inflammation in RA can lead to “rheumatoid cachexia,” characterized by decreased muscle mass, increased adiposity, and increased CVD risk despite a normal or potentially decreased BMI.⁶⁶ Practitioners should be mindful of not only current body weight, but also patients’ weight trajectories when counseling on lifestyle practices such as healthy diet and regular exercise in RA patients. For obese individuals with RA, healthy weight loss should be encouraged. Interestingly, bariatric surgery in RA patients may improve RA disease activity in addition to its known effects on body weight and DM.⁶⁷

Counseling on healthy diet with a focus on limiting foods high in saturated- and trans-fatty acids and high glycemic index foods, and increasing consumption of fruits, vegetables, and mono-unsaturated fatty acids is a well-accepted and common practice to help minimize CVD risk in the general population.⁶⁸ No studies to date have investigated the effect of specific diets on CVD risk in RA patients, and thus we recommend adherence to general population recommendations.

Disease Activity

In addition to traditional risk factors, several studies have identified associations between the level of RA disease activity and risk of CVD. In a cohort of US Veterans with RA, CVD-related mortality increased in a dose-dependent manner with higher disease activity categories. In stark contrast, the CVD mortality rates of those in remission paralleled the rates from the general population (standardized mortality ratio [SMR], 0.68; 95% CI, 0.37-1.27).⁶⁹ In a separate cohort of 1157 RA patients without prior CVD, achieving low disease activity was associated with a lower risk of incident CVD events (HR, 0.65; 95% CI, 0.43-0.99).⁷⁰ Additionally, high disease activity has been associated with surrogate markers of CVD and other CVD risk factors including NT-proBNP and systolic blood pressure.^71,72 While no randomized controlled trial data is available to inform this recommendation, observational data suggest RA should be aggressively treated (ideally to achieve and maintain remission or low disease activity) to minimize CVD risk. While keeping this treatment goal in mind, the differential effects of specific RA therapies on CVD must also be considered.

Glucocorticoids and NSAIDs

With the expanding repertoire of DMARDs available and more aggressive treatment approaches, the role of glucocorticoids and NSAIDs in RA treatment is decreasing over time. While their efficacy for improving pain and stiffness is well established, concern regarding their contribution to CVD risk in RA patients is warranted.

Glucocorticoids are known to have detrimental effects on traditional CVD risk factors such as hypertension, insulin resistance, and dyslipidemia in the general population, as well as in RA patients.^73,74 In a meta-analysis of predominantly observational studies of RA patients, glucocorticoid use was associated with an increased risk of CVD events (RR, 1.47; 95% CI, 1.34-1.60), including MI, congestive heart failure (CHF), and cerebrovascular accident (CVA).⁷⁵ Evidence is conflicting in regards to a clear dose threshold that leads to increased CVD risk with glucocorticoids, though higher doses are associated with greater risk.^76-81 As RA patients requiring glucocorticoids typically have higher disease activity, confounding by indication remains a complicating factor in assessing the relative contributions of glucocorticoid use and RA disease activity to elevated CVD risk in many analyses.

The increased CVD risk with NSAID use is not specific to RA and has been well established in the general population.^82-84 In the previously mentioned meta-analysis, an increased overall risk of CVD events was observed with NSAID use in RA (RR, 1.18; 95% CI, 1.01-1.38). It should be noted that cyclo-oxygenase 2 (COX-2) inhibitors, in particular rofecoxib (now removed from the market), appeared to drive the majority of this risk (RR, 1.36; 95% CI, 1.10-1.67 in COX-2 inhibitors and RR 1.08, 95% CI, 0.94-1.24 in nonselective NSAIDs), suggesting a potential differential risk among NSAIDs.⁷⁵ While naproxen has been thought to carry the lowest risk of CVD based on initial studies, this has not been universally observed, including in a recent randomized controlled trial of more than 24,000 RA and osteoarthritis patients.^82,85,86

Providers should use the lowest possible dose and duration of glucocorticoids and NSAIDs to achieve symptom relief, with continual efforts to taper or discontinue. Candidates for glucocorticoid and NSAID therapy should be selected carefully, and use of these therapies should be avoided in those with prior CVD or at high risk for CVD based on traditional CVD risk factors. Most importantly, providers should focus on utilizing DMARDs for the management of RA, which more effectively treat RA as well as reduce CVD risk.

Methotrexate (MTX), a mainstay in the treatment of RA, is a conventional DMARD observed to improve overall survival and mitigate CVD risk in multiple RA cohorts.^75,87,88 In a recent meta-analysis comprised of 236,525 RA patients and 5410 CVD events, MTX use was associated with a 28% reduction in overall CVD events across 8 studies (RR, 0.72; 95% CI, 0.57-0.91), substantiating similar findings in a prior meta-analysis.^75,88 MTX use was specifically associated with a decreased risk of MI (RR, 0.81; 95% CI, 0.68-0.96). Case-control and cohort studies have cited a 20% to 50% reduced risk of CHF with MTX use.^89,90 The potential cardioprotective effect of MTX appears to be both multifactorial and complex, likely mediated through both direct and indirect mechanisms. MTX directly promotes anti-atherogenic lipoprotein function, improves endothelial function, and scavenges free radicals.^91,92 Indirectly, MTX likely reduces CVD risk by effectively reducing RA disease activity. Based on these and other data, MTX remains the cornerstone of DMARD therapy in RA patients when targeting CVD risk reduction.

Hydroxychloroquine

Emerging evidence suggests that hydroxychloroquine (HCQ), an antimalarial most often utilized in combination with alternative DMARDs in RA, prevents DM and has beneficial effects on lipid profiles. A recent meta-analysis compiled 3 homogenous observational studies that investigated the effect of HCQ on incident DM. RA patients ever exposed to HCQ had a 40% lower incidence of DM (HR, 0.59; 95% CI, 0.49-0.70).⁹³ Increased duration of HCQ use was shown to further reduce risk of incident DM.⁹⁴ The aforementioned meta-analysis also pooled 5 studies investigating the effect of HCQ on lipid profiles, with favorable mean differences in TC (–9.82 mg/dL), LDL (–10.61 mg/dL), HDL (4.13 mg/dL), and triglycerides (–19.15 mg/dL) in HCQ users compared to non-users.⁹³ Given these favorable changes to traditional CVD risk factors, it is not surprising that in a retrospective study of 1266 RA patients without prior CVD, HCQ was associated with significantly lower risk of incident CVD. While external validation of these findings is needed, HCQ is an attractive conventional DMARD to be used in RA for CVD risk reduction. Moreover, its combination with MTX and sulfasalazine also shows promise for CVD risk reduction.^95,96

TNF Inhibitors

Tumor necrosis factor (TNF) inhibitors are often the initial biologic DMARD therapy used in RA patients not responding to conventional DMARDs. In the previously described meta-analysis, TNF inhibitors were associated with similar reductions in CVD events as MTX (RR, 0.70; 95% CI, 0.54-0.90).⁷⁵ Of note, there was a trend toward reduced risk of CHF (RR, 0.75; 95% CI, 0.49-1.15) in this same meta-analysis, an area of concern with TNF inhibitor use due to a prior randomized controlled trial demonstrating worsening clinical status in patients with existing moderate-to-severe CHF treated with high-dose infliximab.⁹⁷ Current RA treatment guidelines recommend avoiding TNF inhibitor use in individuals with CHF.⁹⁸

Aside from the risk of CHF exacerbation, TNF inhibitors appear to be cardioprotective. Similar to MTX, the mechanism by which TNF inhibition reduces cardiovascular risk is complex and likely due to both direct and indirect mechanisms. Substantial research has been conducted on the effect of TNF inhibition on lipids, with a recent meta-analysis demonstrating increases in HDL and TC, with stable LDL and atherogenic index over treatment follow-up.⁹⁹ A subsequent meta-analysis not limited to RA patients yielded similar results.¹⁰⁰ In addition to quantitative lipid changes, alteration of lipoprotein function, improvement in myocardial function, reduced aortic stiffness, improved blood pressure, and reduced RA disease activity may also be responsible for cardioprotective benefits of these agents.^101,102

Non-TNF Biologic and Traditional Synthetic DMARDs

Tocilizumab, an IL-6 inhibitor, can potently increase LDL levels, but it does not appear to increase the risk of CVD events and may actually promote more favorable anti-atherogenic lipoprotein function.^103-106 Although these quantitative lipid changes received significant attention in the wake of early reports detailing this effect, similar lipid changes appear to accompany other DMARDs including TNF inhibitors and tofacitinib.¹⁰⁷ There have been few studies evaluating the risk of CVD with other non-TNF inhibitor biologic DMARDs and traditional synthetic DMARDs, warranting future study.

Conclusion

To mitigate the increased risk of CVD in RA, primary care and subspecialty providers alike must be aware of this heightened risk in RA, perform frequent assessments of CVD risk,³ and aggressively manage both traditional and nontraditional CVD risk factors. The differential roles in this effort may not be clear; thus, we have proposed a co-management strategy detailed in the Figure. Clear communication between providers is of the utmost importance to ensure effective management of CVD risk.

Given limited evidence for RA-specific CVD risk assessments and traditional risk factor treatment targets, management should follow pertinent national guidelines. The importance of lifestyle counseling should not be overlooked, with a focus on smoking cessation, healthy diet and body weight, and regular aerobic exercise. Finally, rheumatologists should aggressively manage RA using a treat-to-target approach, minimize the use of glucocorticoids and NSAIDs, and preferentially select DMARDs that have been associated with lower CVD risk. Through this comprehensive approach, recent trends of improved CVD outcomes in RA will hopefully become more widespread.¹⁰⁸

Corresponding author: Bryant R. England, MD; 986270 Nebraska Medical Center, Omaha, NE 68198-6270; Bryant.england@unmc.edu.

Financial disclosures: Dr. England is supported by UNMC Internal Medicine Scientist Development Award, UNMC Physician-Scientist Training Program, the UNMC Mentored Scholars Program, and the Rheumatology Research Foundation Scientist Development Award. Dr. Mikuls is supported by a VA Merit Award (CX000896) and grants from the National Institutes of Health: National Institute of General Medical Sciences (U54GM115458), National Institute on Alcohol Abuse and Alcoholism (R25AA020818), and National Institute of Arthritis and Musculoskeletal and Skin Diseases (2P50AR60772).

From the Division of Rheumatology & Immunology, University of Nebraska Medical Center, and Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE.

Abstract

• Objective: To review the management of traditional and nontraditional CVD cardiovascular disease risk factors in rheumatoid arthritis (RA).
• Methods: Literature review of the management of CVD risk in RA.
• Results: Because of the increased risk of CVD events and CVD mortality among RA patients, aggressive management of CVD risk is essential. Providers should follow national guidelines for the management of traditional CVD risk factors, including dyslipidemia, hypertension, and diabetes mellitus. Similar efforts are needed in counseling on lifestyle modifications, including smoking cessation, regular exercise, and maintaining a healthy body weight. Because higher RA disease activity is also linked with CVD risk, aggressive treatment of RA to a target of low disease activity or remission is critical. Furthermore, the selection of potentially “cardioprotective” agents such as methotrexate and tumor necrosis factor inhibitors, while limiting use of nonsteroidal anti-inflammatory drugs and glucocorticoids, are strategies that could be employed by rheumatologists to help mitigate CVD risk in their patients with RA.
• Conclusion: Routine assessment of CVD risk, management of traditional CVD risk factors, counseling on healthy lifestyle habits, and aggressive treatment of RA are essential to minimize CVD risk in this population.

Keywords: rheumatoid arthritis; cardiovascular disease; cardiovascular risk assessment; cardiovascular risk management.

Editor’s note: This article is part 2 of a 2-part article. “Assessment of Cardiovascular Disease Risk in Rheumatoid Arthritis” was published in the January/February 2019 issue.

Rheumatoid arthritis (RA) is a systemic autoimmune condition that contributes to an increased risk for cardiovascular disease (CVD) among affected patients. In persons with RA, the risk of incident CVD and CVD mortality are increased by approximately 50% compared with the general population.^1,2 To minimize CVD risk in this population, providers must routinely assess for CVD risk factors³ and aggressively manage both traditional and nontraditional CVD risk factors.

Managing Traditional Risk Factors

As in the general population, identification and management of traditional CVD risk factors are crucial to minimize CVD risk in the RA population. A prospective study of 201 RA patients demonstrated that traditional CVD risk factors were in fact more predictive of endothelial dysfunction and carotid atherosclerosis than were disease-related inflammatory markers in RA.⁴ Management of traditional risk factors is detailed in the following sections, and recommendations for managing all traditional CVD risk factors are summarized in the Table.

Dyslipidemia

The role of dyslipidemia in atherogenesis is well established, and as a result, lipid levels are nearly universally included in CVD risk stratification tools. However, the interpretation of lipid levels in the context of RA is challenging because of the effects of systemic inflammation on their absolute values. Compared to the general population, patients with RA have lower total cholesterol (TC) and low-density lipoprotein (LDL) levels independent of lipid-lowering therapy.^5,6 Despite this, RA patients are at increased risk for CVD. There is even some evidence to suggest a “lipid paradox” in RA, whereby lower TC (< 4 mmol/L) and LDL levels suggest an increased risk of CVD.^7,8 In contrast to LDL, higher levels of high-density lipoprotein (HDL) are typically associated with reduced CVD risk, as in the general population.^8,9 Interestingly, in a cohort of 16,085 RA patients and 48,499 age- and sex-matched controls, there was no significant difference in the relationship between LDL and CVD risk, suggesting that quantitative lipid levels alone may not entirely explain the CVD mortality gap in RA.⁹ As such, there is substantial interest in lipoprotein function within the context of CVD risk in RA. Recent investigations have identified impaired HDL function, with reduced cholesterol efflux capacity and antioxidant properties, as well as increased scavenger receptor expression and foam cell formation, in patients with RA.^10,11 More research is needed to elucidate how these alterations affect CVD morbidity and mortality and how their measurement could be integrated into improved CVD risk assessment.

Meta-analyses of randomized controlled trials have estimated that lipid-lowering therapy with HMG-CoA reductase inhibitors (statins) reduces the risk of CVD by 25% to 30%; as such, statin therapy has become the standard of care for reduction of CVD risk in the general population.¹² Benefits for primary prevention of CVD in RA have also been observed; statin therapy was associated with a reduced risk of CVD events (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.20-0.98) and all-cause mortality (HR, 0.43; 95% CI, 0.20-0.92) in a population-based cohort study.¹³ Statins appear to have similar lipid-lowering effects and result in similar CVD risk reduction when used for primary or secondary prevention in RA patients compared to non-RA controls.^14-16 Additionally, anti-inflammatory properties of statins may act in synergy with disease-modifying antirheumatic drugs (DMARDs) to improve RA disease activity. In a small study of RA patients, statin therapy improved subjective and objective markers of RA disease activity in conjunction with methotrexate.¹⁷

While statins provide robust reduction in CVD risk, some individuals cannot tolerate statin therapy or do not achieve goal LDL levels with statin therapy. Select non-statin LDL-cholesterol-lowering agents have shown promise for reducing CVD events in the general population.¹⁸ Ezetimibe, which inhibits cholesterol absorption in the small intestine, very modestly reduced CVD events when added to atorvastatin (relative risk [RR], 0.94; 95% CI, 0.89-0.99) in a double-blind randomized controlled trial.¹⁹ Novel monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibit the internalization of surface LDL receptors, promoting LDL clearance. Two PCSK-9 inhibitors, alirocumab and evolocumab, were approved by the US Food and Drug Administration (FDA) after randomized controlled trials demonstrated their efficacy in lowering LDL by approximately 60% and reducing CVD events by approximately 15% in patients on maximum-tolerated statin therapy.^20-22 To date, non-statin LDL-cholesterol-lowering agents have been subject to limited study in RA.²³

Identification and management of dyslipidemia offers an opportunity for substantial CVD risk reduction at the RA population level. Unfortunately, current rates of lipid screening are inadequate in this high-risk group. In a study of 3298 Medicare patients with RA, less than half of RA patients with an indication underwent appropriate lipid screening.²⁴ Additionally, statins are often underutilized for both primary and secondary prevention in RA patients. Only 27% of RA patients meeting National Cholesterol Education Program Adult Treatment Panel III criteria were initiated on statin therapy in a population-based cohort study.²⁵ Among patients discharged after a first myocardial infarction (MI), the odds of receiving lipid-lowering therapy were 31% lower for RA patients (odds ratio [OR], 0.69; 95% CI, 0.58-0.82).²⁶ Similar to the general population, adherence to statins in RA patients appears to be poor.^27-30 This raises particular concern considering that a population-based cohort study of RA patients demonstrated a 67% increased risk of MI associated with statin discontinuation, regardless of prior MI status.²⁷ Providers—rheumatologists, primary care providers, and cardiologists alike—need to remain vigilant in efforts to assess CVD risk to identify patients who will benefit from lipid-lowering therapy and to emphasize the importance to patients of statin adherence. Novel models of health-care delivery, health technologies, and patient engagement in care may prove useful for improving lipid screening and management in RA.

Tobacco Use

Cigarette smoking is a shared risk factor for both CVD and RA. Large cohort studies have identified a dose-dependent increased risk of incident RA, particularly seropositive RA, among smokers.^31-34 Tobacco smoking has also been associated with increased levels of inflammation and RA disease activity.³⁵ The consequences of tobacco use in the general population are staggering. Among individuals over the age of 30 years, tobacco use is responsible for 12% of all deaths and 10% of all CVD deaths.³⁶ Similar findings are observed in RA; a recent meta-analysis estimated there is a 50% increased risk of CVD events in RA related to smoking tobacco.³⁷ In the general population, smoking cessation markedly lowers CVD risk, and over time CVD risk may approach that of nonsmokers.^38,39 Thus, regular counseling and interventions to facilitate smoking cessation are critical to reducing CVD risk in RA patients. RA-specific smoking cessation programs have been proposed, but have yet to outperform standard smoking cessation programs.⁴⁰

Diabetes Mellitus

It is estimated that almost 10% of the US population has diabetes mellitus (DM), which in isolation portends substantial CVD risk.⁴¹ There is an increased prevalence of DM in RA, perhaps owing to factors such as physical inactivity and chronic glucocorticoid use, though a higher level of RA disease activity itself has been associated with increased insulin resistance.^42-45 In a cohort of 100 RA patients who were neither obese nor diabetic, RA patients had significantly higher fasting blood glucose and insulin levels than age- and sex-matched controls. These findings were even more pronounced in RA patients with higher levels of disease activity.⁴⁴ Similar to the general population, DM is associated with poor CVD outcomes in RA.³⁷ Therefore, both appropriate management of diabetes and control of RA disease activity are vitally important to minimize CVD risk related to DM.

Though not a universal finding, there may be an increased prevalence of hypertension in RA patients.^31,46 Nonsteroidal anti-inflammatory drug (NSAID) and glucocorticoid use may play a role in the development of hypertension, while DMARDs appear to exert a less substantial effect on blood pressure.^47,48 At least one study found that DMARD initiation (particularly for methotrexate and hydroxychloroquine) was associated with significant, albeit small, declines in both systolic and diastolic blood pressure over the first 6 months of treatment.⁴⁹

Despite its potentially higher prevalence in this population, hypertension is both underdiagnosed and undertreated in RA patients.^24,50-52 This is an important deficiency to target because, as in the general population, hypertension is associated with an increased risk of MI (RR, 1.84; 95% CI, 1.38-2.46) and composite CVD outcomes (RR, 2.24; 95% CI, 1.42-3.06) in RA.³⁷ Thresholds for initiation and escalation of antihypertensive therapy are not specific to the RA population; thus, diagnosis and management of hypertension should be informed by the American College of Cardiology/American Heart Association guidelines, treating those with in-office blood pressures exceeding 140/90 mm Hg (> 130/80 mm Hg if aged > 65 years or with concomitant CVD, DM, chronic kidney disease, or 10-year atherosclerotic cardiovascular disease risk > 10%), typically with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, or thiazide diuretics as comorbidities may dictate or allow.⁵³ Also, the use of NSAIDs and glucocorticoids should be minimized, particularly in those with concomitant hypertension.

Physical Activity

Likely due to factors such as articular pain and stiffness, as well as physical limitations, RA patients are more sedentary than the general population.^54,55 In a study of objectively assessed sedentary behavior in RA patients, greater average sedentary time per day and greater number of sedentary bouts (> 20 min) were associated with increased 10-year risk of CVD as assessed by the QRISK2.⁵⁶ Conversely, the beneficial effects of exercise are well documented. Light to moderate physical activity has been associated with improved cardiovascular outcomes, greater physical function, higher levels of HDL, as well as reduced systemic inflammation and disease activity, and improved endothelial function in RA patients.^57-61 While there has been concern that physical activity may result in accelerated joint damage, even high-intensity exercise was shown to be safe without causing significant progression of joint damage.⁵⁸

Obesity, Weight Loss, and Diet

While obesity is clearly associated with CVD risk in the general population, this relationship is much more complex in RA, as underweight RA patients are also at higher risk for CVD and CVD-related mortality.^62-64 One potential explanation for this finding is that pathological weight loss resulting in an underweight body mass index (BMI) is an independent predictor of CVD. In a study of US Veterans with RA, higher rates of weight loss (> 3 kg/m²/year) were associated with increased CVD mortality (HR, 2.27; 95% CI, 1.61-3.19) independent of BMI.⁶⁵ Systemic inflammation in RA can lead to “rheumatoid cachexia,” characterized by decreased muscle mass, increased adiposity, and increased CVD risk despite a normal or potentially decreased BMI.⁶⁶ Practitioners should be mindful of not only current body weight, but also patients’ weight trajectories when counseling on lifestyle practices such as healthy diet and regular exercise in RA patients. For obese individuals with RA, healthy weight loss should be encouraged. Interestingly, bariatric surgery in RA patients may improve RA disease activity in addition to its known effects on body weight and DM.⁶⁷

Counseling on healthy diet with a focus on limiting foods high in saturated- and trans-fatty acids and high glycemic index foods, and increasing consumption of fruits, vegetables, and mono-unsaturated fatty acids is a well-accepted and common practice to help minimize CVD risk in the general population.⁶⁸ No studies to date have investigated the effect of specific diets on CVD risk in RA patients, and thus we recommend adherence to general population recommendations.

Disease Activity

In addition to traditional risk factors, several studies have identified associations between the level of RA disease activity and risk of CVD. In a cohort of US Veterans with RA, CVD-related mortality increased in a dose-dependent manner with higher disease activity categories. In stark contrast, the CVD mortality rates of those in remission paralleled the rates from the general population (standardized mortality ratio [SMR], 0.68; 95% CI, 0.37-1.27).⁶⁹ In a separate cohort of 1157 RA patients without prior CVD, achieving low disease activity was associated with a lower risk of incident CVD events (HR, 0.65; 95% CI, 0.43-0.99).⁷⁰ Additionally, high disease activity has been associated with surrogate markers of CVD and other CVD risk factors including NT-proBNP and systolic blood pressure.^71,72 While no randomized controlled trial data is available to inform this recommendation, observational data suggest RA should be aggressively treated (ideally to achieve and maintain remission or low disease activity) to minimize CVD risk. While keeping this treatment goal in mind, the differential effects of specific RA therapies on CVD must also be considered.

Glucocorticoids and NSAIDs

With the expanding repertoire of DMARDs available and more aggressive treatment approaches, the role of glucocorticoids and NSAIDs in RA treatment is decreasing over time. While their efficacy for improving pain and stiffness is well established, concern regarding their contribution to CVD risk in RA patients is warranted.

Glucocorticoids are known to have detrimental effects on traditional CVD risk factors such as hypertension, insulin resistance, and dyslipidemia in the general population, as well as in RA patients.^73,74 In a meta-analysis of predominantly observational studies of RA patients, glucocorticoid use was associated with an increased risk of CVD events (RR, 1.47; 95% CI, 1.34-1.60), including MI, congestive heart failure (CHF), and cerebrovascular accident (CVA).⁷⁵ Evidence is conflicting in regards to a clear dose threshold that leads to increased CVD risk with glucocorticoids, though higher doses are associated with greater risk.^76-81 As RA patients requiring glucocorticoids typically have higher disease activity, confounding by indication remains a complicating factor in assessing the relative contributions of glucocorticoid use and RA disease activity to elevated CVD risk in many analyses.

The increased CVD risk with NSAID use is not specific to RA and has been well established in the general population.^82-84 In the previously mentioned meta-analysis, an increased overall risk of CVD events was observed with NSAID use in RA (RR, 1.18; 95% CI, 1.01-1.38). It should be noted that cyclo-oxygenase 2 (COX-2) inhibitors, in particular rofecoxib (now removed from the market), appeared to drive the majority of this risk (RR, 1.36; 95% CI, 1.10-1.67 in COX-2 inhibitors and RR 1.08, 95% CI, 0.94-1.24 in nonselective NSAIDs), suggesting a potential differential risk among NSAIDs.⁷⁵ While naproxen has been thought to carry the lowest risk of CVD based on initial studies, this has not been universally observed, including in a recent randomized controlled trial of more than 24,000 RA and osteoarthritis patients.^82,85,86

Providers should use the lowest possible dose and duration of glucocorticoids and NSAIDs to achieve symptom relief, with continual efforts to taper or discontinue. Candidates for glucocorticoid and NSAID therapy should be selected carefully, and use of these therapies should be avoided in those with prior CVD or at high risk for CVD based on traditional CVD risk factors. Most importantly, providers should focus on utilizing DMARDs for the management of RA, which more effectively treat RA as well as reduce CVD risk.

Methotrexate (MTX), a mainstay in the treatment of RA, is a conventional DMARD observed to improve overall survival and mitigate CVD risk in multiple RA cohorts.^75,87,88 In a recent meta-analysis comprised of 236,525 RA patients and 5410 CVD events, MTX use was associated with a 28% reduction in overall CVD events across 8 studies (RR, 0.72; 95% CI, 0.57-0.91), substantiating similar findings in a prior meta-analysis.^75,88 MTX use was specifically associated with a decreased risk of MI (RR, 0.81; 95% CI, 0.68-0.96). Case-control and cohort studies have cited a 20% to 50% reduced risk of CHF with MTX use.^89,90 The potential cardioprotective effect of MTX appears to be both multifactorial and complex, likely mediated through both direct and indirect mechanisms. MTX directly promotes anti-atherogenic lipoprotein function, improves endothelial function, and scavenges free radicals.^91,92 Indirectly, MTX likely reduces CVD risk by effectively reducing RA disease activity. Based on these and other data, MTX remains the cornerstone of DMARD therapy in RA patients when targeting CVD risk reduction.

Hydroxychloroquine

Emerging evidence suggests that hydroxychloroquine (HCQ), an antimalarial most often utilized in combination with alternative DMARDs in RA, prevents DM and has beneficial effects on lipid profiles. A recent meta-analysis compiled 3 homogenous observational studies that investigated the effect of HCQ on incident DM. RA patients ever exposed to HCQ had a 40% lower incidence of DM (HR, 0.59; 95% CI, 0.49-0.70).⁹³ Increased duration of HCQ use was shown to further reduce risk of incident DM.⁹⁴ The aforementioned meta-analysis also pooled 5 studies investigating the effect of HCQ on lipid profiles, with favorable mean differences in TC (–9.82 mg/dL), LDL (–10.61 mg/dL), HDL (4.13 mg/dL), and triglycerides (–19.15 mg/dL) in HCQ users compared to non-users.⁹³ Given these favorable changes to traditional CVD risk factors, it is not surprising that in a retrospective study of 1266 RA patients without prior CVD, HCQ was associated with significantly lower risk of incident CVD. While external validation of these findings is needed, HCQ is an attractive conventional DMARD to be used in RA for CVD risk reduction. Moreover, its combination with MTX and sulfasalazine also shows promise for CVD risk reduction.^95,96

TNF Inhibitors

Tumor necrosis factor (TNF) inhibitors are often the initial biologic DMARD therapy used in RA patients not responding to conventional DMARDs. In the previously described meta-analysis, TNF inhibitors were associated with similar reductions in CVD events as MTX (RR, 0.70; 95% CI, 0.54-0.90).⁷⁵ Of note, there was a trend toward reduced risk of CHF (RR, 0.75; 95% CI, 0.49-1.15) in this same meta-analysis, an area of concern with TNF inhibitor use due to a prior randomized controlled trial demonstrating worsening clinical status in patients with existing moderate-to-severe CHF treated with high-dose infliximab.⁹⁷ Current RA treatment guidelines recommend avoiding TNF inhibitor use in individuals with CHF.⁹⁸

Aside from the risk of CHF exacerbation, TNF inhibitors appear to be cardioprotective. Similar to MTX, the mechanism by which TNF inhibition reduces cardiovascular risk is complex and likely due to both direct and indirect mechanisms. Substantial research has been conducted on the effect of TNF inhibition on lipids, with a recent meta-analysis demonstrating increases in HDL and TC, with stable LDL and atherogenic index over treatment follow-up.⁹⁹ A subsequent meta-analysis not limited to RA patients yielded similar results.¹⁰⁰ In addition to quantitative lipid changes, alteration of lipoprotein function, improvement in myocardial function, reduced aortic stiffness, improved blood pressure, and reduced RA disease activity may also be responsible for cardioprotective benefits of these agents.^101,102

Non-TNF Biologic and Traditional Synthetic DMARDs

Tocilizumab, an IL-6 inhibitor, can potently increase LDL levels, but it does not appear to increase the risk of CVD events and may actually promote more favorable anti-atherogenic lipoprotein function.^103-106 Although these quantitative lipid changes received significant attention in the wake of early reports detailing this effect, similar lipid changes appear to accompany other DMARDs including TNF inhibitors and tofacitinib.¹⁰⁷ There have been few studies evaluating the risk of CVD with other non-TNF inhibitor biologic DMARDs and traditional synthetic DMARDs, warranting future study.

Conclusion

To mitigate the increased risk of CVD in RA, primary care and subspecialty providers alike must be aware of this heightened risk in RA, perform frequent assessments of CVD risk,³ and aggressively manage both traditional and nontraditional CVD risk factors. The differential roles in this effort may not be clear; thus, we have proposed a co-management strategy detailed in the Figure. Clear communication between providers is of the utmost importance to ensure effective management of CVD risk.

Given limited evidence for RA-specific CVD risk assessments and traditional risk factor treatment targets, management should follow pertinent national guidelines. The importance of lifestyle counseling should not be overlooked, with a focus on smoking cessation, healthy diet and body weight, and regular aerobic exercise. Finally, rheumatologists should aggressively manage RA using a treat-to-target approach, minimize the use of glucocorticoids and NSAIDs, and preferentially select DMARDs that have been associated with lower CVD risk. Through this comprehensive approach, recent trends of improved CVD outcomes in RA will hopefully become more widespread.¹⁰⁸

Corresponding author: Bryant R. England, MD; 986270 Nebraska Medical Center, Omaha, NE 68198-6270; Bryant.england@unmc.edu.

Financial disclosures: Dr. England is supported by UNMC Internal Medicine Scientist Development Award, UNMC Physician-Scientist Training Program, the UNMC Mentored Scholars Program, and the Rheumatology Research Foundation Scientist Development Award. Dr. Mikuls is supported by a VA Merit Award (CX000896) and grants from the National Institutes of Health: National Institute of General Medical Sciences (U54GM115458), National Institute on Alcohol Abuse and Alcoholism (R25AA020818), and National Institute of Arthritis and Musculoskeletal and Skin Diseases (2P50AR60772).

From the Division of Rheumatology & Immunology, University of Nebraska Medical Center, and Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE.

Abstract

• Objective: To review the management of traditional and nontraditional CVD cardiovascular disease risk factors in rheumatoid arthritis (RA).
• Methods: Literature review of the management of CVD risk in RA.
• Results: Because of the increased risk of CVD events and CVD mortality among RA patients, aggressive management of CVD risk is essential. Providers should follow national guidelines for the management of traditional CVD risk factors, including dyslipidemia, hypertension, and diabetes mellitus. Similar efforts are needed in counseling on lifestyle modifications, including smoking cessation, regular exercise, and maintaining a healthy body weight. Because higher RA disease activity is also linked with CVD risk, aggressive treatment of RA to a target of low disease activity or remission is critical. Furthermore, the selection of potentially “cardioprotective” agents such as methotrexate and tumor necrosis factor inhibitors, while limiting use of nonsteroidal anti-inflammatory drugs and glucocorticoids, are strategies that could be employed by rheumatologists to help mitigate CVD risk in their patients with RA.
• Conclusion: Routine assessment of CVD risk, management of traditional CVD risk factors, counseling on healthy lifestyle habits, and aggressive treatment of RA are essential to minimize CVD risk in this population.

Keywords: rheumatoid arthritis; cardiovascular disease; cardiovascular risk assessment; cardiovascular risk management.

Editor’s note: This article is part 2 of a 2-part article. “Assessment of Cardiovascular Disease Risk in Rheumatoid Arthritis” was published in the January/February 2019 issue.

Rheumatoid arthritis (RA) is a systemic autoimmune condition that contributes to an increased risk for cardiovascular disease (CVD) among affected patients. In persons with RA, the risk of incident CVD and CVD mortality are increased by approximately 50% compared with the general population.^1,2 To minimize CVD risk in this population, providers must routinely assess for CVD risk factors³ and aggressively manage both traditional and nontraditional CVD risk factors.

Managing Traditional Risk Factors

As in the general population, identification and management of traditional CVD risk factors are crucial to minimize CVD risk in the RA population. A prospective study of 201 RA patients demonstrated that traditional CVD risk factors were in fact more predictive of endothelial dysfunction and carotid atherosclerosis than were disease-related inflammatory markers in RA.⁴ Management of traditional risk factors is detailed in the following sections, and recommendations for managing all traditional CVD risk factors are summarized in the Table.

Dyslipidemia

The role of dyslipidemia in atherogenesis is well established, and as a result, lipid levels are nearly universally included in CVD risk stratification tools. However, the interpretation of lipid levels in the context of RA is challenging because of the effects of systemic inflammation on their absolute values. Compared to the general population, patients with RA have lower total cholesterol (TC) and low-density lipoprotein (LDL) levels independent of lipid-lowering therapy.^5,6 Despite this, RA patients are at increased risk for CVD. There is even some evidence to suggest a “lipid paradox” in RA, whereby lower TC (< 4 mmol/L) and LDL levels suggest an increased risk of CVD.^7,8 In contrast to LDL, higher levels of high-density lipoprotein (HDL) are typically associated with reduced CVD risk, as in the general population.^8,9 Interestingly, in a cohort of 16,085 RA patients and 48,499 age- and sex-matched controls, there was no significant difference in the relationship between LDL and CVD risk, suggesting that quantitative lipid levels alone may not entirely explain the CVD mortality gap in RA.⁹ As such, there is substantial interest in lipoprotein function within the context of CVD risk in RA. Recent investigations have identified impaired HDL function, with reduced cholesterol efflux capacity and antioxidant properties, as well as increased scavenger receptor expression and foam cell formation, in patients with RA.^10,11 More research is needed to elucidate how these alterations affect CVD morbidity and mortality and how their measurement could be integrated into improved CVD risk assessment.

Meta-analyses of randomized controlled trials have estimated that lipid-lowering therapy with HMG-CoA reductase inhibitors (statins) reduces the risk of CVD by 25% to 30%; as such, statin therapy has become the standard of care for reduction of CVD risk in the general population.¹² Benefits for primary prevention of CVD in RA have also been observed; statin therapy was associated with a reduced risk of CVD events (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.20-0.98) and all-cause mortality (HR, 0.43; 95% CI, 0.20-0.92) in a population-based cohort study.¹³ Statins appear to have similar lipid-lowering effects and result in similar CVD risk reduction when used for primary or secondary prevention in RA patients compared to non-RA controls.^14-16 Additionally, anti-inflammatory properties of statins may act in synergy with disease-modifying antirheumatic drugs (DMARDs) to improve RA disease activity. In a small study of RA patients, statin therapy improved subjective and objective markers of RA disease activity in conjunction with methotrexate.¹⁷

While statins provide robust reduction in CVD risk, some individuals cannot tolerate statin therapy or do not achieve goal LDL levels with statin therapy. Select non-statin LDL-cholesterol-lowering agents have shown promise for reducing CVD events in the general population.¹⁸ Ezetimibe, which inhibits cholesterol absorption in the small intestine, very modestly reduced CVD events when added to atorvastatin (relative risk [RR], 0.94; 95% CI, 0.89-0.99) in a double-blind randomized controlled trial.¹⁹ Novel monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibit the internalization of surface LDL receptors, promoting LDL clearance. Two PCSK-9 inhibitors, alirocumab and evolocumab, were approved by the US Food and Drug Administration (FDA) after randomized controlled trials demonstrated their efficacy in lowering LDL by approximately 60% and reducing CVD events by approximately 15% in patients on maximum-tolerated statin therapy.^20-22 To date, non-statin LDL-cholesterol-lowering agents have been subject to limited study in RA.²³

Identification and management of dyslipidemia offers an opportunity for substantial CVD risk reduction at the RA population level. Unfortunately, current rates of lipid screening are inadequate in this high-risk group. In a study of 3298 Medicare patients with RA, less than half of RA patients with an indication underwent appropriate lipid screening.²⁴ Additionally, statins are often underutilized for both primary and secondary prevention in RA patients. Only 27% of RA patients meeting National Cholesterol Education Program Adult Treatment Panel III criteria were initiated on statin therapy in a population-based cohort study.²⁵ Among patients discharged after a first myocardial infarction (MI), the odds of receiving lipid-lowering therapy were 31% lower for RA patients (odds ratio [OR], 0.69; 95% CI, 0.58-0.82).²⁶ Similar to the general population, adherence to statins in RA patients appears to be poor.^27-30 This raises particular concern considering that a population-based cohort study of RA patients demonstrated a 67% increased risk of MI associated with statin discontinuation, regardless of prior MI status.²⁷ Providers—rheumatologists, primary care providers, and cardiologists alike—need to remain vigilant in efforts to assess CVD risk to identify patients who will benefit from lipid-lowering therapy and to emphasize the importance to patients of statin adherence. Novel models of health-care delivery, health technologies, and patient engagement in care may prove useful for improving lipid screening and management in RA.

Tobacco Use

Cigarette smoking is a shared risk factor for both CVD and RA. Large cohort studies have identified a dose-dependent increased risk of incident RA, particularly seropositive RA, among smokers.^31-34 Tobacco smoking has also been associated with increased levels of inflammation and RA disease activity.³⁵ The consequences of tobacco use in the general population are staggering. Among individuals over the age of 30 years, tobacco use is responsible for 12% of all deaths and 10% of all CVD deaths.³⁶ Similar findings are observed in RA; a recent meta-analysis estimated there is a 50% increased risk of CVD events in RA related to smoking tobacco.³⁷ In the general population, smoking cessation markedly lowers CVD risk, and over time CVD risk may approach that of nonsmokers.^38,39 Thus, regular counseling and interventions to facilitate smoking cessation are critical to reducing CVD risk in RA patients. RA-specific smoking cessation programs have been proposed, but have yet to outperform standard smoking cessation programs.⁴⁰

Diabetes Mellitus

It is estimated that almost 10% of the US population has diabetes mellitus (DM), which in isolation portends substantial CVD risk.⁴¹ There is an increased prevalence of DM in RA, perhaps owing to factors such as physical inactivity and chronic glucocorticoid use, though a higher level of RA disease activity itself has been associated with increased insulin resistance.^42-45 In a cohort of 100 RA patients who were neither obese nor diabetic, RA patients had significantly higher fasting blood glucose and insulin levels than age- and sex-matched controls. These findings were even more pronounced in RA patients with higher levels of disease activity.⁴⁴ Similar to the general population, DM is associated with poor CVD outcomes in RA.³⁷ Therefore, both appropriate management of diabetes and control of RA disease activity are vitally important to minimize CVD risk related to DM.

Though not a universal finding, there may be an increased prevalence of hypertension in RA patients.^31,46 Nonsteroidal anti-inflammatory drug (NSAID) and glucocorticoid use may play a role in the development of hypertension, while DMARDs appear to exert a less substantial effect on blood pressure.^47,48 At least one study found that DMARD initiation (particularly for methotrexate and hydroxychloroquine) was associated with significant, albeit small, declines in both systolic and diastolic blood pressure over the first 6 months of treatment.⁴⁹

Despite its potentially higher prevalence in this population, hypertension is both underdiagnosed and undertreated in RA patients.^24,50-52 This is an important deficiency to target because, as in the general population, hypertension is associated with an increased risk of MI (RR, 1.84; 95% CI, 1.38-2.46) and composite CVD outcomes (RR, 2.24; 95% CI, 1.42-3.06) in RA.³⁷ Thresholds for initiation and escalation of antihypertensive therapy are not specific to the RA population; thus, diagnosis and management of hypertension should be informed by the American College of Cardiology/American Heart Association guidelines, treating those with in-office blood pressures exceeding 140/90 mm Hg (> 130/80 mm Hg if aged > 65 years or with concomitant CVD, DM, chronic kidney disease, or 10-year atherosclerotic cardiovascular disease risk > 10%), typically with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, or thiazide diuretics as comorbidities may dictate or allow.⁵³ Also, the use of NSAIDs and glucocorticoids should be minimized, particularly in those with concomitant hypertension.

Physical Activity

Likely due to factors such as articular pain and stiffness, as well as physical limitations, RA patients are more sedentary than the general population.^54,55 In a study of objectively assessed sedentary behavior in RA patients, greater average sedentary time per day and greater number of sedentary bouts (> 20 min) were associated with increased 10-year risk of CVD as assessed by the QRISK2.⁵⁶ Conversely, the beneficial effects of exercise are well documented. Light to moderate physical activity has been associated with improved cardiovascular outcomes, greater physical function, higher levels of HDL, as well as reduced systemic inflammation and disease activity, and improved endothelial function in RA patients.^57-61 While there has been concern that physical activity may result in accelerated joint damage, even high-intensity exercise was shown to be safe without causing significant progression of joint damage.⁵⁸

Obesity, Weight Loss, and Diet

While obesity is clearly associated with CVD risk in the general population, this relationship is much more complex in RA, as underweight RA patients are also at higher risk for CVD and CVD-related mortality.^62-64 One potential explanation for this finding is that pathological weight loss resulting in an underweight body mass index (BMI) is an independent predictor of CVD. In a study of US Veterans with RA, higher rates of weight loss (> 3 kg/m²/year) were associated with increased CVD mortality (HR, 2.27; 95% CI, 1.61-3.19) independent of BMI.⁶⁵ Systemic inflammation in RA can lead to “rheumatoid cachexia,” characterized by decreased muscle mass, increased adiposity, and increased CVD risk despite a normal or potentially decreased BMI.⁶⁶ Practitioners should be mindful of not only current body weight, but also patients’ weight trajectories when counseling on lifestyle practices such as healthy diet and regular exercise in RA patients. For obese individuals with RA, healthy weight loss should be encouraged. Interestingly, bariatric surgery in RA patients may improve RA disease activity in addition to its known effects on body weight and DM.⁶⁷

Counseling on healthy diet with a focus on limiting foods high in saturated- and trans-fatty acids and high glycemic index foods, and increasing consumption of fruits, vegetables, and mono-unsaturated fatty acids is a well-accepted and common practice to help minimize CVD risk in the general population.⁶⁸ No studies to date have investigated the effect of specific diets on CVD risk in RA patients, and thus we recommend adherence to general population recommendations.

Disease Activity

In addition to traditional risk factors, several studies have identified associations between the level of RA disease activity and risk of CVD. In a cohort of US Veterans with RA, CVD-related mortality increased in a dose-dependent manner with higher disease activity categories. In stark contrast, the CVD mortality rates of those in remission paralleled the rates from the general population (standardized mortality ratio [SMR], 0.68; 95% CI, 0.37-1.27).⁶⁹ In a separate cohort of 1157 RA patients without prior CVD, achieving low disease activity was associated with a lower risk of incident CVD events (HR, 0.65; 95% CI, 0.43-0.99).⁷⁰ Additionally, high disease activity has been associated with surrogate markers of CVD and other CVD risk factors including NT-proBNP and systolic blood pressure.^71,72 While no randomized controlled trial data is available to inform this recommendation, observational data suggest RA should be aggressively treated (ideally to achieve and maintain remission or low disease activity) to minimize CVD risk. While keeping this treatment goal in mind, the differential effects of specific RA therapies on CVD must also be considered.

Glucocorticoids and NSAIDs

With the expanding repertoire of DMARDs available and more aggressive treatment approaches, the role of glucocorticoids and NSAIDs in RA treatment is decreasing over time. While their efficacy for improving pain and stiffness is well established, concern regarding their contribution to CVD risk in RA patients is warranted.

Glucocorticoids are known to have detrimental effects on traditional CVD risk factors such as hypertension, insulin resistance, and dyslipidemia in the general population, as well as in RA patients.^73,74 In a meta-analysis of predominantly observational studies of RA patients, glucocorticoid use was associated with an increased risk of CVD events (RR, 1.47; 95% CI, 1.34-1.60), including MI, congestive heart failure (CHF), and cerebrovascular accident (CVA).⁷⁵ Evidence is conflicting in regards to a clear dose threshold that leads to increased CVD risk with glucocorticoids, though higher doses are associated with greater risk.^76-81 As RA patients requiring glucocorticoids typically have higher disease activity, confounding by indication remains a complicating factor in assessing the relative contributions of glucocorticoid use and RA disease activity to elevated CVD risk in many analyses.

The increased CVD risk with NSAID use is not specific to RA and has been well established in the general population.^82-84 In the previously mentioned meta-analysis, an increased overall risk of CVD events was observed with NSAID use in RA (RR, 1.18; 95% CI, 1.01-1.38). It should be noted that cyclo-oxygenase 2 (COX-2) inhibitors, in particular rofecoxib (now removed from the market), appeared to drive the majority of this risk (RR, 1.36; 95% CI, 1.10-1.67 in COX-2 inhibitors and RR 1.08, 95% CI, 0.94-1.24 in nonselective NSAIDs), suggesting a potential differential risk among NSAIDs.⁷⁵ While naproxen has been thought to carry the lowest risk of CVD based on initial studies, this has not been universally observed, including in a recent randomized controlled trial of more than 24,000 RA and osteoarthritis patients.^82,85,86

Providers should use the lowest possible dose and duration of glucocorticoids and NSAIDs to achieve symptom relief, with continual efforts to taper or discontinue. Candidates for glucocorticoid and NSAID therapy should be selected carefully, and use of these therapies should be avoided in those with prior CVD or at high risk for CVD based on traditional CVD risk factors. Most importantly, providers should focus on utilizing DMARDs for the management of RA, which more effectively treat RA as well as reduce CVD risk.

Methotrexate (MTX), a mainstay in the treatment of RA, is a conventional DMARD observed to improve overall survival and mitigate CVD risk in multiple RA cohorts.^75,87,88 In a recent meta-analysis comprised of 236,525 RA patients and 5410 CVD events, MTX use was associated with a 28% reduction in overall CVD events across 8 studies (RR, 0.72; 95% CI, 0.57-0.91), substantiating similar findings in a prior meta-analysis.^75,88 MTX use was specifically associated with a decreased risk of MI (RR, 0.81; 95% CI, 0.68-0.96). Case-control and cohort studies have cited a 20% to 50% reduced risk of CHF with MTX use.^89,90 The potential cardioprotective effect of MTX appears to be both multifactorial and complex, likely mediated through both direct and indirect mechanisms. MTX directly promotes anti-atherogenic lipoprotein function, improves endothelial function, and scavenges free radicals.^91,92 Indirectly, MTX likely reduces CVD risk by effectively reducing RA disease activity. Based on these and other data, MTX remains the cornerstone of DMARD therapy in RA patients when targeting CVD risk reduction.

Hydroxychloroquine

Emerging evidence suggests that hydroxychloroquine (HCQ), an antimalarial most often utilized in combination with alternative DMARDs in RA, prevents DM and has beneficial effects on lipid profiles. A recent meta-analysis compiled 3 homogenous observational studies that investigated the effect of HCQ on incident DM. RA patients ever exposed to HCQ had a 40% lower incidence of DM (HR, 0.59; 95% CI, 0.49-0.70).⁹³ Increased duration of HCQ use was shown to further reduce risk of incident DM.⁹⁴ The aforementioned meta-analysis also pooled 5 studies investigating the effect of HCQ on lipid profiles, with favorable mean differences in TC (–9.82 mg/dL), LDL (–10.61 mg/dL), HDL (4.13 mg/dL), and triglycerides (–19.15 mg/dL) in HCQ users compared to non-users.⁹³ Given these favorable changes to traditional CVD risk factors, it is not surprising that in a retrospective study of 1266 RA patients without prior CVD, HCQ was associated with significantly lower risk of incident CVD. While external validation of these findings is needed, HCQ is an attractive conventional DMARD to be used in RA for CVD risk reduction. Moreover, its combination with MTX and sulfasalazine also shows promise for CVD risk reduction.^95,96

TNF Inhibitors

Tumor necrosis factor (TNF) inhibitors are often the initial biologic DMARD therapy used in RA patients not responding to conventional DMARDs. In the previously described meta-analysis, TNF inhibitors were associated with similar reductions in CVD events as MTX (RR, 0.70; 95% CI, 0.54-0.90).⁷⁵ Of note, there was a trend toward reduced risk of CHF (RR, 0.75; 95% CI, 0.49-1.15) in this same meta-analysis, an area of concern with TNF inhibitor use due to a prior randomized controlled trial demonstrating worsening clinical status in patients with existing moderate-to-severe CHF treated with high-dose infliximab.⁹⁷ Current RA treatment guidelines recommend avoiding TNF inhibitor use in individuals with CHF.⁹⁸

Aside from the risk of CHF exacerbation, TNF inhibitors appear to be cardioprotective. Similar to MTX, the mechanism by which TNF inhibition reduces cardiovascular risk is complex and likely due to both direct and indirect mechanisms. Substantial research has been conducted on the effect of TNF inhibition on lipids, with a recent meta-analysis demonstrating increases in HDL and TC, with stable LDL and atherogenic index over treatment follow-up.⁹⁹ A subsequent meta-analysis not limited to RA patients yielded similar results.¹⁰⁰ In addition to quantitative lipid changes, alteration of lipoprotein function, improvement in myocardial function, reduced aortic stiffness, improved blood pressure, and reduced RA disease activity may also be responsible for cardioprotective benefits of these agents.^101,102

Non-TNF Biologic and Traditional Synthetic DMARDs

Tocilizumab, an IL-6 inhibitor, can potently increase LDL levels, but it does not appear to increase the risk of CVD events and may actually promote more favorable anti-atherogenic lipoprotein function.^103-106 Although these quantitative lipid changes received significant attention in the wake of early reports detailing this effect, similar lipid changes appear to accompany other DMARDs including TNF inhibitors and tofacitinib.¹⁰⁷ There have been few studies evaluating the risk of CVD with other non-TNF inhibitor biologic DMARDs and traditional synthetic DMARDs, warranting future study.

Conclusion

To mitigate the increased risk of CVD in RA, primary care and subspecialty providers alike must be aware of this heightened risk in RA, perform frequent assessments of CVD risk,³ and aggressively manage both traditional and nontraditional CVD risk factors. The differential roles in this effort may not be clear; thus, we have proposed a co-management strategy detailed in the Figure. Clear communication between providers is of the utmost importance to ensure effective management of CVD risk.

Given limited evidence for RA-specific CVD risk assessments and traditional risk factor treatment targets, management should follow pertinent national guidelines. The importance of lifestyle counseling should not be overlooked, with a focus on smoking cessation, healthy diet and body weight, and regular aerobic exercise. Finally, rheumatologists should aggressively manage RA using a treat-to-target approach, minimize the use of glucocorticoids and NSAIDs, and preferentially select DMARDs that have been associated with lower CVD risk. Through this comprehensive approach, recent trends of improved CVD outcomes in RA will hopefully become more widespread.¹⁰⁸

Corresponding author: Bryant R. England, MD; 986270 Nebraska Medical Center, Omaha, NE 68198-6270; Bryant.england@unmc.edu.

Financial disclosures: Dr. England is supported by UNMC Internal Medicine Scientist Development Award, UNMC Physician-Scientist Training Program, the UNMC Mentored Scholars Program, and the Rheumatology Research Foundation Scientist Development Award. Dr. Mikuls is supported by a VA Merit Award (CX000896) and grants from the National Institutes of Health: National Institute of General Medical Sciences (U54GM115458), National Institute on Alcohol Abuse and Alcoholism (R25AA020818), and National Institute of Arthritis and Musculoskeletal and Skin Diseases (2P50AR60772).

From the Maine Medical Center, Portland, ME (Dr. Kramer, Ms. Palmeri, Dr. Robich, Mr. Groom, Dr. Hayes, Ms. Janoushek, Dr. Rappold, Dr. Swarz, and Dr. Quinn), and the Center for Outcomes Research and Evaluation, Maine Medical Center Research Institute, Portland, ME (Dr. Lucas).

Abstract

• Objective. To determine the accuracy of the glucometer currently used for point-of-care testing (POCT) of blood glucose in our cardiothoracic surgery intensive care unit (CTICU).
• Design. Prospective cohort study.
• Setting. Tertiary care community hospital affiliated with a school of medicine.
• Participants. Coronary artery bypass graft (CABG) surgery patients.
• Measurements. Blood glucose levels obtained via POCT with a glucometer using fingerstick and radial artery blood samples were compared with values obtained via central laboratory testing of radial artery blood samples (gold standard) in 106 CABG patients on continuous insulin infusions (CII) upon arrival to the CTICU from the operating room and 102 CABG patients on CII in the CTICU 6 hours later.
• Results. Fingerstick POCT and central lab blood glucose values correlated well (r = 0.83 for admission and 0.86 for 6-hour values), but the mean values were significantly different as determined by paired t-tests. Upon arrival, the fingerstick POCT mean value was 120.9 mg/dL, while the central laboratory value was 127.9 mg/dL (P value = 0.03). At the 6-hour time point, the mean value for fingerstick POCT was 129.7 mg/dL compared to a central laboratory value of 137.3 (P value = 0.02).
• Conclusion. The blood glucose POCT values correlated well with central laboratory values, but the values were statistically significantly different. Nevertheless, accurate clinical decisions were made despite the inaccuracies of POCT glucose testing, as experienced bedside nurses were able to use the glucometer successfully and safely. The device’s results informed them when the blood glucose was out of a prescibed range and the direction of the change, and they were able to adjust the CII accordingly.

Keywords: quality improvement; glucose management; point-of-care testing; critical care.

Achieving glycemic control in patients with and without diabetes during coronary artery bypass graft (CABG) surgery is associated with reduced perioperative morbidity and mortality and improved long-term survival.¹ Hyperglycemia has detrimental effects on the cardiovascular system and insulin has beneficial effects on the ischemic myocardium.² The current recommendations of the Society of Thoracic Surgery regarding blood glucose management include the use of continuous insulin infusions (CII) during and after surgery in the critical care unit,³ keeping blood glucose in a moderate range. Glucometers are commonly used in the critical care perioperative setting for point-of-care testing (POCT) for timely determinations of blood glucose levels for patients on CII.

POCT for glucose monitoring is a valuable tool for managing patients with diabetes in the outpatient setting. Evolving from urinary test strips that depended on a colorimetric model, glucometers now incoroporate digital technology that allows patients to determine their blood glucose using a drop of blood from a fingerstick. The US Food and Drug Administration’s approval for most glucose POCT technology includes home use by diabetic patients and use in the hospital setting, with the exception of critically ill patients, who may be affected by hypoxemia, poor capillary perfusion, tissue edema, severe anemia⁴ or other pathophysiologic states that could impact the accuracy of the devices. For example, poor peripheral perfusion related to shock or vasoconstrictors and interstitial edema are variables that could contribute to an erroneous reading. Therefore, many glucometers used in the critical care setting are being used off-label. Because much of the current POCT technology for glucose monitoring may provide erroneous results in certain ranges and in some clinical settings, the safety of most glucometers has been called into question.^5,6

Given the concern regarding the potential inaccuracies of commonly used glucometers in the critical care setting, we undertook a quality improvement project to analyze the clinical performance of the glucometer currently used in our critically ill postoperative cardiac surgery population. The cardiac surgery division policy at our institution is to place all patients, both diabetic and nondiabetic, on a CII intraoperatively and to continue the infusion for at least 24 to 48 hours postoperatively. The CII start rate is determined utilizing the division’s Insulin Start Chart, and then the CII is adjusted according to the nomogram through the postoperative course. Both the Insulin Start Chart and nomogram have been previously described by Kramer et al.⁷

Currently, POCT of glucose in all post cardiac surgery patients is done hourly or more frequently in the first 24 to 48 hours after surgery in order to adjust the CII. In patients undergoing the stress of cardiac surgery, the action of insulin is counter-regulated by glucagon, epinephrine, norepinephrine, cortisol, and growth hormone. The resulting varying degrees of insulin resistance in this population of patients requires close monitoring of blood glucose, keeping it in a prescribed range, which in our center is 110 to 150 mg/dL, both in diabetic and nondiabetic patients. Frequent laboratory and POCT determinations of glucose are made. Providers and bedside nurses adjust the CII according to central laboratory values, POCT values, and trends, as previously described.⁷

Methods

Setting

Maine Medical Center is a 600-bed tertiary care teaching hospital. It is a level 1 trauma center where 1000 cardiac surgical operations are performed annually. POCT glucose monitoring is relied upon to monitor blood glucose and adjust the CII accordingly. This project, which did not require any additional procedures outside of the standard of care for this population of patients, was reviewed by the Institutional Review Board, who determined that this activity does not meet either the definition of research as specified under 45 CFR 46.102 (d) or the definition of clinical investigation as specified in 21 CFR 56.102 (c).

Patients

Using central laboratory glucose values drawn from the radial artery as the gold standard, we created a registry of consecutive postoperative cardiac surgery patients who had undergone CABG surgery and had blood glucose determinations from both POCT (fingerstick and radial artery samples) and central laboratory testing (radial artery sample) during a 7-month period (May 2016 through February 2017). To be included in the registry, patients had to (1) be postoperative following isolated CABG or CABG plus Maze procedure; (2) have been on cardiopulmonary bypass (CPB); (3) have radial arterial lines; and (4) be on a CII. A total of 116 patients qualified according to the inclusion criteria. Patients missing glucose results in 1 or more of the variables were excluded from data analysis.

Measurements and Variables

Using a POCT glucometer (FreeStyle Precision Pro, Abbott Laboratories, Abbott Park, IL), blood glucose conentrations were measured on samples obtained from both fingerstick and radial artery. Concurrently, radial arterial blood was sent to the central laboratory for glucose measurement. Blood glucose values were compared in CABG patients on CII upon arrival to the cardiothoracic surgery intensive care unit (CTICU) from the operating room and CABG patients on CII 6 hours after arrival in the CTICU. During the 6-hour interval, blood glucose levels were tested hourly or more frequently, allowing nurses to identify trends in blood glucose changes in order to keep blood glucose in the prescribed goal range of 110 to 150 mg/dL. At each of these 2 time points, on arrival to CTICU and 6 hours later, blood glucose values obtained with radial artery POCT and fingerstick POCT were compared with values obtained with central laboratory testing of radial artery samples. The amount of blood required was 1 drop each for POCT fingerstick and POCT radial artery and 2 mL for central lab testing.

Patient characteristics were identified from the electronic medical record. The variables recorded were type of operation, time on CPB, time of CTICU arrival, temperature, vasoconstrictor infusions (norepinephrine, vasopressin, phenylephrine), preoperative diagnosis of diabetes mellitus, preoperative HbA1c, and hemoglobin/hematocrit. Hemoglobin/hematocrit was only available at the time of the patient’s arrival to CTICU. The study was completed within the confines of our center’s standard of care protocol for postoperative cardiac surgical patients.

Analysis

We used standard statistical techniques to describe the study population, including proportions for categorical variables and means (standard deviations) for continuous variables. Correlation and regression techniques were used to describe the relationship between POCT and laboratory (gold standard) tests, both measured as continuous variables, and paired t-tests with Bonferroni correction were used to compare the central tendency and range of these comparisons. We calculated the differences between the gold standard measure and the POCT measure as an indication of outliers (ie, cases in which the 2 tests gave markedly different results). We examined plots to ascertain at which levels of the gold standard test these outliers occurred. An interim analysis was done at the halfway point and submitted to the Institutional Review Board, but no correction to the P value was done based on this analysis, which was largely qualitative. We used Bonferroni correction to declare a P value of 0.025 statistically significant with the 2-way comparisons of both fingerstick and radial artery values to central laboratory values. When the data was stratified by a clinical characteristic creating a 4-way comparison, we used Bonferroni correction to declare a P value of 0.0125 to be statistically significant when comparing both fingerstick and radial artery values to central laboratory values.

Results

Glucose POCT evaluations were carried out on 116 consecutive patients who underwent CABG surgery with or without a Maze procedure on CPB with a CII and an arterial line. Due to missing glucose results in 1 or more of the variables, 10 patients were excluded from data analysis for the time point of arrival in the CTICU and 14 patients were excluded from data analysis for the time point of 6 hours post CTICU arrival. This gave a final count of 106 CABG patients for CTICU arrival data analysis and 102 CABG patients for the 6 hours after CTICU arrival data analysis.

Patients ranged in age from 43 to 85 years, with a mean of age of 66 years, 22% were were women, 41% were diabetic, and 18% had peripheral vascular disease (Table 1). The average preoperative HbA1c was 6.4% ± 1.3% (range, 4.6% to 11.1%). Mean time on CBP for the group was 101 ± 31 minutes (range, 43 to 233 minutes). Postoperative mean hematocrit and hemoglobin were 32.5% and 11.4 g/dL, respectively. The average core temperature of patients on arrival was 36.0°C, which rose to an average of 36.6°C 6 hours later. A vasoconstrictor drip was infusing on 52% of patients upon CTICU arrival; 65% had a vasoconstrictor drip infusing 6 hours after arrival to the CTICU. Hemoglobin results were available only upon CTICU arrival as they are not routinely checked at 6 hours; 74 (64%) patients had a hemoglobin < 12 g/dL.

Compared to central laboratory testing, which we are defining as the gold standard, fingerstick POCT performed better on arrival, while radial artery POCT performed better at 6 hours (Table 2). At CTICU arrival, the mean blood glucose value for fingerstick POCT was 121 ± 24.1 mg/dL, 116 ± 27.2 mg/dL for radial artery POCT, and 128 ± 23.5 mg/dL for central lab testing. The difference in mean blood glucose between the fingerstick POCT and central lab testing was not statistically significant (P = 0.032), while the difference in mean blood glucose between radial artery POCT and central lab testing was statistically significant (P = 0.001). At 6 hours post arrival to the CTICU, the mean fingerstick POCT blood glucose value was 130 ± 23.9 mg/dL, compared to the mean central lab testing value of 137 ± 22.4 mg/dL; this difference was statistically significant (P = 0.019), while the radial artery POCT blood glucose value (133 ± 24.6 mg/dL) was not significantly different from the central lab testing value.

Blood glucose values from fingerstick POCT and central laboratory testing correlated well (r = 0.83 for admission and 0.86 for 6-hour values), as did radial artery POCT and central lab values (r = 0.87 for admission and 0.90 for 6-hour values) (Figures 1, 2, 3, and 4). Comparing individual values for fingerstick POCT and central lab testing, within-person differences between the 2 values ranged from –45 to 25 mg/dL, with 21% of pairs discrepant by 20 mg/dL or more (Figure 1); results were similar at 6 hours (Figure 2), with slightly less discrepancy.

The differences between radial artery POCT and central lab testing values at CTICU arrival ranged from –43 to 80 mg/dL, with 24% of pairs discrepant by 20 mg/dL or more (Figure 3). At 6 hours post CTICU arrival, the difference between radial artery POCT and central lab testing values ranged from –130 to 27 mg/dL, with 11% of pairs discrepant by 20 mg/dL or more (Figure 4). Ninety-two percent of central laboratory values were either close to (± 20) or within the moderate glycemic control target range (110–150 mg/dL).

When the patient cohort was stratified by anemia, diabetes, body temperature, and receipt of vasoconstrictor, there were no significant differences between mean fingerstick POCT and central lab testing values for any strata on CTICU arrival, while there were significant differences between radial artery POCT and central lab testing means for both vasoconstrictor strata as well as for patients with core temperature > 36.1°C (Table 2). At 6 hours, there were no statistically significant differences when stratified for receipt of vasoconstrictor or presence of diabetes. Stratification for anemia or core body temperature was not done for patients at the 6-hour post CTICU arrival time because no hemoglobin value was available and all patients except 1 reached a core temperature of 36.1°C.

Although we measured POCT values obtained using 2 different blood sample sources, fingerstick POCT performed better than radial artery POCT testing with regard to the mean values when compared with the central lab. However, radial artery POCT performed better with regard to correlation with the central lab value. In other words, fingerstick POCT values were less significantly different than radial artery POCT values when compared with the central lab, while radial artery POCT values correlated better with values from the central lab. In spite of this unexplained variability in differences and correlation, the blood glucose values stayed in the target goal range (Figures 1-4).

Discussion

The accuracy of glucose POCT in the critical care setting has been called into question.^4,5 The clinical demands of glucose management using CII include timely and accurate guidance in postoperaptive cardiac surgery, in this case, CABG. A previous study compared POCT and central laboratory blood glucose values in medical intensive care unit patients,⁸ but not in patients who have had CABG surgery. Another study has reviewed the difference in glucose values from POCT and central lab analysis in the critically ill population, but not in the post cardiac surgical population.⁹ We have shown that the POCT blood glucose values correlate well with the clinical lab values, but the values are statistically different. Our study adds an additional observation in that, although the POCT inconsistencies were statistically significant, they were not clinically significant. That is, POCT of blood glucose was inaccurate, but it still helped guide care by providing enough information to keep the blood glucose in range (most of the time) and allowing the bedside nurse to detect trends and make appropriate adjustments to the infusion. However, given these inconsistencies, we recommend a low threshold for sending additional samples to the central lab to double-check the glucose values, especially when they are outside the prescribed range. Our analysis provides some measure of reassurance with regard to current postoperative CABG glucose management by showing that the limitations of the blood glucose meter do not jeopardize the safety of patients. Nonetheless, we look forward to advances in the accuracy of POCT blood glucose technology so that critical care patients can be better managed when blood glucose is outside the prescribed range.

This analysis of 116 CABG patients points out both the inaccuracy and the utility of a representative POCT glucometer (in this case, the FreeStyle Precision Pro) used at the bedside to manage CIIs in postoperative CABG patients, keeping the blood glucose level in the moderate control range (110-150 mg/dL). The correlation plot shows that in this population the bedside nurses were able to keep blood glucose in range most of the time, in spite of the inaccuracy of POCT of blood glucose, given that the error of the test fits in the wide margin of 40 mg/dL. The fact that the 6-hour values were slightly less variable than the admission values indicates that sequential determinations of blood glucose over the 6-hour period to detect trends allowed good clinical management even in the face of such inaccuracy. The correlation allows the inaccurate number (blood glucose value) to indicate direction, and frequent determinations allow the bedside nurse to keep that number in the prescribed range most of the time in this population of patients.

Conclusion

We have found that glucometer blood glucose determinations in our center used on a homogenous population (CABG surgery) utilizing a single type of glucometer correlated well with those of the central lab, but were not always accurate. In spite of the inaccuracies, experienced bedside nurses were able to use the instrument successfully and safely, as it informed them if the blood glucose was in or out of a predetermined range and in which direction it was going.

Acknowledgment: The authors are indebted to the nurses of the Cardiothoracic Surgery Intensive Care Unit at Maine Medical Center for their support and assistance, without which this analysis would not have been possible.

Corresponding author: Robert S. Kramer, MD, Division of Cardiothoracic Surgery, Maine Medical Center Cardiovascular Institute, 22 Bramhall St., Portland ME 04102; kramer@mmc.org.

Financial disclosures: None.

From the Maine Medical Center, Portland, ME (Dr. Kramer, Ms. Palmeri, Dr. Robich, Mr. Groom, Dr. Hayes, Ms. Janoushek, Dr. Rappold, Dr. Swarz, and Dr. Quinn), and the Center for Outcomes Research and Evaluation, Maine Medical Center Research Institute, Portland, ME (Dr. Lucas).

Abstract

• Objective. To determine the accuracy of the glucometer currently used for point-of-care testing (POCT) of blood glucose in our cardiothoracic surgery intensive care unit (CTICU).
• Design. Prospective cohort study.
• Setting. Tertiary care community hospital affiliated with a school of medicine.
• Participants. Coronary artery bypass graft (CABG) surgery patients.
• Measurements. Blood glucose levels obtained via POCT with a glucometer using fingerstick and radial artery blood samples were compared with values obtained via central laboratory testing of radial artery blood samples (gold standard) in 106 CABG patients on continuous insulin infusions (CII) upon arrival to the CTICU from the operating room and 102 CABG patients on CII in the CTICU 6 hours later.
• Results. Fingerstick POCT and central lab blood glucose values correlated well (r = 0.83 for admission and 0.86 for 6-hour values), but the mean values were significantly different as determined by paired t-tests. Upon arrival, the fingerstick POCT mean value was 120.9 mg/dL, while the central laboratory value was 127.9 mg/dL (P value = 0.03). At the 6-hour time point, the mean value for fingerstick POCT was 129.7 mg/dL compared to a central laboratory value of 137.3 (P value = 0.02).
• Conclusion. The blood glucose POCT values correlated well with central laboratory values, but the values were statistically significantly different. Nevertheless, accurate clinical decisions were made despite the inaccuracies of POCT glucose testing, as experienced bedside nurses were able to use the glucometer successfully and safely. The device’s results informed them when the blood glucose was out of a prescibed range and the direction of the change, and they were able to adjust the CII accordingly.

Keywords: quality improvement; glucose management; point-of-care testing; critical care.

Achieving glycemic control in patients with and without diabetes during coronary artery bypass graft (CABG) surgery is associated with reduced perioperative morbidity and mortality and improved long-term survival.¹ Hyperglycemia has detrimental effects on the cardiovascular system and insulin has beneficial effects on the ischemic myocardium.² The current recommendations of the Society of Thoracic Surgery regarding blood glucose management include the use of continuous insulin infusions (CII) during and after surgery in the critical care unit,³ keeping blood glucose in a moderate range. Glucometers are commonly used in the critical care perioperative setting for point-of-care testing (POCT) for timely determinations of blood glucose levels for patients on CII.

POCT for glucose monitoring is a valuable tool for managing patients with diabetes in the outpatient setting. Evolving from urinary test strips that depended on a colorimetric model, glucometers now incoroporate digital technology that allows patients to determine their blood glucose using a drop of blood from a fingerstick. The US Food and Drug Administration’s approval for most glucose POCT technology includes home use by diabetic patients and use in the hospital setting, with the exception of critically ill patients, who may be affected by hypoxemia, poor capillary perfusion, tissue edema, severe anemia⁴ or other pathophysiologic states that could impact the accuracy of the devices. For example, poor peripheral perfusion related to shock or vasoconstrictors and interstitial edema are variables that could contribute to an erroneous reading. Therefore, many glucometers used in the critical care setting are being used off-label. Because much of the current POCT technology for glucose monitoring may provide erroneous results in certain ranges and in some clinical settings, the safety of most glucometers has been called into question.^5,6

Given the concern regarding the potential inaccuracies of commonly used glucometers in the critical care setting, we undertook a quality improvement project to analyze the clinical performance of the glucometer currently used in our critically ill postoperative cardiac surgery population. The cardiac surgery division policy at our institution is to place all patients, both diabetic and nondiabetic, on a CII intraoperatively and to continue the infusion for at least 24 to 48 hours postoperatively. The CII start rate is determined utilizing the division’s Insulin Start Chart, and then the CII is adjusted according to the nomogram through the postoperative course. Both the Insulin Start Chart and nomogram have been previously described by Kramer et al.⁷

Currently, POCT of glucose in all post cardiac surgery patients is done hourly or more frequently in the first 24 to 48 hours after surgery in order to adjust the CII. In patients undergoing the stress of cardiac surgery, the action of insulin is counter-regulated by glucagon, epinephrine, norepinephrine, cortisol, and growth hormone. The resulting varying degrees of insulin resistance in this population of patients requires close monitoring of blood glucose, keeping it in a prescribed range, which in our center is 110 to 150 mg/dL, both in diabetic and nondiabetic patients. Frequent laboratory and POCT determinations of glucose are made. Providers and bedside nurses adjust the CII according to central laboratory values, POCT values, and trends, as previously described.⁷

Methods

Setting

Maine Medical Center is a 600-bed tertiary care teaching hospital. It is a level 1 trauma center where 1000 cardiac surgical operations are performed annually. POCT glucose monitoring is relied upon to monitor blood glucose and adjust the CII accordingly. This project, which did not require any additional procedures outside of the standard of care for this population of patients, was reviewed by the Institutional Review Board, who determined that this activity does not meet either the definition of research as specified under 45 CFR 46.102 (d) or the definition of clinical investigation as specified in 21 CFR 56.102 (c).

Patients

Using central laboratory glucose values drawn from the radial artery as the gold standard, we created a registry of consecutive postoperative cardiac surgery patients who had undergone CABG surgery and had blood glucose determinations from both POCT (fingerstick and radial artery samples) and central laboratory testing (radial artery sample) during a 7-month period (May 2016 through February 2017). To be included in the registry, patients had to (1) be postoperative following isolated CABG or CABG plus Maze procedure; (2) have been on cardiopulmonary bypass (CPB); (3) have radial arterial lines; and (4) be on a CII. A total of 116 patients qualified according to the inclusion criteria. Patients missing glucose results in 1 or more of the variables were excluded from data analysis.

Measurements and Variables

Using a POCT glucometer (FreeStyle Precision Pro, Abbott Laboratories, Abbott Park, IL), blood glucose conentrations were measured on samples obtained from both fingerstick and radial artery. Concurrently, radial arterial blood was sent to the central laboratory for glucose measurement. Blood glucose values were compared in CABG patients on CII upon arrival to the cardiothoracic surgery intensive care unit (CTICU) from the operating room and CABG patients on CII 6 hours after arrival in the CTICU. During the 6-hour interval, blood glucose levels were tested hourly or more frequently, allowing nurses to identify trends in blood glucose changes in order to keep blood glucose in the prescribed goal range of 110 to 150 mg/dL. At each of these 2 time points, on arrival to CTICU and 6 hours later, blood glucose values obtained with radial artery POCT and fingerstick POCT were compared with values obtained with central laboratory testing of radial artery samples. The amount of blood required was 1 drop each for POCT fingerstick and POCT radial artery and 2 mL for central lab testing.

Patient characteristics were identified from the electronic medical record. The variables recorded were type of operation, time on CPB, time of CTICU arrival, temperature, vasoconstrictor infusions (norepinephrine, vasopressin, phenylephrine), preoperative diagnosis of diabetes mellitus, preoperative HbA1c, and hemoglobin/hematocrit. Hemoglobin/hematocrit was only available at the time of the patient’s arrival to CTICU. The study was completed within the confines of our center’s standard of care protocol for postoperative cardiac surgical patients.

Analysis

We used standard statistical techniques to describe the study population, including proportions for categorical variables and means (standard deviations) for continuous variables. Correlation and regression techniques were used to describe the relationship between POCT and laboratory (gold standard) tests, both measured as continuous variables, and paired t-tests with Bonferroni correction were used to compare the central tendency and range of these comparisons. We calculated the differences between the gold standard measure and the POCT measure as an indication of outliers (ie, cases in which the 2 tests gave markedly different results). We examined plots to ascertain at which levels of the gold standard test these outliers occurred. An interim analysis was done at the halfway point and submitted to the Institutional Review Board, but no correction to the P value was done based on this analysis, which was largely qualitative. We used Bonferroni correction to declare a P value of 0.025 statistically significant with the 2-way comparisons of both fingerstick and radial artery values to central laboratory values. When the data was stratified by a clinical characteristic creating a 4-way comparison, we used Bonferroni correction to declare a P value of 0.0125 to be statistically significant when comparing both fingerstick and radial artery values to central laboratory values.

Results

Glucose POCT evaluations were carried out on 116 consecutive patients who underwent CABG surgery with or without a Maze procedure on CPB with a CII and an arterial line. Due to missing glucose results in 1 or more of the variables, 10 patients were excluded from data analysis for the time point of arrival in the CTICU and 14 patients were excluded from data analysis for the time point of 6 hours post CTICU arrival. This gave a final count of 106 CABG patients for CTICU arrival data analysis and 102 CABG patients for the 6 hours after CTICU arrival data analysis.

Patients ranged in age from 43 to 85 years, with a mean of age of 66 years, 22% were were women, 41% were diabetic, and 18% had peripheral vascular disease (Table 1). The average preoperative HbA1c was 6.4% ± 1.3% (range, 4.6% to 11.1%). Mean time on CBP for the group was 101 ± 31 minutes (range, 43 to 233 minutes). Postoperative mean hematocrit and hemoglobin were 32.5% and 11.4 g/dL, respectively. The average core temperature of patients on arrival was 36.0°C, which rose to an average of 36.6°C 6 hours later. A vasoconstrictor drip was infusing on 52% of patients upon CTICU arrival; 65% had a vasoconstrictor drip infusing 6 hours after arrival to the CTICU. Hemoglobin results were available only upon CTICU arrival as they are not routinely checked at 6 hours; 74 (64%) patients had a hemoglobin < 12 g/dL.

Compared to central laboratory testing, which we are defining as the gold standard, fingerstick POCT performed better on arrival, while radial artery POCT performed better at 6 hours (Table 2). At CTICU arrival, the mean blood glucose value for fingerstick POCT was 121 ± 24.1 mg/dL, 116 ± 27.2 mg/dL for radial artery POCT, and 128 ± 23.5 mg/dL for central lab testing. The difference in mean blood glucose between the fingerstick POCT and central lab testing was not statistically significant (P = 0.032), while the difference in mean blood glucose between radial artery POCT and central lab testing was statistically significant (P = 0.001). At 6 hours post arrival to the CTICU, the mean fingerstick POCT blood glucose value was 130 ± 23.9 mg/dL, compared to the mean central lab testing value of 137 ± 22.4 mg/dL; this difference was statistically significant (P = 0.019), while the radial artery POCT blood glucose value (133 ± 24.6 mg/dL) was not significantly different from the central lab testing value.

Blood glucose values from fingerstick POCT and central laboratory testing correlated well (r = 0.83 for admission and 0.86 for 6-hour values), as did radial artery POCT and central lab values (r = 0.87 for admission and 0.90 for 6-hour values) (Figures 1, 2, 3, and 4). Comparing individual values for fingerstick POCT and central lab testing, within-person differences between the 2 values ranged from –45 to 25 mg/dL, with 21% of pairs discrepant by 20 mg/dL or more (Figure 1); results were similar at 6 hours (Figure 2), with slightly less discrepancy.

The differences between radial artery POCT and central lab testing values at CTICU arrival ranged from –43 to 80 mg/dL, with 24% of pairs discrepant by 20 mg/dL or more (Figure 3). At 6 hours post CTICU arrival, the difference between radial artery POCT and central lab testing values ranged from –130 to 27 mg/dL, with 11% of pairs discrepant by 20 mg/dL or more (Figure 4). Ninety-two percent of central laboratory values were either close to (± 20) or within the moderate glycemic control target range (110–150 mg/dL).

When the patient cohort was stratified by anemia, diabetes, body temperature, and receipt of vasoconstrictor, there were no significant differences between mean fingerstick POCT and central lab testing values for any strata on CTICU arrival, while there were significant differences between radial artery POCT and central lab testing means for both vasoconstrictor strata as well as for patients with core temperature > 36.1°C (Table 2). At 6 hours, there were no statistically significant differences when stratified for receipt of vasoconstrictor or presence of diabetes. Stratification for anemia or core body temperature was not done for patients at the 6-hour post CTICU arrival time because no hemoglobin value was available and all patients except 1 reached a core temperature of 36.1°C.

Although we measured POCT values obtained using 2 different blood sample sources, fingerstick POCT performed better than radial artery POCT testing with regard to the mean values when compared with the central lab. However, radial artery POCT performed better with regard to correlation with the central lab value. In other words, fingerstick POCT values were less significantly different than radial artery POCT values when compared with the central lab, while radial artery POCT values correlated better with values from the central lab. In spite of this unexplained variability in differences and correlation, the blood glucose values stayed in the target goal range (Figures 1-4).

Discussion

The accuracy of glucose POCT in the critical care setting has been called into question.^4,5 The clinical demands of glucose management using CII include timely and accurate guidance in postoperaptive cardiac surgery, in this case, CABG. A previous study compared POCT and central laboratory blood glucose values in medical intensive care unit patients,⁸ but not in patients who have had CABG surgery. Another study has reviewed the difference in glucose values from POCT and central lab analysis in the critically ill population, but not in the post cardiac surgical population.⁹ We have shown that the POCT blood glucose values correlate well with the clinical lab values, but the values are statistically different. Our study adds an additional observation in that, although the POCT inconsistencies were statistically significant, they were not clinically significant. That is, POCT of blood glucose was inaccurate, but it still helped guide care by providing enough information to keep the blood glucose in range (most of the time) and allowing the bedside nurse to detect trends and make appropriate adjustments to the infusion. However, given these inconsistencies, we recommend a low threshold for sending additional samples to the central lab to double-check the glucose values, especially when they are outside the prescribed range. Our analysis provides some measure of reassurance with regard to current postoperative CABG glucose management by showing that the limitations of the blood glucose meter do not jeopardize the safety of patients. Nonetheless, we look forward to advances in the accuracy of POCT blood glucose technology so that critical care patients can be better managed when blood glucose is outside the prescribed range.

This analysis of 116 CABG patients points out both the inaccuracy and the utility of a representative POCT glucometer (in this case, the FreeStyle Precision Pro) used at the bedside to manage CIIs in postoperative CABG patients, keeping the blood glucose level in the moderate control range (110-150 mg/dL). The correlation plot shows that in this population the bedside nurses were able to keep blood glucose in range most of the time, in spite of the inaccuracy of POCT of blood glucose, given that the error of the test fits in the wide margin of 40 mg/dL. The fact that the 6-hour values were slightly less variable than the admission values indicates that sequential determinations of blood glucose over the 6-hour period to detect trends allowed good clinical management even in the face of such inaccuracy. The correlation allows the inaccurate number (blood glucose value) to indicate direction, and frequent determinations allow the bedside nurse to keep that number in the prescribed range most of the time in this population of patients.

Conclusion

We have found that glucometer blood glucose determinations in our center used on a homogenous population (CABG surgery) utilizing a single type of glucometer correlated well with those of the central lab, but were not always accurate. In spite of the inaccuracies, experienced bedside nurses were able to use the instrument successfully and safely, as it informed them if the blood glucose was in or out of a predetermined range and in which direction it was going.

Acknowledgment: The authors are indebted to the nurses of the Cardiothoracic Surgery Intensive Care Unit at Maine Medical Center for their support and assistance, without which this analysis would not have been possible.

Corresponding author: Robert S. Kramer, MD, Division of Cardiothoracic Surgery, Maine Medical Center Cardiovascular Institute, 22 Bramhall St., Portland ME 04102; kramer@mmc.org.

Financial disclosures: None.

From the Maine Medical Center, Portland, ME (Dr. Kramer, Ms. Palmeri, Dr. Robich, Mr. Groom, Dr. Hayes, Ms. Janoushek, Dr. Rappold, Dr. Swarz, and Dr. Quinn), and the Center for Outcomes Research and Evaluation, Maine Medical Center Research Institute, Portland, ME (Dr. Lucas).

Abstract

• Objective. To determine the accuracy of the glucometer currently used for point-of-care testing (POCT) of blood glucose in our cardiothoracic surgery intensive care unit (CTICU).
• Design. Prospective cohort study.
• Setting. Tertiary care community hospital affiliated with a school of medicine.
• Participants. Coronary artery bypass graft (CABG) surgery patients.
• Measurements. Blood glucose levels obtained via POCT with a glucometer using fingerstick and radial artery blood samples were compared with values obtained via central laboratory testing of radial artery blood samples (gold standard) in 106 CABG patients on continuous insulin infusions (CII) upon arrival to the CTICU from the operating room and 102 CABG patients on CII in the CTICU 6 hours later.
• Results. Fingerstick POCT and central lab blood glucose values correlated well (r = 0.83 for admission and 0.86 for 6-hour values), but the mean values were significantly different as determined by paired t-tests. Upon arrival, the fingerstick POCT mean value was 120.9 mg/dL, while the central laboratory value was 127.9 mg/dL (P value = 0.03). At the 6-hour time point, the mean value for fingerstick POCT was 129.7 mg/dL compared to a central laboratory value of 137.3 (P value = 0.02).
• Conclusion. The blood glucose POCT values correlated well with central laboratory values, but the values were statistically significantly different. Nevertheless, accurate clinical decisions were made despite the inaccuracies of POCT glucose testing, as experienced bedside nurses were able to use the glucometer successfully and safely. The device’s results informed them when the blood glucose was out of a prescibed range and the direction of the change, and they were able to adjust the CII accordingly.

Keywords: quality improvement; glucose management; point-of-care testing; critical care.

Achieving glycemic control in patients with and without diabetes during coronary artery bypass graft (CABG) surgery is associated with reduced perioperative morbidity and mortality and improved long-term survival.¹ Hyperglycemia has detrimental effects on the cardiovascular system and insulin has beneficial effects on the ischemic myocardium.² The current recommendations of the Society of Thoracic Surgery regarding blood glucose management include the use of continuous insulin infusions (CII) during and after surgery in the critical care unit,³ keeping blood glucose in a moderate range. Glucometers are commonly used in the critical care perioperative setting for point-of-care testing (POCT) for timely determinations of blood glucose levels for patients on CII.

POCT for glucose monitoring is a valuable tool for managing patients with diabetes in the outpatient setting. Evolving from urinary test strips that depended on a colorimetric model, glucometers now incoroporate digital technology that allows patients to determine their blood glucose using a drop of blood from a fingerstick. The US Food and Drug Administration’s approval for most glucose POCT technology includes home use by diabetic patients and use in the hospital setting, with the exception of critically ill patients, who may be affected by hypoxemia, poor capillary perfusion, tissue edema, severe anemia⁴ or other pathophysiologic states that could impact the accuracy of the devices. For example, poor peripheral perfusion related to shock or vasoconstrictors and interstitial edema are variables that could contribute to an erroneous reading. Therefore, many glucometers used in the critical care setting are being used off-label. Because much of the current POCT technology for glucose monitoring may provide erroneous results in certain ranges and in some clinical settings, the safety of most glucometers has been called into question.^5,6

Given the concern regarding the potential inaccuracies of commonly used glucometers in the critical care setting, we undertook a quality improvement project to analyze the clinical performance of the glucometer currently used in our critically ill postoperative cardiac surgery population. The cardiac surgery division policy at our institution is to place all patients, both diabetic and nondiabetic, on a CII intraoperatively and to continue the infusion for at least 24 to 48 hours postoperatively. The CII start rate is determined utilizing the division’s Insulin Start Chart, and then the CII is adjusted according to the nomogram through the postoperative course. Both the Insulin Start Chart and nomogram have been previously described by Kramer et al.⁷

Currently, POCT of glucose in all post cardiac surgery patients is done hourly or more frequently in the first 24 to 48 hours after surgery in order to adjust the CII. In patients undergoing the stress of cardiac surgery, the action of insulin is counter-regulated by glucagon, epinephrine, norepinephrine, cortisol, and growth hormone. The resulting varying degrees of insulin resistance in this population of patients requires close monitoring of blood glucose, keeping it in a prescribed range, which in our center is 110 to 150 mg/dL, both in diabetic and nondiabetic patients. Frequent laboratory and POCT determinations of glucose are made. Providers and bedside nurses adjust the CII according to central laboratory values, POCT values, and trends, as previously described.⁷

Methods

Setting

Maine Medical Center is a 600-bed tertiary care teaching hospital. It is a level 1 trauma center where 1000 cardiac surgical operations are performed annually. POCT glucose monitoring is relied upon to monitor blood glucose and adjust the CII accordingly. This project, which did not require any additional procedures outside of the standard of care for this population of patients, was reviewed by the Institutional Review Board, who determined that this activity does not meet either the definition of research as specified under 45 CFR 46.102 (d) or the definition of clinical investigation as specified in 21 CFR 56.102 (c).

Patients

Using central laboratory glucose values drawn from the radial artery as the gold standard, we created a registry of consecutive postoperative cardiac surgery patients who had undergone CABG surgery and had blood glucose determinations from both POCT (fingerstick and radial artery samples) and central laboratory testing (radial artery sample) during a 7-month period (May 2016 through February 2017). To be included in the registry, patients had to (1) be postoperative following isolated CABG or CABG plus Maze procedure; (2) have been on cardiopulmonary bypass (CPB); (3) have radial arterial lines; and (4) be on a CII. A total of 116 patients qualified according to the inclusion criteria. Patients missing glucose results in 1 or more of the variables were excluded from data analysis.

Measurements and Variables

Using a POCT glucometer (FreeStyle Precision Pro, Abbott Laboratories, Abbott Park, IL), blood glucose conentrations were measured on samples obtained from both fingerstick and radial artery. Concurrently, radial arterial blood was sent to the central laboratory for glucose measurement. Blood glucose values were compared in CABG patients on CII upon arrival to the cardiothoracic surgery intensive care unit (CTICU) from the operating room and CABG patients on CII 6 hours after arrival in the CTICU. During the 6-hour interval, blood glucose levels were tested hourly or more frequently, allowing nurses to identify trends in blood glucose changes in order to keep blood glucose in the prescribed goal range of 110 to 150 mg/dL. At each of these 2 time points, on arrival to CTICU and 6 hours later, blood glucose values obtained with radial artery POCT and fingerstick POCT were compared with values obtained with central laboratory testing of radial artery samples. The amount of blood required was 1 drop each for POCT fingerstick and POCT radial artery and 2 mL for central lab testing.

Patient characteristics were identified from the electronic medical record. The variables recorded were type of operation, time on CPB, time of CTICU arrival, temperature, vasoconstrictor infusions (norepinephrine, vasopressin, phenylephrine), preoperative diagnosis of diabetes mellitus, preoperative HbA1c, and hemoglobin/hematocrit. Hemoglobin/hematocrit was only available at the time of the patient’s arrival to CTICU. The study was completed within the confines of our center’s standard of care protocol for postoperative cardiac surgical patients.

Analysis

We used standard statistical techniques to describe the study population, including proportions for categorical variables and means (standard deviations) for continuous variables. Correlation and regression techniques were used to describe the relationship between POCT and laboratory (gold standard) tests, both measured as continuous variables, and paired t-tests with Bonferroni correction were used to compare the central tendency and range of these comparisons. We calculated the differences between the gold standard measure and the POCT measure as an indication of outliers (ie, cases in which the 2 tests gave markedly different results). We examined plots to ascertain at which levels of the gold standard test these outliers occurred. An interim analysis was done at the halfway point and submitted to the Institutional Review Board, but no correction to the P value was done based on this analysis, which was largely qualitative. We used Bonferroni correction to declare a P value of 0.025 statistically significant with the 2-way comparisons of both fingerstick and radial artery values to central laboratory values. When the data was stratified by a clinical characteristic creating a 4-way comparison, we used Bonferroni correction to declare a P value of 0.0125 to be statistically significant when comparing both fingerstick and radial artery values to central laboratory values.

Results

Glucose POCT evaluations were carried out on 116 consecutive patients who underwent CABG surgery with or without a Maze procedure on CPB with a CII and an arterial line. Due to missing glucose results in 1 or more of the variables, 10 patients were excluded from data analysis for the time point of arrival in the CTICU and 14 patients were excluded from data analysis for the time point of 6 hours post CTICU arrival. This gave a final count of 106 CABG patients for CTICU arrival data analysis and 102 CABG patients for the 6 hours after CTICU arrival data analysis.

Patients ranged in age from 43 to 85 years, with a mean of age of 66 years, 22% were were women, 41% were diabetic, and 18% had peripheral vascular disease (Table 1). The average preoperative HbA1c was 6.4% ± 1.3% (range, 4.6% to 11.1%). Mean time on CBP for the group was 101 ± 31 minutes (range, 43 to 233 minutes). Postoperative mean hematocrit and hemoglobin were 32.5% and 11.4 g/dL, respectively. The average core temperature of patients on arrival was 36.0°C, which rose to an average of 36.6°C 6 hours later. A vasoconstrictor drip was infusing on 52% of patients upon CTICU arrival; 65% had a vasoconstrictor drip infusing 6 hours after arrival to the CTICU. Hemoglobin results were available only upon CTICU arrival as they are not routinely checked at 6 hours; 74 (64%) patients had a hemoglobin < 12 g/dL.

Compared to central laboratory testing, which we are defining as the gold standard, fingerstick POCT performed better on arrival, while radial artery POCT performed better at 6 hours (Table 2). At CTICU arrival, the mean blood glucose value for fingerstick POCT was 121 ± 24.1 mg/dL, 116 ± 27.2 mg/dL for radial artery POCT, and 128 ± 23.5 mg/dL for central lab testing. The difference in mean blood glucose between the fingerstick POCT and central lab testing was not statistically significant (P = 0.032), while the difference in mean blood glucose between radial artery POCT and central lab testing was statistically significant (P = 0.001). At 6 hours post arrival to the CTICU, the mean fingerstick POCT blood glucose value was 130 ± 23.9 mg/dL, compared to the mean central lab testing value of 137 ± 22.4 mg/dL; this difference was statistically significant (P = 0.019), while the radial artery POCT blood glucose value (133 ± 24.6 mg/dL) was not significantly different from the central lab testing value.

Blood glucose values from fingerstick POCT and central laboratory testing correlated well (r = 0.83 for admission and 0.86 for 6-hour values), as did radial artery POCT and central lab values (r = 0.87 for admission and 0.90 for 6-hour values) (Figures 1, 2, 3, and 4). Comparing individual values for fingerstick POCT and central lab testing, within-person differences between the 2 values ranged from –45 to 25 mg/dL, with 21% of pairs discrepant by 20 mg/dL or more (Figure 1); results were similar at 6 hours (Figure 2), with slightly less discrepancy.

The differences between radial artery POCT and central lab testing values at CTICU arrival ranged from –43 to 80 mg/dL, with 24% of pairs discrepant by 20 mg/dL or more (Figure 3). At 6 hours post CTICU arrival, the difference between radial artery POCT and central lab testing values ranged from –130 to 27 mg/dL, with 11% of pairs discrepant by 20 mg/dL or more (Figure 4). Ninety-two percent of central laboratory values were either close to (± 20) or within the moderate glycemic control target range (110–150 mg/dL).

When the patient cohort was stratified by anemia, diabetes, body temperature, and receipt of vasoconstrictor, there were no significant differences between mean fingerstick POCT and central lab testing values for any strata on CTICU arrival, while there were significant differences between radial artery POCT and central lab testing means for both vasoconstrictor strata as well as for patients with core temperature > 36.1°C (Table 2). At 6 hours, there were no statistically significant differences when stratified for receipt of vasoconstrictor or presence of diabetes. Stratification for anemia or core body temperature was not done for patients at the 6-hour post CTICU arrival time because no hemoglobin value was available and all patients except 1 reached a core temperature of 36.1°C.

Although we measured POCT values obtained using 2 different blood sample sources, fingerstick POCT performed better than radial artery POCT testing with regard to the mean values when compared with the central lab. However, radial artery POCT performed better with regard to correlation with the central lab value. In other words, fingerstick POCT values were less significantly different than radial artery POCT values when compared with the central lab, while radial artery POCT values correlated better with values from the central lab. In spite of this unexplained variability in differences and correlation, the blood glucose values stayed in the target goal range (Figures 1-4).

Discussion

The accuracy of glucose POCT in the critical care setting has been called into question.^4,5 The clinical demands of glucose management using CII include timely and accurate guidance in postoperaptive cardiac surgery, in this case, CABG. A previous study compared POCT and central laboratory blood glucose values in medical intensive care unit patients,⁸ but not in patients who have had CABG surgery. Another study has reviewed the difference in glucose values from POCT and central lab analysis in the critically ill population, but not in the post cardiac surgical population.⁹ We have shown that the POCT blood glucose values correlate well with the clinical lab values, but the values are statistically different. Our study adds an additional observation in that, although the POCT inconsistencies were statistically significant, they were not clinically significant. That is, POCT of blood glucose was inaccurate, but it still helped guide care by providing enough information to keep the blood glucose in range (most of the time) and allowing the bedside nurse to detect trends and make appropriate adjustments to the infusion. However, given these inconsistencies, we recommend a low threshold for sending additional samples to the central lab to double-check the glucose values, especially when they are outside the prescribed range. Our analysis provides some measure of reassurance with regard to current postoperative CABG glucose management by showing that the limitations of the blood glucose meter do not jeopardize the safety of patients. Nonetheless, we look forward to advances in the accuracy of POCT blood glucose technology so that critical care patients can be better managed when blood glucose is outside the prescribed range.

This analysis of 116 CABG patients points out both the inaccuracy and the utility of a representative POCT glucometer (in this case, the FreeStyle Precision Pro) used at the bedside to manage CIIs in postoperative CABG patients, keeping the blood glucose level in the moderate control range (110-150 mg/dL). The correlation plot shows that in this population the bedside nurses were able to keep blood glucose in range most of the time, in spite of the inaccuracy of POCT of blood glucose, given that the error of the test fits in the wide margin of 40 mg/dL. The fact that the 6-hour values were slightly less variable than the admission values indicates that sequential determinations of blood glucose over the 6-hour period to detect trends allowed good clinical management even in the face of such inaccuracy. The correlation allows the inaccurate number (blood glucose value) to indicate direction, and frequent determinations allow the bedside nurse to keep that number in the prescribed range most of the time in this population of patients.

Conclusion

We have found that glucometer blood glucose determinations in our center used on a homogenous population (CABG surgery) utilizing a single type of glucometer correlated well with those of the central lab, but were not always accurate. In spite of the inaccuracies, experienced bedside nurses were able to use the instrument successfully and safely, as it informed them if the blood glucose was in or out of a predetermined range and in which direction it was going.

Acknowledgment: The authors are indebted to the nurses of the Cardiothoracic Surgery Intensive Care Unit at Maine Medical Center for their support and assistance, without which this analysis would not have been possible.

Corresponding author: Robert S. Kramer, MD, Division of Cardiothoracic Surgery, Maine Medical Center Cardiovascular Institute, 22 Bramhall St., Portland ME 04102; kramer@mmc.org.

Financial disclosures: None.

From the Department of Surgery and Perioperative Care, Dell Medical School, The University of Texas at Austin, Austin, TX (Dr. Kortlever, Ms. Haidar, Dr. Reichel, Dr. Driscoll, Dr. Ring, and Dr. Vagner) and University Medical Center Utrecht, Utrecht, The Netherlands (Dr. Teunis).

Abstract

• Objective: Patient satisfaction is considered a quality measure. Satisfaction is typically measured directly after an in-person visit in research and 2 weeks later in practice surveys. We assessed if there was a difference in immediate and delayed measurement of satisfaction.
• Questions: (1) There is no difference in patient satisfaction (measured by Numerical Rating Scale [NRS]) and (2) perceived empathy (measured by the Jefferson Scale of Patient Perceptions of Physician Empathy [JSPPPE]) immediately after the initial visit compared to 2 weeks later. (3) Change in disability (measured by the Patient-Reported Outcome Measurement Information System Physical Function-Upper Extremity [PROMIS PF-UE]) is not independently associated with change in satisfaction and (4) empathy after the initial visit compared to 2 weeks later.
• Methods: 150 new patients completed a survey of demographics, satisfaction with the surgeon, rating of the surgeon’s empathy, and upper extremity specific limitations. The satisfaction, empathy, and limitation questionnaires were repeated 2 weeks later.
• Results: We found a slight but significant decrease in satisfaction 2 weeks after the in-person visit (–0.41, P = 0.001). There was no significant change in perceived empathy (–0.71, P = 0.19). Change in limitations did not account for a change in satisfaction (P = 0.79) or perceived empathy (P = 0.93).
• Conclusion: Satisfaction and perceived empathy are relatively stable constructs that can be measured immediately after the visit.

Keywords: satisfaction, empathy, change, upper extremity, disability.

Patient satisfaction is increasingly being used as a performance measure to evaluate quality of care.^1-8 Patient satisfaction correlates with adherence with recommended treatment.^1,6,8-10 Satisfaction measured on an 11-point ordinal scale immediately after the visit correlates strongly with the perception of clinician empathy.^2,3 Indeed, some satisfaction questionnaires such as the Medical Interview Satisfaction Scale (MISS)^11,12 have questions very similar to empathy questionnaires. It may be that satisfaction is a construct similar to feeling that your doctor listened and cared about you as an individual (perceived physician empathy).

Higher ratings of satisfaction also seem to be related to a physician’s communication style.^1,4,7-10 One study of 13 fertility doctors found that training in effective communication strategies led to improved patient satisfaction.⁷ A qualitative study of 36 patients, health professionals, and clinical support staff in an orthopaedic outpatient setting held interviews and focus group sessions to identify themes influencing patient satisfaction.⁴ Communication and expectation were among the 7 themes identified. We have noticed a high ceiling effect (maximum scores) with measures of patient satisfaction and perceived empathy.^2,3 Another study also noted a high ceiling effect when using an ordinal scale.⁵ It may be that people with a positive feeling shortly after a health care encounter give top ratings out of politeness or gratefulness. It is also possible they will feel differently a few weeks after they leave the office. Furthermore, ratings of satisfaction gathered by a practice or health care system for practice assessment/improvement are often obtained several days to weeks after the visit, while research often obtains satisfaction ratings immediately after the visit for practical reasons. There may be differences between immediate and delayed measurement of satisfaction beyond the mentioned social norms.

Therefore, this study tested the primary null hypothesis that there is no difference in patient satisfaction (measured by Numerical Rating Scale [NRS]) immediately after the initial visit compared to 2 weeks later. Additionally, we assessed the difference in perceived empathy immediately after the initial visit compared to 2 weeks later, and whether change in disability was independently associated with change in satisfaction and empathy after the initial visit compared to 2 weeks later.

Methods

Study Design

After Institutional Review Board approval of this prospective, longitudinal, observational cohort study, we prospectively enrolled 150 adult patients between November 29, 2017 and January 10, 2018. Patients were seen at 5 orthopaedic clinics in a large urban area. We included all new English-speaking patients aged 18 to 89 years who were visiting 1 of 6 participating orthopaedic surgeons for any upper extremity problem and who were able to provide informed consent. We excluded follow-up visits and patients who were unable to speak and understand English. Four research assistants who were not involved with patient treatment described the study to patients before or after the visit with the surgeon. We were granted a waiver of written informed consent; patients indicated their consent by completing the surveys.

Patients could choose either phone or email as their preferred mode of contact for follow-up in this study. For patients who selected email as the preferred mode of contact, the follow-up survey was sent automatically 2 weeks after completion date, and a maximum of 3 reminder emails with 2-day time intervals between them were sent to those who did not respond to the initial invitation. For patients who selected phone as the preferred mode of contact, the follow-up survey was done by an English-speaking research assistant who was not involved with patient treatment. When a response was not obtained on the initial phone call, 3 additional phone calls were made (1 later that same day and 2 the next day). One patient declined participation because he was not interested in the study and had no time after his visit.

Measurements

Patients were asked to complete a set of questionnaires at the end of their visit:

1. A demographic questionnaire consisting of preferred mode of contact for follow-up (phone or email), age, sex, race/ethnicity, marital status, education status, work status, insurance status, and type of visit (first visit or second opinion);

2. An 11-point ordinal measure of satisfaction with the surgeon, with scores ranging from 0 (Worst Surgeon Possible) to 10 (Best Surgeon Possible);

3. The patient’s rating of the surgeon’s empathy, measured by the Jefferson Scale of Patient Perceptions of Physician Empathy (JSPPPE).¹³ The JSPPPE is a 5-item questionnaire, measured on a 7-point Likert scale, with scores ranging from 1 (Strongly Disagree) to 7 (Strongly Agree), that assesses agreement with statements about the physician. The total score is the sum of all item scores (5-35), with higher scores representing a higher degree of perceived physician empathy.

4. Upper extremity disability, measured by the Patient-Reported Outcomes Measurement Information System Physical Function-Upper Extremity (PROMIS PF-UE) Computer Adaptive Test (CAT).^14-16 This is a measure of physical limitations in the upper extremity. It can be completed with as few as 4 questions while still achieving high precision in scoring and thereby decreasing survey burden. PROMIS presents a continuous T-score with a mean of 50 and standard deviation (SD) of 10, with higher scores reflecting better physical function compared to the average of the US general population.¹⁵

After completing the initial questionnaire, the research assistant filled out the office and surgeon name and asked the surgeon to complete the diagnosis. All questionnaires were administered on an encrypted tablet via the secure, HIPAA-compliant electronic platform REDCap (Research Electronic Data Capture), a web-based application for building and managing online surveys and databases.¹⁷ The follow-up survey was sent automatically or was done by phone call as previously described. The follow-up survey consisted of (1) the 11-point ordinal measure of satisfaction with the surgeon, (2) the JSPPPE for perceived empathy, and (3) the PROMIS PF-UE for physical limitations in the upper extremity.

Analysis

Continuous variables are presented as mean ± SD and discrete data as proportions. We used Student’s t-tests to assess baseline differences between continuous variables and Fisher’s exact tests for discrete variables. To assess differences in satisfaction and perceived empathy after 2 weeks, we used Student’s paired t-tests. We created 2 multilevel multivariable linear regression models to assess factors associated with (1) change in satisfaction with the surgeon and (2) change in perceived physician empathy. These models account for correlation of patients treated by the same surgeon. We selected variables to be included in the final models by running multilevel models with only 1 independent variable of interest (Appendix 1). Variables with P < 0.10 were included in our final models. We also included change in PROMIS PF-UE in both models because this was our variable of interest. We considered P < 0.05 significant.

We performed a power analysis for the difference in patient satisfaction immediately after the first visit compared to 2 weeks later. Based on our pilot data where we found an initial mean satisfaction score of 9.4 and mean satisfaction score after 2 weeks of 9.1 (SD of difference 1.0), a priori power analysis showed that we needed a minimum sample size of 90 patients to detect a difference with power set at 0.80 and alpha set at 0.05. In order to account for loss to follow-up as previously noted,¹⁸ we enrolled 67% more patients (total of 150).

Results

Respondent Characteristics

None of the 150 patients were excluded from the analysis. The study patients’ mean age was 51 ± 16 years (range, 18-87 years), and 73 (49%) were men (Table 1). Mean scores directly after the visit were 9.4 ± 1.2 (range, 2-10) for satisfaction with the surgeon, 31 ± 5.2 (range, 9-35) for perceived physician empathy, and 40 ± 10 (range 15-56) for upper extremity disability. Most patients (n = 130, 87%) were seen in 2 of 5 offices, and 106 (71%) were seen by 2 out of 6 participating surgeons.

Ninety-seven (65%) patients completed their follow-up assessment 2 weeks after their initial visit, 49 (51%) by phone and 48 (49%) by email. This is a slightly better rate than the 36% rate reported in previous research.¹⁸ After 2 weeks, the mean score for satisfaction with the surgeon was 9.1 ± 1.5 (range, 0-10), the mean perceived empathy score was 31 ± 5.1 (range, 6-35), and the mean upper extremity disability score was 40 ± 8.7 (range, 23-56). Responders did not differ from nonresponders based on demographic data (Table 2). However, nonresponders had lower perceived empathy scores directly after their visit (P = 0.03) and none had initially chosen phone as their preferred mode of contact for follow-up (P < 0.001). A list of all diagnoses with frequencies the surgeons stated is listed in Appendix 2.

Difference in Satisfaction with the Surgeon

Satisfaction with the surgeon 2 weeks after the in-person visit was slightly, but significantly, lower on bivariate analysis compared to satisfaction with the surgeon immediately after the initial visit (–0.41 ± 1.2, P = 0.001; Table 3).

Difference in Perceived Physician Empathy

Perceived physician empathy 2 weeks after the in-person visit was not significantly lower on bivariate analysis compared to perceived physician empathy immediately after the initial visit (–0.71 ± 5.3, P = 0.19; Table 3).

Factors Associated with Change in Satisfaction with the Surgeon

Accounting for potential interaction of variables using multilevel multivariable analysis, change in disability of the upper extremity was not associated with change in satisfaction with the surgeon (regression coefficient [beta], 0.00 [95% confidence interval {CI}, –0.02 to 0.03]; standard error [SE], 0.01; P = 0.79 [Table 4]). Being Latino was independently associated with less change in satisfaction with the surgeon (beta coefficient, –0.57 [95% CI, –1.1 to 0.00]; SE, 0.29; P = 0.049).

Factors Associated with Change in Perceived Physician Empathy

Accounting for potential interaction of variables using multilevel multivariable analysis, change in disability of the upper extremity was not associated with change in perceived physician empathy (beta coefficient = 0.00 [95% CI, –0.10 to 0.11]; SE, 0.06; P = 0.93 [Table 4]). Race/ethnicity other than white or Latino was independently associated with more change in perceived physician empathy (beta coefficient, 3.5 [95% CI, 0.34 to 6.6]; SE, 1.6; P = 0.030), and preferring email as mode of contact for follow-up was independently associated with less change in perceived physician empathy (beta coefficient, –3.2 [95% CI, –5.2 to –1.3]; SE, 1.0; P = 0.001).

Discussion

Patient satisfaction is considered a quality measure^1-8 and is typically measured directly after an in-person visit. This study tested differences in patient satisfaction and perceived empathy immediately after the initial visit compared to 2 weeks later. In addition, we assessed whether change in disability was independently associated with change in satisfaction and empathy after the initial visit compared to 2 weeks later.

We acknowledge some study limitations. First, we only measured satisfaction based on 1 visit rather than multiple visits over time. It might be that satisfaction ratings differ when the physician-patient relationship is more established. However, we found overall high satisfaction ratings and a well-established relationship might not add to this finding. Second, surgeons were aware of the study and its purpose, which might have resulted in subconsciously altering the behavior to improve satisfaction. The effect of people acting differently as a result of being observed is called the Hawthorne effect.¹⁹ Third, we only used 1 simple ordinal measure to assess patient satisfaction with the surgeon. There is a wide variety of satisfaction measures,²⁰ though the focus of this study was not to test the best possible satisfaction measure but to assess changes in satisfaction over time and its predictors. The simple 11-point ordinal satisfaction measure has proved reliable.⁶ Fourth, 35% of patients did not make a second rating. This is not unusual for phone or email studies. Our response rate was relatively high compared to other studies in our field,¹⁸ perhaps because the time to the second assessment was only 2 weeks and all people were available for follow-up by phone. Fifth, we analyzed 4 surgeons as 1 group and 3 offices as 1 group since we did not enroll enough patients per surgeon and office for individual analysis. However, multilevel linear analysis takes surgeon specific factors into account within that group.

The finding that satisfaction with the surgeon after 2 weeks was significantly lower on bivariate analysis compared to immediately after the initial visit is different from a study that found small increases in satisfaction after 2 weeks and 3 months,¹ but comparable to another study in our field.²¹ Although significant, we believe the decrease in satisfaction is probably not clinically relevant. It might also be that satisfaction at follow-up is lower than measured, but that the least satisfied people did not respond on the follow-up survey.

We found no significant change in perceived empathy after 2 weeks. Since empathy is a strong driver of satisfaction,^2,4-7 we did not expect to find differing results for empathy and for satisfaction over time. Both satisfaction and empathy seem to be relatively durable measures with current measurement tools.

The finding that change in disability was neither independently associated with change in satisfaction nor change in empathy is consistent with prior research.^2,3,21 We cannot adequately study the impact of changes since we did not find an important change in either satisfaction or empathy over time. Jackson et al found higher satisfaction ratings over time in patients who had an increase in physical function and a decrease in symptoms.¹ They also found that met expectations was associated with higher satisfaction immediately after the visit, after 2 weeks, and after 3 months.¹ We feel that met expectations and fewer symptoms and limitations are likely highly co-linear with satisfaction. We therefore may not be able to learn much about one from the others.

The slight change we found in satisfaction with the surgeon among Latino patients was significantly less than the change among white patients. This suggests Latino patients might have a more stable opinion over time (a cultural phenomenon), or it might be spurious given the small number of Latino patients included in the study. The same can be said for the finding that race/ethnicity other than white or Latino was independently associated with greater change in empathy. Providing email as the preferred mode of contact was found to be independently associated with less change in perceived empathy compared to follow-up by phone. We had a 100% success rate for our follow-ups by phone. Our findings suggest that patients might more easily switch ratings on an 11-point ordinal scale than on a 5-item Likert scale. However, both measures are often rated at the ceiling of the scale.^2,21

Conclusion

Satisfaction and perceived empathy are relatively stable constructs, are not clearly associated with other factors, and are strongly correlated with one another. This study supports the research practice of measuring satisfaction immediately after the visit, which is more convenient for both participant and researcher and avoids the loss of more than one third of the patients, and those with a worse experience in particular. To improve the utility and interpretation of patient-reported experience measures such as these, we might direct our efforts to developing scales with less ceiling effect.

Corresponding author: David Ring, MD, PhD, Dell Medical School, The University of Texas at Austin, Health Discovery Building HDB 6.706, 1701 Trinity St., Austin, TX 78705; david.ring@austin.utexas.edu.

Financial disclosures: Dr. Ring has or may receive payment or benefits from Skeletal Dynamics, Wright Medical for elbow implants, Deputy Editor for Clinical Orthopaedics and Related Research, Universities and Hospitals, Lawyers outside the submitted work.

Dr. Teunis has or may receive payment or benefits from VCC, PATIENT+, and AO Trauma TK network unrelated to this work and consultant fees from Synthes.

From the Department of Surgery and Perioperative Care, Dell Medical School, The University of Texas at Austin, Austin, TX (Dr. Kortlever, Ms. Haidar, Dr. Reichel, Dr. Driscoll, Dr. Ring, and Dr. Vagner) and University Medical Center Utrecht, Utrecht, The Netherlands (Dr. Teunis).

Abstract

• Objective: Patient satisfaction is considered a quality measure. Satisfaction is typically measured directly after an in-person visit in research and 2 weeks later in practice surveys. We assessed if there was a difference in immediate and delayed measurement of satisfaction.
• Questions: (1) There is no difference in patient satisfaction (measured by Numerical Rating Scale [NRS]) and (2) perceived empathy (measured by the Jefferson Scale of Patient Perceptions of Physician Empathy [JSPPPE]) immediately after the initial visit compared to 2 weeks later. (3) Change in disability (measured by the Patient-Reported Outcome Measurement Information System Physical Function-Upper Extremity [PROMIS PF-UE]) is not independently associated with change in satisfaction and (4) empathy after the initial visit compared to 2 weeks later.
• Methods: 150 new patients completed a survey of demographics, satisfaction with the surgeon, rating of the surgeon’s empathy, and upper extremity specific limitations. The satisfaction, empathy, and limitation questionnaires were repeated 2 weeks later.
• Results: We found a slight but significant decrease in satisfaction 2 weeks after the in-person visit (–0.41, P = 0.001). There was no significant change in perceived empathy (–0.71, P = 0.19). Change in limitations did not account for a change in satisfaction (P = 0.79) or perceived empathy (P = 0.93).
• Conclusion: Satisfaction and perceived empathy are relatively stable constructs that can be measured immediately after the visit.

Keywords: satisfaction, empathy, change, upper extremity, disability.

Patient satisfaction is increasingly being used as a performance measure to evaluate quality of care.^1-8 Patient satisfaction correlates with adherence with recommended treatment.^1,6,8-10 Satisfaction measured on an 11-point ordinal scale immediately after the visit correlates strongly with the perception of clinician empathy.^2,3 Indeed, some satisfaction questionnaires such as the Medical Interview Satisfaction Scale (MISS)^11,12 have questions very similar to empathy questionnaires. It may be that satisfaction is a construct similar to feeling that your doctor listened and cared about you as an individual (perceived physician empathy).

Higher ratings of satisfaction also seem to be related to a physician’s communication style.^1,4,7-10 One study of 13 fertility doctors found that training in effective communication strategies led to improved patient satisfaction.⁷ A qualitative study of 36 patients, health professionals, and clinical support staff in an orthopaedic outpatient setting held interviews and focus group sessions to identify themes influencing patient satisfaction.⁴ Communication and expectation were among the 7 themes identified. We have noticed a high ceiling effect (maximum scores) with measures of patient satisfaction and perceived empathy.^2,3 Another study also noted a high ceiling effect when using an ordinal scale.⁵ It may be that people with a positive feeling shortly after a health care encounter give top ratings out of politeness or gratefulness. It is also possible they will feel differently a few weeks after they leave the office. Furthermore, ratings of satisfaction gathered by a practice or health care system for practice assessment/improvement are often obtained several days to weeks after the visit, while research often obtains satisfaction ratings immediately after the visit for practical reasons. There may be differences between immediate and delayed measurement of satisfaction beyond the mentioned social norms.

Therefore, this study tested the primary null hypothesis that there is no difference in patient satisfaction (measured by Numerical Rating Scale [NRS]) immediately after the initial visit compared to 2 weeks later. Additionally, we assessed the difference in perceived empathy immediately after the initial visit compared to 2 weeks later, and whether change in disability was independently associated with change in satisfaction and empathy after the initial visit compared to 2 weeks later.

Methods

Study Design

After Institutional Review Board approval of this prospective, longitudinal, observational cohort study, we prospectively enrolled 150 adult patients between November 29, 2017 and January 10, 2018. Patients were seen at 5 orthopaedic clinics in a large urban area. We included all new English-speaking patients aged 18 to 89 years who were visiting 1 of 6 participating orthopaedic surgeons for any upper extremity problem and who were able to provide informed consent. We excluded follow-up visits and patients who were unable to speak and understand English. Four research assistants who were not involved with patient treatment described the study to patients before or after the visit with the surgeon. We were granted a waiver of written informed consent; patients indicated their consent by completing the surveys.

Patients could choose either phone or email as their preferred mode of contact for follow-up in this study. For patients who selected email as the preferred mode of contact, the follow-up survey was sent automatically 2 weeks after completion date, and a maximum of 3 reminder emails with 2-day time intervals between them were sent to those who did not respond to the initial invitation. For patients who selected phone as the preferred mode of contact, the follow-up survey was done by an English-speaking research assistant who was not involved with patient treatment. When a response was not obtained on the initial phone call, 3 additional phone calls were made (1 later that same day and 2 the next day). One patient declined participation because he was not interested in the study and had no time after his visit.

Measurements

Patients were asked to complete a set of questionnaires at the end of their visit:

1. A demographic questionnaire consisting of preferred mode of contact for follow-up (phone or email), age, sex, race/ethnicity, marital status, education status, work status, insurance status, and type of visit (first visit or second opinion);

2. An 11-point ordinal measure of satisfaction with the surgeon, with scores ranging from 0 (Worst Surgeon Possible) to 10 (Best Surgeon Possible);

3. The patient’s rating of the surgeon’s empathy, measured by the Jefferson Scale of Patient Perceptions of Physician Empathy (JSPPPE).¹³ The JSPPPE is a 5-item questionnaire, measured on a 7-point Likert scale, with scores ranging from 1 (Strongly Disagree) to 7 (Strongly Agree), that assesses agreement with statements about the physician. The total score is the sum of all item scores (5-35), with higher scores representing a higher degree of perceived physician empathy.

4. Upper extremity disability, measured by the Patient-Reported Outcomes Measurement Information System Physical Function-Upper Extremity (PROMIS PF-UE) Computer Adaptive Test (CAT).^14-16 This is a measure of physical limitations in the upper extremity. It can be completed with as few as 4 questions while still achieving high precision in scoring and thereby decreasing survey burden. PROMIS presents a continuous T-score with a mean of 50 and standard deviation (SD) of 10, with higher scores reflecting better physical function compared to the average of the US general population.¹⁵

After completing the initial questionnaire, the research assistant filled out the office and surgeon name and asked the surgeon to complete the diagnosis. All questionnaires were administered on an encrypted tablet via the secure, HIPAA-compliant electronic platform REDCap (Research Electronic Data Capture), a web-based application for building and managing online surveys and databases.¹⁷ The follow-up survey was sent automatically or was done by phone call as previously described. The follow-up survey consisted of (1) the 11-point ordinal measure of satisfaction with the surgeon, (2) the JSPPPE for perceived empathy, and (3) the PROMIS PF-UE for physical limitations in the upper extremity.

Analysis

Continuous variables are presented as mean ± SD and discrete data as proportions. We used Student’s t-tests to assess baseline differences between continuous variables and Fisher’s exact tests for discrete variables. To assess differences in satisfaction and perceived empathy after 2 weeks, we used Student’s paired t-tests. We created 2 multilevel multivariable linear regression models to assess factors associated with (1) change in satisfaction with the surgeon and (2) change in perceived physician empathy. These models account for correlation of patients treated by the same surgeon. We selected variables to be included in the final models by running multilevel models with only 1 independent variable of interest (Appendix 1). Variables with P < 0.10 were included in our final models. We also included change in PROMIS PF-UE in both models because this was our variable of interest. We considered P < 0.05 significant.

We performed a power analysis for the difference in patient satisfaction immediately after the first visit compared to 2 weeks later. Based on our pilot data where we found an initial mean satisfaction score of 9.4 and mean satisfaction score after 2 weeks of 9.1 (SD of difference 1.0), a priori power analysis showed that we needed a minimum sample size of 90 patients to detect a difference with power set at 0.80 and alpha set at 0.05. In order to account for loss to follow-up as previously noted,¹⁸ we enrolled 67% more patients (total of 150).

Results

Respondent Characteristics

None of the 150 patients were excluded from the analysis. The study patients’ mean age was 51 ± 16 years (range, 18-87 years), and 73 (49%) were men (Table 1). Mean scores directly after the visit were 9.4 ± 1.2 (range, 2-10) for satisfaction with the surgeon, 31 ± 5.2 (range, 9-35) for perceived physician empathy, and 40 ± 10 (range 15-56) for upper extremity disability. Most patients (n = 130, 87%) were seen in 2 of 5 offices, and 106 (71%) were seen by 2 out of 6 participating surgeons.

Ninety-seven (65%) patients completed their follow-up assessment 2 weeks after their initial visit, 49 (51%) by phone and 48 (49%) by email. This is a slightly better rate than the 36% rate reported in previous research.¹⁸ After 2 weeks, the mean score for satisfaction with the surgeon was 9.1 ± 1.5 (range, 0-10), the mean perceived empathy score was 31 ± 5.1 (range, 6-35), and the mean upper extremity disability score was 40 ± 8.7 (range, 23-56). Responders did not differ from nonresponders based on demographic data (Table 2). However, nonresponders had lower perceived empathy scores directly after their visit (P = 0.03) and none had initially chosen phone as their preferred mode of contact for follow-up (P < 0.001). A list of all diagnoses with frequencies the surgeons stated is listed in Appendix 2.

Difference in Satisfaction with the Surgeon

Satisfaction with the surgeon 2 weeks after the in-person visit was slightly, but significantly, lower on bivariate analysis compared to satisfaction with the surgeon immediately after the initial visit (–0.41 ± 1.2, P = 0.001; Table 3).

Difference in Perceived Physician Empathy

Perceived physician empathy 2 weeks after the in-person visit was not significantly lower on bivariate analysis compared to perceived physician empathy immediately after the initial visit (–0.71 ± 5.3, P = 0.19; Table 3).

Factors Associated with Change in Satisfaction with the Surgeon

Accounting for potential interaction of variables using multilevel multivariable analysis, change in disability of the upper extremity was not associated with change in satisfaction with the surgeon (regression coefficient [beta], 0.00 [95% confidence interval {CI}, –0.02 to 0.03]; standard error [SE], 0.01; P = 0.79 [Table 4]). Being Latino was independently associated with less change in satisfaction with the surgeon (beta coefficient, –0.57 [95% CI, –1.1 to 0.00]; SE, 0.29; P = 0.049).

Factors Associated with Change in Perceived Physician Empathy

Accounting for potential interaction of variables using multilevel multivariable analysis, change in disability of the upper extremity was not associated with change in perceived physician empathy (beta coefficient = 0.00 [95% CI, –0.10 to 0.11]; SE, 0.06; P = 0.93 [Table 4]). Race/ethnicity other than white or Latino was independently associated with more change in perceived physician empathy (beta coefficient, 3.5 [95% CI, 0.34 to 6.6]; SE, 1.6; P = 0.030), and preferring email as mode of contact for follow-up was independently associated with less change in perceived physician empathy (beta coefficient, –3.2 [95% CI, –5.2 to –1.3]; SE, 1.0; P = 0.001).

Discussion

Patient satisfaction is considered a quality measure^1-8 and is typically measured directly after an in-person visit. This study tested differences in patient satisfaction and perceived empathy immediately after the initial visit compared to 2 weeks later. In addition, we assessed whether change in disability was independently associated with change in satisfaction and empathy after the initial visit compared to 2 weeks later.

We acknowledge some study limitations. First, we only measured satisfaction based on 1 visit rather than multiple visits over time. It might be that satisfaction ratings differ when the physician-patient relationship is more established. However, we found overall high satisfaction ratings and a well-established relationship might not add to this finding. Second, surgeons were aware of the study and its purpose, which might have resulted in subconsciously altering the behavior to improve satisfaction. The effect of people acting differently as a result of being observed is called the Hawthorne effect.¹⁹ Third, we only used 1 simple ordinal measure to assess patient satisfaction with the surgeon. There is a wide variety of satisfaction measures,²⁰ though the focus of this study was not to test the best possible satisfaction measure but to assess changes in satisfaction over time and its predictors. The simple 11-point ordinal satisfaction measure has proved reliable.⁶ Fourth, 35% of patients did not make a second rating. This is not unusual for phone or email studies. Our response rate was relatively high compared to other studies in our field,¹⁸ perhaps because the time to the second assessment was only 2 weeks and all people were available for follow-up by phone. Fifth, we analyzed 4 surgeons as 1 group and 3 offices as 1 group since we did not enroll enough patients per surgeon and office for individual analysis. However, multilevel linear analysis takes surgeon specific factors into account within that group.

The finding that satisfaction with the surgeon after 2 weeks was significantly lower on bivariate analysis compared to immediately after the initial visit is different from a study that found small increases in satisfaction after 2 weeks and 3 months,¹ but comparable to another study in our field.²¹ Although significant, we believe the decrease in satisfaction is probably not clinically relevant. It might also be that satisfaction at follow-up is lower than measured, but that the least satisfied people did not respond on the follow-up survey.

We found no significant change in perceived empathy after 2 weeks. Since empathy is a strong driver of satisfaction,^2,4-7 we did not expect to find differing results for empathy and for satisfaction over time. Both satisfaction and empathy seem to be relatively durable measures with current measurement tools.

The finding that change in disability was neither independently associated with change in satisfaction nor change in empathy is consistent with prior research.^2,3,21 We cannot adequately study the impact of changes since we did not find an important change in either satisfaction or empathy over time. Jackson et al found higher satisfaction ratings over time in patients who had an increase in physical function and a decrease in symptoms.¹ They also found that met expectations was associated with higher satisfaction immediately after the visit, after 2 weeks, and after 3 months.¹ We feel that met expectations and fewer symptoms and limitations are likely highly co-linear with satisfaction. We therefore may not be able to learn much about one from the others.

The slight change we found in satisfaction with the surgeon among Latino patients was significantly less than the change among white patients. This suggests Latino patients might have a more stable opinion over time (a cultural phenomenon), or it might be spurious given the small number of Latino patients included in the study. The same can be said for the finding that race/ethnicity other than white or Latino was independently associated with greater change in empathy. Providing email as the preferred mode of contact was found to be independently associated with less change in perceived empathy compared to follow-up by phone. We had a 100% success rate for our follow-ups by phone. Our findings suggest that patients might more easily switch ratings on an 11-point ordinal scale than on a 5-item Likert scale. However, both measures are often rated at the ceiling of the scale.^2,21

Conclusion

Satisfaction and perceived empathy are relatively stable constructs, are not clearly associated with other factors, and are strongly correlated with one another. This study supports the research practice of measuring satisfaction immediately after the visit, which is more convenient for both participant and researcher and avoids the loss of more than one third of the patients, and those with a worse experience in particular. To improve the utility and interpretation of patient-reported experience measures such as these, we might direct our efforts to developing scales with less ceiling effect.

Corresponding author: David Ring, MD, PhD, Dell Medical School, The University of Texas at Austin, Health Discovery Building HDB 6.706, 1701 Trinity St., Austin, TX 78705; david.ring@austin.utexas.edu.

Financial disclosures: Dr. Ring has or may receive payment or benefits from Skeletal Dynamics, Wright Medical for elbow implants, Deputy Editor for Clinical Orthopaedics and Related Research, Universities and Hospitals, Lawyers outside the submitted work.

Dr. Teunis has or may receive payment or benefits from VCC, PATIENT+, and AO Trauma TK network unrelated to this work and consultant fees from Synthes.

From the Department of Surgery and Perioperative Care, Dell Medical School, The University of Texas at Austin, Austin, TX (Dr. Kortlever, Ms. Haidar, Dr. Reichel, Dr. Driscoll, Dr. Ring, and Dr. Vagner) and University Medical Center Utrecht, Utrecht, The Netherlands (Dr. Teunis).

Abstract

• Objective: Patient satisfaction is considered a quality measure. Satisfaction is typically measured directly after an in-person visit in research and 2 weeks later in practice surveys. We assessed if there was a difference in immediate and delayed measurement of satisfaction.
• Questions: (1) There is no difference in patient satisfaction (measured by Numerical Rating Scale [NRS]) and (2) perceived empathy (measured by the Jefferson Scale of Patient Perceptions of Physician Empathy [JSPPPE]) immediately after the initial visit compared to 2 weeks later. (3) Change in disability (measured by the Patient-Reported Outcome Measurement Information System Physical Function-Upper Extremity [PROMIS PF-UE]) is not independently associated with change in satisfaction and (4) empathy after the initial visit compared to 2 weeks later.
• Methods: 150 new patients completed a survey of demographics, satisfaction with the surgeon, rating of the surgeon’s empathy, and upper extremity specific limitations. The satisfaction, empathy, and limitation questionnaires were repeated 2 weeks later.
• Results: We found a slight but significant decrease in satisfaction 2 weeks after the in-person visit (–0.41, P = 0.001). There was no significant change in perceived empathy (–0.71, P = 0.19). Change in limitations did not account for a change in satisfaction (P = 0.79) or perceived empathy (P = 0.93).
• Conclusion: Satisfaction and perceived empathy are relatively stable constructs that can be measured immediately after the visit.

Keywords: satisfaction, empathy, change, upper extremity, disability.

Patient satisfaction is increasingly being used as a performance measure to evaluate quality of care.^1-8 Patient satisfaction correlates with adherence with recommended treatment.^1,6,8-10 Satisfaction measured on an 11-point ordinal scale immediately after the visit correlates strongly with the perception of clinician empathy.^2,3 Indeed, some satisfaction questionnaires such as the Medical Interview Satisfaction Scale (MISS)^11,12 have questions very similar to empathy questionnaires. It may be that satisfaction is a construct similar to feeling that your doctor listened and cared about you as an individual (perceived physician empathy).

Higher ratings of satisfaction also seem to be related to a physician’s communication style.^1,4,7-10 One study of 13 fertility doctors found that training in effective communication strategies led to improved patient satisfaction.⁷ A qualitative study of 36 patients, health professionals, and clinical support staff in an orthopaedic outpatient setting held interviews and focus group sessions to identify themes influencing patient satisfaction.⁴ Communication and expectation were among the 7 themes identified. We have noticed a high ceiling effect (maximum scores) with measures of patient satisfaction and perceived empathy.^2,3 Another study also noted a high ceiling effect when using an ordinal scale.⁵ It may be that people with a positive feeling shortly after a health care encounter give top ratings out of politeness or gratefulness. It is also possible they will feel differently a few weeks after they leave the office. Furthermore, ratings of satisfaction gathered by a practice or health care system for practice assessment/improvement are often obtained several days to weeks after the visit, while research often obtains satisfaction ratings immediately after the visit for practical reasons. There may be differences between immediate and delayed measurement of satisfaction beyond the mentioned social norms.

Therefore, this study tested the primary null hypothesis that there is no difference in patient satisfaction (measured by Numerical Rating Scale [NRS]) immediately after the initial visit compared to 2 weeks later. Additionally, we assessed the difference in perceived empathy immediately after the initial visit compared to 2 weeks later, and whether change in disability was independently associated with change in satisfaction and empathy after the initial visit compared to 2 weeks later.

Methods

Study Design

After Institutional Review Board approval of this prospective, longitudinal, observational cohort study, we prospectively enrolled 150 adult patients between November 29, 2017 and January 10, 2018. Patients were seen at 5 orthopaedic clinics in a large urban area. We included all new English-speaking patients aged 18 to 89 years who were visiting 1 of 6 participating orthopaedic surgeons for any upper extremity problem and who were able to provide informed consent. We excluded follow-up visits and patients who were unable to speak and understand English. Four research assistants who were not involved with patient treatment described the study to patients before or after the visit with the surgeon. We were granted a waiver of written informed consent; patients indicated their consent by completing the surveys.

Patients could choose either phone or email as their preferred mode of contact for follow-up in this study. For patients who selected email as the preferred mode of contact, the follow-up survey was sent automatically 2 weeks after completion date, and a maximum of 3 reminder emails with 2-day time intervals between them were sent to those who did not respond to the initial invitation. For patients who selected phone as the preferred mode of contact, the follow-up survey was done by an English-speaking research assistant who was not involved with patient treatment. When a response was not obtained on the initial phone call, 3 additional phone calls were made (1 later that same day and 2 the next day). One patient declined participation because he was not interested in the study and had no time after his visit.

Measurements

Patients were asked to complete a set of questionnaires at the end of their visit:

1. A demographic questionnaire consisting of preferred mode of contact for follow-up (phone or email), age, sex, race/ethnicity, marital status, education status, work status, insurance status, and type of visit (first visit or second opinion);

2. An 11-point ordinal measure of satisfaction with the surgeon, with scores ranging from 0 (Worst Surgeon Possible) to 10 (Best Surgeon Possible);

3. The patient’s rating of the surgeon’s empathy, measured by the Jefferson Scale of Patient Perceptions of Physician Empathy (JSPPPE).¹³ The JSPPPE is a 5-item questionnaire, measured on a 7-point Likert scale, with scores ranging from 1 (Strongly Disagree) to 7 (Strongly Agree), that assesses agreement with statements about the physician. The total score is the sum of all item scores (5-35), with higher scores representing a higher degree of perceived physician empathy.

4. Upper extremity disability, measured by the Patient-Reported Outcomes Measurement Information System Physical Function-Upper Extremity (PROMIS PF-UE) Computer Adaptive Test (CAT).^14-16 This is a measure of physical limitations in the upper extremity. It can be completed with as few as 4 questions while still achieving high precision in scoring and thereby decreasing survey burden. PROMIS presents a continuous T-score with a mean of 50 and standard deviation (SD) of 10, with higher scores reflecting better physical function compared to the average of the US general population.¹⁵

After completing the initial questionnaire, the research assistant filled out the office and surgeon name and asked the surgeon to complete the diagnosis. All questionnaires were administered on an encrypted tablet via the secure, HIPAA-compliant electronic platform REDCap (Research Electronic Data Capture), a web-based application for building and managing online surveys and databases.¹⁷ The follow-up survey was sent automatically or was done by phone call as previously described. The follow-up survey consisted of (1) the 11-point ordinal measure of satisfaction with the surgeon, (2) the JSPPPE for perceived empathy, and (3) the PROMIS PF-UE for physical limitations in the upper extremity.

Analysis

Continuous variables are presented as mean ± SD and discrete data as proportions. We used Student’s t-tests to assess baseline differences between continuous variables and Fisher’s exact tests for discrete variables. To assess differences in satisfaction and perceived empathy after 2 weeks, we used Student’s paired t-tests. We created 2 multilevel multivariable linear regression models to assess factors associated with (1) change in satisfaction with the surgeon and (2) change in perceived physician empathy. These models account for correlation of patients treated by the same surgeon. We selected variables to be included in the final models by running multilevel models with only 1 independent variable of interest (Appendix 1). Variables with P < 0.10 were included in our final models. We also included change in PROMIS PF-UE in both models because this was our variable of interest. We considered P < 0.05 significant.

We performed a power analysis for the difference in patient satisfaction immediately after the first visit compared to 2 weeks later. Based on our pilot data where we found an initial mean satisfaction score of 9.4 and mean satisfaction score after 2 weeks of 9.1 (SD of difference 1.0), a priori power analysis showed that we needed a minimum sample size of 90 patients to detect a difference with power set at 0.80 and alpha set at 0.05. In order to account for loss to follow-up as previously noted,¹⁸ we enrolled 67% more patients (total of 150).

Results

Respondent Characteristics

None of the 150 patients were excluded from the analysis. The study patients’ mean age was 51 ± 16 years (range, 18-87 years), and 73 (49%) were men (Table 1). Mean scores directly after the visit were 9.4 ± 1.2 (range, 2-10) for satisfaction with the surgeon, 31 ± 5.2 (range, 9-35) for perceived physician empathy, and 40 ± 10 (range 15-56) for upper extremity disability. Most patients (n = 130, 87%) were seen in 2 of 5 offices, and 106 (71%) were seen by 2 out of 6 participating surgeons.

Ninety-seven (65%) patients completed their follow-up assessment 2 weeks after their initial visit, 49 (51%) by phone and 48 (49%) by email. This is a slightly better rate than the 36% rate reported in previous research.¹⁸ After 2 weeks, the mean score for satisfaction with the surgeon was 9.1 ± 1.5 (range, 0-10), the mean perceived empathy score was 31 ± 5.1 (range, 6-35), and the mean upper extremity disability score was 40 ± 8.7 (range, 23-56). Responders did not differ from nonresponders based on demographic data (Table 2). However, nonresponders had lower perceived empathy scores directly after their visit (P = 0.03) and none had initially chosen phone as their preferred mode of contact for follow-up (P < 0.001). A list of all diagnoses with frequencies the surgeons stated is listed in Appendix 2.

Difference in Satisfaction with the Surgeon

Satisfaction with the surgeon 2 weeks after the in-person visit was slightly, but significantly, lower on bivariate analysis compared to satisfaction with the surgeon immediately after the initial visit (–0.41 ± 1.2, P = 0.001; Table 3).

Difference in Perceived Physician Empathy

Perceived physician empathy 2 weeks after the in-person visit was not significantly lower on bivariate analysis compared to perceived physician empathy immediately after the initial visit (–0.71 ± 5.3, P = 0.19; Table 3).

Factors Associated with Change in Satisfaction with the Surgeon

Accounting for potential interaction of variables using multilevel multivariable analysis, change in disability of the upper extremity was not associated with change in satisfaction with the surgeon (regression coefficient [beta], 0.00 [95% confidence interval {CI}, –0.02 to 0.03]; standard error [SE], 0.01; P = 0.79 [Table 4]). Being Latino was independently associated with less change in satisfaction with the surgeon (beta coefficient, –0.57 [95% CI, –1.1 to 0.00]; SE, 0.29; P = 0.049).

Factors Associated with Change in Perceived Physician Empathy

Accounting for potential interaction of variables using multilevel multivariable analysis, change in disability of the upper extremity was not associated with change in perceived physician empathy (beta coefficient = 0.00 [95% CI, –0.10 to 0.11]; SE, 0.06; P = 0.93 [Table 4]). Race/ethnicity other than white or Latino was independently associated with more change in perceived physician empathy (beta coefficient, 3.5 [95% CI, 0.34 to 6.6]; SE, 1.6; P = 0.030), and preferring email as mode of contact for follow-up was independently associated with less change in perceived physician empathy (beta coefficient, –3.2 [95% CI, –5.2 to –1.3]; SE, 1.0; P = 0.001).

Discussion

Patient satisfaction is considered a quality measure^1-8 and is typically measured directly after an in-person visit. This study tested differences in patient satisfaction and perceived empathy immediately after the initial visit compared to 2 weeks later. In addition, we assessed whether change in disability was independently associated with change in satisfaction and empathy after the initial visit compared to 2 weeks later.

We acknowledge some study limitations. First, we only measured satisfaction based on 1 visit rather than multiple visits over time. It might be that satisfaction ratings differ when the physician-patient relationship is more established. However, we found overall high satisfaction ratings and a well-established relationship might not add to this finding. Second, surgeons were aware of the study and its purpose, which might have resulted in subconsciously altering the behavior to improve satisfaction. The effect of people acting differently as a result of being observed is called the Hawthorne effect.¹⁹ Third, we only used 1 simple ordinal measure to assess patient satisfaction with the surgeon. There is a wide variety of satisfaction measures,²⁰ though the focus of this study was not to test the best possible satisfaction measure but to assess changes in satisfaction over time and its predictors. The simple 11-point ordinal satisfaction measure has proved reliable.⁶ Fourth, 35% of patients did not make a second rating. This is not unusual for phone or email studies. Our response rate was relatively high compared to other studies in our field,¹⁸ perhaps because the time to the second assessment was only 2 weeks and all people were available for follow-up by phone. Fifth, we analyzed 4 surgeons as 1 group and 3 offices as 1 group since we did not enroll enough patients per surgeon and office for individual analysis. However, multilevel linear analysis takes surgeon specific factors into account within that group.

The finding that satisfaction with the surgeon after 2 weeks was significantly lower on bivariate analysis compared to immediately after the initial visit is different from a study that found small increases in satisfaction after 2 weeks and 3 months,¹ but comparable to another study in our field.²¹ Although significant, we believe the decrease in satisfaction is probably not clinically relevant. It might also be that satisfaction at follow-up is lower than measured, but that the least satisfied people did not respond on the follow-up survey.

We found no significant change in perceived empathy after 2 weeks. Since empathy is a strong driver of satisfaction,^2,4-7 we did not expect to find differing results for empathy and for satisfaction over time. Both satisfaction and empathy seem to be relatively durable measures with current measurement tools.

The finding that change in disability was neither independently associated with change in satisfaction nor change in empathy is consistent with prior research.^2,3,21 We cannot adequately study the impact of changes since we did not find an important change in either satisfaction or empathy over time. Jackson et al found higher satisfaction ratings over time in patients who had an increase in physical function and a decrease in symptoms.¹ They also found that met expectations was associated with higher satisfaction immediately after the visit, after 2 weeks, and after 3 months.¹ We feel that met expectations and fewer symptoms and limitations are likely highly co-linear with satisfaction. We therefore may not be able to learn much about one from the others.

The slight change we found in satisfaction with the surgeon among Latino patients was significantly less than the change among white patients. This suggests Latino patients might have a more stable opinion over time (a cultural phenomenon), or it might be spurious given the small number of Latino patients included in the study. The same can be said for the finding that race/ethnicity other than white or Latino was independently associated with greater change in empathy. Providing email as the preferred mode of contact was found to be independently associated with less change in perceived empathy compared to follow-up by phone. We had a 100% success rate for our follow-ups by phone. Our findings suggest that patients might more easily switch ratings on an 11-point ordinal scale than on a 5-item Likert scale. However, both measures are often rated at the ceiling of the scale.^2,21

Conclusion

Satisfaction and perceived empathy are relatively stable constructs, are not clearly associated with other factors, and are strongly correlated with one another. This study supports the research practice of measuring satisfaction immediately after the visit, which is more convenient for both participant and researcher and avoids the loss of more than one third of the patients, and those with a worse experience in particular. To improve the utility and interpretation of patient-reported experience measures such as these, we might direct our efforts to developing scales with less ceiling effect.

Corresponding author: David Ring, MD, PhD, Dell Medical School, The University of Texas at Austin, Health Discovery Building HDB 6.706, 1701 Trinity St., Austin, TX 78705; david.ring@austin.utexas.edu.

Financial disclosures: Dr. Ring has or may receive payment or benefits from Skeletal Dynamics, Wright Medical for elbow implants, Deputy Editor for Clinical Orthopaedics and Related Research, Universities and Hospitals, Lawyers outside the submitted work.

Dr. Teunis has or may receive payment or benefits from VCC, PATIENT+, and AO Trauma TK network unrelated to this work and consultant fees from Synthes.

Study Overview

Objective. To assess the effects of an individualized, multicomponent exercise intervention on the functional status of very elderly patients who were acutely hospitalized compared with those who received usual care.

Design. A single-center, single-blind randomized clinical trial comparing elderly (≥ 75 years old) hospitalized patients who received in-hospital exercise (ie, individualized low-intensity resistance, balance, and walking exercises) versus control (ie, usual care that included physical rehabilitation if needed) interventions. The exercise intervention was adapted from the multicomponent physical exercise program Vivifrail and was supervised and conducted by a fitness specialist in 2 daily (1 morning and 1 evening) sessions lasting 20 minutes for 5 to 7 consecutive days. The morning session consisted of supervised and individualized progressive resistance, balance, and walking exercises. The evening session consisted of functional unsupervised exercises including light weights, extension and flexion of knee and hip, and walking.

Setting and participants. The study was conducted in an acute care unit in a tertiary public hospital in Navarra, Spain, between 1 February 2015 and 30 August 2017. A total of 370 elderly patients undergoing acute care hospitalization were enrolled in the study and randomly assigned to receive in-hospital exercise or control intervention. Inclusion criteria were: age ≥ 75 years, Barthel Index score ≥ 60, and ambulatory with or without assistance.

Main outcome measures. The primary outcome was change in functional capacity from baseline (beginning of exercise or control intervention) to hospital discharge as assessed by the Barthel Index of independence and the Short Physical Performance Battery (SPPB). Secondary outcomes were changes in cognitive capacity (Mini-Mental State Examination [MMSE]) and mood status (Yesavage Geriatric Depression Scale [GDS]), quality of life (QoL; EuroQol-5D), handgrip strength (dominant hand), incident delirium (Confusion Assessment Method), length of stay (LOS), falls during hospitalization, transfer after discharge, and readmission rate and mortality at 3 months after discharge. Intention-to-treat analysis was conducted.

Main results. Of the 370 patients included in the study’s analyses, 209 (56.5%) were women, mean age was 87.3 ± 4.9 years (range, 75-101 years; 130 [35.1%] nonagenarians). The median LOS was 8 days in both groups (interquartile range [IQR], 4 and 4 days, respectively). The median duration of the intervention was 5 days (IQR, 0 days), with 5 ± 1 morning and 4 ± 1 evening sessions in the exercise group. Adherence to the exercise intervention was high (95.8% for morning sessions; 83.4% for evening sessions), and no adverse effects were observed with the intervention.

The in-hospital exercise intervention program yielded significant benefits over usual care in functional outcomes in elderly patients. The exercise group had an increased change in measures of functional capacity compared to the usual care group (ie, Barthel Index, 6.9 points; 95% confidence interval [CI], 4.4-9.5; SPPB score, 2.2 points; 95% CI, 1.7-2.6). Furthermore, acute hospitalization led to an impairment in functional capacity from baseline to discharge in the Barthel Index (−5.0 points; 95% CI, −6.8 to −3.2) in the usual care group. In contrast, exercise intervention reversed this decline and improved functional outcomes as assessed by Barthel Index (1.9 points; 95% CI, 0.2-3.7) and SPPB score (2.4 points; 95% CI, 2.1-2.7).

The beneficial effects of the in-hospital exercise intervention extended to secondary end points indicative of cognitive capacity (MMSE, 1.8 points; 95% CI, 1.3-2.3), mood status (GDS, −2.0 points; 95% CI, −2.5 to −1.6), QoL (EuroQol-5D, 13.2 points; 95% CI, 8.2-18.2), and handgrip strength (2.3 kg; 95% CI, 1.8-2.8) compared to those who received usual care. In contrast, no differences were observed between groups that received exercise intervention and usual care in incident delirium, LOS, falls during hospitalization, transfer after discharge, and 3-month hospital readmission rate and mortality.

Conclusion. An individualized, multicomponent physical exercise program that includes low-intensity resistance, balance, and walking exercises performed during the course of hospitalization (average of 5 days) can reverse functional decline associated with acute hospitalization in very elderly patients. Furthermore, this in-hospital exercise intervention is safe and has a high adherence rate, and thus represents an opportunity to improve quality of care in this vulnerable population.

Commentary

Frail elderly patients are highly susceptible to adverse outcomes of acute hospitalization, including functional decline, disability, nursing home placement, rehospitalization, and mortality.¹ Mobility limitation, a major hazard of hospitalization, has been associated with poorer functional recovery and increased vulnerability to these major adverse events after hospital discharge.^2-4 Interdisciplinary care models delivered during hospitalization (eg, Geriatric Evaluation Unit, Acute Care for Elders) that emphasize functional independence and provide protocols for exercise and rehabilitation have demonstrated reduced hospital LOS, discharge to nursing home, and mortality, and improved functional status in elderly patients.^5-7 Despite this evidence, significant gaps in knowledge exist in understanding whether early implementation of an individualized, multicomponent exercise training program can benefit the oldest old patients who are acutely hospitalized.

This study reported by Martinez-Velilla and colleagues provides an important and timely investigation in examining the effects of an individualized, multicomponent (ie, low-intensity resistance, balance, and walking) in-hospital exercise intervention on functional outcomes of hospitalized octogenarians and nonagenarians. The authors reported that such an intervention, administered 2 sessions per day for 5 to 7 consecutive days, can be safely implemented and reverse functional decline (ie, improvement in Barthel Index and SPPB score over course of hospital stay) typically associated with acute hospitalization in these vulnerable individuals. These findings are particularly significant given the paucity of randomized controlled trials evaluating the impact of exercise intervention in preserving functional capacity of geriatric patients in the setting of acute hospitalization. While much more research is needed to facilitate future development of a consensus opinion in this regard, results from this study provide the rationale that implementation of an individualized multicomponent exercise program is feasible and safe and may attenuate functional decline in hospitalized older patients. Finally, the beneficial effects of in-hospital exercise intervention may extend to cognitive capacity, mood status, and QoL—domains that are essential to optimizing patient-centered care in the frailest elderly patients.

The study was well conceived with a number of strengths, including its randomized clinical trial design. In addition, the trial patients were advanced in age (35.1% were nonagenarians), which is particularly important because this is a vulnerable population that is frequently excluded from participation in trials of exercise interventions and because the evidence-base for physical activity guidelines is suboptimal. Moreover, the authors demonstrated that an individualized multicomponent exercise program could be successfully implemented in elderly patients in an acute setting via daily exercise sessions. This test of feasibility is significant in that clinical trials in exercise intervention in geriatrics are commonly performed in nonacute settings in the community, long-term care facilities, or subacute care. The major limitation in this study centers on the generalizability of its findings. It was noted that some patients were not assessed for changes from baseline to discharge on the Barthel Index (6.1%) and SPPB (2.3%) because of their poor condition. The exclusion of the most debilitated patients limits the application of the study’s key findings to the frailest elderly patients, who are most likely to require acute hospital care.

Applications for Clinical Practice

Functional decline is an exceedingly common adverse outcome associated with hospitalization in older patients. While more evidence is needed, early implementation of an individualized, multicomponent exercise regimen during hospitalization may help to prevent functional decline in vulnerable elderly patients.

—Fred Ko, MD, MS

Study Overview

Objective. To assess the effects of an individualized, multicomponent exercise intervention on the functional status of very elderly patients who were acutely hospitalized compared with those who received usual care.

Design. A single-center, single-blind randomized clinical trial comparing elderly (≥ 75 years old) hospitalized patients who received in-hospital exercise (ie, individualized low-intensity resistance, balance, and walking exercises) versus control (ie, usual care that included physical rehabilitation if needed) interventions. The exercise intervention was adapted from the multicomponent physical exercise program Vivifrail and was supervised and conducted by a fitness specialist in 2 daily (1 morning and 1 evening) sessions lasting 20 minutes for 5 to 7 consecutive days. The morning session consisted of supervised and individualized progressive resistance, balance, and walking exercises. The evening session consisted of functional unsupervised exercises including light weights, extension and flexion of knee and hip, and walking.

Setting and participants. The study was conducted in an acute care unit in a tertiary public hospital in Navarra, Spain, between 1 February 2015 and 30 August 2017. A total of 370 elderly patients undergoing acute care hospitalization were enrolled in the study and randomly assigned to receive in-hospital exercise or control intervention. Inclusion criteria were: age ≥ 75 years, Barthel Index score ≥ 60, and ambulatory with or without assistance.

Main outcome measures. The primary outcome was change in functional capacity from baseline (beginning of exercise or control intervention) to hospital discharge as assessed by the Barthel Index of independence and the Short Physical Performance Battery (SPPB). Secondary outcomes were changes in cognitive capacity (Mini-Mental State Examination [MMSE]) and mood status (Yesavage Geriatric Depression Scale [GDS]), quality of life (QoL; EuroQol-5D), handgrip strength (dominant hand), incident delirium (Confusion Assessment Method), length of stay (LOS), falls during hospitalization, transfer after discharge, and readmission rate and mortality at 3 months after discharge. Intention-to-treat analysis was conducted.

Main results. Of the 370 patients included in the study’s analyses, 209 (56.5%) were women, mean age was 87.3 ± 4.9 years (range, 75-101 years; 130 [35.1%] nonagenarians). The median LOS was 8 days in both groups (interquartile range [IQR], 4 and 4 days, respectively). The median duration of the intervention was 5 days (IQR, 0 days), with 5 ± 1 morning and 4 ± 1 evening sessions in the exercise group. Adherence to the exercise intervention was high (95.8% for morning sessions; 83.4% for evening sessions), and no adverse effects were observed with the intervention.

The in-hospital exercise intervention program yielded significant benefits over usual care in functional outcomes in elderly patients. The exercise group had an increased change in measures of functional capacity compared to the usual care group (ie, Barthel Index, 6.9 points; 95% confidence interval [CI], 4.4-9.5; SPPB score, 2.2 points; 95% CI, 1.7-2.6). Furthermore, acute hospitalization led to an impairment in functional capacity from baseline to discharge in the Barthel Index (−5.0 points; 95% CI, −6.8 to −3.2) in the usual care group. In contrast, exercise intervention reversed this decline and improved functional outcomes as assessed by Barthel Index (1.9 points; 95% CI, 0.2-3.7) and SPPB score (2.4 points; 95% CI, 2.1-2.7).

The beneficial effects of the in-hospital exercise intervention extended to secondary end points indicative of cognitive capacity (MMSE, 1.8 points; 95% CI, 1.3-2.3), mood status (GDS, −2.0 points; 95% CI, −2.5 to −1.6), QoL (EuroQol-5D, 13.2 points; 95% CI, 8.2-18.2), and handgrip strength (2.3 kg; 95% CI, 1.8-2.8) compared to those who received usual care. In contrast, no differences were observed between groups that received exercise intervention and usual care in incident delirium, LOS, falls during hospitalization, transfer after discharge, and 3-month hospital readmission rate and mortality.

Conclusion. An individualized, multicomponent physical exercise program that includes low-intensity resistance, balance, and walking exercises performed during the course of hospitalization (average of 5 days) can reverse functional decline associated with acute hospitalization in very elderly patients. Furthermore, this in-hospital exercise intervention is safe and has a high adherence rate, and thus represents an opportunity to improve quality of care in this vulnerable population.

Commentary

Frail elderly patients are highly susceptible to adverse outcomes of acute hospitalization, including functional decline, disability, nursing home placement, rehospitalization, and mortality.¹ Mobility limitation, a major hazard of hospitalization, has been associated with poorer functional recovery and increased vulnerability to these major adverse events after hospital discharge.^2-4 Interdisciplinary care models delivered during hospitalization (eg, Geriatric Evaluation Unit, Acute Care for Elders) that emphasize functional independence and provide protocols for exercise and rehabilitation have demonstrated reduced hospital LOS, discharge to nursing home, and mortality, and improved functional status in elderly patients.^5-7 Despite this evidence, significant gaps in knowledge exist in understanding whether early implementation of an individualized, multicomponent exercise training program can benefit the oldest old patients who are acutely hospitalized.

This study reported by Martinez-Velilla and colleagues provides an important and timely investigation in examining the effects of an individualized, multicomponent (ie, low-intensity resistance, balance, and walking) in-hospital exercise intervention on functional outcomes of hospitalized octogenarians and nonagenarians. The authors reported that such an intervention, administered 2 sessions per day for 5 to 7 consecutive days, can be safely implemented and reverse functional decline (ie, improvement in Barthel Index and SPPB score over course of hospital stay) typically associated with acute hospitalization in these vulnerable individuals. These findings are particularly significant given the paucity of randomized controlled trials evaluating the impact of exercise intervention in preserving functional capacity of geriatric patients in the setting of acute hospitalization. While much more research is needed to facilitate future development of a consensus opinion in this regard, results from this study provide the rationale that implementation of an individualized multicomponent exercise program is feasible and safe and may attenuate functional decline in hospitalized older patients. Finally, the beneficial effects of in-hospital exercise intervention may extend to cognitive capacity, mood status, and QoL—domains that are essential to optimizing patient-centered care in the frailest elderly patients.

The study was well conceived with a number of strengths, including its randomized clinical trial design. In addition, the trial patients were advanced in age (35.1% were nonagenarians), which is particularly important because this is a vulnerable population that is frequently excluded from participation in trials of exercise interventions and because the evidence-base for physical activity guidelines is suboptimal. Moreover, the authors demonstrated that an individualized multicomponent exercise program could be successfully implemented in elderly patients in an acute setting via daily exercise sessions. This test of feasibility is significant in that clinical trials in exercise intervention in geriatrics are commonly performed in nonacute settings in the community, long-term care facilities, or subacute care. The major limitation in this study centers on the generalizability of its findings. It was noted that some patients were not assessed for changes from baseline to discharge on the Barthel Index (6.1%) and SPPB (2.3%) because of their poor condition. The exclusion of the most debilitated patients limits the application of the study’s key findings to the frailest elderly patients, who are most likely to require acute hospital care.

Applications for Clinical Practice

Functional decline is an exceedingly common adverse outcome associated with hospitalization in older patients. While more evidence is needed, early implementation of an individualized, multicomponent exercise regimen during hospitalization may help to prevent functional decline in vulnerable elderly patients.

—Fred Ko, MD, MS

Study Overview

Objective. To assess the effects of an individualized, multicomponent exercise intervention on the functional status of very elderly patients who were acutely hospitalized compared with those who received usual care.

Design. A single-center, single-blind randomized clinical trial comparing elderly (≥ 75 years old) hospitalized patients who received in-hospital exercise (ie, individualized low-intensity resistance, balance, and walking exercises) versus control (ie, usual care that included physical rehabilitation if needed) interventions. The exercise intervention was adapted from the multicomponent physical exercise program Vivifrail and was supervised and conducted by a fitness specialist in 2 daily (1 morning and 1 evening) sessions lasting 20 minutes for 5 to 7 consecutive days. The morning session consisted of supervised and individualized progressive resistance, balance, and walking exercises. The evening session consisted of functional unsupervised exercises including light weights, extension and flexion of knee and hip, and walking.

Setting and participants. The study was conducted in an acute care unit in a tertiary public hospital in Navarra, Spain, between 1 February 2015 and 30 August 2017. A total of 370 elderly patients undergoing acute care hospitalization were enrolled in the study and randomly assigned to receive in-hospital exercise or control intervention. Inclusion criteria were: age ≥ 75 years, Barthel Index score ≥ 60, and ambulatory with or without assistance.

Main outcome measures. The primary outcome was change in functional capacity from baseline (beginning of exercise or control intervention) to hospital discharge as assessed by the Barthel Index of independence and the Short Physical Performance Battery (SPPB). Secondary outcomes were changes in cognitive capacity (Mini-Mental State Examination [MMSE]) and mood status (Yesavage Geriatric Depression Scale [GDS]), quality of life (QoL; EuroQol-5D), handgrip strength (dominant hand), incident delirium (Confusion Assessment Method), length of stay (LOS), falls during hospitalization, transfer after discharge, and readmission rate and mortality at 3 months after discharge. Intention-to-treat analysis was conducted.

Main results. Of the 370 patients included in the study’s analyses, 209 (56.5%) were women, mean age was 87.3 ± 4.9 years (range, 75-101 years; 130 [35.1%] nonagenarians). The median LOS was 8 days in both groups (interquartile range [IQR], 4 and 4 days, respectively). The median duration of the intervention was 5 days (IQR, 0 days), with 5 ± 1 morning and 4 ± 1 evening sessions in the exercise group. Adherence to the exercise intervention was high (95.8% for morning sessions; 83.4% for evening sessions), and no adverse effects were observed with the intervention.

The in-hospital exercise intervention program yielded significant benefits over usual care in functional outcomes in elderly patients. The exercise group had an increased change in measures of functional capacity compared to the usual care group (ie, Barthel Index, 6.9 points; 95% confidence interval [CI], 4.4-9.5; SPPB score, 2.2 points; 95% CI, 1.7-2.6). Furthermore, acute hospitalization led to an impairment in functional capacity from baseline to discharge in the Barthel Index (−5.0 points; 95% CI, −6.8 to −3.2) in the usual care group. In contrast, exercise intervention reversed this decline and improved functional outcomes as assessed by Barthel Index (1.9 points; 95% CI, 0.2-3.7) and SPPB score (2.4 points; 95% CI, 2.1-2.7).

The beneficial effects of the in-hospital exercise intervention extended to secondary end points indicative of cognitive capacity (MMSE, 1.8 points; 95% CI, 1.3-2.3), mood status (GDS, −2.0 points; 95% CI, −2.5 to −1.6), QoL (EuroQol-5D, 13.2 points; 95% CI, 8.2-18.2), and handgrip strength (2.3 kg; 95% CI, 1.8-2.8) compared to those who received usual care. In contrast, no differences were observed between groups that received exercise intervention and usual care in incident delirium, LOS, falls during hospitalization, transfer after discharge, and 3-month hospital readmission rate and mortality.

Conclusion. An individualized, multicomponent physical exercise program that includes low-intensity resistance, balance, and walking exercises performed during the course of hospitalization (average of 5 days) can reverse functional decline associated with acute hospitalization in very elderly patients. Furthermore, this in-hospital exercise intervention is safe and has a high adherence rate, and thus represents an opportunity to improve quality of care in this vulnerable population.

Commentary

Frail elderly patients are highly susceptible to adverse outcomes of acute hospitalization, including functional decline, disability, nursing home placement, rehospitalization, and mortality.¹ Mobility limitation, a major hazard of hospitalization, has been associated with poorer functional recovery and increased vulnerability to these major adverse events after hospital discharge.^2-4 Interdisciplinary care models delivered during hospitalization (eg, Geriatric Evaluation Unit, Acute Care for Elders) that emphasize functional independence and provide protocols for exercise and rehabilitation have demonstrated reduced hospital LOS, discharge to nursing home, and mortality, and improved functional status in elderly patients.^5-7 Despite this evidence, significant gaps in knowledge exist in understanding whether early implementation of an individualized, multicomponent exercise training program can benefit the oldest old patients who are acutely hospitalized.

This study reported by Martinez-Velilla and colleagues provides an important and timely investigation in examining the effects of an individualized, multicomponent (ie, low-intensity resistance, balance, and walking) in-hospital exercise intervention on functional outcomes of hospitalized octogenarians and nonagenarians. The authors reported that such an intervention, administered 2 sessions per day for 5 to 7 consecutive days, can be safely implemented and reverse functional decline (ie, improvement in Barthel Index and SPPB score over course of hospital stay) typically associated with acute hospitalization in these vulnerable individuals. These findings are particularly significant given the paucity of randomized controlled trials evaluating the impact of exercise intervention in preserving functional capacity of geriatric patients in the setting of acute hospitalization. While much more research is needed to facilitate future development of a consensus opinion in this regard, results from this study provide the rationale that implementation of an individualized multicomponent exercise program is feasible and safe and may attenuate functional decline in hospitalized older patients. Finally, the beneficial effects of in-hospital exercise intervention may extend to cognitive capacity, mood status, and QoL—domains that are essential to optimizing patient-centered care in the frailest elderly patients.

The study was well conceived with a number of strengths, including its randomized clinical trial design. In addition, the trial patients were advanced in age (35.1% were nonagenarians), which is particularly important because this is a vulnerable population that is frequently excluded from participation in trials of exercise interventions and because the evidence-base for physical activity guidelines is suboptimal. Moreover, the authors demonstrated that an individualized multicomponent exercise program could be successfully implemented in elderly patients in an acute setting via daily exercise sessions. This test of feasibility is significant in that clinical trials in exercise intervention in geriatrics are commonly performed in nonacute settings in the community, long-term care facilities, or subacute care. The major limitation in this study centers on the generalizability of its findings. It was noted that some patients were not assessed for changes from baseline to discharge on the Barthel Index (6.1%) and SPPB (2.3%) because of their poor condition. The exclusion of the most debilitated patients limits the application of the study’s key findings to the frailest elderly patients, who are most likely to require acute hospital care.

Applications for Clinical Practice

Functional decline is an exceedingly common adverse outcome associated with hospitalization in older patients. While more evidence is needed, early implementation of an individualized, multicomponent exercise regimen during hospitalization may help to prevent functional decline in vulnerable elderly patients.

—Fred Ko, MD, MS

Study Overview

Objective. To compare the outcomes of 18 months versus 36 months of androgen deprivation therapy (ADT) combined with radiation in high-risk prostate cancer (HRPC).

Design. Phase 3 multicenter, randomized superiority trial.

Participants. This study enrolled patients aged ≤ 80 years with HRPC. All patients had no evidence of regional or distant metastasis. High-risk disease was defined as any of the following: clinical stage T3 or T4, prostate-specific antigen (PSA) level > 20 ng/mL, or Gleason score > 7.

Methods. Prior to randomization, all patients received 4 months of ADT with goserelin 10.8 mg and anti-androgen therapy with bicalutamide 50 mg daily for 30 days. Patients were then randomly assigned to 18 (short arm) or 36 (long arm) months of ADT in combination with radiation therapy (RT). The randomization was stratified by stage (T1-2 vs T3-4), Gleason score (< 7 vs > 7) and PSA level (< 20 ng/mL vs > 20 ng/mL). The standard radiation dose was 70 Gy to the prostate and 44 Gy to the pelvis. Computed tomography or magnetic resonance imaging exam of the abdomen and pelvis and a bone scan were performed to rule out regional or distant metastases. PSA level was monitored every 3 months for 18 months, every 6 months up to the third year, and yearly thereafter.

Main outcome measures. The 2 primary outcomes were overall survival (OS) and quality of life (QoL) at 5 years. The secondary end points were biochemical failure (BF)defined as PSA nadir plus 2, disease-free survival (DFS), and site(s) of tumor relapse.

Main results. The 5-year OS was 91% and 86% for the 36- and 18-month groups, respectively (P = 0.07). The 10-year OS was 62% for both groups (P = 0.7), and the global hazard ratio (HR) was 1.02 (P = 0.8). The disease-specific survival (DSS) was similar in both groups at 5 years (98% vs 97%) and at 10 years (91% vs 92%) in the long versus short arm, respectively. The rate of prostate cancer–specific death was 21% versus 23% in the long versus short arm, respectively. In a multivariate analysis for OS, only age and Gleason score > 7 were statistically significant survival predictors. BF rate at 10 years was 25% for 36 months as compared with 31% for 18 months (HR, 0.71, P = 0.02). The 10-year DFS rates were 45% and 39% for 36 and 18 months, respectively (HR, 0.68, P = 0.08). Forty patients in the long arm versus 43 in the short arm developed distant metastasis. Both groups developed similar sites of metastasis, which was predominantly osseous. Some aspects of the EORTC30 and PR25 scales were significant, mostly pertaining to sexual activity, fatigue, and hormone-related symptoms in favor of the 18-month group. The median time to testosterone recovery after completion of ADT was 2.1 years for the short arm versus 4 years in the long arm (P = 0.02). The compliance rate with ADT was 88% in the short arm versus 53% in the long arm. The main reason for nonadherence was side effects in 54% of the patients in the long arm and 31% in the short arm.

Conclusion. The results of the current study suggest that 18 months of ADT in combination with RT yields similar 10-year OS and improved QoL compared with 36 months in patients with HRPC.

Commentary

The role of ADT for HRPC in combination with RT has been well established by evidence from several trials; however, the comparator arms and patient characteristics between these studies have been quite heterogeneous. For instance, the Radiation Therapy Oncology Group (RTOG) 85-31 trial compared indefinite ADT with RT versus RT alone and showed significantly better 10-year OS in the ADT plus RT arm.¹ Similarly, the European Organisation for Research and Treatment of Cancer (EROTC) 22961 trial showed an OS benefit for 36 months versus 6 months of ADT in combination with radiation.² Additionally, the RTOG 92-02 trial, which compared 4 months versus 24 months of ADT with radiation, also found a significantly improved 10-year OS with a longer course of ADT.³ Taken together these data suggest that 4 to 6 months of ADT is inferior to 24 to 36 months of ADT in HRPC.

Several differences, however, exist in patient characteristics between the present trial and the earlier trials, justifiably reflecting the change of practice in the PSA era. For instance, the present study has a higher percentage of patients with Gleason scores 8-10 (60%) compared to the EROTC and RTOG studies (15%-35%) and a lower percentage of patients with T3 and T4 tumors. Patients with high Gleason scores are believed to have a higher risk of micro-metastasis at the time of diagnosis and higher chances of castration resistance. Therefore, inclusion of a (presumably) larger high-risk patient subgroup in the present study lends further credence to results indicating similar OS with a shorter course of ADT. A post hoc analysis including only patients with Gleason score 8-10 performed for OS, DSS, BF, and DFS showed no significant difference in any of these variables between the arms. Analysis of the interaction between ADT duration in the Gleason 8-10 subgroup versus Gleason 7 for OS, DFS, DSS and BF found no significant differences. This again suggests that 18 months of ADT may be sufficient for this high-risk group; however, it is difficult to draw definitive conclusions from this unplanned subgroup analysis.

Based on the results of the current study, it seems that 18 months of ADT is adequate for many, but not necessarily all, patients. For instance, there was a significantly higher incidence of BF in the 18-month arm. Applying this data to younger patients may require a more nuanced approach, as it is possible that with longer follow-up this higher rate of BF may translate into a difference in OS. Therefore, life expectancy and comorbid conditions always need to be incorporated into clinical decision making with regards to ADT duration. In a study by Rose et al, the risk of prostate cancer–specific mortality significantly decreased by using ADT plus RT for men with HRPC with a low, but not a high, competing mortality score.⁴ The clinical significance of this finding is that adding ADT to RT might significantly reduce the risk of death from prostate cancer only in the setting of low competing risks.

Another concept to ponder is the optimum duration of ADT in the era of RT dose escalation. Currently, there are emerging techniques for delivering higher radiation doses and combining brachytherapy with external beam radiotherapy for HRPC, and the role of whole pelvic radiation is being investigated. New data suggests that higher radiation doses can lead to improvement in outcomes for HRPC. The DART01/05 study compared 4 versus 24 months of ADT with 76 to 82 Gy of RT and reported improved 5-year OS, DFS, and metastasis-free survival with longer ADT duration.⁵ Moreover, Kishan et al reported improved prostate cancer–specific mortality when brachytherapy boost was added to radiation compared to radiation alone in patients with Gleason scores 9 and 10.⁶ Therefore, the optimal duration of ADT in the setting of dose-escalated radiotherapy is not yet known. Also, it is important to note that unlike the prior RTOG and EORTC studies, this study did not include patients with evidence of regional nodal disease, and thus the present data should not be applied to this patient population.

Applications to Clinical Practice

This study’s results suggesting that 18 months of ADT in combination with RT yields similar 10-year OS and improved QoL compared with 36 months of ADT in patients with HRPC should be interpreted with caution when treating very young patients, since the higher rate of BF in the short arm may impact the OS with longer follow-up. Additionally, patients’ QoL and tolerance to ADT-related adverse effects should be taken into consideration given that compliance with 36 months of ADT was only 53% in this study.

—Jailan Elayoubi, MD, Michigan State University, East Lansing, MI

Study Overview

Objective. To compare the outcomes of 18 months versus 36 months of androgen deprivation therapy (ADT) combined with radiation in high-risk prostate cancer (HRPC).

Design. Phase 3 multicenter, randomized superiority trial.

Participants. This study enrolled patients aged ≤ 80 years with HRPC. All patients had no evidence of regional or distant metastasis. High-risk disease was defined as any of the following: clinical stage T3 or T4, prostate-specific antigen (PSA) level > 20 ng/mL, or Gleason score > 7.

Methods. Prior to randomization, all patients received 4 months of ADT with goserelin 10.8 mg and anti-androgen therapy with bicalutamide 50 mg daily for 30 days. Patients were then randomly assigned to 18 (short arm) or 36 (long arm) months of ADT in combination with radiation therapy (RT). The randomization was stratified by stage (T1-2 vs T3-4), Gleason score (< 7 vs > 7) and PSA level (< 20 ng/mL vs > 20 ng/mL). The standard radiation dose was 70 Gy to the prostate and 44 Gy to the pelvis. Computed tomography or magnetic resonance imaging exam of the abdomen and pelvis and a bone scan were performed to rule out regional or distant metastases. PSA level was monitored every 3 months for 18 months, every 6 months up to the third year, and yearly thereafter.

Main outcome measures. The 2 primary outcomes were overall survival (OS) and quality of life (QoL) at 5 years. The secondary end points were biochemical failure (BF)defined as PSA nadir plus 2, disease-free survival (DFS), and site(s) of tumor relapse.

Main results. The 5-year OS was 91% and 86% for the 36- and 18-month groups, respectively (P = 0.07). The 10-year OS was 62% for both groups (P = 0.7), and the global hazard ratio (HR) was 1.02 (P = 0.8). The disease-specific survival (DSS) was similar in both groups at 5 years (98% vs 97%) and at 10 years (91% vs 92%) in the long versus short arm, respectively. The rate of prostate cancer–specific death was 21% versus 23% in the long versus short arm, respectively. In a multivariate analysis for OS, only age and Gleason score > 7 were statistically significant survival predictors. BF rate at 10 years was 25% for 36 months as compared with 31% for 18 months (HR, 0.71, P = 0.02). The 10-year DFS rates were 45% and 39% for 36 and 18 months, respectively (HR, 0.68, P = 0.08). Forty patients in the long arm versus 43 in the short arm developed distant metastasis. Both groups developed similar sites of metastasis, which was predominantly osseous. Some aspects of the EORTC30 and PR25 scales were significant, mostly pertaining to sexual activity, fatigue, and hormone-related symptoms in favor of the 18-month group. The median time to testosterone recovery after completion of ADT was 2.1 years for the short arm versus 4 years in the long arm (P = 0.02). The compliance rate with ADT was 88% in the short arm versus 53% in the long arm. The main reason for nonadherence was side effects in 54% of the patients in the long arm and 31% in the short arm.

Conclusion. The results of the current study suggest that 18 months of ADT in combination with RT yields similar 10-year OS and improved QoL compared with 36 months in patients with HRPC.

Commentary

The role of ADT for HRPC in combination with RT has been well established by evidence from several trials; however, the comparator arms and patient characteristics between these studies have been quite heterogeneous. For instance, the Radiation Therapy Oncology Group (RTOG) 85-31 trial compared indefinite ADT with RT versus RT alone and showed significantly better 10-year OS in the ADT plus RT arm.¹ Similarly, the European Organisation for Research and Treatment of Cancer (EROTC) 22961 trial showed an OS benefit for 36 months versus 6 months of ADT in combination with radiation.² Additionally, the RTOG 92-02 trial, which compared 4 months versus 24 months of ADT with radiation, also found a significantly improved 10-year OS with a longer course of ADT.³ Taken together these data suggest that 4 to 6 months of ADT is inferior to 24 to 36 months of ADT in HRPC.

Several differences, however, exist in patient characteristics between the present trial and the earlier trials, justifiably reflecting the change of practice in the PSA era. For instance, the present study has a higher percentage of patients with Gleason scores 8-10 (60%) compared to the EROTC and RTOG studies (15%-35%) and a lower percentage of patients with T3 and T4 tumors. Patients with high Gleason scores are believed to have a higher risk of micro-metastasis at the time of diagnosis and higher chances of castration resistance. Therefore, inclusion of a (presumably) larger high-risk patient subgroup in the present study lends further credence to results indicating similar OS with a shorter course of ADT. A post hoc analysis including only patients with Gleason score 8-10 performed for OS, DSS, BF, and DFS showed no significant difference in any of these variables between the arms. Analysis of the interaction between ADT duration in the Gleason 8-10 subgroup versus Gleason 7 for OS, DFS, DSS and BF found no significant differences. This again suggests that 18 months of ADT may be sufficient for this high-risk group; however, it is difficult to draw definitive conclusions from this unplanned subgroup analysis.

Based on the results of the current study, it seems that 18 months of ADT is adequate for many, but not necessarily all, patients. For instance, there was a significantly higher incidence of BF in the 18-month arm. Applying this data to younger patients may require a more nuanced approach, as it is possible that with longer follow-up this higher rate of BF may translate into a difference in OS. Therefore, life expectancy and comorbid conditions always need to be incorporated into clinical decision making with regards to ADT duration. In a study by Rose et al, the risk of prostate cancer–specific mortality significantly decreased by using ADT plus RT for men with HRPC with a low, but not a high, competing mortality score.⁴ The clinical significance of this finding is that adding ADT to RT might significantly reduce the risk of death from prostate cancer only in the setting of low competing risks.

Another concept to ponder is the optimum duration of ADT in the era of RT dose escalation. Currently, there are emerging techniques for delivering higher radiation doses and combining brachytherapy with external beam radiotherapy for HRPC, and the role of whole pelvic radiation is being investigated. New data suggests that higher radiation doses can lead to improvement in outcomes for HRPC. The DART01/05 study compared 4 versus 24 months of ADT with 76 to 82 Gy of RT and reported improved 5-year OS, DFS, and metastasis-free survival with longer ADT duration.⁵ Moreover, Kishan et al reported improved prostate cancer–specific mortality when brachytherapy boost was added to radiation compared to radiation alone in patients with Gleason scores 9 and 10.⁶ Therefore, the optimal duration of ADT in the setting of dose-escalated radiotherapy is not yet known. Also, it is important to note that unlike the prior RTOG and EORTC studies, this study did not include patients with evidence of regional nodal disease, and thus the present data should not be applied to this patient population.

Applications to Clinical Practice

This study’s results suggesting that 18 months of ADT in combination with RT yields similar 10-year OS and improved QoL compared with 36 months of ADT in patients with HRPC should be interpreted with caution when treating very young patients, since the higher rate of BF in the short arm may impact the OS with longer follow-up. Additionally, patients’ QoL and tolerance to ADT-related adverse effects should be taken into consideration given that compliance with 36 months of ADT was only 53% in this study.

—Jailan Elayoubi, MD, Michigan State University, East Lansing, MI

Study Overview

Objective. To compare the outcomes of 18 months versus 36 months of androgen deprivation therapy (ADT) combined with radiation in high-risk prostate cancer (HRPC).

Design. Phase 3 multicenter, randomized superiority trial.

Participants. This study enrolled patients aged ≤ 80 years with HRPC. All patients had no evidence of regional or distant metastasis. High-risk disease was defined as any of the following: clinical stage T3 or T4, prostate-specific antigen (PSA) level > 20 ng/mL, or Gleason score > 7.

Methods. Prior to randomization, all patients received 4 months of ADT with goserelin 10.8 mg and anti-androgen therapy with bicalutamide 50 mg daily for 30 days. Patients were then randomly assigned to 18 (short arm) or 36 (long arm) months of ADT in combination with radiation therapy (RT). The randomization was stratified by stage (T1-2 vs T3-4), Gleason score (< 7 vs > 7) and PSA level (< 20 ng/mL vs > 20 ng/mL). The standard radiation dose was 70 Gy to the prostate and 44 Gy to the pelvis. Computed tomography or magnetic resonance imaging exam of the abdomen and pelvis and a bone scan were performed to rule out regional or distant metastases. PSA level was monitored every 3 months for 18 months, every 6 months up to the third year, and yearly thereafter.

Main outcome measures. The 2 primary outcomes were overall survival (OS) and quality of life (QoL) at 5 years. The secondary end points were biochemical failure (BF)defined as PSA nadir plus 2, disease-free survival (DFS), and site(s) of tumor relapse.

Main results. The 5-year OS was 91% and 86% for the 36- and 18-month groups, respectively (P = 0.07). The 10-year OS was 62% for both groups (P = 0.7), and the global hazard ratio (HR) was 1.02 (P = 0.8). The disease-specific survival (DSS) was similar in both groups at 5 years (98% vs 97%) and at 10 years (91% vs 92%) in the long versus short arm, respectively. The rate of prostate cancer–specific death was 21% versus 23% in the long versus short arm, respectively. In a multivariate analysis for OS, only age and Gleason score > 7 were statistically significant survival predictors. BF rate at 10 years was 25% for 36 months as compared with 31% for 18 months (HR, 0.71, P = 0.02). The 10-year DFS rates were 45% and 39% for 36 and 18 months, respectively (HR, 0.68, P = 0.08). Forty patients in the long arm versus 43 in the short arm developed distant metastasis. Both groups developed similar sites of metastasis, which was predominantly osseous. Some aspects of the EORTC30 and PR25 scales were significant, mostly pertaining to sexual activity, fatigue, and hormone-related symptoms in favor of the 18-month group. The median time to testosterone recovery after completion of ADT was 2.1 years for the short arm versus 4 years in the long arm (P = 0.02). The compliance rate with ADT was 88% in the short arm versus 53% in the long arm. The main reason for nonadherence was side effects in 54% of the patients in the long arm and 31% in the short arm.

Conclusion. The results of the current study suggest that 18 months of ADT in combination with RT yields similar 10-year OS and improved QoL compared with 36 months in patients with HRPC.

Commentary

The role of ADT for HRPC in combination with RT has been well established by evidence from several trials; however, the comparator arms and patient characteristics between these studies have been quite heterogeneous. For instance, the Radiation Therapy Oncology Group (RTOG) 85-31 trial compared indefinite ADT with RT versus RT alone and showed significantly better 10-year OS in the ADT plus RT arm.¹ Similarly, the European Organisation for Research and Treatment of Cancer (EROTC) 22961 trial showed an OS benefit for 36 months versus 6 months of ADT in combination with radiation.² Additionally, the RTOG 92-02 trial, which compared 4 months versus 24 months of ADT with radiation, also found a significantly improved 10-year OS with a longer course of ADT.³ Taken together these data suggest that 4 to 6 months of ADT is inferior to 24 to 36 months of ADT in HRPC.

Several differences, however, exist in patient characteristics between the present trial and the earlier trials, justifiably reflecting the change of practice in the PSA era. For instance, the present study has a higher percentage of patients with Gleason scores 8-10 (60%) compared to the EROTC and RTOG studies (15%-35%) and a lower percentage of patients with T3 and T4 tumors. Patients with high Gleason scores are believed to have a higher risk of micro-metastasis at the time of diagnosis and higher chances of castration resistance. Therefore, inclusion of a (presumably) larger high-risk patient subgroup in the present study lends further credence to results indicating similar OS with a shorter course of ADT. A post hoc analysis including only patients with Gleason score 8-10 performed for OS, DSS, BF, and DFS showed no significant difference in any of these variables between the arms. Analysis of the interaction between ADT duration in the Gleason 8-10 subgroup versus Gleason 7 for OS, DFS, DSS and BF found no significant differences. This again suggests that 18 months of ADT may be sufficient for this high-risk group; however, it is difficult to draw definitive conclusions from this unplanned subgroup analysis.

Based on the results of the current study, it seems that 18 months of ADT is adequate for many, but not necessarily all, patients. For instance, there was a significantly higher incidence of BF in the 18-month arm. Applying this data to younger patients may require a more nuanced approach, as it is possible that with longer follow-up this higher rate of BF may translate into a difference in OS. Therefore, life expectancy and comorbid conditions always need to be incorporated into clinical decision making with regards to ADT duration. In a study by Rose et al, the risk of prostate cancer–specific mortality significantly decreased by using ADT plus RT for men with HRPC with a low, but not a high, competing mortality score.⁴ The clinical significance of this finding is that adding ADT to RT might significantly reduce the risk of death from prostate cancer only in the setting of low competing risks.

Another concept to ponder is the optimum duration of ADT in the era of RT dose escalation. Currently, there are emerging techniques for delivering higher radiation doses and combining brachytherapy with external beam radiotherapy for HRPC, and the role of whole pelvic radiation is being investigated. New data suggests that higher radiation doses can lead to improvement in outcomes for HRPC. The DART01/05 study compared 4 versus 24 months of ADT with 76 to 82 Gy of RT and reported improved 5-year OS, DFS, and metastasis-free survival with longer ADT duration.⁵ Moreover, Kishan et al reported improved prostate cancer–specific mortality when brachytherapy boost was added to radiation compared to radiation alone in patients with Gleason scores 9 and 10.⁶ Therefore, the optimal duration of ADT in the setting of dose-escalated radiotherapy is not yet known. Also, it is important to note that unlike the prior RTOG and EORTC studies, this study did not include patients with evidence of regional nodal disease, and thus the present data should not be applied to this patient population.

Applications to Clinical Practice

This study’s results suggesting that 18 months of ADT in combination with RT yields similar 10-year OS and improved QoL compared with 36 months of ADT in patients with HRPC should be interpreted with caution when treating very young patients, since the higher rate of BF in the short arm may impact the OS with longer follow-up. Additionally, patients’ QoL and tolerance to ADT-related adverse effects should be taken into consideration given that compliance with 36 months of ADT was only 53% in this study.

—Jailan Elayoubi, MD, Michigan State University, East Lansing, MI

In a previous Letter from Maine I wrote about a study performed in China in which more than half a million patients were diagnosed by an artificial intelligence (A.I.) system that was able to extract and analyze information from their electronic medical records. The system was at least as accurate as physicians who had access to the same data (“A.I. Shows Promise Assisting Physicians,” by Cade Metz, The New York Times, Feb. 11, 2019). I ended my column with the hopeful assumption that despite incredible advances in A.I., the practice of medicine always would include a human element. However, I left unexplained exactly how physicians would fit into the post-A.I. revolution. In the weeks since I submitted that column, I have been searching for roles that might remain for physicians after A.I. has snatched their bread and butter of diagnosis and management.

gpointstudio/Thinkstock

I discovered there always will be a need be someone in the health care delivery system to serve as a communicator and translator for the patient. I easily can envision a system in which the patient enters her chief complaint and current symptoms into her smartphone or tablet. Using its database of the patient’s past, family, and social history, the system generates a list of laboratory and imaging studies, some of which the patient may be able to submit directly from her handheld device. For example, the system may be able to use the patient’s phone to “examine” her. The A.I. system then generates a diagnosis.

If the diagnosed condition and management is simple and straightforward, such as a rash, the information could be communicated to the patient directly, with a short paragraph of explanation and list of persistent symptoms that would indicate that the condition was not improving as expected. A contact dermatitis comes to mind here.

However, suppose the A.I. system determines that the patient has a 90% chance of having stage IV pancreatic cancer, with a life expectancy of 6 months. Is this the kind of information you would like to learn about yourself by clicking “Your Diagnosis” box on your phone while you were having lunch with a friend? Obviously, a diagnosis of this severity should be communicated human to human, even though it was generated by a highly accurate computer system. And this communication would best be done in the form of a dialogue with someone who knows the patient and has some understanding of how she might understand and cope with the information. In the absence of a prior relationship, the dialogue should occur in real time and face to face at a minimum. I guess we have to acknowledge that FaceTime or Skype might be acceptable here.

Fortunately, stage IV cancers are rare, but there are a bazillion other conditions that, while not serious, require a nuanced explanation as part of a successful management plan that takes into account the patient’s level of anxiety and cognitive abilities. A boilerplate paragraph or two spit out by an A.I. system isn’t good health care. Although I know many physicians do rely on printed handouts for conditions they feel is a no-brainer.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at pdnews@mdedge.com.

In a previous Letter from Maine I wrote about a study performed in China in which more than half a million patients were diagnosed by an artificial intelligence (A.I.) system that was able to extract and analyze information from their electronic medical records. The system was at least as accurate as physicians who had access to the same data (“A.I. Shows Promise Assisting Physicians,” by Cade Metz, The New York Times, Feb. 11, 2019). I ended my column with the hopeful assumption that despite incredible advances in A.I., the practice of medicine always would include a human element. However, I left unexplained exactly how physicians would fit into the post-A.I. revolution. In the weeks since I submitted that column, I have been searching for roles that might remain for physicians after A.I. has snatched their bread and butter of diagnosis and management.

gpointstudio/Thinkstock

I discovered there always will be a need be someone in the health care delivery system to serve as a communicator and translator for the patient. I easily can envision a system in which the patient enters her chief complaint and current symptoms into her smartphone or tablet. Using its database of the patient’s past, family, and social history, the system generates a list of laboratory and imaging studies, some of which the patient may be able to submit directly from her handheld device. For example, the system may be able to use the patient’s phone to “examine” her. The A.I. system then generates a diagnosis.

If the diagnosed condition and management is simple and straightforward, such as a rash, the information could be communicated to the patient directly, with a short paragraph of explanation and list of persistent symptoms that would indicate that the condition was not improving as expected. A contact dermatitis comes to mind here.

However, suppose the A.I. system determines that the patient has a 90% chance of having stage IV pancreatic cancer, with a life expectancy of 6 months. Is this the kind of information you would like to learn about yourself by clicking “Your Diagnosis” box on your phone while you were having lunch with a friend? Obviously, a diagnosis of this severity should be communicated human to human, even though it was generated by a highly accurate computer system. And this communication would best be done in the form of a dialogue with someone who knows the patient and has some understanding of how she might understand and cope with the information. In the absence of a prior relationship, the dialogue should occur in real time and face to face at a minimum. I guess we have to acknowledge that FaceTime or Skype might be acceptable here.

Fortunately, stage IV cancers are rare, but there are a bazillion other conditions that, while not serious, require a nuanced explanation as part of a successful management plan that takes into account the patient’s level of anxiety and cognitive abilities. A boilerplate paragraph or two spit out by an A.I. system isn’t good health care. Although I know many physicians do rely on printed handouts for conditions they feel is a no-brainer.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at pdnews@mdedge.com.

In a previous Letter from Maine I wrote about a study performed in China in which more than half a million patients were diagnosed by an artificial intelligence (A.I.) system that was able to extract and analyze information from their electronic medical records. The system was at least as accurate as physicians who had access to the same data (“A.I. Shows Promise Assisting Physicians,” by Cade Metz, The New York Times, Feb. 11, 2019). I ended my column with the hopeful assumption that despite incredible advances in A.I., the practice of medicine always would include a human element. However, I left unexplained exactly how physicians would fit into the post-A.I. revolution. In the weeks since I submitted that column, I have been searching for roles that might remain for physicians after A.I. has snatched their bread and butter of diagnosis and management.

gpointstudio/Thinkstock

I discovered there always will be a need be someone in the health care delivery system to serve as a communicator and translator for the patient. I easily can envision a system in which the patient enters her chief complaint and current symptoms into her smartphone or tablet. Using its database of the patient’s past, family, and social history, the system generates a list of laboratory and imaging studies, some of which the patient may be able to submit directly from her handheld device. For example, the system may be able to use the patient’s phone to “examine” her. The A.I. system then generates a diagnosis.

If the diagnosed condition and management is simple and straightforward, such as a rash, the information could be communicated to the patient directly, with a short paragraph of explanation and list of persistent symptoms that would indicate that the condition was not improving as expected. A contact dermatitis comes to mind here.

However, suppose the A.I. system determines that the patient has a 90% chance of having stage IV pancreatic cancer, with a life expectancy of 6 months. Is this the kind of information you would like to learn about yourself by clicking “Your Diagnosis” box on your phone while you were having lunch with a friend? Obviously, a diagnosis of this severity should be communicated human to human, even though it was generated by a highly accurate computer system. And this communication would best be done in the form of a dialogue with someone who knows the patient and has some understanding of how she might understand and cope with the information. In the absence of a prior relationship, the dialogue should occur in real time and face to face at a minimum. I guess we have to acknowledge that FaceTime or Skype might be acceptable here.

Fortunately, stage IV cancers are rare, but there are a bazillion other conditions that, while not serious, require a nuanced explanation as part of a successful management plan that takes into account the patient’s level of anxiety and cognitive abilities. A boilerplate paragraph or two spit out by an A.I. system isn’t good health care. Although I know many physicians do rely on printed handouts for conditions they feel is a no-brainer.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at pdnews@mdedge.com.

Children with both atopic dermatitis (AD) and food allergy (FA) have structural and molecular differences in the top layers of their skin, according to a study of children with and without AD and FA.

The researchers included 62 children aged 4-17 years, who were divided into three groups: atopic dermatitis and food allergy (AD FA+, n = 21), atopic dermatitis and no food allergy (AD FA−, n = 19), and nonatopic controls (NA, n = 22).

“In this prospective clinical study with laboratory personnel blinded to minimize bias, we demonstrate that children with AD FA+ represent a unique endotype that can be distinguished from AD FA− or NA,” wrote Donald Y. M. Leung, MD, of National Jewish Health, Denver, and his coauthors. Their work was published online in Science Translational Medicine.

According to three different scoring systems, the two AD groups were measured to have similar skin disease severity. Dr. Leung and colleagues then used skin tape stripping to measure the first layer of skin tissue for transepidermal water loss (TEWL) and stratum corneum (SC) composition, along with other variables that would indicate a difference between AD FA+ and the other groups.

Upon analysis, children in the AD FA+ group were found to have “a constellation of SC attributes,” including increased TEWL and lower levels of filaggrin gene breakdown products (urocanic acid and pyroglutamic acid) at nonlesional layers. In addition, there was an increase of Staphylococcus aureus on the nonlesional skin of AD FA+, compared with NA.

The coauthors shared the study’s limitations, which included transcriptome analysis being successful for only a fraction of the patients and the lack of skin biopsies, which would be useful to confirm “the potential role of changes in the deeper layers of skin.” However, they also noted that using minimally invasive STS led to more patients providing samples, and thus less bias in collection. “Although future studies are needed to validate our findings,” Dr. Leung and his associates wrote, “our current data support the concept that primary and secondary prevention of AD and FA in this subset of AD should focus on improving skin barrier function.”

The study was funded by the National Institute of Health/The National Institute of Allergy and Infectious Diseases’ Atopic Dermatitis Research Network, with partial support from the Edelstein Family Chair for Pediatric Allergy at NIH and a NIH/National Center for Advancing Translational Sciences Colorado Clinical and Translational Science Awards grant. Three of the authors declared being inventors of a patent that covers methods of identifying AD with FA as a unique endotype. No other conflicts of interest were reported.

SOURCE: Leung DYM et al. Sci Transl Med. 2019 Feb 20. doi: 10.1126/scitranslmed.aav2685.

Children with both atopic dermatitis (AD) and food allergy (FA) have structural and molecular differences in the top layers of their skin, according to a study of children with and without AD and FA.

The researchers included 62 children aged 4-17 years, who were divided into three groups: atopic dermatitis and food allergy (AD FA+, n = 21), atopic dermatitis and no food allergy (AD FA−, n = 19), and nonatopic controls (NA, n = 22).

“In this prospective clinical study with laboratory personnel blinded to minimize bias, we demonstrate that children with AD FA+ represent a unique endotype that can be distinguished from AD FA− or NA,” wrote Donald Y. M. Leung, MD, of National Jewish Health, Denver, and his coauthors. Their work was published online in Science Translational Medicine.

According to three different scoring systems, the two AD groups were measured to have similar skin disease severity. Dr. Leung and colleagues then used skin tape stripping to measure the first layer of skin tissue for transepidermal water loss (TEWL) and stratum corneum (SC) composition, along with other variables that would indicate a difference between AD FA+ and the other groups.

Upon analysis, children in the AD FA+ group were found to have “a constellation of SC attributes,” including increased TEWL and lower levels of filaggrin gene breakdown products (urocanic acid and pyroglutamic acid) at nonlesional layers. In addition, there was an increase of Staphylococcus aureus on the nonlesional skin of AD FA+, compared with NA.

The coauthors shared the study’s limitations, which included transcriptome analysis being successful for only a fraction of the patients and the lack of skin biopsies, which would be useful to confirm “the potential role of changes in the deeper layers of skin.” However, they also noted that using minimally invasive STS led to more patients providing samples, and thus less bias in collection. “Although future studies are needed to validate our findings,” Dr. Leung and his associates wrote, “our current data support the concept that primary and secondary prevention of AD and FA in this subset of AD should focus on improving skin barrier function.”

The study was funded by the National Institute of Health/The National Institute of Allergy and Infectious Diseases’ Atopic Dermatitis Research Network, with partial support from the Edelstein Family Chair for Pediatric Allergy at NIH and a NIH/National Center for Advancing Translational Sciences Colorado Clinical and Translational Science Awards grant. Three of the authors declared being inventors of a patent that covers methods of identifying AD with FA as a unique endotype. No other conflicts of interest were reported.

SOURCE: Leung DYM et al. Sci Transl Med. 2019 Feb 20. doi: 10.1126/scitranslmed.aav2685.

Children with both atopic dermatitis (AD) and food allergy (FA) have structural and molecular differences in the top layers of their skin, according to a study of children with and without AD and FA.

The researchers included 62 children aged 4-17 years, who were divided into three groups: atopic dermatitis and food allergy (AD FA+, n = 21), atopic dermatitis and no food allergy (AD FA−, n = 19), and nonatopic controls (NA, n = 22).

“In this prospective clinical study with laboratory personnel blinded to minimize bias, we demonstrate that children with AD FA+ represent a unique endotype that can be distinguished from AD FA− or NA,” wrote Donald Y. M. Leung, MD, of National Jewish Health, Denver, and his coauthors. Their work was published online in Science Translational Medicine.

According to three different scoring systems, the two AD groups were measured to have similar skin disease severity. Dr. Leung and colleagues then used skin tape stripping to measure the first layer of skin tissue for transepidermal water loss (TEWL) and stratum corneum (SC) composition, along with other variables that would indicate a difference between AD FA+ and the other groups.

Upon analysis, children in the AD FA+ group were found to have “a constellation of SC attributes,” including increased TEWL and lower levels of filaggrin gene breakdown products (urocanic acid and pyroglutamic acid) at nonlesional layers. In addition, there was an increase of Staphylococcus aureus on the nonlesional skin of AD FA+, compared with NA.

The coauthors shared the study’s limitations, which included transcriptome analysis being successful for only a fraction of the patients and the lack of skin biopsies, which would be useful to confirm “the potential role of changes in the deeper layers of skin.” However, they also noted that using minimally invasive STS led to more patients providing samples, and thus less bias in collection. “Although future studies are needed to validate our findings,” Dr. Leung and his associates wrote, “our current data support the concept that primary and secondary prevention of AD and FA in this subset of AD should focus on improving skin barrier function.”

The study was funded by the National Institute of Health/The National Institute of Allergy and Infectious Diseases’ Atopic Dermatitis Research Network, with partial support from the Edelstein Family Chair for Pediatric Allergy at NIH and a NIH/National Center for Advancing Translational Sciences Colorado Clinical and Translational Science Awards grant. Three of the authors declared being inventors of a patent that covers methods of identifying AD with FA as a unique endotype. No other conflicts of interest were reported.

SOURCE: Leung DYM et al. Sci Transl Med. 2019 Feb 20. doi: 10.1126/scitranslmed.aav2685.