The narrative review by Modesto-Lowe et al¹ in this issue on the potential therapeutic use of cannabis for peripheral neuropathy is only the latest in a vogue string of examinations on how medical marijuana may be used to manage complex conditions. While the authors should be lauded for acknowledging that the role of cannabis in treating peripheral neuropathy is far from settled (“the unknown” in their title), the high stakes involved warrant even more stringent scrutiny than they suggest.

See related article

We are in the midst of an epidemic of chronic opioid use with massive repercussions, and it did not start overnight. Mounting calls for liberalizing narcotic use across a broad range of pain conditions accumulated gradually during the patient-advocacy era of the 1990s, with supporting “evidence” coming mostly from small uncontrolled studies, anecdotal reports, and industry pressure.² Although cannabis and opioids are not interchangeable, we should be cautious about concluding that cannabis is effective and that it should be used to treat chronic pain.

CHRONIC PAIN IS COMPLICATED

Peripheral neuropathy, by definition, is a chronic pain condition. Unlike acute pain, chronic pain is characterized by biologic, psychologic, and social complexities that require nuance to manage and study.

Such nuance is lacking in most recent reviews of the medical use of cannabis. The conditions in question are often studied as if they were transient and acute, eg, employing short-term studies and rudimentary measures such as numeric pain-rating scales or other snapshots of pain intensity. Results of these shortsighted assessments are impossible to extrapolate to long-term outcomes.

Whether cannabis therapy for chronic pain conditions is sustainable remains to be seen. Outcomes in chronic pain should not be defined simply by pain reduction, but by other dimensions such as changes in pain-related disability and quality of life, development of pharmacologic tolerance or dependence, adverse effects, and other “collateral damage.” We are far from understanding these issues, which require highly controlled and regulated longitudinal studies.

A recent Cochrane review³ of the efficacy of cannabis-based medicines for chronic neuropathic pain found that harms might outweigh the benefits. The quality of evidence was rated as very low to moderate; the reviewers cited small sample sizes and exclusion of important subgroups of patients (eg, those with substance abuse or other psychiatric comorbidities). Such exclusions are the crux of a major problem with cannabis research: studies are not naturalistic. The gritty reality of chronic pain management is paramount, and failing to consider the high-risk biopsychosocial factors typical of patients with chronic pain is naïve and, frankly, dangerous.

The true danger of cannabis lies in what we already know with certainty. As the authors discuss, cannabis undisputedly results in dose-dependent cognitive and motivational problems. If we are preaching physical therapy and home exercise to counter deconditioning, socialization to reverse depression, cognitive-behavioral therapy to increase coping, returning to work to prevent prolonged disability, and other active measures to prevent pain from becoming chronic, then why would we suggest treatments known to blunt motivation, energy, concentration, and overall mood? As a general central nervous system suppressant,⁴ cannabis works broadly against our best efforts to rehabilitate patients and restore their overall function.

ALL CANNABIS IS NOT THE SAME

The authors use the general term cannabis in their title, yet rightly unpack the differences between medical marijuana, tetrahydrocannabinol (THC), and cannabidiol (CBD). However, in the minds of untrained and pain-stricken patients seeking rapid relief and practical solutions, such distinctions are likely irrelevant.

The danger in the barrage of publications examining cannabis vs medical marijuana vs THC vs CBD is that they all communicate an unintentional yet problematic message: that marijuana of some sort for pain is acceptable to try. And in the face of financial pressures, changing legal landscapes, insurance coverage volatility, and access issues, are patients really going to always secure prescriptions for well-regulated CBD (lacking psychoactive THC) from thoughtful and well-informed physicians, or will they turn to convenient street suppliers?

Simplified perceptions of safety and efficacy across all cannabis products do not help. More troublesome would be to extrapolate safety to other forms of marijuana known to be dangerous, such as synthetic cannabinoids, which in some instances have been associated with catastrophic outcomes.⁵ The slippery slope is real: if the message becomes that some (or most) marijuana is benign or even therapeutic, what is to curb a widespread and unregulated epidemic?

YOUTH AT RISK

Some groups are more vulnerable than others to the potential negative effects of cannabis. In a study at a medical cannabis dispensary in San Francisco,⁶ adolescents and young adults used more marijuana than older users did and had higher rates of “use when bored” and eventual pharmacologic dependence. Sustained use of marijuana by young people places them at risk of serious psychiatric disorders, with numerous studies demonstrating the unfolding of schizophrenia, depression, bipolar disorder, and more.⁷

As the authors point out, cannabis may be contraindicated in those already burdened with mental health problems. If we recall that comorbid psychiatric disorders are the norm rather than the exception in chronic pain conditions,⁸ can we recommend cannabis therapy for most patients with chronic pain with confidence that it will not cause unintended problems? Evidence already shows that even well-established medical marijuana services attract (and perhaps unintentionally debilitate) a certain high-risk demographic: young, socioeconomically disadvantaged men with other comorbid psychiatric and substance use disorders, who ultimately rank poorly in functional health measures compared with the general population.⁹

NOT REEFER MADNESS, BUT REEFER CAUTION

I am not advocating the fear-mongering misinformation campaigns of the past. We should not exaggerate and warn about “reefer madness” or equate marijuana with untruths about random violence or complete bedlam. Nonetheless, concerns for widespread amotivation, worsening psychiatric states, chronic disability, and chemical dependence are very real.

Needed are tightly regulated, well-controlled, and long-term prospective studies involving isolated CBD formulations lacking THC. Over time, perhaps only formulations approved by the US Food and Drug Administration will be embraced. In the meantime, more comprehensive approaches should be recommended, such as team-based interdisciplinary rehabilitation programs that have shown efficacy in handling chronic pain complexities.^10,11

If such steps are unlikely, physicians should nonetheless stand united in sending a message of cautious optimism regarding medical marijuana, educating their patients not only about recently advertised potential yet inconclusive benefits, but also about the well-known and actual certitudes of its harms for use in chronic pain management. There is plenty of bad and worse information to share with patients, and there is a slippery slope of epidemic proportions to be wary about.

The narrative review by Modesto-Lowe et al¹ in this issue on the potential therapeutic use of cannabis for peripheral neuropathy is only the latest in a vogue string of examinations on how medical marijuana may be used to manage complex conditions. While the authors should be lauded for acknowledging that the role of cannabis in treating peripheral neuropathy is far from settled (“the unknown” in their title), the high stakes involved warrant even more stringent scrutiny than they suggest.

See related article

We are in the midst of an epidemic of chronic opioid use with massive repercussions, and it did not start overnight. Mounting calls for liberalizing narcotic use across a broad range of pain conditions accumulated gradually during the patient-advocacy era of the 1990s, with supporting “evidence” coming mostly from small uncontrolled studies, anecdotal reports, and industry pressure.² Although cannabis and opioids are not interchangeable, we should be cautious about concluding that cannabis is effective and that it should be used to treat chronic pain.

CHRONIC PAIN IS COMPLICATED

Peripheral neuropathy, by definition, is a chronic pain condition. Unlike acute pain, chronic pain is characterized by biologic, psychologic, and social complexities that require nuance to manage and study.

Such nuance is lacking in most recent reviews of the medical use of cannabis. The conditions in question are often studied as if they were transient and acute, eg, employing short-term studies and rudimentary measures such as numeric pain-rating scales or other snapshots of pain intensity. Results of these shortsighted assessments are impossible to extrapolate to long-term outcomes.

Whether cannabis therapy for chronic pain conditions is sustainable remains to be seen. Outcomes in chronic pain should not be defined simply by pain reduction, but by other dimensions such as changes in pain-related disability and quality of life, development of pharmacologic tolerance or dependence, adverse effects, and other “collateral damage.” We are far from understanding these issues, which require highly controlled and regulated longitudinal studies.

A recent Cochrane review³ of the efficacy of cannabis-based medicines for chronic neuropathic pain found that harms might outweigh the benefits. The quality of evidence was rated as very low to moderate; the reviewers cited small sample sizes and exclusion of important subgroups of patients (eg, those with substance abuse or other psychiatric comorbidities). Such exclusions are the crux of a major problem with cannabis research: studies are not naturalistic. The gritty reality of chronic pain management is paramount, and failing to consider the high-risk biopsychosocial factors typical of patients with chronic pain is naïve and, frankly, dangerous.

The true danger of cannabis lies in what we already know with certainty. As the authors discuss, cannabis undisputedly results in dose-dependent cognitive and motivational problems. If we are preaching physical therapy and home exercise to counter deconditioning, socialization to reverse depression, cognitive-behavioral therapy to increase coping, returning to work to prevent prolonged disability, and other active measures to prevent pain from becoming chronic, then why would we suggest treatments known to blunt motivation, energy, concentration, and overall mood? As a general central nervous system suppressant,⁴ cannabis works broadly against our best efforts to rehabilitate patients and restore their overall function.

ALL CANNABIS IS NOT THE SAME

The authors use the general term cannabis in their title, yet rightly unpack the differences between medical marijuana, tetrahydrocannabinol (THC), and cannabidiol (CBD). However, in the minds of untrained and pain-stricken patients seeking rapid relief and practical solutions, such distinctions are likely irrelevant.

The danger in the barrage of publications examining cannabis vs medical marijuana vs THC vs CBD is that they all communicate an unintentional yet problematic message: that marijuana of some sort for pain is acceptable to try. And in the face of financial pressures, changing legal landscapes, insurance coverage volatility, and access issues, are patients really going to always secure prescriptions for well-regulated CBD (lacking psychoactive THC) from thoughtful and well-informed physicians, or will they turn to convenient street suppliers?

Simplified perceptions of safety and efficacy across all cannabis products do not help. More troublesome would be to extrapolate safety to other forms of marijuana known to be dangerous, such as synthetic cannabinoids, which in some instances have been associated with catastrophic outcomes.⁵ The slippery slope is real: if the message becomes that some (or most) marijuana is benign or even therapeutic, what is to curb a widespread and unregulated epidemic?

YOUTH AT RISK

Some groups are more vulnerable than others to the potential negative effects of cannabis. In a study at a medical cannabis dispensary in San Francisco,⁶ adolescents and young adults used more marijuana than older users did and had higher rates of “use when bored” and eventual pharmacologic dependence. Sustained use of marijuana by young people places them at risk of serious psychiatric disorders, with numerous studies demonstrating the unfolding of schizophrenia, depression, bipolar disorder, and more.⁷

As the authors point out, cannabis may be contraindicated in those already burdened with mental health problems. If we recall that comorbid psychiatric disorders are the norm rather than the exception in chronic pain conditions,⁸ can we recommend cannabis therapy for most patients with chronic pain with confidence that it will not cause unintended problems? Evidence already shows that even well-established medical marijuana services attract (and perhaps unintentionally debilitate) a certain high-risk demographic: young, socioeconomically disadvantaged men with other comorbid psychiatric and substance use disorders, who ultimately rank poorly in functional health measures compared with the general population.⁹

NOT REEFER MADNESS, BUT REEFER CAUTION

I am not advocating the fear-mongering misinformation campaigns of the past. We should not exaggerate and warn about “reefer madness” or equate marijuana with untruths about random violence or complete bedlam. Nonetheless, concerns for widespread amotivation, worsening psychiatric states, chronic disability, and chemical dependence are very real.

Needed are tightly regulated, well-controlled, and long-term prospective studies involving isolated CBD formulations lacking THC. Over time, perhaps only formulations approved by the US Food and Drug Administration will be embraced. In the meantime, more comprehensive approaches should be recommended, such as team-based interdisciplinary rehabilitation programs that have shown efficacy in handling chronic pain complexities.^10,11

If such steps are unlikely, physicians should nonetheless stand united in sending a message of cautious optimism regarding medical marijuana, educating their patients not only about recently advertised potential yet inconclusive benefits, but also about the well-known and actual certitudes of its harms for use in chronic pain management. There is plenty of bad and worse information to share with patients, and there is a slippery slope of epidemic proportions to be wary about.

The narrative review by Modesto-Lowe et al¹ in this issue on the potential therapeutic use of cannabis for peripheral neuropathy is only the latest in a vogue string of examinations on how medical marijuana may be used to manage complex conditions. While the authors should be lauded for acknowledging that the role of cannabis in treating peripheral neuropathy is far from settled (“the unknown” in their title), the high stakes involved warrant even more stringent scrutiny than they suggest.

See related article

We are in the midst of an epidemic of chronic opioid use with massive repercussions, and it did not start overnight. Mounting calls for liberalizing narcotic use across a broad range of pain conditions accumulated gradually during the patient-advocacy era of the 1990s, with supporting “evidence” coming mostly from small uncontrolled studies, anecdotal reports, and industry pressure.² Although cannabis and opioids are not interchangeable, we should be cautious about concluding that cannabis is effective and that it should be used to treat chronic pain.

CHRONIC PAIN IS COMPLICATED

Peripheral neuropathy, by definition, is a chronic pain condition. Unlike acute pain, chronic pain is characterized by biologic, psychologic, and social complexities that require nuance to manage and study.

Such nuance is lacking in most recent reviews of the medical use of cannabis. The conditions in question are often studied as if they were transient and acute, eg, employing short-term studies and rudimentary measures such as numeric pain-rating scales or other snapshots of pain intensity. Results of these shortsighted assessments are impossible to extrapolate to long-term outcomes.

Whether cannabis therapy for chronic pain conditions is sustainable remains to be seen. Outcomes in chronic pain should not be defined simply by pain reduction, but by other dimensions such as changes in pain-related disability and quality of life, development of pharmacologic tolerance or dependence, adverse effects, and other “collateral damage.” We are far from understanding these issues, which require highly controlled and regulated longitudinal studies.

A recent Cochrane review³ of the efficacy of cannabis-based medicines for chronic neuropathic pain found that harms might outweigh the benefits. The quality of evidence was rated as very low to moderate; the reviewers cited small sample sizes and exclusion of important subgroups of patients (eg, those with substance abuse or other psychiatric comorbidities). Such exclusions are the crux of a major problem with cannabis research: studies are not naturalistic. The gritty reality of chronic pain management is paramount, and failing to consider the high-risk biopsychosocial factors typical of patients with chronic pain is naïve and, frankly, dangerous.

The true danger of cannabis lies in what we already know with certainty. As the authors discuss, cannabis undisputedly results in dose-dependent cognitive and motivational problems. If we are preaching physical therapy and home exercise to counter deconditioning, socialization to reverse depression, cognitive-behavioral therapy to increase coping, returning to work to prevent prolonged disability, and other active measures to prevent pain from becoming chronic, then why would we suggest treatments known to blunt motivation, energy, concentration, and overall mood? As a general central nervous system suppressant,⁴ cannabis works broadly against our best efforts to rehabilitate patients and restore their overall function.

ALL CANNABIS IS NOT THE SAME

The authors use the general term cannabis in their title, yet rightly unpack the differences between medical marijuana, tetrahydrocannabinol (THC), and cannabidiol (CBD). However, in the minds of untrained and pain-stricken patients seeking rapid relief and practical solutions, such distinctions are likely irrelevant.

The danger in the barrage of publications examining cannabis vs medical marijuana vs THC vs CBD is that they all communicate an unintentional yet problematic message: that marijuana of some sort for pain is acceptable to try. And in the face of financial pressures, changing legal landscapes, insurance coverage volatility, and access issues, are patients really going to always secure prescriptions for well-regulated CBD (lacking psychoactive THC) from thoughtful and well-informed physicians, or will they turn to convenient street suppliers?

Simplified perceptions of safety and efficacy across all cannabis products do not help. More troublesome would be to extrapolate safety to other forms of marijuana known to be dangerous, such as synthetic cannabinoids, which in some instances have been associated with catastrophic outcomes.⁵ The slippery slope is real: if the message becomes that some (or most) marijuana is benign or even therapeutic, what is to curb a widespread and unregulated epidemic?

YOUTH AT RISK

Some groups are more vulnerable than others to the potential negative effects of cannabis. In a study at a medical cannabis dispensary in San Francisco,⁶ adolescents and young adults used more marijuana than older users did and had higher rates of “use when bored” and eventual pharmacologic dependence. Sustained use of marijuana by young people places them at risk of serious psychiatric disorders, with numerous studies demonstrating the unfolding of schizophrenia, depression, bipolar disorder, and more.⁷

As the authors point out, cannabis may be contraindicated in those already burdened with mental health problems. If we recall that comorbid psychiatric disorders are the norm rather than the exception in chronic pain conditions,⁸ can we recommend cannabis therapy for most patients with chronic pain with confidence that it will not cause unintended problems? Evidence already shows that even well-established medical marijuana services attract (and perhaps unintentionally debilitate) a certain high-risk demographic: young, socioeconomically disadvantaged men with other comorbid psychiatric and substance use disorders, who ultimately rank poorly in functional health measures compared with the general population.⁹

NOT REEFER MADNESS, BUT REEFER CAUTION

I am not advocating the fear-mongering misinformation campaigns of the past. We should not exaggerate and warn about “reefer madness” or equate marijuana with untruths about random violence or complete bedlam. Nonetheless, concerns for widespread amotivation, worsening psychiatric states, chronic disability, and chemical dependence are very real.

Needed are tightly regulated, well-controlled, and long-term prospective studies involving isolated CBD formulations lacking THC. Over time, perhaps only formulations approved by the US Food and Drug Administration will be embraced. In the meantime, more comprehensive approaches should be recommended, such as team-based interdisciplinary rehabilitation programs that have shown efficacy in handling chronic pain complexities.^10,11

If such steps are unlikely, physicians should nonetheless stand united in sending a message of cautious optimism regarding medical marijuana, educating their patients not only about recently advertised potential yet inconclusive benefits, but also about the well-known and actual certitudes of its harms for use in chronic pain management. There is plenty of bad and worse information to share with patients, and there is a slippery slope of epidemic proportions to be wary about.

To the Editor: In their article on men’s health,¹Chaitoff and colleagues present the scenario of a 60-year-old patient, with no other history given, whose recent screening prostate-specific antigen (PSA) level was 5.1 ng/mL, and who asks his doctor:

1. Should I have agreed to the screening?
2. How effective is the screening?
3. What are the next steps?

These questions are consistent with the patient having read the latest US Preventive Services Task Force (USPSTF) report on PSA screening, which states: “Screening offers a small potential benefit of reducing the chance of death from prostate cancer in some men. However, many men will experience potential harms of screening, including false-positive results…”²

I would tell the patient that he can expect greater benefit from PSA screening than reported by the USPSTF simply by adhering to the screening protocol. Intention-to-treat analysis applied to the trial results diminished the apparent benefits of PSA screening by counting fatal prostate cancers experienced by nonadherent study participants as screening failures.³ In other words, screening works better in those who actually get screened!

The authors state¹ that “in 2014, an estimated 172,258 men in the United States were diagnosed with prostate cancer, but only 28,343 men died of it.” Nevertheless, prostate cancer remains the second most common cause of cancer deaths in American men, after lung cancer.⁴ In addition to the reduction in prostate cancer-specific mortality with screening, patients should consider the reduction in morbidity from painful bone metastases and pathologic fractures, which are common in advanced prostate cancer.

A false-positive elevated PSA can be caused by reversible benign conditions, such as prostate infection or trauma, which can resolve over time, returning the PSA to its baseline level. Studies have demonstrated that simply repeating the PSA test a few weeks later will significantly reduce the number of false-positive PSA screening tests.⁵

Also, it is not optimal to screen for prostate cancer using a single PSA measurement. This patient’s PSA of 5.1 ng/mL cannot distinguish between chronic benign prostatic hyperplasia and a fast-growing but still curable malignancy. If the patient’s PSA had been tested annually and was known to be stable at its current level, a benign or indolent condition would be most likely, allowing for the possibility of continuing noninvasive observation. If his PSA was 1.1 ng/mL a year ago, and his PSA remains elevated when retested in a few weeks, the likelihood of malignancy would increase, increasing the yield of biopsy.

Lastly, consider false-negatives. A man with a PSA of 2.0 ng/mL would not have undergone biopsy in any of the trials, but if he had a history of several consecutive annual PSA levels less than 1.0 ng/mL, the doubling of his PSA during an interval less than or equal to 1 year could signal an early aggressive prostate cancer. Increases in PSA velocity can reveal the rapid proliferation of malignant prostate cells before the tumor is large enough to cross a static threshold PSA. We have zero data indicating how much benefit can be derived from the use of PSA velocity in this fashion. However, clinicians who carefully track serial PSA changes in each patient have anecdotes of success in early detection and cure of aggressive prostate cancers that would not have been detected by the trial protocols using fixed PSA thresholds. Until such trials are done, we can only tell patients that the ability to compute PSA velocity may be another source of benefit of annual screening of PSA.

To the Editor: In their article on men’s health,¹Chaitoff and colleagues present the scenario of a 60-year-old patient, with no other history given, whose recent screening prostate-specific antigen (PSA) level was 5.1 ng/mL, and who asks his doctor:

1. Should I have agreed to the screening?
2. How effective is the screening?
3. What are the next steps?

These questions are consistent with the patient having read the latest US Preventive Services Task Force (USPSTF) report on PSA screening, which states: “Screening offers a small potential benefit of reducing the chance of death from prostate cancer in some men. However, many men will experience potential harms of screening, including false-positive results…”²

I would tell the patient that he can expect greater benefit from PSA screening than reported by the USPSTF simply by adhering to the screening protocol. Intention-to-treat analysis applied to the trial results diminished the apparent benefits of PSA screening by counting fatal prostate cancers experienced by nonadherent study participants as screening failures.³ In other words, screening works better in those who actually get screened!

The authors state¹ that “in 2014, an estimated 172,258 men in the United States were diagnosed with prostate cancer, but only 28,343 men died of it.” Nevertheless, prostate cancer remains the second most common cause of cancer deaths in American men, after lung cancer.⁴ In addition to the reduction in prostate cancer-specific mortality with screening, patients should consider the reduction in morbidity from painful bone metastases and pathologic fractures, which are common in advanced prostate cancer.

A false-positive elevated PSA can be caused by reversible benign conditions, such as prostate infection or trauma, which can resolve over time, returning the PSA to its baseline level. Studies have demonstrated that simply repeating the PSA test a few weeks later will significantly reduce the number of false-positive PSA screening tests.⁵

Also, it is not optimal to screen for prostate cancer using a single PSA measurement. This patient’s PSA of 5.1 ng/mL cannot distinguish between chronic benign prostatic hyperplasia and a fast-growing but still curable malignancy. If the patient’s PSA had been tested annually and was known to be stable at its current level, a benign or indolent condition would be most likely, allowing for the possibility of continuing noninvasive observation. If his PSA was 1.1 ng/mL a year ago, and his PSA remains elevated when retested in a few weeks, the likelihood of malignancy would increase, increasing the yield of biopsy.

Lastly, consider false-negatives. A man with a PSA of 2.0 ng/mL would not have undergone biopsy in any of the trials, but if he had a history of several consecutive annual PSA levels less than 1.0 ng/mL, the doubling of his PSA during an interval less than or equal to 1 year could signal an early aggressive prostate cancer. Increases in PSA velocity can reveal the rapid proliferation of malignant prostate cells before the tumor is large enough to cross a static threshold PSA. We have zero data indicating how much benefit can be derived from the use of PSA velocity in this fashion. However, clinicians who carefully track serial PSA changes in each patient have anecdotes of success in early detection and cure of aggressive prostate cancers that would not have been detected by the trial protocols using fixed PSA thresholds. Until such trials are done, we can only tell patients that the ability to compute PSA velocity may be another source of benefit of annual screening of PSA.

To the Editor: In their article on men’s health,¹Chaitoff and colleagues present the scenario of a 60-year-old patient, with no other history given, whose recent screening prostate-specific antigen (PSA) level was 5.1 ng/mL, and who asks his doctor:

1. Should I have agreed to the screening?
2. How effective is the screening?
3. What are the next steps?

These questions are consistent with the patient having read the latest US Preventive Services Task Force (USPSTF) report on PSA screening, which states: “Screening offers a small potential benefit of reducing the chance of death from prostate cancer in some men. However, many men will experience potential harms of screening, including false-positive results…”²

I would tell the patient that he can expect greater benefit from PSA screening than reported by the USPSTF simply by adhering to the screening protocol. Intention-to-treat analysis applied to the trial results diminished the apparent benefits of PSA screening by counting fatal prostate cancers experienced by nonadherent study participants as screening failures.³ In other words, screening works better in those who actually get screened!

The authors state¹ that “in 2014, an estimated 172,258 men in the United States were diagnosed with prostate cancer, but only 28,343 men died of it.” Nevertheless, prostate cancer remains the second most common cause of cancer deaths in American men, after lung cancer.⁴ In addition to the reduction in prostate cancer-specific mortality with screening, patients should consider the reduction in morbidity from painful bone metastases and pathologic fractures, which are common in advanced prostate cancer.

A false-positive elevated PSA can be caused by reversible benign conditions, such as prostate infection or trauma, which can resolve over time, returning the PSA to its baseline level. Studies have demonstrated that simply repeating the PSA test a few weeks later will significantly reduce the number of false-positive PSA screening tests.⁵

Also, it is not optimal to screen for prostate cancer using a single PSA measurement. This patient’s PSA of 5.1 ng/mL cannot distinguish between chronic benign prostatic hyperplasia and a fast-growing but still curable malignancy. If the patient’s PSA had been tested annually and was known to be stable at its current level, a benign or indolent condition would be most likely, allowing for the possibility of continuing noninvasive observation. If his PSA was 1.1 ng/mL a year ago, and his PSA remains elevated when retested in a few weeks, the likelihood of malignancy would increase, increasing the yield of biopsy.

Lastly, consider false-negatives. A man with a PSA of 2.0 ng/mL would not have undergone biopsy in any of the trials, but if he had a history of several consecutive annual PSA levels less than 1.0 ng/mL, the doubling of his PSA during an interval less than or equal to 1 year could signal an early aggressive prostate cancer. Increases in PSA velocity can reveal the rapid proliferation of malignant prostate cells before the tumor is large enough to cross a static threshold PSA. We have zero data indicating how much benefit can be derived from the use of PSA velocity in this fashion. However, clinicians who carefully track serial PSA changes in each patient have anecdotes of success in early detection and cure of aggressive prostate cancers that would not have been detected by the trial protocols using fixed PSA thresholds. Until such trials are done, we can only tell patients that the ability to compute PSA velocity may be another source of benefit of annual screening of PSA.

In the article by Chaitoff et al (Men’s health 2018: BPH, prostate cancer, erectile dysfunction, supplements. Cleve Clin J Med 2018; 85(11):871–880, doi:10.3949/ccjm.85a.18011), the prostate-specific antigen level of a 60-year-old man was given as 5.1 mg/dL. The unit of measure should have been 5.1 ng/mL. This has been corrected online.

In the article by Chaitoff et al (Men’s health 2018: BPH, prostate cancer, erectile dysfunction, supplements. Cleve Clin J Med 2018; 85(11):871–880, doi:10.3949/ccjm.85a.18011), the prostate-specific antigen level of a 60-year-old man was given as 5.1 mg/dL. The unit of measure should have been 5.1 ng/mL. This has been corrected online.

In the article by Chaitoff et al (Men’s health 2018: BPH, prostate cancer, erectile dysfunction, supplements. Cleve Clin J Med 2018; 85(11):871–880, doi:10.3949/ccjm.85a.18011), the prostate-specific antigen level of a 60-year-old man was given as 5.1 mg/dL. The unit of measure should have been 5.1 ng/mL. This has been corrected online.

Three commonly used brief cognitive tests erroneously identified dementia. Also today, disease-modifying anti-rheumatic drugs improve vascular abnormalities in early RA, mandating insurance coverage of PrEP for HIV prevention, and polycystic ovary syndrome is linked to increased cancer risk in pre-menopausal women.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

Three commonly used brief cognitive tests erroneously identified dementia. Also today, disease-modifying anti-rheumatic drugs improve vascular abnormalities in early RA, mandating insurance coverage of PrEP for HIV prevention, and polycystic ovary syndrome is linked to increased cancer risk in pre-menopausal women.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

Three commonly used brief cognitive tests erroneously identified dementia. Also today, disease-modifying anti-rheumatic drugs improve vascular abnormalities in early RA, mandating insurance coverage of PrEP for HIV prevention, and polycystic ovary syndrome is linked to increased cancer risk in pre-menopausal women.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

© ASH/Scott Morgan 2018

SAN DIEGO—Results of the randomized, phase 3 Medalist trial show that the erythroid maturation agent luspatercept can reduce transfusion burden in patients with anemia due to myelodysplastic syndromes (MDS) and ring sideroblasts.

Almost 38% of luspatercept-treated patients achieved red blood cell (RBC) transfusion independence for 8 weeks or more, compared with 13% of patients receiving placebo.

And 28% of luspatercept-treated patients achieved transfusion independence for 12 weeks or more, compared to 8% in the placebo group.

Investigators reported these results as abstract 1 at the 2018 ASH Annual Meeting.

Treatment with luspatercept was “very well tolerated,” and responses were durable, with approximately 40% of patients remaining transfusion-free after 1 year of therapy, said senior investigator Alan F. List, MD, of Moffitt Cancer Center in Tampa, Florida, during a press conference at the meeting.

The first-in-class erythroid maturation agent is being developed as a treatment for anemia related to MDS and beta-thalassemia, Dr. List said.

“Luspatercept is a potential new therapy that we think could be very effective in patients with lower-risk MDS with ring sideroblasts who are red blood cell transfusion-dependent,” Dr. List affirmed.

Luspatercept is a soluble receptor chimera that binds to an array of ligands in the TGF-β superfamily, which is known to be very important in suppressing erythropoiesis in patients with MDS, Dr. List noted.

The Medalist study (NCT02631070) included patients with very low-, low-, or intermediate-risk disease and ring sideroblasts who were RBC transfusion-dependent and were refractory to, unresponsive to, or ineligible for first-line treatment with an erythropoiesis-stimulating agent (ESA).

A total of 153 patients were randomized to receive luspatercept at 1.0 mg/kg, administered subcutaneously every 21 days for at least 24 weeks, while 76 were randomized to placebo every 21 days.

The primary endpoint was the proportion of patients achieving RBC transfusion independence for at least 8 weeks during the first 24 weeks of treatment.

The primary endpoint was achieved by 37.9% of luspatercept-treated patients and 13.2% of placebo-treated patients (P<0.0001).

The luspatercept-treated patients also had a higher rate of erythroid response compared with the placebo group, at 52.9% and 11.8%, respectively (P<0.0001).

The investigators reported no differences in treatment-emergent adverse events, severe adverse events, or frequency of progression of acute myeloid leukemia (AML).

The safety profile was consistent with that of the phase 2 PACE-MDS study, which included treatment-related grade 3 myalgia (2%), increased blast cell count (2%), and general physical health deterioration (2%).

“This was a very clean drug and a very safe drug,” Dr. List said.

The decision to study luspatercept in patients with ring sideroblasts was based on results of the phase 2 PACE study showing a higher response rate in that subset of MDS patients, according to Dr. List.

The PACE study also included a small number of patients who had not previously received an ESA.

Currently underway is a phase 3 trial (NCT03682536) investigating luspatercept in ESA-naïve lower-risk MDS patients with anemia who require RBC transfusions.

Luspatercept would be a useful therapy to have in clinic for patients with ring sideroblasts, which represent about 25% of patients overall, according to MDS expert David Steensma, MD, of Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts.

“It’s been 12 years since we had an FDA-approved drug in MDS, and there have been 7 in acute myeloid leukemia in the last year and a half, so it’s our turn, I think,” said Dr. Steensma, who moderated the press conference.

The Medalist study was sponsored by Celgene in collaboration with Acceleron Pharma, Inc.

Dr. List reported research funding from Celgene. 

© ASH/Scott Morgan 2018

SAN DIEGO—Results of the randomized, phase 3 Medalist trial show that the erythroid maturation agent luspatercept can reduce transfusion burden in patients with anemia due to myelodysplastic syndromes (MDS) and ring sideroblasts.

Almost 38% of luspatercept-treated patients achieved red blood cell (RBC) transfusion independence for 8 weeks or more, compared with 13% of patients receiving placebo.

And 28% of luspatercept-treated patients achieved transfusion independence for 12 weeks or more, compared to 8% in the placebo group.

Investigators reported these results as abstract 1 at the 2018 ASH Annual Meeting.

Treatment with luspatercept was “very well tolerated,” and responses were durable, with approximately 40% of patients remaining transfusion-free after 1 year of therapy, said senior investigator Alan F. List, MD, of Moffitt Cancer Center in Tampa, Florida, during a press conference at the meeting.

The first-in-class erythroid maturation agent is being developed as a treatment for anemia related to MDS and beta-thalassemia, Dr. List said.

“Luspatercept is a potential new therapy that we think could be very effective in patients with lower-risk MDS with ring sideroblasts who are red blood cell transfusion-dependent,” Dr. List affirmed.

Luspatercept is a soluble receptor chimera that binds to an array of ligands in the TGF-β superfamily, which is known to be very important in suppressing erythropoiesis in patients with MDS, Dr. List noted.

The Medalist study (NCT02631070) included patients with very low-, low-, or intermediate-risk disease and ring sideroblasts who were RBC transfusion-dependent and were refractory to, unresponsive to, or ineligible for first-line treatment with an erythropoiesis-stimulating agent (ESA).

A total of 153 patients were randomized to receive luspatercept at 1.0 mg/kg, administered subcutaneously every 21 days for at least 24 weeks, while 76 were randomized to placebo every 21 days.

The primary endpoint was the proportion of patients achieving RBC transfusion independence for at least 8 weeks during the first 24 weeks of treatment.

The primary endpoint was achieved by 37.9% of luspatercept-treated patients and 13.2% of placebo-treated patients (P<0.0001).

The luspatercept-treated patients also had a higher rate of erythroid response compared with the placebo group, at 52.9% and 11.8%, respectively (P<0.0001).

The investigators reported no differences in treatment-emergent adverse events, severe adverse events, or frequency of progression of acute myeloid leukemia (AML).

The safety profile was consistent with that of the phase 2 PACE-MDS study, which included treatment-related grade 3 myalgia (2%), increased blast cell count (2%), and general physical health deterioration (2%).

“This was a very clean drug and a very safe drug,” Dr. List said.

The decision to study luspatercept in patients with ring sideroblasts was based on results of the phase 2 PACE study showing a higher response rate in that subset of MDS patients, according to Dr. List.

The PACE study also included a small number of patients who had not previously received an ESA.

Currently underway is a phase 3 trial (NCT03682536) investigating luspatercept in ESA-naïve lower-risk MDS patients with anemia who require RBC transfusions.

Luspatercept would be a useful therapy to have in clinic for patients with ring sideroblasts, which represent about 25% of patients overall, according to MDS expert David Steensma, MD, of Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts.

“It’s been 12 years since we had an FDA-approved drug in MDS, and there have been 7 in acute myeloid leukemia in the last year and a half, so it’s our turn, I think,” said Dr. Steensma, who moderated the press conference.

The Medalist study was sponsored by Celgene in collaboration with Acceleron Pharma, Inc.

Dr. List reported research funding from Celgene. 

© ASH/Scott Morgan 2018

SAN DIEGO—Results of the randomized, phase 3 Medalist trial show that the erythroid maturation agent luspatercept can reduce transfusion burden in patients with anemia due to myelodysplastic syndromes (MDS) and ring sideroblasts.

Almost 38% of luspatercept-treated patients achieved red blood cell (RBC) transfusion independence for 8 weeks or more, compared with 13% of patients receiving placebo.

And 28% of luspatercept-treated patients achieved transfusion independence for 12 weeks or more, compared to 8% in the placebo group.

Investigators reported these results as abstract 1 at the 2018 ASH Annual Meeting.

Treatment with luspatercept was “very well tolerated,” and responses were durable, with approximately 40% of patients remaining transfusion-free after 1 year of therapy, said senior investigator Alan F. List, MD, of Moffitt Cancer Center in Tampa, Florida, during a press conference at the meeting.

The first-in-class erythroid maturation agent is being developed as a treatment for anemia related to MDS and beta-thalassemia, Dr. List said.

“Luspatercept is a potential new therapy that we think could be very effective in patients with lower-risk MDS with ring sideroblasts who are red blood cell transfusion-dependent,” Dr. List affirmed.

Luspatercept is a soluble receptor chimera that binds to an array of ligands in the TGF-β superfamily, which is known to be very important in suppressing erythropoiesis in patients with MDS, Dr. List noted.

The Medalist study (NCT02631070) included patients with very low-, low-, or intermediate-risk disease and ring sideroblasts who were RBC transfusion-dependent and were refractory to, unresponsive to, or ineligible for first-line treatment with an erythropoiesis-stimulating agent (ESA).

A total of 153 patients were randomized to receive luspatercept at 1.0 mg/kg, administered subcutaneously every 21 days for at least 24 weeks, while 76 were randomized to placebo every 21 days.

The primary endpoint was the proportion of patients achieving RBC transfusion independence for at least 8 weeks during the first 24 weeks of treatment.

The primary endpoint was achieved by 37.9% of luspatercept-treated patients and 13.2% of placebo-treated patients (P<0.0001).

The luspatercept-treated patients also had a higher rate of erythroid response compared with the placebo group, at 52.9% and 11.8%, respectively (P<0.0001).

The investigators reported no differences in treatment-emergent adverse events, severe adverse events, or frequency of progression of acute myeloid leukemia (AML).

The safety profile was consistent with that of the phase 2 PACE-MDS study, which included treatment-related grade 3 myalgia (2%), increased blast cell count (2%), and general physical health deterioration (2%).

“This was a very clean drug and a very safe drug,” Dr. List said.

The decision to study luspatercept in patients with ring sideroblasts was based on results of the phase 2 PACE study showing a higher response rate in that subset of MDS patients, according to Dr. List.

The PACE study also included a small number of patients who had not previously received an ESA.

Currently underway is a phase 3 trial (NCT03682536) investigating luspatercept in ESA-naïve lower-risk MDS patients with anemia who require RBC transfusions.

Luspatercept would be a useful therapy to have in clinic for patients with ring sideroblasts, which represent about 25% of patients overall, according to MDS expert David Steensma, MD, of Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts.

“It’s been 12 years since we had an FDA-approved drug in MDS, and there have been 7 in acute myeloid leukemia in the last year and a half, so it’s our turn, I think,” said Dr. Steensma, who moderated the press conference.

The Medalist study was sponsored by Celgene in collaboration with Acceleron Pharma, Inc.

Dr. List reported research funding from Celgene. 

Image by Kevin MacKenzie

The American Society of Hematology (ASH) has released a new set of guidelines for the prevention, diagnosis, and management of venous thromboembolism (VTE).

The new guidelines contain more than 150 individual recommendations, including sections devoted to managing VTE during pregnancy and in pediatric patients.

Guideline highlights cited by some of the writing panel include a high reliance on low-molecular-weight heparin (LMWH) as the preferred treatment for many patients, reliance on the D-dimer test to rule out VTE in patients with a low pretest probability of disease, and reliance on the 4Ts score to identify patients with heparin-induced thrombocytopenia.

An updated set of VTE guidelines were needed because clinicians now have a “greater understanding of risk factors” for VTE as well as having “more options available for treating VTE, including new medications,” Adam C. Cuker, MD, of the University of Pennsylvania in Philadelphia and co-chair of the guideline-writing group, said during a webcast to unveil the new guidelines.

The guidelines, released on November 27, took more than 3 years to develop, an effort that began in 2015.

Prevention

For preventing VTE in hospitalized medical patients, the guidelines recommend initial assessment of the patient’s risk for both VTE and bleeding.

Patients with a high bleeding risk who need VTE prevention should preferentially receive mechanical prophylaxis, either compression stockings or pneumatic sleeves.

But in patients with a high VTE risk and an “acceptable” bleeding risk, prophylaxis with an anticoagulant is preferred over mechanical measures, said Mary Cushman, MD, of the University of Vermont in Burlington and member of the guideline writing group.

For prevention of VTE in medical inpatients, LMWH is preferred over unfractionated heparin because of its once-daily dosing and fewer complications, Dr. Cushman said.

The panel also endorsed LMWH over a direct-acting oral anticoagulant (DOAC), both during hospitalization and following discharge.

The guidelines for prevention in medical patients explicitly “recommended against” using a DOAC “over other treatments” both for hospitalized medical patients and after discharge. The guidelines further recommend against extended prophylaxis after discharge with any other anticoagulant.

Another important take-away from the prevention section is a statement that combining both mechanical and medical prophylaxis is not needed for medical inpatients.

And once patients are discharged, they have no need for compression stockings or aspirin on a long plane trip if their risk for thrombosis is not elevated.

People with a “substantially increased” thrombosis risk “may benefit” from compression stockings or treatment with LMWH, Dr. Cushman said.

Diagnosis

For diagnosis, Wendy Lim, MD, of McMaster University in Hamilton, Ontario, Canada, highlighted the need for first categorizing patients as having a low or high probability for VTE, a judgment that can aid the accuracy of the diagnosis and that helps avoid unnecessary testing.

For patients with low pretest probability, the guidelines recommend the D-dimer test as the best first step. Further testing isn’t needed when the D-dimer is negative, Dr. Lim noted.

The guidelines also recommend using ventilation-perfusion scintigraphy (V/Q scan) for imaging a pulmonary embolism over a CT scan, which uses more radiation. But V/Q scans are not ideal for assessing older patients or patients with lung disease, Dr. Lim cautioned.

Management

Management of VTE should occur, when feasible, through a specialized anticoagulation management service center, which can provide care that is best suited to the complexities of anticoagulation therapy.

But it’s a level of care that many U.S. patients don’t currently receive and, hence, is an area ripe for growth, said Daniel M. Witt, PharmD, of the University of Utah in Salt Lake City.

The guidelines recommend against bridging therapy with LMWH for most patients who need to stop warfarin when undergoing an invasive procedure.

The guidelines also call for “thoughtful” use of anticoagulant reversal agents, and they advise that patients who survive a major bleed while on anticoagulation should often resume the anticoagulant once they are stabilized.

For patients who develop heparin-induced thrombocytopenia, the 4Ts score is the best way to make a more accurate diagnosis and boost the prospects for recovery, according to Dr. Cuker, lead author of a paper on the subject published in Blood.

The guidelines cite several agents now available to treat this common complication, which affects about 1% of the 12 million Americans treated each year with heparin, argatroban, bivalirudin, danaparoid, fondaparinux, apixaban, dabigatran, edoxaban, and rivaroxaban.

ASH has a VTE website with links to detailed information for each of the guideline subcategories: prophylaxis for medical patients, diagnosis, anticoagulation therapy, heparin-induced thrombocytopenia, VTE in pregnancy, and VTE in children.

The website indicates that additional guidelines will soon be released on managing VTE in patients with cancer, in patients with thrombophilia, and for prophylaxis in surgical patients, as well as further information on treatment. A spokesperson for ASH said these additional documents will post sometime in 2019.

At the time of the release, the guidelines panel published the following six articles in the journal Blood Advances that detail the guidelines and their documentation relating to VTE and:

• Prophylaxis
• Diagnosis
• Anticoagulation
• Heparin-induced thrombocytopenia
• Pregnancy
• Pediatrics

Drs. Cushman, Lim, and Witt reported having no relevant disclosures. Dr. Cuker reported receiving research support from T2 Biosystems. 

Image by Kevin MacKenzie

The American Society of Hematology (ASH) has released a new set of guidelines for the prevention, diagnosis, and management of venous thromboembolism (VTE).

The new guidelines contain more than 150 individual recommendations, including sections devoted to managing VTE during pregnancy and in pediatric patients.

Guideline highlights cited by some of the writing panel include a high reliance on low-molecular-weight heparin (LMWH) as the preferred treatment for many patients, reliance on the D-dimer test to rule out VTE in patients with a low pretest probability of disease, and reliance on the 4Ts score to identify patients with heparin-induced thrombocytopenia.

An updated set of VTE guidelines were needed because clinicians now have a “greater understanding of risk factors” for VTE as well as having “more options available for treating VTE, including new medications,” Adam C. Cuker, MD, of the University of Pennsylvania in Philadelphia and co-chair of the guideline-writing group, said during a webcast to unveil the new guidelines.

The guidelines, released on November 27, took more than 3 years to develop, an effort that began in 2015.

Prevention

For preventing VTE in hospitalized medical patients, the guidelines recommend initial assessment of the patient’s risk for both VTE and bleeding.

Patients with a high bleeding risk who need VTE prevention should preferentially receive mechanical prophylaxis, either compression stockings or pneumatic sleeves.

But in patients with a high VTE risk and an “acceptable” bleeding risk, prophylaxis with an anticoagulant is preferred over mechanical measures, said Mary Cushman, MD, of the University of Vermont in Burlington and member of the guideline writing group.

For prevention of VTE in medical inpatients, LMWH is preferred over unfractionated heparin because of its once-daily dosing and fewer complications, Dr. Cushman said.

The panel also endorsed LMWH over a direct-acting oral anticoagulant (DOAC), both during hospitalization and following discharge.

The guidelines for prevention in medical patients explicitly “recommended against” using a DOAC “over other treatments” both for hospitalized medical patients and after discharge. The guidelines further recommend against extended prophylaxis after discharge with any other anticoagulant.

Another important take-away from the prevention section is a statement that combining both mechanical and medical prophylaxis is not needed for medical inpatients.

And once patients are discharged, they have no need for compression stockings or aspirin on a long plane trip if their risk for thrombosis is not elevated.

People with a “substantially increased” thrombosis risk “may benefit” from compression stockings or treatment with LMWH, Dr. Cushman said.

Diagnosis

For diagnosis, Wendy Lim, MD, of McMaster University in Hamilton, Ontario, Canada, highlighted the need for first categorizing patients as having a low or high probability for VTE, a judgment that can aid the accuracy of the diagnosis and that helps avoid unnecessary testing.

For patients with low pretest probability, the guidelines recommend the D-dimer test as the best first step. Further testing isn’t needed when the D-dimer is negative, Dr. Lim noted.

The guidelines also recommend using ventilation-perfusion scintigraphy (V/Q scan) for imaging a pulmonary embolism over a CT scan, which uses more radiation. But V/Q scans are not ideal for assessing older patients or patients with lung disease, Dr. Lim cautioned.

Management

Management of VTE should occur, when feasible, through a specialized anticoagulation management service center, which can provide care that is best suited to the complexities of anticoagulation therapy.

But it’s a level of care that many U.S. patients don’t currently receive and, hence, is an area ripe for growth, said Daniel M. Witt, PharmD, of the University of Utah in Salt Lake City.

The guidelines recommend against bridging therapy with LMWH for most patients who need to stop warfarin when undergoing an invasive procedure.

The guidelines also call for “thoughtful” use of anticoagulant reversal agents, and they advise that patients who survive a major bleed while on anticoagulation should often resume the anticoagulant once they are stabilized.

For patients who develop heparin-induced thrombocytopenia, the 4Ts score is the best way to make a more accurate diagnosis and boost the prospects for recovery, according to Dr. Cuker, lead author of a paper on the subject published in Blood.

The guidelines cite several agents now available to treat this common complication, which affects about 1% of the 12 million Americans treated each year with heparin, argatroban, bivalirudin, danaparoid, fondaparinux, apixaban, dabigatran, edoxaban, and rivaroxaban.

ASH has a VTE website with links to detailed information for each of the guideline subcategories: prophylaxis for medical patients, diagnosis, anticoagulation therapy, heparin-induced thrombocytopenia, VTE in pregnancy, and VTE in children.

The website indicates that additional guidelines will soon be released on managing VTE in patients with cancer, in patients with thrombophilia, and for prophylaxis in surgical patients, as well as further information on treatment. A spokesperson for ASH said these additional documents will post sometime in 2019.

At the time of the release, the guidelines panel published the following six articles in the journal Blood Advances that detail the guidelines and their documentation relating to VTE and:

• Prophylaxis
• Diagnosis
• Anticoagulation
• Heparin-induced thrombocytopenia
• Pregnancy
• Pediatrics

Drs. Cushman, Lim, and Witt reported having no relevant disclosures. Dr. Cuker reported receiving research support from T2 Biosystems. 

Image by Kevin MacKenzie

The American Society of Hematology (ASH) has released a new set of guidelines for the prevention, diagnosis, and management of venous thromboembolism (VTE).

The new guidelines contain more than 150 individual recommendations, including sections devoted to managing VTE during pregnancy and in pediatric patients.

Guideline highlights cited by some of the writing panel include a high reliance on low-molecular-weight heparin (LMWH) as the preferred treatment for many patients, reliance on the D-dimer test to rule out VTE in patients with a low pretest probability of disease, and reliance on the 4Ts score to identify patients with heparin-induced thrombocytopenia.

An updated set of VTE guidelines were needed because clinicians now have a “greater understanding of risk factors” for VTE as well as having “more options available for treating VTE, including new medications,” Adam C. Cuker, MD, of the University of Pennsylvania in Philadelphia and co-chair of the guideline-writing group, said during a webcast to unveil the new guidelines.

The guidelines, released on November 27, took more than 3 years to develop, an effort that began in 2015.

Prevention

For preventing VTE in hospitalized medical patients, the guidelines recommend initial assessment of the patient’s risk for both VTE and bleeding.

Patients with a high bleeding risk who need VTE prevention should preferentially receive mechanical prophylaxis, either compression stockings or pneumatic sleeves.

But in patients with a high VTE risk and an “acceptable” bleeding risk, prophylaxis with an anticoagulant is preferred over mechanical measures, said Mary Cushman, MD, of the University of Vermont in Burlington and member of the guideline writing group.

For prevention of VTE in medical inpatients, LMWH is preferred over unfractionated heparin because of its once-daily dosing and fewer complications, Dr. Cushman said.

The panel also endorsed LMWH over a direct-acting oral anticoagulant (DOAC), both during hospitalization and following discharge.

The guidelines for prevention in medical patients explicitly “recommended against” using a DOAC “over other treatments” both for hospitalized medical patients and after discharge. The guidelines further recommend against extended prophylaxis after discharge with any other anticoagulant.

Another important take-away from the prevention section is a statement that combining both mechanical and medical prophylaxis is not needed for medical inpatients.

And once patients are discharged, they have no need for compression stockings or aspirin on a long plane trip if their risk for thrombosis is not elevated.

People with a “substantially increased” thrombosis risk “may benefit” from compression stockings or treatment with LMWH, Dr. Cushman said.

Diagnosis

For diagnosis, Wendy Lim, MD, of McMaster University in Hamilton, Ontario, Canada, highlighted the need for first categorizing patients as having a low or high probability for VTE, a judgment that can aid the accuracy of the diagnosis and that helps avoid unnecessary testing.

For patients with low pretest probability, the guidelines recommend the D-dimer test as the best first step. Further testing isn’t needed when the D-dimer is negative, Dr. Lim noted.

The guidelines also recommend using ventilation-perfusion scintigraphy (V/Q scan) for imaging a pulmonary embolism over a CT scan, which uses more radiation. But V/Q scans are not ideal for assessing older patients or patients with lung disease, Dr. Lim cautioned.

Management

Management of VTE should occur, when feasible, through a specialized anticoagulation management service center, which can provide care that is best suited to the complexities of anticoagulation therapy.

But it’s a level of care that many U.S. patients don’t currently receive and, hence, is an area ripe for growth, said Daniel M. Witt, PharmD, of the University of Utah in Salt Lake City.

The guidelines recommend against bridging therapy with LMWH for most patients who need to stop warfarin when undergoing an invasive procedure.

The guidelines also call for “thoughtful” use of anticoagulant reversal agents, and they advise that patients who survive a major bleed while on anticoagulation should often resume the anticoagulant once they are stabilized.

For patients who develop heparin-induced thrombocytopenia, the 4Ts score is the best way to make a more accurate diagnosis and boost the prospects for recovery, according to Dr. Cuker, lead author of a paper on the subject published in Blood.

The guidelines cite several agents now available to treat this common complication, which affects about 1% of the 12 million Americans treated each year with heparin, argatroban, bivalirudin, danaparoid, fondaparinux, apixaban, dabigatran, edoxaban, and rivaroxaban.

ASH has a VTE website with links to detailed information for each of the guideline subcategories: prophylaxis for medical patients, diagnosis, anticoagulation therapy, heparin-induced thrombocytopenia, VTE in pregnancy, and VTE in children.

The website indicates that additional guidelines will soon be released on managing VTE in patients with cancer, in patients with thrombophilia, and for prophylaxis in surgical patients, as well as further information on treatment. A spokesperson for ASH said these additional documents will post sometime in 2019.

At the time of the release, the guidelines panel published the following six articles in the journal Blood Advances that detail the guidelines and their documentation relating to VTE and:

• Prophylaxis
• Diagnosis
• Anticoagulation
• Heparin-induced thrombocytopenia
• Pregnancy
• Pediatrics

Drs. Cushman, Lim, and Witt reported having no relevant disclosures. Dr. Cuker reported receiving research support from T2 Biosystems. 

Recently, the Association of American Medical Colleges (AAMC) reiterated its projection of a physician shortage in the United States, predicting a shortfall of up to 121,300 physicians by 2030. The shortage would affect primary care as well as medical and surgical specialties. These projections are consistent with prior estimates and, AAMC says, take into account both utilization of NPs and PAs and future changes in how care is delivered.¹

However, other entities have suggested we are misinterpreting the situation. The Institute of Medicine (IOM) has argued that there is no physician shortage. According to their analysis, the health care system isn’t undermanned—rather, it’s inefficient and relies too heavily on physicians and not enough on advanced practice providers. Furthermore, the IOM posits that many of the studies upon which physician workforce projections have been based fail to account for advances in medicine and technology that impact care delivery: telehealth, new medications, and medical devices that give patients a more active role in their health maintenance.²

Who’s right? You might say, “Who cares?” but this isn’t simply a matter of institutional reputation; the data have informed action plans for offsetting the projected shortage. Since 2002, medical schools have increased class sizes by 30% and are working to ensure that the supply of physicians will be sufficient to meet future needs—even though funding for residency training has been frozen since 1997. At the same time, many thought leaders—including the IOM—have recognized NPs and PAs as significant contributors to the health care workforce. In 2007, for example, Cooper called on the NP and PA professions to expand their training capacity, predicting that neither would have a supply of practitioners to meet needs in the event of a physician shortage.³

Both professions took that message to heart. There are now more than 123,000 certified PAs (70% of whom work in specialty practice) and 248,000 licensed NPs (87% in primary care) in the United States.^4,5 There are 239 accredited PA programs (including those with provisional or probationary status), with the number of new graduates per year expected to reach 18,000 by 2026 (compared to 9,000 in 2018).^6,7 There are about 400 academic institutions in the US that have an NP program; in 2016-2017, more than 26,000 new graduates completed their training.^5,8 Overall, the Bureau of Labor Statistics projects that by 2024 the NP profession will have grown by 36%, the PA profession by 37%, and the physician population by 13% (excluding anesthesiologists and surgeons).⁹

There is no argument that NPs and PAs are making an enormous impact on the quality and accessibility of health care in this country. But I am starting to hear rumblings that we may be educating too many NPs and PAs—especially if the physician shortage is not as dire as predicted.

This entire conversation takes me back to the 1970s, when the Graduate Medical Education National Advisory Committee (GMENAC) projected a surplus of physicians, and a moratorium was placed on medical school enrollment. Those projections were validated and repeated through the 1990s; in fact, the aforementioned Cooper was among the first to flip the message around, using new calculations and considerations to project a physician shortage.¹⁰

GMENAC is a classic example of what happens when people and entities overreact to a projection of some kind. If there is a physician shortage today, GMENAC is probably partly responsible because their prediction of an oversupply triggered an arguably over-the-top response. Everyone worked so hard to avoid a surplus that they are creating a deficit!

Continue to: As I listen to...

As I listen to those rumblings of “too many NPs and PAs,” I wonder if this is a mirror to that GMENAC response. Have the NP and PA professions worked so hard to offset the physician shortage (real or imagined) that we may face a glut of NPs and PAs? If so, the concern is that within five to 10 years, we won’t have employment opportunities for all of them. That’s the fear driving these whispers, isn’t it?

As far back as 2000—when this conversation was in its infancy—Dehn and Cawley discussed the consequences of expanding the supply of NPs and PAs. They questioned how the number of, and demand for, NPs and PAs would be balanced in America’s future health care marketplace and wondered if a sharp growth in NP and PA graduates (in conjunction with similar increases in other health professions) could surpass demand and prompt an oversupply, resulting in underemployment and market saturation.¹¹

So, is it time to pause and take another look at the numbers and needs? Maybe. But I believe one of the aspects we must continue to focus on is the quality of our professions. In the wake of the projected physician shortage, the NP profession developed its Doctor of Nursing Practice and the PA profession added postgraduate training opportunities in specific specialties. These not only enhance NPs’ and PAs’ professional credentials—they equip us to provide better patient care. At the end of the day, our ability to care for patients will be the rubric upon which we are judged.

We’ve already been making the case for our professions and gaining recognition throughout this process. When Salsberg wrote about the physician shortage in Health Affairs (2015), he reminded us that a critical factor is the supply and availability of clinicians other than physicians (NPs, PAs, midwives) who can make a significant contribution to access and efficiency of health care. He called for NPs and PAs to be fully integrated into the delivery system and to be allowed scope of practice consistent with their education and training.⁷

Continue to: Both NPs and PAs have become...

Both NPs and PAs have become participants in dialogues on health policy and health care reform. Both professions are spending increasing dollars on national advertising to raise awareness of their critical role in expanding access to primary care for millions of Americans. In fact, Princeton University Professor of Economics Uwe E. Reinhardt told the New York Times, “The doctors are fighting a losing battle. The nurses are like insurgents. They are occasionally beaten back, but they’ll win in the long run. They have economics and common sense on their side.”¹² Some suggest that PAs need to fight a similar battle.

So, dear reader, what do you think? Should we be concerned that we are educating too many NPs and PAs? Does that argument become somewhat irrelevant if we can firmly establish a substantial role for ourselves in the future of health care? I would love to hear your thoughts; email me at PAeditor@mdedge.com.

Recently, the Association of American Medical Colleges (AAMC) reiterated its projection of a physician shortage in the United States, predicting a shortfall of up to 121,300 physicians by 2030. The shortage would affect primary care as well as medical and surgical specialties. These projections are consistent with prior estimates and, AAMC says, take into account both utilization of NPs and PAs and future changes in how care is delivered.¹

However, other entities have suggested we are misinterpreting the situation. The Institute of Medicine (IOM) has argued that there is no physician shortage. According to their analysis, the health care system isn’t undermanned—rather, it’s inefficient and relies too heavily on physicians and not enough on advanced practice providers. Furthermore, the IOM posits that many of the studies upon which physician workforce projections have been based fail to account for advances in medicine and technology that impact care delivery: telehealth, new medications, and medical devices that give patients a more active role in their health maintenance.²

Who’s right? You might say, “Who cares?” but this isn’t simply a matter of institutional reputation; the data have informed action plans for offsetting the projected shortage. Since 2002, medical schools have increased class sizes by 30% and are working to ensure that the supply of physicians will be sufficient to meet future needs—even though funding for residency training has been frozen since 1997. At the same time, many thought leaders—including the IOM—have recognized NPs and PAs as significant contributors to the health care workforce. In 2007, for example, Cooper called on the NP and PA professions to expand their training capacity, predicting that neither would have a supply of practitioners to meet needs in the event of a physician shortage.³

Both professions took that message to heart. There are now more than 123,000 certified PAs (70% of whom work in specialty practice) and 248,000 licensed NPs (87% in primary care) in the United States.^4,5 There are 239 accredited PA programs (including those with provisional or probationary status), with the number of new graduates per year expected to reach 18,000 by 2026 (compared to 9,000 in 2018).^6,7 There are about 400 academic institutions in the US that have an NP program; in 2016-2017, more than 26,000 new graduates completed their training.^5,8 Overall, the Bureau of Labor Statistics projects that by 2024 the NP profession will have grown by 36%, the PA profession by 37%, and the physician population by 13% (excluding anesthesiologists and surgeons).⁹

There is no argument that NPs and PAs are making an enormous impact on the quality and accessibility of health care in this country. But I am starting to hear rumblings that we may be educating too many NPs and PAs—especially if the physician shortage is not as dire as predicted.

This entire conversation takes me back to the 1970s, when the Graduate Medical Education National Advisory Committee (GMENAC) projected a surplus of physicians, and a moratorium was placed on medical school enrollment. Those projections were validated and repeated through the 1990s; in fact, the aforementioned Cooper was among the first to flip the message around, using new calculations and considerations to project a physician shortage.¹⁰

GMENAC is a classic example of what happens when people and entities overreact to a projection of some kind. If there is a physician shortage today, GMENAC is probably partly responsible because their prediction of an oversupply triggered an arguably over-the-top response. Everyone worked so hard to avoid a surplus that they are creating a deficit!

Continue to: As I listen to...

As I listen to those rumblings of “too many NPs and PAs,” I wonder if this is a mirror to that GMENAC response. Have the NP and PA professions worked so hard to offset the physician shortage (real or imagined) that we may face a glut of NPs and PAs? If so, the concern is that within five to 10 years, we won’t have employment opportunities for all of them. That’s the fear driving these whispers, isn’t it?

As far back as 2000—when this conversation was in its infancy—Dehn and Cawley discussed the consequences of expanding the supply of NPs and PAs. They questioned how the number of, and demand for, NPs and PAs would be balanced in America’s future health care marketplace and wondered if a sharp growth in NP and PA graduates (in conjunction with similar increases in other health professions) could surpass demand and prompt an oversupply, resulting in underemployment and market saturation.¹¹

So, is it time to pause and take another look at the numbers and needs? Maybe. But I believe one of the aspects we must continue to focus on is the quality of our professions. In the wake of the projected physician shortage, the NP profession developed its Doctor of Nursing Practice and the PA profession added postgraduate training opportunities in specific specialties. These not only enhance NPs’ and PAs’ professional credentials—they equip us to provide better patient care. At the end of the day, our ability to care for patients will be the rubric upon which we are judged.

We’ve already been making the case for our professions and gaining recognition throughout this process. When Salsberg wrote about the physician shortage in Health Affairs (2015), he reminded us that a critical factor is the supply and availability of clinicians other than physicians (NPs, PAs, midwives) who can make a significant contribution to access and efficiency of health care. He called for NPs and PAs to be fully integrated into the delivery system and to be allowed scope of practice consistent with their education and training.⁷

Continue to: Both NPs and PAs have become...

Both NPs and PAs have become participants in dialogues on health policy and health care reform. Both professions are spending increasing dollars on national advertising to raise awareness of their critical role in expanding access to primary care for millions of Americans. In fact, Princeton University Professor of Economics Uwe E. Reinhardt told the New York Times, “The doctors are fighting a losing battle. The nurses are like insurgents. They are occasionally beaten back, but they’ll win in the long run. They have economics and common sense on their side.”¹² Some suggest that PAs need to fight a similar battle.

So, dear reader, what do you think? Should we be concerned that we are educating too many NPs and PAs? Does that argument become somewhat irrelevant if we can firmly establish a substantial role for ourselves in the future of health care? I would love to hear your thoughts; email me at PAeditor@mdedge.com.

Recently, the Association of American Medical Colleges (AAMC) reiterated its projection of a physician shortage in the United States, predicting a shortfall of up to 121,300 physicians by 2030. The shortage would affect primary care as well as medical and surgical specialties. These projections are consistent with prior estimates and, AAMC says, take into account both utilization of NPs and PAs and future changes in how care is delivered.¹

However, other entities have suggested we are misinterpreting the situation. The Institute of Medicine (IOM) has argued that there is no physician shortage. According to their analysis, the health care system isn’t undermanned—rather, it’s inefficient and relies too heavily on physicians and not enough on advanced practice providers. Furthermore, the IOM posits that many of the studies upon which physician workforce projections have been based fail to account for advances in medicine and technology that impact care delivery: telehealth, new medications, and medical devices that give patients a more active role in their health maintenance.²

Who’s right? You might say, “Who cares?” but this isn’t simply a matter of institutional reputation; the data have informed action plans for offsetting the projected shortage. Since 2002, medical schools have increased class sizes by 30% and are working to ensure that the supply of physicians will be sufficient to meet future needs—even though funding for residency training has been frozen since 1997. At the same time, many thought leaders—including the IOM—have recognized NPs and PAs as significant contributors to the health care workforce. In 2007, for example, Cooper called on the NP and PA professions to expand their training capacity, predicting that neither would have a supply of practitioners to meet needs in the event of a physician shortage.³

Both professions took that message to heart. There are now more than 123,000 certified PAs (70% of whom work in specialty practice) and 248,000 licensed NPs (87% in primary care) in the United States.^4,5 There are 239 accredited PA programs (including those with provisional or probationary status), with the number of new graduates per year expected to reach 18,000 by 2026 (compared to 9,000 in 2018).^6,7 There are about 400 academic institutions in the US that have an NP program; in 2016-2017, more than 26,000 new graduates completed their training.^5,8 Overall, the Bureau of Labor Statistics projects that by 2024 the NP profession will have grown by 36%, the PA profession by 37%, and the physician population by 13% (excluding anesthesiologists and surgeons).⁹

There is no argument that NPs and PAs are making an enormous impact on the quality and accessibility of health care in this country. But I am starting to hear rumblings that we may be educating too many NPs and PAs—especially if the physician shortage is not as dire as predicted.

This entire conversation takes me back to the 1970s, when the Graduate Medical Education National Advisory Committee (GMENAC) projected a surplus of physicians, and a moratorium was placed on medical school enrollment. Those projections were validated and repeated through the 1990s; in fact, the aforementioned Cooper was among the first to flip the message around, using new calculations and considerations to project a physician shortage.¹⁰

GMENAC is a classic example of what happens when people and entities overreact to a projection of some kind. If there is a physician shortage today, GMENAC is probably partly responsible because their prediction of an oversupply triggered an arguably over-the-top response. Everyone worked so hard to avoid a surplus that they are creating a deficit!

Continue to: As I listen to...

As I listen to those rumblings of “too many NPs and PAs,” I wonder if this is a mirror to that GMENAC response. Have the NP and PA professions worked so hard to offset the physician shortage (real or imagined) that we may face a glut of NPs and PAs? If so, the concern is that within five to 10 years, we won’t have employment opportunities for all of them. That’s the fear driving these whispers, isn’t it?

As far back as 2000—when this conversation was in its infancy—Dehn and Cawley discussed the consequences of expanding the supply of NPs and PAs. They questioned how the number of, and demand for, NPs and PAs would be balanced in America’s future health care marketplace and wondered if a sharp growth in NP and PA graduates (in conjunction with similar increases in other health professions) could surpass demand and prompt an oversupply, resulting in underemployment and market saturation.¹¹

So, is it time to pause and take another look at the numbers and needs? Maybe. But I believe one of the aspects we must continue to focus on is the quality of our professions. In the wake of the projected physician shortage, the NP profession developed its Doctor of Nursing Practice and the PA profession added postgraduate training opportunities in specific specialties. These not only enhance NPs’ and PAs’ professional credentials—they equip us to provide better patient care. At the end of the day, our ability to care for patients will be the rubric upon which we are judged.

We’ve already been making the case for our professions and gaining recognition throughout this process. When Salsberg wrote about the physician shortage in Health Affairs (2015), he reminded us that a critical factor is the supply and availability of clinicians other than physicians (NPs, PAs, midwives) who can make a significant contribution to access and efficiency of health care. He called for NPs and PAs to be fully integrated into the delivery system and to be allowed scope of practice consistent with their education and training.⁷

Continue to: Both NPs and PAs have become...

Both NPs and PAs have become participants in dialogues on health policy and health care reform. Both professions are spending increasing dollars on national advertising to raise awareness of their critical role in expanding access to primary care for millions of Americans. In fact, Princeton University Professor of Economics Uwe E. Reinhardt told the New York Times, “The doctors are fighting a losing battle. The nurses are like insurgents. They are occasionally beaten back, but they’ll win in the long run. They have economics and common sense on their side.”¹² Some suggest that PAs need to fight a similar battle.

So, dear reader, what do you think? Should we be concerned that we are educating too many NPs and PAs? Does that argument become somewhat irrelevant if we can firmly establish a substantial role for ourselves in the future of health care? I would love to hear your thoughts; email me at PAeditor@mdedge.com.

The September 2018 Practice Alert, “CDC recommendations for the 2018-2019 influenza season” contained an error (J Fam Pract. 2018. 67:550-553). On page 552, under “Available vaccine products,” the article listed “one standard dose IIV4 intradermal option.” This was incorrect. Sanofi Pasteur, the manufacturer of standard dose Intradermal IIV4, discontinued the production and supply of Fluzone Intradermal Quadrivalent vaccine at the conclusion of the 2017-2018 influenza season.

The September 2018 Practice Alert, “CDC recommendations for the 2018-2019 influenza season” contained an error (J Fam Pract. 2018. 67:550-553). On page 552, under “Available vaccine products,” the article listed “one standard dose IIV4 intradermal option.” This was incorrect. Sanofi Pasteur, the manufacturer of standard dose Intradermal IIV4, discontinued the production and supply of Fluzone Intradermal Quadrivalent vaccine at the conclusion of the 2017-2018 influenza season.

The September 2018 Practice Alert, “CDC recommendations for the 2018-2019 influenza season” contained an error (J Fam Pract. 2018. 67:550-553). On page 552, under “Available vaccine products,” the article listed “one standard dose IIV4 intradermal option.” This was incorrect. Sanofi Pasteur, the manufacturer of standard dose Intradermal IIV4, discontinued the production and supply of Fluzone Intradermal Quadrivalent vaccine at the conclusion of the 2017-2018 influenza season.

In the Clinical Inquiry, “Does prophylactic azithromycin reduce the number of COPD exacerbations or hospitalizations?” (J Fam Pract. 2018;67:384-385), Lyon et al state that azithromycin “doesn’t benefit patients ≤65 years, patients with GOLD [Global Initiative for Obstructive Lung Disease] stage IV COPD [chronic obstructive pulmonary disease], current smokers, or patients not using oxygen (strength of recommendation [SOR]: B, randomized controlled trials [RCTs]).” These categorical statements are misleading, and clinicians should ignore most of them when considering azithromycin for their patients with severe COPD.

It would be more accurate to say that there may be a diminished efficacy of azithromycin for patients with GOLD IV COPD and age ≤65 years.

The authors cited groups that were identified in a posthoc analysis¹ of the only large trial involving azithromycin for the treatment of COPD to date.²P values for the interaction of azithromycin with GOLD stage (P=.04), smoking (P=.03), and age (P=.02) were significant, but the mean effects (hazard ratios [HRs]) for GOLD stage IV, smoking, and age ≤65 were .84, .99, and .84, respectively. It would be more accurate to say that there may be a diminished efficacy of azithromycin for patients with GOLD IV COPD and age ≤65 years. Only smokers appear to show no response, although the lower end of the 95% confidence interval was 0.71. The P value for the interaction of azithromycin with no long-term oxygen use (P=.23) was not significant, and it is incorrect to infer that oxygen use or nonuse predicts response.

The authors correctly state that the “significance of the results is limited because the study was not originally powered for this level of subgroup analysis,” but this statement is buried later in the article.

David L. Hahn, MD, MS
Madison, Wis

1. Han MK, Tayob N, Murray S, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med. 2014;189:1503-1508.

2. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689-698.

Continue to: Author's response...

Author’s response:

Your statement that the evidence-based answer regarding the lack of benefit of azithromycin in patients ≤65 years of age, with stage IV COPD, current smokers, and patients not using oxygen is “misleading” is a bit of an overstatement.

It is fair to say, however, that our statement regarding lack of efficacy among these subgroups of patients should be softened a bit since the data are from subgroup analyses, which should never be the source of definitive conclusions. And you point out that the 95% confidence intervals [CIs] of the HRs for these subgroups of patients do not include a potentially significant effect (0.68, 0.71, 0.61, and 0.65, respectively), so it is possible there is a Type II error, which would lead one to conclude there is no effect for these subgroups when there is one.

Regarding oxygen therapy, in this Clinical Inquiry, we presented data from the direct subgroup analysis, which revealed no difference in COPD exacerbations between the azithromycin and placebo groups for patients not receiving long-term supplemental oxygen (HR=0.80; 95% CI, 0.62-1.03); however, you are correct to point out that the oxygen use subgroup interaction (patients on oxygen vs patients not on oxygen), which we did not include in this Clinical Inquiry, did not reach significance (P=.23), casting some doubt on the authors’ conclusion of no effect for patients not on oxygen.

On the whole, I feel this Clinical Inquiry accurately summarized the existing evidence and that additional research is needed to better define the utility of azithromycin in these subgroups of patients.

Corey Lyon, DO
Denver, Colo

In the Clinical Inquiry, “Does prophylactic azithromycin reduce the number of COPD exacerbations or hospitalizations?” (J Fam Pract. 2018;67:384-385), Lyon et al state that azithromycin “doesn’t benefit patients ≤65 years, patients with GOLD [Global Initiative for Obstructive Lung Disease] stage IV COPD [chronic obstructive pulmonary disease], current smokers, or patients not using oxygen (strength of recommendation [SOR]: B, randomized controlled trials [RCTs]).” These categorical statements are misleading, and clinicians should ignore most of them when considering azithromycin for their patients with severe COPD.

It would be more accurate to say that there may be a diminished efficacy of azithromycin for patients with GOLD IV COPD and age ≤65 years.

The authors cited groups that were identified in a posthoc analysis¹ of the only large trial involving azithromycin for the treatment of COPD to date.²P values for the interaction of azithromycin with GOLD stage (P=.04), smoking (P=.03), and age (P=.02) were significant, but the mean effects (hazard ratios [HRs]) for GOLD stage IV, smoking, and age ≤65 were .84, .99, and .84, respectively. It would be more accurate to say that there may be a diminished efficacy of azithromycin for patients with GOLD IV COPD and age ≤65 years. Only smokers appear to show no response, although the lower end of the 95% confidence interval was 0.71. The P value for the interaction of azithromycin with no long-term oxygen use (P=.23) was not significant, and it is incorrect to infer that oxygen use or nonuse predicts response.

The authors correctly state that the “significance of the results is limited because the study was not originally powered for this level of subgroup analysis,” but this statement is buried later in the article.

David L. Hahn, MD, MS
Madison, Wis

1. Han MK, Tayob N, Murray S, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med. 2014;189:1503-1508.

2. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689-698.

Continue to: Author's response...

Author’s response:

Your statement that the evidence-based answer regarding the lack of benefit of azithromycin in patients ≤65 years of age, with stage IV COPD, current smokers, and patients not using oxygen is “misleading” is a bit of an overstatement.

It is fair to say, however, that our statement regarding lack of efficacy among these subgroups of patients should be softened a bit since the data are from subgroup analyses, which should never be the source of definitive conclusions. And you point out that the 95% confidence intervals [CIs] of the HRs for these subgroups of patients do not include a potentially significant effect (0.68, 0.71, 0.61, and 0.65, respectively), so it is possible there is a Type II error, which would lead one to conclude there is no effect for these subgroups when there is one.

Regarding oxygen therapy, in this Clinical Inquiry, we presented data from the direct subgroup analysis, which revealed no difference in COPD exacerbations between the azithromycin and placebo groups for patients not receiving long-term supplemental oxygen (HR=0.80; 95% CI, 0.62-1.03); however, you are correct to point out that the oxygen use subgroup interaction (patients on oxygen vs patients not on oxygen), which we did not include in this Clinical Inquiry, did not reach significance (P=.23), casting some doubt on the authors’ conclusion of no effect for patients not on oxygen.

On the whole, I feel this Clinical Inquiry accurately summarized the existing evidence and that additional research is needed to better define the utility of azithromycin in these subgroups of patients.

Corey Lyon, DO
Denver, Colo

In the Clinical Inquiry, “Does prophylactic azithromycin reduce the number of COPD exacerbations or hospitalizations?” (J Fam Pract. 2018;67:384-385), Lyon et al state that azithromycin “doesn’t benefit patients ≤65 years, patients with GOLD [Global Initiative for Obstructive Lung Disease] stage IV COPD [chronic obstructive pulmonary disease], current smokers, or patients not using oxygen (strength of recommendation [SOR]: B, randomized controlled trials [RCTs]).” These categorical statements are misleading, and clinicians should ignore most of them when considering azithromycin for their patients with severe COPD.

It would be more accurate to say that there may be a diminished efficacy of azithromycin for patients with GOLD IV COPD and age ≤65 years.

The authors cited groups that were identified in a posthoc analysis¹ of the only large trial involving azithromycin for the treatment of COPD to date.²P values for the interaction of azithromycin with GOLD stage (P=.04), smoking (P=.03), and age (P=.02) were significant, but the mean effects (hazard ratios [HRs]) for GOLD stage IV, smoking, and age ≤65 were .84, .99, and .84, respectively. It would be more accurate to say that there may be a diminished efficacy of azithromycin for patients with GOLD IV COPD and age ≤65 years. Only smokers appear to show no response, although the lower end of the 95% confidence interval was 0.71. The P value for the interaction of azithromycin with no long-term oxygen use (P=.23) was not significant, and it is incorrect to infer that oxygen use or nonuse predicts response.

The authors correctly state that the “significance of the results is limited because the study was not originally powered for this level of subgroup analysis,” but this statement is buried later in the article.

David L. Hahn, MD, MS
Madison, Wis

1. Han MK, Tayob N, Murray S, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med. 2014;189:1503-1508.

2. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689-698.

Continue to: Author's response...

Author’s response:

Your statement that the evidence-based answer regarding the lack of benefit of azithromycin in patients ≤65 years of age, with stage IV COPD, current smokers, and patients not using oxygen is “misleading” is a bit of an overstatement.

It is fair to say, however, that our statement regarding lack of efficacy among these subgroups of patients should be softened a bit since the data are from subgroup analyses, which should never be the source of definitive conclusions. And you point out that the 95% confidence intervals [CIs] of the HRs for these subgroups of patients do not include a potentially significant effect (0.68, 0.71, 0.61, and 0.65, respectively), so it is possible there is a Type II error, which would lead one to conclude there is no effect for these subgroups when there is one.

Regarding oxygen therapy, in this Clinical Inquiry, we presented data from the direct subgroup analysis, which revealed no difference in COPD exacerbations between the azithromycin and placebo groups for patients not receiving long-term supplemental oxygen (HR=0.80; 95% CI, 0.62-1.03); however, you are correct to point out that the oxygen use subgroup interaction (patients on oxygen vs patients not on oxygen), which we did not include in this Clinical Inquiry, did not reach significance (P=.23), casting some doubt on the authors’ conclusion of no effect for patients not on oxygen.

On the whole, I feel this Clinical Inquiry accurately summarized the existing evidence and that additional research is needed to better define the utility of azithromycin in these subgroups of patients.

Corey Lyon, DO
Denver, Colo

EVIDENCE SUMMARY

A meta-analysis of 15 RCTs (5583 women) compared intentional artificial rupture of the amniotic membranes during labor (amniotomy) with intention to preserve the membranes (no amniotomy). The study found no differences in any of the measured primary outcomes: length of first stage of labor, cesarean section, maternal satisfaction with childbirth, or Apgar score <7 at 5 minutes.¹

Investigators included 9 trials with both nulliparous and multiparous women and 6 trials with only nulliparous women. Thirteen trials compared amniotomy with intention to preserve the membranes, and 2 trials performed amniotomy in the control group if the membranes were intact at full cervical dilation.

Amniotomy doesn’t affect first-stage labor or cesarean risk

Five trials (1127 women) reported no difference in length of the first stage of labor between the amniotomy and no amniotomy groups (mean difference [MD]= −20 minutes; 95% confidence interval [CI], −96 to 55). Subgroups of primiparous and multiparous women showed no difference (MD= −58 minutes; 95% CI, −153 to 37 and MD= +23 minutes; 95% CI, −51 to 97, respectively).

Nine trials (5021 women) reported no significant difference in cesarean section risk overall or when compared by parity, multiparous vs primiparous (risk ratio [RR]= 1.27; 95% CI, 0.99-1.63). One trial (84 women) found no difference in maternal satisfaction scores with childbirth experience. Six trials (3598 women) that reported risk of low Apgar score (<4 at 1 minute or <7 at 5 minutes) found no difference overall (RR=0.53; 95% CI, 0.28-1.00), or when compared by parity (multiparous vs primiparous).

Amniotomy doesn’t shorten spontaneous labor nor improve length of first-stage labor, cesarean section rate, or maternal satisfaction with childbirth.

Investigators reported that the included trials varied in quality and described the following limitations: inconsistent or unspecified timing of amniotomy during labor, proportion of women in the control group undergoing amniotomy, and ≥30% of women not getting the allocated treatment in all but one of the trials.

Secondary outcomes: Amniotomy reduces oxytocin use

Eight trials (4264 women) evaluated oxytocin augmentation and found that amniotomy decreased its use in multiparous (RR=0.43; 95% CI, 0.30-0.60), but not primiparous, women.

Eight trials (1927 women) reported length of second stage of labor as a secondary outcome, with no difference overall (MD= −1.33 minutes; 95% CI, −2.92 to 0.26). Amniotomy produced a statistical but not clinically significant shortening in subanalysis of primiparous women (MD= −5.43 minutes; 95% CI, −9.98 to −0.89) but not multiparous women.

Continue to: Three trials...

Three trials (1695 women) evaluated dysfunctional labor, defined as no progress in cervical dilation in 2 hours or ineffective uterine contractions. Amniotomy reduced dysfunctional labor in both primiparous (RR=0.49; 95% CI, 0.33-0.73) and multiparous women (RR=0.44; 95% CI, 0.31-0.62).

No differences found in other maternal and fetal outcomes

Investigators reported no differences in other secondary maternal outcomes: instrumental vaginal birth (10 trials, 5121 women); pain relief (8 trials, 3475 women); postpartum hemorrhage (2 trials, 1822 women); serious maternal morbidity or death (3 trials, 1740 women); umbilical cord prolapse (2 trials, 1615 women); and cesarean section for fetal distress, prolonged labor, or antepartum hemorrhage (1 RCT, 690 women).

Investigators also found no differences in secondary fetal outcomes: serious neonatal morbidity or perinatal death (8 trials, 3397 women); neonatal admission to neonatal intensive care (5 trials, 2686 women); abnormal fetal heart rate tracing in first stage of labor (4 trials, 1284 women); meconium aspiration (2 trials, 1615 women); and fetal acidosis (2 trials, 1014 women). Similarly, 1 RCT (39 women) that compared amniotomy with intent to preserve membranes in spontaneous labors that became prolonged found no difference in cesarean section, maternal satisfaction, or Apgar scores.

A few studies claim shorter labor with amniotomy

However, a later Iranian RCT (300 women) reported that early amniotomy shortened labor (labor duration: 7.5 ± 0.7 hours with amniotomy vs 9.9 ± 1.0 hours without amniotomy; P<.001) and reduced the risk of dystocia (RR=0.81; 95% CI, 0.59-0.90) and cesarean section (RR=0.82; 95% CI, 0.66-0.90).²

A similar Nigerian RCT (214 women) and an Indian RCT (144 women) both claimed that amniotomy also shortened labor (4.7 ± 0.9 hours vs 5.9 ± 1.3, and 3.9 ± 2 hours vs 6.1 ± 2.8 hours, respectively).^3,4 In neither trial, however, did investigators explain how the difference was significant when the duration of labor times overlapped within the margin of error.

EVIDENCE SUMMARY

A meta-analysis of 15 RCTs (5583 women) compared intentional artificial rupture of the amniotic membranes during labor (amniotomy) with intention to preserve the membranes (no amniotomy). The study found no differences in any of the measured primary outcomes: length of first stage of labor, cesarean section, maternal satisfaction with childbirth, or Apgar score <7 at 5 minutes.¹

Investigators included 9 trials with both nulliparous and multiparous women and 6 trials with only nulliparous women. Thirteen trials compared amniotomy with intention to preserve the membranes, and 2 trials performed amniotomy in the control group if the membranes were intact at full cervical dilation.

Amniotomy doesn’t affect first-stage labor or cesarean risk

Five trials (1127 women) reported no difference in length of the first stage of labor between the amniotomy and no amniotomy groups (mean difference [MD]= −20 minutes; 95% confidence interval [CI], −96 to 55). Subgroups of primiparous and multiparous women showed no difference (MD= −58 minutes; 95% CI, −153 to 37 and MD= +23 minutes; 95% CI, −51 to 97, respectively).

Nine trials (5021 women) reported no significant difference in cesarean section risk overall or when compared by parity, multiparous vs primiparous (risk ratio [RR]= 1.27; 95% CI, 0.99-1.63). One trial (84 women) found no difference in maternal satisfaction scores with childbirth experience. Six trials (3598 women) that reported risk of low Apgar score (<4 at 1 minute or <7 at 5 minutes) found no difference overall (RR=0.53; 95% CI, 0.28-1.00), or when compared by parity (multiparous vs primiparous).

Amniotomy doesn’t shorten spontaneous labor nor improve length of first-stage labor, cesarean section rate, or maternal satisfaction with childbirth.

Investigators reported that the included trials varied in quality and described the following limitations: inconsistent or unspecified timing of amniotomy during labor, proportion of women in the control group undergoing amniotomy, and ≥30% of women not getting the allocated treatment in all but one of the trials.

Secondary outcomes: Amniotomy reduces oxytocin use

Eight trials (4264 women) evaluated oxytocin augmentation and found that amniotomy decreased its use in multiparous (RR=0.43; 95% CI, 0.30-0.60), but not primiparous, women.

Eight trials (1927 women) reported length of second stage of labor as a secondary outcome, with no difference overall (MD= −1.33 minutes; 95% CI, −2.92 to 0.26). Amniotomy produced a statistical but not clinically significant shortening in subanalysis of primiparous women (MD= −5.43 minutes; 95% CI, −9.98 to −0.89) but not multiparous women.

Continue to: Three trials...

Three trials (1695 women) evaluated dysfunctional labor, defined as no progress in cervical dilation in 2 hours or ineffective uterine contractions. Amniotomy reduced dysfunctional labor in both primiparous (RR=0.49; 95% CI, 0.33-0.73) and multiparous women (RR=0.44; 95% CI, 0.31-0.62).

No differences found in other maternal and fetal outcomes

Investigators reported no differences in other secondary maternal outcomes: instrumental vaginal birth (10 trials, 5121 women); pain relief (8 trials, 3475 women); postpartum hemorrhage (2 trials, 1822 women); serious maternal morbidity or death (3 trials, 1740 women); umbilical cord prolapse (2 trials, 1615 women); and cesarean section for fetal distress, prolonged labor, or antepartum hemorrhage (1 RCT, 690 women).

Investigators also found no differences in secondary fetal outcomes: serious neonatal morbidity or perinatal death (8 trials, 3397 women); neonatal admission to neonatal intensive care (5 trials, 2686 women); abnormal fetal heart rate tracing in first stage of labor (4 trials, 1284 women); meconium aspiration (2 trials, 1615 women); and fetal acidosis (2 trials, 1014 women). Similarly, 1 RCT (39 women) that compared amniotomy with intent to preserve membranes in spontaneous labors that became prolonged found no difference in cesarean section, maternal satisfaction, or Apgar scores.

A few studies claim shorter labor with amniotomy

However, a later Iranian RCT (300 women) reported that early amniotomy shortened labor (labor duration: 7.5 ± 0.7 hours with amniotomy vs 9.9 ± 1.0 hours without amniotomy; P<.001) and reduced the risk of dystocia (RR=0.81; 95% CI, 0.59-0.90) and cesarean section (RR=0.82; 95% CI, 0.66-0.90).²

A similar Nigerian RCT (214 women) and an Indian RCT (144 women) both claimed that amniotomy also shortened labor (4.7 ± 0.9 hours vs 5.9 ± 1.3, and 3.9 ± 2 hours vs 6.1 ± 2.8 hours, respectively).^3,4 In neither trial, however, did investigators explain how the difference was significant when the duration of labor times overlapped within the margin of error.

EVIDENCE SUMMARY

A meta-analysis of 15 RCTs (5583 women) compared intentional artificial rupture of the amniotic membranes during labor (amniotomy) with intention to preserve the membranes (no amniotomy). The study found no differences in any of the measured primary outcomes: length of first stage of labor, cesarean section, maternal satisfaction with childbirth, or Apgar score <7 at 5 minutes.¹

Investigators included 9 trials with both nulliparous and multiparous women and 6 trials with only nulliparous women. Thirteen trials compared amniotomy with intention to preserve the membranes, and 2 trials performed amniotomy in the control group if the membranes were intact at full cervical dilation.

Amniotomy doesn’t affect first-stage labor or cesarean risk

Five trials (1127 women) reported no difference in length of the first stage of labor between the amniotomy and no amniotomy groups (mean difference [MD]= −20 minutes; 95% confidence interval [CI], −96 to 55). Subgroups of primiparous and multiparous women showed no difference (MD= −58 minutes; 95% CI, −153 to 37 and MD= +23 minutes; 95% CI, −51 to 97, respectively).

Nine trials (5021 women) reported no significant difference in cesarean section risk overall or when compared by parity, multiparous vs primiparous (risk ratio [RR]= 1.27; 95% CI, 0.99-1.63). One trial (84 women) found no difference in maternal satisfaction scores with childbirth experience. Six trials (3598 women) that reported risk of low Apgar score (<4 at 1 minute or <7 at 5 minutes) found no difference overall (RR=0.53; 95% CI, 0.28-1.00), or when compared by parity (multiparous vs primiparous).

Amniotomy doesn’t shorten spontaneous labor nor improve length of first-stage labor, cesarean section rate, or maternal satisfaction with childbirth.

Investigators reported that the included trials varied in quality and described the following limitations: inconsistent or unspecified timing of amniotomy during labor, proportion of women in the control group undergoing amniotomy, and ≥30% of women not getting the allocated treatment in all but one of the trials.

Secondary outcomes: Amniotomy reduces oxytocin use

Eight trials (4264 women) evaluated oxytocin augmentation and found that amniotomy decreased its use in multiparous (RR=0.43; 95% CI, 0.30-0.60), but not primiparous, women.

Eight trials (1927 women) reported length of second stage of labor as a secondary outcome, with no difference overall (MD= −1.33 minutes; 95% CI, −2.92 to 0.26). Amniotomy produced a statistical but not clinically significant shortening in subanalysis of primiparous women (MD= −5.43 minutes; 95% CI, −9.98 to −0.89) but not multiparous women.

Continue to: Three trials...

Three trials (1695 women) evaluated dysfunctional labor, defined as no progress in cervical dilation in 2 hours or ineffective uterine contractions. Amniotomy reduced dysfunctional labor in both primiparous (RR=0.49; 95% CI, 0.33-0.73) and multiparous women (RR=0.44; 95% CI, 0.31-0.62).

No differences found in other maternal and fetal outcomes

Investigators reported no differences in other secondary maternal outcomes: instrumental vaginal birth (10 trials, 5121 women); pain relief (8 trials, 3475 women); postpartum hemorrhage (2 trials, 1822 women); serious maternal morbidity or death (3 trials, 1740 women); umbilical cord prolapse (2 trials, 1615 women); and cesarean section for fetal distress, prolonged labor, or antepartum hemorrhage (1 RCT, 690 women).

Investigators also found no differences in secondary fetal outcomes: serious neonatal morbidity or perinatal death (8 trials, 3397 women); neonatal admission to neonatal intensive care (5 trials, 2686 women); abnormal fetal heart rate tracing in first stage of labor (4 trials, 1284 women); meconium aspiration (2 trials, 1615 women); and fetal acidosis (2 trials, 1014 women). Similarly, 1 RCT (39 women) that compared amniotomy with intent to preserve membranes in spontaneous labors that became prolonged found no difference in cesarean section, maternal satisfaction, or Apgar scores.

A few studies claim shorter labor with amniotomy

However, a later Iranian RCT (300 women) reported that early amniotomy shortened labor (labor duration: 7.5 ± 0.7 hours with amniotomy vs 9.9 ± 1.0 hours without amniotomy; P<.001) and reduced the risk of dystocia (RR=0.81; 95% CI, 0.59-0.90) and cesarean section (RR=0.82; 95% CI, 0.66-0.90).²

A similar Nigerian RCT (214 women) and an Indian RCT (144 women) both claimed that amniotomy also shortened labor (4.7 ± 0.9 hours vs 5.9 ± 1.3, and 3.9 ± 2 hours vs 6.1 ± 2.8 hours, respectively).^3,4 In neither trial, however, did investigators explain how the difference was significant when the duration of labor times overlapped within the margin of error.