The Journal of Family Practice

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The patient was given a diagnosis of sialadenosis (also known as sialosis), a noninflammatory, non-neoplastic enlargement of the parotid glands. It can often manifest as fatty degeneration of the parotid glands, which may be associated with underlying conditions such as hypertriglyceridemia, diabetes, and metabolic syndrome.^1-3

Ultrasonography and a subsequent computed tomography with contrast demonstrated fatty hypertrophy of the parotid glands without any concerning parotid mass or enlarged cervical lymph nodes. No abnormalities of the ductal system (eg, stricture or obstruction with stone) were noted, so sialography and sialendoscopy were not indicated.

Evaluation for inflammatory, autoimmune, and granulomatous diseases was negative, including negative anti-Ro/SSA and anti-La/SSB antibodies and negative HIV screen. However, our patient had an elevated serum triglyceride level of 589 mg/dL (reference range, < 150 mg/dL), while serum total cholesterol was within the reference range (< 200 mg/dL). (Interestingly, his triglycerides were normal a year earlier.) The patient’s A1c level was normal.

The differential diagnosis for this patient included Sjögren syndrome, abscess, viral infection (eg, mumps, HIV sialopathy), Kimura disease, sarcoidosis, masseter hypertrophy, and tumors of the parotid gland (eg, Warthin tumor and pleomorphic adenoma). Drug-induced sialadenitis was another possibility, as several drugs may be associated with salivary gland enlargement.⁴ However, no association was found for our patient.

Primary management is focused on treating the underlying disorder. The application of heat, massage, and sialagogues (eg, pilocarpine 5 mg orally tid) can be used to stimulate salivation, which may help reduce the swelling. Bilateral parotid gland swelling in patients with increased triglyceride levels often resolves after treatment of hypertriglyceridemia.^3,5 Less common modalities include botulinum neurotoxin injection, tympanic neurectomy, and parotidectomy.⁶

The treatment plan for this patient included aggressive dietary modification and increasing his current dosage of atorvastatin from 20 mg to 80 mg at bedtime. Increasing the dosage of statin was preferred over adding another agent (such as fibrates) to decrease the risk of myopathy. Fine-needle aspiration biopsy may be considered if the swelling does not resolve after correction of lipid abnormalities, which can take between 6 months and 3 years.³

‌

Photo courtesy of Faryal Tahir, MD. Text courtesy of Faryal Tahir, MD, Assistant Professor, and Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University, Homer Stryker, MD School of Medicine, Kalamazoo.

JFP07211_4.jpg

The patient was given a diagnosis of sialadenosis (also known as sialosis), a noninflammatory, non-neoplastic enlargement of the parotid glands. It can often manifest as fatty degeneration of the parotid glands, which may be associated with underlying conditions such as hypertriglyceridemia, diabetes, and metabolic syndrome.^1-3

Ultrasonography and a subsequent computed tomography with contrast demonstrated fatty hypertrophy of the parotid glands without any concerning parotid mass or enlarged cervical lymph nodes. No abnormalities of the ductal system (eg, stricture or obstruction with stone) were noted, so sialography and sialendoscopy were not indicated.

Evaluation for inflammatory, autoimmune, and granulomatous diseases was negative, including negative anti-Ro/SSA and anti-La/SSB antibodies and negative HIV screen. However, our patient had an elevated serum triglyceride level of 589 mg/dL (reference range, < 150 mg/dL), while serum total cholesterol was within the reference range (< 200 mg/dL). (Interestingly, his triglycerides were normal a year earlier.) The patient’s A1c level was normal.

The differential diagnosis for this patient included Sjögren syndrome, abscess, viral infection (eg, mumps, HIV sialopathy), Kimura disease, sarcoidosis, masseter hypertrophy, and tumors of the parotid gland (eg, Warthin tumor and pleomorphic adenoma). Drug-induced sialadenitis was another possibility, as several drugs may be associated with salivary gland enlargement.⁴ However, no association was found for our patient.

Primary management is focused on treating the underlying disorder. The application of heat, massage, and sialagogues (eg, pilocarpine 5 mg orally tid) can be used to stimulate salivation, which may help reduce the swelling. Bilateral parotid gland swelling in patients with increased triglyceride levels often resolves after treatment of hypertriglyceridemia.^3,5 Less common modalities include botulinum neurotoxin injection, tympanic neurectomy, and parotidectomy.⁶

The treatment plan for this patient included aggressive dietary modification and increasing his current dosage of atorvastatin from 20 mg to 80 mg at bedtime. Increasing the dosage of statin was preferred over adding another agent (such as fibrates) to decrease the risk of myopathy. Fine-needle aspiration biopsy may be considered if the swelling does not resolve after correction of lipid abnormalities, which can take between 6 months and 3 years.³

‌

Photo courtesy of Faryal Tahir, MD. Text courtesy of Faryal Tahir, MD, Assistant Professor, and Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University, Homer Stryker, MD School of Medicine, Kalamazoo.

JFP07211_4.jpg

The patient was given a diagnosis of sialadenosis (also known as sialosis), a noninflammatory, non-neoplastic enlargement of the parotid glands. It can often manifest as fatty degeneration of the parotid glands, which may be associated with underlying conditions such as hypertriglyceridemia, diabetes, and metabolic syndrome.^1-3

Ultrasonography and a subsequent computed tomography with contrast demonstrated fatty hypertrophy of the parotid glands without any concerning parotid mass or enlarged cervical lymph nodes. No abnormalities of the ductal system (eg, stricture or obstruction with stone) were noted, so sialography and sialendoscopy were not indicated.

Evaluation for inflammatory, autoimmune, and granulomatous diseases was negative, including negative anti-Ro/SSA and anti-La/SSB antibodies and negative HIV screen. However, our patient had an elevated serum triglyceride level of 589 mg/dL (reference range, < 150 mg/dL), while serum total cholesterol was within the reference range (< 200 mg/dL). (Interestingly, his triglycerides were normal a year earlier.) The patient’s A1c level was normal.

The differential diagnosis for this patient included Sjögren syndrome, abscess, viral infection (eg, mumps, HIV sialopathy), Kimura disease, sarcoidosis, masseter hypertrophy, and tumors of the parotid gland (eg, Warthin tumor and pleomorphic adenoma). Drug-induced sialadenitis was another possibility, as several drugs may be associated with salivary gland enlargement.⁴ However, no association was found for our patient.

Primary management is focused on treating the underlying disorder. The application of heat, massage, and sialagogues (eg, pilocarpine 5 mg orally tid) can be used to stimulate salivation, which may help reduce the swelling. Bilateral parotid gland swelling in patients with increased triglyceride levels often resolves after treatment of hypertriglyceridemia.^3,5 Less common modalities include botulinum neurotoxin injection, tympanic neurectomy, and parotidectomy.⁶

The treatment plan for this patient included aggressive dietary modification and increasing his current dosage of atorvastatin from 20 mg to 80 mg at bedtime. Increasing the dosage of statin was preferred over adding another agent (such as fibrates) to decrease the risk of myopathy. Fine-needle aspiration biopsy may be considered if the swelling does not resolve after correction of lipid abnormalities, which can take between 6 months and 3 years.³

‌

Photo courtesy of Faryal Tahir, MD. Text courtesy of Faryal Tahir, MD, Assistant Professor, and Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University, Homer Stryker, MD School of Medicine, Kalamazoo.

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Nonalcoholic steatohepatitis, or NASH,^a is the most severe form of nonalcoholic fatty liver disease (NAFLD).

Read More

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Nonalcoholic steatohepatitis, or NASH,^a is the most severe form of nonalcoholic fatty liver disease (NAFLD).

Read More

‌

‌

‌

capture.jpg

Nonalcoholic steatohepatitis, or NASH,^a is the most severe form of nonalcoholic fatty liver disease (NAFLD).

Read More

‌

‌

‌

In the past year, there has been significant progress in the availability of interventions to prevent respiratory syncytial virus (RSV) and its complications. Four products have been approved by the US Food and Drug Administration (FDA) and recommended by the Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP). They include 2 vaccines for adults ages 60 years and older, a monoclonal antibody for infants and high-risk children, and a maternal vaccine to prevent RSV infection in newborns.

JFP07211e17_t1.jpg

RSV in adults

While there is some uncertainty about the total burden of RSV in adults in the United States, the CDC estimates that each year it causes 0.9 to 1.4 million medical encounters, 60,000 to 160,000 hospitalizations, and 6000 to 10,000 deaths.¹ The rate of RSV-caused hospitalization increases with age,² and the infection is more severe in those with certain chronic medical conditions (TABLE 1¹). The FIGURE² demonstrates the outcomes of adults who are hospitalized for RSV. Adults older than 65 years have a 5% mortality rate if hospitalized for RSV infection.²

JFP07211e17_f1.jpg

Vaccine options for adults

Two vaccines were recently approved for the prevention of RSV-associated lower respiratory tract disease (LRTD) in those ages 60 years and older: RSVPreF3 (Arexvy, GSK), which is an adjuvanted recombinant F protein vaccine, and RSVpreF (Abrysvo, Pfizer), which is a recombinant stabilized vaccine. Both require only a single dose (0.5 mL IM), which provides protection for 2 years.

The efficacy of the GSK vaccine in preventing laboratory-confirmed, RSV-­associated LRTD was 82.6% during the first RSV season and 56.1% during the second season. The efficacy of the Pfizer vaccine in preventing symptomatic, laboratory-confirmed LRTD was 88.9% during the first RSV season and 78.6% during the second season.¹ However, the trials leading to licensure of both vaccines were underpowered to show efficacy in the oldest adults and those who are frail or to show efficacy against RSV-caused hospitalization.

Safety of the adult RSV vaccines. The safety trials for both vaccines had a total of 38,177 participants. There were a total of 6 neurologic inflammatory conditions that developed within 42 days of vaccination, including 2 cases of suspected Guillain-Barré syndrome (GBS), 2 cases of possible acute disseminated encephalomyelitis, and 1 case each of chronic inflammatory demyelinating polyneuropathy and undifferentiated motor-­sensory axonal polyneuropathy.¹ That is a rate of 1 case of a neurologic inflammatory condition for every 6363 people vaccinated. Since the trials were not powered to determine whether the small number of cases were due to chance, postmarketing surveillance will be needed to clarify the true risk for GBS or other neurologic inflammatory events from RSV vaccination.

The lack of efficacy data for the most vulnerable older adults and the lingering questions about safety prompted the ACIP to recommend that adults ages 60 years and older may receive a single dose of RSV vaccine, using shared clinical decision-­making—which is different from a routine or risk-based vaccine recommendation. For RSV vaccination, the decision to vaccinate should be based on a risk/benefit discussion between the clinician and the patient. Those most likely to benefit from the vaccine are listed in ­TABLE 1.¹

While data on coadministration of RSV vaccines with other adult vaccines are sparse, the ACIP states that co-administration with other vaccines is acceptable.¹ It is not known yet whether boosters will be needed after 2 years.

Continue to: RSV in infants and children

RSV in infants and children

RSV is the most common cause of hospitalization among infants and children in the United States. The CDC estimates that each year in children younger than 5 years, RSV is responsible for 1.5 million outpatient clinic visits, 520,000 emergency department visits, 58,000 to 80,000 hospitalizations, and 100 to 200 deaths.³ The risk for hospitalization from RSV is highest in the second and third months of life and decreases with increasing age.³

There are racial disparities in RSV severity: Intensive care unit admission rates are 1.2 to 1.6 times higher among non-Hispanic Black infants younger than 6 months than among non-Hispanic White infants, and hospitalization rates are up to 5 times higher in American Indian and Alaska Native populations.³

The months of highest RSV transmission in most locations are December through February, but this can vary. For practical purposes, RSV season runs from October through March.

Prevention in infants and children

The monoclonal antibody nirsevimab is now available for use in infants younger than 8 months born during or entering their first RSV season and children ages 8 to 19 months who are at increased risk for severe RSV disease and entering their second RSV season. Details regarding the use of this product were described in a recent Practice Alert Brief.⁴

Early studies on nirsevimab demonstrated 79% effectiveness in preventing ­medical-attended LRTD, 80.6% effectiveness in preventing hospitalization, and 90% effectiveness in preventing ICU admission. The number needed to immunize with nirsevimab to prevent an outpatient visit is estimated to be 17; to prevent an ED visit, 48; and to prevent an inpatient admission, 128. Due to the low RSV death rate, the studies were not able to demonstrate reduced mortality.⁵

Continue to: RSV vaccine in pregnancy

In August, the FDA approved Pfizer’s RSVpreF vaccine for use during pregnancy—as a single dose given at 32 to 36 weeks’ ­gestation—for the prevention of RSV LRTD in infants in the first 6 months of life. In the clinical trials, the vaccine was given at 24 to 36 weeks’ gestation. However, there was a statistically nonsignificant increase in preterm births in the RSVpreF group compared to the placebo group.⁶ While there were insufficient data to prove or rule out a causal relationship, the FDA advisory committee was more comfortable approving the vaccine for use only later in pregnancy, to avoid the possibility of very early preterm births after vaccination. The ACIP agreed.

From time of maternal vaccination, at least 14 days are needed to develop and transfer maternal antibodies across the placenta to protect the infant. Therefore, infants born less than 14 days after maternal vaccination should be considered unprotected.

Both maternal vaccination with RSVpreF and infant injection with nirsevimab are now options to protect newborns and infants from RSV. However, use of both products is not needed, since combined they do not offer significant added protection compared to either product alone (exceptions to be discussed shortly).⁶ When the estimated due date will occur in the RSV season, maternity clinicians should provide information on both products and assist the mother in deciding whether to be vaccinated or rely on administration of nirsevimab to the infant after birth. The benefits and risks of these 2 options are listed in TABLE 2.⁶

JFP07211e17_t2.jpg

There are some rare situations in which use of both products is recommended, and they include⁶:

• When the baby is born less than 14 days from the time of maternal ­vaccination
• When the mother has a condition that could produce an inadequate response to the vaccine
• When the infant has had cardiopulmonary bypass, which would lead to loss of maternal antibodies
• When the infant has severe disease placing them at increased risk for ­severe RSV.

Conclusion

All of these new RSV preventive products should soon be widely available and covered with no out-of-pocket expense by commercial and government payers. The exception might be nirsevimab—because of the time needed to produce it, it might not be universally available in the 2023-2024 season.

In the past year, there has been significant progress in the availability of interventions to prevent respiratory syncytial virus (RSV) and its complications. Four products have been approved by the US Food and Drug Administration (FDA) and recommended by the Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP). They include 2 vaccines for adults ages 60 years and older, a monoclonal antibody for infants and high-risk children, and a maternal vaccine to prevent RSV infection in newborns.

JFP07211e17_t1.jpg

RSV in adults

While there is some uncertainty about the total burden of RSV in adults in the United States, the CDC estimates that each year it causes 0.9 to 1.4 million medical encounters, 60,000 to 160,000 hospitalizations, and 6000 to 10,000 deaths.¹ The rate of RSV-caused hospitalization increases with age,² and the infection is more severe in those with certain chronic medical conditions (TABLE 1¹). The FIGURE² demonstrates the outcomes of adults who are hospitalized for RSV. Adults older than 65 years have a 5% mortality rate if hospitalized for RSV infection.²

JFP07211e17_f1.jpg

Vaccine options for adults

Two vaccines were recently approved for the prevention of RSV-associated lower respiratory tract disease (LRTD) in those ages 60 years and older: RSVPreF3 (Arexvy, GSK), which is an adjuvanted recombinant F protein vaccine, and RSVpreF (Abrysvo, Pfizer), which is a recombinant stabilized vaccine. Both require only a single dose (0.5 mL IM), which provides protection for 2 years.

The efficacy of the GSK vaccine in preventing laboratory-confirmed, RSV-­associated LRTD was 82.6% during the first RSV season and 56.1% during the second season. The efficacy of the Pfizer vaccine in preventing symptomatic, laboratory-confirmed LRTD was 88.9% during the first RSV season and 78.6% during the second season.¹ However, the trials leading to licensure of both vaccines were underpowered to show efficacy in the oldest adults and those who are frail or to show efficacy against RSV-caused hospitalization.

Safety of the adult RSV vaccines. The safety trials for both vaccines had a total of 38,177 participants. There were a total of 6 neurologic inflammatory conditions that developed within 42 days of vaccination, including 2 cases of suspected Guillain-Barré syndrome (GBS), 2 cases of possible acute disseminated encephalomyelitis, and 1 case each of chronic inflammatory demyelinating polyneuropathy and undifferentiated motor-­sensory axonal polyneuropathy.¹ That is a rate of 1 case of a neurologic inflammatory condition for every 6363 people vaccinated. Since the trials were not powered to determine whether the small number of cases were due to chance, postmarketing surveillance will be needed to clarify the true risk for GBS or other neurologic inflammatory events from RSV vaccination.

The lack of efficacy data for the most vulnerable older adults and the lingering questions about safety prompted the ACIP to recommend that adults ages 60 years and older may receive a single dose of RSV vaccine, using shared clinical decision-­making—which is different from a routine or risk-based vaccine recommendation. For RSV vaccination, the decision to vaccinate should be based on a risk/benefit discussion between the clinician and the patient. Those most likely to benefit from the vaccine are listed in ­TABLE 1.¹

While data on coadministration of RSV vaccines with other adult vaccines are sparse, the ACIP states that co-administration with other vaccines is acceptable.¹ It is not known yet whether boosters will be needed after 2 years.

Continue to: RSV in infants and children

RSV in infants and children

RSV is the most common cause of hospitalization among infants and children in the United States. The CDC estimates that each year in children younger than 5 years, RSV is responsible for 1.5 million outpatient clinic visits, 520,000 emergency department visits, 58,000 to 80,000 hospitalizations, and 100 to 200 deaths.³ The risk for hospitalization from RSV is highest in the second and third months of life and decreases with increasing age.³

There are racial disparities in RSV severity: Intensive care unit admission rates are 1.2 to 1.6 times higher among non-Hispanic Black infants younger than 6 months than among non-Hispanic White infants, and hospitalization rates are up to 5 times higher in American Indian and Alaska Native populations.³

The months of highest RSV transmission in most locations are December through February, but this can vary. For practical purposes, RSV season runs from October through March.

Prevention in infants and children

The monoclonal antibody nirsevimab is now available for use in infants younger than 8 months born during or entering their first RSV season and children ages 8 to 19 months who are at increased risk for severe RSV disease and entering their second RSV season. Details regarding the use of this product were described in a recent Practice Alert Brief.⁴

Early studies on nirsevimab demonstrated 79% effectiveness in preventing ­medical-attended LRTD, 80.6% effectiveness in preventing hospitalization, and 90% effectiveness in preventing ICU admission. The number needed to immunize with nirsevimab to prevent an outpatient visit is estimated to be 17; to prevent an ED visit, 48; and to prevent an inpatient admission, 128. Due to the low RSV death rate, the studies were not able to demonstrate reduced mortality.⁵

Continue to: RSV vaccine in pregnancy

In August, the FDA approved Pfizer’s RSVpreF vaccine for use during pregnancy—as a single dose given at 32 to 36 weeks’ ­gestation—for the prevention of RSV LRTD in infants in the first 6 months of life. In the clinical trials, the vaccine was given at 24 to 36 weeks’ gestation. However, there was a statistically nonsignificant increase in preterm births in the RSVpreF group compared to the placebo group.⁶ While there were insufficient data to prove or rule out a causal relationship, the FDA advisory committee was more comfortable approving the vaccine for use only later in pregnancy, to avoid the possibility of very early preterm births after vaccination. The ACIP agreed.

From time of maternal vaccination, at least 14 days are needed to develop and transfer maternal antibodies across the placenta to protect the infant. Therefore, infants born less than 14 days after maternal vaccination should be considered unprotected.

Both maternal vaccination with RSVpreF and infant injection with nirsevimab are now options to protect newborns and infants from RSV. However, use of both products is not needed, since combined they do not offer significant added protection compared to either product alone (exceptions to be discussed shortly).⁶ When the estimated due date will occur in the RSV season, maternity clinicians should provide information on both products and assist the mother in deciding whether to be vaccinated or rely on administration of nirsevimab to the infant after birth. The benefits and risks of these 2 options are listed in TABLE 2.⁶

JFP07211e17_t2.jpg

There are some rare situations in which use of both products is recommended, and they include⁶:

• When the baby is born less than 14 days from the time of maternal ­vaccination
• When the mother has a condition that could produce an inadequate response to the vaccine
• When the infant has had cardiopulmonary bypass, which would lead to loss of maternal antibodies
• When the infant has severe disease placing them at increased risk for ­severe RSV.

Conclusion

All of these new RSV preventive products should soon be widely available and covered with no out-of-pocket expense by commercial and government payers. The exception might be nirsevimab—because of the time needed to produce it, it might not be universally available in the 2023-2024 season.

In the past year, there has been significant progress in the availability of interventions to prevent respiratory syncytial virus (RSV) and its complications. Four products have been approved by the US Food and Drug Administration (FDA) and recommended by the Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP). They include 2 vaccines for adults ages 60 years and older, a monoclonal antibody for infants and high-risk children, and a maternal vaccine to prevent RSV infection in newborns.

JFP07211e17_t1.jpg

RSV in adults

While there is some uncertainty about the total burden of RSV in adults in the United States, the CDC estimates that each year it causes 0.9 to 1.4 million medical encounters, 60,000 to 160,000 hospitalizations, and 6000 to 10,000 deaths.¹ The rate of RSV-caused hospitalization increases with age,² and the infection is more severe in those with certain chronic medical conditions (TABLE 1¹). The FIGURE² demonstrates the outcomes of adults who are hospitalized for RSV. Adults older than 65 years have a 5% mortality rate if hospitalized for RSV infection.²

JFP07211e17_f1.jpg

Vaccine options for adults

Two vaccines were recently approved for the prevention of RSV-associated lower respiratory tract disease (LRTD) in those ages 60 years and older: RSVPreF3 (Arexvy, GSK), which is an adjuvanted recombinant F protein vaccine, and RSVpreF (Abrysvo, Pfizer), which is a recombinant stabilized vaccine. Both require only a single dose (0.5 mL IM), which provides protection for 2 years.

The efficacy of the GSK vaccine in preventing laboratory-confirmed, RSV-­associated LRTD was 82.6% during the first RSV season and 56.1% during the second season. The efficacy of the Pfizer vaccine in preventing symptomatic, laboratory-confirmed LRTD was 88.9% during the first RSV season and 78.6% during the second season.¹ However, the trials leading to licensure of both vaccines were underpowered to show efficacy in the oldest adults and those who are frail or to show efficacy against RSV-caused hospitalization.

Safety of the adult RSV vaccines. The safety trials for both vaccines had a total of 38,177 participants. There were a total of 6 neurologic inflammatory conditions that developed within 42 days of vaccination, including 2 cases of suspected Guillain-Barré syndrome (GBS), 2 cases of possible acute disseminated encephalomyelitis, and 1 case each of chronic inflammatory demyelinating polyneuropathy and undifferentiated motor-­sensory axonal polyneuropathy.¹ That is a rate of 1 case of a neurologic inflammatory condition for every 6363 people vaccinated. Since the trials were not powered to determine whether the small number of cases were due to chance, postmarketing surveillance will be needed to clarify the true risk for GBS or other neurologic inflammatory events from RSV vaccination.

The lack of efficacy data for the most vulnerable older adults and the lingering questions about safety prompted the ACIP to recommend that adults ages 60 years and older may receive a single dose of RSV vaccine, using shared clinical decision-­making—which is different from a routine or risk-based vaccine recommendation. For RSV vaccination, the decision to vaccinate should be based on a risk/benefit discussion between the clinician and the patient. Those most likely to benefit from the vaccine are listed in ­TABLE 1.¹

While data on coadministration of RSV vaccines with other adult vaccines are sparse, the ACIP states that co-administration with other vaccines is acceptable.¹ It is not known yet whether boosters will be needed after 2 years.

Continue to: RSV in infants and children

RSV in infants and children

RSV is the most common cause of hospitalization among infants and children in the United States. The CDC estimates that each year in children younger than 5 years, RSV is responsible for 1.5 million outpatient clinic visits, 520,000 emergency department visits, 58,000 to 80,000 hospitalizations, and 100 to 200 deaths.³ The risk for hospitalization from RSV is highest in the second and third months of life and decreases with increasing age.³

There are racial disparities in RSV severity: Intensive care unit admission rates are 1.2 to 1.6 times higher among non-Hispanic Black infants younger than 6 months than among non-Hispanic White infants, and hospitalization rates are up to 5 times higher in American Indian and Alaska Native populations.³

The months of highest RSV transmission in most locations are December through February, but this can vary. For practical purposes, RSV season runs from October through March.

Prevention in infants and children

The monoclonal antibody nirsevimab is now available for use in infants younger than 8 months born during or entering their first RSV season and children ages 8 to 19 months who are at increased risk for severe RSV disease and entering their second RSV season. Details regarding the use of this product were described in a recent Practice Alert Brief.⁴

Early studies on nirsevimab demonstrated 79% effectiveness in preventing ­medical-attended LRTD, 80.6% effectiveness in preventing hospitalization, and 90% effectiveness in preventing ICU admission. The number needed to immunize with nirsevimab to prevent an outpatient visit is estimated to be 17; to prevent an ED visit, 48; and to prevent an inpatient admission, 128. Due to the low RSV death rate, the studies were not able to demonstrate reduced mortality.⁵

Continue to: RSV vaccine in pregnancy

In August, the FDA approved Pfizer’s RSVpreF vaccine for use during pregnancy—as a single dose given at 32 to 36 weeks’ ­gestation—for the prevention of RSV LRTD in infants in the first 6 months of life. In the clinical trials, the vaccine was given at 24 to 36 weeks’ gestation. However, there was a statistically nonsignificant increase in preterm births in the RSVpreF group compared to the placebo group.⁶ While there were insufficient data to prove or rule out a causal relationship, the FDA advisory committee was more comfortable approving the vaccine for use only later in pregnancy, to avoid the possibility of very early preterm births after vaccination. The ACIP agreed.

From time of maternal vaccination, at least 14 days are needed to develop and transfer maternal antibodies across the placenta to protect the infant. Therefore, infants born less than 14 days after maternal vaccination should be considered unprotected.

Both maternal vaccination with RSVpreF and infant injection with nirsevimab are now options to protect newborns and infants from RSV. However, use of both products is not needed, since combined they do not offer significant added protection compared to either product alone (exceptions to be discussed shortly).⁶ When the estimated due date will occur in the RSV season, maternity clinicians should provide information on both products and assist the mother in deciding whether to be vaccinated or rely on administration of nirsevimab to the infant after birth. The benefits and risks of these 2 options are listed in TABLE 2.⁶

JFP07211e17_t2.jpg

There are some rare situations in which use of both products is recommended, and they include⁶:

• When the baby is born less than 14 days from the time of maternal ­vaccination
• When the mother has a condition that could produce an inadequate response to the vaccine
• When the infant has had cardiopulmonary bypass, which would lead to loss of maternal antibodies
• When the infant has severe disease placing them at increased risk for ­severe RSV.

Conclusion

All of these new RSV preventive products should soon be widely available and covered with no out-of-pocket expense by commercial and government payers. The exception might be nirsevimab—because of the time needed to produce it, it might not be universally available in the 2023-2024 season.

ILLUSTRATIVE CASE

A 72-year-old man with well-controlled hypertension and chronic obstructive pulmonary disease is scheduled for right total hip arthroplasty (THA) due to severe arthritis. He will be admitted to the hospital overnight, and his orthopedic surgeon anticipates 2 to 3 days of inpatient recovery time. In addition to medical management of the patient’s comorbid conditions, the surgeon asks if you have any insight regarding VTE prophylaxis for this patient. Specifically, do you think aspirin is equal to LMWH for VTE prophylaxis?

All adults undergoing major orthopedic surgery are considered to be at high risk for postoperative VTE development, with those having lower-limb procedures at highest risk.² Of the more than 2.2 million THAs and total knee arthroplasties (TKAs) performed in the United States between 2012 and 2020, 55% were primary TKAs and 39% primary THAs.³ The American College of Chest Physicians (ACCP) estimated a baseline 35-day risk for VTE of 4.3% in patients undergoing major orthopedic surgery.⁴ The highest VTE risk occurs during the first 7 to 14 days post surgery (1.8% for symptomatic deep vein thrombosis [DVT] and 1% for pulmonary embolism [PE]), with a slightly lower risk during the subsequent 15 to 35 days (1% for symptomatic DVT and 0.5% for PE).⁴

Aspirin’s low cost, availability, and ease of administration make it an attractive choice for VTE prevention in patients post THA and TKA surgery. The Pulmonary Embolism Prevention (PEP) trial evaluated 13,356 patients undergoing hip fracture repair and 4088 patients undergoing arthroplasty and found aspirin to be safe and effective in prevention of VTEs compared with placebo. The investigators concluded that “there is now good evidence for considering aspirin routinely in a wide range of surgical and medical groups at high risk of venous thromboembolism.”⁵ The PEP study, along with others, led to the emergence of aspirin monotherapy for VTE prophylaxis.

Current guidelines for perioperative VTE prophylaxis are based on American Society of Hematology (ASH) and ACCP recommendations. For patients undergoing THA or TKA, ASH suggests using aspirin or anticoagulants for VTE prophylaxis; when anticoagulants are used, they suggest using a direct oral anticoagulant (DOAC) over LMWH.⁶ The ASH guidelines are conditional recommendations based on very low certainty of effects, and the ASH panel recognized the need for further investigation with large, high-quality clinical trials.

The ACCP guidelines are clearer in recommending VTE prophylaxis vs no prophylaxis for major orthopedic surgeries and recommend the use of LMWH over other agents, including aspirin, DOACs, warfarin, and intermittent pneumatic compression (IPC) devices.⁴

Although prophylaxis is widely recommended to mitigate the elevated risk for VTE among patients undergoing orthopedic surgery, aspirin as monotherapy remains controversial.⁷ Many orthopedic surgeons prescribe aspirin as a sole VTE prophylaxis agent; however, this practice is not well supported by data from large, well-conducted, randomized trials or inferiority trials.²

STUDY SUMMARY

Aspirin did not meet the noninferiority criterion for postoperative VTE

The CRISTAL trial compared the use of aspirin vs LMWH (enoxaparin) for VTE prophylaxis in patients ages 18 years or older undergoing primary THA or TKA for osteoarthritis.¹ This Australian study used a cluster-randomized, crossover, registry-nested, noninferiority trial design. Of note, in Australia, aspirin is formulated in 100-mg tablets, equivalent to the standard 81-mg low-dose tablet in the United States.

Continue to: Patients taking prescribed antiplatelet...

Patients taking prescribed antiplatelet medication for preexisting conditions (~20% of patients in each group) were allowed to continue antiplatelet therapy during the trial. Patients were excluded if they were receiving an anticoagulant prior to their procedure or had a medical contraindication to aspirin or enoxaparin.

Thirty-one hospital sites were randomly assigned a treatment protocol using either aspirin or enoxaparin. Once target patient enrollment was met with the initial assigned medication, the site switched to the second/other agent. This resulted in 5675 patients in the aspirin group and 4036 in the enoxaparin group enrolled between April 2019 and ­December 2020, with final follow-up in ­August 2021; of these, 259 in the aspirin group and 249 in the enoxaparin group were lost to follow-up, opted out, or died.

Although this study was designed as a noninferiority trial, analysis showed enoxaparin to be significantly superior to aspirin for postoperative VTE prophylaxis.

The aspirin group was given 100 mg PO daily and the enoxaparin group was given 40 mg SC daily (20 mg daily for patients weighing < 50 kg or with an estimated glomerular filtration rate < 30 mL/min/1.73 m²) for 35 days after THA and 14 days after TKA. Both treatment groups received IPC calf devices intraoperatively and postoperatively, and mobilization was offered on postoperative Day 0 or 1.

The primary outcome—development of symptomatic VTE within 90 days of the procedure—occurred in 187 (3.5%) patients in the aspirin group and 69 (1.8%) patients in the enoxaparin group (estimated difference = 1.97%; 95% CI, 0.54%-3.41%). This did not meet the noninferiority criterion for aspirin, based on an estimated assumed rate of 2% and a noninferiority margin of 1%, and in fact was statistically superior for enoxaparin (P = .007). There were no significant differences between the 2 groups in major bleeding or death within 90 days.¹

WHAT’S NEW

Enoxaparin was significantly superior to aspirin for VTE prophylaxis

Although this study was designed as a noninferiority trial, analysis showed enoxaparin to be significantly superior for postoperative VTE prophylaxis compared with aspirin.

Continue to: CAVEATS

Study aspirin dosing differed from US standard

This study showed significantly lower rates of symptomatic VTE in the enoxaparin group compared with the aspirin group; however, the majority of this difference was driven by rates of below-the-knee DVTs, which are clinically less relevant.⁸ Also, this trial used a 100-mg aspirin formulation, which is not available in the United States.

CHALLENGES TO IMPLEMENTATION

Aspirin is far cheaper and administered orally

Aspirin is significantly cheaper than enoxaparin, costing about $0.13 per dose (~$4 for 30 tablets at the 81-mg dose) vs roughly $9 per 40 mg/0.4 mL dose for enoxaparin.⁹ However, a cost-effectiveness analysis may be useful to determine (for example) whether the higher cost of enoxaparin may be offset by fewer DVTs and other sequelae. Lastly, LMWH is an injection, which some patients may refuse.

ILLUSTRATIVE CASE

A 72-year-old man with well-controlled hypertension and chronic obstructive pulmonary disease is scheduled for right total hip arthroplasty (THA) due to severe arthritis. He will be admitted to the hospital overnight, and his orthopedic surgeon anticipates 2 to 3 days of inpatient recovery time. In addition to medical management of the patient’s comorbid conditions, the surgeon asks if you have any insight regarding VTE prophylaxis for this patient. Specifically, do you think aspirin is equal to LMWH for VTE prophylaxis?

All adults undergoing major orthopedic surgery are considered to be at high risk for postoperative VTE development, with those having lower-limb procedures at highest risk.² Of the more than 2.2 million THAs and total knee arthroplasties (TKAs) performed in the United States between 2012 and 2020, 55% were primary TKAs and 39% primary THAs.³ The American College of Chest Physicians (ACCP) estimated a baseline 35-day risk for VTE of 4.3% in patients undergoing major orthopedic surgery.⁴ The highest VTE risk occurs during the first 7 to 14 days post surgery (1.8% for symptomatic deep vein thrombosis [DVT] and 1% for pulmonary embolism [PE]), with a slightly lower risk during the subsequent 15 to 35 days (1% for symptomatic DVT and 0.5% for PE).⁴

Aspirin’s low cost, availability, and ease of administration make it an attractive choice for VTE prevention in patients post THA and TKA surgery. The Pulmonary Embolism Prevention (PEP) trial evaluated 13,356 patients undergoing hip fracture repair and 4088 patients undergoing arthroplasty and found aspirin to be safe and effective in prevention of VTEs compared with placebo. The investigators concluded that “there is now good evidence for considering aspirin routinely in a wide range of surgical and medical groups at high risk of venous thromboembolism.”⁵ The PEP study, along with others, led to the emergence of aspirin monotherapy for VTE prophylaxis.

Current guidelines for perioperative VTE prophylaxis are based on American Society of Hematology (ASH) and ACCP recommendations. For patients undergoing THA or TKA, ASH suggests using aspirin or anticoagulants for VTE prophylaxis; when anticoagulants are used, they suggest using a direct oral anticoagulant (DOAC) over LMWH.⁶ The ASH guidelines are conditional recommendations based on very low certainty of effects, and the ASH panel recognized the need for further investigation with large, high-quality clinical trials.

The ACCP guidelines are clearer in recommending VTE prophylaxis vs no prophylaxis for major orthopedic surgeries and recommend the use of LMWH over other agents, including aspirin, DOACs, warfarin, and intermittent pneumatic compression (IPC) devices.⁴

Although prophylaxis is widely recommended to mitigate the elevated risk for VTE among patients undergoing orthopedic surgery, aspirin as monotherapy remains controversial.⁷ Many orthopedic surgeons prescribe aspirin as a sole VTE prophylaxis agent; however, this practice is not well supported by data from large, well-conducted, randomized trials or inferiority trials.²

STUDY SUMMARY

Aspirin did not meet the noninferiority criterion for postoperative VTE

The CRISTAL trial compared the use of aspirin vs LMWH (enoxaparin) for VTE prophylaxis in patients ages 18 years or older undergoing primary THA or TKA for osteoarthritis.¹ This Australian study used a cluster-randomized, crossover, registry-nested, noninferiority trial design. Of note, in Australia, aspirin is formulated in 100-mg tablets, equivalent to the standard 81-mg low-dose tablet in the United States.

Continue to: Patients taking prescribed antiplatelet...

Patients taking prescribed antiplatelet medication for preexisting conditions (~20% of patients in each group) were allowed to continue antiplatelet therapy during the trial. Patients were excluded if they were receiving an anticoagulant prior to their procedure or had a medical contraindication to aspirin or enoxaparin.

Thirty-one hospital sites were randomly assigned a treatment protocol using either aspirin or enoxaparin. Once target patient enrollment was met with the initial assigned medication, the site switched to the second/other agent. This resulted in 5675 patients in the aspirin group and 4036 in the enoxaparin group enrolled between April 2019 and ­December 2020, with final follow-up in ­August 2021; of these, 259 in the aspirin group and 249 in the enoxaparin group were lost to follow-up, opted out, or died.

Although this study was designed as a noninferiority trial, analysis showed enoxaparin to be significantly superior to aspirin for postoperative VTE prophylaxis.

The aspirin group was given 100 mg PO daily and the enoxaparin group was given 40 mg SC daily (20 mg daily for patients weighing < 50 kg or with an estimated glomerular filtration rate < 30 mL/min/1.73 m²) for 35 days after THA and 14 days after TKA. Both treatment groups received IPC calf devices intraoperatively and postoperatively, and mobilization was offered on postoperative Day 0 or 1.

The primary outcome—development of symptomatic VTE within 90 days of the procedure—occurred in 187 (3.5%) patients in the aspirin group and 69 (1.8%) patients in the enoxaparin group (estimated difference = 1.97%; 95% CI, 0.54%-3.41%). This did not meet the noninferiority criterion for aspirin, based on an estimated assumed rate of 2% and a noninferiority margin of 1%, and in fact was statistically superior for enoxaparin (P = .007). There were no significant differences between the 2 groups in major bleeding or death within 90 days.¹

WHAT’S NEW

Enoxaparin was significantly superior to aspirin for VTE prophylaxis

Although this study was designed as a noninferiority trial, analysis showed enoxaparin to be significantly superior for postoperative VTE prophylaxis compared with aspirin.

Continue to: CAVEATS

Study aspirin dosing differed from US standard

This study showed significantly lower rates of symptomatic VTE in the enoxaparin group compared with the aspirin group; however, the majority of this difference was driven by rates of below-the-knee DVTs, which are clinically less relevant.⁸ Also, this trial used a 100-mg aspirin formulation, which is not available in the United States.

CHALLENGES TO IMPLEMENTATION

Aspirin is far cheaper and administered orally

Aspirin is significantly cheaper than enoxaparin, costing about $0.13 per dose (~$4 for 30 tablets at the 81-mg dose) vs roughly $9 per 40 mg/0.4 mL dose for enoxaparin.⁹ However, a cost-effectiveness analysis may be useful to determine (for example) whether the higher cost of enoxaparin may be offset by fewer DVTs and other sequelae. Lastly, LMWH is an injection, which some patients may refuse.

ILLUSTRATIVE CASE

A 72-year-old man with well-controlled hypertension and chronic obstructive pulmonary disease is scheduled for right total hip arthroplasty (THA) due to severe arthritis. He will be admitted to the hospital overnight, and his orthopedic surgeon anticipates 2 to 3 days of inpatient recovery time. In addition to medical management of the patient’s comorbid conditions, the surgeon asks if you have any insight regarding VTE prophylaxis for this patient. Specifically, do you think aspirin is equal to LMWH for VTE prophylaxis?

All adults undergoing major orthopedic surgery are considered to be at high risk for postoperative VTE development, with those having lower-limb procedures at highest risk.² Of the more than 2.2 million THAs and total knee arthroplasties (TKAs) performed in the United States between 2012 and 2020, 55% were primary TKAs and 39% primary THAs.³ The American College of Chest Physicians (ACCP) estimated a baseline 35-day risk for VTE of 4.3% in patients undergoing major orthopedic surgery.⁴ The highest VTE risk occurs during the first 7 to 14 days post surgery (1.8% for symptomatic deep vein thrombosis [DVT] and 1% for pulmonary embolism [PE]), with a slightly lower risk during the subsequent 15 to 35 days (1% for symptomatic DVT and 0.5% for PE).⁴

Aspirin’s low cost, availability, and ease of administration make it an attractive choice for VTE prevention in patients post THA and TKA surgery. The Pulmonary Embolism Prevention (PEP) trial evaluated 13,356 patients undergoing hip fracture repair and 4088 patients undergoing arthroplasty and found aspirin to be safe and effective in prevention of VTEs compared with placebo. The investigators concluded that “there is now good evidence for considering aspirin routinely in a wide range of surgical and medical groups at high risk of venous thromboembolism.”⁵ The PEP study, along with others, led to the emergence of aspirin monotherapy for VTE prophylaxis.

Current guidelines for perioperative VTE prophylaxis are based on American Society of Hematology (ASH) and ACCP recommendations. For patients undergoing THA or TKA, ASH suggests using aspirin or anticoagulants for VTE prophylaxis; when anticoagulants are used, they suggest using a direct oral anticoagulant (DOAC) over LMWH.⁶ The ASH guidelines are conditional recommendations based on very low certainty of effects, and the ASH panel recognized the need for further investigation with large, high-quality clinical trials.

The ACCP guidelines are clearer in recommending VTE prophylaxis vs no prophylaxis for major orthopedic surgeries and recommend the use of LMWH over other agents, including aspirin, DOACs, warfarin, and intermittent pneumatic compression (IPC) devices.⁴

Although prophylaxis is widely recommended to mitigate the elevated risk for VTE among patients undergoing orthopedic surgery, aspirin as monotherapy remains controversial.⁷ Many orthopedic surgeons prescribe aspirin as a sole VTE prophylaxis agent; however, this practice is not well supported by data from large, well-conducted, randomized trials or inferiority trials.²

STUDY SUMMARY

Aspirin did not meet the noninferiority criterion for postoperative VTE

The CRISTAL trial compared the use of aspirin vs LMWH (enoxaparin) for VTE prophylaxis in patients ages 18 years or older undergoing primary THA or TKA for osteoarthritis.¹ This Australian study used a cluster-randomized, crossover, registry-nested, noninferiority trial design. Of note, in Australia, aspirin is formulated in 100-mg tablets, equivalent to the standard 81-mg low-dose tablet in the United States.

Continue to: Patients taking prescribed antiplatelet...

Patients taking prescribed antiplatelet medication for preexisting conditions (~20% of patients in each group) were allowed to continue antiplatelet therapy during the trial. Patients were excluded if they were receiving an anticoagulant prior to their procedure or had a medical contraindication to aspirin or enoxaparin.

Thirty-one hospital sites were randomly assigned a treatment protocol using either aspirin or enoxaparin. Once target patient enrollment was met with the initial assigned medication, the site switched to the second/other agent. This resulted in 5675 patients in the aspirin group and 4036 in the enoxaparin group enrolled between April 2019 and ­December 2020, with final follow-up in ­August 2021; of these, 259 in the aspirin group and 249 in the enoxaparin group were lost to follow-up, opted out, or died.

Although this study was designed as a noninferiority trial, analysis showed enoxaparin to be significantly superior to aspirin for postoperative VTE prophylaxis.

The aspirin group was given 100 mg PO daily and the enoxaparin group was given 40 mg SC daily (20 mg daily for patients weighing < 50 kg or with an estimated glomerular filtration rate < 30 mL/min/1.73 m²) for 35 days after THA and 14 days after TKA. Both treatment groups received IPC calf devices intraoperatively and postoperatively, and mobilization was offered on postoperative Day 0 or 1.

The primary outcome—development of symptomatic VTE within 90 days of the procedure—occurred in 187 (3.5%) patients in the aspirin group and 69 (1.8%) patients in the enoxaparin group (estimated difference = 1.97%; 95% CI, 0.54%-3.41%). This did not meet the noninferiority criterion for aspirin, based on an estimated assumed rate of 2% and a noninferiority margin of 1%, and in fact was statistically superior for enoxaparin (P = .007). There were no significant differences between the 2 groups in major bleeding or death within 90 days.¹

WHAT’S NEW

Enoxaparin was significantly superior to aspirin for VTE prophylaxis

Although this study was designed as a noninferiority trial, analysis showed enoxaparin to be significantly superior for postoperative VTE prophylaxis compared with aspirin.

Continue to: CAVEATS

Study aspirin dosing differed from US standard

This study showed significantly lower rates of symptomatic VTE in the enoxaparin group compared with the aspirin group; however, the majority of this difference was driven by rates of below-the-knee DVTs, which are clinically less relevant.⁸ Also, this trial used a 100-mg aspirin formulation, which is not available in the United States.

CHALLENGES TO IMPLEMENTATION

Aspirin is far cheaper and administered orally

Aspirin is significantly cheaper than enoxaparin, costing about $0.13 per dose (~$4 for 30 tablets at the 81-mg dose) vs roughly $9 per 40 mg/0.4 mL dose for enoxaparin.⁹ However, a cost-effectiveness analysis may be useful to determine (for example) whether the higher cost of enoxaparin may be offset by fewer DVTs and other sequelae. Lastly, LMWH is an injection, which some patients may refuse.

Evidence summary

Recent UK study shows no difference by timing

A 2022 UK prospective, randomized, multicenter trial assigned 21,104 predominantly White adults (58% men) with hypertension to take their usual antihypertensive medication either in the morning (6 am to 10 am) or evening (8 pm to midnight).¹ A computer algorithm randomized patients, but neither the patients nor the investigators were masked to allocation.

All patient baseline characteristics were equivalent between groups. If troubled by nocturia, patients in the evening group taking diuretics were told to take only the diuretic earlier (6 pm) and subsequently to change to morning if they experienced persistent bothersome symptoms. More patients in the evening administration group than in the morning administration group reported having to change the time of day that they took their diuretic (546 [5.2%] vs 71 [0.7%]; P < .0001).

The median follow-up was 5.2 years. Data were collected at regular intervals through patient completion of online questionnaires and researcher analysis of ­National Health Service data on hospitalization and death. The intention-to-treat analysis showed no difference in the primary outcome (a composite of vascular death, nonfatal myocardial infarction, or nonfatal stroke) between the evening and morning administration groups (0.69 events vs 0.72 events per 100 person-years; hazard ratio [HR] = 0.95; 95% CI, 0.83-1.10; P = .53).

The controversial Hygia Project favored evening

Prior to the UK study was the Hygia Chronotherapy Trial, a prospective, controlled, multicenter study conducted within the primary care setting in Spain. Caucasian Spanish adults (N = 19,168; mean age, 61 years; 56% men) with hypertension were randomly assigned to take all prescribed antihypertensive medication either at bedtime or upon waking.²

The Hygia Project initially sought to establish the value of ambulatory blood pressure monitoring (ABPM) compared to office blood pressure (BP) monitoring and to explore the prognostic value of sleeping BP.³ The study objectives evolved over time. The randomization process was not clearly described,^2,3 but multiple randomizations were alluded to. The authors stated that “for any of these chronotherapy trials” randomizations were done separately for “each participating center” and “randomization of participants to treatment-time regimen is done separately for each hypertension medication or combination being tested.”

A 2022 UK multicenter trial found no difference between the evening and morning administration groups in a composite outcome of vascular death, nonfatal myocardial infarction, or nonfatal stroke.

The baseline characteristics of patients in the evening and morning administration groups were similar, but statistically significant differences existed in BMI (29.6 vs 29.7; P = .030) and sleep-time systolic BP percent decline (9.3 vs 9.0; P < .001). Mean baseline 48-hour BP was 132/77 mm Hg. Hypertension was defined as an awake systolic BP ≥ 135 mm Hg or diastolic BP ≥ 85 mm Hg, or asleep systolic BP ≥ 120 mm Hg or diastolic BP ≥ 70 mm Hg. BP readings were confirmed with 48-hour ABPM. Exclusion criteria included pregnancy, a history of substance use disorder, night-shift work, and cardiovascular disease (defined as unstable angina, heart failure, life-threatening arrhythmia, atrial fibrillation, kidney failure, and grade III-IV retinopathy).

Prescribers were free to prescribe medicines from 5 classes (diuretic, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or beta-blocker) as they thought appropriate, were encouraged to use fixed-dose combination pills, and were told not to use split (eg, twice per day) dosing. Annual ­48-hour ABPM was completed, and patients’ electronic health records were analyzed by blinded investigators. Median follow-up was 6.3 years, and only 84 participants failed to complete the minimum 1-year participation requirement.

Continue to: The primary outcome...

The primary outcome—a composite of cardiovascular death, myocardial infarction, coronary revascularization, heart failure, or stroke—occurred in 1752 patients, favoring the bedtime group (HR = 0.55; 95% CI, 0.50-0.61; P < .001). The calculated number of events was 1130 in the morning administration group and 622 in the evening administration group; the authors did not explicitly report the event numbers in each group. Each component of the composite outcome also favored evening administration (P < .001 for all): cardiovascular death (HR = 0.44; 95% CI, 0.34-0.56), myocardial infarction (HR = 0.66; 95% CI, 0.52-0.84), coronary revascularization (HR = 0.60; 95% CI, 0.47-0.75), heart failure (HR = 0.58; 95% CI, 0.49-0.70), and stroke (HR = 0.51; 95% CI, 0.41-0.63).

The complicated, layered study design and randomization methods limit the ability to critically appraise the study.

Smaller Spanish study also supported evening administration

A prior, smaller, prospective randomized trial conducted by the same researchers as the Hygia Project found even greater benefits to evening BP medication administration.⁴ The 2156 Spanish patients (52% men; average age, 55 years) from multiple primary care offices were randomized 1:1 to BP medication administration either upon awakening or at bedtime. Dozens of baseline characteristics were evenly distributed except for age (55.0 vs 56.3; P = .021) and creatinine (0.96 vs 0.98; P = .028), both of which were lower in the evening group.

After a median follow-up of 5.6 years, the bedtime group had significantly lower total events (187 events in the morning group vs 68 in the evening group; relative risk [RR] = 0.39; 95% CI, 0.29-0.51; P < .001). Individual cardiovascular outcomes also dramatically favored the evening group: total deaths (12 vs 28; P = .008), cardiovascular deaths (3 vs 14; P = .006), cardiovascular disease events (30 vs 74; P < .001), stroke (7 vs 24; P = .001), and heart failure (8 vs 33; P < .001).

Limits of both the UK trial and the Hygia Project trial included single countries of study with a lack of racial and ethnic diversity, and greater nonadherence to the evening administration of the medications.

Recommendations from others

A 2022 consensus statement from the International Society of Hypertension, published before the UK trial, recommended against bedtime dosing until more high-quality data became available. They pointed to evidence showing higher medication adherence with morning dosing, risk for asleep BP dropping, and worsening daytime BP control as reasons to continue morning administration.⁵ Other reviewers have questioned the Hygia Project results due to their reported implausibly large effects on cardiovascular outcomes, noting that independent attempts to verify the methods and the data have proven challenging and are not completed.⁶

Editor’s takeaway

I confess that I was swayed by the results of the Hygia Project; for a year or so, I advised my patients to take at least 1 BP pill at night. But after the UK study came out, I needed to reconsider. I began to worry that the great outcomes of nocturnal therapy may have been a mirage. I have returned to counseling patients to take their BP medications in whichever way fosters consistency while minimizing adverse effects for them.

Evidence summary

Recent UK study shows no difference by timing

A 2022 UK prospective, randomized, multicenter trial assigned 21,104 predominantly White adults (58% men) with hypertension to take their usual antihypertensive medication either in the morning (6 am to 10 am) or evening (8 pm to midnight).¹ A computer algorithm randomized patients, but neither the patients nor the investigators were masked to allocation.

All patient baseline characteristics were equivalent between groups. If troubled by nocturia, patients in the evening group taking diuretics were told to take only the diuretic earlier (6 pm) and subsequently to change to morning if they experienced persistent bothersome symptoms. More patients in the evening administration group than in the morning administration group reported having to change the time of day that they took their diuretic (546 [5.2%] vs 71 [0.7%]; P < .0001).

The median follow-up was 5.2 years. Data were collected at regular intervals through patient completion of online questionnaires and researcher analysis of ­National Health Service data on hospitalization and death. The intention-to-treat analysis showed no difference in the primary outcome (a composite of vascular death, nonfatal myocardial infarction, or nonfatal stroke) between the evening and morning administration groups (0.69 events vs 0.72 events per 100 person-years; hazard ratio [HR] = 0.95; 95% CI, 0.83-1.10; P = .53).

The controversial Hygia Project favored evening

Prior to the UK study was the Hygia Chronotherapy Trial, a prospective, controlled, multicenter study conducted within the primary care setting in Spain. Caucasian Spanish adults (N = 19,168; mean age, 61 years; 56% men) with hypertension were randomly assigned to take all prescribed antihypertensive medication either at bedtime or upon waking.²

The Hygia Project initially sought to establish the value of ambulatory blood pressure monitoring (ABPM) compared to office blood pressure (BP) monitoring and to explore the prognostic value of sleeping BP.³ The study objectives evolved over time. The randomization process was not clearly described,^2,3 but multiple randomizations were alluded to. The authors stated that “for any of these chronotherapy trials” randomizations were done separately for “each participating center” and “randomization of participants to treatment-time regimen is done separately for each hypertension medication or combination being tested.”

A 2022 UK multicenter trial found no difference between the evening and morning administration groups in a composite outcome of vascular death, nonfatal myocardial infarction, or nonfatal stroke.

The baseline characteristics of patients in the evening and morning administration groups were similar, but statistically significant differences existed in BMI (29.6 vs 29.7; P = .030) and sleep-time systolic BP percent decline (9.3 vs 9.0; P < .001). Mean baseline 48-hour BP was 132/77 mm Hg. Hypertension was defined as an awake systolic BP ≥ 135 mm Hg or diastolic BP ≥ 85 mm Hg, or asleep systolic BP ≥ 120 mm Hg or diastolic BP ≥ 70 mm Hg. BP readings were confirmed with 48-hour ABPM. Exclusion criteria included pregnancy, a history of substance use disorder, night-shift work, and cardiovascular disease (defined as unstable angina, heart failure, life-threatening arrhythmia, atrial fibrillation, kidney failure, and grade III-IV retinopathy).

Prescribers were free to prescribe medicines from 5 classes (diuretic, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or beta-blocker) as they thought appropriate, were encouraged to use fixed-dose combination pills, and were told not to use split (eg, twice per day) dosing. Annual ­48-hour ABPM was completed, and patients’ electronic health records were analyzed by blinded investigators. Median follow-up was 6.3 years, and only 84 participants failed to complete the minimum 1-year participation requirement.

Continue to: The primary outcome...

The primary outcome—a composite of cardiovascular death, myocardial infarction, coronary revascularization, heart failure, or stroke—occurred in 1752 patients, favoring the bedtime group (HR = 0.55; 95% CI, 0.50-0.61; P < .001). The calculated number of events was 1130 in the morning administration group and 622 in the evening administration group; the authors did not explicitly report the event numbers in each group. Each component of the composite outcome also favored evening administration (P < .001 for all): cardiovascular death (HR = 0.44; 95% CI, 0.34-0.56), myocardial infarction (HR = 0.66; 95% CI, 0.52-0.84), coronary revascularization (HR = 0.60; 95% CI, 0.47-0.75), heart failure (HR = 0.58; 95% CI, 0.49-0.70), and stroke (HR = 0.51; 95% CI, 0.41-0.63).

The complicated, layered study design and randomization methods limit the ability to critically appraise the study.

Smaller Spanish study also supported evening administration

A prior, smaller, prospective randomized trial conducted by the same researchers as the Hygia Project found even greater benefits to evening BP medication administration.⁴ The 2156 Spanish patients (52% men; average age, 55 years) from multiple primary care offices were randomized 1:1 to BP medication administration either upon awakening or at bedtime. Dozens of baseline characteristics were evenly distributed except for age (55.0 vs 56.3; P = .021) and creatinine (0.96 vs 0.98; P = .028), both of which were lower in the evening group.

After a median follow-up of 5.6 years, the bedtime group had significantly lower total events (187 events in the morning group vs 68 in the evening group; relative risk [RR] = 0.39; 95% CI, 0.29-0.51; P < .001). Individual cardiovascular outcomes also dramatically favored the evening group: total deaths (12 vs 28; P = .008), cardiovascular deaths (3 vs 14; P = .006), cardiovascular disease events (30 vs 74; P < .001), stroke (7 vs 24; P = .001), and heart failure (8 vs 33; P < .001).

Limits of both the UK trial and the Hygia Project trial included single countries of study with a lack of racial and ethnic diversity, and greater nonadherence to the evening administration of the medications.

Recommendations from others

A 2022 consensus statement from the International Society of Hypertension, published before the UK trial, recommended against bedtime dosing until more high-quality data became available. They pointed to evidence showing higher medication adherence with morning dosing, risk for asleep BP dropping, and worsening daytime BP control as reasons to continue morning administration.⁵ Other reviewers have questioned the Hygia Project results due to their reported implausibly large effects on cardiovascular outcomes, noting that independent attempts to verify the methods and the data have proven challenging and are not completed.⁶

Editor’s takeaway

I confess that I was swayed by the results of the Hygia Project; for a year or so, I advised my patients to take at least 1 BP pill at night. But after the UK study came out, I needed to reconsider. I began to worry that the great outcomes of nocturnal therapy may have been a mirage. I have returned to counseling patients to take their BP medications in whichever way fosters consistency while minimizing adverse effects for them.

Evidence summary

Recent UK study shows no difference by timing

A 2022 UK prospective, randomized, multicenter trial assigned 21,104 predominantly White adults (58% men) with hypertension to take their usual antihypertensive medication either in the morning (6 am to 10 am) or evening (8 pm to midnight).¹ A computer algorithm randomized patients, but neither the patients nor the investigators were masked to allocation.

All patient baseline characteristics were equivalent between groups. If troubled by nocturia, patients in the evening group taking diuretics were told to take only the diuretic earlier (6 pm) and subsequently to change to morning if they experienced persistent bothersome symptoms. More patients in the evening administration group than in the morning administration group reported having to change the time of day that they took their diuretic (546 [5.2%] vs 71 [0.7%]; P < .0001).

The median follow-up was 5.2 years. Data were collected at regular intervals through patient completion of online questionnaires and researcher analysis of ­National Health Service data on hospitalization and death. The intention-to-treat analysis showed no difference in the primary outcome (a composite of vascular death, nonfatal myocardial infarction, or nonfatal stroke) between the evening and morning administration groups (0.69 events vs 0.72 events per 100 person-years; hazard ratio [HR] = 0.95; 95% CI, 0.83-1.10; P = .53).

The controversial Hygia Project favored evening

Prior to the UK study was the Hygia Chronotherapy Trial, a prospective, controlled, multicenter study conducted within the primary care setting in Spain. Caucasian Spanish adults (N = 19,168; mean age, 61 years; 56% men) with hypertension were randomly assigned to take all prescribed antihypertensive medication either at bedtime or upon waking.²

The Hygia Project initially sought to establish the value of ambulatory blood pressure monitoring (ABPM) compared to office blood pressure (BP) monitoring and to explore the prognostic value of sleeping BP.³ The study objectives evolved over time. The randomization process was not clearly described,^2,3 but multiple randomizations were alluded to. The authors stated that “for any of these chronotherapy trials” randomizations were done separately for “each participating center” and “randomization of participants to treatment-time regimen is done separately for each hypertension medication or combination being tested.”

A 2022 UK multicenter trial found no difference between the evening and morning administration groups in a composite outcome of vascular death, nonfatal myocardial infarction, or nonfatal stroke.

The baseline characteristics of patients in the evening and morning administration groups were similar, but statistically significant differences existed in BMI (29.6 vs 29.7; P = .030) and sleep-time systolic BP percent decline (9.3 vs 9.0; P < .001). Mean baseline 48-hour BP was 132/77 mm Hg. Hypertension was defined as an awake systolic BP ≥ 135 mm Hg or diastolic BP ≥ 85 mm Hg, or asleep systolic BP ≥ 120 mm Hg or diastolic BP ≥ 70 mm Hg. BP readings were confirmed with 48-hour ABPM. Exclusion criteria included pregnancy, a history of substance use disorder, night-shift work, and cardiovascular disease (defined as unstable angina, heart failure, life-threatening arrhythmia, atrial fibrillation, kidney failure, and grade III-IV retinopathy).

Prescribers were free to prescribe medicines from 5 classes (diuretic, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or beta-blocker) as they thought appropriate, were encouraged to use fixed-dose combination pills, and were told not to use split (eg, twice per day) dosing. Annual ­48-hour ABPM was completed, and patients’ electronic health records were analyzed by blinded investigators. Median follow-up was 6.3 years, and only 84 participants failed to complete the minimum 1-year participation requirement.

Continue to: The primary outcome...

The primary outcome—a composite of cardiovascular death, myocardial infarction, coronary revascularization, heart failure, or stroke—occurred in 1752 patients, favoring the bedtime group (HR = 0.55; 95% CI, 0.50-0.61; P < .001). The calculated number of events was 1130 in the morning administration group and 622 in the evening administration group; the authors did not explicitly report the event numbers in each group. Each component of the composite outcome also favored evening administration (P < .001 for all): cardiovascular death (HR = 0.44; 95% CI, 0.34-0.56), myocardial infarction (HR = 0.66; 95% CI, 0.52-0.84), coronary revascularization (HR = 0.60; 95% CI, 0.47-0.75), heart failure (HR = 0.58; 95% CI, 0.49-0.70), and stroke (HR = 0.51; 95% CI, 0.41-0.63).

The complicated, layered study design and randomization methods limit the ability to critically appraise the study.

Smaller Spanish study also supported evening administration

A prior, smaller, prospective randomized trial conducted by the same researchers as the Hygia Project found even greater benefits to evening BP medication administration.⁴ The 2156 Spanish patients (52% men; average age, 55 years) from multiple primary care offices were randomized 1:1 to BP medication administration either upon awakening or at bedtime. Dozens of baseline characteristics were evenly distributed except for age (55.0 vs 56.3; P = .021) and creatinine (0.96 vs 0.98; P = .028), both of which were lower in the evening group.

After a median follow-up of 5.6 years, the bedtime group had significantly lower total events (187 events in the morning group vs 68 in the evening group; relative risk [RR] = 0.39; 95% CI, 0.29-0.51; P < .001). Individual cardiovascular outcomes also dramatically favored the evening group: total deaths (12 vs 28; P = .008), cardiovascular deaths (3 vs 14; P = .006), cardiovascular disease events (30 vs 74; P < .001), stroke (7 vs 24; P = .001), and heart failure (8 vs 33; P < .001).

Limits of both the UK trial and the Hygia Project trial included single countries of study with a lack of racial and ethnic diversity, and greater nonadherence to the evening administration of the medications.

Recommendations from others

A 2022 consensus statement from the International Society of Hypertension, published before the UK trial, recommended against bedtime dosing until more high-quality data became available. They pointed to evidence showing higher medication adherence with morning dosing, risk for asleep BP dropping, and worsening daytime BP control as reasons to continue morning administration.⁵ Other reviewers have questioned the Hygia Project results due to their reported implausibly large effects on cardiovascular outcomes, noting that independent attempts to verify the methods and the data have proven challenging and are not completed.⁶

Editor’s takeaway

I confess that I was swayed by the results of the Hygia Project; for a year or so, I advised my patients to take at least 1 BP pill at night. But after the UK study came out, I needed to reconsider. I began to worry that the great outcomes of nocturnal therapy may have been a mirage. I have returned to counseling patients to take their BP medications in whichever way fosters consistency while minimizing adverse effects for them.

THE CASE

A 51-year-old Japanese woman presented with fever, sore throat, and dyspnea of less than 1 day’s duration. Although she had developed general fatigue, palpitations, and tremors of the hands 2 months earlier, she had not sought medical care.

Her medical history included Graves disease, which had been diagnosed 13 years earlier. She reported that her only medication was methimazole 10 mg/d. She did not have any family history of endocrinopathies or hematologic diseases.

Physical examination revealed a body temperature of 99.7 °F; heart rate, 130 beats/min; blood pressure, 182/62 mm Hg; respiratory rate, 46 breaths/min; and oxygen saturation, 100% on room air. Pharyngeal erythema was seen. Lung sounds were clear. The patient had tremors in her hands, tenderness of the thyroid gland, and exophthalmos. No leg edema or jugular vein distension was seen.

Laboratory tests indicated hyperthyroidism, with a thyroid-stimulating hormone level < 0.01 µIU/mL (normal range, 0.5-5 µIU/mL); free T3 level, 4.87 pg/mL (normal range, 2.3-4.3 pg/mL); and free T4 level, 2.97 ng/dL (normal range, 0.9-1.7 ng/dL). The patient also had a white blood cell (WBC) count of 1020 cells/µL (normal range, 3500-9000 cells/µL) and neutrophil count of 5 cells/µL (normal range, 1500-6500 cells/µL).

Other blood cell counts were normal, and a chest x-ray did not reveal any abnormal findings. In addition, there was no evidence to suggest hematologic malignancies or congenital neutropenia.

THE DIAGNOSIS

Based on the patient’s low WBC and neutrophil counts, agranulocytosis due to antithyroid drug therapy was suspected; however, this diagnosis would be highly unusual in the context of a 13-year history of therapy. Further history taking revealed that, because of her lack of financial means, unstable living conditions, and lack of understanding of the necessity for medication adherence, the patient had not taken methimazole regularly until 2 months prior to presentation, when she started taking it because of worsening symptoms. She had hesitated to report her social and medication status due to embarrassment.

In consideration of these factors, a diagnosis of exacerbation of hyperthyroidism and agranulocytosis (due to methimazole restart and upper respiratory infection) was made.

Continue to: DISCUSSION

Agranulocytosis is a severe adverse event of antithyroid agents and requires prompt diagnosis and treatment. In a 26-year study at one clinic, it occurred in approximately 0.4% of patients taking antithyroid agents.¹ The possible mechanisms of agranulocytosis are the direct toxicity of drugs and immune-mediated responses.² Older age, female sex, and some HLA genotypes are reported to be associated with susceptibility to agranulocytosis.²

Although the development of agranulocytosis tends to be dose related, a small dose of antithyroid agent can sometimes cause the condition.^3,4 It usually occurs within the first 3 months of treatment initiation, but occasionally patients develop agranulocytosis after long-term therapy.⁵ Interruption and subsequent resumption of the same antithyroid drug treatment also can be a risk factor for agranulocytosis, as in this case.⁵

Treatment includes drug cessation, administration of broad-spectrum antibiotics if infection is suspected, and granulocyte-­colony stimulating factor (G-CSF) therapy.⁵

Our patient was hospitalized, and methimazole was stopped immediately. Administration of potassium iodide 50 mg/d and G-CSF was started. Meropenem 3 g/d also was administered for neutropenic fever.

The patient’s condition improved, and her WBC count increased to 1640 cells/µL on Day 8 and 10,890 cells/µL on Day 9. G-CSF was stopped on Day 12 and meropenem on Day 13. Bone marrow aspiration was not performed because of improvement in lab values and her overall condition. Although monitoring of WBC count during methimazole therapy is controversial,⁵ we decided to routinely monitor this patient due to the possibility of drug cross-reactivity.

Continue to: Despite repeated explanations...

Despite repeated explanations that it was dangerous for a patient who had developed agranulocytosis to take another antithyroid medication, the patient refused surgical treatment or radioiodine ablation because of her financial situation. (While all Japanese citizens are covered by a national health insurance program, patients ages 6 to 70 years are required to pay approximately 30% of medical and pharmaceutical costs.) On Day 21, potassium iodide was stopped, and propylthiouracil 300 mg/d was administered with careful follow-up. Agranulocytosis did not recur.

Immediate problem solved, but what about the future?

During her hospital stay, the medical team spoke with the patient many times, during which she expressed anxiety about her health conditions and the difficulties that she had experienced in her life. The clinicians acknowledged her concerns and assured the patient of their continuing commitment to her well-being even after discharge. The patient also was advised that she should take her medication as prescribed and that if she had a fever or sore throat, she should stop the medication and seek medical care as soon as possible. The patient accepted the medical team’s advice and expressed hope for the future.

Conversations about medication adherence. In 1 survey, about 60% of patients taking antithyroid drugs were unfamiliar with the symptoms of agranulocytosis.⁶ To deliver safe and effective treatment and detect conditions such as agranulocytosis at an early stage, clinicians must communicate clearly with patients who have hyperthyroidism, providing sufficient explanation and ensuring understanding on the patient’s part.

Interruption and subsequent resumption of the same antithyroid drug treatment also can be a risk factor for agranulocytosis, as in this case.

Patients may be reluctant to provide the details of medication adherence.⁷ Although it is common for patients to need services for socioeconomic issues,⁸ health care professionals sometimes fail to adequately discuss these issues with patients, especially if the patients are marginalized and/or have lower economic status.⁹ Cases such as ours underscore the importance of improving clinicians’ awareness and sensitivity to patients’ socioeconomic challenges.^10,11

Our patient received information about welfare and other government services from a medical social worker during her hospital stay. She also was informed that she could seek assistance from medical social workers in the future if needed.

Continue to: The patient was discharged...

The patient was discharged on Day 28. After discharge, she took propylthiouracil as prescribed (300 mg/d), and her Graves disease was well controlled. Outpatient follow-up visits were performed every 1 or 2 months. No adverse events of propylthiouracil were seen in the ensuing time.

THE TAKEAWAY

Patients with chronic conditions sometimes discontinue medications, and they may not talk about it with their medical team, especially if they have socioeconomic or other difficulties in their lives. Clinicians should consider medication nonadherence and its risk factors when patients with chronic conditions develop unexpected adverse events.

ACKNOWLEDGMENT
We thank Jane Charbonneau, DVM, from Edanz for doing an English-language review of a draft of this manuscript.

CORRESPONDENCE
Takuya Maejima, MD, Department of General Medicine and Primary Care, University of Tsukuba Hospital, 2-1-1 Amakubo, Tsukuba, Ibaraki 305-8576 Japan; t.maejima.2019@gmail.com

THE CASE

A 51-year-old Japanese woman presented with fever, sore throat, and dyspnea of less than 1 day’s duration. Although she had developed general fatigue, palpitations, and tremors of the hands 2 months earlier, she had not sought medical care.

Her medical history included Graves disease, which had been diagnosed 13 years earlier. She reported that her only medication was methimazole 10 mg/d. She did not have any family history of endocrinopathies or hematologic diseases.

Physical examination revealed a body temperature of 99.7 °F; heart rate, 130 beats/min; blood pressure, 182/62 mm Hg; respiratory rate, 46 breaths/min; and oxygen saturation, 100% on room air. Pharyngeal erythema was seen. Lung sounds were clear. The patient had tremors in her hands, tenderness of the thyroid gland, and exophthalmos. No leg edema or jugular vein distension was seen.

Laboratory tests indicated hyperthyroidism, with a thyroid-stimulating hormone level < 0.01 µIU/mL (normal range, 0.5-5 µIU/mL); free T3 level, 4.87 pg/mL (normal range, 2.3-4.3 pg/mL); and free T4 level, 2.97 ng/dL (normal range, 0.9-1.7 ng/dL). The patient also had a white blood cell (WBC) count of 1020 cells/µL (normal range, 3500-9000 cells/µL) and neutrophil count of 5 cells/µL (normal range, 1500-6500 cells/µL).

Other blood cell counts were normal, and a chest x-ray did not reveal any abnormal findings. In addition, there was no evidence to suggest hematologic malignancies or congenital neutropenia.

THE DIAGNOSIS

Based on the patient’s low WBC and neutrophil counts, agranulocytosis due to antithyroid drug therapy was suspected; however, this diagnosis would be highly unusual in the context of a 13-year history of therapy. Further history taking revealed that, because of her lack of financial means, unstable living conditions, and lack of understanding of the necessity for medication adherence, the patient had not taken methimazole regularly until 2 months prior to presentation, when she started taking it because of worsening symptoms. She had hesitated to report her social and medication status due to embarrassment.

In consideration of these factors, a diagnosis of exacerbation of hyperthyroidism and agranulocytosis (due to methimazole restart and upper respiratory infection) was made.

Continue to: DISCUSSION

Agranulocytosis is a severe adverse event of antithyroid agents and requires prompt diagnosis and treatment. In a 26-year study at one clinic, it occurred in approximately 0.4% of patients taking antithyroid agents.¹ The possible mechanisms of agranulocytosis are the direct toxicity of drugs and immune-mediated responses.² Older age, female sex, and some HLA genotypes are reported to be associated with susceptibility to agranulocytosis.²

Although the development of agranulocytosis tends to be dose related, a small dose of antithyroid agent can sometimes cause the condition.^3,4 It usually occurs within the first 3 months of treatment initiation, but occasionally patients develop agranulocytosis after long-term therapy.⁵ Interruption and subsequent resumption of the same antithyroid drug treatment also can be a risk factor for agranulocytosis, as in this case.⁵

Treatment includes drug cessation, administration of broad-spectrum antibiotics if infection is suspected, and granulocyte-­colony stimulating factor (G-CSF) therapy.⁵

Our patient was hospitalized, and methimazole was stopped immediately. Administration of potassium iodide 50 mg/d and G-CSF was started. Meropenem 3 g/d also was administered for neutropenic fever.

The patient’s condition improved, and her WBC count increased to 1640 cells/µL on Day 8 and 10,890 cells/µL on Day 9. G-CSF was stopped on Day 12 and meropenem on Day 13. Bone marrow aspiration was not performed because of improvement in lab values and her overall condition. Although monitoring of WBC count during methimazole therapy is controversial,⁵ we decided to routinely monitor this patient due to the possibility of drug cross-reactivity.

Continue to: Despite repeated explanations...

Despite repeated explanations that it was dangerous for a patient who had developed agranulocytosis to take another antithyroid medication, the patient refused surgical treatment or radioiodine ablation because of her financial situation. (While all Japanese citizens are covered by a national health insurance program, patients ages 6 to 70 years are required to pay approximately 30% of medical and pharmaceutical costs.) On Day 21, potassium iodide was stopped, and propylthiouracil 300 mg/d was administered with careful follow-up. Agranulocytosis did not recur.

Immediate problem solved, but what about the future?

During her hospital stay, the medical team spoke with the patient many times, during which she expressed anxiety about her health conditions and the difficulties that she had experienced in her life. The clinicians acknowledged her concerns and assured the patient of their continuing commitment to her well-being even after discharge. The patient also was advised that she should take her medication as prescribed and that if she had a fever or sore throat, she should stop the medication and seek medical care as soon as possible. The patient accepted the medical team’s advice and expressed hope for the future.

Conversations about medication adherence. In 1 survey, about 60% of patients taking antithyroid drugs were unfamiliar with the symptoms of agranulocytosis.⁶ To deliver safe and effective treatment and detect conditions such as agranulocytosis at an early stage, clinicians must communicate clearly with patients who have hyperthyroidism, providing sufficient explanation and ensuring understanding on the patient’s part.

Interruption and subsequent resumption of the same antithyroid drug treatment also can be a risk factor for agranulocytosis, as in this case.

Patients may be reluctant to provide the details of medication adherence.⁷ Although it is common for patients to need services for socioeconomic issues,⁸ health care professionals sometimes fail to adequately discuss these issues with patients, especially if the patients are marginalized and/or have lower economic status.⁹ Cases such as ours underscore the importance of improving clinicians’ awareness and sensitivity to patients’ socioeconomic challenges.^10,11

Our patient received information about welfare and other government services from a medical social worker during her hospital stay. She also was informed that she could seek assistance from medical social workers in the future if needed.

Continue to: The patient was discharged...

The patient was discharged on Day 28. After discharge, she took propylthiouracil as prescribed (300 mg/d), and her Graves disease was well controlled. Outpatient follow-up visits were performed every 1 or 2 months. No adverse events of propylthiouracil were seen in the ensuing time.

THE TAKEAWAY

Patients with chronic conditions sometimes discontinue medications, and they may not talk about it with their medical team, especially if they have socioeconomic or other difficulties in their lives. Clinicians should consider medication nonadherence and its risk factors when patients with chronic conditions develop unexpected adverse events.

ACKNOWLEDGMENT
We thank Jane Charbonneau, DVM, from Edanz for doing an English-language review of a draft of this manuscript.

CORRESPONDENCE
Takuya Maejima, MD, Department of General Medicine and Primary Care, University of Tsukuba Hospital, 2-1-1 Amakubo, Tsukuba, Ibaraki 305-8576 Japan; t.maejima.2019@gmail.com

THE CASE

A 51-year-old Japanese woman presented with fever, sore throat, and dyspnea of less than 1 day’s duration. Although she had developed general fatigue, palpitations, and tremors of the hands 2 months earlier, she had not sought medical care.

Her medical history included Graves disease, which had been diagnosed 13 years earlier. She reported that her only medication was methimazole 10 mg/d. She did not have any family history of endocrinopathies or hematologic diseases.

Physical examination revealed a body temperature of 99.7 °F; heart rate, 130 beats/min; blood pressure, 182/62 mm Hg; respiratory rate, 46 breaths/min; and oxygen saturation, 100% on room air. Pharyngeal erythema was seen. Lung sounds were clear. The patient had tremors in her hands, tenderness of the thyroid gland, and exophthalmos. No leg edema or jugular vein distension was seen.

Laboratory tests indicated hyperthyroidism, with a thyroid-stimulating hormone level < 0.01 µIU/mL (normal range, 0.5-5 µIU/mL); free T3 level, 4.87 pg/mL (normal range, 2.3-4.3 pg/mL); and free T4 level, 2.97 ng/dL (normal range, 0.9-1.7 ng/dL). The patient also had a white blood cell (WBC) count of 1020 cells/µL (normal range, 3500-9000 cells/µL) and neutrophil count of 5 cells/µL (normal range, 1500-6500 cells/µL).

Other blood cell counts were normal, and a chest x-ray did not reveal any abnormal findings. In addition, there was no evidence to suggest hematologic malignancies or congenital neutropenia.

THE DIAGNOSIS

Based on the patient’s low WBC and neutrophil counts, agranulocytosis due to antithyroid drug therapy was suspected; however, this diagnosis would be highly unusual in the context of a 13-year history of therapy. Further history taking revealed that, because of her lack of financial means, unstable living conditions, and lack of understanding of the necessity for medication adherence, the patient had not taken methimazole regularly until 2 months prior to presentation, when she started taking it because of worsening symptoms. She had hesitated to report her social and medication status due to embarrassment.

In consideration of these factors, a diagnosis of exacerbation of hyperthyroidism and agranulocytosis (due to methimazole restart and upper respiratory infection) was made.

Continue to: DISCUSSION

Agranulocytosis is a severe adverse event of antithyroid agents and requires prompt diagnosis and treatment. In a 26-year study at one clinic, it occurred in approximately 0.4% of patients taking antithyroid agents.¹ The possible mechanisms of agranulocytosis are the direct toxicity of drugs and immune-mediated responses.² Older age, female sex, and some HLA genotypes are reported to be associated with susceptibility to agranulocytosis.²

Although the development of agranulocytosis tends to be dose related, a small dose of antithyroid agent can sometimes cause the condition.^3,4 It usually occurs within the first 3 months of treatment initiation, but occasionally patients develop agranulocytosis after long-term therapy.⁵ Interruption and subsequent resumption of the same antithyroid drug treatment also can be a risk factor for agranulocytosis, as in this case.⁵

Treatment includes drug cessation, administration of broad-spectrum antibiotics if infection is suspected, and granulocyte-­colony stimulating factor (G-CSF) therapy.⁵

Our patient was hospitalized, and methimazole was stopped immediately. Administration of potassium iodide 50 mg/d and G-CSF was started. Meropenem 3 g/d also was administered for neutropenic fever.

The patient’s condition improved, and her WBC count increased to 1640 cells/µL on Day 8 and 10,890 cells/µL on Day 9. G-CSF was stopped on Day 12 and meropenem on Day 13. Bone marrow aspiration was not performed because of improvement in lab values and her overall condition. Although monitoring of WBC count during methimazole therapy is controversial,⁵ we decided to routinely monitor this patient due to the possibility of drug cross-reactivity.

Continue to: Despite repeated explanations...

Despite repeated explanations that it was dangerous for a patient who had developed agranulocytosis to take another antithyroid medication, the patient refused surgical treatment or radioiodine ablation because of her financial situation. (While all Japanese citizens are covered by a national health insurance program, patients ages 6 to 70 years are required to pay approximately 30% of medical and pharmaceutical costs.) On Day 21, potassium iodide was stopped, and propylthiouracil 300 mg/d was administered with careful follow-up. Agranulocytosis did not recur.

Immediate problem solved, but what about the future?

During her hospital stay, the medical team spoke with the patient many times, during which she expressed anxiety about her health conditions and the difficulties that she had experienced in her life. The clinicians acknowledged her concerns and assured the patient of their continuing commitment to her well-being even after discharge. The patient also was advised that she should take her medication as prescribed and that if she had a fever or sore throat, she should stop the medication and seek medical care as soon as possible. The patient accepted the medical team’s advice and expressed hope for the future.

Conversations about medication adherence. In 1 survey, about 60% of patients taking antithyroid drugs were unfamiliar with the symptoms of agranulocytosis.⁶ To deliver safe and effective treatment and detect conditions such as agranulocytosis at an early stage, clinicians must communicate clearly with patients who have hyperthyroidism, providing sufficient explanation and ensuring understanding on the patient’s part.

Interruption and subsequent resumption of the same antithyroid drug treatment also can be a risk factor for agranulocytosis, as in this case.

Patients may be reluctant to provide the details of medication adherence.⁷ Although it is common for patients to need services for socioeconomic issues,⁸ health care professionals sometimes fail to adequately discuss these issues with patients, especially if the patients are marginalized and/or have lower economic status.⁹ Cases such as ours underscore the importance of improving clinicians’ awareness and sensitivity to patients’ socioeconomic challenges.^10,11

Our patient received information about welfare and other government services from a medical social worker during her hospital stay. She also was informed that she could seek assistance from medical social workers in the future if needed.

Continue to: The patient was discharged...

The patient was discharged on Day 28. After discharge, she took propylthiouracil as prescribed (300 mg/d), and her Graves disease was well controlled. Outpatient follow-up visits were performed every 1 or 2 months. No adverse events of propylthiouracil were seen in the ensuing time.

THE TAKEAWAY

Patients with chronic conditions sometimes discontinue medications, and they may not talk about it with their medical team, especially if they have socioeconomic or other difficulties in their lives. Clinicians should consider medication nonadherence and its risk factors when patients with chronic conditions develop unexpected adverse events.

ACKNOWLEDGMENT
We thank Jane Charbonneau, DVM, from Edanz for doing an English-language review of a draft of this manuscript.

CORRESPONDENCE
Takuya Maejima, MD, Department of General Medicine and Primary Care, University of Tsukuba Hospital, 2-1-1 Amakubo, Tsukuba, Ibaraki 305-8576 Japan; t.maejima.2019@gmail.com

More than 1.2 million Americans are living with HIV, and more than 30,000 new cases are diagnosed each year. While total incidence has declined since 2016, HIV remains a nationwide epidemic.¹

Medications that prevent HIV acquisition, termed preexposure prophylaxis (PrEP), are an important tool to initiate in the primary care setting to reduce HIV transmission. However, while there are an estimated 1.2 million people eligible for PrEP, only 36% have received PrEP prescriptions.² Several barriers that have impeded its widespread adoption include a lack of clinician knowledge and clinical resources for testing, high medication costs, and stigma around sexual health and intravenous (IV) drug use.

The value of PrEP

PrEP is chemoprophylaxis against the acquisition of HIV infection through the administration of an oral or injectable medication to people at risk for HIV. This practice began in the early 2000s, with the first oral regimen approved in 2012, and since has become an important tool in preventing HIV transmission.

When taken as prescribed, PrEP medications reduce the risk for acquiring HIV through sex by approximately 99% and can reduce the risk for acquiring HIV from injection drug use by approximately 74%.³ The US Preventive Services Task Force issued a Grade “A” recommendation to offer PrEP to people at high risk for HIV acquisition in June 2019 and reaffirmed it in a 2023 update.⁴

PrEP is notably distinct from postexposure prophylaxis (PEP), which is the administration of medication to prevent HIV infection after a possible exposure.

The available regimens

Regimens for PrEP include oral tablets or intramuscular (IM) injections.⁵ There are 3 PrEP regimens approved by the US Food and Drug Administration (FDA): tenofovir disoproxil fumarate/­emtricitabine (Truvada), tenofovir ­alafenamide/emtricitabine (Descovy), and cabotegravir (Apretude).

Incomplete adherence to or abrupt discontinuation of oral PrEP could precipitate a hepatitis B flare.

Truvada is once-daily oral PrEP that was approved in 2012 and is now available in a generic formulation. Notable adverse effects of Truvada include a small negative impact on renal function and small reductions in bone mineral density; these have been noted in individual trials, but in meta-­analyses such differences were not found to be statistically significant.^6-8 The most common adverse effects of Truvada, experienced by up to 6% of patients, are gastrointestinal symptoms, fatigue, headache/dizziness, depression, and insomnia; most symptoms resolve within weeks.

Continue to: Descovy

Descovy is daily oral PrEP that was approved in 2019. Descovy is associated with increases in LDL and triglycerides but has less impact on renal and bone health.⁹ The most common adverse effect of Descovy, experienced by about 5% of patients, is diarrhea, followed by nausea.

Apretude was approved in 2021 and is a 600-mg IM injection given monthly for 2 months, then every 2 months (± 7 days). The advantages of Apretude are frequency and discreteness of dosing and the ability to use in patients with estimated creatinine clearance (eCrCl) > 15 mL/min. The most common adverse effects of Apretude are injection-site reactions, which occur in 30% to 80% of patients but are rarely significant enough to lead to discontinuation (< 2% of patients discontinue use due to injection-site reactions).¹⁰ 

Who should take PrEP?

The latest Centers for Disease Control and Prevention (CDC) guidelines recommend that all sexually active adults receive information about PrEP.⁵ Indications for PrEP are broad and summarized in the FIGURE.⁵

JFP07211e1_f1.jpg

PrEP is indicated in patients who report sexual or injection drug use behaviors that place them at substantial ongoing risk for HIV exposure. Specific indications include patients with sexual partner(s) with unknown HIV status with whom they have inconsistent or no condom use, a history of bacterial sexually transmitted infection (STI) in the past 6 months, an HIV-positive sexual partner, or the sharing of injection drug equipment.

Hepatitis B infection is not a contraindication for PrEP use, but knowledge of infection status is essential. All current oral medications used for PrEP have activity against hepatitis B. Incomplete adherence to or abrupt discontinuation of oral PrEP could precipitate a hepatitis B flare. Hepatitis B surface antigen should be tested at the time of PrEP initiation, although PrEP can begin while testing is in process.

Continue to: How to use PrEP

At PrEP initiation, acute or chronic HIV infection must be excluded with a documented negative HIV antigen/antibody test within 1 week of prescribing PrEP.⁵ The CDC guidelines provide an updated HIV testing algorithm (www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2021.pdf, p 30-31, Figures 4a and 4b), which considers whether patients have received PrEP recently.

Patients with recent high-risk exposures or symptoms of acute HIV at the time of desired PrEP initiation should have an HIV-1 viral load checked with negative results before PrEP is prescribed. Additional criteria for PrEP include weight > 35 kg; screening for hepatitis B virus infection; screening for drug interactions; and drug-specific eCrCl cutoffs of > 60 mL/min for Truvada, > 30 mL/min for Descovy, and > 15 mL/min for Apretude.⁵

Studies regarding time to medication effectiveness are limited. Pharmacokinetic studies of Truvada demonstrate sufficient drug concentrations should be present in peripheral blood mononuclear cells and rectal tissue within 7 days of initiation of oral dosing and around 20 days in vaginal tissue.

Of note, while expedited partner therapy is used as a harm-reduction strategy to treat the sexual partners of patients diagnosed with certain STIs, PrEP is not recommended to be used in this way.

Ongoing monitoring with PrEP. Once oral PrEP is started, STI risk assessment and HIV testing via 4th generation antibody/antigen­ test should be completed at least every 3 months. PrEP oral prescription refills should be limited to 3 months. For patients receiving IM PrEP (Apretude), HIV testing via viral load and antibody/antigen testing should be done at the time of each injection (every 2 months).⁵

Continue to: With oral PrEP...

With oral PrEP, renal function should be checked every 6 months in patients older than 50 years or those with eCrCl < 90 mL/min at initiation. For patients younger than 50 years with no baseline renal dysfunction, the latest guidelines now recommend monitoring every 12 months instead of 6 months.⁵

For patients on Descovy, a lipid panel is recommended at PrEP initiation and every 12 months. Testing for other STIs can be considered on this schedule, based on clinical assessment. The TABLE⁵ summarizes recommended monitoring for patients taking oral PrEP.

JFP07211e1_t1.jpg

Recommended follow-up provides an opportunity to have frequent contact with a potentially high-risk population, and PrEP should be one part of a comprehensive HIV prevention and risk reduction plan. Many patients at high risk for HIV acquisition may benefit from frequent follow-up to address screening, referral, and treatment of substance use disorders, mental health conditions, and chronic medical conditions (including hepatitis C infection) and provide ongoing preventive health care. 

Special uses of PrEP 

Same-day PrEP. Starting PrEP on the day of the initial appointment may be appropriate based on patient risk factors and barriers to care, such as a high risk for contracting HIV before the subsequent appointment for a prescription of PrEP or an inability to return to the clinic in a timely fashion due to transportation or work constraints, or clinician availability. For these patients, assuming there is a low concern for acute or chronic HIV infection, PrEP can be initiated on the day of the initial visit.⁵

In these cases, point-of-care HIV and creatinine testing with same-day results should be completed. Antigen/antibody fingerstick testing or HIV-1 RNA test are preferred; oral fluid HIV testing should not be used for same-day PrEP due to its lower sensitivity for HIV detection. If same-day testing is unavailable, blood should be drawn at the visit so that HIV and creatinine testing can be completed as soon as possible.

Continue to: In addition to initial laboratory testing...

In addition to initial laboratory testing, clinics offering same-day PrEP should be able to provide: (1) assistance for patients to enroll in health insurance or a medication assistance program (eg, Ready, Set, PrEP) for those ineligible for insurance coverage, (2) rapid follow-­up on all laboratory results with reliable patient contact information, and (3) follow-up appointments with clinicians able to prescribe and administer PrEP medications.

Off-label “on-demand” PrEP. An off-label treatment regimen for men who have sex with men (MSM) is termed “on-demand” PrEP or “2-1-1 PrEP” and is included in the CDC guidelines for consideration by clinicians.⁵ This alternative dosing schedule can be used for individuals who have sex less frequently and in a more planned fashion.

On-demand PrEP requires a patient to take 2 tablets of Truvada 2 to 24 hours before sex, followed by 1 tablet 24 hours and 1 tablet 48 hours after sexual activity. If a sexual act occurs at 48 hours, the patient should extend the daily dose for 48 additional hours, such that PrEP is always used daily for 48 hours after the last sex act.

This method has been studied with Truvada in MSM in Europe and Canada through the IPERGAY and PREVENIR trials and shown to have ≥ 86% efficacy in preventing HIV acquisition.^11,12 The only US-based study showed lower efficacy; however, based on the currently available data, the International Antiviral Society-USA Panel has recommended it as an alternative regimen.^13,14

PrEP via telehealth. Visits for PrEP initiation and continuation can be completed via telehealth.⁵ Patients then can complete necessary laboratory tests by going to a physical laboratory location or using mailed specimen kits in which they can self-collect urine, oral/rectal swabs, and fingerstick blood samples.

Continue to: PrEP use in specific populations

Adolescents

Truvada, Descovy, and Apretude all are now approved for use in adolescents weighing ≥ 35 kg. Two important considerations when prescribing to this population are the effects of Truvada on bone health and the unique barriers to access.

In studies of adolescent MSM using Truvada for PrEP, bone mineral density declined, especially among those ages 15 to 19 years.¹⁵ As such, the clinical impact of decreased bone mineral density should be weighed against the risk for HIV acquisition; however, bone mineral density monitoring is not recommended in the current guidelines. CDC guidelines suggest considering Descovy for male adolescents given its potential lower impact on bone mineral density.⁵

Confidentiality and legal issues exist when prescribing PrEP to minors. In terms of parental/guardian involvement, clinicians who are prescribing PrEP for patients younger than 18 years should consult the CDC website for guidance on local and state regulations that govern prescribing and confidentiality (www.cdc.gov/hiv/policies/law/states/­minors.html).

CDC guidelines suggest considering Descovy for male adolescents given its potential lower impact on bone mineral density.

Insurance billing statements may lead to inadvertent disclosure of a minor’s decision to take PrEP to their legal guardian.¹⁶ Generic Truvada costs less than $100 for a 3-month supply when using goodrx.com, which may offer an alternative to insurance for medication payment. 

Peripartum patients

The increased risk for HIV acquisition in the peripartum period for female patients is well documented.¹⁷ Guidelines recommend offering PrEP with Truvada to female patients at risk for conception, currently pregnant, or breastfeeding when that patient’s partner has HIV and the partner’s viral load is unknown or detectable. Descovy is not recommended for pregnant or breastfeeding patients.⁵ Cabotegravir­-containing regimens (Apretude) have not been approved by the FDA for pregnant or breastfeeding patients.⁵

Continue to: Data on the impact of...

Data on the impact of Truvada for PrEP on fetal health are still emerging. A large study in Kenya showed no significant differences in preterm birth, low birth weight, or early infant growth, and a randomized, noninferiority trial in South Africa showed no association between Truvada for PrEP and preterm birth or the birth of small-for-­gestational-age infants.^18,19 There are no definitive studies of breastfeeding infants exposed to Truvada, but data from previous trials of breastfeeding mothers who were taking the individual components that are combined in the Truvada pill indicated there is minimal medication exposure to the infant.⁵

PrEP studies in the peripartum period to date have been conducted exclusively among cisgender women, and data do not yet reflect the experiences of transgender men, genderqueer people, and nonbinary individuals in the peripartum period.⁵

Transgender people

Transgender women should be strongly considered candidates for PrEP as they are at an extremely high risk for HIV acquisition. The most recent National HIV Behavioral Surveillance survey found that approximately 42% of transgender women were living with HIV.²⁰ The survey revealed stark racial and ethnic disparities among transgender women living with HIV: 62% identified as Black/African American, compared with 35% Hispanic/Latina and 17% White.²⁰

Transgender women report high rates of sexual assault, unprotected receptive anal sex, commercial sex work, homelessness, mental health disorders, and substance use, putting them at increased risk for HIV acquisition.²¹ However, transgender women are less likely to have discussed PrEP with a clinician, are less likely to be on PrEP even when interested in starting, and have higher rates of medication nonadherence compared with cisgender MSM.^21,22 PrEP has not been found to decrease levels of feminizing hormones; however, studies are mixed as to whether feminizing hormones decrease Truvada concentrations in rectal mucosa, so clinicians should emphasize the importance of daily medication adherence.²³

Transgender men have not been included in any PrEP trials, so no specific recommendations are available. 

Continue to: Disparities in PrEP access and use exist

The lifetime risk for HIV acquisition is 9% among White MSM, 50% among Black MSM, and 20% among Hispanic MSM.²⁴ Despite this large disparity in disease burden, Black and Hispanic individuals are less likely to be aware of PrEP, have discussed PrEP with a health care professional, or used PrEP compared with their White counterparts.²⁵ As a result, in 2020, PrEP coverage for eligible White individuals was 61%, while coverage among eligible Black and Hispanic/Latino individuals was just 8% and 14%, respectively.²⁶

Rural areas have been shown to lag behind urban areas in PrEP awareness and use.

Surveillance data comparing male and female PrEP coverage reveal further disparities between the sexes, with PrEP coverage for eligible female-at-birth patients estimated to be 9% compared with 25.8% for male-at-birth patients.²⁶ The gap between the risk for HIV infection and the access to and uptake of PrEP coverage is most pronounced among Black women, for whom the rate of new HIV diagnosis is > 10 times higher than it is for White women, but who have some of the lowest awareness and utilization rates of all demographics.²⁷

The rural population at risk. Disparities in HIV awareness and PrEP use also exist between rural and urban populations, as well as by health insurance status. Rural areas have been shown to lag behind urban areas in PrEP awareness and use. Two potential explanations for this disparity are differences­ in HIV- and drug use–associated stigma and health insurance status. Greater stigma against drug use and HIV in rural areas has been associated with lower rates of PrEP use.²⁸

Individuals younger than 65 years in rural areas are less likely to have private health insurance and more likely to be uninsured compared with their urban counterparts, which may impact access to clinicians knowledgeable about PrEP.²⁹ Notably, MSM who live in states that have expanded Medicaid have higher rates of PrEP use compared with MSM living in states that have not expanded Medicaid.³⁰

Health insurers in the United States are required to cover PrEP medication, clinician visits, and associated blood work with no patient cost-sharing, although implementation barriers such as prior authorizations still exist. 

Conclusion

Family physicians are well positioned to identify patients at risk for HIV infection, prescribe PrEP, organize comprehensive follow-up care, and partner with their health systems and local communities to reduce barriers to care. Those who can leverage existing relationships with local health departments, school-based health clinics, congregate housing programs, LGBTQIA+ advocacy groups, harm-reduction coalitions, and other community-based organizations to raise PrEP awareness play a critical role in preventing HIV transmission and reducing health care disparities in their communities.

CORRESPONDENCE
Andrew V.A. Foley, MD, MPH, Erie Family Health Centers, 2418 W Division Street, Chicago, IL 60622; andrewvafoley@gmail.com