Article

ILLUSTRATIVE CASE

A 32-year-old primigravida at 10 weeks’ gestation presents for an initial prenatal visit. Medical history includes hypertension that is currently well controlled on labetalol 200 mg twice daily. The patient’s blood pressure (BP) at today’s visit is 125/80 mm Hg. Should labetalol be discontinued?

Chronic hypertension in pregnancy is hypertension that predates the pregnancy or with onset prior to 20 weeks’ gestation. Diagnostic criteria include systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg, use of antihypertensive medications prior to pregnancy, or pregnancy-related hypertension persisting > 12 weeks postpartum.^2,3 Chronic hypertension affects 0.9% to 5% of pregnancies and is associated with increased risk for complications, such as superimposed preeclampsia, small-for-gestational-age infant, preterm birth, cesarean delivery, and neonatal intensive care unit admission.⁴ Superimposed preeclampsia occurs in about 17% to 25% of pregnancies affected by chronic hypertension, compared with 3% to 5% of the general population.³

Historically, a higher treatment threshold of 160/110 mm Hg was preferred to avoid theoretical complications of low placental perfusion.² Practically, this often meant discontinuing antihypertensives at the onset of prenatal care if BP was well controlled. A few small trials previously demonstrated that tight BP goals reduced the risk for severe hypertension, but they did not show an improvement in pregnancy outcomes.^5-7 This larger RCT evaluated whether treatment of mild chronic hypertension in pregnancy at lower BP thresholds is associated with improved pregnancy outcomes without negative impact on fetal growth.

STUDY SUMMARY

Active BP treatment yielded better pregnancy outcomes

In a US multicenter, open-label RCT, 2419 pregnant patients with chronic hypertension and singleton fetuses at gestational age < 23 weeks were randomized to receive either active pharmacologic treatment with a BP goal of 140/90 mm Hg or standard treatment, in which BP medication was withheld unless BP reached 160/105 mm Hg (severe hypertension). If medication was initiated in the standard-treatment group, the goal was also 140/90 mm Hg. Exclusion criteria included severe hypertension or suspected intrauterine growth restriction at randomization, known secondary hypertension, certain high-risk comorbidities (eg, cardiac or renal disease), or a major fetal anomaly.

The American College of Obstetricians and Gynecologists and the Society for Maternal– Fetal Medicine have issued statements recommending a change in practice based on this trial.

First-line medications were labetalol or extended-release nifedipine in the majority of patients in the active-treatment group and in standard-treatment patients who developed severe hypertension. Patients were followed until 6 weeks after delivery. Intention­-to-treat analyses were performed. The primary outcome was a composite of fetal or neonatal death before 28 days of life, superimposed preeclampsia with severe features up to 2 weeks postpartum, placental abruption leading to delivery, and medically indicated preterm birth before 35 weeks’ gestation. Safety outcomes included birthweight < 10th and < 5th percentile for gestational age.

Primary outcome events occurred in 30.2% of the active-treatment group compared with 37% of the standard-treatment group (adjusted risk ratio [aRR] = 0.82; 95% CI, 0.74-0.92; number needed to treat [NNT] = 15). Preeclampsia with severe features (23.3% vs 29.1%; aRR = 0.80; 95% CI, 0.70-0.92) and medically indicated preterm birth before 35 weeks (12.2% vs 16.7%; aRR = 0.73; 95% CI, 0.6-0.89) occurred less often in the active-treatment group compared with the standard-treatment group. There were no differences in rates of placental abruption, fetal or neonatal death, or small-for-gestational-age infants.

WHAT’S NEW

Target BP of < 140/90 mm Hg reduced risk

This trial provides high-quality evidence that initiating or maintaining treatment at a nonsevere BP threshold (< 140/90 mm Hg) in pregnant patients with mild chronic hypertension reduces maternal and neonatal risk without increasing the risk for small-for-­gestational-age infants. The American College of Obstetricians and Gynecologists and the Society for Maternal–Fetal Medicine have issued statements recommending a change in practice based on this trial.^8,9

Continue to: CAVEATS

 

 

CAVEATS

Patient characteristics and medication choices were limited

This trial does not identify a BP goal for patients who are at highest risk for complications of hypertension or who already have been given a diagnosis of a growth-restricted fetus, as those patients were excluded.

Most patients in the trial who required medications received labetalol or extended-­release nifedipine. It is unclear if other medications would produce similar outcomes.

CHALLENGES TO IMPLEMENTATION

Limited challenges anticipated

There should be limited challenges to implementation.

ILLUSTRATIVE CASE

A 32-year-old primigravida at 10 weeks’ gestation presents for an initial prenatal visit. Medical history includes hypertension that is currently well controlled on labetalol 200 mg twice daily. The patient’s blood pressure (BP) at today’s visit is 125/80 mm Hg. Should labetalol be discontinued?

Chronic hypertension in pregnancy is hypertension that predates the pregnancy or with onset prior to 20 weeks’ gestation. Diagnostic criteria include systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg, use of antihypertensive medications prior to pregnancy, or pregnancy-related hypertension persisting > 12 weeks postpartum.^2,3 Chronic hypertension affects 0.9% to 5% of pregnancies and is associated with increased risk for complications, such as superimposed preeclampsia, small-for-gestational-age infant, preterm birth, cesarean delivery, and neonatal intensive care unit admission.⁴ Superimposed preeclampsia occurs in about 17% to 25% of pregnancies affected by chronic hypertension, compared with 3% to 5% of the general population.³

Historically, a higher treatment threshold of 160/110 mm Hg was preferred to avoid theoretical complications of low placental perfusion.² Practically, this often meant discontinuing antihypertensives at the onset of prenatal care if BP was well controlled. A few small trials previously demonstrated that tight BP goals reduced the risk for severe hypertension, but they did not show an improvement in pregnancy outcomes.^5-7 This larger RCT evaluated whether treatment of mild chronic hypertension in pregnancy at lower BP thresholds is associated with improved pregnancy outcomes without negative impact on fetal growth.

STUDY SUMMARY

Active BP treatment yielded better pregnancy outcomes

In a US multicenter, open-label RCT, 2419 pregnant patients with chronic hypertension and singleton fetuses at gestational age < 23 weeks were randomized to receive either active pharmacologic treatment with a BP goal of 140/90 mm Hg or standard treatment, in which BP medication was withheld unless BP reached 160/105 mm Hg (severe hypertension). If medication was initiated in the standard-treatment group, the goal was also 140/90 mm Hg. Exclusion criteria included severe hypertension or suspected intrauterine growth restriction at randomization, known secondary hypertension, certain high-risk comorbidities (eg, cardiac or renal disease), or a major fetal anomaly.

The American College of Obstetricians and Gynecologists and the Society for Maternal– Fetal Medicine have issued statements recommending a change in practice based on this trial.

First-line medications were labetalol or extended-release nifedipine in the majority of patients in the active-treatment group and in standard-treatment patients who developed severe hypertension. Patients were followed until 6 weeks after delivery. Intention­-to-treat analyses were performed. The primary outcome was a composite of fetal or neonatal death before 28 days of life, superimposed preeclampsia with severe features up to 2 weeks postpartum, placental abruption leading to delivery, and medically indicated preterm birth before 35 weeks’ gestation. Safety outcomes included birthweight < 10th and < 5th percentile for gestational age.

Primary outcome events occurred in 30.2% of the active-treatment group compared with 37% of the standard-treatment group (adjusted risk ratio [aRR] = 0.82; 95% CI, 0.74-0.92; number needed to treat [NNT] = 15). Preeclampsia with severe features (23.3% vs 29.1%; aRR = 0.80; 95% CI, 0.70-0.92) and medically indicated preterm birth before 35 weeks (12.2% vs 16.7%; aRR = 0.73; 95% CI, 0.6-0.89) occurred less often in the active-treatment group compared with the standard-treatment group. There were no differences in rates of placental abruption, fetal or neonatal death, or small-for-gestational-age infants.

WHAT’S NEW

Target BP of < 140/90 mm Hg reduced risk

This trial provides high-quality evidence that initiating or maintaining treatment at a nonsevere BP threshold (< 140/90 mm Hg) in pregnant patients with mild chronic hypertension reduces maternal and neonatal risk without increasing the risk for small-for-­gestational-age infants. The American College of Obstetricians and Gynecologists and the Society for Maternal–Fetal Medicine have issued statements recommending a change in practice based on this trial.^8,9

Continue to: CAVEATS

 

 

CAVEATS

Patient characteristics and medication choices were limited

This trial does not identify a BP goal for patients who are at highest risk for complications of hypertension or who already have been given a diagnosis of a growth-restricted fetus, as those patients were excluded.

Most patients in the trial who required medications received labetalol or extended-­release nifedipine. It is unclear if other medications would produce similar outcomes.

CHALLENGES TO IMPLEMENTATION

Limited challenges anticipated

There should be limited challenges to implementation.

ILLUSTRATIVE CASE

A 32-year-old primigravida at 10 weeks’ gestation presents for an initial prenatal visit. Medical history includes hypertension that is currently well controlled on labetalol 200 mg twice daily. The patient’s blood pressure (BP) at today’s visit is 125/80 mm Hg. Should labetalol be discontinued?

Chronic hypertension in pregnancy is hypertension that predates the pregnancy or with onset prior to 20 weeks’ gestation. Diagnostic criteria include systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg, use of antihypertensive medications prior to pregnancy, or pregnancy-related hypertension persisting > 12 weeks postpartum.^2,3 Chronic hypertension affects 0.9% to 5% of pregnancies and is associated with increased risk for complications, such as superimposed preeclampsia, small-for-gestational-age infant, preterm birth, cesarean delivery, and neonatal intensive care unit admission.⁴ Superimposed preeclampsia occurs in about 17% to 25% of pregnancies affected by chronic hypertension, compared with 3% to 5% of the general population.³

Historically, a higher treatment threshold of 160/110 mm Hg was preferred to avoid theoretical complications of low placental perfusion.² Practically, this often meant discontinuing antihypertensives at the onset of prenatal care if BP was well controlled. A few small trials previously demonstrated that tight BP goals reduced the risk for severe hypertension, but they did not show an improvement in pregnancy outcomes.^5-7 This larger RCT evaluated whether treatment of mild chronic hypertension in pregnancy at lower BP thresholds is associated with improved pregnancy outcomes without negative impact on fetal growth.

STUDY SUMMARY

Active BP treatment yielded better pregnancy outcomes

In a US multicenter, open-label RCT, 2419 pregnant patients with chronic hypertension and singleton fetuses at gestational age < 23 weeks were randomized to receive either active pharmacologic treatment with a BP goal of 140/90 mm Hg or standard treatment, in which BP medication was withheld unless BP reached 160/105 mm Hg (severe hypertension). If medication was initiated in the standard-treatment group, the goal was also 140/90 mm Hg. Exclusion criteria included severe hypertension or suspected intrauterine growth restriction at randomization, known secondary hypertension, certain high-risk comorbidities (eg, cardiac or renal disease), or a major fetal anomaly.

The American College of Obstetricians and Gynecologists and the Society for Maternal– Fetal Medicine have issued statements recommending a change in practice based on this trial.

First-line medications were labetalol or extended-release nifedipine in the majority of patients in the active-treatment group and in standard-treatment patients who developed severe hypertension. Patients were followed until 6 weeks after delivery. Intention­-to-treat analyses were performed. The primary outcome was a composite of fetal or neonatal death before 28 days of life, superimposed preeclampsia with severe features up to 2 weeks postpartum, placental abruption leading to delivery, and medically indicated preterm birth before 35 weeks’ gestation. Safety outcomes included birthweight < 10th and < 5th percentile for gestational age.

Primary outcome events occurred in 30.2% of the active-treatment group compared with 37% of the standard-treatment group (adjusted risk ratio [aRR] = 0.82; 95% CI, 0.74-0.92; number needed to treat [NNT] = 15). Preeclampsia with severe features (23.3% vs 29.1%; aRR = 0.80; 95% CI, 0.70-0.92) and medically indicated preterm birth before 35 weeks (12.2% vs 16.7%; aRR = 0.73; 95% CI, 0.6-0.89) occurred less often in the active-treatment group compared with the standard-treatment group. There were no differences in rates of placental abruption, fetal or neonatal death, or small-for-gestational-age infants.

WHAT’S NEW

Target BP of < 140/90 mm Hg reduced risk

This trial provides high-quality evidence that initiating or maintaining treatment at a nonsevere BP threshold (< 140/90 mm Hg) in pregnant patients with mild chronic hypertension reduces maternal and neonatal risk without increasing the risk for small-for-­gestational-age infants. The American College of Obstetricians and Gynecologists and the Society for Maternal–Fetal Medicine have issued statements recommending a change in practice based on this trial.^8,9

Continue to: CAVEATS

 

 

CAVEATS

Patient characteristics and medication choices were limited

This trial does not identify a BP goal for patients who are at highest risk for complications of hypertension or who already have been given a diagnosis of a growth-restricted fetus, as those patients were excluded.

Most patients in the trial who required medications received labetalol or extended-­release nifedipine. It is unclear if other medications would produce similar outcomes.

CHALLENGES TO IMPLEMENTATION

Limited challenges anticipated

There should be limited challenges to implementation.

The US Preventive Services Task Force (USPSTF) had a productive year in 2022. In total, the USPSTF

• reviewed and made recommendations on 4 new topics
• re-assessed 19 previous recommendations on 11 topics
• made 24 separate recommendations, including 1 “A,” 3 “B,” 3 “C,” and 5 “D” recommendations and 12 “I” statements (see TABLE 1¹).

A note about grading. TABLE 2² outlines the USPSTF’s grade definitions and suggestions for practice. The importance of an “A” or “B” recommendation rests historically with the requirement in the Affordable Care Act (ACA) that all USPSTF-recommended services with either of these grades have to be provided by commercial health insurance plans with no co-pay or deductible applied. (The legal challenge in Texas to the ACA’s preventive care provision may change that.)

What’s new?

The USPSTF’s review of 4 new topics exceeds the entity’s output in each of the prior 4 years, when the Task Force was able to add only 1 or 2 topics annually. However, 3 of the 4 new topics in 2022 resulted in an insufficient evidence or “I” statement, which means there was not enough evidence to judge the relative benefits and harms of the intervention.

These 3 included screening for type 2 diabetes in children and adolescents younger than 18 years; screening for obstructive sleep apnea in the general adult population (ages ≥ 18 years); and screening for eating disorders in adolescents and adults. The fourth new topic, screening for anxiety in children and adolescents, resulted in a “B” recommendation and was described in a recent Practice Alert.³

Major revision to 1 prior recommendation

Only 1 of the 19 revisited recommendations resulted in a major revision: the use of daily aspirin for primary prevention of cardiovascular disease (CVD). Note that it does not apply to those who have established CVD, in whom the use of aspirin would be considered tertiary prevention or harm reduction.

In 2016, the USPSTF recommended (with a “B” grade) the use of daily low-dose aspirin for those ages 50 to 59 years who had a 10-year risk for a CVD event > 10%; no increased risk for bleeding; at least a 10-year life expectancy; and a willingness to take aspirin for 10 years. For those ages 60 to 69 years with a 10-year risk for a CVD event > 10%, the recommendation was a “C.” For those younger than 50 and older than 70, an “I” statement was issued.

In 2022, the USPSTF was much less enthusiastic about daily aspirin as a primary preventative.⁴ The recommendation is now a “C” for those ages 40 to 59 years who have a 10-year CVD risk ≥ 10%. Those most likely to benefit have a 10-year CVD risk > 15%.

Continue to: The recommendation pertains...

The recommendation pertains to the initiation of aspirin, not the continuation or discontinuation for those who have been using aspirin without complications. The ­USPSTF suggests that the dose of aspirin, if used, should be 81 mg and that it should not be continued past age 75 years. A more detailed discussion of this recommendation and some of its clinical considerations is contained in a recent Practice Alert.⁵

“D” is for “don’t”(with a few caveats)

Avoiding unnecessary or harmful testing and treatments is just as important as offering preventive services of proven benefit. Those practices listed in TABLE 1¹ with a “D” recommendation should be avoided in practice.

However, it is worth mentioning that, while postmenopausal hormone replacement therapy should not be prescribed for the prevention of chronic conditions, this does not mean it should not be used to alleviate postmenopausal vasomotor symptoms—albeit for a limited period of time.

Also, it is important to appreciate the difference between screening and diagnostic tests. When the USPSTF recommends for or against screening, they are referring to the practice in asymptomatic people. The recommendation does not pertain to diagnostic testing to confirm or rule out a condition in a person with symptoms suggestive of a condition. Thus, the recommendation against screening adults for chronic obstructive pulmonary disease applies only to those without symptoms.

Be selective with services graded “C” or “I”

The USPSTF recommendations that require the most clinical judgment and are the most difficult to implement are those with a “C.” Few individuals will benefit from these interventions, and those most likely to benefit usually are described in the clinical considerations that accompany the recommendation. These interventions are time consuming and may be subject to insurance co-pays and deductibles. All 3 “C” recommendations made in 2022 (see TABLE 1¹) pertained to the prevention of CVD, still the leading cause of death in the United States.

Continue it: As "I" statement is not the same...

An “I” statement is not the same as a recommendation against the service—but if the service is offered, both the physician and the patient should understand the uncertainty involved. The services the USPSTF has determined lack sufficient evidence of benefits and/or harms are often recommended by other­ organizations—and in fact, the use of the “I” statement distinguishes the USPSTF from other clinical guideline groups.

If good evidence does not exist, the ­USPSTF will not make a recommendation. This is the main reason that, when the USPSTF reevaluates a topic (about every 6 to 7 years), they seldom make significant changes to their previous recommendations. Good evidence tends to survive the test of time.

However, adherence to this standard can cause the USPSTF to lag behind other guideline producers for some commonly used interventions. This delay can be considered a detriment if the intervention eventually proves to be effective, but it is a benefit if the intervention proves to be nonbeneficial or even harmful.

Putting recommendations into best practice

Given the time constraints in primary care practice, the most efficient way of providing high-quality, clinical preventive services is by implementing USPSTF “A” and “B” recommendations, being very selective about who receives an intervention with a “C” recommendation or “I” statement, and avoiding interventions with a “D” recommendation. 

BREAKING NEWS

At press time, the USPSTF issued a draft recommendation statement that women begin receiving biennial mammograms starting at age 40 years (through age 74 years). For more, see: www.uspreventiveservicestaskforce.org/uspstf/draft-recommendation/breast-cancer-screening-adults#fullrecommendation start

The US Preventive Services Task Force (USPSTF) had a productive year in 2022. In total, the USPSTF

• reviewed and made recommendations on 4 new topics
• re-assessed 19 previous recommendations on 11 topics
• made 24 separate recommendations, including 1 “A,” 3 “B,” 3 “C,” and 5 “D” recommendations and 12 “I” statements (see TABLE 1¹).

A note about grading. TABLE 2² outlines the USPSTF’s grade definitions and suggestions for practice. The importance of an “A” or “B” recommendation rests historically with the requirement in the Affordable Care Act (ACA) that all USPSTF-recommended services with either of these grades have to be provided by commercial health insurance plans with no co-pay or deductible applied. (The legal challenge in Texas to the ACA’s preventive care provision may change that.)

What’s new?

The USPSTF’s review of 4 new topics exceeds the entity’s output in each of the prior 4 years, when the Task Force was able to add only 1 or 2 topics annually. However, 3 of the 4 new topics in 2022 resulted in an insufficient evidence or “I” statement, which means there was not enough evidence to judge the relative benefits and harms of the intervention.

These 3 included screening for type 2 diabetes in children and adolescents younger than 18 years; screening for obstructive sleep apnea in the general adult population (ages ≥ 18 years); and screening for eating disorders in adolescents and adults. The fourth new topic, screening for anxiety in children and adolescents, resulted in a “B” recommendation and was described in a recent Practice Alert.³

Major revision to 1 prior recommendation

Only 1 of the 19 revisited recommendations resulted in a major revision: the use of daily aspirin for primary prevention of cardiovascular disease (CVD). Note that it does not apply to those who have established CVD, in whom the use of aspirin would be considered tertiary prevention or harm reduction.

In 2016, the USPSTF recommended (with a “B” grade) the use of daily low-dose aspirin for those ages 50 to 59 years who had a 10-year risk for a CVD event > 10%; no increased risk for bleeding; at least a 10-year life expectancy; and a willingness to take aspirin for 10 years. For those ages 60 to 69 years with a 10-year risk for a CVD event > 10%, the recommendation was a “C.” For those younger than 50 and older than 70, an “I” statement was issued.

In 2022, the USPSTF was much less enthusiastic about daily aspirin as a primary preventative.⁴ The recommendation is now a “C” for those ages 40 to 59 years who have a 10-year CVD risk ≥ 10%. Those most likely to benefit have a 10-year CVD risk > 15%.

Continue to: The recommendation pertains...

The recommendation pertains to the initiation of aspirin, not the continuation or discontinuation for those who have been using aspirin without complications. The ­USPSTF suggests that the dose of aspirin, if used, should be 81 mg and that it should not be continued past age 75 years. A more detailed discussion of this recommendation and some of its clinical considerations is contained in a recent Practice Alert.⁵

“D” is for “don’t”(with a few caveats)

Avoiding unnecessary or harmful testing and treatments is just as important as offering preventive services of proven benefit. Those practices listed in TABLE 1¹ with a “D” recommendation should be avoided in practice.

However, it is worth mentioning that, while postmenopausal hormone replacement therapy should not be prescribed for the prevention of chronic conditions, this does not mean it should not be used to alleviate postmenopausal vasomotor symptoms—albeit for a limited period of time.

Also, it is important to appreciate the difference between screening and diagnostic tests. When the USPSTF recommends for or against screening, they are referring to the practice in asymptomatic people. The recommendation does not pertain to diagnostic testing to confirm or rule out a condition in a person with symptoms suggestive of a condition. Thus, the recommendation against screening adults for chronic obstructive pulmonary disease applies only to those without symptoms.

Be selective with services graded “C” or “I”

The USPSTF recommendations that require the most clinical judgment and are the most difficult to implement are those with a “C.” Few individuals will benefit from these interventions, and those most likely to benefit usually are described in the clinical considerations that accompany the recommendation. These interventions are time consuming and may be subject to insurance co-pays and deductibles. All 3 “C” recommendations made in 2022 (see TABLE 1¹) pertained to the prevention of CVD, still the leading cause of death in the United States.

Continue it: As "I" statement is not the same...

An “I” statement is not the same as a recommendation against the service—but if the service is offered, both the physician and the patient should understand the uncertainty involved. The services the USPSTF has determined lack sufficient evidence of benefits and/or harms are often recommended by other­ organizations—and in fact, the use of the “I” statement distinguishes the USPSTF from other clinical guideline groups.

If good evidence does not exist, the ­USPSTF will not make a recommendation. This is the main reason that, when the USPSTF reevaluates a topic (about every 6 to 7 years), they seldom make significant changes to their previous recommendations. Good evidence tends to survive the test of time.

However, adherence to this standard can cause the USPSTF to lag behind other guideline producers for some commonly used interventions. This delay can be considered a detriment if the intervention eventually proves to be effective, but it is a benefit if the intervention proves to be nonbeneficial or even harmful.

Putting recommendations into best practice

Given the time constraints in primary care practice, the most efficient way of providing high-quality, clinical preventive services is by implementing USPSTF “A” and “B” recommendations, being very selective about who receives an intervention with a “C” recommendation or “I” statement, and avoiding interventions with a “D” recommendation. 

BREAKING NEWS

At press time, the USPSTF issued a draft recommendation statement that women begin receiving biennial mammograms starting at age 40 years (through age 74 years). For more, see: www.uspreventiveservicestaskforce.org/uspstf/draft-recommendation/breast-cancer-screening-adults#fullrecommendation start

The US Preventive Services Task Force (USPSTF) had a productive year in 2022. In total, the USPSTF

• reviewed and made recommendations on 4 new topics
• re-assessed 19 previous recommendations on 11 topics
• made 24 separate recommendations, including 1 “A,” 3 “B,” 3 “C,” and 5 “D” recommendations and 12 “I” statements (see TABLE 1¹).

A note about grading. TABLE 2² outlines the USPSTF’s grade definitions and suggestions for practice. The importance of an “A” or “B” recommendation rests historically with the requirement in the Affordable Care Act (ACA) that all USPSTF-recommended services with either of these grades have to be provided by commercial health insurance plans with no co-pay or deductible applied. (The legal challenge in Texas to the ACA’s preventive care provision may change that.)

What’s new?

The USPSTF’s review of 4 new topics exceeds the entity’s output in each of the prior 4 years, when the Task Force was able to add only 1 or 2 topics annually. However, 3 of the 4 new topics in 2022 resulted in an insufficient evidence or “I” statement, which means there was not enough evidence to judge the relative benefits and harms of the intervention.

These 3 included screening for type 2 diabetes in children and adolescents younger than 18 years; screening for obstructive sleep apnea in the general adult population (ages ≥ 18 years); and screening for eating disorders in adolescents and adults. The fourth new topic, screening for anxiety in children and adolescents, resulted in a “B” recommendation and was described in a recent Practice Alert.³

Major revision to 1 prior recommendation

Only 1 of the 19 revisited recommendations resulted in a major revision: the use of daily aspirin for primary prevention of cardiovascular disease (CVD). Note that it does not apply to those who have established CVD, in whom the use of aspirin would be considered tertiary prevention or harm reduction.

In 2016, the USPSTF recommended (with a “B” grade) the use of daily low-dose aspirin for those ages 50 to 59 years who had a 10-year risk for a CVD event > 10%; no increased risk for bleeding; at least a 10-year life expectancy; and a willingness to take aspirin for 10 years. For those ages 60 to 69 years with a 10-year risk for a CVD event > 10%, the recommendation was a “C.” For those younger than 50 and older than 70, an “I” statement was issued.

In 2022, the USPSTF was much less enthusiastic about daily aspirin as a primary preventative.⁴ The recommendation is now a “C” for those ages 40 to 59 years who have a 10-year CVD risk ≥ 10%. Those most likely to benefit have a 10-year CVD risk > 15%.

Continue to: The recommendation pertains...

The recommendation pertains to the initiation of aspirin, not the continuation or discontinuation for those who have been using aspirin without complications. The ­USPSTF suggests that the dose of aspirin, if used, should be 81 mg and that it should not be continued past age 75 years. A more detailed discussion of this recommendation and some of its clinical considerations is contained in a recent Practice Alert.⁵

“D” is for “don’t”(with a few caveats)

Avoiding unnecessary or harmful testing and treatments is just as important as offering preventive services of proven benefit. Those practices listed in TABLE 1¹ with a “D” recommendation should be avoided in practice.

However, it is worth mentioning that, while postmenopausal hormone replacement therapy should not be prescribed for the prevention of chronic conditions, this does not mean it should not be used to alleviate postmenopausal vasomotor symptoms—albeit for a limited period of time.

Also, it is important to appreciate the difference between screening and diagnostic tests. When the USPSTF recommends for or against screening, they are referring to the practice in asymptomatic people. The recommendation does not pertain to diagnostic testing to confirm or rule out a condition in a person with symptoms suggestive of a condition. Thus, the recommendation against screening adults for chronic obstructive pulmonary disease applies only to those without symptoms.

Be selective with services graded “C” or “I”

The USPSTF recommendations that require the most clinical judgment and are the most difficult to implement are those with a “C.” Few individuals will benefit from these interventions, and those most likely to benefit usually are described in the clinical considerations that accompany the recommendation. These interventions are time consuming and may be subject to insurance co-pays and deductibles. All 3 “C” recommendations made in 2022 (see TABLE 1¹) pertained to the prevention of CVD, still the leading cause of death in the United States.

Continue it: As "I" statement is not the same...

An “I” statement is not the same as a recommendation against the service—but if the service is offered, both the physician and the patient should understand the uncertainty involved. The services the USPSTF has determined lack sufficient evidence of benefits and/or harms are often recommended by other­ organizations—and in fact, the use of the “I” statement distinguishes the USPSTF from other clinical guideline groups.

If good evidence does not exist, the ­USPSTF will not make a recommendation. This is the main reason that, when the USPSTF reevaluates a topic (about every 6 to 7 years), they seldom make significant changes to their previous recommendations. Good evidence tends to survive the test of time.

However, adherence to this standard can cause the USPSTF to lag behind other guideline producers for some commonly used interventions. This delay can be considered a detriment if the intervention eventually proves to be effective, but it is a benefit if the intervention proves to be nonbeneficial or even harmful.

Putting recommendations into best practice

Given the time constraints in primary care practice, the most efficient way of providing high-quality, clinical preventive services is by implementing USPSTF “A” and “B” recommendations, being very selective about who receives an intervention with a “C” recommendation or “I” statement, and avoiding interventions with a “D” recommendation. 

BREAKING NEWS

At press time, the USPSTF issued a draft recommendation statement that women begin receiving biennial mammograms starting at age 40 years (through age 74 years). For more, see: www.uspreventiveservicestaskforce.org/uspstf/draft-recommendation/breast-cancer-screening-adults#fullrecommendation start

Medication-assisted recovery (MAR)—the preferred terminology for the service formerly known as medication­-assisted treatment—entails a comprehensive set of interventions for managing opioid use disorder (OUD), including medications for opioid use disorder (MOUD). Despite the benefits of MAR—reducing opioid use, opioid-related mortality, and health care costs^1-3—only 11% of patients with a diagnosis of OUD received MOUD in 2020.³

When medication-assisted recovery services are rendered in primary care, treatment retention improves by 25%—highlighting a role for family medicine clinicians in treating OUD.

Primary care physicians, including family physicians, are well positioned to provide MAR across the patient’s lifespan. However, many family medicine clinicians do not possess the logistical knowledge or resources to implement this service.⁴ In this article, we describe options for, and barriers to, MAR and societal issues that have an impact on the care of these patients.

Pathophysiology of OUD

Opioids relieve pain by stimulating μ-opioid receptors and activating the brain’s reward system. These pleasurable effects motivate repeated use.⁵ Frequent opioid exposure causes neuroadaptation, tolerance, and dependence. For patients with OUD who are misusing illicit or prescription opioids, periods of abstinence following neuroadaptation lead to withdrawal symptoms that vary in intensity, depending on the drug, dose, and duration of use. Upregulated noradrenergic tone and dopamine deficiency manifest as numerous signs and symptoms of withdrawal, including⁵:

• Physiologic: secretory (diaphoresis, rhinorrhea, lacrimation, vomiting, diarrhea) and stimulatory (mydriasis, piloerection, hypertension, tachycardia, insomnia)
• Psychological: pain, cravings, dysphoria, anxiety.

A single episode of opioid withdrawal is not directly life-threatening, but untreated episodes can progressively amplify negative feedback and reinforce continued opioid use.⁶ Left untreated, withdrawal can be terminal.

Image: Copyright Joe Gorman

Medication-assisted recovery: Effective intervention

MAR services that integrate medical, behavioral, and psychosocial programs can reduce mortality from OUD 2-fold.^7,8 A meta-analysis found that, when MAR services are rendered in primary care, treatment retention improves by 25% (number needed to treat [NNT] = 6) and ongoing illicit opioid use is reduced by 50% (NNT = 6), relative to care at a specialty clinic⁹—highlighting a role for family medicine clinicians in treating OUD.

All 3 US Food and Drug Administration (FDA)–approved MOUD (methadone, buprenorphine, and naltrexone) reduce cravings; 2 (methadone and buprenorphine) mitigate withdrawal symptoms by activating the μ-opioid receptor; and naltrexone diminishes the reinforcing effects of use (TABLE^10-12). It is crucial to recognize the pharmacologic distinctions among MOUD because untreated withdrawal syndromes increase dropout from treatment programs and subsequent relapse.¹³

The Hx of medication-assisted recovery

To understand the landscape of MAR, it is important to understand the history of opioid treatment in the United States. In 1966, Congress passed the Narcotic Addiction Rehabilitation Act (NARA), which secured federal assistance by which state and local governments could develop drug treatment programs.¹⁴ NARA permitted legal offenders with OUD to be civilly committed to treatment programs, rather than prosecuted. However, limited resources and a burgeoning population led, instead, to low-cost outpatient programs saddled by strict requirements that lacked a basis for improving clinical outcomes.

Continue to: At the time NARA...

At the time NARA was passed by Congress, OUD was viewed—inaccurately—as a criminal problem, not a medical one. Subsequent legislation was crafted through that lens, which has placed a heavy burden on patients until today.¹⁴ Although medical understanding of OUD has advanced tremendously over the past 50 years, treatment remains siloed from mainstream medicine, even in primary care.

There is no one-size-fits-all approach to MAR, and relapse is common. Patient-specific factors and the availability of resources should be considered when designing the most individualized, advantageous plan for MAR.

Methadone

Background. Methadone has the most extensive history for treating OUD and consistently has demonstrated efficacy.¹³ A meta-analysis of randomized controlled trials comparing methadone to nonpharmacotherapy alone found that methadone improved treatment retention by an absolute 57% (NNT = 2).¹⁰

Methadone was approved by the FDA for detoxification and maintenance treatment in the early 1970s, although the Narcotic Addict Treatment Act (NATA) of 1974 restricted dispensing of maintenance treatment to highly regulated clinics known as opioid treatment programs (OTPs).¹⁴ NATA required the treating physician to register with the US Drug Enforcement Agency (DEA) and to comply with conservative dosing regimens and observed dosing.

Over time, regulations evolved to give the physician greater flexibility in developing a care plan, allowing “take-home” doses, and improving patients’ access to care. Although access to methadone for the treatment of OUD remains limited to federally certified OTPs, regulations facilitate incorporation of a whole-person approach to care, including counseling, individual and group therapy, and toxicology testing.⁷

Continue to: Clinical considerations

Clinical considerations. Methadone requires slow titration. For patients starting methadone as an outpatient, federal law¹⁵ limits the initial dose to 30 mg and requires physician documentation when the first-day total dosage exceeds 40 mg. This dosing constraint makes it challenging to provide care because a daily dosage ≥ 60 mg has been found to produce, first, higher program retention (relative risk = 1.36; 95% CI, 1.13-1.63) and, second, greater reduction in illicit opioid use (relative risk = 1.59; 95% CI, 1.16-2.18) than is seen in patients who receive a lower daily dosage.¹⁶

Due to a prolonged elimination half-life, methadone reaches steady-state in 3 to 5 days. Patients and their families should be educated that withdrawal symptoms might not feel fully managed in the first few days of therapy and that time is required to experience safely the regimen’s full effects.

Aggressive dose-titration during methadone induction can result in drug accumulation and respiratory depression. The risk for methadone-related mortality is highest in the first 2 weeks of therapy, mostly related to overdose potential if the drug is combined with other opioids.¹⁷

Buprenorphine

Background. The prescribing rate for buprenorphine, particularly in primary care, is accelerating.¹⁸ A meta-analysis of randomized controlled trials found that¹¹:

• compared to placebo, buprenorphine, at any dosage, improves treatment retention by an absolute 21% to 28% (NNT = 4-5)
• patients receiving high-dose buprenorphine (≥ 16 mg/d) had fewer evident cases of illicit opioid use.

Unlike methadone, buprenorphine exerts partial agonism at the μ-opioid receptor, resulting in a so-called ceiling effect that significantly reduces the adverse effect profile, including respiratory depression and euphoria, relative to a full-agonist opioid, such as methadone.¹⁹

Continue to: Whereas accessing methadone...

Whereas accessing methadone is limited to OTPs, buprenorphine is available for office-based treatment. By hosting OUD treatment and primary care in the same place, primary care physicians can provide comprehensive medical care including and beyond OUD, thereby improving retention and managing comorbidity.²⁰

Integrated models involving support staff—eg, nurses, behavioral health providers, and pharmacists—have produced the greatest success with office-based treatment models.²¹ Office-based treatment normalizes OUD as a chronic disease managed by the primary care physician, enabling concurrent harm-reduction strategies; medication reconciliation; and convenient, regular prescribing intervals (eg, every 30 days).²²
Nevertheless, access to buprenorphine is limited. Because buprenorphine is a controlled substance, the Ryan Haight Online Pharmacy Consumer Protection Act of 2008 prevents initial prescribing of buprenorphine without in-person evaluation. Telehealth consultations increased access to buprenorphine through temporary exceptions during the COVID-19 pandemic. However, revised rules and regulations for telehealth visits for these controlled substances are forthcoming from the DEA as temporary exceptions for telehealth consultations come to an end. Additionally, prescribing buprenorphine for OUD requires that the treating physician undergo specific training and obtain qualifications, which have evolved over time through federal legislation.

The Drug Addiction Treatment Act of 2000 (DATA 2000) authorized what is known as an X-waiver, which allows physicians to prescribe controlled substances for office-based treatment of OUD, provided that:

• they are registered to do so with the Substance Abuse and Mental Health Services Administration and the DEA
• they have had subspecialty training in addiction or completed an 8-hour training course
• they are able to refer patients to appropriate counseling and ancillary services.

DATA 2000 restricted patient panel sizes­ to 30 patients in the first year, expanding thereafter upon appropriate certification.

Although medical understanding of OUD has advanced tremendously over the past 50 years, treatment remains siloed from mainstream medicine, even in primary care.

The Comprehensive Addiction and Recovery Act of 2016 (CARA) and the Substance Use Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities Act of 2018 (the SUPPORT Act) collectively extended prescribing authority for MOUD to other qualifying practitioners (eg, advanced practice clinicians). Despite these attempts to expand access to services, the overdose death rate has continued to increase.

Continue to: To further expand access to MAR...

To further expand access to MAR, the US Department of Health and Human Services updated its practice guidelines in April 2021, allowing clinicians to bypass X-waiver training requirements by applying for a notification-of-intent (NOI) buprenorphine waiver.^a However, clinicians are still limited to prescribing buprenorphine for 30 patients at a time. Clinicians who undergo complete X-waiver training may prescribe for 100 patients in the first year and, if eligible, 275 patients thereafter.

In addition, as a component of the Consolidation Appropriations Act of 2023, Congress passed the Mainstreaming Addiction Treatment Act of 2021, or MAT 2021, and Medication Access and Training Expansion Act of 2021, or MATE 2021. MAT eliminated the X-waiver, NOI, and restrictions on the number of patients for whom a provider could prescribe buprenorphine, under federal authority; however, restrictions within one’s state might limit the ability to prescribe buprenorphine. MATE 2021 is an educational requirement for licensing by the DEA (at application and renewal) that will require prescribers to complete 8 hours of training in substance use disorders starting in June 2023.

Patients and their families should be educated that withdrawal symptoms might not feel fully managed in the first few days of methadone therapy.

Use of the monthly injectable extended-release buprenorphine product^b is limited by an FDA Risk Evaluation and Mitigation Strategy (REMS) program, which requires specialized training and certification by the prescriber, distributor, and administering clinician. REMS reduces buprenorphine accessibility due to time, cost, and regulatory barriers; although such restrictions have been instituted with the patient’s safety in mind, any limitation to buprenorphine prescribing, apart from controlled substance licensure, serves only to limit access to a primary component of MAR.

Clinical considerations. Due to the competitive nature of buprenorphine and its high affinity for the μ-opioid receptor, the drug can displace other opioid agonists and precipitate acute withdrawal. The withdrawal experience can thereby condition fear and disfavor toward buprenorphine among patients.

It is vital, therefore, that (1) patients’ expectations for treatment be managed appropriately and (2) the treating physician be prepared to provide additional buprenorphine for adequate maintenance doses and utilize adjunct comfort agents (clonidine, nonsteroidal anti-inflammatory drugs, ondansetron) to manage acute withdrawal symptoms. Newer buprenorphine dosing strategies, such as micro-induction and macro-­induction, have emerged to curtail these risks.^23,24 This is an evolving area of MAR; newer low-threshold initiation strategies²⁵ (see “Low-threshold MOUD prescribing models,” in the text that follows) and evidence that supports micro-induction²⁶ might eliminate the practice of requiring active withdrawal for treatment.

Continue to: Regardless of the strategy...

Regardless of the strategy for dosing buprenorphine, it’s critical that patients be educated on how to initiate treatment outside a clinical setting, such as at home, where they occupy a familiar haven during a potentially uncomfortable time and can be as effective at initiation as they would be in a clinical setting, with no difference in precipitation of adverse effects.

At-home induction might be more appropriate for patients who are not yet in significant enough withdrawal while in the physician's office.²⁷ Guidance should be provided on dosing instructions, self-assessment of withdrawal­ symptoms, and, if applicable, patience with the slow-dissolving sublingual tablet or film formulation.

Naltrexone

Background. Naltrexone is available as an oral tablet and an extended-release, once-monthly intramuscular injection; the latter has demonstrated superiority in MAR.²⁸ Oral naltrexone has limited supporting evidence, is inferior to other MOUD options, and should not be used to treat OUD.⁷ Altogether, approval of naltrexone for OUD is controversial, due to potentially unethical trials and approval processes,²⁹ although a multicenter randomized controlled trial demonstrated the drug’s noninferiority with respect to treatment retention relative to buprenorphine.³⁰ Used over time, naltrexone does not relieve withdrawal symptoms but can reduce cravings.

Clinical considerations. There are numerous clinical barriers that limit the use of naltrexone.

First, patients should be abstinent from opioids for 7 to 14 days prior to starting therapy; usually, this means undergoing medically supervised withdrawal in a controlled environment. This is an obvious limitation for patients who are constrained financially—those who lack, or have inadequate, health insurance or are unable to be away from their job for an extended time.

Continue to: Second, because naltrexone...

Second, because naltrexone does not address withdrawal symptoms, supportive therapies should be incorporated into the treatment plan, including:

• clonidine for hyperadrenergic symptoms (anxiety, diaphoresis, hypertension)
• nonopioid analgesics for pain
• antiemetics, such as ondansetron and metoclopramide, for nausea or vomiting
• loperamide for diarrhea
• diphenhydramine for insomnia.

Third, patients taking naltrexone have a diminished response to opioids. This complicates pain management in the event of an emergent surgical procedure.

Last, when naltrexone wears off, patients are effectively opioid-naïve, which increases the risk for overdose in those who stop therapy abruptly.²⁹ The increased risk for overdose should be communicated to all patients with OUD who are being treated with naltrexone.

This nonopioid option is appealing to policymakers and is often prioritized in the criminal justice system; however, the decreased efficacy of naltrexone (compared to methadone and buprenorphine), potential for overdose, and challenges in initiating treatment are concerning and limit the drug’s use in many real-world settings.

Because naltrexone is not a controlled substance, regulations regarding maintaining inventory and distribution are more flexible.

Continue to: Overall, the cost-effectiveness...

Overall, the cost-effectiveness of intramuscular naltrexone is unclear. State-administered insurance programs vary in their requirements for coverage of naltrexone treatment.³¹

Comprehensive medication reconciliation is vital

Overall fragmentation of care within OTPs places patients at risk for adverse events, such as drug interactions.³² Under Title 42 of the US Code,³³ patients must provide written consent for an OTP provider to disclose their history of a substance use disorder. Allowing the patient to decide which medical providers can access their treatment records for an OUD benefits patient confidentiality but poses­ numerous issues worth exploring.

All prescribed controlled substances are recorded in the prescription drug monitoring program, or PDMP, a state-level electronic database accessible to health care professionals to inform prescribing decisions and identify drug interactions. The PDMP has substantially reduced opioid overprescribing and improved identification of patients at risk for overdose or misuse of opioids.

Buprenorphine, available for office-based treatment, has a so-called ceiling effect that reduces the adverse effect profile, including respiratory depression and euphoria.

Unlike all other controlled substances, however, prescriptions ordered by an OTP are not recorded in the PDMP (although there are recent exceptions to this scenario). Without such information, a physician might not have important information about the patient when making medical decisions—placing the patient at risk for harmful outcomes, such as drug–drug and drug–disease interactions.

For example: Methadone is associated with a prolonged QT interval,³⁴ increasing the risk for a fatal arrhythmia. Concurrent QT-prolonging medications, such as azithromycin and citalopram, further increase this risk.³⁵ Because methadone dispensing is isolated from the patient’s medical record, the clinician who prescribes MOUD has an incomplete patient history and could make a potentially fatal treatment decision.

Continue to: Diversion is unlikely

Diversion is unlikely

Health care providers often express concern about diversion in MOUD. However, misuse and diversion rates of methadone and buprenorphine have declined steadily since 2011, and, in fact, are actually lower than the diversion rate of prescription antibiotics.³⁶

Regardless, diversion of buprenorphine should not be a concern for physicians prescribing MOUD. Although a prescriber might worry about manipulation of the formulation of buprenorphine for intravenous administration, addition of naloxone to buprenorphine in tablet form diminishes the potential for overdose. Additionally, the ceiling effect of buprenorphine limits the likelihood of significant respiratory depression and euphoria.

Should buprenorphine reach a patient for whom it was not prescribed, it is highly unlikely that an overdose would result. Rather, the medication would protect against the effects of illicit opioids and relieve withdrawal symptoms. Most people with OUD who have misused buprenorphine have done so to relieve withdrawal symptoms,³⁷ not to experience intoxication.

Health care deserts

So-called health care deserts in parts of the United States are an ongoing problem that disproportionately affects lower-income and segregated Black and Hispanic communities³⁸—communities that shoulder the highest burden of OUD and OUD-related mortality³⁹ and whose populace is in greatest need of MAR. Even when health care is accessible in such a desert, some clinicians and pharmacies refuse to prescribe or dispense MOUD because of the accompanying stigma of OUD.

Prescribing buprenorphine for OUD requires that the treating physician undergo specific training, including subspecialty training in addiction or an 8-hour training course.

A MAR desert, like a pharmacy desert, is a geographic region—one without access to a MAR or an OTP provider, thereby preventing patients from reaching appropriate care; for some patients, having to travel to the nearest provider can render treatment inaccessible.⁴⁰

Continue to: Efforts are in place to identify...

Efforts are in place to identify areas at greatest need of OUD-related medical services, such as heat maps that identify areas of increased utilization of emergency medical services for opioid overdose. State-run programs have been implemented to increase access, such as the Illinois Helpline (https://helplineil.org) that provides support and resources for patients, friends, family, and providers.

Novel solutions

Key strategies to increase access to care and slow the opioid epidemic include low-threshold prescribing of MOUD and mobile OTPs.⁴¹

Low-threshold MOUD prescribing models. Adoption of one of these models in a medical practice that provides MAR might increase absolute enrollment. A low-threshold prescribing model involves⁴²:

• same-day treatment
• leniency with respect to abstinence periods and a concomitant substance use disorder
• enhanced accessibility to MOUD through nontraditional medical settings.

Do not use oral naltrexone to treat OUD; this route of administration has limited supporting evidence.

Low-threshold prescribing is flexible in regard to patients’ needs and bypasses many of the barriers discussed in this article. Impressive multicenter success has been achieved by the CA Bridge program in California (https://cabridge.org), including an increase in recognition of OUD, treatment initiations, and outpatient engagement.²⁵

The cost-effectiveness of low-threshold MOUD prescribing programs remains to be determined.

Mobile OTPs. In July 2021, the DEA authorized a mobile component to existing OTP registrants that is permitted to dispense methadone and buprenorphine. Mobile units are physically separate from the OTP but have similar functions, depending on available space. Services that cannot be provided on the mobile unit of an OTP must be available at its brick-and-mortar location.⁷ Logistically, OTP registrants no longer need a separate registration to implement a mobile unit, thus expanding care to patients in underserved or remote areas who often encounter barriers to access.⁴³

Conclusion

Understanding the distinct clinical and accessibility benefits and limitations among available MOUD is essential for prescribing clinicians. Accessing treatment is limited by federal regulation, stigma, and the existence of health care deserts that limit access to necessary care for patients with OUD. Newer harm-reduction models, such as low-threshold prescribing and mobile OTPs, represent progress, but many patients remain untreated.

a At buprenorphine.samhsa.gov/forms/select-practitioner-type.php

b Sold under the brand name Sublocade.

CORRESPONDENCE
Jennie B. Jarrett, PharmD, MMedEd, Department of Pharmacy Practice, University of Illinois Chicago College of Pharmacy, 833 South Wood Street (MC 886), Chicago, IL 60612; jarrett8@uic.edu

Medication-assisted recovery (MAR)—the preferred terminology for the service formerly known as medication­-assisted treatment—entails a comprehensive set of interventions for managing opioid use disorder (OUD), including medications for opioid use disorder (MOUD). Despite the benefits of MAR—reducing opioid use, opioid-related mortality, and health care costs^1-3—only 11% of patients with a diagnosis of OUD received MOUD in 2020.³

When medication-assisted recovery services are rendered in primary care, treatment retention improves by 25%—highlighting a role for family medicine clinicians in treating OUD.

Primary care physicians, including family physicians, are well positioned to provide MAR across the patient’s lifespan. However, many family medicine clinicians do not possess the logistical knowledge or resources to implement this service.⁴ In this article, we describe options for, and barriers to, MAR and societal issues that have an impact on the care of these patients.

Pathophysiology of OUD

Opioids relieve pain by stimulating μ-opioid receptors and activating the brain’s reward system. These pleasurable effects motivate repeated use.⁵ Frequent opioid exposure causes neuroadaptation, tolerance, and dependence. For patients with OUD who are misusing illicit or prescription opioids, periods of abstinence following neuroadaptation lead to withdrawal symptoms that vary in intensity, depending on the drug, dose, and duration of use. Upregulated noradrenergic tone and dopamine deficiency manifest as numerous signs and symptoms of withdrawal, including⁵:

• Physiologic: secretory (diaphoresis, rhinorrhea, lacrimation, vomiting, diarrhea) and stimulatory (mydriasis, piloerection, hypertension, tachycardia, insomnia)
• Psychological: pain, cravings, dysphoria, anxiety.

A single episode of opioid withdrawal is not directly life-threatening, but untreated episodes can progressively amplify negative feedback and reinforce continued opioid use.⁶ Left untreated, withdrawal can be terminal.

Image: Copyright Joe Gorman

Medication-assisted recovery: Effective intervention

MAR services that integrate medical, behavioral, and psychosocial programs can reduce mortality from OUD 2-fold.^7,8 A meta-analysis found that, when MAR services are rendered in primary care, treatment retention improves by 25% (number needed to treat [NNT] = 6) and ongoing illicit opioid use is reduced by 50% (NNT = 6), relative to care at a specialty clinic⁹—highlighting a role for family medicine clinicians in treating OUD.

All 3 US Food and Drug Administration (FDA)–approved MOUD (methadone, buprenorphine, and naltrexone) reduce cravings; 2 (methadone and buprenorphine) mitigate withdrawal symptoms by activating the μ-opioid receptor; and naltrexone diminishes the reinforcing effects of use (TABLE^10-12). It is crucial to recognize the pharmacologic distinctions among MOUD because untreated withdrawal syndromes increase dropout from treatment programs and subsequent relapse.¹³

The Hx of medication-assisted recovery

To understand the landscape of MAR, it is important to understand the history of opioid treatment in the United States. In 1966, Congress passed the Narcotic Addiction Rehabilitation Act (NARA), which secured federal assistance by which state and local governments could develop drug treatment programs.¹⁴ NARA permitted legal offenders with OUD to be civilly committed to treatment programs, rather than prosecuted. However, limited resources and a burgeoning population led, instead, to low-cost outpatient programs saddled by strict requirements that lacked a basis for improving clinical outcomes.

Continue to: At the time NARA...

At the time NARA was passed by Congress, OUD was viewed—inaccurately—as a criminal problem, not a medical one. Subsequent legislation was crafted through that lens, which has placed a heavy burden on patients until today.¹⁴ Although medical understanding of OUD has advanced tremendously over the past 50 years, treatment remains siloed from mainstream medicine, even in primary care.

There is no one-size-fits-all approach to MAR, and relapse is common. Patient-specific factors and the availability of resources should be considered when designing the most individualized, advantageous plan for MAR.

Methadone

Background. Methadone has the most extensive history for treating OUD and consistently has demonstrated efficacy.¹³ A meta-analysis of randomized controlled trials comparing methadone to nonpharmacotherapy alone found that methadone improved treatment retention by an absolute 57% (NNT = 2).¹⁰

Methadone was approved by the FDA for detoxification and maintenance treatment in the early 1970s, although the Narcotic Addict Treatment Act (NATA) of 1974 restricted dispensing of maintenance treatment to highly regulated clinics known as opioid treatment programs (OTPs).¹⁴ NATA required the treating physician to register with the US Drug Enforcement Agency (DEA) and to comply with conservative dosing regimens and observed dosing.

Over time, regulations evolved to give the physician greater flexibility in developing a care plan, allowing “take-home” doses, and improving patients’ access to care. Although access to methadone for the treatment of OUD remains limited to federally certified OTPs, regulations facilitate incorporation of a whole-person approach to care, including counseling, individual and group therapy, and toxicology testing.⁷

Continue to: Clinical considerations

Clinical considerations. Methadone requires slow titration. For patients starting methadone as an outpatient, federal law¹⁵ limits the initial dose to 30 mg and requires physician documentation when the first-day total dosage exceeds 40 mg. This dosing constraint makes it challenging to provide care because a daily dosage ≥ 60 mg has been found to produce, first, higher program retention (relative risk = 1.36; 95% CI, 1.13-1.63) and, second, greater reduction in illicit opioid use (relative risk = 1.59; 95% CI, 1.16-2.18) than is seen in patients who receive a lower daily dosage.¹⁶

Due to a prolonged elimination half-life, methadone reaches steady-state in 3 to 5 days. Patients and their families should be educated that withdrawal symptoms might not feel fully managed in the first few days of therapy and that time is required to experience safely the regimen’s full effects.

Aggressive dose-titration during methadone induction can result in drug accumulation and respiratory depression. The risk for methadone-related mortality is highest in the first 2 weeks of therapy, mostly related to overdose potential if the drug is combined with other opioids.¹⁷

Buprenorphine

Background. The prescribing rate for buprenorphine, particularly in primary care, is accelerating.¹⁸ A meta-analysis of randomized controlled trials found that¹¹:

• compared to placebo, buprenorphine, at any dosage, improves treatment retention by an absolute 21% to 28% (NNT = 4-5)
• patients receiving high-dose buprenorphine (≥ 16 mg/d) had fewer evident cases of illicit opioid use.

Unlike methadone, buprenorphine exerts partial agonism at the μ-opioid receptor, resulting in a so-called ceiling effect that significantly reduces the adverse effect profile, including respiratory depression and euphoria, relative to a full-agonist opioid, such as methadone.¹⁹

Continue to: Whereas accessing methadone...

Whereas accessing methadone is limited to OTPs, buprenorphine is available for office-based treatment. By hosting OUD treatment and primary care in the same place, primary care physicians can provide comprehensive medical care including and beyond OUD, thereby improving retention and managing comorbidity.²⁰

Integrated models involving support staff—eg, nurses, behavioral health providers, and pharmacists—have produced the greatest success with office-based treatment models.²¹ Office-based treatment normalizes OUD as a chronic disease managed by the primary care physician, enabling concurrent harm-reduction strategies; medication reconciliation; and convenient, regular prescribing intervals (eg, every 30 days).²²
Nevertheless, access to buprenorphine is limited. Because buprenorphine is a controlled substance, the Ryan Haight Online Pharmacy Consumer Protection Act of 2008 prevents initial prescribing of buprenorphine without in-person evaluation. Telehealth consultations increased access to buprenorphine through temporary exceptions during the COVID-19 pandemic. However, revised rules and regulations for telehealth visits for these controlled substances are forthcoming from the DEA as temporary exceptions for telehealth consultations come to an end. Additionally, prescribing buprenorphine for OUD requires that the treating physician undergo specific training and obtain qualifications, which have evolved over time through federal legislation.

The Drug Addiction Treatment Act of 2000 (DATA 2000) authorized what is known as an X-waiver, which allows physicians to prescribe controlled substances for office-based treatment of OUD, provided that:

• they are registered to do so with the Substance Abuse and Mental Health Services Administration and the DEA
• they have had subspecialty training in addiction or completed an 8-hour training course
• they are able to refer patients to appropriate counseling and ancillary services.

DATA 2000 restricted patient panel sizes­ to 30 patients in the first year, expanding thereafter upon appropriate certification.

Although medical understanding of OUD has advanced tremendously over the past 50 years, treatment remains siloed from mainstream medicine, even in primary care.

The Comprehensive Addiction and Recovery Act of 2016 (CARA) and the Substance Use Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities Act of 2018 (the SUPPORT Act) collectively extended prescribing authority for MOUD to other qualifying practitioners (eg, advanced practice clinicians). Despite these attempts to expand access to services, the overdose death rate has continued to increase.

Continue to: To further expand access to MAR...

To further expand access to MAR, the US Department of Health and Human Services updated its practice guidelines in April 2021, allowing clinicians to bypass X-waiver training requirements by applying for a notification-of-intent (NOI) buprenorphine waiver.^a However, clinicians are still limited to prescribing buprenorphine for 30 patients at a time. Clinicians who undergo complete X-waiver training may prescribe for 100 patients in the first year and, if eligible, 275 patients thereafter.

In addition, as a component of the Consolidation Appropriations Act of 2023, Congress passed the Mainstreaming Addiction Treatment Act of 2021, or MAT 2021, and Medication Access and Training Expansion Act of 2021, or MATE 2021. MAT eliminated the X-waiver, NOI, and restrictions on the number of patients for whom a provider could prescribe buprenorphine, under federal authority; however, restrictions within one’s state might limit the ability to prescribe buprenorphine. MATE 2021 is an educational requirement for licensing by the DEA (at application and renewal) that will require prescribers to complete 8 hours of training in substance use disorders starting in June 2023.

Patients and their families should be educated that withdrawal symptoms might not feel fully managed in the first few days of methadone therapy.

Use of the monthly injectable extended-release buprenorphine product^b is limited by an FDA Risk Evaluation and Mitigation Strategy (REMS) program, which requires specialized training and certification by the prescriber, distributor, and administering clinician. REMS reduces buprenorphine accessibility due to time, cost, and regulatory barriers; although such restrictions have been instituted with the patient’s safety in mind, any limitation to buprenorphine prescribing, apart from controlled substance licensure, serves only to limit access to a primary component of MAR.

Clinical considerations. Due to the competitive nature of buprenorphine and its high affinity for the μ-opioid receptor, the drug can displace other opioid agonists and precipitate acute withdrawal. The withdrawal experience can thereby condition fear and disfavor toward buprenorphine among patients.

It is vital, therefore, that (1) patients’ expectations for treatment be managed appropriately and (2) the treating physician be prepared to provide additional buprenorphine for adequate maintenance doses and utilize adjunct comfort agents (clonidine, nonsteroidal anti-inflammatory drugs, ondansetron) to manage acute withdrawal symptoms. Newer buprenorphine dosing strategies, such as micro-induction and macro-­induction, have emerged to curtail these risks.^23,24 This is an evolving area of MAR; newer low-threshold initiation strategies²⁵ (see “Low-threshold MOUD prescribing models,” in the text that follows) and evidence that supports micro-induction²⁶ might eliminate the practice of requiring active withdrawal for treatment.

Continue to: Regardless of the strategy...

Regardless of the strategy for dosing buprenorphine, it’s critical that patients be educated on how to initiate treatment outside a clinical setting, such as at home, where they occupy a familiar haven during a potentially uncomfortable time and can be as effective at initiation as they would be in a clinical setting, with no difference in precipitation of adverse effects.

At-home induction might be more appropriate for patients who are not yet in significant enough withdrawal while in the physician's office.²⁷ Guidance should be provided on dosing instructions, self-assessment of withdrawal­ symptoms, and, if applicable, patience with the slow-dissolving sublingual tablet or film formulation.

Naltrexone

Background. Naltrexone is available as an oral tablet and an extended-release, once-monthly intramuscular injection; the latter has demonstrated superiority in MAR.²⁸ Oral naltrexone has limited supporting evidence, is inferior to other MOUD options, and should not be used to treat OUD.⁷ Altogether, approval of naltrexone for OUD is controversial, due to potentially unethical trials and approval processes,²⁹ although a multicenter randomized controlled trial demonstrated the drug’s noninferiority with respect to treatment retention relative to buprenorphine.³⁰ Used over time, naltrexone does not relieve withdrawal symptoms but can reduce cravings.

Clinical considerations. There are numerous clinical barriers that limit the use of naltrexone.

First, patients should be abstinent from opioids for 7 to 14 days prior to starting therapy; usually, this means undergoing medically supervised withdrawal in a controlled environment. This is an obvious limitation for patients who are constrained financially—those who lack, or have inadequate, health insurance or are unable to be away from their job for an extended time.

Continue to: Second, because naltrexone...

Second, because naltrexone does not address withdrawal symptoms, supportive therapies should be incorporated into the treatment plan, including:

• clonidine for hyperadrenergic symptoms (anxiety, diaphoresis, hypertension)
• nonopioid analgesics for pain
• antiemetics, such as ondansetron and metoclopramide, for nausea or vomiting
• loperamide for diarrhea
• diphenhydramine for insomnia.

Third, patients taking naltrexone have a diminished response to opioids. This complicates pain management in the event of an emergent surgical procedure.

Last, when naltrexone wears off, patients are effectively opioid-naïve, which increases the risk for overdose in those who stop therapy abruptly.²⁹ The increased risk for overdose should be communicated to all patients with OUD who are being treated with naltrexone.

This nonopioid option is appealing to policymakers and is often prioritized in the criminal justice system; however, the decreased efficacy of naltrexone (compared to methadone and buprenorphine), potential for overdose, and challenges in initiating treatment are concerning and limit the drug’s use in many real-world settings.

Because naltrexone is not a controlled substance, regulations regarding maintaining inventory and distribution are more flexible.

Continue to: Overall, the cost-effectiveness...

Overall, the cost-effectiveness of intramuscular naltrexone is unclear. State-administered insurance programs vary in their requirements for coverage of naltrexone treatment.³¹

Comprehensive medication reconciliation is vital

Overall fragmentation of care within OTPs places patients at risk for adverse events, such as drug interactions.³² Under Title 42 of the US Code,³³ patients must provide written consent for an OTP provider to disclose their history of a substance use disorder. Allowing the patient to decide which medical providers can access their treatment records for an OUD benefits patient confidentiality but poses­ numerous issues worth exploring.

All prescribed controlled substances are recorded in the prescription drug monitoring program, or PDMP, a state-level electronic database accessible to health care professionals to inform prescribing decisions and identify drug interactions. The PDMP has substantially reduced opioid overprescribing and improved identification of patients at risk for overdose or misuse of opioids.

Buprenorphine, available for office-based treatment, has a so-called ceiling effect that reduces the adverse effect profile, including respiratory depression and euphoria.

Unlike all other controlled substances, however, prescriptions ordered by an OTP are not recorded in the PDMP (although there are recent exceptions to this scenario). Without such information, a physician might not have important information about the patient when making medical decisions—placing the patient at risk for harmful outcomes, such as drug–drug and drug–disease interactions.

For example: Methadone is associated with a prolonged QT interval,³⁴ increasing the risk for a fatal arrhythmia. Concurrent QT-prolonging medications, such as azithromycin and citalopram, further increase this risk.³⁵ Because methadone dispensing is isolated from the patient’s medical record, the clinician who prescribes MOUD has an incomplete patient history and could make a potentially fatal treatment decision.

Continue to: Diversion is unlikely

Diversion is unlikely

Health care providers often express concern about diversion in MOUD. However, misuse and diversion rates of methadone and buprenorphine have declined steadily since 2011, and, in fact, are actually lower than the diversion rate of prescription antibiotics.³⁶

Regardless, diversion of buprenorphine should not be a concern for physicians prescribing MOUD. Although a prescriber might worry about manipulation of the formulation of buprenorphine for intravenous administration, addition of naloxone to buprenorphine in tablet form diminishes the potential for overdose. Additionally, the ceiling effect of buprenorphine limits the likelihood of significant respiratory depression and euphoria.

Should buprenorphine reach a patient for whom it was not prescribed, it is highly unlikely that an overdose would result. Rather, the medication would protect against the effects of illicit opioids and relieve withdrawal symptoms. Most people with OUD who have misused buprenorphine have done so to relieve withdrawal symptoms,³⁷ not to experience intoxication.

Health care deserts

So-called health care deserts in parts of the United States are an ongoing problem that disproportionately affects lower-income and segregated Black and Hispanic communities³⁸—communities that shoulder the highest burden of OUD and OUD-related mortality³⁹ and whose populace is in greatest need of MAR. Even when health care is accessible in such a desert, some clinicians and pharmacies refuse to prescribe or dispense MOUD because of the accompanying stigma of OUD.

Prescribing buprenorphine for OUD requires that the treating physician undergo specific training, including subspecialty training in addiction or an 8-hour training course.

A MAR desert, like a pharmacy desert, is a geographic region—one without access to a MAR or an OTP provider, thereby preventing patients from reaching appropriate care; for some patients, having to travel to the nearest provider can render treatment inaccessible.⁴⁰

Continue to: Efforts are in place to identify...

Efforts are in place to identify areas at greatest need of OUD-related medical services, such as heat maps that identify areas of increased utilization of emergency medical services for opioid overdose. State-run programs have been implemented to increase access, such as the Illinois Helpline (https://helplineil.org) that provides support and resources for patients, friends, family, and providers.

Novel solutions

Key strategies to increase access to care and slow the opioid epidemic include low-threshold prescribing of MOUD and mobile OTPs.⁴¹

Low-threshold MOUD prescribing models. Adoption of one of these models in a medical practice that provides MAR might increase absolute enrollment. A low-threshold prescribing model involves⁴²:

• same-day treatment
• leniency with respect to abstinence periods and a concomitant substance use disorder
• enhanced accessibility to MOUD through nontraditional medical settings.

Do not use oral naltrexone to treat OUD; this route of administration has limited supporting evidence.

Low-threshold prescribing is flexible in regard to patients’ needs and bypasses many of the barriers discussed in this article. Impressive multicenter success has been achieved by the CA Bridge program in California (https://cabridge.org), including an increase in recognition of OUD, treatment initiations, and outpatient engagement.²⁵

The cost-effectiveness of low-threshold MOUD prescribing programs remains to be determined.

Mobile OTPs. In July 2021, the DEA authorized a mobile component to existing OTP registrants that is permitted to dispense methadone and buprenorphine. Mobile units are physically separate from the OTP but have similar functions, depending on available space. Services that cannot be provided on the mobile unit of an OTP must be available at its brick-and-mortar location.⁷ Logistically, OTP registrants no longer need a separate registration to implement a mobile unit, thus expanding care to patients in underserved or remote areas who often encounter barriers to access.⁴³

Conclusion

Understanding the distinct clinical and accessibility benefits and limitations among available MOUD is essential for prescribing clinicians. Accessing treatment is limited by federal regulation, stigma, and the existence of health care deserts that limit access to necessary care for patients with OUD. Newer harm-reduction models, such as low-threshold prescribing and mobile OTPs, represent progress, but many patients remain untreated.

a At buprenorphine.samhsa.gov/forms/select-practitioner-type.php

b Sold under the brand name Sublocade.

CORRESPONDENCE
Jennie B. Jarrett, PharmD, MMedEd, Department of Pharmacy Practice, University of Illinois Chicago College of Pharmacy, 833 South Wood Street (MC 886), Chicago, IL 60612; jarrett8@uic.edu

Medication-assisted recovery (MAR)—the preferred terminology for the service formerly known as medication­-assisted treatment—entails a comprehensive set of interventions for managing opioid use disorder (OUD), including medications for opioid use disorder (MOUD). Despite the benefits of MAR—reducing opioid use, opioid-related mortality, and health care costs^1-3—only 11% of patients with a diagnosis of OUD received MOUD in 2020.³

When medication-assisted recovery services are rendered in primary care, treatment retention improves by 25%—highlighting a role for family medicine clinicians in treating OUD.

Primary care physicians, including family physicians, are well positioned to provide MAR across the patient’s lifespan. However, many family medicine clinicians do not possess the logistical knowledge or resources to implement this service.⁴ In this article, we describe options for, and barriers to, MAR and societal issues that have an impact on the care of these patients.

Pathophysiology of OUD

Opioids relieve pain by stimulating μ-opioid receptors and activating the brain’s reward system. These pleasurable effects motivate repeated use.⁵ Frequent opioid exposure causes neuroadaptation, tolerance, and dependence. For patients with OUD who are misusing illicit or prescription opioids, periods of abstinence following neuroadaptation lead to withdrawal symptoms that vary in intensity, depending on the drug, dose, and duration of use. Upregulated noradrenergic tone and dopamine deficiency manifest as numerous signs and symptoms of withdrawal, including⁵:

• Physiologic: secretory (diaphoresis, rhinorrhea, lacrimation, vomiting, diarrhea) and stimulatory (mydriasis, piloerection, hypertension, tachycardia, insomnia)
• Psychological: pain, cravings, dysphoria, anxiety.

A single episode of opioid withdrawal is not directly life-threatening, but untreated episodes can progressively amplify negative feedback and reinforce continued opioid use.⁶ Left untreated, withdrawal can be terminal.

Image: Copyright Joe Gorman

Medication-assisted recovery: Effective intervention

MAR services that integrate medical, behavioral, and psychosocial programs can reduce mortality from OUD 2-fold.^7,8 A meta-analysis found that, when MAR services are rendered in primary care, treatment retention improves by 25% (number needed to treat [NNT] = 6) and ongoing illicit opioid use is reduced by 50% (NNT = 6), relative to care at a specialty clinic⁹—highlighting a role for family medicine clinicians in treating OUD.

All 3 US Food and Drug Administration (FDA)–approved MOUD (methadone, buprenorphine, and naltrexone) reduce cravings; 2 (methadone and buprenorphine) mitigate withdrawal symptoms by activating the μ-opioid receptor; and naltrexone diminishes the reinforcing effects of use (TABLE^10-12). It is crucial to recognize the pharmacologic distinctions among MOUD because untreated withdrawal syndromes increase dropout from treatment programs and subsequent relapse.¹³

The Hx of medication-assisted recovery

To understand the landscape of MAR, it is important to understand the history of opioid treatment in the United States. In 1966, Congress passed the Narcotic Addiction Rehabilitation Act (NARA), which secured federal assistance by which state and local governments could develop drug treatment programs.¹⁴ NARA permitted legal offenders with OUD to be civilly committed to treatment programs, rather than prosecuted. However, limited resources and a burgeoning population led, instead, to low-cost outpatient programs saddled by strict requirements that lacked a basis for improving clinical outcomes.

Continue to: At the time NARA...

At the time NARA was passed by Congress, OUD was viewed—inaccurately—as a criminal problem, not a medical one. Subsequent legislation was crafted through that lens, which has placed a heavy burden on patients until today.¹⁴ Although medical understanding of OUD has advanced tremendously over the past 50 years, treatment remains siloed from mainstream medicine, even in primary care.

There is no one-size-fits-all approach to MAR, and relapse is common. Patient-specific factors and the availability of resources should be considered when designing the most individualized, advantageous plan for MAR.

Methadone

Background. Methadone has the most extensive history for treating OUD and consistently has demonstrated efficacy.¹³ A meta-analysis of randomized controlled trials comparing methadone to nonpharmacotherapy alone found that methadone improved treatment retention by an absolute 57% (NNT = 2).¹⁰

Methadone was approved by the FDA for detoxification and maintenance treatment in the early 1970s, although the Narcotic Addict Treatment Act (NATA) of 1974 restricted dispensing of maintenance treatment to highly regulated clinics known as opioid treatment programs (OTPs).¹⁴ NATA required the treating physician to register with the US Drug Enforcement Agency (DEA) and to comply with conservative dosing regimens and observed dosing.

Over time, regulations evolved to give the physician greater flexibility in developing a care plan, allowing “take-home” doses, and improving patients’ access to care. Although access to methadone for the treatment of OUD remains limited to federally certified OTPs, regulations facilitate incorporation of a whole-person approach to care, including counseling, individual and group therapy, and toxicology testing.⁷

Continue to: Clinical considerations

Clinical considerations. Methadone requires slow titration. For patients starting methadone as an outpatient, federal law¹⁵ limits the initial dose to 30 mg and requires physician documentation when the first-day total dosage exceeds 40 mg. This dosing constraint makes it challenging to provide care because a daily dosage ≥ 60 mg has been found to produce, first, higher program retention (relative risk = 1.36; 95% CI, 1.13-1.63) and, second, greater reduction in illicit opioid use (relative risk = 1.59; 95% CI, 1.16-2.18) than is seen in patients who receive a lower daily dosage.¹⁶

Due to a prolonged elimination half-life, methadone reaches steady-state in 3 to 5 days. Patients and their families should be educated that withdrawal symptoms might not feel fully managed in the first few days of therapy and that time is required to experience safely the regimen’s full effects.

Aggressive dose-titration during methadone induction can result in drug accumulation and respiratory depression. The risk for methadone-related mortality is highest in the first 2 weeks of therapy, mostly related to overdose potential if the drug is combined with other opioids.¹⁷

Buprenorphine

Background. The prescribing rate for buprenorphine, particularly in primary care, is accelerating.¹⁸ A meta-analysis of randomized controlled trials found that¹¹:

• compared to placebo, buprenorphine, at any dosage, improves treatment retention by an absolute 21% to 28% (NNT = 4-5)
• patients receiving high-dose buprenorphine (≥ 16 mg/d) had fewer evident cases of illicit opioid use.

Unlike methadone, buprenorphine exerts partial agonism at the μ-opioid receptor, resulting in a so-called ceiling effect that significantly reduces the adverse effect profile, including respiratory depression and euphoria, relative to a full-agonist opioid, such as methadone.¹⁹

Continue to: Whereas accessing methadone...

Whereas accessing methadone is limited to OTPs, buprenorphine is available for office-based treatment. By hosting OUD treatment and primary care in the same place, primary care physicians can provide comprehensive medical care including and beyond OUD, thereby improving retention and managing comorbidity.²⁰

Integrated models involving support staff—eg, nurses, behavioral health providers, and pharmacists—have produced the greatest success with office-based treatment models.²¹ Office-based treatment normalizes OUD as a chronic disease managed by the primary care physician, enabling concurrent harm-reduction strategies; medication reconciliation; and convenient, regular prescribing intervals (eg, every 30 days).²²
Nevertheless, access to buprenorphine is limited. Because buprenorphine is a controlled substance, the Ryan Haight Online Pharmacy Consumer Protection Act of 2008 prevents initial prescribing of buprenorphine without in-person evaluation. Telehealth consultations increased access to buprenorphine through temporary exceptions during the COVID-19 pandemic. However, revised rules and regulations for telehealth visits for these controlled substances are forthcoming from the DEA as temporary exceptions for telehealth consultations come to an end. Additionally, prescribing buprenorphine for OUD requires that the treating physician undergo specific training and obtain qualifications, which have evolved over time through federal legislation.

The Drug Addiction Treatment Act of 2000 (DATA 2000) authorized what is known as an X-waiver, which allows physicians to prescribe controlled substances for office-based treatment of OUD, provided that:

• they are registered to do so with the Substance Abuse and Mental Health Services Administration and the DEA
• they have had subspecialty training in addiction or completed an 8-hour training course
• they are able to refer patients to appropriate counseling and ancillary services.

DATA 2000 restricted patient panel sizes­ to 30 patients in the first year, expanding thereafter upon appropriate certification.

Although medical understanding of OUD has advanced tremendously over the past 50 years, treatment remains siloed from mainstream medicine, even in primary care.

The Comprehensive Addiction and Recovery Act of 2016 (CARA) and the Substance Use Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities Act of 2018 (the SUPPORT Act) collectively extended prescribing authority for MOUD to other qualifying practitioners (eg, advanced practice clinicians). Despite these attempts to expand access to services, the overdose death rate has continued to increase.

Continue to: To further expand access to MAR...

To further expand access to MAR, the US Department of Health and Human Services updated its practice guidelines in April 2021, allowing clinicians to bypass X-waiver training requirements by applying for a notification-of-intent (NOI) buprenorphine waiver.^a However, clinicians are still limited to prescribing buprenorphine for 30 patients at a time. Clinicians who undergo complete X-waiver training may prescribe for 100 patients in the first year and, if eligible, 275 patients thereafter.

In addition, as a component of the Consolidation Appropriations Act of 2023, Congress passed the Mainstreaming Addiction Treatment Act of 2021, or MAT 2021, and Medication Access and Training Expansion Act of 2021, or MATE 2021. MAT eliminated the X-waiver, NOI, and restrictions on the number of patients for whom a provider could prescribe buprenorphine, under federal authority; however, restrictions within one’s state might limit the ability to prescribe buprenorphine. MATE 2021 is an educational requirement for licensing by the DEA (at application and renewal) that will require prescribers to complete 8 hours of training in substance use disorders starting in June 2023.

Patients and their families should be educated that withdrawal symptoms might not feel fully managed in the first few days of methadone therapy.

Use of the monthly injectable extended-release buprenorphine product^b is limited by an FDA Risk Evaluation and Mitigation Strategy (REMS) program, which requires specialized training and certification by the prescriber, distributor, and administering clinician. REMS reduces buprenorphine accessibility due to time, cost, and regulatory barriers; although such restrictions have been instituted with the patient’s safety in mind, any limitation to buprenorphine prescribing, apart from controlled substance licensure, serves only to limit access to a primary component of MAR.

Clinical considerations. Due to the competitive nature of buprenorphine and its high affinity for the μ-opioid receptor, the drug can displace other opioid agonists and precipitate acute withdrawal. The withdrawal experience can thereby condition fear and disfavor toward buprenorphine among patients.

It is vital, therefore, that (1) patients’ expectations for treatment be managed appropriately and (2) the treating physician be prepared to provide additional buprenorphine for adequate maintenance doses and utilize adjunct comfort agents (clonidine, nonsteroidal anti-inflammatory drugs, ondansetron) to manage acute withdrawal symptoms. Newer buprenorphine dosing strategies, such as micro-induction and macro-­induction, have emerged to curtail these risks.^23,24 This is an evolving area of MAR; newer low-threshold initiation strategies²⁵ (see “Low-threshold MOUD prescribing models,” in the text that follows) and evidence that supports micro-induction²⁶ might eliminate the practice of requiring active withdrawal for treatment.

Continue to: Regardless of the strategy...

Regardless of the strategy for dosing buprenorphine, it’s critical that patients be educated on how to initiate treatment outside a clinical setting, such as at home, where they occupy a familiar haven during a potentially uncomfortable time and can be as effective at initiation as they would be in a clinical setting, with no difference in precipitation of adverse effects.

At-home induction might be more appropriate for patients who are not yet in significant enough withdrawal while in the physician's office.²⁷ Guidance should be provided on dosing instructions, self-assessment of withdrawal­ symptoms, and, if applicable, patience with the slow-dissolving sublingual tablet or film formulation.

Naltrexone

Background. Naltrexone is available as an oral tablet and an extended-release, once-monthly intramuscular injection; the latter has demonstrated superiority in MAR.²⁸ Oral naltrexone has limited supporting evidence, is inferior to other MOUD options, and should not be used to treat OUD.⁷ Altogether, approval of naltrexone for OUD is controversial, due to potentially unethical trials and approval processes,²⁹ although a multicenter randomized controlled trial demonstrated the drug’s noninferiority with respect to treatment retention relative to buprenorphine.³⁰ Used over time, naltrexone does not relieve withdrawal symptoms but can reduce cravings.

Clinical considerations. There are numerous clinical barriers that limit the use of naltrexone.

First, patients should be abstinent from opioids for 7 to 14 days prior to starting therapy; usually, this means undergoing medically supervised withdrawal in a controlled environment. This is an obvious limitation for patients who are constrained financially—those who lack, or have inadequate, health insurance or are unable to be away from their job for an extended time.

Continue to: Second, because naltrexone...

Second, because naltrexone does not address withdrawal symptoms, supportive therapies should be incorporated into the treatment plan, including:

• clonidine for hyperadrenergic symptoms (anxiety, diaphoresis, hypertension)
• nonopioid analgesics for pain
• antiemetics, such as ondansetron and metoclopramide, for nausea or vomiting
• loperamide for diarrhea
• diphenhydramine for insomnia.

Third, patients taking naltrexone have a diminished response to opioids. This complicates pain management in the event of an emergent surgical procedure.

Last, when naltrexone wears off, patients are effectively opioid-naïve, which increases the risk for overdose in those who stop therapy abruptly.²⁹ The increased risk for overdose should be communicated to all patients with OUD who are being treated with naltrexone.

This nonopioid option is appealing to policymakers and is often prioritized in the criminal justice system; however, the decreased efficacy of naltrexone (compared to methadone and buprenorphine), potential for overdose, and challenges in initiating treatment are concerning and limit the drug’s use in many real-world settings.

Because naltrexone is not a controlled substance, regulations regarding maintaining inventory and distribution are more flexible.

Continue to: Overall, the cost-effectiveness...

Overall, the cost-effectiveness of intramuscular naltrexone is unclear. State-administered insurance programs vary in their requirements for coverage of naltrexone treatment.³¹

Comprehensive medication reconciliation is vital

Overall fragmentation of care within OTPs places patients at risk for adverse events, such as drug interactions.³² Under Title 42 of the US Code,³³ patients must provide written consent for an OTP provider to disclose their history of a substance use disorder. Allowing the patient to decide which medical providers can access their treatment records for an OUD benefits patient confidentiality but poses­ numerous issues worth exploring.

All prescribed controlled substances are recorded in the prescription drug monitoring program, or PDMP, a state-level electronic database accessible to health care professionals to inform prescribing decisions and identify drug interactions. The PDMP has substantially reduced opioid overprescribing and improved identification of patients at risk for overdose or misuse of opioids.

Buprenorphine, available for office-based treatment, has a so-called ceiling effect that reduces the adverse effect profile, including respiratory depression and euphoria.

Unlike all other controlled substances, however, prescriptions ordered by an OTP are not recorded in the PDMP (although there are recent exceptions to this scenario). Without such information, a physician might not have important information about the patient when making medical decisions—placing the patient at risk for harmful outcomes, such as drug–drug and drug–disease interactions.

For example: Methadone is associated with a prolonged QT interval,³⁴ increasing the risk for a fatal arrhythmia. Concurrent QT-prolonging medications, such as azithromycin and citalopram, further increase this risk.³⁵ Because methadone dispensing is isolated from the patient’s medical record, the clinician who prescribes MOUD has an incomplete patient history and could make a potentially fatal treatment decision.

Continue to: Diversion is unlikely

Diversion is unlikely

Health care providers often express concern about diversion in MOUD. However, misuse and diversion rates of methadone and buprenorphine have declined steadily since 2011, and, in fact, are actually lower than the diversion rate of prescription antibiotics.³⁶

Regardless, diversion of buprenorphine should not be a concern for physicians prescribing MOUD. Although a prescriber might worry about manipulation of the formulation of buprenorphine for intravenous administration, addition of naloxone to buprenorphine in tablet form diminishes the potential for overdose. Additionally, the ceiling effect of buprenorphine limits the likelihood of significant respiratory depression and euphoria.

Should buprenorphine reach a patient for whom it was not prescribed, it is highly unlikely that an overdose would result. Rather, the medication would protect against the effects of illicit opioids and relieve withdrawal symptoms. Most people with OUD who have misused buprenorphine have done so to relieve withdrawal symptoms,³⁷ not to experience intoxication.

Health care deserts

So-called health care deserts in parts of the United States are an ongoing problem that disproportionately affects lower-income and segregated Black and Hispanic communities³⁸—communities that shoulder the highest burden of OUD and OUD-related mortality³⁹ and whose populace is in greatest need of MAR. Even when health care is accessible in such a desert, some clinicians and pharmacies refuse to prescribe or dispense MOUD because of the accompanying stigma of OUD.

Prescribing buprenorphine for OUD requires that the treating physician undergo specific training, including subspecialty training in addiction or an 8-hour training course.

A MAR desert, like a pharmacy desert, is a geographic region—one without access to a MAR or an OTP provider, thereby preventing patients from reaching appropriate care; for some patients, having to travel to the nearest provider can render treatment inaccessible.⁴⁰

Continue to: Efforts are in place to identify...

Efforts are in place to identify areas at greatest need of OUD-related medical services, such as heat maps that identify areas of increased utilization of emergency medical services for opioid overdose. State-run programs have been implemented to increase access, such as the Illinois Helpline (https://helplineil.org) that provides support and resources for patients, friends, family, and providers.

Novel solutions

Key strategies to increase access to care and slow the opioid epidemic include low-threshold prescribing of MOUD and mobile OTPs.⁴¹

Low-threshold MOUD prescribing models. Adoption of one of these models in a medical practice that provides MAR might increase absolute enrollment. A low-threshold prescribing model involves⁴²:

• same-day treatment
• leniency with respect to abstinence periods and a concomitant substance use disorder
• enhanced accessibility to MOUD through nontraditional medical settings.

Do not use oral naltrexone to treat OUD; this route of administration has limited supporting evidence.

Low-threshold prescribing is flexible in regard to patients’ needs and bypasses many of the barriers discussed in this article. Impressive multicenter success has been achieved by the CA Bridge program in California (https://cabridge.org), including an increase in recognition of OUD, treatment initiations, and outpatient engagement.²⁵

The cost-effectiveness of low-threshold MOUD prescribing programs remains to be determined.

Mobile OTPs. In July 2021, the DEA authorized a mobile component to existing OTP registrants that is permitted to dispense methadone and buprenorphine. Mobile units are physically separate from the OTP but have similar functions, depending on available space. Services that cannot be provided on the mobile unit of an OTP must be available at its brick-and-mortar location.⁷ Logistically, OTP registrants no longer need a separate registration to implement a mobile unit, thus expanding care to patients in underserved or remote areas who often encounter barriers to access.⁴³

Conclusion

Understanding the distinct clinical and accessibility benefits and limitations among available MOUD is essential for prescribing clinicians. Accessing treatment is limited by federal regulation, stigma, and the existence of health care deserts that limit access to necessary care for patients with OUD. Newer harm-reduction models, such as low-threshold prescribing and mobile OTPs, represent progress, but many patients remain untreated.

a At buprenorphine.samhsa.gov/forms/select-practitioner-type.php

b Sold under the brand name Sublocade.

CORRESPONDENCE
Jennie B. Jarrett, PharmD, MMedEd, Department of Pharmacy Practice, University of Illinois Chicago College of Pharmacy, 833 South Wood Street (MC 886), Chicago, IL 60612; jarrett8@uic.edu

A potassium hydroxide (KOH) preparation of pus and dry superficial skin taken from 1 of the pustules revealed multiple hyphae and confirmed a diagnosis of nodular granulomatous perifolliculitis, also called Majocchi granuloma.

Majocchi granuloma is a reactive process of inflammation caused by infection of the follicular unit(s) by a dermatophyte—most often the same Trichophyton species responsible for more superficial tinea. On exam, there may be a solitary papule, pustule, or nodule. More often, there are multiple papules and pustules grouped within an annular plaque in hair-bearing areas on the head, trunk, or extremities. Majocchi granuloma can occur in patients who are healthy and those who are immunosuppressed.¹ It can also occur when a topical steroid is applied to unsuspected tinea, as occurred here. In this case, the patient was accustomed to having multiple skin plaques of psoriasis and assumed this was a stubborn manifestation of that.

Because the infection penetrates deeper than most topical therapies can effectively reach at adequate concentrations, systemic medications are the treatments of choice. Terbinafine, itraconazole, and fluconazole are all effective options but need to be used for several weeks to be effective.

This patient received terbinafine 250 mg/d for 6 weeks and the pustules cleared completely. He continued with his other psoriasis medications throughout his treatment.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME. 

A potassium hydroxide (KOH) preparation of pus and dry superficial skin taken from 1 of the pustules revealed multiple hyphae and confirmed a diagnosis of nodular granulomatous perifolliculitis, also called Majocchi granuloma.

Majocchi granuloma is a reactive process of inflammation caused by infection of the follicular unit(s) by a dermatophyte—most often the same Trichophyton species responsible for more superficial tinea. On exam, there may be a solitary papule, pustule, or nodule. More often, there are multiple papules and pustules grouped within an annular plaque in hair-bearing areas on the head, trunk, or extremities. Majocchi granuloma can occur in patients who are healthy and those who are immunosuppressed.¹ It can also occur when a topical steroid is applied to unsuspected tinea, as occurred here. In this case, the patient was accustomed to having multiple skin plaques of psoriasis and assumed this was a stubborn manifestation of that.

Because the infection penetrates deeper than most topical therapies can effectively reach at adequate concentrations, systemic medications are the treatments of choice. Terbinafine, itraconazole, and fluconazole are all effective options but need to be used for several weeks to be effective.

This patient received terbinafine 250 mg/d for 6 weeks and the pustules cleared completely. He continued with his other psoriasis medications throughout his treatment.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME. 

A potassium hydroxide (KOH) preparation of pus and dry superficial skin taken from 1 of the pustules revealed multiple hyphae and confirmed a diagnosis of nodular granulomatous perifolliculitis, also called Majocchi granuloma.

Majocchi granuloma is a reactive process of inflammation caused by infection of the follicular unit(s) by a dermatophyte—most often the same Trichophyton species responsible for more superficial tinea. On exam, there may be a solitary papule, pustule, or nodule. More often, there are multiple papules and pustules grouped within an annular plaque in hair-bearing areas on the head, trunk, or extremities. Majocchi granuloma can occur in patients who are healthy and those who are immunosuppressed.¹ It can also occur when a topical steroid is applied to unsuspected tinea, as occurred here. In this case, the patient was accustomed to having multiple skin plaques of psoriasis and assumed this was a stubborn manifestation of that.

Because the infection penetrates deeper than most topical therapies can effectively reach at adequate concentrations, systemic medications are the treatments of choice. Terbinafine, itraconazole, and fluconazole are all effective options but need to be used for several weeks to be effective.

This patient received terbinafine 250 mg/d for 6 weeks and the pustules cleared completely. He continued with his other psoriasis medications throughout his treatment.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME. 

To the Editor:

Pemphigoid gestationis (PG), or gestational pemphigoid, is a rare autoimmune bullous disease (AIBD) occurring in 1 in 50,000 pregnancies. It is characterized by abrupt development of intensely pruritic papules and urticarial plaques, followed by an eruption of blisters.¹ We present a case of new-onset PG that erupted 10 days following SARs-CoV-2 messenger RNA (mRNA) vaccination with BNT162b2 (Pfizer-BioNTech).

A 36-year-old pregnant woman (gravida 1, para 0, aborta 0) at 37 weeks’ gestation presented to our AIBD clinic with a pruritic dermatitis of 6 weeks’ duration that developed 10 days after receiving the second dose of BNT162b2. Multiple intensely pruritic, red bumps presented first on the forearms and within days spread to the thighs, hands, and abdomen, followed by progression to the ankles, feet, and back 2 weeks later. An initial biopsy was consistent with subacute spongiotic dermatitis with rare eosinophils. She found minimal relief from diphenhydramine or topical steroids. She denied oral, nasal, ocular, or genital involvement or history of any other skin disease. The pregnancy had been otherwise uneventful.

Physical examination revealed annular edematous plaques on the trunk and buttocks; excoriated and erythematous papules on the neck, trunk, arms, and legs; and scattered vesicles along the fingers, arms, hands, abdomen, back, legs, and feet (Figure 1). The Bullous Pemphigoid Disease Area Index (BPDAI) total skin activity score was 25.3, corresponding to moderate disease activity (validated at 20–56).² The BPDAI total pruritus component score was 20. A repeat biopsy for direct immunofluorescence showed faint linear deposits of IgG and bright linear deposits of C3 along the basement membrane zone. Indirect immunofluorescence showed linear deposits of IgG localized to the blister roof of salt-split skin at a dilution of 1:40. An enzyme-linked immunosorbent assay for anti-BP180 was 62 U/mL (negative, <9 U/mL; positive, ≥9 U/mL), and anti-BP230 autoantibodies were less than 9 U/mL (negative <9 U/mL; positive, ≥9 U/mL). Given these clinical and histopathologic findings, PG was diagnosed. 

The patient was started on prednisone 20 mg and antihistamines while continuing topical steroids. Pruritus and blistering improved close to delivery. Fetal monitoring with regular biophysical profiles remained normal. The patient delivered a healthy neonate without skin lesions at 40 weeks’ gestation. The disease flared 2 days after delivery, and prednisone was increased to 40 mg and slowly tapered. Two months after delivery, the patient remained on prednisone 10 mg daily with ongoing but reduced blistering and pruritus (Figure 2). The BPDAI total skin activity and pruritus component scores remained elevated at 20.3 and 14, respectively, and anti-BP180 was 44 U/mL. After a discussion with the patient on safe systemic therapy while breastfeeding, intravenous immunoglobulin (IVIG) was initiated. The patient received 3 monthly infusions at 2 g/kg and was able to taper the prednisone to 5 mg every other day without new lesions. Four months after completion of IVIG therapy, she achieved complete remission off all therapy.

Management of PG begins with topical corticosteroids, but most patients require systemic steroid therapy.¹ Remission commonly occurs close to delivery, and 75% of patients flare post partum, though the disease typically resolves 6 months following delivery.^1,3,4 For persistent intrapartum cases requiring more than prednisone 20 mg daily, therapy can include dapsone, IVIG, azathioprine, rituximab, or plasmapheresis.^4,5 Dapsone and IVIG are compatible with breastfeeding postpartum, but if dapsone is selected, the infant must be monitored for hemolytic anemia.⁵ Pemphigoid gestationis increases the risk for a premature or small-for-gestational-age neonate, necessitating regular fetal monitoring until delivery.¹ Cutaneous lesions may affect the newborn, though this occurrence is rare and self-limiting.⁶ Pemphigoid gestationis may recur in subsequent pregnancies at a rate of 33% to 55%, with earlier and more severe presentations.⁴

Clinically and histologically, PG closely resembles bullous pemphigoid (BP), but the exact pathogenesis is not fully understood. Recently, another case of what was termed pseudo-PG has been described 3 days following administration of the second dose of the Pfizer-BioNTech COVID-19 vaccine.⁷ Since the introduction of COVID-19 mRNA vaccines, cases of postvaccination BP, BP-like eruptions, and pemphigus vulgaris have been described.^8-11 Tomayko et al¹⁰ reported 12 cases of subepidermal eruptions, including BP, in which 7 patients developed blisters after the second dose of either the Pfizer-BioNTech or Moderna mRNA vaccine. Three patients who developed BP after the first dose of the vaccine and chose to receive the second dose tolerated it well, with a mild flare observed in 1 patient.¹⁰ Similarly, subsequent vaccine doses in reports of vaccine-associated AIBD resulted in increased disease activity in 21% of cases.¹² COVID-19 vaccine–associated BP, similar to drug-induced BP, seemingly displays a milder course of disease compared to the classic form of BP.^10,13 More follow-up is needed to better understand these reactions and inform appropriate discussions on the administration of booster doses. Currently, completion of the vaccination series against COVID-19 is advisable given the paucity of reports of postvaccination AIBD and the risk for COVID-19 infection, but careful discussions on a case-by-case basis are warranted related to the risk for disease exacerbation following subsequent vaccinations.

The clinical presentation and diagnostic evaluation of our patient’s rash were consistent with PG. The temporal relationship between vaccine administration and PG lesion onset suggests the mRNA vaccine triggered AIBD in our patient. Interestingly, AIBD associated with COVID-19 is not unique to only the vaccines and has been observed following infection with the virus itself.¹⁴ The high rate of vaccination against COVID-19 in contrast with the low number of reported cases of AIBD after vaccination supports the overall safety of COVID-19 vaccines but identifies a need for further understanding of the processes that lead to the development of autoimmune conditions in at-risk populations.

To the Editor:

Pemphigoid gestationis (PG), or gestational pemphigoid, is a rare autoimmune bullous disease (AIBD) occurring in 1 in 50,000 pregnancies. It is characterized by abrupt development of intensely pruritic papules and urticarial plaques, followed by an eruption of blisters.¹ We present a case of new-onset PG that erupted 10 days following SARs-CoV-2 messenger RNA (mRNA) vaccination with BNT162b2 (Pfizer-BioNTech).

A 36-year-old pregnant woman (gravida 1, para 0, aborta 0) at 37 weeks’ gestation presented to our AIBD clinic with a pruritic dermatitis of 6 weeks’ duration that developed 10 days after receiving the second dose of BNT162b2. Multiple intensely pruritic, red bumps presented first on the forearms and within days spread to the thighs, hands, and abdomen, followed by progression to the ankles, feet, and back 2 weeks later. An initial biopsy was consistent with subacute spongiotic dermatitis with rare eosinophils. She found minimal relief from diphenhydramine or topical steroids. She denied oral, nasal, ocular, or genital involvement or history of any other skin disease. The pregnancy had been otherwise uneventful.

Physical examination revealed annular edematous plaques on the trunk and buttocks; excoriated and erythematous papules on the neck, trunk, arms, and legs; and scattered vesicles along the fingers, arms, hands, abdomen, back, legs, and feet (Figure 1). The Bullous Pemphigoid Disease Area Index (BPDAI) total skin activity score was 25.3, corresponding to moderate disease activity (validated at 20–56).² The BPDAI total pruritus component score was 20. A repeat biopsy for direct immunofluorescence showed faint linear deposits of IgG and bright linear deposits of C3 along the basement membrane zone. Indirect immunofluorescence showed linear deposits of IgG localized to the blister roof of salt-split skin at a dilution of 1:40. An enzyme-linked immunosorbent assay for anti-BP180 was 62 U/mL (negative, <9 U/mL; positive, ≥9 U/mL), and anti-BP230 autoantibodies were less than 9 U/mL (negative <9 U/mL; positive, ≥9 U/mL). Given these clinical and histopathologic findings, PG was diagnosed. 

The patient was started on prednisone 20 mg and antihistamines while continuing topical steroids. Pruritus and blistering improved close to delivery. Fetal monitoring with regular biophysical profiles remained normal. The patient delivered a healthy neonate without skin lesions at 40 weeks’ gestation. The disease flared 2 days after delivery, and prednisone was increased to 40 mg and slowly tapered. Two months after delivery, the patient remained on prednisone 10 mg daily with ongoing but reduced blistering and pruritus (Figure 2). The BPDAI total skin activity and pruritus component scores remained elevated at 20.3 and 14, respectively, and anti-BP180 was 44 U/mL. After a discussion with the patient on safe systemic therapy while breastfeeding, intravenous immunoglobulin (IVIG) was initiated. The patient received 3 monthly infusions at 2 g/kg and was able to taper the prednisone to 5 mg every other day without new lesions. Four months after completion of IVIG therapy, she achieved complete remission off all therapy.

Management of PG begins with topical corticosteroids, but most patients require systemic steroid therapy.¹ Remission commonly occurs close to delivery, and 75% of patients flare post partum, though the disease typically resolves 6 months following delivery.^1,3,4 For persistent intrapartum cases requiring more than prednisone 20 mg daily, therapy can include dapsone, IVIG, azathioprine, rituximab, or plasmapheresis.^4,5 Dapsone and IVIG are compatible with breastfeeding postpartum, but if dapsone is selected, the infant must be monitored for hemolytic anemia.⁵ Pemphigoid gestationis increases the risk for a premature or small-for-gestational-age neonate, necessitating regular fetal monitoring until delivery.¹ Cutaneous lesions may affect the newborn, though this occurrence is rare and self-limiting.⁶ Pemphigoid gestationis may recur in subsequent pregnancies at a rate of 33% to 55%, with earlier and more severe presentations.⁴

Clinically and histologically, PG closely resembles bullous pemphigoid (BP), but the exact pathogenesis is not fully understood. Recently, another case of what was termed pseudo-PG has been described 3 days following administration of the second dose of the Pfizer-BioNTech COVID-19 vaccine.⁷ Since the introduction of COVID-19 mRNA vaccines, cases of postvaccination BP, BP-like eruptions, and pemphigus vulgaris have been described.^8-11 Tomayko et al¹⁰ reported 12 cases of subepidermal eruptions, including BP, in which 7 patients developed blisters after the second dose of either the Pfizer-BioNTech or Moderna mRNA vaccine. Three patients who developed BP after the first dose of the vaccine and chose to receive the second dose tolerated it well, with a mild flare observed in 1 patient.¹⁰ Similarly, subsequent vaccine doses in reports of vaccine-associated AIBD resulted in increased disease activity in 21% of cases.¹² COVID-19 vaccine–associated BP, similar to drug-induced BP, seemingly displays a milder course of disease compared to the classic form of BP.^10,13 More follow-up is needed to better understand these reactions and inform appropriate discussions on the administration of booster doses. Currently, completion of the vaccination series against COVID-19 is advisable given the paucity of reports of postvaccination AIBD and the risk for COVID-19 infection, but careful discussions on a case-by-case basis are warranted related to the risk for disease exacerbation following subsequent vaccinations.

The clinical presentation and diagnostic evaluation of our patient’s rash were consistent with PG. The temporal relationship between vaccine administration and PG lesion onset suggests the mRNA vaccine triggered AIBD in our patient. Interestingly, AIBD associated with COVID-19 is not unique to only the vaccines and has been observed following infection with the virus itself.¹⁴ The high rate of vaccination against COVID-19 in contrast with the low number of reported cases of AIBD after vaccination supports the overall safety of COVID-19 vaccines but identifies a need for further understanding of the processes that lead to the development of autoimmune conditions in at-risk populations.

To the Editor:

Pemphigoid gestationis (PG), or gestational pemphigoid, is a rare autoimmune bullous disease (AIBD) occurring in 1 in 50,000 pregnancies. It is characterized by abrupt development of intensely pruritic papules and urticarial plaques, followed by an eruption of blisters.¹ We present a case of new-onset PG that erupted 10 days following SARs-CoV-2 messenger RNA (mRNA) vaccination with BNT162b2 (Pfizer-BioNTech).

A 36-year-old pregnant woman (gravida 1, para 0, aborta 0) at 37 weeks’ gestation presented to our AIBD clinic with a pruritic dermatitis of 6 weeks’ duration that developed 10 days after receiving the second dose of BNT162b2. Multiple intensely pruritic, red bumps presented first on the forearms and within days spread to the thighs, hands, and abdomen, followed by progression to the ankles, feet, and back 2 weeks later. An initial biopsy was consistent with subacute spongiotic dermatitis with rare eosinophils. She found minimal relief from diphenhydramine or topical steroids. She denied oral, nasal, ocular, or genital involvement or history of any other skin disease. The pregnancy had been otherwise uneventful.

Physical examination revealed annular edematous plaques on the trunk and buttocks; excoriated and erythematous papules on the neck, trunk, arms, and legs; and scattered vesicles along the fingers, arms, hands, abdomen, back, legs, and feet (Figure 1). The Bullous Pemphigoid Disease Area Index (BPDAI) total skin activity score was 25.3, corresponding to moderate disease activity (validated at 20–56).² The BPDAI total pruritus component score was 20. A repeat biopsy for direct immunofluorescence showed faint linear deposits of IgG and bright linear deposits of C3 along the basement membrane zone. Indirect immunofluorescence showed linear deposits of IgG localized to the blister roof of salt-split skin at a dilution of 1:40. An enzyme-linked immunosorbent assay for anti-BP180 was 62 U/mL (negative, <9 U/mL; positive, ≥9 U/mL), and anti-BP230 autoantibodies were less than 9 U/mL (negative <9 U/mL; positive, ≥9 U/mL). Given these clinical and histopathologic findings, PG was diagnosed. 

The patient was started on prednisone 20 mg and antihistamines while continuing topical steroids. Pruritus and blistering improved close to delivery. Fetal monitoring with regular biophysical profiles remained normal. The patient delivered a healthy neonate without skin lesions at 40 weeks’ gestation. The disease flared 2 days after delivery, and prednisone was increased to 40 mg and slowly tapered. Two months after delivery, the patient remained on prednisone 10 mg daily with ongoing but reduced blistering and pruritus (Figure 2). The BPDAI total skin activity and pruritus component scores remained elevated at 20.3 and 14, respectively, and anti-BP180 was 44 U/mL. After a discussion with the patient on safe systemic therapy while breastfeeding, intravenous immunoglobulin (IVIG) was initiated. The patient received 3 monthly infusions at 2 g/kg and was able to taper the prednisone to 5 mg every other day without new lesions. Four months after completion of IVIG therapy, she achieved complete remission off all therapy.

Management of PG begins with topical corticosteroids, but most patients require systemic steroid therapy.¹ Remission commonly occurs close to delivery, and 75% of patients flare post partum, though the disease typically resolves 6 months following delivery.^1,3,4 For persistent intrapartum cases requiring more than prednisone 20 mg daily, therapy can include dapsone, IVIG, azathioprine, rituximab, or plasmapheresis.^4,5 Dapsone and IVIG are compatible with breastfeeding postpartum, but if dapsone is selected, the infant must be monitored for hemolytic anemia.⁵ Pemphigoid gestationis increases the risk for a premature or small-for-gestational-age neonate, necessitating regular fetal monitoring until delivery.¹ Cutaneous lesions may affect the newborn, though this occurrence is rare and self-limiting.⁶ Pemphigoid gestationis may recur in subsequent pregnancies at a rate of 33% to 55%, with earlier and more severe presentations.⁴

Clinically and histologically, PG closely resembles bullous pemphigoid (BP), but the exact pathogenesis is not fully understood. Recently, another case of what was termed pseudo-PG has been described 3 days following administration of the second dose of the Pfizer-BioNTech COVID-19 vaccine.⁷ Since the introduction of COVID-19 mRNA vaccines, cases of postvaccination BP, BP-like eruptions, and pemphigus vulgaris have been described.^8-11 Tomayko et al¹⁰ reported 12 cases of subepidermal eruptions, including BP, in which 7 patients developed blisters after the second dose of either the Pfizer-BioNTech or Moderna mRNA vaccine. Three patients who developed BP after the first dose of the vaccine and chose to receive the second dose tolerated it well, with a mild flare observed in 1 patient.¹⁰ Similarly, subsequent vaccine doses in reports of vaccine-associated AIBD resulted in increased disease activity in 21% of cases.¹² COVID-19 vaccine–associated BP, similar to drug-induced BP, seemingly displays a milder course of disease compared to the classic form of BP.^10,13 More follow-up is needed to better understand these reactions and inform appropriate discussions on the administration of booster doses. Currently, completion of the vaccination series against COVID-19 is advisable given the paucity of reports of postvaccination AIBD and the risk for COVID-19 infection, but careful discussions on a case-by-case basis are warranted related to the risk for disease exacerbation following subsequent vaccinations.

The clinical presentation and diagnostic evaluation of our patient’s rash were consistent with PG. The temporal relationship between vaccine administration and PG lesion onset suggests the mRNA vaccine triggered AIBD in our patient. Interestingly, AIBD associated with COVID-19 is not unique to only the vaccines and has been observed following infection with the virus itself.¹⁴ The high rate of vaccination against COVID-19 in contrast with the low number of reported cases of AIBD after vaccination supports the overall safety of COVID-19 vaccines but identifies a need for further understanding of the processes that lead to the development of autoimmune conditions in at-risk populations.

The Diagnosis: Prurigo Pigmentosa 

Histopathology of the punch biopsy revealed subcorneal collections of neutrophils flanked by a spongiotic epidermis with neutrophil and eosinophil exocytosis. Rare dyskeratotic keratinocytes were identified at the dermoepidermal junction, and grampositive bacterial organisms were seen in a follicular infundibulum with purulent inflammation. The dermis demonstrated a mildly dense superficial perivascular and interstitial infiltrate composed of lymphocytes, histiocytes, scattered neutrophils, and eosinophils (Figure).

Given the combination of clinical and histologic findings, a diagnosis of prurigo pigmentosa (PP) was rendered and a urinalysis was ordered, which confirmed ketonuria. The patient was started on minocycline 100 mg twice daily and was advised to reintroduce carbohydrates into her diet. Resolution of the inflammatory component of the rash was achieved at 3-week follow-up, with residual reticulated postinflammatory hyperpigmentation.

Prurigo pigmentosa is a rare, albeit globally underrecognized, inflammatory dermatosis characterized by pruritic, symmetric, erythematous papules and plaques on the chest, back, neck, and rarely the arms and forehead that subsequently involute, leaving reticular postinflammatory hyperpigmentation.1 Prurigo pigmentosa is predominant in females (2.6:1 ratio). The mean age at presentation is 24.4 years, and it most commonly has been documented among populations in Asian countries, though it is unclear if a genetic predilection exists, as reports of PP are increasing globally with improved clinical awareness.^1,2

The etiology of PP remains unknown; however, associations are well documented between PP and a ketogenic state secondary to uncontrolled diabetes, a low-carbohydrate diet, anorexia nervosa, or bariatric surgery.³ It is theorized that high serum ketones lead to perivascular ketone deposition, which induces neutrophil migration and chemotaxis,⁴ as substantiated by evidence of rash resolution with correction of the ketogenic state and improvement after administration of tetracyclines, a drug class known for neutrophil chemotaxis inhibition.⁵ Improvement of PP via these treatment mechanisms suggests that ketone bodies may play a role in the pathogenesis of PP.

Interestingly, Kafle et al⁶ reported that patients with PP commonly have bacterial colonies and associated inflammatory sequelae at the level of the hair follicles, which suggests that follicular involvement plays a role in the pathogenesis of PP. These findings are consistent with our patient’s histopathology consisting of gram-positive organisms and purulent inflammation at the infundibulum. The histopathologic features of PP are stage specific.¹ Early stages are characterized by a superficial perivascular infiltrate of neutrophils that then spread to dermal papillae. Neutrophils then quickly sweep through the epidermis, causing spongiosis, ballooning, necrotic keratocytes, and consequent surface epithelium abscess formation. Over time, the dermal infiltrate assumes a lichenoid pattern as eosinophils and lymphocytes invade and predominate over neutrophils. Eventually, melanophages appear in the dermis as the epidermis undergoes hyperplasia, parakeratosis, and hyperpigmentation.¹ The histologic differential diagnosis for PP is broad and varies based on the stage-specific progression of clinical and histopathologic findings.

Similar to PP, subacute cutaneous lupus erythematosus has a female predominance and resolves with subsequent dyspigmentation; however, it initially is characterized by annular plaques with central clearing or papulosquamous lesions restricted to sun-exposed skin. Photosensitivity is a prominent feature, and roughly 50% of patients meet diagnostic criteria for systemic lupus erythematosus.⁷ Histopathology shows interface changes with increased dermal mucin and a perivascular lymphoplasmacytic inflammatory infiltrate.

Papular pityriasis rosea can present as a pruritic papular rash on the back and chest; however, it most commonly is associated with a herald patch and typically follows a flulike prodrome.⁸ Biopsy reveals mounds of parakeratosis with mild spongiosis, perivascular inflammation, and extravasated erythrocytes.

Galli-Galli disease can present as a pruritic rash with follicular papules under the breasts and other flexural areas but histopathologically shows elongated rete ridges with dermal melanosis and acantholysis.⁹

Hailey-Hailey disease commonly presents in the third decade of life and can manifest as painful, pruritic, vesicular lesions on erythematous skin distributed on the back, neck, and inframammary region, as seen in our case; however, it is histopathologically associated with widespread epidermal acantholysis unlike the findings seen in our patient.¹⁰

First-line treatment of PP includes antibiotics such as minocycline, doxycycline, and dapsone due to their anti-inflammatory properties and ability to inhibit neutrophil chemotaxis. In patients with nutritional deficiencies or ketosis, reintroduction of carbohydrates alone has been effective.^5,11

Prurigo pigmentosa is an underrecognized inflammatory dermatosis with a complex stage-dependent clinicopathologic presentation. Clinicians should be aware of the etiologic and histopathologic patterns of this unique dermatosis. Rash presentation in the context of a low-carbohydrate diet should prompt biopsy as well as treatment with antibiotics and dietary reintroduction of carbohydrates.

The Diagnosis: Prurigo Pigmentosa 

Histopathology of the punch biopsy revealed subcorneal collections of neutrophils flanked by a spongiotic epidermis with neutrophil and eosinophil exocytosis. Rare dyskeratotic keratinocytes were identified at the dermoepidermal junction, and grampositive bacterial organisms were seen in a follicular infundibulum with purulent inflammation. The dermis demonstrated a mildly dense superficial perivascular and interstitial infiltrate composed of lymphocytes, histiocytes, scattered neutrophils, and eosinophils (Figure).

Given the combination of clinical and histologic findings, a diagnosis of prurigo pigmentosa (PP) was rendered and a urinalysis was ordered, which confirmed ketonuria. The patient was started on minocycline 100 mg twice daily and was advised to reintroduce carbohydrates into her diet. Resolution of the inflammatory component of the rash was achieved at 3-week follow-up, with residual reticulated postinflammatory hyperpigmentation.

Prurigo pigmentosa is a rare, albeit globally underrecognized, inflammatory dermatosis characterized by pruritic, symmetric, erythematous papules and plaques on the chest, back, neck, and rarely the arms and forehead that subsequently involute, leaving reticular postinflammatory hyperpigmentation.1 Prurigo pigmentosa is predominant in females (2.6:1 ratio). The mean age at presentation is 24.4 years, and it most commonly has been documented among populations in Asian countries, though it is unclear if a genetic predilection exists, as reports of PP are increasing globally with improved clinical awareness.^1,2

The etiology of PP remains unknown; however, associations are well documented between PP and a ketogenic state secondary to uncontrolled diabetes, a low-carbohydrate diet, anorexia nervosa, or bariatric surgery.³ It is theorized that high serum ketones lead to perivascular ketone deposition, which induces neutrophil migration and chemotaxis,⁴ as substantiated by evidence of rash resolution with correction of the ketogenic state and improvement after administration of tetracyclines, a drug class known for neutrophil chemotaxis inhibition.⁵ Improvement of PP via these treatment mechanisms suggests that ketone bodies may play a role in the pathogenesis of PP.

Interestingly, Kafle et al⁶ reported that patients with PP commonly have bacterial colonies and associated inflammatory sequelae at the level of the hair follicles, which suggests that follicular involvement plays a role in the pathogenesis of PP. These findings are consistent with our patient’s histopathology consisting of gram-positive organisms and purulent inflammation at the infundibulum. The histopathologic features of PP are stage specific.¹ Early stages are characterized by a superficial perivascular infiltrate of neutrophils that then spread to dermal papillae. Neutrophils then quickly sweep through the epidermis, causing spongiosis, ballooning, necrotic keratocytes, and consequent surface epithelium abscess formation. Over time, the dermal infiltrate assumes a lichenoid pattern as eosinophils and lymphocytes invade and predominate over neutrophils. Eventually, melanophages appear in the dermis as the epidermis undergoes hyperplasia, parakeratosis, and hyperpigmentation.¹ The histologic differential diagnosis for PP is broad and varies based on the stage-specific progression of clinical and histopathologic findings.

Similar to PP, subacute cutaneous lupus erythematosus has a female predominance and resolves with subsequent dyspigmentation; however, it initially is characterized by annular plaques with central clearing or papulosquamous lesions restricted to sun-exposed skin. Photosensitivity is a prominent feature, and roughly 50% of patients meet diagnostic criteria for systemic lupus erythematosus.⁷ Histopathology shows interface changes with increased dermal mucin and a perivascular lymphoplasmacytic inflammatory infiltrate.

Papular pityriasis rosea can present as a pruritic papular rash on the back and chest; however, it most commonly is associated with a herald patch and typically follows a flulike prodrome.⁸ Biopsy reveals mounds of parakeratosis with mild spongiosis, perivascular inflammation, and extravasated erythrocytes.

Galli-Galli disease can present as a pruritic rash with follicular papules under the breasts and other flexural areas but histopathologically shows elongated rete ridges with dermal melanosis and acantholysis.⁹

Hailey-Hailey disease commonly presents in the third decade of life and can manifest as painful, pruritic, vesicular lesions on erythematous skin distributed on the back, neck, and inframammary region, as seen in our case; however, it is histopathologically associated with widespread epidermal acantholysis unlike the findings seen in our patient.¹⁰

First-line treatment of PP includes antibiotics such as minocycline, doxycycline, and dapsone due to their anti-inflammatory properties and ability to inhibit neutrophil chemotaxis. In patients with nutritional deficiencies or ketosis, reintroduction of carbohydrates alone has been effective.^5,11

Prurigo pigmentosa is an underrecognized inflammatory dermatosis with a complex stage-dependent clinicopathologic presentation. Clinicians should be aware of the etiologic and histopathologic patterns of this unique dermatosis. Rash presentation in the context of a low-carbohydrate diet should prompt biopsy as well as treatment with antibiotics and dietary reintroduction of carbohydrates.

The Diagnosis: Prurigo Pigmentosa 

Histopathology of the punch biopsy revealed subcorneal collections of neutrophils flanked by a spongiotic epidermis with neutrophil and eosinophil exocytosis. Rare dyskeratotic keratinocytes were identified at the dermoepidermal junction, and grampositive bacterial organisms were seen in a follicular infundibulum with purulent inflammation. The dermis demonstrated a mildly dense superficial perivascular and interstitial infiltrate composed of lymphocytes, histiocytes, scattered neutrophils, and eosinophils (Figure).

Given the combination of clinical and histologic findings, a diagnosis of prurigo pigmentosa (PP) was rendered and a urinalysis was ordered, which confirmed ketonuria. The patient was started on minocycline 100 mg twice daily and was advised to reintroduce carbohydrates into her diet. Resolution of the inflammatory component of the rash was achieved at 3-week follow-up, with residual reticulated postinflammatory hyperpigmentation.

Prurigo pigmentosa is a rare, albeit globally underrecognized, inflammatory dermatosis characterized by pruritic, symmetric, erythematous papules and plaques on the chest, back, neck, and rarely the arms and forehead that subsequently involute, leaving reticular postinflammatory hyperpigmentation.1 Prurigo pigmentosa is predominant in females (2.6:1 ratio). The mean age at presentation is 24.4 years, and it most commonly has been documented among populations in Asian countries, though it is unclear if a genetic predilection exists, as reports of PP are increasing globally with improved clinical awareness.^1,2

The etiology of PP remains unknown; however, associations are well documented between PP and a ketogenic state secondary to uncontrolled diabetes, a low-carbohydrate diet, anorexia nervosa, or bariatric surgery.³ It is theorized that high serum ketones lead to perivascular ketone deposition, which induces neutrophil migration and chemotaxis,⁴ as substantiated by evidence of rash resolution with correction of the ketogenic state and improvement after administration of tetracyclines, a drug class known for neutrophil chemotaxis inhibition.⁵ Improvement of PP via these treatment mechanisms suggests that ketone bodies may play a role in the pathogenesis of PP.

Interestingly, Kafle et al⁶ reported that patients with PP commonly have bacterial colonies and associated inflammatory sequelae at the level of the hair follicles, which suggests that follicular involvement plays a role in the pathogenesis of PP. These findings are consistent with our patient’s histopathology consisting of gram-positive organisms and purulent inflammation at the infundibulum. The histopathologic features of PP are stage specific.¹ Early stages are characterized by a superficial perivascular infiltrate of neutrophils that then spread to dermal papillae. Neutrophils then quickly sweep through the epidermis, causing spongiosis, ballooning, necrotic keratocytes, and consequent surface epithelium abscess formation. Over time, the dermal infiltrate assumes a lichenoid pattern as eosinophils and lymphocytes invade and predominate over neutrophils. Eventually, melanophages appear in the dermis as the epidermis undergoes hyperplasia, parakeratosis, and hyperpigmentation.¹ The histologic differential diagnosis for PP is broad and varies based on the stage-specific progression of clinical and histopathologic findings.

Similar to PP, subacute cutaneous lupus erythematosus has a female predominance and resolves with subsequent dyspigmentation; however, it initially is characterized by annular plaques with central clearing or papulosquamous lesions restricted to sun-exposed skin. Photosensitivity is a prominent feature, and roughly 50% of patients meet diagnostic criteria for systemic lupus erythematosus.⁷ Histopathology shows interface changes with increased dermal mucin and a perivascular lymphoplasmacytic inflammatory infiltrate.

Papular pityriasis rosea can present as a pruritic papular rash on the back and chest; however, it most commonly is associated with a herald patch and typically follows a flulike prodrome.⁸ Biopsy reveals mounds of parakeratosis with mild spongiosis, perivascular inflammation, and extravasated erythrocytes.

Galli-Galli disease can present as a pruritic rash with follicular papules under the breasts and other flexural areas but histopathologically shows elongated rete ridges with dermal melanosis and acantholysis.⁹

Hailey-Hailey disease commonly presents in the third decade of life and can manifest as painful, pruritic, vesicular lesions on erythematous skin distributed on the back, neck, and inframammary region, as seen in our case; however, it is histopathologically associated with widespread epidermal acantholysis unlike the findings seen in our patient.¹⁰

First-line treatment of PP includes antibiotics such as minocycline, doxycycline, and dapsone due to their anti-inflammatory properties and ability to inhibit neutrophil chemotaxis. In patients with nutritional deficiencies or ketosis, reintroduction of carbohydrates alone has been effective.^5,11

Prurigo pigmentosa is an underrecognized inflammatory dermatosis with a complex stage-dependent clinicopathologic presentation. Clinicians should be aware of the etiologic and histopathologic patterns of this unique dermatosis. Rash presentation in the context of a low-carbohydrate diet should prompt biopsy as well as treatment with antibiotics and dietary reintroduction of carbohydrates.

Sleep apnea is a heterogeneous group of conditions that may be attributable to a wide array of underlying conditions, with varying contributions of obstructive or central sleep-disordered breathing. The spectrum from obstructive sleep apnea (OSA) to central sleep apnea (CSA) includes mixed sleep apnea, treatment-emergent CSA (TECSA), and Cheyne-Stokes respiration (CSR).¹ The pathophysiologic causes of CSA can be attributed to delayed cardiopulmonary circulation in heart failure, decreased brainstem ventilatory response due to stroke, blunting of central chemoreceptors in chronic opioid use, and/or stimulation of the Hering-Breuer reflex from activation of pulmonary stretch receptors after initiating positive airway pressure (PAP) for treatment of OSA.^2,3 Medications are commonly implicated in many forms of sleep-disordered breathing; importantly, opioids and benzodiazepines may blunt the respiratory drive, leading to CSA, and/or impair upper airway patency, resulting in or worsening OSA.

Continuous positive airway pressure (CPAP) therapy is largely ineffective in correcting CSA or improving outcomes and is often poorly tolerated in these patients.⁴ Adaptive servo-ventilation (ASV) is a form of bilevel PAP (BPAP) therapy that delivers variable adjusting pressure support, primarily to treat CSA. PAP also may relieve upper airway obstructions, thereby effectively treating any comorbid obstructive component. ASV has been well documented to improve sleep-related disorders and improve apnea-hypopnea index (AHI) in patients with CSA. However, longitudinal data have demonstrated increased mortality in patients with heart failure with reduced ejection fraction (HFrEF) who were treated with ASV.⁵ Since the SERVE-HF trial results came to light in 2015, there has been no consensus regarding the optimal use, if any, of ASV therapy.^6-8 This is partly related to the inability to fully explain the study’s major findings, which were unexpected at the time, and partly due to the absence of similar relevant mortality data in patients with CSA but without HFrEF.

TECSA may present in some patients with OSA who are new to PAP therapy. These events are frequently seen during PAP titration sleep studies, though patients can also experience significant TECSA shortly after initiating home PAP therapy. TECSA is felt to result from a combination of stimulating pulmonary stretch receptors and lowering arterial carbon dioxide below the apneic threshold. Chemoreceptors located in the medulla respond by attenuating the respiratory drive.⁹ Previous studies have shown most cases of mild TECSA resolve over time with CPAP treatment. However, in patients with persistent or worsening TECSA, ASV may be considered as an alternative to CPAP.

The prevalence of OSA in the veteran population is estimated to be as high as 60%, considerably higher than the general population estimation.¹⁰ Patients with more significant comorbidities may also experience a higher frequency of central events. Patients with CSA have also been shown to have a higher risk for cardiac-related hospital admissions, providing plausible justification for correcting CSA.¹⁰

In the current study, we aim to characterize the group of patients using ASV therapy in the modern era. We will assess the objective efficacy and adherence of ASV therapy in patients with primarily CSA compared with those having primarily OSA (ie, TECSA). Secondarily, we aim to identify baseline clinical and polysomnographic features that may be predictive of ASV adherence, as a surrogate for subjective benefit.¹¹ In the wake of the SERVE-HF study, the sleep medicine community has paused prescribing ASV therapy for CSA. We hope to provide more perspective on the treatment of veterans with CSA and identify the patient groups that would benefit most from ASV therapy.

Methods

This retrospective chart review examined patients prescribed ASV therapy at the Hampton Veterans Affairs Medical Center (HVAMC) in Virginia who had therapy data between January 1, 2015, and April 30, 2020. The start date was chosen to approximate the phase-in of wireless PAP devices at HVAMC and to correspond with the release of preliminary results from the SERVE-HF trial.

Patients were initially identified through a query into commercial wireless PAP management databases and cross-referenced with HVAMC patients. Adherence and efficacy data were obtained from the most recent clinical PAP data, which allowed for the evaluation of patients who discontinued therapy for reasons other than intolerance. Clinical, demographic, and polysomnography (PSG) data were obtained from the electronic health record. One patient, identified through the database query but not found in the electronic health record, was excluded. In cases of missing PSG data, especially AHI or similar values, all attempts were made to calculate the data with other provided values. This study was determined to be exempt by the HVAMC Institutional Review Board (protocol #20-01).

Statistics

Statistical analyses were designed to compare clinical characteristics and adherence to therapy of those with primarily CSA on PSG and those with primarily OSA. Because it was not currently known how many patients would fit into each of these categories, we also planned secondary comparisons of the clinical and PSG characteristics of those patients who were adherent with therapy and those who were not. Adherence with ASV therapy was defined as device use for ≥ 4 hours for ≥ 70% of nights.

Comparisons between the means of 2 normally distributed groups were performed with an unpaired t test. Comparisons between 2 nonnormally distributed groups and groups of dates were done with the Mann-Whitney U test. The normality of a group distribution was determined using D’Agostino-Pearson omnibus normality test. Two groups of dichotomous variables were compared with the Fisher exact test. P value < .05 was considered statistically significant.

Results

Thirty-one patients were prescribed ASV therapy and had follow-up at HVAMC since 2015. All patients were male. The mean (SD) age was 67.2 (11.4) years, mean body mass index (BMI) was 34.0 (5.9), and the mean (SD) Epworth Sleepiness Scale (ESS) score was 10.9 (5.8). Patient comorbidities included 30 (97%) with hypertension, 17 (55%) with diabetes mellitus, 16 (52%) with coronary artery disease, and 11 (35%) with congestive heart failure. Three patients had no echocardiogram or other documentation of left ventricular ejection fraction (LVEF). One of these patients had voluntarily stopped using PAP therapy, another had been erroneously started on ASV (ordered for fixed BPAP), and the third had since been retitrated to CPAP. In the 28 patients with documented LVEF, the mean (SD) LVEF was 61.8% (6.9). Ten patients (32%) had opioids documented on their medication lists and 6 (19%) had benzodiazepines.

The median date of diagnostic sleep testing was January 9, 2015, and testing was completed after the release of the initial field safety notice regarding the SERVE-HF trial preliminary findings May 13, 2015, for 14 patients (45%).¹² On diagnostic sleep testing, the mean (SD) AHI was 47.3 (25.6) events/h and the median (IQR) oxygen saturation (SpO₂) nadir was 82% (78-84). Three patients (10%) were initially diagnosed with CSA, 19 (61%) with OSA, and 9 (29%) with both. Sixteen patients (52%) had ASV with fixed expiratory PAP (EPAP), and 15 (48%) had variable adjusting EPAP. Mean (SD) usage of ASV was 6.5 (2.6) hours and 66.0% (34.2) of nights for ≥ 4 hours. Mean (SD) titrated EPAP (set or 90th/95th percentile autotitrated) was 10.1 (3.4) cm H₂O and inspiratory PAP (IPAP) (90th/95th percentile) was 17.1 (3.3) cm H₂O. The median (IQR) residual AHI on ASV was 2.7 events/h (1.1-5.1), apnea index (AI) was 0.4 (0.1-1.0), and hypopnea index (HI) was 1.4 (1.0-3.2); the residual central and obstructive events were not available in most cases.

Adherence

There were no significant differences between the proportions of patients on ASV with set EPAP or the titrated EPAP and IPAP. The median (IQR) residual AHI was lower in the adherent group compared with the nonadherent group, both in absolute values (1.7 [0.9-3.2] events/h vs 4.7 [2.4-10.3] events/h, respectively [P = .004]), and as a percentage of the pretreatment AHI (3.1% [2.5-6.0] vs 10.2% [5.3-34.4], respectively; P = .002) (Figure 2).

Primarily Obstructive Sleep Apnea

Sleep apnea was a mixed picture of obstructive and central events in many patients. Only 3 patients had “pure” CSA. Thus, we were unable to define discrete comparison groups based on the sleep-disordered breathing phenotype. We identified 19 patients with primarily OSA (ie, initially diagnosed with OSA, OSA with TECSA, or complex sleep apnea). The mean (SD) age was 66.1 (12.8) years, BMI was 36.2 (4.7), and ESS was 11.4 (5.6). The mean (SD) baseline AHI was 46.9 (29.5), obstructive AHI was 40.5 (30.4), and central AHI was 0.4 (1.2); the median (IQR) SpO₂ nadir was 81% (78%-84%). The mean (SD) titrated EPAP was 10.2 (3.5) cm H₂O, and the 90th/95th percentile IPAP was 17.9 (3.5) cm H₂O. The mean (SD) usage of ASV was 7.9 (5.3) hours with 11 patients (58%) meeting the minimum standard for adherence to ASV therapy.

No significant differences were seen between the adherent and nonadherent groups in clinical or demographic characteristics or date of diagnostic sleep testing (eAppendix, available online at doi:10.12788/fp.0374). In baseline sleep studies the mean (SD) HI was 32.3 (15.8) in the adherent group compared with 14.7 (8.8) in the nonadherent group (P = .049). In contrast, obstructive AHI was not significantly lower in the adherent group: 51.9 (30.9) in the adherent group compared with 22.2 (20.6) in the nonadherent group (P = .09). The median (IQR) residual AHI on ASV as a percentage of the pretreatment AHI was 3.0% (2.4%-6.5%) in the adherent group compared with 11.3% (5.4%-89.1%) in the nonadherent group, a statistically significant difference (P = .01). No other significant differences were seen between the groups.

Discussion

This study describes a real-world cohort of patients using ASV therapy and the characteristics associated with benefit from therapy. The patients that were prescribed and started ASV therapy most often had a significant degree of obstructive component to sleep-disordered breathing, whether primary OSA with TECSA or comorbid OSA and CSA. Moreover, we found that a higher obstructive AHI on the baseline PSG was associated with adherence to ASV therapy. Another important finding was that a lower residual AHI on ASV as a proportion of the baseline was associated with PAP adherence. Adherent patients had similar clinical characteristics as the nonadherent patients, including comorbidities, severity of sleep-disordered breathing, and obesity.

Though the results of the SERVE-HF trial have dampened the enthusiasm somewhat, ASV therapy has long been considered an effective and well-tolerated treatment for many types of CSA.¹³ In fact, treatments that can eliminate the central AHI are fairly limited.^4,14 Our data suggest that ASV is also effective and tolerated in OSA with TECSA and/or comorbid CSA. Recent studies suggest that CSA resolves spontaneously in a majority of TECSA patients within 2 to 3 months of regular CPAP use.¹⁵ Other estimates suggest that persistent TESCA may be present in 2% of patients with OSA on treatment.¹⁶

Given the high and rising prevalence of OSA, many people are at risk for clinically significant TESCA. Another retrospective case series found that 72% of patients that failed treatment with CPAP or BPAP during PSG, met diagnostic criteria (at the time) for CSA; ASV was objectively beneficial in these patients.¹⁷ ASV can be an especially useful modality to treat OSA in patients with CSA that either prevents tolerance of standard therapies or causes clinical consequences, presuming the patient does not also have HFrEF.¹⁸ The long-term outcomes of treatment with ASV therapy remain a matter of debate.

The SERVE-HF trial remains among the only studies that have assessed the mortality effects of CSA treatments, with unfavorable findings. Treatment of OSA has been associated with favorable chronic health benefits, though recent studies have questioned the degree of benefit attributable to OSA treatment.^19-24 Similar studies have not been done for comorbidities represented by our study cohort (ie, OSA with TECSA and/or comorbid CSA).

The lack of CSA diagnosis alone in our cohort may be partially attributable to changing practice patterns following the SERVE-HF trial, though it is not clear from these data why a higher baseline obstructive AHI was associated with adherence to ASV therapy. Our data in this regard are somewhat at odds with the preliminary results of the ADVENT-HF trial. In that study, adherence to ASV therapy in patients with predominantly OSA declined significantly more than in patients with predominantly CSA.²⁵ Most of our patients were diagnosed with predominantly OSA, so a direct comparison with the CSA group is problematic; additionally, the primary brand and the pressure adjustments algorithm used in our study differed from the ADVENT-HF trial.

OSA and CSA may present with similar clinical symptoms, including sleep fragmentation, insomnia, and excessive daytime sleepiness; however, the degree of symptomatology, especially daytime sleepiness, and the response to treatment, may be less in CSA.^2,26 Both the subjective report of symptoms (ESS) and PSG measures of sleep fragmentation were similar in our patients, again likely explained by the predominance of obstructive events.

The pathophysiology of CSA is more varied than OSA, which is probably relevant in this case. ASV was originally designed for the management of CSA with CSR, accomplishing this goal by stabilizing the periods of central apnea and hyperpnea characteristic of CSR.²⁷ Although other forms of CSA demonstrate breathing patterns distinct from CSR, ASV has become an accepted treatment for most of these. It is plausible that the long-term subjective benefit and tolerance of ASV in CSA without CSR is less than for CSA with CSR or OSA. None of the patients in our study had CSA with CSR.

Ultimately, it may be the objective treatment effect that lends to adherence, as has been shown previously in OSA patients; our group of adherent patients showed a greater improvement in AHI, relative to baseline, than the nonadherent patients did.²⁸ The technology behind ASV therapy can greatly reduce the frequencies of central apneas, yet this same treatment effectively splints the upper airway and even more effectively eliminates obstructive apneas and hypopneas. Variable adjusting EPAP devices would plausibly provide even more benefit in these patients, as has been shown in prior studies.²⁹ To the contrary, our small sample of patients with TESCA showed a nonsignificant trend toward adherence with fixed EPAP ASV.

Opioid use was substantial in our population, without significant differences between the groups. CPAP therapy is ineffective in improving opioid-associated CSA. In a recent study, 20 patients on opioid therapy with CSA were treated with CPAP therapy; after several weeks, the average therapeutic use was 4 to 5 hours per night and CPAP was abandoned in favor of ASV therapy due to persistent central apnea. ASV treatment was associated with a considerable reduction in central apnea index, AHI, arousal index, and oxygen desaturations in a remarkable improvement over CPAP.³⁰

Limitations and Future Directions

This retrospective, single-center study may have limited applicability to other populations. Adherence was used as a surrogate for subjective benefit from treatment, though benefit was not confirmed by the patients directly. Only patients seen in follow-up for documentation of the ASV download were identified for inclusion and data analysis. As a single center, we risk homogeneity in the treatment algorithms, though sleep medicine treatments are often decided at the time of the sleep studies. Studies and treatment recommendations were made at a variety of sites, including our sleep center, other US Department of Veterans Affairs hospitals, in the community network, and at US Department of Defense centers. Our population was homogenous in some ways; notably, 100% of our group was male, which is substantially higher than both the veteran population and the general population. Risk factors for OSA and CSA are more common in male patients, which may partially explain this anomaly. Lastly, with our small sample size, there is increased risk that the results seen occurred by chance.

There are several areas for further study. A larger multicenter study may permit these results to be generalized to the population and should include subjective measures of benefit. Patients with primarily CSA were largely absent in our group and may be the focus of future studies; data on predictors of treatment adherence in CSA are lacking. With the availability of consistent older adherence data, comparisons may be made between the efficacies of clinical practice habits, including treatment efficacy, before and after the results of the SERVE-HF trial became known.

Conclusions

In selected patients with preserved LVEF, ASV therapy appears especially effective in patients with OSA combined with CSA. Adherence to ASV treatment was associated with higher obstructive AHI during the baseline PSG and with a greater reduction in the AHI. This understanding may help guide sleep specialists in personalizing treatments for sleep-disordered breathing. Because objective efficacy appears to be important for therapy adherence, clinicians should be able to consistently determine the obstructive and central components of the residual AHI, thus taking all information into account when optimizing the treatment. Additionally, both OSA and CSA pressure requirements should be considered when developing ASV devices.

Acknowledgments

We thank Martha Harper, RRT, of Hampton Veterans Affairs Medical Center (HVAMC) for helping to identify our patients and assisting with data collection. This material is the result of work supported with resources and the use of HVAMC facilities.

Sleep apnea is a heterogeneous group of conditions that may be attributable to a wide array of underlying conditions, with varying contributions of obstructive or central sleep-disordered breathing. The spectrum from obstructive sleep apnea (OSA) to central sleep apnea (CSA) includes mixed sleep apnea, treatment-emergent CSA (TECSA), and Cheyne-Stokes respiration (CSR).¹ The pathophysiologic causes of CSA can be attributed to delayed cardiopulmonary circulation in heart failure, decreased brainstem ventilatory response due to stroke, blunting of central chemoreceptors in chronic opioid use, and/or stimulation of the Hering-Breuer reflex from activation of pulmonary stretch receptors after initiating positive airway pressure (PAP) for treatment of OSA.^2,3 Medications are commonly implicated in many forms of sleep-disordered breathing; importantly, opioids and benzodiazepines may blunt the respiratory drive, leading to CSA, and/or impair upper airway patency, resulting in or worsening OSA.

Continuous positive airway pressure (CPAP) therapy is largely ineffective in correcting CSA or improving outcomes and is often poorly tolerated in these patients.⁴ Adaptive servo-ventilation (ASV) is a form of bilevel PAP (BPAP) therapy that delivers variable adjusting pressure support, primarily to treat CSA. PAP also may relieve upper airway obstructions, thereby effectively treating any comorbid obstructive component. ASV has been well documented to improve sleep-related disorders and improve apnea-hypopnea index (AHI) in patients with CSA. However, longitudinal data have demonstrated increased mortality in patients with heart failure with reduced ejection fraction (HFrEF) who were treated with ASV.⁵ Since the SERVE-HF trial results came to light in 2015, there has been no consensus regarding the optimal use, if any, of ASV therapy.^6-8 This is partly related to the inability to fully explain the study’s major findings, which were unexpected at the time, and partly due to the absence of similar relevant mortality data in patients with CSA but without HFrEF.

TECSA may present in some patients with OSA who are new to PAP therapy. These events are frequently seen during PAP titration sleep studies, though patients can also experience significant TECSA shortly after initiating home PAP therapy. TECSA is felt to result from a combination of stimulating pulmonary stretch receptors and lowering arterial carbon dioxide below the apneic threshold. Chemoreceptors located in the medulla respond by attenuating the respiratory drive.⁹ Previous studies have shown most cases of mild TECSA resolve over time with CPAP treatment. However, in patients with persistent or worsening TECSA, ASV may be considered as an alternative to CPAP.

The prevalence of OSA in the veteran population is estimated to be as high as 60%, considerably higher than the general population estimation.¹⁰ Patients with more significant comorbidities may also experience a higher frequency of central events. Patients with CSA have also been shown to have a higher risk for cardiac-related hospital admissions, providing plausible justification for correcting CSA.¹⁰

In the current study, we aim to characterize the group of patients using ASV therapy in the modern era. We will assess the objective efficacy and adherence of ASV therapy in patients with primarily CSA compared with those having primarily OSA (ie, TECSA). Secondarily, we aim to identify baseline clinical and polysomnographic features that may be predictive of ASV adherence, as a surrogate for subjective benefit.¹¹ In the wake of the SERVE-HF study, the sleep medicine community has paused prescribing ASV therapy for CSA. We hope to provide more perspective on the treatment of veterans with CSA and identify the patient groups that would benefit most from ASV therapy.

Methods

This retrospective chart review examined patients prescribed ASV therapy at the Hampton Veterans Affairs Medical Center (HVAMC) in Virginia who had therapy data between January 1, 2015, and April 30, 2020. The start date was chosen to approximate the phase-in of wireless PAP devices at HVAMC and to correspond with the release of preliminary results from the SERVE-HF trial.

Patients were initially identified through a query into commercial wireless PAP management databases and cross-referenced with HVAMC patients. Adherence and efficacy data were obtained from the most recent clinical PAP data, which allowed for the evaluation of patients who discontinued therapy for reasons other than intolerance. Clinical, demographic, and polysomnography (PSG) data were obtained from the electronic health record. One patient, identified through the database query but not found in the electronic health record, was excluded. In cases of missing PSG data, especially AHI or similar values, all attempts were made to calculate the data with other provided values. This study was determined to be exempt by the HVAMC Institutional Review Board (protocol #20-01).

Statistics

Statistical analyses were designed to compare clinical characteristics and adherence to therapy of those with primarily CSA on PSG and those with primarily OSA. Because it was not currently known how many patients would fit into each of these categories, we also planned secondary comparisons of the clinical and PSG characteristics of those patients who were adherent with therapy and those who were not. Adherence with ASV therapy was defined as device use for ≥ 4 hours for ≥ 70% of nights.

Comparisons between the means of 2 normally distributed groups were performed with an unpaired t test. Comparisons between 2 nonnormally distributed groups and groups of dates were done with the Mann-Whitney U test. The normality of a group distribution was determined using D’Agostino-Pearson omnibus normality test. Two groups of dichotomous variables were compared with the Fisher exact test. P value < .05 was considered statistically significant.

Results

Thirty-one patients were prescribed ASV therapy and had follow-up at HVAMC since 2015. All patients were male. The mean (SD) age was 67.2 (11.4) years, mean body mass index (BMI) was 34.0 (5.9), and the mean (SD) Epworth Sleepiness Scale (ESS) score was 10.9 (5.8). Patient comorbidities included 30 (97%) with hypertension, 17 (55%) with diabetes mellitus, 16 (52%) with coronary artery disease, and 11 (35%) with congestive heart failure. Three patients had no echocardiogram or other documentation of left ventricular ejection fraction (LVEF). One of these patients had voluntarily stopped using PAP therapy, another had been erroneously started on ASV (ordered for fixed BPAP), and the third had since been retitrated to CPAP. In the 28 patients with documented LVEF, the mean (SD) LVEF was 61.8% (6.9). Ten patients (32%) had opioids documented on their medication lists and 6 (19%) had benzodiazepines.

The median date of diagnostic sleep testing was January 9, 2015, and testing was completed after the release of the initial field safety notice regarding the SERVE-HF trial preliminary findings May 13, 2015, for 14 patients (45%).¹² On diagnostic sleep testing, the mean (SD) AHI was 47.3 (25.6) events/h and the median (IQR) oxygen saturation (SpO₂) nadir was 82% (78-84). Three patients (10%) were initially diagnosed with CSA, 19 (61%) with OSA, and 9 (29%) with both. Sixteen patients (52%) had ASV with fixed expiratory PAP (EPAP), and 15 (48%) had variable adjusting EPAP. Mean (SD) usage of ASV was 6.5 (2.6) hours and 66.0% (34.2) of nights for ≥ 4 hours. Mean (SD) titrated EPAP (set or 90th/95th percentile autotitrated) was 10.1 (3.4) cm H₂O and inspiratory PAP (IPAP) (90th/95th percentile) was 17.1 (3.3) cm H₂O. The median (IQR) residual AHI on ASV was 2.7 events/h (1.1-5.1), apnea index (AI) was 0.4 (0.1-1.0), and hypopnea index (HI) was 1.4 (1.0-3.2); the residual central and obstructive events were not available in most cases.

Adherence

There were no significant differences between the proportions of patients on ASV with set EPAP or the titrated EPAP and IPAP. The median (IQR) residual AHI was lower in the adherent group compared with the nonadherent group, both in absolute values (1.7 [0.9-3.2] events/h vs 4.7 [2.4-10.3] events/h, respectively [P = .004]), and as a percentage of the pretreatment AHI (3.1% [2.5-6.0] vs 10.2% [5.3-34.4], respectively; P = .002) (Figure 2).

Primarily Obstructive Sleep Apnea

Sleep apnea was a mixed picture of obstructive and central events in many patients. Only 3 patients had “pure” CSA. Thus, we were unable to define discrete comparison groups based on the sleep-disordered breathing phenotype. We identified 19 patients with primarily OSA (ie, initially diagnosed with OSA, OSA with TECSA, or complex sleep apnea). The mean (SD) age was 66.1 (12.8) years, BMI was 36.2 (4.7), and ESS was 11.4 (5.6). The mean (SD) baseline AHI was 46.9 (29.5), obstructive AHI was 40.5 (30.4), and central AHI was 0.4 (1.2); the median (IQR) SpO₂ nadir was 81% (78%-84%). The mean (SD) titrated EPAP was 10.2 (3.5) cm H₂O, and the 90th/95th percentile IPAP was 17.9 (3.5) cm H₂O. The mean (SD) usage of ASV was 7.9 (5.3) hours with 11 patients (58%) meeting the minimum standard for adherence to ASV therapy.

No significant differences were seen between the adherent and nonadherent groups in clinical or demographic characteristics or date of diagnostic sleep testing (eAppendix, available online at doi:10.12788/fp.0374). In baseline sleep studies the mean (SD) HI was 32.3 (15.8) in the adherent group compared with 14.7 (8.8) in the nonadherent group (P = .049). In contrast, obstructive AHI was not significantly lower in the adherent group: 51.9 (30.9) in the adherent group compared with 22.2 (20.6) in the nonadherent group (P = .09). The median (IQR) residual AHI on ASV as a percentage of the pretreatment AHI was 3.0% (2.4%-6.5%) in the adherent group compared with 11.3% (5.4%-89.1%) in the nonadherent group, a statistically significant difference (P = .01). No other significant differences were seen between the groups.

Discussion

This study describes a real-world cohort of patients using ASV therapy and the characteristics associated with benefit from therapy. The patients that were prescribed and started ASV therapy most often had a significant degree of obstructive component to sleep-disordered breathing, whether primary OSA with TECSA or comorbid OSA and CSA. Moreover, we found that a higher obstructive AHI on the baseline PSG was associated with adherence to ASV therapy. Another important finding was that a lower residual AHI on ASV as a proportion of the baseline was associated with PAP adherence. Adherent patients had similar clinical characteristics as the nonadherent patients, including comorbidities, severity of sleep-disordered breathing, and obesity.

Though the results of the SERVE-HF trial have dampened the enthusiasm somewhat, ASV therapy has long been considered an effective and well-tolerated treatment for many types of CSA.¹³ In fact, treatments that can eliminate the central AHI are fairly limited.^4,14 Our data suggest that ASV is also effective and tolerated in OSA with TECSA and/or comorbid CSA. Recent studies suggest that CSA resolves spontaneously in a majority of TECSA patients within 2 to 3 months of regular CPAP use.¹⁵ Other estimates suggest that persistent TESCA may be present in 2% of patients with OSA on treatment.¹⁶

Given the high and rising prevalence of OSA, many people are at risk for clinically significant TESCA. Another retrospective case series found that 72% of patients that failed treatment with CPAP or BPAP during PSG, met diagnostic criteria (at the time) for CSA; ASV was objectively beneficial in these patients.¹⁷ ASV can be an especially useful modality to treat OSA in patients with CSA that either prevents tolerance of standard therapies or causes clinical consequences, presuming the patient does not also have HFrEF.¹⁸ The long-term outcomes of treatment with ASV therapy remain a matter of debate.

The SERVE-HF trial remains among the only studies that have assessed the mortality effects of CSA treatments, with unfavorable findings. Treatment of OSA has been associated with favorable chronic health benefits, though recent studies have questioned the degree of benefit attributable to OSA treatment.^19-24 Similar studies have not been done for comorbidities represented by our study cohort (ie, OSA with TECSA and/or comorbid CSA).

The lack of CSA diagnosis alone in our cohort may be partially attributable to changing practice patterns following the SERVE-HF trial, though it is not clear from these data why a higher baseline obstructive AHI was associated with adherence to ASV therapy. Our data in this regard are somewhat at odds with the preliminary results of the ADVENT-HF trial. In that study, adherence to ASV therapy in patients with predominantly OSA declined significantly more than in patients with predominantly CSA.²⁵ Most of our patients were diagnosed with predominantly OSA, so a direct comparison with the CSA group is problematic; additionally, the primary brand and the pressure adjustments algorithm used in our study differed from the ADVENT-HF trial.

OSA and CSA may present with similar clinical symptoms, including sleep fragmentation, insomnia, and excessive daytime sleepiness; however, the degree of symptomatology, especially daytime sleepiness, and the response to treatment, may be less in CSA.^2,26 Both the subjective report of symptoms (ESS) and PSG measures of sleep fragmentation were similar in our patients, again likely explained by the predominance of obstructive events.

The pathophysiology of CSA is more varied than OSA, which is probably relevant in this case. ASV was originally designed for the management of CSA with CSR, accomplishing this goal by stabilizing the periods of central apnea and hyperpnea characteristic of CSR.²⁷ Although other forms of CSA demonstrate breathing patterns distinct from CSR, ASV has become an accepted treatment for most of these. It is plausible that the long-term subjective benefit and tolerance of ASV in CSA without CSR is less than for CSA with CSR or OSA. None of the patients in our study had CSA with CSR.

Ultimately, it may be the objective treatment effect that lends to adherence, as has been shown previously in OSA patients; our group of adherent patients showed a greater improvement in AHI, relative to baseline, than the nonadherent patients did.²⁸ The technology behind ASV therapy can greatly reduce the frequencies of central apneas, yet this same treatment effectively splints the upper airway and even more effectively eliminates obstructive apneas and hypopneas. Variable adjusting EPAP devices would plausibly provide even more benefit in these patients, as has been shown in prior studies.²⁹ To the contrary, our small sample of patients with TESCA showed a nonsignificant trend toward adherence with fixed EPAP ASV.

Opioid use was substantial in our population, without significant differences between the groups. CPAP therapy is ineffective in improving opioid-associated CSA. In a recent study, 20 patients on opioid therapy with CSA were treated with CPAP therapy; after several weeks, the average therapeutic use was 4 to 5 hours per night and CPAP was abandoned in favor of ASV therapy due to persistent central apnea. ASV treatment was associated with a considerable reduction in central apnea index, AHI, arousal index, and oxygen desaturations in a remarkable improvement over CPAP.³⁰

Limitations and Future Directions

This retrospective, single-center study may have limited applicability to other populations. Adherence was used as a surrogate for subjective benefit from treatment, though benefit was not confirmed by the patients directly. Only patients seen in follow-up for documentation of the ASV download were identified for inclusion and data analysis. As a single center, we risk homogeneity in the treatment algorithms, though sleep medicine treatments are often decided at the time of the sleep studies. Studies and treatment recommendations were made at a variety of sites, including our sleep center, other US Department of Veterans Affairs hospitals, in the community network, and at US Department of Defense centers. Our population was homogenous in some ways; notably, 100% of our group was male, which is substantially higher than both the veteran population and the general population. Risk factors for OSA and CSA are more common in male patients, which may partially explain this anomaly. Lastly, with our small sample size, there is increased risk that the results seen occurred by chance.

There are several areas for further study. A larger multicenter study may permit these results to be generalized to the population and should include subjective measures of benefit. Patients with primarily CSA were largely absent in our group and may be the focus of future studies; data on predictors of treatment adherence in CSA are lacking. With the availability of consistent older adherence data, comparisons may be made between the efficacies of clinical practice habits, including treatment efficacy, before and after the results of the SERVE-HF trial became known.

Conclusions

In selected patients with preserved LVEF, ASV therapy appears especially effective in patients with OSA combined with CSA. Adherence to ASV treatment was associated with higher obstructive AHI during the baseline PSG and with a greater reduction in the AHI. This understanding may help guide sleep specialists in personalizing treatments for sleep-disordered breathing. Because objective efficacy appears to be important for therapy adherence, clinicians should be able to consistently determine the obstructive and central components of the residual AHI, thus taking all information into account when optimizing the treatment. Additionally, both OSA and CSA pressure requirements should be considered when developing ASV devices.

Acknowledgments

We thank Martha Harper, RRT, of Hampton Veterans Affairs Medical Center (HVAMC) for helping to identify our patients and assisting with data collection. This material is the result of work supported with resources and the use of HVAMC facilities.

Sleep apnea is a heterogeneous group of conditions that may be attributable to a wide array of underlying conditions, with varying contributions of obstructive or central sleep-disordered breathing. The spectrum from obstructive sleep apnea (OSA) to central sleep apnea (CSA) includes mixed sleep apnea, treatment-emergent CSA (TECSA), and Cheyne-Stokes respiration (CSR).¹ The pathophysiologic causes of CSA can be attributed to delayed cardiopulmonary circulation in heart failure, decreased brainstem ventilatory response due to stroke, blunting of central chemoreceptors in chronic opioid use, and/or stimulation of the Hering-Breuer reflex from activation of pulmonary stretch receptors after initiating positive airway pressure (PAP) for treatment of OSA.^2,3 Medications are commonly implicated in many forms of sleep-disordered breathing; importantly, opioids and benzodiazepines may blunt the respiratory drive, leading to CSA, and/or impair upper airway patency, resulting in or worsening OSA.

Continuous positive airway pressure (CPAP) therapy is largely ineffective in correcting CSA or improving outcomes and is often poorly tolerated in these patients.⁴ Adaptive servo-ventilation (ASV) is a form of bilevel PAP (BPAP) therapy that delivers variable adjusting pressure support, primarily to treat CSA. PAP also may relieve upper airway obstructions, thereby effectively treating any comorbid obstructive component. ASV has been well documented to improve sleep-related disorders and improve apnea-hypopnea index (AHI) in patients with CSA. However, longitudinal data have demonstrated increased mortality in patients with heart failure with reduced ejection fraction (HFrEF) who were treated with ASV.⁵ Since the SERVE-HF trial results came to light in 2015, there has been no consensus regarding the optimal use, if any, of ASV therapy.^6-8 This is partly related to the inability to fully explain the study’s major findings, which were unexpected at the time, and partly due to the absence of similar relevant mortality data in patients with CSA but without HFrEF.

TECSA may present in some patients with OSA who are new to PAP therapy. These events are frequently seen during PAP titration sleep studies, though patients can also experience significant TECSA shortly after initiating home PAP therapy. TECSA is felt to result from a combination of stimulating pulmonary stretch receptors and lowering arterial carbon dioxide below the apneic threshold. Chemoreceptors located in the medulla respond by attenuating the respiratory drive.⁹ Previous studies have shown most cases of mild TECSA resolve over time with CPAP treatment. However, in patients with persistent or worsening TECSA, ASV may be considered as an alternative to CPAP.

The prevalence of OSA in the veteran population is estimated to be as high as 60%, considerably higher than the general population estimation.¹⁰ Patients with more significant comorbidities may also experience a higher frequency of central events. Patients with CSA have also been shown to have a higher risk for cardiac-related hospital admissions, providing plausible justification for correcting CSA.¹⁰

In the current study, we aim to characterize the group of patients using ASV therapy in the modern era. We will assess the objective efficacy and adherence of ASV therapy in patients with primarily CSA compared with those having primarily OSA (ie, TECSA). Secondarily, we aim to identify baseline clinical and polysomnographic features that may be predictive of ASV adherence, as a surrogate for subjective benefit.¹¹ In the wake of the SERVE-HF study, the sleep medicine community has paused prescribing ASV therapy for CSA. We hope to provide more perspective on the treatment of veterans with CSA and identify the patient groups that would benefit most from ASV therapy.

Methods

This retrospective chart review examined patients prescribed ASV therapy at the Hampton Veterans Affairs Medical Center (HVAMC) in Virginia who had therapy data between January 1, 2015, and April 30, 2020. The start date was chosen to approximate the phase-in of wireless PAP devices at HVAMC and to correspond with the release of preliminary results from the SERVE-HF trial.

Patients were initially identified through a query into commercial wireless PAP management databases and cross-referenced with HVAMC patients. Adherence and efficacy data were obtained from the most recent clinical PAP data, which allowed for the evaluation of patients who discontinued therapy for reasons other than intolerance. Clinical, demographic, and polysomnography (PSG) data were obtained from the electronic health record. One patient, identified through the database query but not found in the electronic health record, was excluded. In cases of missing PSG data, especially AHI or similar values, all attempts were made to calculate the data with other provided values. This study was determined to be exempt by the HVAMC Institutional Review Board (protocol #20-01).

Statistics

Statistical analyses were designed to compare clinical characteristics and adherence to therapy of those with primarily CSA on PSG and those with primarily OSA. Because it was not currently known how many patients would fit into each of these categories, we also planned secondary comparisons of the clinical and PSG characteristics of those patients who were adherent with therapy and those who were not. Adherence with ASV therapy was defined as device use for ≥ 4 hours for ≥ 70% of nights.

Comparisons between the means of 2 normally distributed groups were performed with an unpaired t test. Comparisons between 2 nonnormally distributed groups and groups of dates were done with the Mann-Whitney U test. The normality of a group distribution was determined using D’Agostino-Pearson omnibus normality test. Two groups of dichotomous variables were compared with the Fisher exact test. P value < .05 was considered statistically significant.

Results

Thirty-one patients were prescribed ASV therapy and had follow-up at HVAMC since 2015. All patients were male. The mean (SD) age was 67.2 (11.4) years, mean body mass index (BMI) was 34.0 (5.9), and the mean (SD) Epworth Sleepiness Scale (ESS) score was 10.9 (5.8). Patient comorbidities included 30 (97%) with hypertension, 17 (55%) with diabetes mellitus, 16 (52%) with coronary artery disease, and 11 (35%) with congestive heart failure. Three patients had no echocardiogram or other documentation of left ventricular ejection fraction (LVEF). One of these patients had voluntarily stopped using PAP therapy, another had been erroneously started on ASV (ordered for fixed BPAP), and the third had since been retitrated to CPAP. In the 28 patients with documented LVEF, the mean (SD) LVEF was 61.8% (6.9). Ten patients (32%) had opioids documented on their medication lists and 6 (19%) had benzodiazepines.

The median date of diagnostic sleep testing was January 9, 2015, and testing was completed after the release of the initial field safety notice regarding the SERVE-HF trial preliminary findings May 13, 2015, for 14 patients (45%).¹² On diagnostic sleep testing, the mean (SD) AHI was 47.3 (25.6) events/h and the median (IQR) oxygen saturation (SpO₂) nadir was 82% (78-84). Three patients (10%) were initially diagnosed with CSA, 19 (61%) with OSA, and 9 (29%) with both. Sixteen patients (52%) had ASV with fixed expiratory PAP (EPAP), and 15 (48%) had variable adjusting EPAP. Mean (SD) usage of ASV was 6.5 (2.6) hours and 66.0% (34.2) of nights for ≥ 4 hours. Mean (SD) titrated EPAP (set or 90th/95th percentile autotitrated) was 10.1 (3.4) cm H₂O and inspiratory PAP (IPAP) (90th/95th percentile) was 17.1 (3.3) cm H₂O. The median (IQR) residual AHI on ASV was 2.7 events/h (1.1-5.1), apnea index (AI) was 0.4 (0.1-1.0), and hypopnea index (HI) was 1.4 (1.0-3.2); the residual central and obstructive events were not available in most cases.

Adherence

There were no significant differences between the proportions of patients on ASV with set EPAP or the titrated EPAP and IPAP. The median (IQR) residual AHI was lower in the adherent group compared with the nonadherent group, both in absolute values (1.7 [0.9-3.2] events/h vs 4.7 [2.4-10.3] events/h, respectively [P = .004]), and as a percentage of the pretreatment AHI (3.1% [2.5-6.0] vs 10.2% [5.3-34.4], respectively; P = .002) (Figure 2).

Primarily Obstructive Sleep Apnea

Sleep apnea was a mixed picture of obstructive and central events in many patients. Only 3 patients had “pure” CSA. Thus, we were unable to define discrete comparison groups based on the sleep-disordered breathing phenotype. We identified 19 patients with primarily OSA (ie, initially diagnosed with OSA, OSA with TECSA, or complex sleep apnea). The mean (SD) age was 66.1 (12.8) years, BMI was 36.2 (4.7), and ESS was 11.4 (5.6). The mean (SD) baseline AHI was 46.9 (29.5), obstructive AHI was 40.5 (30.4), and central AHI was 0.4 (1.2); the median (IQR) SpO₂ nadir was 81% (78%-84%). The mean (SD) titrated EPAP was 10.2 (3.5) cm H₂O, and the 90th/95th percentile IPAP was 17.9 (3.5) cm H₂O. The mean (SD) usage of ASV was 7.9 (5.3) hours with 11 patients (58%) meeting the minimum standard for adherence to ASV therapy.

No significant differences were seen between the adherent and nonadherent groups in clinical or demographic characteristics or date of diagnostic sleep testing (eAppendix, available online at doi:10.12788/fp.0374). In baseline sleep studies the mean (SD) HI was 32.3 (15.8) in the adherent group compared with 14.7 (8.8) in the nonadherent group (P = .049). In contrast, obstructive AHI was not significantly lower in the adherent group: 51.9 (30.9) in the adherent group compared with 22.2 (20.6) in the nonadherent group (P = .09). The median (IQR) residual AHI on ASV as a percentage of the pretreatment AHI was 3.0% (2.4%-6.5%) in the adherent group compared with 11.3% (5.4%-89.1%) in the nonadherent group, a statistically significant difference (P = .01). No other significant differences were seen between the groups.

Discussion

This study describes a real-world cohort of patients using ASV therapy and the characteristics associated with benefit from therapy. The patients that were prescribed and started ASV therapy most often had a significant degree of obstructive component to sleep-disordered breathing, whether primary OSA with TECSA or comorbid OSA and CSA. Moreover, we found that a higher obstructive AHI on the baseline PSG was associated with adherence to ASV therapy. Another important finding was that a lower residual AHI on ASV as a proportion of the baseline was associated with PAP adherence. Adherent patients had similar clinical characteristics as the nonadherent patients, including comorbidities, severity of sleep-disordered breathing, and obesity.

Though the results of the SERVE-HF trial have dampened the enthusiasm somewhat, ASV therapy has long been considered an effective and well-tolerated treatment for many types of CSA.¹³ In fact, treatments that can eliminate the central AHI are fairly limited.^4,14 Our data suggest that ASV is also effective and tolerated in OSA with TECSA and/or comorbid CSA. Recent studies suggest that CSA resolves spontaneously in a majority of TECSA patients within 2 to 3 months of regular CPAP use.¹⁵ Other estimates suggest that persistent TESCA may be present in 2% of patients with OSA on treatment.¹⁶

Given the high and rising prevalence of OSA, many people are at risk for clinically significant TESCA. Another retrospective case series found that 72% of patients that failed treatment with CPAP or BPAP during PSG, met diagnostic criteria (at the time) for CSA; ASV was objectively beneficial in these patients.¹⁷ ASV can be an especially useful modality to treat OSA in patients with CSA that either prevents tolerance of standard therapies or causes clinical consequences, presuming the patient does not also have HFrEF.¹⁸ The long-term outcomes of treatment with ASV therapy remain a matter of debate.

The SERVE-HF trial remains among the only studies that have assessed the mortality effects of CSA treatments, with unfavorable findings. Treatment of OSA has been associated with favorable chronic health benefits, though recent studies have questioned the degree of benefit attributable to OSA treatment.^19-24 Similar studies have not been done for comorbidities represented by our study cohort (ie, OSA with TECSA and/or comorbid CSA).

The lack of CSA diagnosis alone in our cohort may be partially attributable to changing practice patterns following the SERVE-HF trial, though it is not clear from these data why a higher baseline obstructive AHI was associated with adherence to ASV therapy. Our data in this regard are somewhat at odds with the preliminary results of the ADVENT-HF trial. In that study, adherence to ASV therapy in patients with predominantly OSA declined significantly more than in patients with predominantly CSA.²⁵ Most of our patients were diagnosed with predominantly OSA, so a direct comparison with the CSA group is problematic; additionally, the primary brand and the pressure adjustments algorithm used in our study differed from the ADVENT-HF trial.

OSA and CSA may present with similar clinical symptoms, including sleep fragmentation, insomnia, and excessive daytime sleepiness; however, the degree of symptomatology, especially daytime sleepiness, and the response to treatment, may be less in CSA.^2,26 Both the subjective report of symptoms (ESS) and PSG measures of sleep fragmentation were similar in our patients, again likely explained by the predominance of obstructive events.

The pathophysiology of CSA is more varied than OSA, which is probably relevant in this case. ASV was originally designed for the management of CSA with CSR, accomplishing this goal by stabilizing the periods of central apnea and hyperpnea characteristic of CSR.²⁷ Although other forms of CSA demonstrate breathing patterns distinct from CSR, ASV has become an accepted treatment for most of these. It is plausible that the long-term subjective benefit and tolerance of ASV in CSA without CSR is less than for CSA with CSR or OSA. None of the patients in our study had CSA with CSR.

Ultimately, it may be the objective treatment effect that lends to adherence, as has been shown previously in OSA patients; our group of adherent patients showed a greater improvement in AHI, relative to baseline, than the nonadherent patients did.²⁸ The technology behind ASV therapy can greatly reduce the frequencies of central apneas, yet this same treatment effectively splints the upper airway and even more effectively eliminates obstructive apneas and hypopneas. Variable adjusting EPAP devices would plausibly provide even more benefit in these patients, as has been shown in prior studies.²⁹ To the contrary, our small sample of patients with TESCA showed a nonsignificant trend toward adherence with fixed EPAP ASV.

Opioid use was substantial in our population, without significant differences between the groups. CPAP therapy is ineffective in improving opioid-associated CSA. In a recent study, 20 patients on opioid therapy with CSA were treated with CPAP therapy; after several weeks, the average therapeutic use was 4 to 5 hours per night and CPAP was abandoned in favor of ASV therapy due to persistent central apnea. ASV treatment was associated with a considerable reduction in central apnea index, AHI, arousal index, and oxygen desaturations in a remarkable improvement over CPAP.³⁰

Limitations and Future Directions

This retrospective, single-center study may have limited applicability to other populations. Adherence was used as a surrogate for subjective benefit from treatment, though benefit was not confirmed by the patients directly. Only patients seen in follow-up for documentation of the ASV download were identified for inclusion and data analysis. As a single center, we risk homogeneity in the treatment algorithms, though sleep medicine treatments are often decided at the time of the sleep studies. Studies and treatment recommendations were made at a variety of sites, including our sleep center, other US Department of Veterans Affairs hospitals, in the community network, and at US Department of Defense centers. Our population was homogenous in some ways; notably, 100% of our group was male, which is substantially higher than both the veteran population and the general population. Risk factors for OSA and CSA are more common in male patients, which may partially explain this anomaly. Lastly, with our small sample size, there is increased risk that the results seen occurred by chance.

There are several areas for further study. A larger multicenter study may permit these results to be generalized to the population and should include subjective measures of benefit. Patients with primarily CSA were largely absent in our group and may be the focus of future studies; data on predictors of treatment adherence in CSA are lacking. With the availability of consistent older adherence data, comparisons may be made between the efficacies of clinical practice habits, including treatment efficacy, before and after the results of the SERVE-HF trial became known.

Conclusions

In selected patients with preserved LVEF, ASV therapy appears especially effective in patients with OSA combined with CSA. Adherence to ASV treatment was associated with higher obstructive AHI during the baseline PSG and with a greater reduction in the AHI. This understanding may help guide sleep specialists in personalizing treatments for sleep-disordered breathing. Because objective efficacy appears to be important for therapy adherence, clinicians should be able to consistently determine the obstructive and central components of the residual AHI, thus taking all information into account when optimizing the treatment. Additionally, both OSA and CSA pressure requirements should be considered when developing ASV devices.

Acknowledgments

We thank Martha Harper, RRT, of Hampton Veterans Affairs Medical Center (HVAMC) for helping to identify our patients and assisting with data collection. This material is the result of work supported with resources and the use of HVAMC facilities.

The inappropriate use of antibiotics is associated with an increased risk of antibiotic resistance, health care costs, and risk of adverse drug reactions.¹ According to the Centers for Disease Control and Prevention (CDC), a 10% decrease in overall antibiotic use across different wards was associated with a 34% decrease in Clostridioides difficile (C difficile) infections.² In addition, antimicrobial resistance accounts for > 2.8 million infections and > 35,000 deaths each year.³ The estimated total economic costs of antibiotic resistance to the US economy have ranged as high as $20 billion in excess direct health care costs.⁴ A main goal of an antimicrobial stewardship program (ASP) is to optimize antibiotic use to prevent the adverse consequences of inappropriate antibiotic prescribing.

During the COVID-19 pandemic, increased use of empiric antibiotic therapy has been observed. According to the CDC, almost 80% of patients hospitalized with COVID-19 received an antibiotic from March 2020 to October 2020.⁵ Studies were conducted to investigate the prevalence of bacterial coinfection in patients with COVID-19 and whether antibiotics were indicated in this patient population. A United Kingdom multicenter, prospective cohort study showed a high proportion of patients hospitalized with COVID-19 received antimicrobials despite microbiologically confirmed bacterial infections being rare and more likely to be secondary infections.⁶

Many other studies have reported similar findings. Langord and colleagues found the prevalence of bacterial coinfection in patients with COVID-19 was 3.5% but that 71.9% received antibiotics.⁷ Coenen and colleagues identified 12.4% of the patients with possible and 1.1% of patients with probable bacterial coinfection, while 81% of the study population and 78% of patients were classified as unlikely bacterial coinfection received antibiotics.⁸

At Veterans Affairs Southern Nevada Healthcare System (VASNHS), an ASP team consisting of an infectious disease (ID) physician and 2 pharmacists provide daily prospective audits with intervention and feedback along with other interventions, such as providing restricted order menus, institutional treatment guidelines, and staff education to help improve antibiotic prescribing. The ASP pharmacists have a scope of practice to make changes to anti-infective therapies. The purpose of this study was to describe antibiotic prescribing in patients hospitalized with COVID-19 from November 1, 2020, to January 31, 2021, in an ASP setting led by pharmacists.

Methods

This retrospective descriptive study included patients who were hospitalized for the treatment of laboratory-confirmed COVID-19 infection. The Theradoc clinical surveillance system was used to retrieve a list of patients who were admitted to VASNHS from November 1, 2020, to January 31, 2021, and tested positive for COVID-19. Patients with incidental positive COVID-19 test results or those who received antibiotics for extrapulmonary indications on hospital admission were excluded.

Each patient chart was reviewed and data, including clinical presentations, procalcitonin (PCT), the requirement of supplemental oxygen, vital signs, imaging findings, antibiotic orders on admission, ASP interventions such as discontinuation or changes to antibiotic therapy during the first 72 hours of hospital admission, clinical outcomes, culture results, and readmission rate, defined as any hospital admission related to COVID-19 or respiratory tract infection within 30 days from the previous discharge, were collected.

The primary objective of the study was to describe antibiotic prescribing in patients hospitalized with COVID-19. The secondary outcomes included the prevalence of bacterial coinfection and nosocomial bacterial infection in patients hospitalized with COVID-19.

Results

A total of 199 patients were admitted to the hospital for laboratory-confirmed COVID-19 infection from November 1, 2020, to January 31, 2021. Sixty-one patients (31%) received at least 1 antibiotic on hospital admission. Among those patients who received empiric antibiotic treatment, 29 patients (48%) met the Systemic Inflammatory Response Syndrome (SIRS) criteria. Fifty-six patients (92%) had ≥ 1 PCT level obtained, and 26 of those (46%) presented with elevated PCT levels (PCT > 0.25). Fifty patients (82%) required oxygen supplement and 49 (80%) presented with remarkable imaging findings. Of 138 patients who did not receive empiric antibiotic therapy within 72 hours of hospital admission, 56 (41%) met the SIRS criteria, 31 (29%) had elevated PCT levels, 100 (72%) required oxygen supplement, and 79 (59%) presented with remarkable imaging findings.

Antibiotic Prescribing

Forty-six of 61 patients (75%) received antibiotic treatment for community-acquired pneumonia (CAP) that included ceftriaxone and azithromycin. Three patients (5%) received ≥ 1 broad-spectrum antibiotic (4th generation cephalosporin [cefepime] or piperacillin-tazobactam), 2 (3%) received vancomycin, and 1 (2%) received a fluoroquinolone (levofloxacin) on admission.

Among 61 patients who received empiric antibiotics, the readmission rate was 6%. The mortality rate was 20%, and the mean (SD) duration of hospital stay was 13.1 (12.5) days. There were 47 patients (77%) who had antibiotics discontinued by the ASP within 72 hours of admission. Among these patients, the readmission rate was 8% and the mortality rate was 15%. The mean (SD) duration of hospital stay was 12.7 (13.3) days. In the group of patients without empiric antibiotic therapy, the readmission rate was 6%, the mortality rate was 10%, and the mean (SD) duration of hospital stay was 10.1 (9.5) days.

Six of 199 patients (3%) had microbiologically confirmed bacterial coinfection on hospital admission: 3 were Pseudomonas aeruginosa (P aeruginosa) and 2 were Klebsiella oxytoca (Table 1).

Discussion

Prospective audit and feedback and preauthorization are recommended in guidelines as “core components of any stewardship program.”⁹ At VASNHS, the ASP performs daily prospective audits with intervention and feedback. Efforts have been made to maintain daily ASP activities during the pandemic. This study aimed to describe antibiotic prescribing for patients hospitalized with COVID-19 in a pharmacist-led ASP setting. It was found that up to 31% of the patients received ≥ 1 antibiotic on admission for empiric treatment of bacterial coinfection. About half of these patients met the SIRS criteria. Most of these patients received ceftriaxone and azithromycin for concern of CAP. ASP discontinued antibiotics within 72 hours in most of the patients. Chart review and discussion with ID physicians and/or hospitalists determined the probability of bacterial coinfection as well as any potential complication or patient-specific risk factor. It is important to note that most patients who received antibiotics on admission had ≥ 1 PCT level and up to 46% of them had a PCT level > 0.25. However, according to Relph and colleagues, PCT may not be a reliable indicator of bacterial infection in severe viral diseases with raised interleukin-6 levels.¹⁰ An elevated PCT level should not be the sole indicator for empiric antibiotic treatment.

Study findings confirmed the low prevalence of bacterial coinfection in patients hospitalized with COVID-19. The overuse of empiric antibiotics in a patient population unlikely to present with bacterial coinfection is concerning. It is essential to continue promoting antimicrobial stewardship during the COVID-19 pandemic to ensure appropriate and responsible antimicrobial prescribing. A thorough clinical assessment consisting of comorbidities, clinical symptoms, radiologic and microbiologic findings, as well as other relevant workup or biomarker results is crucial to determine whether the antibiotic is strongly indicated in patients hospitalized with COVID-19. Empiric antibiotic therapy should be considered only in patients with clinical findings suggestive of bacterial coinfection.

Limitations

Limitations of our study included the study design (single-center, retrospective review, lack of comparative group) and small sample size with a 3-month study period. In addition, respiratory cultures are not commonly obtained in patients who present with mild-to-moderate CAP. Using culture results solely to confirm bacterial coinfection in patients with COVID-19 could have underestimated the prevalence of bacterial infection. Developing diagnostic criteria that include clinical signs and symptoms, imaging findings, and laboratory results as well as culture results would help to better assess the presence of bacterial coinfection in this patient population.

Conclusions

The study findings showed that up to 30% of patients hospitalized for COVID-19 infection received empiric antibiotic treatment for concern of bacterial coinfection. A pharmacist-led ASP provided interventions, including early discontinuation of antibiotics in 77% of these patients.

A low prevalence of bacterial coinfection (3%) in patients hospitalized with COVID-19 also was reported. A thorough clinical workup to determine the risk of bacterial coinfection in patients with COVID-19 is important before starting empiric antibiotic therapy. Continuing to promote the ASP during the COVID-19 pandemic to ensure responsible antibiotic use and prevent antimicrobial resistance is essential.

The inappropriate use of antibiotics is associated with an increased risk of antibiotic resistance, health care costs, and risk of adverse drug reactions.¹ According to the Centers for Disease Control and Prevention (CDC), a 10% decrease in overall antibiotic use across different wards was associated with a 34% decrease in Clostridioides difficile (C difficile) infections.² In addition, antimicrobial resistance accounts for > 2.8 million infections and > 35,000 deaths each year.³ The estimated total economic costs of antibiotic resistance to the US economy have ranged as high as $20 billion in excess direct health care costs.⁴ A main goal of an antimicrobial stewardship program (ASP) is to optimize antibiotic use to prevent the adverse consequences of inappropriate antibiotic prescribing.

During the COVID-19 pandemic, increased use of empiric antibiotic therapy has been observed. According to the CDC, almost 80% of patients hospitalized with COVID-19 received an antibiotic from March 2020 to October 2020.⁵ Studies were conducted to investigate the prevalence of bacterial coinfection in patients with COVID-19 and whether antibiotics were indicated in this patient population. A United Kingdom multicenter, prospective cohort study showed a high proportion of patients hospitalized with COVID-19 received antimicrobials despite microbiologically confirmed bacterial infections being rare and more likely to be secondary infections.⁶

Many other studies have reported similar findings. Langord and colleagues found the prevalence of bacterial coinfection in patients with COVID-19 was 3.5% but that 71.9% received antibiotics.⁷ Coenen and colleagues identified 12.4% of the patients with possible and 1.1% of patients with probable bacterial coinfection, while 81% of the study population and 78% of patients were classified as unlikely bacterial coinfection received antibiotics.⁸

At Veterans Affairs Southern Nevada Healthcare System (VASNHS), an ASP team consisting of an infectious disease (ID) physician and 2 pharmacists provide daily prospective audits with intervention and feedback along with other interventions, such as providing restricted order menus, institutional treatment guidelines, and staff education to help improve antibiotic prescribing. The ASP pharmacists have a scope of practice to make changes to anti-infective therapies. The purpose of this study was to describe antibiotic prescribing in patients hospitalized with COVID-19 from November 1, 2020, to January 31, 2021, in an ASP setting led by pharmacists.

Methods

This retrospective descriptive study included patients who were hospitalized for the treatment of laboratory-confirmed COVID-19 infection. The Theradoc clinical surveillance system was used to retrieve a list of patients who were admitted to VASNHS from November 1, 2020, to January 31, 2021, and tested positive for COVID-19. Patients with incidental positive COVID-19 test results or those who received antibiotics for extrapulmonary indications on hospital admission were excluded.

Each patient chart was reviewed and data, including clinical presentations, procalcitonin (PCT), the requirement of supplemental oxygen, vital signs, imaging findings, antibiotic orders on admission, ASP interventions such as discontinuation or changes to antibiotic therapy during the first 72 hours of hospital admission, clinical outcomes, culture results, and readmission rate, defined as any hospital admission related to COVID-19 or respiratory tract infection within 30 days from the previous discharge, were collected.

The primary objective of the study was to describe antibiotic prescribing in patients hospitalized with COVID-19. The secondary outcomes included the prevalence of bacterial coinfection and nosocomial bacterial infection in patients hospitalized with COVID-19.

Results

A total of 199 patients were admitted to the hospital for laboratory-confirmed COVID-19 infection from November 1, 2020, to January 31, 2021. Sixty-one patients (31%) received at least 1 antibiotic on hospital admission. Among those patients who received empiric antibiotic treatment, 29 patients (48%) met the Systemic Inflammatory Response Syndrome (SIRS) criteria. Fifty-six patients (92%) had ≥ 1 PCT level obtained, and 26 of those (46%) presented with elevated PCT levels (PCT > 0.25). Fifty patients (82%) required oxygen supplement and 49 (80%) presented with remarkable imaging findings. Of 138 patients who did not receive empiric antibiotic therapy within 72 hours of hospital admission, 56 (41%) met the SIRS criteria, 31 (29%) had elevated PCT levels, 100 (72%) required oxygen supplement, and 79 (59%) presented with remarkable imaging findings.

Antibiotic Prescribing

Forty-six of 61 patients (75%) received antibiotic treatment for community-acquired pneumonia (CAP) that included ceftriaxone and azithromycin. Three patients (5%) received ≥ 1 broad-spectrum antibiotic (4th generation cephalosporin [cefepime] or piperacillin-tazobactam), 2 (3%) received vancomycin, and 1 (2%) received a fluoroquinolone (levofloxacin) on admission.

Among 61 patients who received empiric antibiotics, the readmission rate was 6%. The mortality rate was 20%, and the mean (SD) duration of hospital stay was 13.1 (12.5) days. There were 47 patients (77%) who had antibiotics discontinued by the ASP within 72 hours of admission. Among these patients, the readmission rate was 8% and the mortality rate was 15%. The mean (SD) duration of hospital stay was 12.7 (13.3) days. In the group of patients without empiric antibiotic therapy, the readmission rate was 6%, the mortality rate was 10%, and the mean (SD) duration of hospital stay was 10.1 (9.5) days.

Six of 199 patients (3%) had microbiologically confirmed bacterial coinfection on hospital admission: 3 were Pseudomonas aeruginosa (P aeruginosa) and 2 were Klebsiella oxytoca (Table 1).

Discussion

Prospective audit and feedback and preauthorization are recommended in guidelines as “core components of any stewardship program.”⁹ At VASNHS, the ASP performs daily prospective audits with intervention and feedback. Efforts have been made to maintain daily ASP activities during the pandemic. This study aimed to describe antibiotic prescribing for patients hospitalized with COVID-19 in a pharmacist-led ASP setting. It was found that up to 31% of the patients received ≥ 1 antibiotic on admission for empiric treatment of bacterial coinfection. About half of these patients met the SIRS criteria. Most of these patients received ceftriaxone and azithromycin for concern of CAP. ASP discontinued antibiotics within 72 hours in most of the patients. Chart review and discussion with ID physicians and/or hospitalists determined the probability of bacterial coinfection as well as any potential complication or patient-specific risk factor. It is important to note that most patients who received antibiotics on admission had ≥ 1 PCT level and up to 46% of them had a PCT level > 0.25. However, according to Relph and colleagues, PCT may not be a reliable indicator of bacterial infection in severe viral diseases with raised interleukin-6 levels.¹⁰ An elevated PCT level should not be the sole indicator for empiric antibiotic treatment.

Study findings confirmed the low prevalence of bacterial coinfection in patients hospitalized with COVID-19. The overuse of empiric antibiotics in a patient population unlikely to present with bacterial coinfection is concerning. It is essential to continue promoting antimicrobial stewardship during the COVID-19 pandemic to ensure appropriate and responsible antimicrobial prescribing. A thorough clinical assessment consisting of comorbidities, clinical symptoms, radiologic and microbiologic findings, as well as other relevant workup or biomarker results is crucial to determine whether the antibiotic is strongly indicated in patients hospitalized with COVID-19. Empiric antibiotic therapy should be considered only in patients with clinical findings suggestive of bacterial coinfection.

Limitations

Limitations of our study included the study design (single-center, retrospective review, lack of comparative group) and small sample size with a 3-month study period. In addition, respiratory cultures are not commonly obtained in patients who present with mild-to-moderate CAP. Using culture results solely to confirm bacterial coinfection in patients with COVID-19 could have underestimated the prevalence of bacterial infection. Developing diagnostic criteria that include clinical signs and symptoms, imaging findings, and laboratory results as well as culture results would help to better assess the presence of bacterial coinfection in this patient population.

Conclusions

The study findings showed that up to 30% of patients hospitalized for COVID-19 infection received empiric antibiotic treatment for concern of bacterial coinfection. A pharmacist-led ASP provided interventions, including early discontinuation of antibiotics in 77% of these patients.

A low prevalence of bacterial coinfection (3%) in patients hospitalized with COVID-19 also was reported. A thorough clinical workup to determine the risk of bacterial coinfection in patients with COVID-19 is important before starting empiric antibiotic therapy. Continuing to promote the ASP during the COVID-19 pandemic to ensure responsible antibiotic use and prevent antimicrobial resistance is essential.

The inappropriate use of antibiotics is associated with an increased risk of antibiotic resistance, health care costs, and risk of adverse drug reactions.¹ According to the Centers for Disease Control and Prevention (CDC), a 10% decrease in overall antibiotic use across different wards was associated with a 34% decrease in Clostridioides difficile (C difficile) infections.² In addition, antimicrobial resistance accounts for > 2.8 million infections and > 35,000 deaths each year.³ The estimated total economic costs of antibiotic resistance to the US economy have ranged as high as $20 billion in excess direct health care costs.⁴ A main goal of an antimicrobial stewardship program (ASP) is to optimize antibiotic use to prevent the adverse consequences of inappropriate antibiotic prescribing.

During the COVID-19 pandemic, increased use of empiric antibiotic therapy has been observed. According to the CDC, almost 80% of patients hospitalized with COVID-19 received an antibiotic from March 2020 to October 2020.⁵ Studies were conducted to investigate the prevalence of bacterial coinfection in patients with COVID-19 and whether antibiotics were indicated in this patient population. A United Kingdom multicenter, prospective cohort study showed a high proportion of patients hospitalized with COVID-19 received antimicrobials despite microbiologically confirmed bacterial infections being rare and more likely to be secondary infections.⁶

Many other studies have reported similar findings. Langord and colleagues found the prevalence of bacterial coinfection in patients with COVID-19 was 3.5% but that 71.9% received antibiotics.⁷ Coenen and colleagues identified 12.4% of the patients with possible and 1.1% of patients with probable bacterial coinfection, while 81% of the study population and 78% of patients were classified as unlikely bacterial coinfection received antibiotics.⁸

At Veterans Affairs Southern Nevada Healthcare System (VASNHS), an ASP team consisting of an infectious disease (ID) physician and 2 pharmacists provide daily prospective audits with intervention and feedback along with other interventions, such as providing restricted order menus, institutional treatment guidelines, and staff education to help improve antibiotic prescribing. The ASP pharmacists have a scope of practice to make changes to anti-infective therapies. The purpose of this study was to describe antibiotic prescribing in patients hospitalized with COVID-19 from November 1, 2020, to January 31, 2021, in an ASP setting led by pharmacists.

Methods

This retrospective descriptive study included patients who were hospitalized for the treatment of laboratory-confirmed COVID-19 infection. The Theradoc clinical surveillance system was used to retrieve a list of patients who were admitted to VASNHS from November 1, 2020, to January 31, 2021, and tested positive for COVID-19. Patients with incidental positive COVID-19 test results or those who received antibiotics for extrapulmonary indications on hospital admission were excluded.

Each patient chart was reviewed and data, including clinical presentations, procalcitonin (PCT), the requirement of supplemental oxygen, vital signs, imaging findings, antibiotic orders on admission, ASP interventions such as discontinuation or changes to antibiotic therapy during the first 72 hours of hospital admission, clinical outcomes, culture results, and readmission rate, defined as any hospital admission related to COVID-19 or respiratory tract infection within 30 days from the previous discharge, were collected.

The primary objective of the study was to describe antibiotic prescribing in patients hospitalized with COVID-19. The secondary outcomes included the prevalence of bacterial coinfection and nosocomial bacterial infection in patients hospitalized with COVID-19.

Results

A total of 199 patients were admitted to the hospital for laboratory-confirmed COVID-19 infection from November 1, 2020, to January 31, 2021. Sixty-one patients (31%) received at least 1 antibiotic on hospital admission. Among those patients who received empiric antibiotic treatment, 29 patients (48%) met the Systemic Inflammatory Response Syndrome (SIRS) criteria. Fifty-six patients (92%) had ≥ 1 PCT level obtained, and 26 of those (46%) presented with elevated PCT levels (PCT > 0.25). Fifty patients (82%) required oxygen supplement and 49 (80%) presented with remarkable imaging findings. Of 138 patients who did not receive empiric antibiotic therapy within 72 hours of hospital admission, 56 (41%) met the SIRS criteria, 31 (29%) had elevated PCT levels, 100 (72%) required oxygen supplement, and 79 (59%) presented with remarkable imaging findings.

Antibiotic Prescribing

Forty-six of 61 patients (75%) received antibiotic treatment for community-acquired pneumonia (CAP) that included ceftriaxone and azithromycin. Three patients (5%) received ≥ 1 broad-spectrum antibiotic (4th generation cephalosporin [cefepime] or piperacillin-tazobactam), 2 (3%) received vancomycin, and 1 (2%) received a fluoroquinolone (levofloxacin) on admission.

Among 61 patients who received empiric antibiotics, the readmission rate was 6%. The mortality rate was 20%, and the mean (SD) duration of hospital stay was 13.1 (12.5) days. There were 47 patients (77%) who had antibiotics discontinued by the ASP within 72 hours of admission. Among these patients, the readmission rate was 8% and the mortality rate was 15%. The mean (SD) duration of hospital stay was 12.7 (13.3) days. In the group of patients without empiric antibiotic therapy, the readmission rate was 6%, the mortality rate was 10%, and the mean (SD) duration of hospital stay was 10.1 (9.5) days.

Six of 199 patients (3%) had microbiologically confirmed bacterial coinfection on hospital admission: 3 were Pseudomonas aeruginosa (P aeruginosa) and 2 were Klebsiella oxytoca (Table 1).

Discussion

Prospective audit and feedback and preauthorization are recommended in guidelines as “core components of any stewardship program.”⁹ At VASNHS, the ASP performs daily prospective audits with intervention and feedback. Efforts have been made to maintain daily ASP activities during the pandemic. This study aimed to describe antibiotic prescribing for patients hospitalized with COVID-19 in a pharmacist-led ASP setting. It was found that up to 31% of the patients received ≥ 1 antibiotic on admission for empiric treatment of bacterial coinfection. About half of these patients met the SIRS criteria. Most of these patients received ceftriaxone and azithromycin for concern of CAP. ASP discontinued antibiotics within 72 hours in most of the patients. Chart review and discussion with ID physicians and/or hospitalists determined the probability of bacterial coinfection as well as any potential complication or patient-specific risk factor. It is important to note that most patients who received antibiotics on admission had ≥ 1 PCT level and up to 46% of them had a PCT level > 0.25. However, according to Relph and colleagues, PCT may not be a reliable indicator of bacterial infection in severe viral diseases with raised interleukin-6 levels.¹⁰ An elevated PCT level should not be the sole indicator for empiric antibiotic treatment.

Study findings confirmed the low prevalence of bacterial coinfection in patients hospitalized with COVID-19. The overuse of empiric antibiotics in a patient population unlikely to present with bacterial coinfection is concerning. It is essential to continue promoting antimicrobial stewardship during the COVID-19 pandemic to ensure appropriate and responsible antimicrobial prescribing. A thorough clinical assessment consisting of comorbidities, clinical symptoms, radiologic and microbiologic findings, as well as other relevant workup or biomarker results is crucial to determine whether the antibiotic is strongly indicated in patients hospitalized with COVID-19. Empiric antibiotic therapy should be considered only in patients with clinical findings suggestive of bacterial coinfection.

Limitations

Limitations of our study included the study design (single-center, retrospective review, lack of comparative group) and small sample size with a 3-month study period. In addition, respiratory cultures are not commonly obtained in patients who present with mild-to-moderate CAP. Using culture results solely to confirm bacterial coinfection in patients with COVID-19 could have underestimated the prevalence of bacterial infection. Developing diagnostic criteria that include clinical signs and symptoms, imaging findings, and laboratory results as well as culture results would help to better assess the presence of bacterial coinfection in this patient population.

Conclusions

The study findings showed that up to 30% of patients hospitalized for COVID-19 infection received empiric antibiotic treatment for concern of bacterial coinfection. A pharmacist-led ASP provided interventions, including early discontinuation of antibiotics in 77% of these patients.

A low prevalence of bacterial coinfection (3%) in patients hospitalized with COVID-19 also was reported. A thorough clinical workup to determine the risk of bacterial coinfection in patients with COVID-19 is important before starting empiric antibiotic therapy. Continuing to promote the ASP during the COVID-19 pandemic to ensure responsible antibiotic use and prevent antimicrobial resistance is essential.

Infectious diseases are the most common reason for rehospitalization among patients with spinal cord injuries (SCI), regardless of the number of years postinjury.¹ The appropriate use and selection of antibiotics for properly diagnosed infectious diseases is especially important for this population. This principle helps to avoid the development of drug-resistant organisms and reduces the risk of recurrent infections, aligning with antibiotic stewardship.

Antibiotics are the most common class of drug allergies in the general population, and penicillin is the most frequently reported allergen (up to 10%).² Prescription drug–induced anaphylaxis is severe and life threatening with a reported frequency of 1.1%. Penicillin and sulfonamide (46 and 15 per 10,000 patients, respectively) are the most common allergens.³ Although there is a significant difference between an adverse drug reaction (ADR) and true hypersensitivity, once documented in the electronic health record (EHR) as an allergy, this information deters use of the listed drugs.

Genitourinary, skin, and respiratory diseases are the leading causes for rehospitalization in patients with SCI.¹ A large proportion of these are infectious in etiology and require antibiotic treatment. In fact, persons with SCI are at high risk for antibiotic overuse and hospital-acquired infection due to chronic bacteriuria, frequent health care exposure, implanted medical devices, and other factors.⁴ Concurrently, there is a crisis of antibiotic-resistant bacteria proliferation, described as a threat to patient safety and public health.^5,6 Its severity is illustrated by the report that 38% of the cultures from patients with spinal cord injury are multidrug resistant gram-negative organisms.⁷

The SCI center at James A. Haley Veterans’ Hospital (JAHVH) in Tampa, Florida, serves a high concentration of active-duty military members and veterans with SCI. A study that reviews the exact frequency of antibiotic drug allergies listed on the EHR would be a key first step to identify the magnitude of this issue. The results could guide investigation into differentiating true allergies from ADRs, thereby widening the options for potentially life-saving antibiotic treatment.

Methods

We performed a retrospective chart review of patients included in the local SCI registry between October 1, 2015, and September 30, 2017. We collected data on patient demographics (age, sex, race and ethnicity) and a description of patients’ injuries (International Standards for Neurological Classification of Spinal Cord Injury [ISNCSCI] and etiology of injury [traumatic vs atraumatic]). The outcomes included antibiotic allergy and ADRs.

In the EHR, allergies can be listed toward an antibiotic class or a specific antibiotic. An allergy to each specific antibiotic would be recorded separately; however, overlap among antibiotic classes was not duplicated. For example, if a subject has a listed antibiotic allergy to ceftriaxone and cefepime with listed reactions, we would record allergies to each of these antibiotics but would only report a single allergy to the cephalosporin subclass.

Since we did not differentiate hypersensitivity reactions (HSRs) from other ADRs, the reported reactions were grouped by signs and symptoms. There is a variety of terms used to report similar reactions, and best efforts were made to record the data as accurately as possible. Patient-reported history for risk stratification is a tool we used to group these historical reactions into high- vs low-risk for severe reactions. High-risk signs are those listed as anaphylaxis; anaphylactic reactions; angioedema presenting as swelling of mouth, eyes, lips, or tongue; blisters or ulcers involving the lips, mouth, eyes, urethra, vagina, or peeling skin; respiratory changes; shortness of breath; dyspnea; hypotension; or organ involvement (kidneys, lungs, liver).⁶

Inclusion criteria were all veterans who were diagnosed with tetraplegia or paraplegia and received annual evaluation between October 1, 2015, and September 30, 2017. We chose this period because it was the beginning of a financial year at the JAHVH SCI department using the SCI registry. The SCI annual evaluation is a routine practitioner encounter with the veteran, along with appropriate laboratory testing and imaging to follow up potential chronic health issues specific to patients with SCI. Annual evaluations provide an opportunity to maintain routine health screening and preventive care. Patients who had significant portions of data missing or missing elements of primary outcomes were excluded from analysis. The study was reviewed and approved by the University of South Florida Institutional Review Board (VA IRBNet #1573370-4 on September 9, 2019).

Results

Of 1866 patients reviewed, 207 (11.1%) were excluded due to missing data, resulting in 1659 records that were analyzed. Mean age was 64 years, and male to female ratio was about 10 to 1. Most of the SCI or diseases were classified as incomplete (n = 1249) per ISNCSCI (absence of sensory and motor function in the lowest sacral segments) compared with 373 classified as complete.

Of the 1659 patients, 494 (29.8%) had a recorded allergy to antibiotics. The most frequently recorded were 217 penicillin (13.1%), 159 sulfa drugs (9.6%), 75 fluoroquinolone (4.5%), 66 cephalosporin (4.0%), and 44 vancomycin (2.7%) allergies.

Discussion

In this study, we evaluated the frequency and characteristics of antibiotic allergies at a single SCI center to better identify potential areas for quality improvement when recording drug allergies. A study in the general population used self-reported methods to collect such information found about a 15% prevalence of antibiotic allergy, which was lower than the 29.8% prevalence noted in our study.⁸

Regarding the most common antibiotic allergies, one study reported allergy to penicillin in the EHR in 12.8% of patients at a major US regional health care system, while 13.1% of patients with SCI had documented allergy to penicillin in our study.⁹ Regarding the other antibiotic classes, the percentage of allergies were higher than those reported in the general population: sulfonamide (9.6% vs 7.4%), fluoroquinolones (4.5% vs 1.3%), and cephalosporins (4.0% vs 1.7%).¹⁰ The EHR appears to capture a much higher rate of antibiotic allergies than that in self-reported studies, such as a study of self-reported allergy in the general adult population in Portugal, where only 4.5% of patients reported allergy to any β-lactam medications.¹⁰

The prevalence of an antibiotic allergy could be affected by the health care setting and sex distribution. For example, the Zhou and colleagues’ study conducted in the Greater Boston area showed higher reported antibiotic rates than those in a study from a Southern California medical group. The higher proportion of tertiary referral patients in that specific network was suggested to be the cause of the difference.^8,9 Our results in the SCI population are more comparable to that in a tertiary setting. This is consistent with the fact that persons with SCI generally have more exposure to antibiotics and consequently a higher reported rate of allergic reactions to antibiotics.

Similarly, the same study in Southern California noted that female patients use more antibiotics than do male patients, thus potentially contributing to higher rates of reported allergy toward all classes of antibiotics.⁸ Our study did not investigate antibiotic allergy by sex; however, the significantly higher proportion of male sex among the veteran population would have impacted these results.

Limitations

Our study was limited as a single-center retrospective study. However, our center is one of the major SCI specialty hubs, and the results should be somewhat reflective of those in the veterans with SCI population. Veterans under the US Department of Veterans Affairs (VA) medical care have the option to seek care or procedures in non-VA facilities. If allergies to antibiotics occurred outside of the VA system, there is no mechanism to automatically merge with the VA EHR allergy list, unless they are later recorded and added to the VA EHR. Thus, there is potential for underreporting.

Drug anaphylaxis incidence was noted to change over time.^4,8,9 For example, a downtrend of reported antibiotic allergy was reported between 1990 and 2013.¹⁰ Our study only reflects an overall prevalence of a single cohort, without demonstration of relationship to time.

Lastly, this study did not aim to differentiate HSRs from other ADRs. This is exactly the point of the study, which investigated the frequency of EHR-recorded antibiotic allergies in our SCI population and reflects the issue with indiscriminate recording of ADRs and HSRs under the umbrella of allergy in the EHR. Further diagnosing true allergies should be considered in the SCI population after weighing the risks and benefits of assessment, aligning with the wishes of the veteran, obtaining informed consent, and addressing the cost-effectiveness of specific tests. We suggest that primary care practitioners work closely with allergy specialists to formulate a mechanism to diagnose various antibiotic allergic reactions, including serum tryptase, epicutaneous skin testing, intradermal skin testing, patch testing, delayed intradermal testing, and drug challenge as appropriate. It is also possible that in cases where very mild reactions/adverse effects of antibiotics were recorded in the EHR, the clinicians and veterans may discuss reintroducing the same antibiotics or proceeding with further testing if necessary. In contrast, the 12% of those with a high risk of severe allergic reactions to penicillin in our study would benefit from allergist evaluation and access to epinephrine auto-injectors at all times. Differentiating true allergy is the only clear way to deter unnecessary avoidance of first-line therapies for antibiotic treatment and avoid promotion of antibiotic resistance.

Future studies can analyze antibiotic allergy based on demographics, including sex and age difference, as well as exploring outpatient vs inpatient settings. Aside from prevalence, we hope to demonstrate antibiotic allergy over time, especially after integration of diagnostic allergy testing, to evaluate the impact to EHR-recorded allergies.

Conclusions

Almost 30% of patients with SCI had a recorded allergy to at least 1 antibiotic. The most common allergy was to penicillin, which is similar to what has previously been reported for the general adult US population. However, only 12% of those with a penicillin allergy were considered high risk of true allergic reactions. Consequently, there are opportunities to examine whether approaches to confirm true reactions (such as skin testing) would help to mitigate unnecessary avoidance of certain antibiotic classes due to mild ADRs, rather than a true allergy, in persons with SCI. This would be an important effort to combat both individual safety concerns and the public health crisis of antibiotic resistance. Given the available evidence, it is reasonable for SCI health care practitioners to discuss the potential risks and benefits of allergy testing with patients with SCI; this maintains a patient-centered approach that can ensure judicious use of antibiotics when necessary.

Acknowledgments

This material is based on work supported (or supported in part) with resources and the use of facilities at the James A. Haley Veterans’ Hospital

Infectious diseases are the most common reason for rehospitalization among patients with spinal cord injuries (SCI), regardless of the number of years postinjury.¹ The appropriate use and selection of antibiotics for properly diagnosed infectious diseases is especially important for this population. This principle helps to avoid the development of drug-resistant organisms and reduces the risk of recurrent infections, aligning with antibiotic stewardship.

Antibiotics are the most common class of drug allergies in the general population, and penicillin is the most frequently reported allergen (up to 10%).² Prescription drug–induced anaphylaxis is severe and life threatening with a reported frequency of 1.1%. Penicillin and sulfonamide (46 and 15 per 10,000 patients, respectively) are the most common allergens.³ Although there is a significant difference between an adverse drug reaction (ADR) and true hypersensitivity, once documented in the electronic health record (EHR) as an allergy, this information deters use of the listed drugs.

Genitourinary, skin, and respiratory diseases are the leading causes for rehospitalization in patients with SCI.¹ A large proportion of these are infectious in etiology and require antibiotic treatment. In fact, persons with SCI are at high risk for antibiotic overuse and hospital-acquired infection due to chronic bacteriuria, frequent health care exposure, implanted medical devices, and other factors.⁴ Concurrently, there is a crisis of antibiotic-resistant bacteria proliferation, described as a threat to patient safety and public health.^5,6 Its severity is illustrated by the report that 38% of the cultures from patients with spinal cord injury are multidrug resistant gram-negative organisms.⁷

The SCI center at James A. Haley Veterans’ Hospital (JAHVH) in Tampa, Florida, serves a high concentration of active-duty military members and veterans with SCI. A study that reviews the exact frequency of antibiotic drug allergies listed on the EHR would be a key first step to identify the magnitude of this issue. The results could guide investigation into differentiating true allergies from ADRs, thereby widening the options for potentially life-saving antibiotic treatment.

Methods

We performed a retrospective chart review of patients included in the local SCI registry between October 1, 2015, and September 30, 2017. We collected data on patient demographics (age, sex, race and ethnicity) and a description of patients’ injuries (International Standards for Neurological Classification of Spinal Cord Injury [ISNCSCI] and etiology of injury [traumatic vs atraumatic]). The outcomes included antibiotic allergy and ADRs.

In the EHR, allergies can be listed toward an antibiotic class or a specific antibiotic. An allergy to each specific antibiotic would be recorded separately; however, overlap among antibiotic classes was not duplicated. For example, if a subject has a listed antibiotic allergy to ceftriaxone and cefepime with listed reactions, we would record allergies to each of these antibiotics but would only report a single allergy to the cephalosporin subclass.

Since we did not differentiate hypersensitivity reactions (HSRs) from other ADRs, the reported reactions were grouped by signs and symptoms. There is a variety of terms used to report similar reactions, and best efforts were made to record the data as accurately as possible. Patient-reported history for risk stratification is a tool we used to group these historical reactions into high- vs low-risk for severe reactions. High-risk signs are those listed as anaphylaxis; anaphylactic reactions; angioedema presenting as swelling of mouth, eyes, lips, or tongue; blisters or ulcers involving the lips, mouth, eyes, urethra, vagina, or peeling skin; respiratory changes; shortness of breath; dyspnea; hypotension; or organ involvement (kidneys, lungs, liver).⁶

Inclusion criteria were all veterans who were diagnosed with tetraplegia or paraplegia and received annual evaluation between October 1, 2015, and September 30, 2017. We chose this period because it was the beginning of a financial year at the JAHVH SCI department using the SCI registry. The SCI annual evaluation is a routine practitioner encounter with the veteran, along with appropriate laboratory testing and imaging to follow up potential chronic health issues specific to patients with SCI. Annual evaluations provide an opportunity to maintain routine health screening and preventive care. Patients who had significant portions of data missing or missing elements of primary outcomes were excluded from analysis. The study was reviewed and approved by the University of South Florida Institutional Review Board (VA IRBNet #1573370-4 on September 9, 2019).

Results

Of 1866 patients reviewed, 207 (11.1%) were excluded due to missing data, resulting in 1659 records that were analyzed. Mean age was 64 years, and male to female ratio was about 10 to 1. Most of the SCI or diseases were classified as incomplete (n = 1249) per ISNCSCI (absence of sensory and motor function in the lowest sacral segments) compared with 373 classified as complete.

Of the 1659 patients, 494 (29.8%) had a recorded allergy to antibiotics. The most frequently recorded were 217 penicillin (13.1%), 159 sulfa drugs (9.6%), 75 fluoroquinolone (4.5%), 66 cephalosporin (4.0%), and 44 vancomycin (2.7%) allergies.

Discussion

In this study, we evaluated the frequency and characteristics of antibiotic allergies at a single SCI center to better identify potential areas for quality improvement when recording drug allergies. A study in the general population used self-reported methods to collect such information found about a 15% prevalence of antibiotic allergy, which was lower than the 29.8% prevalence noted in our study.⁸

Regarding the most common antibiotic allergies, one study reported allergy to penicillin in the EHR in 12.8% of patients at a major US regional health care system, while 13.1% of patients with SCI had documented allergy to penicillin in our study.⁹ Regarding the other antibiotic classes, the percentage of allergies were higher than those reported in the general population: sulfonamide (9.6% vs 7.4%), fluoroquinolones (4.5% vs 1.3%), and cephalosporins (4.0% vs 1.7%).¹⁰ The EHR appears to capture a much higher rate of antibiotic allergies than that in self-reported studies, such as a study of self-reported allergy in the general adult population in Portugal, where only 4.5% of patients reported allergy to any β-lactam medications.¹⁰

The prevalence of an antibiotic allergy could be affected by the health care setting and sex distribution. For example, the Zhou and colleagues’ study conducted in the Greater Boston area showed higher reported antibiotic rates than those in a study from a Southern California medical group. The higher proportion of tertiary referral patients in that specific network was suggested to be the cause of the difference.^8,9 Our results in the SCI population are more comparable to that in a tertiary setting. This is consistent with the fact that persons with SCI generally have more exposure to antibiotics and consequently a higher reported rate of allergic reactions to antibiotics.

Similarly, the same study in Southern California noted that female patients use more antibiotics than do male patients, thus potentially contributing to higher rates of reported allergy toward all classes of antibiotics.⁸ Our study did not investigate antibiotic allergy by sex; however, the significantly higher proportion of male sex among the veteran population would have impacted these results.

Limitations

Our study was limited as a single-center retrospective study. However, our center is one of the major SCI specialty hubs, and the results should be somewhat reflective of those in the veterans with SCI population. Veterans under the US Department of Veterans Affairs (VA) medical care have the option to seek care or procedures in non-VA facilities. If allergies to antibiotics occurred outside of the VA system, there is no mechanism to automatically merge with the VA EHR allergy list, unless they are later recorded and added to the VA EHR. Thus, there is potential for underreporting.

Drug anaphylaxis incidence was noted to change over time.^4,8,9 For example, a downtrend of reported antibiotic allergy was reported between 1990 and 2013.¹⁰ Our study only reflects an overall prevalence of a single cohort, without demonstration of relationship to time.

Lastly, this study did not aim to differentiate HSRs from other ADRs. This is exactly the point of the study, which investigated the frequency of EHR-recorded antibiotic allergies in our SCI population and reflects the issue with indiscriminate recording of ADRs and HSRs under the umbrella of allergy in the EHR. Further diagnosing true allergies should be considered in the SCI population after weighing the risks and benefits of assessment, aligning with the wishes of the veteran, obtaining informed consent, and addressing the cost-effectiveness of specific tests. We suggest that primary care practitioners work closely with allergy specialists to formulate a mechanism to diagnose various antibiotic allergic reactions, including serum tryptase, epicutaneous skin testing, intradermal skin testing, patch testing, delayed intradermal testing, and drug challenge as appropriate. It is also possible that in cases where very mild reactions/adverse effects of antibiotics were recorded in the EHR, the clinicians and veterans may discuss reintroducing the same antibiotics or proceeding with further testing if necessary. In contrast, the 12% of those with a high risk of severe allergic reactions to penicillin in our study would benefit from allergist evaluation and access to epinephrine auto-injectors at all times. Differentiating true allergy is the only clear way to deter unnecessary avoidance of first-line therapies for antibiotic treatment and avoid promotion of antibiotic resistance.

Future studies can analyze antibiotic allergy based on demographics, including sex and age difference, as well as exploring outpatient vs inpatient settings. Aside from prevalence, we hope to demonstrate antibiotic allergy over time, especially after integration of diagnostic allergy testing, to evaluate the impact to EHR-recorded allergies.

Conclusions

Almost 30% of patients with SCI had a recorded allergy to at least 1 antibiotic. The most common allergy was to penicillin, which is similar to what has previously been reported for the general adult US population. However, only 12% of those with a penicillin allergy were considered high risk of true allergic reactions. Consequently, there are opportunities to examine whether approaches to confirm true reactions (such as skin testing) would help to mitigate unnecessary avoidance of certain antibiotic classes due to mild ADRs, rather than a true allergy, in persons with SCI. This would be an important effort to combat both individual safety concerns and the public health crisis of antibiotic resistance. Given the available evidence, it is reasonable for SCI health care practitioners to discuss the potential risks and benefits of allergy testing with patients with SCI; this maintains a patient-centered approach that can ensure judicious use of antibiotics when necessary.

Acknowledgments

This material is based on work supported (or supported in part) with resources and the use of facilities at the James A. Haley Veterans’ Hospital

Infectious diseases are the most common reason for rehospitalization among patients with spinal cord injuries (SCI), regardless of the number of years postinjury.¹ The appropriate use and selection of antibiotics for properly diagnosed infectious diseases is especially important for this population. This principle helps to avoid the development of drug-resistant organisms and reduces the risk of recurrent infections, aligning with antibiotic stewardship.

Antibiotics are the most common class of drug allergies in the general population, and penicillin is the most frequently reported allergen (up to 10%).² Prescription drug–induced anaphylaxis is severe and life threatening with a reported frequency of 1.1%. Penicillin and sulfonamide (46 and 15 per 10,000 patients, respectively) are the most common allergens.³ Although there is a significant difference between an adverse drug reaction (ADR) and true hypersensitivity, once documented in the electronic health record (EHR) as an allergy, this information deters use of the listed drugs.

Genitourinary, skin, and respiratory diseases are the leading causes for rehospitalization in patients with SCI.¹ A large proportion of these are infectious in etiology and require antibiotic treatment. In fact, persons with SCI are at high risk for antibiotic overuse and hospital-acquired infection due to chronic bacteriuria, frequent health care exposure, implanted medical devices, and other factors.⁴ Concurrently, there is a crisis of antibiotic-resistant bacteria proliferation, described as a threat to patient safety and public health.^5,6 Its severity is illustrated by the report that 38% of the cultures from patients with spinal cord injury are multidrug resistant gram-negative organisms.⁷

The SCI center at James A. Haley Veterans’ Hospital (JAHVH) in Tampa, Florida, serves a high concentration of active-duty military members and veterans with SCI. A study that reviews the exact frequency of antibiotic drug allergies listed on the EHR would be a key first step to identify the magnitude of this issue. The results could guide investigation into differentiating true allergies from ADRs, thereby widening the options for potentially life-saving antibiotic treatment.

Methods

We performed a retrospective chart review of patients included in the local SCI registry between October 1, 2015, and September 30, 2017. We collected data on patient demographics (age, sex, race and ethnicity) and a description of patients’ injuries (International Standards for Neurological Classification of Spinal Cord Injury [ISNCSCI] and etiology of injury [traumatic vs atraumatic]). The outcomes included antibiotic allergy and ADRs.

In the EHR, allergies can be listed toward an antibiotic class or a specific antibiotic. An allergy to each specific antibiotic would be recorded separately; however, overlap among antibiotic classes was not duplicated. For example, if a subject has a listed antibiotic allergy to ceftriaxone and cefepime with listed reactions, we would record allergies to each of these antibiotics but would only report a single allergy to the cephalosporin subclass.

Since we did not differentiate hypersensitivity reactions (HSRs) from other ADRs, the reported reactions were grouped by signs and symptoms. There is a variety of terms used to report similar reactions, and best efforts were made to record the data as accurately as possible. Patient-reported history for risk stratification is a tool we used to group these historical reactions into high- vs low-risk for severe reactions. High-risk signs are those listed as anaphylaxis; anaphylactic reactions; angioedema presenting as swelling of mouth, eyes, lips, or tongue; blisters or ulcers involving the lips, mouth, eyes, urethra, vagina, or peeling skin; respiratory changes; shortness of breath; dyspnea; hypotension; or organ involvement (kidneys, lungs, liver).⁶

Inclusion criteria were all veterans who were diagnosed with tetraplegia or paraplegia and received annual evaluation between October 1, 2015, and September 30, 2017. We chose this period because it was the beginning of a financial year at the JAHVH SCI department using the SCI registry. The SCI annual evaluation is a routine practitioner encounter with the veteran, along with appropriate laboratory testing and imaging to follow up potential chronic health issues specific to patients with SCI. Annual evaluations provide an opportunity to maintain routine health screening and preventive care. Patients who had significant portions of data missing or missing elements of primary outcomes were excluded from analysis. The study was reviewed and approved by the University of South Florida Institutional Review Board (VA IRBNet #1573370-4 on September 9, 2019).

Results

Of 1866 patients reviewed, 207 (11.1%) were excluded due to missing data, resulting in 1659 records that were analyzed. Mean age was 64 years, and male to female ratio was about 10 to 1. Most of the SCI or diseases were classified as incomplete (n = 1249) per ISNCSCI (absence of sensory and motor function in the lowest sacral segments) compared with 373 classified as complete.

Of the 1659 patients, 494 (29.8%) had a recorded allergy to antibiotics. The most frequently recorded were 217 penicillin (13.1%), 159 sulfa drugs (9.6%), 75 fluoroquinolone (4.5%), 66 cephalosporin (4.0%), and 44 vancomycin (2.7%) allergies.

Discussion

In this study, we evaluated the frequency and characteristics of antibiotic allergies at a single SCI center to better identify potential areas for quality improvement when recording drug allergies. A study in the general population used self-reported methods to collect such information found about a 15% prevalence of antibiotic allergy, which was lower than the 29.8% prevalence noted in our study.⁸

Regarding the most common antibiotic allergies, one study reported allergy to penicillin in the EHR in 12.8% of patients at a major US regional health care system, while 13.1% of patients with SCI had documented allergy to penicillin in our study.⁹ Regarding the other antibiotic classes, the percentage of allergies were higher than those reported in the general population: sulfonamide (9.6% vs 7.4%), fluoroquinolones (4.5% vs 1.3%), and cephalosporins (4.0% vs 1.7%).¹⁰ The EHR appears to capture a much higher rate of antibiotic allergies than that in self-reported studies, such as a study of self-reported allergy in the general adult population in Portugal, where only 4.5% of patients reported allergy to any β-lactam medications.¹⁰

The prevalence of an antibiotic allergy could be affected by the health care setting and sex distribution. For example, the Zhou and colleagues’ study conducted in the Greater Boston area showed higher reported antibiotic rates than those in a study from a Southern California medical group. The higher proportion of tertiary referral patients in that specific network was suggested to be the cause of the difference.^8,9 Our results in the SCI population are more comparable to that in a tertiary setting. This is consistent with the fact that persons with SCI generally have more exposure to antibiotics and consequently a higher reported rate of allergic reactions to antibiotics.

Similarly, the same study in Southern California noted that female patients use more antibiotics than do male patients, thus potentially contributing to higher rates of reported allergy toward all classes of antibiotics.⁸ Our study did not investigate antibiotic allergy by sex; however, the significantly higher proportion of male sex among the veteran population would have impacted these results.

Limitations

Our study was limited as a single-center retrospective study. However, our center is one of the major SCI specialty hubs, and the results should be somewhat reflective of those in the veterans with SCI population. Veterans under the US Department of Veterans Affairs (VA) medical care have the option to seek care or procedures in non-VA facilities. If allergies to antibiotics occurred outside of the VA system, there is no mechanism to automatically merge with the VA EHR allergy list, unless they are later recorded and added to the VA EHR. Thus, there is potential for underreporting.

Drug anaphylaxis incidence was noted to change over time.^4,8,9 For example, a downtrend of reported antibiotic allergy was reported between 1990 and 2013.¹⁰ Our study only reflects an overall prevalence of a single cohort, without demonstration of relationship to time.

Lastly, this study did not aim to differentiate HSRs from other ADRs. This is exactly the point of the study, which investigated the frequency of EHR-recorded antibiotic allergies in our SCI population and reflects the issue with indiscriminate recording of ADRs and HSRs under the umbrella of allergy in the EHR. Further diagnosing true allergies should be considered in the SCI population after weighing the risks and benefits of assessment, aligning with the wishes of the veteran, obtaining informed consent, and addressing the cost-effectiveness of specific tests. We suggest that primary care practitioners work closely with allergy specialists to formulate a mechanism to diagnose various antibiotic allergic reactions, including serum tryptase, epicutaneous skin testing, intradermal skin testing, patch testing, delayed intradermal testing, and drug challenge as appropriate. It is also possible that in cases where very mild reactions/adverse effects of antibiotics were recorded in the EHR, the clinicians and veterans may discuss reintroducing the same antibiotics or proceeding with further testing if necessary. In contrast, the 12% of those with a high risk of severe allergic reactions to penicillin in our study would benefit from allergist evaluation and access to epinephrine auto-injectors at all times. Differentiating true allergy is the only clear way to deter unnecessary avoidance of first-line therapies for antibiotic treatment and avoid promotion of antibiotic resistance.

Future studies can analyze antibiotic allergy based on demographics, including sex and age difference, as well as exploring outpatient vs inpatient settings. Aside from prevalence, we hope to demonstrate antibiotic allergy over time, especially after integration of diagnostic allergy testing, to evaluate the impact to EHR-recorded allergies.

Conclusions

Almost 30% of patients with SCI had a recorded allergy to at least 1 antibiotic. The most common allergy was to penicillin, which is similar to what has previously been reported for the general adult US population. However, only 12% of those with a penicillin allergy were considered high risk of true allergic reactions. Consequently, there are opportunities to examine whether approaches to confirm true reactions (such as skin testing) would help to mitigate unnecessary avoidance of certain antibiotic classes due to mild ADRs, rather than a true allergy, in persons with SCI. This would be an important effort to combat both individual safety concerns and the public health crisis of antibiotic resistance. Given the available evidence, it is reasonable for SCI health care practitioners to discuss the potential risks and benefits of allergy testing with patients with SCI; this maintains a patient-centered approach that can ensure judicious use of antibiotics when necessary.

Acknowledgments

This material is based on work supported (or supported in part) with resources and the use of facilities at the James A. Haley Veterans’ Hospital

Prostate Cancer

18F-DCFPyL PET/CT Impact on Treatment Strategies for Patients With Prostate Cancer (PROSPYL)

The main purpose of this phase II trial study is to determine whether a positron emission tomography (PET)/computed tomography (CT) scan using 18F-DCFPyL affects the clinical management plan in veterans. In this study, the management plan prior to and after 18F-DCFPyL PET/CT will be recorded by specific questionnaires and corresponding changes in management will be analyzed. The scan will be used to see how the disease has spread. Both the treatment strategies and probable disease outcomes as relevant to clinical endpoints will be assessed. This study is open to veterans only.

ID: NCT04390880

Sponsor: VA Greater Los Angeles Healthcare System

Location: VA Greater Los Angeles Healthcare System

Patient Decision-Making About Precision Oncology in Veterans With Advanced Prostate Cancer

This project proposes to understand and improve veterans’ decision-making in precision oncology (germline testing, somatic tumor testing, and targeted therapy) for advanced prostate cancer. As precision oncology expands, a comprehensive strategy to support patient informed decision-making has not been developed.

ID: NCT05396872

Sponsor; Collaborator: University of California, San Francisco; US Department of Defense

Location: San Francisco VA Medical Center

Intramuscular Mechanisms of Androgen Deprivation-Related Sarcopenia

Prostate cancer is the most common cancer among men and is even more common in the military and veteran population. For patients with advanced prostate cancer, the most common treatment includes lowering the levels of the hormone testosterone as much as possible, which is called androgen deprivation therapy (ADT). Unfortunately, ADT also causes patients to be fatigued, weak, and to lose muscle. This is often referred to as sarcopenia, and it leads to falls, poor quality of life, and higher risk of death. Currently, there is no treatment for sarcopenia because investigators do not understand the mechanisms that cause it. The mitochondria is the part of the cells responsible for providing energy to muscles but to date the investigators do not know if it is affected in prostate cancer patients with sarcopenia due to ADT. The overall goal of this proposal is to establish if the mitochondria is responsible for sarcopenia in patients with prostate cancer receiving ADT. The investigators will measure mitochondrial function, muscle mass and strength, and feelings of fatigue and quality of life in patients with prostate cancer before starting and after 6 months of ADT.

ID: NCT03867357

Sponsor; Collaborator: Seattle Institute for Biomedical and Clinical Research; US Department of Defense

Location: VA Puget Sound Health Care System

VA Seamless Phase II/III Randomized Trial of Standard Systemic Therapy With or Without PET-Directed Local Therapy for OligoRecurrent Prostate Cancer (VA STARPORT)

The primary goal of this study is to determine if adding PET-directed local therapy improves disease control compared to standard systemic therapy alone (SST) in veterans with oligorecurrent prostate cancer on PET/CT. The investigators will conduct a multi-institutional phase II/III randomized trial comparing SST with or without PET-directed local therapy using radiation or surgery to all metastases and if a local recurrence is present.

ID: NCT04787744

Sponsor: VA Office of Research and Development

Locations: VA Long Beach Healthcare System, VA Greater Los Angeles Healthcare System, Bay Pines VA Healthcare System, Edward Hines Jr. VA Hospital, Richard L. Roudebush VA Medical Center, VA Boston Healthcare System Jamaica Plain Campus, VA Ann Arbor Healthcare System, Minneapolis VA Health Care System, Kansas City VA Medical Center, St. Louis VA Medical Center John Cochran Division, East Orange Campus of the VA New Jersey Health Care System, Durham VA Medical Center, Louis Stokes VA Medical Center, Michael E. DeBakey VA Medical Center, Hunter Holmes McGuire VA Medical Center, Clement J. Zablocki VA Medical Center

Standard Systemic Therapy With or Without Definitive Treatment in Treating Participants With Metastatic Prostate Cancer

This phase III trial studies how well standard systemic therapy with or without definitive treatment (prostate removal surgery or radiation therapy) works in treating participants with prostate cancer that has spread to other places in the body. The addition of prostate removal surgery or radiation therapy to standard systemic therapy for prostate cancer may lower the chance of the cancer growing or spreading.

ID: NCT03678025

Sponsor; Collaborator: Southwest Oncology Group; National Cancer Institute (NCI)

Locations: 328 sites, including Tibor Rubin VA Medical Center, Atlanta VA Medical Center, James J. Peters VA Medical Center, Michael E. DeBakey VA Medical Center, and Audie L. Murphy VA Hospital

A Clinical Study Evaluating the Benefit of Adding Rucaparib to Enzalutamide for Men With Metastatic Prostate Cancer That Has Become Resistant to Testosterone-Deprivation Therapy (CASPAR)

This randomized, placebo-controlled, phase III trial is evaluating the benefit of rucaparib and enzalutamide combination therapy vs enzalutamide alone for the treatment of men with prostate cancer that has spread to other places in the body (metastatic) and has become resistant to testosterone-deprivation therapy (castration-resistant). Enzalutamide helps fight prostate cancer by blocking the use of testosterone by the tumor cells for growth. Poly adenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitors, such as rucaparib, fight prostate cancer by prevent tumor cells from repairing their DNA. Giving enzalutamide and rucaparib may make patients live longer or prevent their cancer from growing or spreading for a longer time, or both. It may also help doctors learn if a mutation in any of the homologous recombination DNA repair genes is helpful to decide which treatment is best for the patient.

ID: NCT04455750

Sponsor; Collaborator: Alliance for Clinical Trials in Oncology; National Cancer Institute (NCI)

Locations: 413 sites

Digitally Captured Activity Data and PROs to Monitor Physical Function in Prostate Cancer Patients (DigiPRO)

Physical function is a known predictor of quality of life in advanced prostate cancer patients and key measure of treatment tolerability. While treatment with androgen deprivation therapy (ADT) improves survival, it is associated with significant toxicities that lead to physical function (PF) decline. The average age of incident prostate cancer is 66 years, and in this older group of men, chronic comorbid conditions often co-occur with diagnosis, further adding to the risk for PF decline. With over 2.9 million prostate cancer survivors in the US, there is an increasing demand for adequate symptom monitoring and PF assessment throughout cancer care. However, there are currently no validated methods to systematically evaluate and predict PF decline. Thus, the overarching objective of this proposal is to determine whether the use of wearable technology to monitor objective daily activity combined with routine symptom reporting can predict PF decline. To accomplish this, we propose a mixed-methods approach that will provide quantitative information to help identify PC survivors at higher risk for PF decline as well as a qualitative aim gain a deeper understanding of the perceived relationships that PC survivors have with their physical activity levels and treatment symptoms.

ID: NCT04575402

Sponsor; Collaborator: Cedars-Sinai Medical Center; US Department of Defense

Location: Cedars Sinai Medical Center

The BurnAlong Pilot Study for Adolescent and Young Adult Cancer Survivors

The purpose of this prospective, interventional, single-arm pilot study is to evaluate whether virtually delivered group-based physical activity is feasible for adolescent and young adult (AYA) cancer survivors. AYAs who were diagnosed with cancer and have completed cancer treatment will be recruited for this study. This study will enroll 20 participants in total and will last approximately 3 months.

ID: NCT05131815

Sponsor; Collaborator: Cedars-Sinai Medical Center; Walter Reed National Military Medical Center

Location: Cedars-Sinai Medical Center

Lung Cancer

DECAMP 1 PLUS: Prediction of Lung Cancer Using Noninvasive Biomarkers

The Detection of Early lung Cancer Among Military Personnel (DECAMP) consortium is a multidisciplinary and translational research program for lung cancer early detection. DECAMP 1 PLUS aims to improve the efficiency of the diagnostic evaluation of patients with indeterminate pulmonary nodules (8-25 mm). Molecular biomarkers for lung cancer diagnosis measured in minimally invasive and noninvasive biospecimens may be able to distinguish between malignant or benign indeterminate pulmonary nodules in high-risk smokers. Ultimately, this study aims to validate molecular as well as clinical and imaging biomarkers of lung cancer in individuals with indeterminate lung nodules.

ID: NCT04165564

Sponsor: Boston University

Locations: 3 VA medical centers (VA Greater LA Healthcare System, VA Boston Healthcare System, and VA Tennessee Valley Healthcare System), 3 military treatment facilities (Naval Medical Center San Diego, Walter Reed National Military Medical Center, and Naval Medical Center Portsmouth) and 12 academic hospitals

DECAMP-2: Screening of Patients With Early Stage Lung Cancer or at High Risk for Developing Lung Cancer (DECAMP-2)

The goal of this project is to improve lung cancer screening in high-risk individuals by identifying biomarkers of preclinical disease and disease risk that are measured in minimally invasive and noninvasive biospecimens. Existing biomarkers for lung cancer diagnosis as well as new biomarkers discovered specifically in this clinical setting will be examined. Biomarkers that identify individuals at highest risk for being diagnosed with lung cancer prior to the appearance of concerning symptoms could increase the utility of lung cancer surveillance and the efficiency of lung cancer chemoprevention clinical trials. Achieving these goals would improve the detection and treatment of early-stage and incipient lung cancer, while restricting the risk of these procedures to those individuals who currently exhibit the early molecular warning signs of impending disease.

ID: NCT02504697

Sponsor: Boston University

Locations: VA medical centers (including Los Angeles VA Healthcare System, Boston VA Research Institute, Inc, Philadelphia VA Medical Center, Veterans Research Foundation of Pittsburgh, and VA North Texas Health Care System), 4 military treatment facilities (Naval Medical Center San Diego, Walter Reed National Military Medical Center, San Antonio Military Medical Center, and Naval Medical Center Portsmouth), and 4 academic hospitals

Improving Decision-Making Encounters in Lung Cancer Using a Low-Literacy Conversation Tool (iDECIDE)

This clinical trial evaluates the effectiveness of a conversation tool on patient-centered health and decision-making outcomes in patients with lung cancer making treatment decisions. This research is being conducted to help doctors understand the information patients need to participate in shared decision-making about their lung cancer treatment options. The focus of this research is to study how patients choose lung cancer treatment options and the information needed to make that choice, with a focus on patients with lower health literacy.

ID: NCT05407168

Sponsor: Oregon Health & Science University Knight Cancer Institute

Locations: Portland VA Medical Center and Oregon Health & Science University Knight Cancer Institute

VA Lung Cancer Surgery or Stereotactic Radiotherapy (VALOR)

The standard of care for stage I non–small cell lung cancer has historically been surgical resection in patients who are medically fit to tolerate an operation. Recent data now suggest that stereotactic radiotherapy may be a suitable alternative. This includes the results from a pooled analysis of 2 incomplete phase III studies that reported a 15% overall survival advantage with stereotactic radiotherapy at 3 years. While these data are promising, the median follow-up period was short, the results underpowered, and the findings were in contradiction to multiple retrospective studies that demonstrate the outcomes with surgery are likely equal or superior. Therefore, the herein trial aims to evaluate these 2 treatments in a prospective randomized fashion with a goal to compare the overall survival beyond 5 years. It has been designed to enroll patients who have a long life expectancy and are fit enough to tolerate an anatomic pulmonary resection with intraoperative lymph node sampling.

This study is designed to open at VA medical centers with expertise in both treatments. The recruitment process includes shared decision making and multidisciplinary evaluations with lung cancer specialists. Mandatory evaluations before randomization include tissue confirmation of NSCLC, staging with FDG-PET/CT, and biopsies of all hilar and/or mediastinal lymph nodes > 10 mm that have a SUV > 2.5. Prerandomization elective lymph node sampling is strongly encouraged, but not required. Following treatment, patients will be followed for a minimum of 5 years.

ID: NCT02984761

Sponsor: VA Office of Research and Development

Locations: 17 VA medical centers, including VA Long Beach Healthcare System, VA Greater Los Angeles Healthcare System, Bay Pines VA Healthcare System, Miami VA Healthcare System, Edward Hines Jr. VA Hospital, Richard L. Roudebush VA Medical Center, Baltimore VA Medical Center, VA Boston Healthcare System Jamaica Plain Campus, VA Ann Arbor Healthcare System, Minneapolis VA Health Care System, Durham VA Medical Center, Louis Stokes VA Medical Center, Corporal Micheal J. Crescenz VA Medical Center, VA Pittsburgh Healthcare System University Drive Division, Michael E. DeBakey VA Medical Center, Hunter Holmes McGuire VA Medical Center, and Clement J. Zablocki VA Medical Center

Utility of CAML as Diagnostic for Early Stage Lung Cancer

The primary objective of this study is to determine the prevalence of cancer associated macrophage-like cells (CAMLS) in patients with pulmonary nodules. Secondary objectives include the following: determine the positive and negative predictive value of CAMLS in patients with pulmonary nodules who undergo biopsy; model combinations of clinical factors with the presence/absence of CAMLS to refine strategies for assessment of patients with pulmonary nodules; and evaluate whether these measures result in enhanced T-cell activity and/or natural killer cell function and number.

ID: NCT03992183

Sponsor; Collaborators: Fox Chase Cancer Center; US Department of Defense

Locations: Corporal Michael J. Crescenz VA Medical Center and Fox Chase Cancer Center

PROSPECT - Profiling of Resistance Patterns & Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax and Therapeutic Target Identification

This study will use therapeutic target-focused (TTF) profiling, genome-wide mRNA profiling, and assessments of tumor phosphopeptides and DNA that are shed into the bloodstream to define how various molecular factors alone and in combination relate to resistance to therapy, to prognosis, and to metastatic patterns at relapse. This study will examine how the presence of factors that drive cell growth, antagonize apoptosis, or confer resistance in other ways may counter the effect of systemic therapies and/or promote rapid tumor recurrence. In this way, the investigators will identify new, previously unappreciated potential therapeutic targets while also identifying which targets are most likely to increase resistance to therapy and worsen prognosis.

ID: NCT05049837

Sponsor; Collaborators: MD Anderson Cancer Center; US Department of Defense, National Institutes of Health (NIH), and National Cancer Institute (NCI)

Location: MD Anderson Cancer Center

Tribally Engaged Approaches to Lung Screening (TEALS)

Lung cancer is the leading cause of cancer mortality among American Indians and Alaska Natives (AI/AN), and AI/AN have worse lung cancer incidence rates, survival, and death compared to the general population. Because lung cancer screening (LCS) with low-dose computed tomography (LDCT) has been shown to reduce lung cancer mortality by roughly 20%, the US Preventive Services Task Force now recommends LCS for persons aged 55 to 80 years who meet specific eligibility criteria (grade-B evidence), and subsequently the Center for Medicare and Medicaid Services (CMS) opted to cover this test. However, the uptake of LCS implementation has been slow in most health care systems, and LCS implementation among AI/AN has never been studied.

To address this knowledge, the Tribally Engaged Approaches to Lung Screening (TEALS) study, a collaborative effort between the Choctaw Nation of Oklahoma, the Stephenson Cancer Center, and the University of Oklahoma Health Sciences Center, will address the following over the course of 5 years: conduct focus groups and semistructured interviews with Choctaw Nation Health Services Authority (CNHSA) patients, clinicians, and health administrators to elucidate individual- and system-level barriers and facilitators that affect the implementation of LCS; develop an LCS care coordination intervention that will identify eligible persons for LCS, help these patients navigate the screening process, and link them with smoking cessation services, when applicable; measure the impact of the TEALS intervention on the receipt of screening and a set of patient- and practice-level outcomes by conducting a cluster-randomized clinical trial of LCS implementation; and disseminate the TEALS program to other researchers and healthcare systems that serve AI/AN patients. TEALS will bridge the gap between evidence and clinical practice for LCS in a high-need, low-resource setting by intervening at the level of the healthcare system.

System-level interventions for guideline implementation tend to be understudied compared to those evaluating individual-level, behavioral interventions. However, the careful development and evaluation of an LCS screening program at the level of the healthcare system would be critical to ensure that more patients can receive LCS. Our research will create a critically needed platform from which future studies could be launched that will examine how to tailor the application of the LCS guideline to the individual preferences of AI/AN patients. TEALS will establish an effective LCS program in a tribal system and thus provide a direct benefit to the Choctaw Nation by increasing LCS participation. TEALS will serve as a blueprint for establishing a sustainable and accessible infrastructure for LCS in AI/AN and other community health systems. By increasing screening for early stage lung cancer, TEALS could ultimately reduce lung cancer mortality in AI/AN communities.

ID: NCT04948060

Sponsor; Collaborator: University of Oklahoma; Choctaw Nation of Oklahoma

Location: University of Oklahoma Health Sciences Center

Prostate Cancer

18F-DCFPyL PET/CT Impact on Treatment Strategies for Patients With Prostate Cancer (PROSPYL)

The main purpose of this phase II trial study is to determine whether a positron emission tomography (PET)/computed tomography (CT) scan using 18F-DCFPyL affects the clinical management plan in veterans. In this study, the management plan prior to and after 18F-DCFPyL PET/CT will be recorded by specific questionnaires and corresponding changes in management will be analyzed. The scan will be used to see how the disease has spread. Both the treatment strategies and probable disease outcomes as relevant to clinical endpoints will be assessed. This study is open to veterans only.

ID: NCT04390880

Sponsor: VA Greater Los Angeles Healthcare System

Location: VA Greater Los Angeles Healthcare System

Patient Decision-Making About Precision Oncology in Veterans With Advanced Prostate Cancer

This project proposes to understand and improve veterans’ decision-making in precision oncology (germline testing, somatic tumor testing, and targeted therapy) for advanced prostate cancer. As precision oncology expands, a comprehensive strategy to support patient informed decision-making has not been developed.

ID: NCT05396872

Sponsor; Collaborator: University of California, San Francisco; US Department of Defense

Location: San Francisco VA Medical Center

Intramuscular Mechanisms of Androgen Deprivation-Related Sarcopenia

Prostate cancer is the most common cancer among men and is even more common in the military and veteran population. For patients with advanced prostate cancer, the most common treatment includes lowering the levels of the hormone testosterone as much as possible, which is called androgen deprivation therapy (ADT). Unfortunately, ADT also causes patients to be fatigued, weak, and to lose muscle. This is often referred to as sarcopenia, and it leads to falls, poor quality of life, and higher risk of death. Currently, there is no treatment for sarcopenia because investigators do not understand the mechanisms that cause it. The mitochondria is the part of the cells responsible for providing energy to muscles but to date the investigators do not know if it is affected in prostate cancer patients with sarcopenia due to ADT. The overall goal of this proposal is to establish if the mitochondria is responsible for sarcopenia in patients with prostate cancer receiving ADT. The investigators will measure mitochondrial function, muscle mass and strength, and feelings of fatigue and quality of life in patients with prostate cancer before starting and after 6 months of ADT.

ID: NCT03867357

Sponsor; Collaborator: Seattle Institute for Biomedical and Clinical Research; US Department of Defense

Location: VA Puget Sound Health Care System

VA Seamless Phase II/III Randomized Trial of Standard Systemic Therapy With or Without PET-Directed Local Therapy for OligoRecurrent Prostate Cancer (VA STARPORT)

The primary goal of this study is to determine if adding PET-directed local therapy improves disease control compared to standard systemic therapy alone (SST) in veterans with oligorecurrent prostate cancer on PET/CT. The investigators will conduct a multi-institutional phase II/III randomized trial comparing SST with or without PET-directed local therapy using radiation or surgery to all metastases and if a local recurrence is present.

ID: NCT04787744

Sponsor: VA Office of Research and Development

Locations: VA Long Beach Healthcare System, VA Greater Los Angeles Healthcare System, Bay Pines VA Healthcare System, Edward Hines Jr. VA Hospital, Richard L. Roudebush VA Medical Center, VA Boston Healthcare System Jamaica Plain Campus, VA Ann Arbor Healthcare System, Minneapolis VA Health Care System, Kansas City VA Medical Center, St. Louis VA Medical Center John Cochran Division, East Orange Campus of the VA New Jersey Health Care System, Durham VA Medical Center, Louis Stokes VA Medical Center, Michael E. DeBakey VA Medical Center, Hunter Holmes McGuire VA Medical Center, Clement J. Zablocki VA Medical Center

Standard Systemic Therapy With or Without Definitive Treatment in Treating Participants With Metastatic Prostate Cancer

This phase III trial studies how well standard systemic therapy with or without definitive treatment (prostate removal surgery or radiation therapy) works in treating participants with prostate cancer that has spread to other places in the body. The addition of prostate removal surgery or radiation therapy to standard systemic therapy for prostate cancer may lower the chance of the cancer growing or spreading.

ID: NCT03678025

Sponsor; Collaborator: Southwest Oncology Group; National Cancer Institute (NCI)

Locations: 328 sites, including Tibor Rubin VA Medical Center, Atlanta VA Medical Center, James J. Peters VA Medical Center, Michael E. DeBakey VA Medical Center, and Audie L. Murphy VA Hospital

A Clinical Study Evaluating the Benefit of Adding Rucaparib to Enzalutamide for Men With Metastatic Prostate Cancer That Has Become Resistant to Testosterone-Deprivation Therapy (CASPAR)

This randomized, placebo-controlled, phase III trial is evaluating the benefit of rucaparib and enzalutamide combination therapy vs enzalutamide alone for the treatment of men with prostate cancer that has spread to other places in the body (metastatic) and has become resistant to testosterone-deprivation therapy (castration-resistant). Enzalutamide helps fight prostate cancer by blocking the use of testosterone by the tumor cells for growth. Poly adenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitors, such as rucaparib, fight prostate cancer by prevent tumor cells from repairing their DNA. Giving enzalutamide and rucaparib may make patients live longer or prevent their cancer from growing or spreading for a longer time, or both. It may also help doctors learn if a mutation in any of the homologous recombination DNA repair genes is helpful to decide which treatment is best for the patient.

ID: NCT04455750

Sponsor; Collaborator: Alliance for Clinical Trials in Oncology; National Cancer Institute (NCI)

Locations: 413 sites

Digitally Captured Activity Data and PROs to Monitor Physical Function in Prostate Cancer Patients (DigiPRO)

Physical function is a known predictor of quality of life in advanced prostate cancer patients and key measure of treatment tolerability. While treatment with androgen deprivation therapy (ADT) improves survival, it is associated with significant toxicities that lead to physical function (PF) decline. The average age of incident prostate cancer is 66 years, and in this older group of men, chronic comorbid conditions often co-occur with diagnosis, further adding to the risk for PF decline. With over 2.9 million prostate cancer survivors in the US, there is an increasing demand for adequate symptom monitoring and PF assessment throughout cancer care. However, there are currently no validated methods to systematically evaluate and predict PF decline. Thus, the overarching objective of this proposal is to determine whether the use of wearable technology to monitor objective daily activity combined with routine symptom reporting can predict PF decline. To accomplish this, we propose a mixed-methods approach that will provide quantitative information to help identify PC survivors at higher risk for PF decline as well as a qualitative aim gain a deeper understanding of the perceived relationships that PC survivors have with their physical activity levels and treatment symptoms.

ID: NCT04575402

Sponsor; Collaborator: Cedars-Sinai Medical Center; US Department of Defense

Location: Cedars Sinai Medical Center

The BurnAlong Pilot Study for Adolescent and Young Adult Cancer Survivors

The purpose of this prospective, interventional, single-arm pilot study is to evaluate whether virtually delivered group-based physical activity is feasible for adolescent and young adult (AYA) cancer survivors. AYAs who were diagnosed with cancer and have completed cancer treatment will be recruited for this study. This study will enroll 20 participants in total and will last approximately 3 months.

ID: NCT05131815

Sponsor; Collaborator: Cedars-Sinai Medical Center; Walter Reed National Military Medical Center

Location: Cedars-Sinai Medical Center

Lung Cancer

DECAMP 1 PLUS: Prediction of Lung Cancer Using Noninvasive Biomarkers

The Detection of Early lung Cancer Among Military Personnel (DECAMP) consortium is a multidisciplinary and translational research program for lung cancer early detection. DECAMP 1 PLUS aims to improve the efficiency of the diagnostic evaluation of patients with indeterminate pulmonary nodules (8-25 mm). Molecular biomarkers for lung cancer diagnosis measured in minimally invasive and noninvasive biospecimens may be able to distinguish between malignant or benign indeterminate pulmonary nodules in high-risk smokers. Ultimately, this study aims to validate molecular as well as clinical and imaging biomarkers of lung cancer in individuals with indeterminate lung nodules.

ID: NCT04165564

Sponsor: Boston University

Locations: 3 VA medical centers (VA Greater LA Healthcare System, VA Boston Healthcare System, and VA Tennessee Valley Healthcare System), 3 military treatment facilities (Naval Medical Center San Diego, Walter Reed National Military Medical Center, and Naval Medical Center Portsmouth) and 12 academic hospitals

DECAMP-2: Screening of Patients With Early Stage Lung Cancer or at High Risk for Developing Lung Cancer (DECAMP-2)

The goal of this project is to improve lung cancer screening in high-risk individuals by identifying biomarkers of preclinical disease and disease risk that are measured in minimally invasive and noninvasive biospecimens. Existing biomarkers for lung cancer diagnosis as well as new biomarkers discovered specifically in this clinical setting will be examined. Biomarkers that identify individuals at highest risk for being diagnosed with lung cancer prior to the appearance of concerning symptoms could increase the utility of lung cancer surveillance and the efficiency of lung cancer chemoprevention clinical trials. Achieving these goals would improve the detection and treatment of early-stage and incipient lung cancer, while restricting the risk of these procedures to those individuals who currently exhibit the early molecular warning signs of impending disease.

ID: NCT02504697

Sponsor: Boston University

Locations: VA medical centers (including Los Angeles VA Healthcare System, Boston VA Research Institute, Inc, Philadelphia VA Medical Center, Veterans Research Foundation of Pittsburgh, and VA North Texas Health Care System), 4 military treatment facilities (Naval Medical Center San Diego, Walter Reed National Military Medical Center, San Antonio Military Medical Center, and Naval Medical Center Portsmouth), and 4 academic hospitals

Improving Decision-Making Encounters in Lung Cancer Using a Low-Literacy Conversation Tool (iDECIDE)

This clinical trial evaluates the effectiveness of a conversation tool on patient-centered health and decision-making outcomes in patients with lung cancer making treatment decisions. This research is being conducted to help doctors understand the information patients need to participate in shared decision-making about their lung cancer treatment options. The focus of this research is to study how patients choose lung cancer treatment options and the information needed to make that choice, with a focus on patients with lower health literacy.

ID: NCT05407168

Sponsor: Oregon Health & Science University Knight Cancer Institute

Locations: Portland VA Medical Center and Oregon Health & Science University Knight Cancer Institute

VA Lung Cancer Surgery or Stereotactic Radiotherapy (VALOR)

The standard of care for stage I non–small cell lung cancer has historically been surgical resection in patients who are medically fit to tolerate an operation. Recent data now suggest that stereotactic radiotherapy may be a suitable alternative. This includes the results from a pooled analysis of 2 incomplete phase III studies that reported a 15% overall survival advantage with stereotactic radiotherapy at 3 years. While these data are promising, the median follow-up period was short, the results underpowered, and the findings were in contradiction to multiple retrospective studies that demonstrate the outcomes with surgery are likely equal or superior. Therefore, the herein trial aims to evaluate these 2 treatments in a prospective randomized fashion with a goal to compare the overall survival beyond 5 years. It has been designed to enroll patients who have a long life expectancy and are fit enough to tolerate an anatomic pulmonary resection with intraoperative lymph node sampling.

This study is designed to open at VA medical centers with expertise in both treatments. The recruitment process includes shared decision making and multidisciplinary evaluations with lung cancer specialists. Mandatory evaluations before randomization include tissue confirmation of NSCLC, staging with FDG-PET/CT, and biopsies of all hilar and/or mediastinal lymph nodes > 10 mm that have a SUV > 2.5. Prerandomization elective lymph node sampling is strongly encouraged, but not required. Following treatment, patients will be followed for a minimum of 5 years.

ID: NCT02984761

Sponsor: VA Office of Research and Development

Locations: 17 VA medical centers, including VA Long Beach Healthcare System, VA Greater Los Angeles Healthcare System, Bay Pines VA Healthcare System, Miami VA Healthcare System, Edward Hines Jr. VA Hospital, Richard L. Roudebush VA Medical Center, Baltimore VA Medical Center, VA Boston Healthcare System Jamaica Plain Campus, VA Ann Arbor Healthcare System, Minneapolis VA Health Care System, Durham VA Medical Center, Louis Stokes VA Medical Center, Corporal Micheal J. Crescenz VA Medical Center, VA Pittsburgh Healthcare System University Drive Division, Michael E. DeBakey VA Medical Center, Hunter Holmes McGuire VA Medical Center, and Clement J. Zablocki VA Medical Center

Utility of CAML as Diagnostic for Early Stage Lung Cancer

The primary objective of this study is to determine the prevalence of cancer associated macrophage-like cells (CAMLS) in patients with pulmonary nodules. Secondary objectives include the following: determine the positive and negative predictive value of CAMLS in patients with pulmonary nodules who undergo biopsy; model combinations of clinical factors with the presence/absence of CAMLS to refine strategies for assessment of patients with pulmonary nodules; and evaluate whether these measures result in enhanced T-cell activity and/or natural killer cell function and number.

ID: NCT03992183

Sponsor; Collaborators: Fox Chase Cancer Center; US Department of Defense

Locations: Corporal Michael J. Crescenz VA Medical Center and Fox Chase Cancer Center

PROSPECT - Profiling of Resistance Patterns & Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax and Therapeutic Target Identification

This study will use therapeutic target-focused (TTF) profiling, genome-wide mRNA profiling, and assessments of tumor phosphopeptides and DNA that are shed into the bloodstream to define how various molecular factors alone and in combination relate to resistance to therapy, to prognosis, and to metastatic patterns at relapse. This study will examine how the presence of factors that drive cell growth, antagonize apoptosis, or confer resistance in other ways may counter the effect of systemic therapies and/or promote rapid tumor recurrence. In this way, the investigators will identify new, previously unappreciated potential therapeutic targets while also identifying which targets are most likely to increase resistance to therapy and worsen prognosis.

ID: NCT05049837

Sponsor; Collaborators: MD Anderson Cancer Center; US Department of Defense, National Institutes of Health (NIH), and National Cancer Institute (NCI)

Location: MD Anderson Cancer Center

Tribally Engaged Approaches to Lung Screening (TEALS)

Lung cancer is the leading cause of cancer mortality among American Indians and Alaska Natives (AI/AN), and AI/AN have worse lung cancer incidence rates, survival, and death compared to the general population. Because lung cancer screening (LCS) with low-dose computed tomography (LDCT) has been shown to reduce lung cancer mortality by roughly 20%, the US Preventive Services Task Force now recommends LCS for persons aged 55 to 80 years who meet specific eligibility criteria (grade-B evidence), and subsequently the Center for Medicare and Medicaid Services (CMS) opted to cover this test. However, the uptake of LCS implementation has been slow in most health care systems, and LCS implementation among AI/AN has never been studied.

To address this knowledge, the Tribally Engaged Approaches to Lung Screening (TEALS) study, a collaborative effort between the Choctaw Nation of Oklahoma, the Stephenson Cancer Center, and the University of Oklahoma Health Sciences Center, will address the following over the course of 5 years: conduct focus groups and semistructured interviews with Choctaw Nation Health Services Authority (CNHSA) patients, clinicians, and health administrators to elucidate individual- and system-level barriers and facilitators that affect the implementation of LCS; develop an LCS care coordination intervention that will identify eligible persons for LCS, help these patients navigate the screening process, and link them with smoking cessation services, when applicable; measure the impact of the TEALS intervention on the receipt of screening and a set of patient- and practice-level outcomes by conducting a cluster-randomized clinical trial of LCS implementation; and disseminate the TEALS program to other researchers and healthcare systems that serve AI/AN patients. TEALS will bridge the gap between evidence and clinical practice for LCS in a high-need, low-resource setting by intervening at the level of the healthcare system.

System-level interventions for guideline implementation tend to be understudied compared to those evaluating individual-level, behavioral interventions. However, the careful development and evaluation of an LCS screening program at the level of the healthcare system would be critical to ensure that more patients can receive LCS. Our research will create a critically needed platform from which future studies could be launched that will examine how to tailor the application of the LCS guideline to the individual preferences of AI/AN patients. TEALS will establish an effective LCS program in a tribal system and thus provide a direct benefit to the Choctaw Nation by increasing LCS participation. TEALS will serve as a blueprint for establishing a sustainable and accessible infrastructure for LCS in AI/AN and other community health systems. By increasing screening for early stage lung cancer, TEALS could ultimately reduce lung cancer mortality in AI/AN communities.

ID: NCT04948060

Sponsor; Collaborator: University of Oklahoma; Choctaw Nation of Oklahoma

Location: University of Oklahoma Health Sciences Center

Prostate Cancer

18F-DCFPyL PET/CT Impact on Treatment Strategies for Patients With Prostate Cancer (PROSPYL)

The main purpose of this phase II trial study is to determine whether a positron emission tomography (PET)/computed tomography (CT) scan using 18F-DCFPyL affects the clinical management plan in veterans. In this study, the management plan prior to and after 18F-DCFPyL PET/CT will be recorded by specific questionnaires and corresponding changes in management will be analyzed. The scan will be used to see how the disease has spread. Both the treatment strategies and probable disease outcomes as relevant to clinical endpoints will be assessed. This study is open to veterans only.

ID: NCT04390880

Sponsor: VA Greater Los Angeles Healthcare System

Location: VA Greater Los Angeles Healthcare System

Patient Decision-Making About Precision Oncology in Veterans With Advanced Prostate Cancer

This project proposes to understand and improve veterans’ decision-making in precision oncology (germline testing, somatic tumor testing, and targeted therapy) for advanced prostate cancer. As precision oncology expands, a comprehensive strategy to support patient informed decision-making has not been developed.

ID: NCT05396872

Sponsor; Collaborator: University of California, San Francisco; US Department of Defense

Location: San Francisco VA Medical Center

Intramuscular Mechanisms of Androgen Deprivation-Related Sarcopenia

Prostate cancer is the most common cancer among men and is even more common in the military and veteran population. For patients with advanced prostate cancer, the most common treatment includes lowering the levels of the hormone testosterone as much as possible, which is called androgen deprivation therapy (ADT). Unfortunately, ADT also causes patients to be fatigued, weak, and to lose muscle. This is often referred to as sarcopenia, and it leads to falls, poor quality of life, and higher risk of death. Currently, there is no treatment for sarcopenia because investigators do not understand the mechanisms that cause it. The mitochondria is the part of the cells responsible for providing energy to muscles but to date the investigators do not know if it is affected in prostate cancer patients with sarcopenia due to ADT. The overall goal of this proposal is to establish if the mitochondria is responsible for sarcopenia in patients with prostate cancer receiving ADT. The investigators will measure mitochondrial function, muscle mass and strength, and feelings of fatigue and quality of life in patients with prostate cancer before starting and after 6 months of ADT.

ID: NCT03867357

Sponsor; Collaborator: Seattle Institute for Biomedical and Clinical Research; US Department of Defense

Location: VA Puget Sound Health Care System

VA Seamless Phase II/III Randomized Trial of Standard Systemic Therapy With or Without PET-Directed Local Therapy for OligoRecurrent Prostate Cancer (VA STARPORT)

The primary goal of this study is to determine if adding PET-directed local therapy improves disease control compared to standard systemic therapy alone (SST) in veterans with oligorecurrent prostate cancer on PET/CT. The investigators will conduct a multi-institutional phase II/III randomized trial comparing SST with or without PET-directed local therapy using radiation or surgery to all metastases and if a local recurrence is present.

ID: NCT04787744

Sponsor: VA Office of Research and Development

Locations: VA Long Beach Healthcare System, VA Greater Los Angeles Healthcare System, Bay Pines VA Healthcare System, Edward Hines Jr. VA Hospital, Richard L. Roudebush VA Medical Center, VA Boston Healthcare System Jamaica Plain Campus, VA Ann Arbor Healthcare System, Minneapolis VA Health Care System, Kansas City VA Medical Center, St. Louis VA Medical Center John Cochran Division, East Orange Campus of the VA New Jersey Health Care System, Durham VA Medical Center, Louis Stokes VA Medical Center, Michael E. DeBakey VA Medical Center, Hunter Holmes McGuire VA Medical Center, Clement J. Zablocki VA Medical Center

Standard Systemic Therapy With or Without Definitive Treatment in Treating Participants With Metastatic Prostate Cancer

This phase III trial studies how well standard systemic therapy with or without definitive treatment (prostate removal surgery or radiation therapy) works in treating participants with prostate cancer that has spread to other places in the body. The addition of prostate removal surgery or radiation therapy to standard systemic therapy for prostate cancer may lower the chance of the cancer growing or spreading.

ID: NCT03678025

Sponsor; Collaborator: Southwest Oncology Group; National Cancer Institute (NCI)

Locations: 328 sites, including Tibor Rubin VA Medical Center, Atlanta VA Medical Center, James J. Peters VA Medical Center, Michael E. DeBakey VA Medical Center, and Audie L. Murphy VA Hospital

A Clinical Study Evaluating the Benefit of Adding Rucaparib to Enzalutamide for Men With Metastatic Prostate Cancer That Has Become Resistant to Testosterone-Deprivation Therapy (CASPAR)

This randomized, placebo-controlled, phase III trial is evaluating the benefit of rucaparib and enzalutamide combination therapy vs enzalutamide alone for the treatment of men with prostate cancer that has spread to other places in the body (metastatic) and has become resistant to testosterone-deprivation therapy (castration-resistant). Enzalutamide helps fight prostate cancer by blocking the use of testosterone by the tumor cells for growth. Poly adenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitors, such as rucaparib, fight prostate cancer by prevent tumor cells from repairing their DNA. Giving enzalutamide and rucaparib may make patients live longer or prevent their cancer from growing or spreading for a longer time, or both. It may also help doctors learn if a mutation in any of the homologous recombination DNA repair genes is helpful to decide which treatment is best for the patient.

ID: NCT04455750

Sponsor; Collaborator: Alliance for Clinical Trials in Oncology; National Cancer Institute (NCI)

Locations: 413 sites

Digitally Captured Activity Data and PROs to Monitor Physical Function in Prostate Cancer Patients (DigiPRO)

Physical function is a known predictor of quality of life in advanced prostate cancer patients and key measure of treatment tolerability. While treatment with androgen deprivation therapy (ADT) improves survival, it is associated with significant toxicities that lead to physical function (PF) decline. The average age of incident prostate cancer is 66 years, and in this older group of men, chronic comorbid conditions often co-occur with diagnosis, further adding to the risk for PF decline. With over 2.9 million prostate cancer survivors in the US, there is an increasing demand for adequate symptom monitoring and PF assessment throughout cancer care. However, there are currently no validated methods to systematically evaluate and predict PF decline. Thus, the overarching objective of this proposal is to determine whether the use of wearable technology to monitor objective daily activity combined with routine symptom reporting can predict PF decline. To accomplish this, we propose a mixed-methods approach that will provide quantitative information to help identify PC survivors at higher risk for PF decline as well as a qualitative aim gain a deeper understanding of the perceived relationships that PC survivors have with their physical activity levels and treatment symptoms.

ID: NCT04575402

Sponsor; Collaborator: Cedars-Sinai Medical Center; US Department of Defense

Location: Cedars Sinai Medical Center

The BurnAlong Pilot Study for Adolescent and Young Adult Cancer Survivors

The purpose of this prospective, interventional, single-arm pilot study is to evaluate whether virtually delivered group-based physical activity is feasible for adolescent and young adult (AYA) cancer survivors. AYAs who were diagnosed with cancer and have completed cancer treatment will be recruited for this study. This study will enroll 20 participants in total and will last approximately 3 months.

ID: NCT05131815

Sponsor; Collaborator: Cedars-Sinai Medical Center; Walter Reed National Military Medical Center

Location: Cedars-Sinai Medical Center

Lung Cancer

DECAMP 1 PLUS: Prediction of Lung Cancer Using Noninvasive Biomarkers

The Detection of Early lung Cancer Among Military Personnel (DECAMP) consortium is a multidisciplinary and translational research program for lung cancer early detection. DECAMP 1 PLUS aims to improve the efficiency of the diagnostic evaluation of patients with indeterminate pulmonary nodules (8-25 mm). Molecular biomarkers for lung cancer diagnosis measured in minimally invasive and noninvasive biospecimens may be able to distinguish between malignant or benign indeterminate pulmonary nodules in high-risk smokers. Ultimately, this study aims to validate molecular as well as clinical and imaging biomarkers of lung cancer in individuals with indeterminate lung nodules.

ID: NCT04165564

Sponsor: Boston University

Locations: 3 VA medical centers (VA Greater LA Healthcare System, VA Boston Healthcare System, and VA Tennessee Valley Healthcare System), 3 military treatment facilities (Naval Medical Center San Diego, Walter Reed National Military Medical Center, and Naval Medical Center Portsmouth) and 12 academic hospitals

DECAMP-2: Screening of Patients With Early Stage Lung Cancer or at High Risk for Developing Lung Cancer (DECAMP-2)

The goal of this project is to improve lung cancer screening in high-risk individuals by identifying biomarkers of preclinical disease and disease risk that are measured in minimally invasive and noninvasive biospecimens. Existing biomarkers for lung cancer diagnosis as well as new biomarkers discovered specifically in this clinical setting will be examined. Biomarkers that identify individuals at highest risk for being diagnosed with lung cancer prior to the appearance of concerning symptoms could increase the utility of lung cancer surveillance and the efficiency of lung cancer chemoprevention clinical trials. Achieving these goals would improve the detection and treatment of early-stage and incipient lung cancer, while restricting the risk of these procedures to those individuals who currently exhibit the early molecular warning signs of impending disease.

ID: NCT02504697

Sponsor: Boston University

Locations: VA medical centers (including Los Angeles VA Healthcare System, Boston VA Research Institute, Inc, Philadelphia VA Medical Center, Veterans Research Foundation of Pittsburgh, and VA North Texas Health Care System), 4 military treatment facilities (Naval Medical Center San Diego, Walter Reed National Military Medical Center, San Antonio Military Medical Center, and Naval Medical Center Portsmouth), and 4 academic hospitals

Improving Decision-Making Encounters in Lung Cancer Using a Low-Literacy Conversation Tool (iDECIDE)

This clinical trial evaluates the effectiveness of a conversation tool on patient-centered health and decision-making outcomes in patients with lung cancer making treatment decisions. This research is being conducted to help doctors understand the information patients need to participate in shared decision-making about their lung cancer treatment options. The focus of this research is to study how patients choose lung cancer treatment options and the information needed to make that choice, with a focus on patients with lower health literacy.

ID: NCT05407168

Sponsor: Oregon Health & Science University Knight Cancer Institute

Locations: Portland VA Medical Center and Oregon Health & Science University Knight Cancer Institute

VA Lung Cancer Surgery or Stereotactic Radiotherapy (VALOR)

The standard of care for stage I non–small cell lung cancer has historically been surgical resection in patients who are medically fit to tolerate an operation. Recent data now suggest that stereotactic radiotherapy may be a suitable alternative. This includes the results from a pooled analysis of 2 incomplete phase III studies that reported a 15% overall survival advantage with stereotactic radiotherapy at 3 years. While these data are promising, the median follow-up period was short, the results underpowered, and the findings were in contradiction to multiple retrospective studies that demonstrate the outcomes with surgery are likely equal or superior. Therefore, the herein trial aims to evaluate these 2 treatments in a prospective randomized fashion with a goal to compare the overall survival beyond 5 years. It has been designed to enroll patients who have a long life expectancy and are fit enough to tolerate an anatomic pulmonary resection with intraoperative lymph node sampling.

This study is designed to open at VA medical centers with expertise in both treatments. The recruitment process includes shared decision making and multidisciplinary evaluations with lung cancer specialists. Mandatory evaluations before randomization include tissue confirmation of NSCLC, staging with FDG-PET/CT, and biopsies of all hilar and/or mediastinal lymph nodes > 10 mm that have a SUV > 2.5. Prerandomization elective lymph node sampling is strongly encouraged, but not required. Following treatment, patients will be followed for a minimum of 5 years.

ID: NCT02984761

Sponsor: VA Office of Research and Development

Locations: 17 VA medical centers, including VA Long Beach Healthcare System, VA Greater Los Angeles Healthcare System, Bay Pines VA Healthcare System, Miami VA Healthcare System, Edward Hines Jr. VA Hospital, Richard L. Roudebush VA Medical Center, Baltimore VA Medical Center, VA Boston Healthcare System Jamaica Plain Campus, VA Ann Arbor Healthcare System, Minneapolis VA Health Care System, Durham VA Medical Center, Louis Stokes VA Medical Center, Corporal Micheal J. Crescenz VA Medical Center, VA Pittsburgh Healthcare System University Drive Division, Michael E. DeBakey VA Medical Center, Hunter Holmes McGuire VA Medical Center, and Clement J. Zablocki VA Medical Center

Utility of CAML as Diagnostic for Early Stage Lung Cancer

The primary objective of this study is to determine the prevalence of cancer associated macrophage-like cells (CAMLS) in patients with pulmonary nodules. Secondary objectives include the following: determine the positive and negative predictive value of CAMLS in patients with pulmonary nodules who undergo biopsy; model combinations of clinical factors with the presence/absence of CAMLS to refine strategies for assessment of patients with pulmonary nodules; and evaluate whether these measures result in enhanced T-cell activity and/or natural killer cell function and number.

ID: NCT03992183

Sponsor; Collaborators: Fox Chase Cancer Center; US Department of Defense

Locations: Corporal Michael J. Crescenz VA Medical Center and Fox Chase Cancer Center

PROSPECT - Profiling of Resistance Patterns & Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax and Therapeutic Target Identification

This study will use therapeutic target-focused (TTF) profiling, genome-wide mRNA profiling, and assessments of tumor phosphopeptides and DNA that are shed into the bloodstream to define how various molecular factors alone and in combination relate to resistance to therapy, to prognosis, and to metastatic patterns at relapse. This study will examine how the presence of factors that drive cell growth, antagonize apoptosis, or confer resistance in other ways may counter the effect of systemic therapies and/or promote rapid tumor recurrence. In this way, the investigators will identify new, previously unappreciated potential therapeutic targets while also identifying which targets are most likely to increase resistance to therapy and worsen prognosis.

ID: NCT05049837

Sponsor; Collaborators: MD Anderson Cancer Center; US Department of Defense, National Institutes of Health (NIH), and National Cancer Institute (NCI)

Location: MD Anderson Cancer Center

Tribally Engaged Approaches to Lung Screening (TEALS)

Lung cancer is the leading cause of cancer mortality among American Indians and Alaska Natives (AI/AN), and AI/AN have worse lung cancer incidence rates, survival, and death compared to the general population. Because lung cancer screening (LCS) with low-dose computed tomography (LDCT) has been shown to reduce lung cancer mortality by roughly 20%, the US Preventive Services Task Force now recommends LCS for persons aged 55 to 80 years who meet specific eligibility criteria (grade-B evidence), and subsequently the Center for Medicare and Medicaid Services (CMS) opted to cover this test. However, the uptake of LCS implementation has been slow in most health care systems, and LCS implementation among AI/AN has never been studied.

To address this knowledge, the Tribally Engaged Approaches to Lung Screening (TEALS) study, a collaborative effort between the Choctaw Nation of Oklahoma, the Stephenson Cancer Center, and the University of Oklahoma Health Sciences Center, will address the following over the course of 5 years: conduct focus groups and semistructured interviews with Choctaw Nation Health Services Authority (CNHSA) patients, clinicians, and health administrators to elucidate individual- and system-level barriers and facilitators that affect the implementation of LCS; develop an LCS care coordination intervention that will identify eligible persons for LCS, help these patients navigate the screening process, and link them with smoking cessation services, when applicable; measure the impact of the TEALS intervention on the receipt of screening and a set of patient- and practice-level outcomes by conducting a cluster-randomized clinical trial of LCS implementation; and disseminate the TEALS program to other researchers and healthcare systems that serve AI/AN patients. TEALS will bridge the gap between evidence and clinical practice for LCS in a high-need, low-resource setting by intervening at the level of the healthcare system.

System-level interventions for guideline implementation tend to be understudied compared to those evaluating individual-level, behavioral interventions. However, the careful development and evaluation of an LCS screening program at the level of the healthcare system would be critical to ensure that more patients can receive LCS. Our research will create a critically needed platform from which future studies could be launched that will examine how to tailor the application of the LCS guideline to the individual preferences of AI/AN patients. TEALS will establish an effective LCS program in a tribal system and thus provide a direct benefit to the Choctaw Nation by increasing LCS participation. TEALS will serve as a blueprint for establishing a sustainable and accessible infrastructure for LCS in AI/AN and other community health systems. By increasing screening for early stage lung cancer, TEALS could ultimately reduce lung cancer mortality in AI/AN communities.

ID: NCT04948060

Sponsor; Collaborator: University of Oklahoma; Choctaw Nation of Oklahoma

Location: University of Oklahoma Health Sciences Center