TOPLINE:

In 2020, U.S. counties that were without psychiatric care or broadband coverage had significantly more drug overdose deaths and completed suicides, compared with other counties, new research shows.

METHODOLOGY:

• In the United States, there is a severe lack of psychiatrists and access to mental health care. In 2019, 21.3 million U.S. residents were without broadband access. These patients were forced either to use telephone consultation or to not use telehealth services at all, although use of telehealth during COVID-19 somewhat improved access to psychiatric care.
• For the study, researchers gathered sociodemographic and other county-level information from the American Community Survey. They also used data on the psychiatrist workforce from the Health Resources and Services Administration (HRSA) Area Health Resources Files.
• Information on broadband Internet coverage came from the Federal Communications Commission, and measures of mental health outcomes were from the Centers for Disease Control and Prevention.

TAKEAWAY:

• The study identified 596 counties (19% of all U.S. counties) that were without psychiatrists and in which there was inadequate broadband coverage. The population represented 10.5 million residents.
• Compared with other counties, those with lack of coverage were more likely to be rural (adjusted odds ratio, 3.05; 95% confidence interval, 2.41-3.84), to have higher unemployment (aOR, 1.12; 95% CI, 1.02-1.24), and to have higher uninsurance rates (aOR, 1.03; 95% CI, 1.00-1.06). In those counties, there were also fewer residents with a bachelor’s degree (aOR, 0.92; 95% CI, 0.90-0.94) and fewer Hispanics (aOR 0.98; 95% CI, 0.97-0.99), although those counties were not designated by the HRSA as having a psychiatrist shortage. That designation brings additional funding for the recruitment of clinicians.
• After adjustment for sociodemographic factors, counties without psychiatrists and broadband had significantly higher rates of adult depression, frequent mental distress, drug overdose mortality, and completed suicide, compared with other counties.
• Further analysis showed that the adjusted difference remained statistically significant for drug overdose mortality per 100,000 (9.2; 95% CI, 8.0-10.5, vs. 5.2; 95% CI, 4.9-5.6; P < .001) and completed suicide (10.6; 95% CI, 8.9-12.3, vs. 7.6; 95% CI, 7.0-8.2; P < .001), but not for the other two measures.

IN PRACTICE:

“Our finding suggests that lacking access to virtual and in-person psychiatric care continues to be a key factor associated with adverse outcomes,” the investigators write. They note that federal and state-level investments in broadband and the psychiatric workforce are needed.

SOURCE:

The study was conducted by Tarun Ramesh, BS, department of population medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, and colleagues. It was published online as a research letter in JAMA Network Open.

LIMITATIONS:

The investigators did not consider whether recent legislation, including the Consolidated Appropriations Act of 2021 and the American Rescue Plan, which expanded psychiatry residency slots and broadband infrastructure, reduces adverse outcomes, something the authors say future research should examine.

DISCLOSURES:

The study received support from the National Institutes of Health, including the National Institute on Minority Health and Health Disparities and the National Institute of Mental Health. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

TOPLINE:

In 2020, U.S. counties that were without psychiatric care or broadband coverage had significantly more drug overdose deaths and completed suicides, compared with other counties, new research shows.

METHODOLOGY:

• In the United States, there is a severe lack of psychiatrists and access to mental health care. In 2019, 21.3 million U.S. residents were without broadband access. These patients were forced either to use telephone consultation or to not use telehealth services at all, although use of telehealth during COVID-19 somewhat improved access to psychiatric care.
• For the study, researchers gathered sociodemographic and other county-level information from the American Community Survey. They also used data on the psychiatrist workforce from the Health Resources and Services Administration (HRSA) Area Health Resources Files.
• Information on broadband Internet coverage came from the Federal Communications Commission, and measures of mental health outcomes were from the Centers for Disease Control and Prevention.

TAKEAWAY:

• The study identified 596 counties (19% of all U.S. counties) that were without psychiatrists and in which there was inadequate broadband coverage. The population represented 10.5 million residents.
• Compared with other counties, those with lack of coverage were more likely to be rural (adjusted odds ratio, 3.05; 95% confidence interval, 2.41-3.84), to have higher unemployment (aOR, 1.12; 95% CI, 1.02-1.24), and to have higher uninsurance rates (aOR, 1.03; 95% CI, 1.00-1.06). In those counties, there were also fewer residents with a bachelor’s degree (aOR, 0.92; 95% CI, 0.90-0.94) and fewer Hispanics (aOR 0.98; 95% CI, 0.97-0.99), although those counties were not designated by the HRSA as having a psychiatrist shortage. That designation brings additional funding for the recruitment of clinicians.
• After adjustment for sociodemographic factors, counties without psychiatrists and broadband had significantly higher rates of adult depression, frequent mental distress, drug overdose mortality, and completed suicide, compared with other counties.
• Further analysis showed that the adjusted difference remained statistically significant for drug overdose mortality per 100,000 (9.2; 95% CI, 8.0-10.5, vs. 5.2; 95% CI, 4.9-5.6; P < .001) and completed suicide (10.6; 95% CI, 8.9-12.3, vs. 7.6; 95% CI, 7.0-8.2; P < .001), but not for the other two measures.

IN PRACTICE:

“Our finding suggests that lacking access to virtual and in-person psychiatric care continues to be a key factor associated with adverse outcomes,” the investigators write. They note that federal and state-level investments in broadband and the psychiatric workforce are needed.

SOURCE:

The study was conducted by Tarun Ramesh, BS, department of population medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, and colleagues. It was published online as a research letter in JAMA Network Open.

LIMITATIONS:

The investigators did not consider whether recent legislation, including the Consolidated Appropriations Act of 2021 and the American Rescue Plan, which expanded psychiatry residency slots and broadband infrastructure, reduces adverse outcomes, something the authors say future research should examine.

DISCLOSURES:

The study received support from the National Institutes of Health, including the National Institute on Minority Health and Health Disparities and the National Institute of Mental Health. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

TOPLINE:

In 2020, U.S. counties that were without psychiatric care or broadband coverage had significantly more drug overdose deaths and completed suicides, compared with other counties, new research shows.

METHODOLOGY:

• In the United States, there is a severe lack of psychiatrists and access to mental health care. In 2019, 21.3 million U.S. residents were without broadband access. These patients were forced either to use telephone consultation or to not use telehealth services at all, although use of telehealth during COVID-19 somewhat improved access to psychiatric care.
• For the study, researchers gathered sociodemographic and other county-level information from the American Community Survey. They also used data on the psychiatrist workforce from the Health Resources and Services Administration (HRSA) Area Health Resources Files.
• Information on broadband Internet coverage came from the Federal Communications Commission, and measures of mental health outcomes were from the Centers for Disease Control and Prevention.

TAKEAWAY:

• The study identified 596 counties (19% of all U.S. counties) that were without psychiatrists and in which there was inadequate broadband coverage. The population represented 10.5 million residents.
• Compared with other counties, those with lack of coverage were more likely to be rural (adjusted odds ratio, 3.05; 95% confidence interval, 2.41-3.84), to have higher unemployment (aOR, 1.12; 95% CI, 1.02-1.24), and to have higher uninsurance rates (aOR, 1.03; 95% CI, 1.00-1.06). In those counties, there were also fewer residents with a bachelor’s degree (aOR, 0.92; 95% CI, 0.90-0.94) and fewer Hispanics (aOR 0.98; 95% CI, 0.97-0.99), although those counties were not designated by the HRSA as having a psychiatrist shortage. That designation brings additional funding for the recruitment of clinicians.
• After adjustment for sociodemographic factors, counties without psychiatrists and broadband had significantly higher rates of adult depression, frequent mental distress, drug overdose mortality, and completed suicide, compared with other counties.
• Further analysis showed that the adjusted difference remained statistically significant for drug overdose mortality per 100,000 (9.2; 95% CI, 8.0-10.5, vs. 5.2; 95% CI, 4.9-5.6; P < .001) and completed suicide (10.6; 95% CI, 8.9-12.3, vs. 7.6; 95% CI, 7.0-8.2; P < .001), but not for the other two measures.

IN PRACTICE:

“Our finding suggests that lacking access to virtual and in-person psychiatric care continues to be a key factor associated with adverse outcomes,” the investigators write. They note that federal and state-level investments in broadband and the psychiatric workforce are needed.

SOURCE:

The study was conducted by Tarun Ramesh, BS, department of population medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, and colleagues. It was published online as a research letter in JAMA Network Open.

LIMITATIONS:

The investigators did not consider whether recent legislation, including the Consolidated Appropriations Act of 2021 and the American Rescue Plan, which expanded psychiatry residency slots and broadband infrastructure, reduces adverse outcomes, something the authors say future research should examine.

DISCLOSURES:

The study received support from the National Institutes of Health, including the National Institute on Minority Health and Health Disparities and the National Institute of Mental Health. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The American College of Physicians has issued an updated version of its living, rapid practice point guideline on the best treatment options for outpatients with confirmed COVID-19 in the era of the dominant Omicron variant of SARS-CoV-2. The recommendations in version 2 apply to persons presenting with mild to moderate infection and symptom onset in the past 5 days who are at high risk for progression to severe disease and potential hospitalization or death.

Version 1 appeared in late 2022.

While outpatient management is appropriate for most patients, treatment should be personalized and based on careful risk stratification and informed decision-making, said the guideline authors, led by Amir Qaseem, MD, PhD, MHA, vice president of clinical policy and the Center for Evidence Reviews at the ACP in Philadelphia.
 

Practice points

• Consider the oral antivirals nirmatrelvir-ritonavir (Paxlovid) or molnupiravir (Lagevrio) for symptomatic outpatients with confirmed mild to moderate COVID-19 who are within 5 days of the onset of symptoms and at high risk for progressing to severe disease.

New evidence for the Omicron variant suggests a possible net benefit of the antiviral molnupiravir versus standard or no treatment in terms of reducing recovery time if treatment is initiated within 5 days of symptom onset. Nirmatrelvir-ritonavir was associated with reductions in COVID-19 hospitalization and all-cause mortality.

“The practice points only address [whether] treatments work compared to placebo, no treatment, or usual care,” cautioned Linda L. Humphrey, MD, MPH, MACP, chair of the ACP’s Population Health and Medical Science Committee and a professor of medicine at Oregon Health and Science University VA Portland Health Care System. The ACP continues to monitor the evidence. “Once enough evidence has emerged, it will be possible to compare treatments to each other. Until that time we are unable to determine if there is an advantage to using one treatment over another.”

• Do not use the antiparasitic ivermectin (Stromectol) or the monoclonal antibody sotrovimab (Xevudy) to treat this patient population. “It is not expected to be effective against the Omicron variant,” Dr. Humphrey said.

There was no evidence to support the use of medications such as corticosteroids, antibiotics, antihistamines, SSRIs, and multiple other agents.

“The guideline is not a departure from previous knowledge and reflects what appears in other guidelines and is already being done generally in practice,” said Mirella Salvatore, MD, an associate professor of medicine and population health sciences at Weill Cornell Medicine, New York, who was not involved in the ACP statement. It is therefore unlikely the recommendations will trigger controversy or negative feedback, added Dr. Salvatore, who is also a spokesperson for the Infectious Diseases Society of America. “We believe that our evidence-based approach, which considers the balance of benefits and harms of various treatments, will be embraced by the physician community,” Dr. Humphrey said.

The updated recommendations are based on new data from the evidence review of multiple treatments, which concluded that both nirmatrelvir-ritonavir and molnupiravir likely improve outcomes for outpatients with mild to moderate COVID-19. The review was conducted after the emergence of the Omicron variant by the ACP Center for Evidence Reviews at Cochrane Austria/University for Continuing Education Krems (Austria).


 

Review details

Inclusion criteria were modified to focus on the Omicron variant by limiting eligible studies to only those enrolling patients on or after Nov. 26, 2021. The investigators included two randomized controlled trials and six retrospective cohort studies and ranked quality of evidence for the effectiveness of the following treatments, compared with usual care or no treatment: azithromycin, camostat mesylate, chloroquine-hydroxychloroquine, chlorpheniramine, colchicine, convalescent plasma, corticosteroids, ensitrelvir, favipiravir, fluvoxamine, ivermectin, lopinavir-ritonavir, molnupiravir, neutralizing monoclonal antibodies, metformin, niclosamide, nitazoxanide, nirmatrelvir-ritonavir, and remdesivir.

It compared results for all-cause and COVID-specific mortality, recovery, time to recovery, COVID hospitalization, and adverse and serious adverse events.

Nirmatrelvir-ritonavir was associated with a reduction in hospitalization caused by COVID-19 of 0.7% versus 1.2% (moderate certainty of evidence [COE]) and a reduction in all-cause mortality of less than 0.1% versus 0.2% (moderate COE).

Molnupiravir led to a higher recovery rate of 31.8% versus 22.6% (moderate COE) and a reduced time to recovery of 9 versus 15 median days (moderate COE). It had no effect, however, on all-cause mortality: 0.02% versus 0.04% (moderate COE). Nor did it affect the incidence of serious adverse events: 0.4% versus 0.3% (moderate COE).

“There have been no head-to-head comparative studies of these two treatments, but nirmatrelvir-ritonavir appears to be the preferred treatment,” Dr. Salvatore said. She noted that molnupiravir cannot be used in pregnant women or young persons under age 18, while nirmatrelvir-ritonavir carries the risk of drug interactions. Viral rebound and recurrence of symptoms have been reported in some patients receiving nirmatrelvir-ritonavir.

In other review findings, ivermectin had no effect on time to recovery (moderate COE) and adverse events versus placebo (low COE). Sotrovimab resulted in no difference in all-cause mortality, compared with no treatment (low COE). There were no eligible studies for all of the other treatments of interest nor were there any that specifically evaluated the benefits and harms of treatments for the Omicron variant.

The panel pointed to the need for more evaluation of the efficacy, effectiveness, and comparative effectiveness, as well as harms of pharmacologic and biologic treatments of COVID-19 in the outpatient setting, particularly in the context of changing dominant SARS-CoV-2 variants and subvariants.

Another area requiring further research is the effectiveness of retreatment in patients with previous COVID-19 infection. Subgroup analyses are also needed to assess whether the efficacy and effectiveness of outpatient treatments vary by age, sex, socioeconomic status, and comorbid conditions – or by SARS-CoV-2 variant, immunity status (prior SARS-CoV-2 infection, vaccination status, or time since infection or vaccination), symptom duration, or disease severity.

Dr. Salvatore agreed that more research is needed in special convalescent groups. “For instance, those with cancer who are immunocompromised may need longer treatment and adjunctive treatment with convalescent plasma. But is difficult to find a large enough study with 5,000 immunocompromised patients.”

Financial support for the development of the practice points came exclusively from the ACP operating budget. The evidence review was funded by the ACP. The authors disclosed no relevant high-level competing interests with regard to this guidance, although several authors reported intellectual interests in various areas of research. Dr. Salvatore disclosed no conflicts of interest relevant to her comments but is engaged in influenza research for Genentech.

The American College of Physicians has issued an updated version of its living, rapid practice point guideline on the best treatment options for outpatients with confirmed COVID-19 in the era of the dominant Omicron variant of SARS-CoV-2. The recommendations in version 2 apply to persons presenting with mild to moderate infection and symptom onset in the past 5 days who are at high risk for progression to severe disease and potential hospitalization or death.

Version 1 appeared in late 2022.

While outpatient management is appropriate for most patients, treatment should be personalized and based on careful risk stratification and informed decision-making, said the guideline authors, led by Amir Qaseem, MD, PhD, MHA, vice president of clinical policy and the Center for Evidence Reviews at the ACP in Philadelphia.
 

Practice points

• Consider the oral antivirals nirmatrelvir-ritonavir (Paxlovid) or molnupiravir (Lagevrio) for symptomatic outpatients with confirmed mild to moderate COVID-19 who are within 5 days of the onset of symptoms and at high risk for progressing to severe disease.

New evidence for the Omicron variant suggests a possible net benefit of the antiviral molnupiravir versus standard or no treatment in terms of reducing recovery time if treatment is initiated within 5 days of symptom onset. Nirmatrelvir-ritonavir was associated with reductions in COVID-19 hospitalization and all-cause mortality.

“The practice points only address [whether] treatments work compared to placebo, no treatment, or usual care,” cautioned Linda L. Humphrey, MD, MPH, MACP, chair of the ACP’s Population Health and Medical Science Committee and a professor of medicine at Oregon Health and Science University VA Portland Health Care System. The ACP continues to monitor the evidence. “Once enough evidence has emerged, it will be possible to compare treatments to each other. Until that time we are unable to determine if there is an advantage to using one treatment over another.”

• Do not use the antiparasitic ivermectin (Stromectol) or the monoclonal antibody sotrovimab (Xevudy) to treat this patient population. “It is not expected to be effective against the Omicron variant,” Dr. Humphrey said.

There was no evidence to support the use of medications such as corticosteroids, antibiotics, antihistamines, SSRIs, and multiple other agents.

“The guideline is not a departure from previous knowledge and reflects what appears in other guidelines and is already being done generally in practice,” said Mirella Salvatore, MD, an associate professor of medicine and population health sciences at Weill Cornell Medicine, New York, who was not involved in the ACP statement. It is therefore unlikely the recommendations will trigger controversy or negative feedback, added Dr. Salvatore, who is also a spokesperson for the Infectious Diseases Society of America. “We believe that our evidence-based approach, which considers the balance of benefits and harms of various treatments, will be embraced by the physician community,” Dr. Humphrey said.

The updated recommendations are based on new data from the evidence review of multiple treatments, which concluded that both nirmatrelvir-ritonavir and molnupiravir likely improve outcomes for outpatients with mild to moderate COVID-19. The review was conducted after the emergence of the Omicron variant by the ACP Center for Evidence Reviews at Cochrane Austria/University for Continuing Education Krems (Austria).


 

Review details

Inclusion criteria were modified to focus on the Omicron variant by limiting eligible studies to only those enrolling patients on or after Nov. 26, 2021. The investigators included two randomized controlled trials and six retrospective cohort studies and ranked quality of evidence for the effectiveness of the following treatments, compared with usual care or no treatment: azithromycin, camostat mesylate, chloroquine-hydroxychloroquine, chlorpheniramine, colchicine, convalescent plasma, corticosteroids, ensitrelvir, favipiravir, fluvoxamine, ivermectin, lopinavir-ritonavir, molnupiravir, neutralizing monoclonal antibodies, metformin, niclosamide, nitazoxanide, nirmatrelvir-ritonavir, and remdesivir.

It compared results for all-cause and COVID-specific mortality, recovery, time to recovery, COVID hospitalization, and adverse and serious adverse events.

Nirmatrelvir-ritonavir was associated with a reduction in hospitalization caused by COVID-19 of 0.7% versus 1.2% (moderate certainty of evidence [COE]) and a reduction in all-cause mortality of less than 0.1% versus 0.2% (moderate COE).

Molnupiravir led to a higher recovery rate of 31.8% versus 22.6% (moderate COE) and a reduced time to recovery of 9 versus 15 median days (moderate COE). It had no effect, however, on all-cause mortality: 0.02% versus 0.04% (moderate COE). Nor did it affect the incidence of serious adverse events: 0.4% versus 0.3% (moderate COE).

“There have been no head-to-head comparative studies of these two treatments, but nirmatrelvir-ritonavir appears to be the preferred treatment,” Dr. Salvatore said. She noted that molnupiravir cannot be used in pregnant women or young persons under age 18, while nirmatrelvir-ritonavir carries the risk of drug interactions. Viral rebound and recurrence of symptoms have been reported in some patients receiving nirmatrelvir-ritonavir.

In other review findings, ivermectin had no effect on time to recovery (moderate COE) and adverse events versus placebo (low COE). Sotrovimab resulted in no difference in all-cause mortality, compared with no treatment (low COE). There were no eligible studies for all of the other treatments of interest nor were there any that specifically evaluated the benefits and harms of treatments for the Omicron variant.

The panel pointed to the need for more evaluation of the efficacy, effectiveness, and comparative effectiveness, as well as harms of pharmacologic and biologic treatments of COVID-19 in the outpatient setting, particularly in the context of changing dominant SARS-CoV-2 variants and subvariants.

Another area requiring further research is the effectiveness of retreatment in patients with previous COVID-19 infection. Subgroup analyses are also needed to assess whether the efficacy and effectiveness of outpatient treatments vary by age, sex, socioeconomic status, and comorbid conditions – or by SARS-CoV-2 variant, immunity status (prior SARS-CoV-2 infection, vaccination status, or time since infection or vaccination), symptom duration, or disease severity.

Dr. Salvatore agreed that more research is needed in special convalescent groups. “For instance, those with cancer who are immunocompromised may need longer treatment and adjunctive treatment with convalescent plasma. But is difficult to find a large enough study with 5,000 immunocompromised patients.”

Financial support for the development of the practice points came exclusively from the ACP operating budget. The evidence review was funded by the ACP. The authors disclosed no relevant high-level competing interests with regard to this guidance, although several authors reported intellectual interests in various areas of research. Dr. Salvatore disclosed no conflicts of interest relevant to her comments but is engaged in influenza research for Genentech.

The American College of Physicians has issued an updated version of its living, rapid practice point guideline on the best treatment options for outpatients with confirmed COVID-19 in the era of the dominant Omicron variant of SARS-CoV-2. The recommendations in version 2 apply to persons presenting with mild to moderate infection and symptom onset in the past 5 days who are at high risk for progression to severe disease and potential hospitalization or death.

Version 1 appeared in late 2022.

While outpatient management is appropriate for most patients, treatment should be personalized and based on careful risk stratification and informed decision-making, said the guideline authors, led by Amir Qaseem, MD, PhD, MHA, vice president of clinical policy and the Center for Evidence Reviews at the ACP in Philadelphia.
 

Practice points

• Consider the oral antivirals nirmatrelvir-ritonavir (Paxlovid) or molnupiravir (Lagevrio) for symptomatic outpatients with confirmed mild to moderate COVID-19 who are within 5 days of the onset of symptoms and at high risk for progressing to severe disease.

New evidence for the Omicron variant suggests a possible net benefit of the antiviral molnupiravir versus standard or no treatment in terms of reducing recovery time if treatment is initiated within 5 days of symptom onset. Nirmatrelvir-ritonavir was associated with reductions in COVID-19 hospitalization and all-cause mortality.

“The practice points only address [whether] treatments work compared to placebo, no treatment, or usual care,” cautioned Linda L. Humphrey, MD, MPH, MACP, chair of the ACP’s Population Health and Medical Science Committee and a professor of medicine at Oregon Health and Science University VA Portland Health Care System. The ACP continues to monitor the evidence. “Once enough evidence has emerged, it will be possible to compare treatments to each other. Until that time we are unable to determine if there is an advantage to using one treatment over another.”

• Do not use the antiparasitic ivermectin (Stromectol) or the monoclonal antibody sotrovimab (Xevudy) to treat this patient population. “It is not expected to be effective against the Omicron variant,” Dr. Humphrey said.

There was no evidence to support the use of medications such as corticosteroids, antibiotics, antihistamines, SSRIs, and multiple other agents.

“The guideline is not a departure from previous knowledge and reflects what appears in other guidelines and is already being done generally in practice,” said Mirella Salvatore, MD, an associate professor of medicine and population health sciences at Weill Cornell Medicine, New York, who was not involved in the ACP statement. It is therefore unlikely the recommendations will trigger controversy or negative feedback, added Dr. Salvatore, who is also a spokesperson for the Infectious Diseases Society of America. “We believe that our evidence-based approach, which considers the balance of benefits and harms of various treatments, will be embraced by the physician community,” Dr. Humphrey said.

The updated recommendations are based on new data from the evidence review of multiple treatments, which concluded that both nirmatrelvir-ritonavir and molnupiravir likely improve outcomes for outpatients with mild to moderate COVID-19. The review was conducted after the emergence of the Omicron variant by the ACP Center for Evidence Reviews at Cochrane Austria/University for Continuing Education Krems (Austria).


 

Review details

Inclusion criteria were modified to focus on the Omicron variant by limiting eligible studies to only those enrolling patients on or after Nov. 26, 2021. The investigators included two randomized controlled trials and six retrospective cohort studies and ranked quality of evidence for the effectiveness of the following treatments, compared with usual care or no treatment: azithromycin, camostat mesylate, chloroquine-hydroxychloroquine, chlorpheniramine, colchicine, convalescent plasma, corticosteroids, ensitrelvir, favipiravir, fluvoxamine, ivermectin, lopinavir-ritonavir, molnupiravir, neutralizing monoclonal antibodies, metformin, niclosamide, nitazoxanide, nirmatrelvir-ritonavir, and remdesivir.

It compared results for all-cause and COVID-specific mortality, recovery, time to recovery, COVID hospitalization, and adverse and serious adverse events.

Nirmatrelvir-ritonavir was associated with a reduction in hospitalization caused by COVID-19 of 0.7% versus 1.2% (moderate certainty of evidence [COE]) and a reduction in all-cause mortality of less than 0.1% versus 0.2% (moderate COE).

Molnupiravir led to a higher recovery rate of 31.8% versus 22.6% (moderate COE) and a reduced time to recovery of 9 versus 15 median days (moderate COE). It had no effect, however, on all-cause mortality: 0.02% versus 0.04% (moderate COE). Nor did it affect the incidence of serious adverse events: 0.4% versus 0.3% (moderate COE).

“There have been no head-to-head comparative studies of these two treatments, but nirmatrelvir-ritonavir appears to be the preferred treatment,” Dr. Salvatore said. She noted that molnupiravir cannot be used in pregnant women or young persons under age 18, while nirmatrelvir-ritonavir carries the risk of drug interactions. Viral rebound and recurrence of symptoms have been reported in some patients receiving nirmatrelvir-ritonavir.

In other review findings, ivermectin had no effect on time to recovery (moderate COE) and adverse events versus placebo (low COE). Sotrovimab resulted in no difference in all-cause mortality, compared with no treatment (low COE). There were no eligible studies for all of the other treatments of interest nor were there any that specifically evaluated the benefits and harms of treatments for the Omicron variant.

The panel pointed to the need for more evaluation of the efficacy, effectiveness, and comparative effectiveness, as well as harms of pharmacologic and biologic treatments of COVID-19 in the outpatient setting, particularly in the context of changing dominant SARS-CoV-2 variants and subvariants.

Another area requiring further research is the effectiveness of retreatment in patients with previous COVID-19 infection. Subgroup analyses are also needed to assess whether the efficacy and effectiveness of outpatient treatments vary by age, sex, socioeconomic status, and comorbid conditions – or by SARS-CoV-2 variant, immunity status (prior SARS-CoV-2 infection, vaccination status, or time since infection or vaccination), symptom duration, or disease severity.

Dr. Salvatore agreed that more research is needed in special convalescent groups. “For instance, those with cancer who are immunocompromised may need longer treatment and adjunctive treatment with convalescent plasma. But is difficult to find a large enough study with 5,000 immunocompromised patients.”

Financial support for the development of the practice points came exclusively from the ACP operating budget. The evidence review was funded by the ACP. The authors disclosed no relevant high-level competing interests with regard to this guidance, although several authors reported intellectual interests in various areas of research. Dr. Salvatore disclosed no conflicts of interest relevant to her comments but is engaged in influenza research for Genentech.

MDedge: What were the earliest acute care medications available for migraine?

Dr. Rapoport: In the 1940s, ergotamine tartrate tablets and sublingual tablets were introduced as therapy to treat migraine. They were not that well absorbed, caused nausea, and were not very effective—but they were the only treatment option. Then, beginning in the early 1990s, doctors began prescribing a class of medications called triptans to stop a migraine in progress. Patients are instructed to quickly take the triptan as soon as they know it is or will be a migraine headache; if they wait too long, it may not work as well—or at all. If they don’t have any improvement in 2 hours, they are encouraged to repeat the dosage, even though it often does not work well.

As I strongly recommend to my patients, triptans should not be used more than 2 days per week. An average of 3 days per week or more is too much, and triptan medications can cause medication overuse headache (MOH). If the patient develops MOH, they usually have more headaches rather than fewer—and the medication stops working well.

These medicines work in about 60% of patients and not so well in the other 40%. They do cause side effects in certain people, which may include some pain in their chest or neck muscles and  constriction of blood vessels. Some patients also feel a warm-to-hot feeling all over, tingling sensation, drowsiness, dizziness, and other side effects. Some will experience these side effects but continue to take these medications because they work; however, some patients can’t take them because they find the side effects to be too bothersome.

The first triptan to be marketed (in 1992) was a 6-mg, self-injected, subcutaneous injection of sumatriptan (Imitrex). Injection was the only available delivery method for a triptan until 1994, when the tablet form became available.

Typically, patients who hadn’t taken the sumatriptan injections preferred to start with the tablets, but the patients who had been taking the injection form were used to it and preferred to keep taking it. They knew that it worked well, and if they had mild side effects, they weren’t troubled by them. However, most new patients, when given a choice, asked for the tablet instead of the injection. In 1996, sumatriptan nasal spray was introduced, which is inconsistently absorbed, and patients report it does not taste or smell good. 

Within a few years, more triptan tablets became available: zolmitriptan (1997), rizatriptan (1998), naratriptan (1998), almotriptan and frovatriptan (2001), and eletriptan (2002). An oral film form of rizatriptan (RizaFilm) was FDA-approved in 2023. The zolmitriptan nasal spray was approved in 2003 and is easy to use, with few adverse effects and good efficacy. There is also a new type of sumatriptan nasal spray (approved in 2019) with a permeation enhancer that makes it adhere to the mucous membranes of the nose and allows it to work faster. It does not have the same disliked taste and smell that caused patients to avoid other similar medications. However, most patients still seem to prefer triptans in tablet form over the nasal spray or injection. 

Now there are a total of 2 triptan nasal sprays and 7 triptans in tablet form, 2 of which are orally disintegrating tablets (ODT), and there are several sumatriptan injections available that come in 3- 4- or 6-mg dosages. 

Do you prefer to prescribe a particular triptan medication to your patients, and if so, why?

Of the different forms of triptans (nasal sprays, tablets, and injections), my favorite is the nasal spray form of zolmitriptan 5 mg (it also comes in 2.5-mg doses, which I sometimes prescribe to pediatric patients). I prefer it because of how quickly it works to provide my patients relief from migraine. All tablets must go down the esophagus, into the stomach, then into the small intestine to the level of the jejunum, where it is absorbed. It then goes to the liver, where it is metabolized, and then (once it finally gets into the bloodstream), it starts working. By contrast, when medication is administered into the nasal cavity, it is quickly absorbed from the mucous membrane and enters the bloodstream there and begins working faster than the tablet does. Zolmitriptan also has fewer side effects than the tablet, and my patients appreciate that. If tablets of triptans do not work, I switch to zolmitriptan nasal spray and, in rare situations, the sumatriptan injection.

When would I switch a patient from a triptan any of the new classes of medicines? 

If a patient takes a triptan at the first sign of migraine and it doesn’t begin to work for 2 hours, that is taking too long. If the triptan relieves only 50% of the head pain, there is a good chance that the headache will linger and later return with a vengeance. That would make me consider switching a patient to one of the other types of migraine medications. Even if the patient repeats the triptan at 2 hours after the first one, it probably won’t be very effective at that point. I also want to know if a patient experiences any side effects from the triptan. If they say it works, but they get chest pain, drowsiness, or dizziness and can’t function, I may want to switch them to a newer medication.

Triptans can stimulate the serotonin 1B receptors on the nerves on the small blood vessels in various parts of the body. Because of that, they may constrict blood vessels, such as the coronary arteries in the heart or others in brain, which could possibly lead to a heart attack or stroke or hypertension in some patients. I might switch a medication from a triptan for a patient who is older (over 50), has high blood pressure or cholesterol, has obesity, does not regularly exercise, or has a family history of a heart attack or stroke at an early age. You really don’t want to constrict blood vessels in these patients and should consider a newer therapy.

Can you tell us more about the nasal sprays for acute care of migraine?

Other than the standard sumatriptan nasal spray, the half-dose of sumatriptan nasal spray with a permeation enhancer, and zolmitriptan nasal spray, there are 2 additional options on the market. They are both dihydroergotamine (DHE) mesylate, an ergot alkaloid liquid nasal spray. They are identical chemicals with different devices that produce the sprays. The older DHE nasal spray is called Migranal; it is used 1 time in each nostril, then 15 minutes later is repeated. I feel like it takes too long to get the medicine into the bloodstream because the nasal spray only emits a gentle spray that lays on the bottom of the nose. It doesn’t get to the top or back of the nasal cavity, where there are more blood vessels, which would result in better absorption and efficacy. The second nasal spray is called Trudhesa, which came out just a few years ago when another company took the same exact chemical entity and delivered it with a bigger sprayer that fires it up to the top and back of the nose, where it is better absorbed. That nasal spray seems to work better than the old nasal spray. We don’t have data showing how much better it works than the other, but patients tend to like it more. We may also see a fine DHE nasal powder soon, which may take slightly longer to work but with good efficacy that lasts longer.

Have any adverse events been reported with the DHE nasal sprays for migraine?

A patient may experience some pain or burning in the nose, have a funny taste in the mouth, or even experience a change in the way a food tastes for a while after taking the DHE nasal spray. It could also cause some chest discomfort because it stimulates the same receptors as the triptans, plus other receptors as well. 

Are there any newer acute care medications for migraine?

There are 2 newer groups of migraine medications that have come out within the past few years: gepants and a ditan. There are 2 gepants currently available. The first one to be FDA-approved for acute care of migraine (in 2019) was ubrogepant (Ubrelvy), and the second gepant, rimegepant (Nurtec), was approved in 2020. They both work approximately the same way, but they may cause different adverse events. They both sit on the calcitonin gene-related peptide (CGRP) receptors. These receptors are all over the body and the brain, but the place where researchers believe they work most effectively is on the first branch of the trigeminal nerve between the brainstem and the meninges. This is the trigeminovascular system. It works outside of the central nervous system and modulates what goes on inside the central nervous system.

Ubrogepant is a regular tablet that has 2 sizes, 50 and 100 mg. I might start a patient on a 50-mg tablet, and I will instruct them to take another dose (up to 200 mg a day) if they have not improved in 2 hours. Rimegepant comes only as a 75-mg ODT, or fast melt tablet which means a patient can put it on their tongue and they don’t need water with it. For example, if a patient is stuck on an interstate in a traffic jam at rush hour, is getting a terrible headache, and doesn’t happen to have water, they could just place the tablet it in their mouth, where it will dissolve in 5 to 10 seconds. A second dose doesn’t seem to be necessary; if the headache persists, I will switch to another type of medication that day.

The other category of acute migraine medicine that has been approved in the last few years is called a ditan. Only 1 ditan in the class is available right now, lasmiditan (Reyvow). It was FDA-approved in 2019 and works a little bit differently from the gepants, as it’s more like a triptan. Instead of stimulating the serotonin 1B and 1D receptors, it stimulates the serotonin 1F receptor. This is important because it doesn’t stimulate the 1B receptor and therefore doesn’t constrict blood vessels. The one good thing about this medication is it can be prescribed to an older patient or a patient that has any kind of coronary artery risk factors like smoking or obesity. It does enter the central nervous system to begin working, and when a drug does that, it’s more likely to have different side effects, such as dizziness or drowsiness—and this medication does cause both. The drug works well, but the side effects must be carefully observed. Patients are advised not to drive a car or operate machinery for 8 hours after taking this drug.

The advancements in the pharmacologic treatment options for the acute care of migraine offer a wide range of options for patients with migraine—allowing for more personalized and effective approaches for relief, with fewer adverse events than ever before.

MDedge: What were the earliest acute care medications available for migraine?

Dr. Rapoport: In the 1940s, ergotamine tartrate tablets and sublingual tablets were introduced as therapy to treat migraine. They were not that well absorbed, caused nausea, and were not very effective—but they were the only treatment option. Then, beginning in the early 1990s, doctors began prescribing a class of medications called triptans to stop a migraine in progress. Patients are instructed to quickly take the triptan as soon as they know it is or will be a migraine headache; if they wait too long, it may not work as well—or at all. If they don’t have any improvement in 2 hours, they are encouraged to repeat the dosage, even though it often does not work well.

As I strongly recommend to my patients, triptans should not be used more than 2 days per week. An average of 3 days per week or more is too much, and triptan medications can cause medication overuse headache (MOH). If the patient develops MOH, they usually have more headaches rather than fewer—and the medication stops working well.

These medicines work in about 60% of patients and not so well in the other 40%. They do cause side effects in certain people, which may include some pain in their chest or neck muscles and  constriction of blood vessels. Some patients also feel a warm-to-hot feeling all over, tingling sensation, drowsiness, dizziness, and other side effects. Some will experience these side effects but continue to take these medications because they work; however, some patients can’t take them because they find the side effects to be too bothersome.

The first triptan to be marketed (in 1992) was a 6-mg, self-injected, subcutaneous injection of sumatriptan (Imitrex). Injection was the only available delivery method for a triptan until 1994, when the tablet form became available.

Typically, patients who hadn’t taken the sumatriptan injections preferred to start with the tablets, but the patients who had been taking the injection form were used to it and preferred to keep taking it. They knew that it worked well, and if they had mild side effects, they weren’t troubled by them. However, most new patients, when given a choice, asked for the tablet instead of the injection. In 1996, sumatriptan nasal spray was introduced, which is inconsistently absorbed, and patients report it does not taste or smell good. 

Within a few years, more triptan tablets became available: zolmitriptan (1997), rizatriptan (1998), naratriptan (1998), almotriptan and frovatriptan (2001), and eletriptan (2002). An oral film form of rizatriptan (RizaFilm) was FDA-approved in 2023. The zolmitriptan nasal spray was approved in 2003 and is easy to use, with few adverse effects and good efficacy. There is also a new type of sumatriptan nasal spray (approved in 2019) with a permeation enhancer that makes it adhere to the mucous membranes of the nose and allows it to work faster. It does not have the same disliked taste and smell that caused patients to avoid other similar medications. However, most patients still seem to prefer triptans in tablet form over the nasal spray or injection. 

Now there are a total of 2 triptan nasal sprays and 7 triptans in tablet form, 2 of which are orally disintegrating tablets (ODT), and there are several sumatriptan injections available that come in 3- 4- or 6-mg dosages. 

Do you prefer to prescribe a particular triptan medication to your patients, and if so, why?

Of the different forms of triptans (nasal sprays, tablets, and injections), my favorite is the nasal spray form of zolmitriptan 5 mg (it also comes in 2.5-mg doses, which I sometimes prescribe to pediatric patients). I prefer it because of how quickly it works to provide my patients relief from migraine. All tablets must go down the esophagus, into the stomach, then into the small intestine to the level of the jejunum, where it is absorbed. It then goes to the liver, where it is metabolized, and then (once it finally gets into the bloodstream), it starts working. By contrast, when medication is administered into the nasal cavity, it is quickly absorbed from the mucous membrane and enters the bloodstream there and begins working faster than the tablet does. Zolmitriptan also has fewer side effects than the tablet, and my patients appreciate that. If tablets of triptans do not work, I switch to zolmitriptan nasal spray and, in rare situations, the sumatriptan injection.

When would I switch a patient from a triptan any of the new classes of medicines? 

If a patient takes a triptan at the first sign of migraine and it doesn’t begin to work for 2 hours, that is taking too long. If the triptan relieves only 50% of the head pain, there is a good chance that the headache will linger and later return with a vengeance. That would make me consider switching a patient to one of the other types of migraine medications. Even if the patient repeats the triptan at 2 hours after the first one, it probably won’t be very effective at that point. I also want to know if a patient experiences any side effects from the triptan. If they say it works, but they get chest pain, drowsiness, or dizziness and can’t function, I may want to switch them to a newer medication.

Triptans can stimulate the serotonin 1B receptors on the nerves on the small blood vessels in various parts of the body. Because of that, they may constrict blood vessels, such as the coronary arteries in the heart or others in brain, which could possibly lead to a heart attack or stroke or hypertension in some patients. I might switch a medication from a triptan for a patient who is older (over 50), has high blood pressure or cholesterol, has obesity, does not regularly exercise, or has a family history of a heart attack or stroke at an early age. You really don’t want to constrict blood vessels in these patients and should consider a newer therapy.

Can you tell us more about the nasal sprays for acute care of migraine?

Other than the standard sumatriptan nasal spray, the half-dose of sumatriptan nasal spray with a permeation enhancer, and zolmitriptan nasal spray, there are 2 additional options on the market. They are both dihydroergotamine (DHE) mesylate, an ergot alkaloid liquid nasal spray. They are identical chemicals with different devices that produce the sprays. The older DHE nasal spray is called Migranal; it is used 1 time in each nostril, then 15 minutes later is repeated. I feel like it takes too long to get the medicine into the bloodstream because the nasal spray only emits a gentle spray that lays on the bottom of the nose. It doesn’t get to the top or back of the nasal cavity, where there are more blood vessels, which would result in better absorption and efficacy. The second nasal spray is called Trudhesa, which came out just a few years ago when another company took the same exact chemical entity and delivered it with a bigger sprayer that fires it up to the top and back of the nose, where it is better absorbed. That nasal spray seems to work better than the old nasal spray. We don’t have data showing how much better it works than the other, but patients tend to like it more. We may also see a fine DHE nasal powder soon, which may take slightly longer to work but with good efficacy that lasts longer.

Have any adverse events been reported with the DHE nasal sprays for migraine?

A patient may experience some pain or burning in the nose, have a funny taste in the mouth, or even experience a change in the way a food tastes for a while after taking the DHE nasal spray. It could also cause some chest discomfort because it stimulates the same receptors as the triptans, plus other receptors as well. 

Are there any newer acute care medications for migraine?

There are 2 newer groups of migraine medications that have come out within the past few years: gepants and a ditan. There are 2 gepants currently available. The first one to be FDA-approved for acute care of migraine (in 2019) was ubrogepant (Ubrelvy), and the second gepant, rimegepant (Nurtec), was approved in 2020. They both work approximately the same way, but they may cause different adverse events. They both sit on the calcitonin gene-related peptide (CGRP) receptors. These receptors are all over the body and the brain, but the place where researchers believe they work most effectively is on the first branch of the trigeminal nerve between the brainstem and the meninges. This is the trigeminovascular system. It works outside of the central nervous system and modulates what goes on inside the central nervous system.

Ubrogepant is a regular tablet that has 2 sizes, 50 and 100 mg. I might start a patient on a 50-mg tablet, and I will instruct them to take another dose (up to 200 mg a day) if they have not improved in 2 hours. Rimegepant comes only as a 75-mg ODT, or fast melt tablet which means a patient can put it on their tongue and they don’t need water with it. For example, if a patient is stuck on an interstate in a traffic jam at rush hour, is getting a terrible headache, and doesn’t happen to have water, they could just place the tablet it in their mouth, where it will dissolve in 5 to 10 seconds. A second dose doesn’t seem to be necessary; if the headache persists, I will switch to another type of medication that day.

The other category of acute migraine medicine that has been approved in the last few years is called a ditan. Only 1 ditan in the class is available right now, lasmiditan (Reyvow). It was FDA-approved in 2019 and works a little bit differently from the gepants, as it’s more like a triptan. Instead of stimulating the serotonin 1B and 1D receptors, it stimulates the serotonin 1F receptor. This is important because it doesn’t stimulate the 1B receptor and therefore doesn’t constrict blood vessels. The one good thing about this medication is it can be prescribed to an older patient or a patient that has any kind of coronary artery risk factors like smoking or obesity. It does enter the central nervous system to begin working, and when a drug does that, it’s more likely to have different side effects, such as dizziness or drowsiness—and this medication does cause both. The drug works well, but the side effects must be carefully observed. Patients are advised not to drive a car or operate machinery for 8 hours after taking this drug.

The advancements in the pharmacologic treatment options for the acute care of migraine offer a wide range of options for patients with migraine—allowing for more personalized and effective approaches for relief, with fewer adverse events than ever before.

MDedge: What were the earliest acute care medications available for migraine?

Dr. Rapoport: In the 1940s, ergotamine tartrate tablets and sublingual tablets were introduced as therapy to treat migraine. They were not that well absorbed, caused nausea, and were not very effective—but they were the only treatment option. Then, beginning in the early 1990s, doctors began prescribing a class of medications called triptans to stop a migraine in progress. Patients are instructed to quickly take the triptan as soon as they know it is or will be a migraine headache; if they wait too long, it may not work as well—or at all. If they don’t have any improvement in 2 hours, they are encouraged to repeat the dosage, even though it often does not work well.

As I strongly recommend to my patients, triptans should not be used more than 2 days per week. An average of 3 days per week or more is too much, and triptan medications can cause medication overuse headache (MOH). If the patient develops MOH, they usually have more headaches rather than fewer—and the medication stops working well.

These medicines work in about 60% of patients and not so well in the other 40%. They do cause side effects in certain people, which may include some pain in their chest or neck muscles and  constriction of blood vessels. Some patients also feel a warm-to-hot feeling all over, tingling sensation, drowsiness, dizziness, and other side effects. Some will experience these side effects but continue to take these medications because they work; however, some patients can’t take them because they find the side effects to be too bothersome.

The first triptan to be marketed (in 1992) was a 6-mg, self-injected, subcutaneous injection of sumatriptan (Imitrex). Injection was the only available delivery method for a triptan until 1994, when the tablet form became available.

Typically, patients who hadn’t taken the sumatriptan injections preferred to start with the tablets, but the patients who had been taking the injection form were used to it and preferred to keep taking it. They knew that it worked well, and if they had mild side effects, they weren’t troubled by them. However, most new patients, when given a choice, asked for the tablet instead of the injection. In 1996, sumatriptan nasal spray was introduced, which is inconsistently absorbed, and patients report it does not taste or smell good. 

Within a few years, more triptan tablets became available: zolmitriptan (1997), rizatriptan (1998), naratriptan (1998), almotriptan and frovatriptan (2001), and eletriptan (2002). An oral film form of rizatriptan (RizaFilm) was FDA-approved in 2023. The zolmitriptan nasal spray was approved in 2003 and is easy to use, with few adverse effects and good efficacy. There is also a new type of sumatriptan nasal spray (approved in 2019) with a permeation enhancer that makes it adhere to the mucous membranes of the nose and allows it to work faster. It does not have the same disliked taste and smell that caused patients to avoid other similar medications. However, most patients still seem to prefer triptans in tablet form over the nasal spray or injection. 

Now there are a total of 2 triptan nasal sprays and 7 triptans in tablet form, 2 of which are orally disintegrating tablets (ODT), and there are several sumatriptan injections available that come in 3- 4- or 6-mg dosages. 

Do you prefer to prescribe a particular triptan medication to your patients, and if so, why?

Of the different forms of triptans (nasal sprays, tablets, and injections), my favorite is the nasal spray form of zolmitriptan 5 mg (it also comes in 2.5-mg doses, which I sometimes prescribe to pediatric patients). I prefer it because of how quickly it works to provide my patients relief from migraine. All tablets must go down the esophagus, into the stomach, then into the small intestine to the level of the jejunum, where it is absorbed. It then goes to the liver, where it is metabolized, and then (once it finally gets into the bloodstream), it starts working. By contrast, when medication is administered into the nasal cavity, it is quickly absorbed from the mucous membrane and enters the bloodstream there and begins working faster than the tablet does. Zolmitriptan also has fewer side effects than the tablet, and my patients appreciate that. If tablets of triptans do not work, I switch to zolmitriptan nasal spray and, in rare situations, the sumatriptan injection.

When would I switch a patient from a triptan any of the new classes of medicines? 

If a patient takes a triptan at the first sign of migraine and it doesn’t begin to work for 2 hours, that is taking too long. If the triptan relieves only 50% of the head pain, there is a good chance that the headache will linger and later return with a vengeance. That would make me consider switching a patient to one of the other types of migraine medications. Even if the patient repeats the triptan at 2 hours after the first one, it probably won’t be very effective at that point. I also want to know if a patient experiences any side effects from the triptan. If they say it works, but they get chest pain, drowsiness, or dizziness and can’t function, I may want to switch them to a newer medication.

Triptans can stimulate the serotonin 1B receptors on the nerves on the small blood vessels in various parts of the body. Because of that, they may constrict blood vessels, such as the coronary arteries in the heart or others in brain, which could possibly lead to a heart attack or stroke or hypertension in some patients. I might switch a medication from a triptan for a patient who is older (over 50), has high blood pressure or cholesterol, has obesity, does not regularly exercise, or has a family history of a heart attack or stroke at an early age. You really don’t want to constrict blood vessels in these patients and should consider a newer therapy.

Can you tell us more about the nasal sprays for acute care of migraine?

Other than the standard sumatriptan nasal spray, the half-dose of sumatriptan nasal spray with a permeation enhancer, and zolmitriptan nasal spray, there are 2 additional options on the market. They are both dihydroergotamine (DHE) mesylate, an ergot alkaloid liquid nasal spray. They are identical chemicals with different devices that produce the sprays. The older DHE nasal spray is called Migranal; it is used 1 time in each nostril, then 15 minutes later is repeated. I feel like it takes too long to get the medicine into the bloodstream because the nasal spray only emits a gentle spray that lays on the bottom of the nose. It doesn’t get to the top or back of the nasal cavity, where there are more blood vessels, which would result in better absorption and efficacy. The second nasal spray is called Trudhesa, which came out just a few years ago when another company took the same exact chemical entity and delivered it with a bigger sprayer that fires it up to the top and back of the nose, where it is better absorbed. That nasal spray seems to work better than the old nasal spray. We don’t have data showing how much better it works than the other, but patients tend to like it more. We may also see a fine DHE nasal powder soon, which may take slightly longer to work but with good efficacy that lasts longer.

Have any adverse events been reported with the DHE nasal sprays for migraine?

A patient may experience some pain or burning in the nose, have a funny taste in the mouth, or even experience a change in the way a food tastes for a while after taking the DHE nasal spray. It could also cause some chest discomfort because it stimulates the same receptors as the triptans, plus other receptors as well. 

Are there any newer acute care medications for migraine?

There are 2 newer groups of migraine medications that have come out within the past few years: gepants and a ditan. There are 2 gepants currently available. The first one to be FDA-approved for acute care of migraine (in 2019) was ubrogepant (Ubrelvy), and the second gepant, rimegepant (Nurtec), was approved in 2020. They both work approximately the same way, but they may cause different adverse events. They both sit on the calcitonin gene-related peptide (CGRP) receptors. These receptors are all over the body and the brain, but the place where researchers believe they work most effectively is on the first branch of the trigeminal nerve between the brainstem and the meninges. This is the trigeminovascular system. It works outside of the central nervous system and modulates what goes on inside the central nervous system.

Ubrogepant is a regular tablet that has 2 sizes, 50 and 100 mg. I might start a patient on a 50-mg tablet, and I will instruct them to take another dose (up to 200 mg a day) if they have not improved in 2 hours. Rimegepant comes only as a 75-mg ODT, or fast melt tablet which means a patient can put it on their tongue and they don’t need water with it. For example, if a patient is stuck on an interstate in a traffic jam at rush hour, is getting a terrible headache, and doesn’t happen to have water, they could just place the tablet it in their mouth, where it will dissolve in 5 to 10 seconds. A second dose doesn’t seem to be necessary; if the headache persists, I will switch to another type of medication that day.

The other category of acute migraine medicine that has been approved in the last few years is called a ditan. Only 1 ditan in the class is available right now, lasmiditan (Reyvow). It was FDA-approved in 2019 and works a little bit differently from the gepants, as it’s more like a triptan. Instead of stimulating the serotonin 1B and 1D receptors, it stimulates the serotonin 1F receptor. This is important because it doesn’t stimulate the 1B receptor and therefore doesn’t constrict blood vessels. The one good thing about this medication is it can be prescribed to an older patient or a patient that has any kind of coronary artery risk factors like smoking or obesity. It does enter the central nervous system to begin working, and when a drug does that, it’s more likely to have different side effects, such as dizziness or drowsiness—and this medication does cause both. The drug works well, but the side effects must be carefully observed. Patients are advised not to drive a car or operate machinery for 8 hours after taking this drug.

The advancements in the pharmacologic treatment options for the acute care of migraine offer a wide range of options for patients with migraine—allowing for more personalized and effective approaches for relief, with fewer adverse events than ever before.

TOPLINE:

Prevalence of sexual dysfunction in schizophrenia patients remains high, with improved screening and treatment of depression possibly improving sexual health of these patients, results of a systematic review and meta-analysis show.

METHODOLOGY:

• Data on sexual dysfunction prevalence in people with schizophrenia should be updated because the only meta-analysis on this topic was published over 10 years ago, and factors that could explain the heterogeneity of sexual dysfunctions in schizophrenia also need reexamining.
• After carrying out a literature search for observational studies reporting prevalence of sexual dysfunction in outpatients receiving treatment for schizophrenia or schizoaffective disorder, researchers included 72 studies with 21,076 patients from 33 countries published between 1979 and 2021 in their review.
• They determined pooled estimates of sexual dysfunction prevalence in men and women and of each specific dysfunction.

TAKEAWAY:

• Pooled estimates for global prevalence were: 56.4% for sexual dysfunctions (95% confidence interval, 50.5-62.2), 40.6% for loss of libido (95% CI, 30.7-51.4), 28.0% for orgasm dysfunction (95% CI, 18.4-40.2), and 6.1% for genital pain (95% CI, 2.8-12.7), with study design, sociodemographic data, and other factors associated with the high heterogeneity of sexual dysfunctions.
• In men, estimates were: 55.7% for sexual dysfunction (95% CI, 48.1-63.1), 44.0% for erectile dysfunction (95% CI, 33.5-55.2), and 38.6% ejaculation dysfunction (95% CI, 26.8-51.8).
• In women, estimates were: 60.0% for sexual dysfunction (95% CI, 48.0-70.8), 25.1% for amenorrhea (95% CI, 17.3-35.0), and 7.7% for galactorrhea (95% CI, 3.7-15.3).
• Studies with the highest proportion of antidepressant prescriptions reported lower rates of sexual dysfunctions.

IN PRACTICE:

The review shows that sexual dysfunction is “extremely frequent” in schizophrenia and uncovers “important evidence” suggesting that better screening and treatment of depression “may be an effective strategy to improve sexual health in patients with schizophrenia,” write the authors.

SOURCE:

The study was carried out by Théo Korchia, MD, Assistance Publique-Hopitaux de Marseille, Aix-Marseille University, CEReSS: Health Service Research and Quality of Life Center, France, and colleagues. It was published online in JAMA Psychiatry.

LIMITATIONS:

Most factors known to increase sexual dysfunction, including hypertension, diabetes, obesity, smoking, and sleep disorders, were poorly explored in the included studies. Results may not be extrapolated to continents such as Africa and Polynesia because they were underrepresented in the review. The presence of publication bias in the meta-analysis can’t be entirely ruled out. Heterogeneity or methodological differences may have contributed to the observed results.

DISCLOSURES:

The authors have no relevant conflict of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

Prevalence of sexual dysfunction in schizophrenia patients remains high, with improved screening and treatment of depression possibly improving sexual health of these patients, results of a systematic review and meta-analysis show.

METHODOLOGY:

• Data on sexual dysfunction prevalence in people with schizophrenia should be updated because the only meta-analysis on this topic was published over 10 years ago, and factors that could explain the heterogeneity of sexual dysfunctions in schizophrenia also need reexamining.
• After carrying out a literature search for observational studies reporting prevalence of sexual dysfunction in outpatients receiving treatment for schizophrenia or schizoaffective disorder, researchers included 72 studies with 21,076 patients from 33 countries published between 1979 and 2021 in their review.
• They determined pooled estimates of sexual dysfunction prevalence in men and women and of each specific dysfunction.

TAKEAWAY:

• Pooled estimates for global prevalence were: 56.4% for sexual dysfunctions (95% confidence interval, 50.5-62.2), 40.6% for loss of libido (95% CI, 30.7-51.4), 28.0% for orgasm dysfunction (95% CI, 18.4-40.2), and 6.1% for genital pain (95% CI, 2.8-12.7), with study design, sociodemographic data, and other factors associated with the high heterogeneity of sexual dysfunctions.
• In men, estimates were: 55.7% for sexual dysfunction (95% CI, 48.1-63.1), 44.0% for erectile dysfunction (95% CI, 33.5-55.2), and 38.6% ejaculation dysfunction (95% CI, 26.8-51.8).
• In women, estimates were: 60.0% for sexual dysfunction (95% CI, 48.0-70.8), 25.1% for amenorrhea (95% CI, 17.3-35.0), and 7.7% for galactorrhea (95% CI, 3.7-15.3).
• Studies with the highest proportion of antidepressant prescriptions reported lower rates of sexual dysfunctions.

IN PRACTICE:

The review shows that sexual dysfunction is “extremely frequent” in schizophrenia and uncovers “important evidence” suggesting that better screening and treatment of depression “may be an effective strategy to improve sexual health in patients with schizophrenia,” write the authors.

SOURCE:

The study was carried out by Théo Korchia, MD, Assistance Publique-Hopitaux de Marseille, Aix-Marseille University, CEReSS: Health Service Research and Quality of Life Center, France, and colleagues. It was published online in JAMA Psychiatry.

LIMITATIONS:

Most factors known to increase sexual dysfunction, including hypertension, diabetes, obesity, smoking, and sleep disorders, were poorly explored in the included studies. Results may not be extrapolated to continents such as Africa and Polynesia because they were underrepresented in the review. The presence of publication bias in the meta-analysis can’t be entirely ruled out. Heterogeneity or methodological differences may have contributed to the observed results.

DISCLOSURES:

The authors have no relevant conflict of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

Prevalence of sexual dysfunction in schizophrenia patients remains high, with improved screening and treatment of depression possibly improving sexual health of these patients, results of a systematic review and meta-analysis show.

METHODOLOGY:

• Data on sexual dysfunction prevalence in people with schizophrenia should be updated because the only meta-analysis on this topic was published over 10 years ago, and factors that could explain the heterogeneity of sexual dysfunctions in schizophrenia also need reexamining.
• After carrying out a literature search for observational studies reporting prevalence of sexual dysfunction in outpatients receiving treatment for schizophrenia or schizoaffective disorder, researchers included 72 studies with 21,076 patients from 33 countries published between 1979 and 2021 in their review.
• They determined pooled estimates of sexual dysfunction prevalence in men and women and of each specific dysfunction.

TAKEAWAY:

• Pooled estimates for global prevalence were: 56.4% for sexual dysfunctions (95% confidence interval, 50.5-62.2), 40.6% for loss of libido (95% CI, 30.7-51.4), 28.0% for orgasm dysfunction (95% CI, 18.4-40.2), and 6.1% for genital pain (95% CI, 2.8-12.7), with study design, sociodemographic data, and other factors associated with the high heterogeneity of sexual dysfunctions.
• In men, estimates were: 55.7% for sexual dysfunction (95% CI, 48.1-63.1), 44.0% for erectile dysfunction (95% CI, 33.5-55.2), and 38.6% ejaculation dysfunction (95% CI, 26.8-51.8).
• In women, estimates were: 60.0% for sexual dysfunction (95% CI, 48.0-70.8), 25.1% for amenorrhea (95% CI, 17.3-35.0), and 7.7% for galactorrhea (95% CI, 3.7-15.3).
• Studies with the highest proportion of antidepressant prescriptions reported lower rates of sexual dysfunctions.

IN PRACTICE:

The review shows that sexual dysfunction is “extremely frequent” in schizophrenia and uncovers “important evidence” suggesting that better screening and treatment of depression “may be an effective strategy to improve sexual health in patients with schizophrenia,” write the authors.

SOURCE:

The study was carried out by Théo Korchia, MD, Assistance Publique-Hopitaux de Marseille, Aix-Marseille University, CEReSS: Health Service Research and Quality of Life Center, France, and colleagues. It was published online in JAMA Psychiatry.

LIMITATIONS:

Most factors known to increase sexual dysfunction, including hypertension, diabetes, obesity, smoking, and sleep disorders, were poorly explored in the included studies. Results may not be extrapolated to continents such as Africa and Polynesia because they were underrepresented in the review. The presence of publication bias in the meta-analysis can’t be entirely ruled out. Heterogeneity or methodological differences may have contributed to the observed results.

DISCLOSURES:

The authors have no relevant conflict of interest.

A version of this article first appeared on Medscape.com.

I’m a creature of habit. I suspect most of us are.

One can of Diet Coke on the drive to my office. Turn on the WiFi and air conditioning. Fire up the computer and unload my briefcase. Then do online refills, check the Astronomy Picture of the Day, look over the day’s schedule, turn on the Keurig, and make one cup of coffee. And so on.

I’m sure most of us have similar routines. Our brains are probably wired that way for survival, though the reasons aren’t the same anymore. Once it was get up, look outside the cave for predators, make sure the tribe is all accounted for, go to the stream for water, look for berries.

The fact is that automatic habits are critical for everything we do. Driving a car is really a series of repetitive tasks. Being able to put most of the ride on our brain’s autopilot allows us to move our attention to scanning the surroundings for changes, and to think about other items such as wonder what to do for dinner and if I remembered to turn off theWiFi and Keurig.

The practice of medicine is similar. Some things are internalized. Watching patients walk back to my office, looking at their hands as they fill out forms, hearing them introduce themselves, and other things that we subconsciously process as part of the exam before we’ve even officially begun the appointment. I quietly file such things away to be used later in the visit.

It certainly wasn’t always that way. In training we learn to filter out signal from noise, because the information available is huge. We all read tests of some sort. When I began reading EEGs, the images and lines were overwhelming, but with time and experience I became skilled at whittling down the mass of information into the things that really needed to be noted so I could turn pages faster (yes, youngsters, EEGs used to be on paper). Now, scanning the screen becomes a background habit, with the brain focusing more on things that stand out (or going back to thinking about what to do for dinner).

Over the millennia we’ve changed daily routines from something critical for survival to what we need for individual success in a chosen field. The brain in this way is the ultimate Swiss Army Knife – many tools available, but how we adapt and use them for our individual needs is variable.

Which is pretty impressive, actually. In the era of AI and computers, we each come with a (roughly) 2.5-petabyte hard drive that’s not only capable of storing all that information, but figuring out how to use it when we need to. The process is so smooth that we’re rarely aware of it. But what a marvel it is.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I’m a creature of habit. I suspect most of us are.

One can of Diet Coke on the drive to my office. Turn on the WiFi and air conditioning. Fire up the computer and unload my briefcase. Then do online refills, check the Astronomy Picture of the Day, look over the day’s schedule, turn on the Keurig, and make one cup of coffee. And so on.

I’m sure most of us have similar routines. Our brains are probably wired that way for survival, though the reasons aren’t the same anymore. Once it was get up, look outside the cave for predators, make sure the tribe is all accounted for, go to the stream for water, look for berries.

The fact is that automatic habits are critical for everything we do. Driving a car is really a series of repetitive tasks. Being able to put most of the ride on our brain’s autopilot allows us to move our attention to scanning the surroundings for changes, and to think about other items such as wonder what to do for dinner and if I remembered to turn off theWiFi and Keurig.

The practice of medicine is similar. Some things are internalized. Watching patients walk back to my office, looking at their hands as they fill out forms, hearing them introduce themselves, and other things that we subconsciously process as part of the exam before we’ve even officially begun the appointment. I quietly file such things away to be used later in the visit.

It certainly wasn’t always that way. In training we learn to filter out signal from noise, because the information available is huge. We all read tests of some sort. When I began reading EEGs, the images and lines were overwhelming, but with time and experience I became skilled at whittling down the mass of information into the things that really needed to be noted so I could turn pages faster (yes, youngsters, EEGs used to be on paper). Now, scanning the screen becomes a background habit, with the brain focusing more on things that stand out (or going back to thinking about what to do for dinner).

Over the millennia we’ve changed daily routines from something critical for survival to what we need for individual success in a chosen field. The brain in this way is the ultimate Swiss Army Knife – many tools available, but how we adapt and use them for our individual needs is variable.

Which is pretty impressive, actually. In the era of AI and computers, we each come with a (roughly) 2.5-petabyte hard drive that’s not only capable of storing all that information, but figuring out how to use it when we need to. The process is so smooth that we’re rarely aware of it. But what a marvel it is.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I’m a creature of habit. I suspect most of us are.

One can of Diet Coke on the drive to my office. Turn on the WiFi and air conditioning. Fire up the computer and unload my briefcase. Then do online refills, check the Astronomy Picture of the Day, look over the day’s schedule, turn on the Keurig, and make one cup of coffee. And so on.

I’m sure most of us have similar routines. Our brains are probably wired that way for survival, though the reasons aren’t the same anymore. Once it was get up, look outside the cave for predators, make sure the tribe is all accounted for, go to the stream for water, look for berries.

The fact is that automatic habits are critical for everything we do. Driving a car is really a series of repetitive tasks. Being able to put most of the ride on our brain’s autopilot allows us to move our attention to scanning the surroundings for changes, and to think about other items such as wonder what to do for dinner and if I remembered to turn off theWiFi and Keurig.

The practice of medicine is similar. Some things are internalized. Watching patients walk back to my office, looking at their hands as they fill out forms, hearing them introduce themselves, and other things that we subconsciously process as part of the exam before we’ve even officially begun the appointment. I quietly file such things away to be used later in the visit.

It certainly wasn’t always that way. In training we learn to filter out signal from noise, because the information available is huge. We all read tests of some sort. When I began reading EEGs, the images and lines were overwhelming, but with time and experience I became skilled at whittling down the mass of information into the things that really needed to be noted so I could turn pages faster (yes, youngsters, EEGs used to be on paper). Now, scanning the screen becomes a background habit, with the brain focusing more on things that stand out (or going back to thinking about what to do for dinner).

Over the millennia we’ve changed daily routines from something critical for survival to what we need for individual success in a chosen field. The brain in this way is the ultimate Swiss Army Knife – many tools available, but how we adapt and use them for our individual needs is variable.

Which is pretty impressive, actually. In the era of AI and computers, we each come with a (roughly) 2.5-petabyte hard drive that’s not only capable of storing all that information, but figuring out how to use it when we need to. The process is so smooth that we’re rarely aware of it. But what a marvel it is.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

The first randomized trial to evaluate postprocedural anticoagulation (PPA) in patients undergoing a primary percutaneous coronary intervention (PCI) for an ST-segment elevation myocardial infarction (STEMI) did not associate significant benefit – or significant harm – with any of the three tested regimens relative to placebo.

There has been a signal from nonrandomized studies that PPA reduces the risk for ischemic events, but no controlled prospective trials have evaluated the risk-benefit relationship in STEMI patients, said Yan Yan, MD, a researcher in Beijing Anzhen Hospital.

The results of the randomized trial, called RIGHT, were presented at the annual congress of the European Society of Cardiology by Dr. Yan, on behalf of a team of coinvestigators led by Nie Shaoping, MD, PhD, a cardiologist affiliated with Capital Medical University, Beijing.

The bottom line is that “routine PPA with low-dose anticoagulation after primary PCI in STEMI patients is safe, but it does not improve ischemic outcome at 30 days,” Dr. Yan concluded.
 

Objective study

In her presentation, Dr. Yan explained that an objective study has been needed to validate the common use of empirically administered PPA. According to Dr. Yan, PPA is being offered to up to 40% of STEMI patients in Europe, with even higher rates in China.

In the investigator-initiated RIGHT trial, 2,856 STEMI patients undergoing PCI were randomized to PPA or placebo in a 1:1 ratio. In the PPA arm, patients received one of three low-dose anticoagulation regimens over 48 hours or until discharge if this was longer: 0.2 mg/kg per hour of bivalirudin administered intravenously; 40 mg of enoxaparin administered subcutaneously; or 10 U/kg per hour of unfractionated heparin (UFH) to maintain an activated coagulation time between 150 and 200 seconds.

Each of the 53 participating Chinese centers selected one of the anticoagulation regimens. Matching placebos were employed in the double-blind design. All received bivalirudin anticoagulation during PCI. Exclusion criteria included unstable disease, such as cardiogenic shock, prior coronary artery bypass grafting, or an indication for anticoagulation other than PPA.

For the composite primary endpoint of all-cause death, nonfatal MI, nonfatal stroke, stent thrombosis, or urgent revascularization at 30 days, there was no difference between PPA and placebo. The event rate in both arms was 2.5%.

There were also no significant differences between PPA and placebo for any of the secondary ischemic endpoints, which included the individual components of the primary endpoint and cardiovascular death.

For the primary safety endpoint of Bleeding Academic Research Consortium (BARC) grade 3-5 bleeding, the slight increase in events among those in the placebo group did not approach statistical significance (P = .551). On other definitions of bleeding, which were secondary endpoints, PPA and placebo also did not differ significantly.

Compared for safety, the three anticoagulation regimens performed similarly with no significant interaction for the primary endpoint (P = .679).

For efficacy, the differences did range sufficiently to produce a significant interaction (P = .01) with enoxaparin appearing to be more effective, UFH less effective, and bivalirudin falling in between. This led Dr. Yan to speculate that the three anticoagulants “may not be equivalent,” although she said larger trials are needed to explore potential differences.
 

Design flawed?

The ESC-invited discussant, Pascal Vranckx, MD, PhD, medical director, cardiac critical care services, Hartcentrum Hasselt, Belgium, liked the question being asked in the study, but concluded that the design was flawed.

“There are a variety of anticoagulants employed in a variety of doses [for PPA] but we have very limited data. The research question is totally appropriate,” he said. However, he asked, “What went wrong? Was it the drugs, the trial, or both?”

The problem, he thinks, is the dose. Much of the design of RIGHT was based on the 2015 MATRIX trial, which did show a benefit from a single dose of bivalirudin following PCI relative to two other comparators. In that study, STEMI patients randomized to bivalirudin received a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg per hour for at least 4 hours. The comparators were UFH or a control arm of low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors.

At 30 days, bivalirudin was associated with a 40% reduction (hazard ratio, 0.60; P = .001) relative to control for the composite primary endpoint of death or bleeding. Dr. Vranckx pointed out that MATRIX was a trial of a single-dose prolongation of PPA, whereas RIGHT was “a prolongation of a prolongation,” but he believes MATRIX data support higher doses of anticoagulation, particularly of bivalirudin.

“Perhaps low dose bivalirudin is not the way to go,” he speculated.

He further advised the authors to reevaluate the expected benefit from PPA following STEMI. In MATRIX, the risk for events was highly concentrated in the immediate period after PCI, suggesting that the opportunity to reduce risk is much lower as anticoagulation is prolonged. He suggested that the low number of events in RIGHT are consistent with the diminishing risk for events over time.

Nevertheless, Dr. Vranckx praised the authors for addressing a research question that is “timely and highly relevant.” He called the data “important” by drawing attention to a potential target for risk reduction, and encouraged additional trials to determine what PPA strategy, if any, can further reduce early ischemic events after PCI.

Dr. Yan and colleagues report financial relationships with Abbott, Boston Scientific, East China Pharmaceuticals, Saniju Medical and Pharmaceuticals, and Jiangsu Hengrui Pharmaceuticals, which provided funding for this study. Dr. Vranckx reports no potential conflicts of interest.

A version of this article first appeared on Medscape.com.

The first randomized trial to evaluate postprocedural anticoagulation (PPA) in patients undergoing a primary percutaneous coronary intervention (PCI) for an ST-segment elevation myocardial infarction (STEMI) did not associate significant benefit – or significant harm – with any of the three tested regimens relative to placebo.

There has been a signal from nonrandomized studies that PPA reduces the risk for ischemic events, but no controlled prospective trials have evaluated the risk-benefit relationship in STEMI patients, said Yan Yan, MD, a researcher in Beijing Anzhen Hospital.

The results of the randomized trial, called RIGHT, were presented at the annual congress of the European Society of Cardiology by Dr. Yan, on behalf of a team of coinvestigators led by Nie Shaoping, MD, PhD, a cardiologist affiliated with Capital Medical University, Beijing.

The bottom line is that “routine PPA with low-dose anticoagulation after primary PCI in STEMI patients is safe, but it does not improve ischemic outcome at 30 days,” Dr. Yan concluded.
 

Objective study

In her presentation, Dr. Yan explained that an objective study has been needed to validate the common use of empirically administered PPA. According to Dr. Yan, PPA is being offered to up to 40% of STEMI patients in Europe, with even higher rates in China.

In the investigator-initiated RIGHT trial, 2,856 STEMI patients undergoing PCI were randomized to PPA or placebo in a 1:1 ratio. In the PPA arm, patients received one of three low-dose anticoagulation regimens over 48 hours or until discharge if this was longer: 0.2 mg/kg per hour of bivalirudin administered intravenously; 40 mg of enoxaparin administered subcutaneously; or 10 U/kg per hour of unfractionated heparin (UFH) to maintain an activated coagulation time between 150 and 200 seconds.

Each of the 53 participating Chinese centers selected one of the anticoagulation regimens. Matching placebos were employed in the double-blind design. All received bivalirudin anticoagulation during PCI. Exclusion criteria included unstable disease, such as cardiogenic shock, prior coronary artery bypass grafting, or an indication for anticoagulation other than PPA.

For the composite primary endpoint of all-cause death, nonfatal MI, nonfatal stroke, stent thrombosis, or urgent revascularization at 30 days, there was no difference between PPA and placebo. The event rate in both arms was 2.5%.

There were also no significant differences between PPA and placebo for any of the secondary ischemic endpoints, which included the individual components of the primary endpoint and cardiovascular death.

For the primary safety endpoint of Bleeding Academic Research Consortium (BARC) grade 3-5 bleeding, the slight increase in events among those in the placebo group did not approach statistical significance (P = .551). On other definitions of bleeding, which were secondary endpoints, PPA and placebo also did not differ significantly.

Compared for safety, the three anticoagulation regimens performed similarly with no significant interaction for the primary endpoint (P = .679).

For efficacy, the differences did range sufficiently to produce a significant interaction (P = .01) with enoxaparin appearing to be more effective, UFH less effective, and bivalirudin falling in between. This led Dr. Yan to speculate that the three anticoagulants “may not be equivalent,” although she said larger trials are needed to explore potential differences.
 

Design flawed?

The ESC-invited discussant, Pascal Vranckx, MD, PhD, medical director, cardiac critical care services, Hartcentrum Hasselt, Belgium, liked the question being asked in the study, but concluded that the design was flawed.

“There are a variety of anticoagulants employed in a variety of doses [for PPA] but we have very limited data. The research question is totally appropriate,” he said. However, he asked, “What went wrong? Was it the drugs, the trial, or both?”

The problem, he thinks, is the dose. Much of the design of RIGHT was based on the 2015 MATRIX trial, which did show a benefit from a single dose of bivalirudin following PCI relative to two other comparators. In that study, STEMI patients randomized to bivalirudin received a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg per hour for at least 4 hours. The comparators were UFH or a control arm of low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors.

At 30 days, bivalirudin was associated with a 40% reduction (hazard ratio, 0.60; P = .001) relative to control for the composite primary endpoint of death or bleeding. Dr. Vranckx pointed out that MATRIX was a trial of a single-dose prolongation of PPA, whereas RIGHT was “a prolongation of a prolongation,” but he believes MATRIX data support higher doses of anticoagulation, particularly of bivalirudin.

“Perhaps low dose bivalirudin is not the way to go,” he speculated.

He further advised the authors to reevaluate the expected benefit from PPA following STEMI. In MATRIX, the risk for events was highly concentrated in the immediate period after PCI, suggesting that the opportunity to reduce risk is much lower as anticoagulation is prolonged. He suggested that the low number of events in RIGHT are consistent with the diminishing risk for events over time.

Nevertheless, Dr. Vranckx praised the authors for addressing a research question that is “timely and highly relevant.” He called the data “important” by drawing attention to a potential target for risk reduction, and encouraged additional trials to determine what PPA strategy, if any, can further reduce early ischemic events after PCI.

Dr. Yan and colleagues report financial relationships with Abbott, Boston Scientific, East China Pharmaceuticals, Saniju Medical and Pharmaceuticals, and Jiangsu Hengrui Pharmaceuticals, which provided funding for this study. Dr. Vranckx reports no potential conflicts of interest.

A version of this article first appeared on Medscape.com.

The first randomized trial to evaluate postprocedural anticoagulation (PPA) in patients undergoing a primary percutaneous coronary intervention (PCI) for an ST-segment elevation myocardial infarction (STEMI) did not associate significant benefit – or significant harm – with any of the three tested regimens relative to placebo.

There has been a signal from nonrandomized studies that PPA reduces the risk for ischemic events, but no controlled prospective trials have evaluated the risk-benefit relationship in STEMI patients, said Yan Yan, MD, a researcher in Beijing Anzhen Hospital.

The results of the randomized trial, called RIGHT, were presented at the annual congress of the European Society of Cardiology by Dr. Yan, on behalf of a team of coinvestigators led by Nie Shaoping, MD, PhD, a cardiologist affiliated with Capital Medical University, Beijing.

The bottom line is that “routine PPA with low-dose anticoagulation after primary PCI in STEMI patients is safe, but it does not improve ischemic outcome at 30 days,” Dr. Yan concluded.
 

Objective study

In her presentation, Dr. Yan explained that an objective study has been needed to validate the common use of empirically administered PPA. According to Dr. Yan, PPA is being offered to up to 40% of STEMI patients in Europe, with even higher rates in China.

In the investigator-initiated RIGHT trial, 2,856 STEMI patients undergoing PCI were randomized to PPA or placebo in a 1:1 ratio. In the PPA arm, patients received one of three low-dose anticoagulation regimens over 48 hours or until discharge if this was longer: 0.2 mg/kg per hour of bivalirudin administered intravenously; 40 mg of enoxaparin administered subcutaneously; or 10 U/kg per hour of unfractionated heparin (UFH) to maintain an activated coagulation time between 150 and 200 seconds.

Each of the 53 participating Chinese centers selected one of the anticoagulation regimens. Matching placebos were employed in the double-blind design. All received bivalirudin anticoagulation during PCI. Exclusion criteria included unstable disease, such as cardiogenic shock, prior coronary artery bypass grafting, or an indication for anticoagulation other than PPA.

For the composite primary endpoint of all-cause death, nonfatal MI, nonfatal stroke, stent thrombosis, or urgent revascularization at 30 days, there was no difference between PPA and placebo. The event rate in both arms was 2.5%.

There were also no significant differences between PPA and placebo for any of the secondary ischemic endpoints, which included the individual components of the primary endpoint and cardiovascular death.

For the primary safety endpoint of Bleeding Academic Research Consortium (BARC) grade 3-5 bleeding, the slight increase in events among those in the placebo group did not approach statistical significance (P = .551). On other definitions of bleeding, which were secondary endpoints, PPA and placebo also did not differ significantly.

Compared for safety, the three anticoagulation regimens performed similarly with no significant interaction for the primary endpoint (P = .679).

For efficacy, the differences did range sufficiently to produce a significant interaction (P = .01) with enoxaparin appearing to be more effective, UFH less effective, and bivalirudin falling in between. This led Dr. Yan to speculate that the three anticoagulants “may not be equivalent,” although she said larger trials are needed to explore potential differences.
 

Design flawed?

The ESC-invited discussant, Pascal Vranckx, MD, PhD, medical director, cardiac critical care services, Hartcentrum Hasselt, Belgium, liked the question being asked in the study, but concluded that the design was flawed.

“There are a variety of anticoagulants employed in a variety of doses [for PPA] but we have very limited data. The research question is totally appropriate,” he said. However, he asked, “What went wrong? Was it the drugs, the trial, or both?”

The problem, he thinks, is the dose. Much of the design of RIGHT was based on the 2015 MATRIX trial, which did show a benefit from a single dose of bivalirudin following PCI relative to two other comparators. In that study, STEMI patients randomized to bivalirudin received a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg per hour for at least 4 hours. The comparators were UFH or a control arm of low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors.

At 30 days, bivalirudin was associated with a 40% reduction (hazard ratio, 0.60; P = .001) relative to control for the composite primary endpoint of death or bleeding. Dr. Vranckx pointed out that MATRIX was a trial of a single-dose prolongation of PPA, whereas RIGHT was “a prolongation of a prolongation,” but he believes MATRIX data support higher doses of anticoagulation, particularly of bivalirudin.

“Perhaps low dose bivalirudin is not the way to go,” he speculated.

He further advised the authors to reevaluate the expected benefit from PPA following STEMI. In MATRIX, the risk for events was highly concentrated in the immediate period after PCI, suggesting that the opportunity to reduce risk is much lower as anticoagulation is prolonged. He suggested that the low number of events in RIGHT are consistent with the diminishing risk for events over time.

Nevertheless, Dr. Vranckx praised the authors for addressing a research question that is “timely and highly relevant.” He called the data “important” by drawing attention to a potential target for risk reduction, and encouraged additional trials to determine what PPA strategy, if any, can further reduce early ischemic events after PCI.

Dr. Yan and colleagues report financial relationships with Abbott, Boston Scientific, East China Pharmaceuticals, Saniju Medical and Pharmaceuticals, and Jiangsu Hengrui Pharmaceuticals, which provided funding for this study. Dr. Vranckx reports no potential conflicts of interest.

A version of this article first appeared on Medscape.com.

Most patients with non–small cell lung cancer (NSCLC) who are long-term responders to immunotherapy will continue receiving treatment beyond 2 years. However, the best available evidence to date indicates that receiving immunotherapy after this 2-year mark likely offers no survival benefit.

Given the data, why do many clinicians keep having their patients receive immunotherapy beyond 2 years?

Is it an overabundance of caution? A desire for more definitive data? Or is it simply a judgment call oncologists make on the basis of the individual patient?

Lova Sun, MD, MSCE, of the University of Pennsylvania in Philadelphia, believes the general inconsistency between the data and clinical practice “likely reflects significant hesitation on the part of clinicians, patients, or both to stop a treatment that is still ‘working.’ ”

H. Jack West, MD, agreed, adding that “in an ambiguous situation, a U.S.-based population is going to err on the side of overtreatment.”

Without “incontrovertible evidence” that immunotherapy should stop at 2 years, “many, many, many patients and clinicians are going to favor continuing ‘doing what you’re doing’ in the absence of either prohibitive toxicity or clinically significant disease progression,” said Dr. West of the City of Hope Comprehensive Cancer Center, Duarte, Calif.

One factor adding to this ambiguity: Most pivotal studies that examine first-line immunotherapy in NSCLC limit therapy duration to 2 years.

Another key factor is the absence of prospective data as to when to stop treatment for these patients, according to Martin Reck, MD, PhD, head of thoracic oncology at the Lung Clinic Grosshansdorf (Germany).

“We have never prospectively investigated the correlation of the duration of a checkpoint blockade and the efficacy of treatment,” Dr. Reck said. “And this is a big problem.” It means “we really do not know how long we should treat the patient.”

To make matters muddier, some data do suggest that more therapy may be better. The recent Checkmate 153 trial, for instance, found that patients who had no signs of disease progression and who received 1-year fixed-duration nivolumab had significantly shorter progression-free and overall survival than those who received treatment indefinitely.

However, randomized trials with longer-term follow-up suggest durable responses can be maintained for years after immunotherapy is stopped.

Data from the KEYNOTE-024 trial, for instance, showed that more than 45% of patients with metastatic NSCLC and high tumor PD-L1 expression who received pembrolizumab for 2 years remained alive at 5 years without further treatment or disease progression. Another trial, KEYNOTE-407, demonstrated similar 5-year survival outcomes among patients with advanced squamous NSCLC, regardless of PD-L1 status, who completed 2 years of chemotherapy plus pembrolizumab followed by maintenance pembrolizumab.

With these studies, however, “we can only speculate about whether the proportion of patients alive without progression would be substantially higher if treatment with immunotherapy continued longer,” Dr. West wrote in a recent editorial .

Perhaps the most telling data so far come from a recent retrospective analysis from Dr. Sun and colleagues. The researchers directly compared survival outcomes among patients who continued receiving immunotherapy indefinitely with outcomes among patients for whom immunotherapy was discontinued at 2 years.

The JAMA Oncology study, which focused on 706 patients with NSCLC who completed 2 years of therapy, found that only 16% stopped receiving immune checkpoint inhibitor therapy at 2 years, whereas the remaining 84% continued receiving treatment indefinitely.

Among patients who continued receiving immunotherapy for 2 additional years, overall survival was not better than among those who stopped receiving immunotherapy at the 2-year mark. Even among the 11 patients whose condition progressed when therapy was discontinued, most still did well after treatment was resumed.

However, the retrospective design of the study limits its impact.

Without more definitive “data about when the treatment can be stopped,” many continue “indefinitely as long as the patient is tolerating treatment and the disease is not progressing,” Conor E. Steuer, MD, and Suresh S. Ramalingam, MD, of Winship Cancer Institute at Emory University, Atlanta, wrote in a recent review.
 

Impact on practice?

Dr. Sun views her team’s findings not as a recommendation to halt immunotherapy for every patient at 2 years but rather as “one piece of data that may provide reassurance to providers and patients who wish to stop at 2 years.”

Ultimately, however, the decision as to when or whether to stop immunotherapy for long-term responders is “an individualized one that requires shared decision-making and consideration of each patient’s clinical history, preferences, and risk tolerance,” Dr. Sun explained.

Dr. Reck agreed, noting that until prospective trials evaluate a fixed approach, the duration of immunotherapy “has to be determined by the treating physician and the individual patient.”

For a patient with metastatic NSCLC who is having an excellent response to checkpoint blockade, “we are somewhat afraid to stop the immunotherapy,” explained Dr. Reck, “because we are afraid the disease might relapse.” However, he noted, for patients who have a stable response to therapy, it may make sense to consider discontinuing checkpoint blockade.

Outside of survival outcomes, oncologists should also consider quality of life. Stopping treatment at 2 years comes with a “lower risk of toxic effects, less time in treatment for patients, and considerably lower costs for our health care system,” said Dr. West.

But for a fixed strategy to become more standard practice, the burden of proof is high, Dr. West said.

Jonathan W. Goldman, MD, says he understands the mentality, “If it’s going well, why would I change?”

In his experience, at 2 years of immunotherapy, most patients “say they’re feeling great” and “don’t mind coming in every 4 or 6 weeks, depending on the drug,” said Dr. Goldman, director of clinical trials in thoracic oncology at UCLA Medical Center in Santa Monica, Calif.

Dr. Goldman noted that in the future, instead of continuing immunotherapy indefinitely, clinicians may aim to maintain the patient “in the best response possible,” adding an intervention, such as stereotactic body radiotherapy or radiologic ablation, when needed.

“It may be that many of these long-term disease control patients are not cured in a traditional sense,” Dr. Goldman said, “but have controlled cancer that could potentially last years or even decades with ongoing care.”

Dr. Sun has relationships with Regeneron, GenMab, Seagen, and Bayer and has received institutional funding from Blueprint Research, Seagen Research, and IO Biotech Research. Dr. West has relationships with AstraZeneca, Genentech/Roche, Merck, and Regeneron outside the submitted work. Dr. Reck has relationships with Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Daiichi-Sankyo, GSK, Lilly, Merck, MSD, Mirati, Novartis, Roche Regeneron, and Pfizer.

A version of this article appeared on Medscape.com.

Most patients with non–small cell lung cancer (NSCLC) who are long-term responders to immunotherapy will continue receiving treatment beyond 2 years. However, the best available evidence to date indicates that receiving immunotherapy after this 2-year mark likely offers no survival benefit.

Given the data, why do many clinicians keep having their patients receive immunotherapy beyond 2 years?

Is it an overabundance of caution? A desire for more definitive data? Or is it simply a judgment call oncologists make on the basis of the individual patient?

Lova Sun, MD, MSCE, of the University of Pennsylvania in Philadelphia, believes the general inconsistency between the data and clinical practice “likely reflects significant hesitation on the part of clinicians, patients, or both to stop a treatment that is still ‘working.’ ”

H. Jack West, MD, agreed, adding that “in an ambiguous situation, a U.S.-based population is going to err on the side of overtreatment.”

Without “incontrovertible evidence” that immunotherapy should stop at 2 years, “many, many, many patients and clinicians are going to favor continuing ‘doing what you’re doing’ in the absence of either prohibitive toxicity or clinically significant disease progression,” said Dr. West of the City of Hope Comprehensive Cancer Center, Duarte, Calif.

One factor adding to this ambiguity: Most pivotal studies that examine first-line immunotherapy in NSCLC limit therapy duration to 2 years.

Another key factor is the absence of prospective data as to when to stop treatment for these patients, according to Martin Reck, MD, PhD, head of thoracic oncology at the Lung Clinic Grosshansdorf (Germany).

“We have never prospectively investigated the correlation of the duration of a checkpoint blockade and the efficacy of treatment,” Dr. Reck said. “And this is a big problem.” It means “we really do not know how long we should treat the patient.”

To make matters muddier, some data do suggest that more therapy may be better. The recent Checkmate 153 trial, for instance, found that patients who had no signs of disease progression and who received 1-year fixed-duration nivolumab had significantly shorter progression-free and overall survival than those who received treatment indefinitely.

However, randomized trials with longer-term follow-up suggest durable responses can be maintained for years after immunotherapy is stopped.

Data from the KEYNOTE-024 trial, for instance, showed that more than 45% of patients with metastatic NSCLC and high tumor PD-L1 expression who received pembrolizumab for 2 years remained alive at 5 years without further treatment or disease progression. Another trial, KEYNOTE-407, demonstrated similar 5-year survival outcomes among patients with advanced squamous NSCLC, regardless of PD-L1 status, who completed 2 years of chemotherapy plus pembrolizumab followed by maintenance pembrolizumab.

With these studies, however, “we can only speculate about whether the proportion of patients alive without progression would be substantially higher if treatment with immunotherapy continued longer,” Dr. West wrote in a recent editorial .

Perhaps the most telling data so far come from a recent retrospective analysis from Dr. Sun and colleagues. The researchers directly compared survival outcomes among patients who continued receiving immunotherapy indefinitely with outcomes among patients for whom immunotherapy was discontinued at 2 years.

The JAMA Oncology study, which focused on 706 patients with NSCLC who completed 2 years of therapy, found that only 16% stopped receiving immune checkpoint inhibitor therapy at 2 years, whereas the remaining 84% continued receiving treatment indefinitely.

Among patients who continued receiving immunotherapy for 2 additional years, overall survival was not better than among those who stopped receiving immunotherapy at the 2-year mark. Even among the 11 patients whose condition progressed when therapy was discontinued, most still did well after treatment was resumed.

However, the retrospective design of the study limits its impact.

Without more definitive “data about when the treatment can be stopped,” many continue “indefinitely as long as the patient is tolerating treatment and the disease is not progressing,” Conor E. Steuer, MD, and Suresh S. Ramalingam, MD, of Winship Cancer Institute at Emory University, Atlanta, wrote in a recent review.
 

Impact on practice?

Dr. Sun views her team’s findings not as a recommendation to halt immunotherapy for every patient at 2 years but rather as “one piece of data that may provide reassurance to providers and patients who wish to stop at 2 years.”

Ultimately, however, the decision as to when or whether to stop immunotherapy for long-term responders is “an individualized one that requires shared decision-making and consideration of each patient’s clinical history, preferences, and risk tolerance,” Dr. Sun explained.

Dr. Reck agreed, noting that until prospective trials evaluate a fixed approach, the duration of immunotherapy “has to be determined by the treating physician and the individual patient.”

For a patient with metastatic NSCLC who is having an excellent response to checkpoint blockade, “we are somewhat afraid to stop the immunotherapy,” explained Dr. Reck, “because we are afraid the disease might relapse.” However, he noted, for patients who have a stable response to therapy, it may make sense to consider discontinuing checkpoint blockade.

Outside of survival outcomes, oncologists should also consider quality of life. Stopping treatment at 2 years comes with a “lower risk of toxic effects, less time in treatment for patients, and considerably lower costs for our health care system,” said Dr. West.

But for a fixed strategy to become more standard practice, the burden of proof is high, Dr. West said.

Jonathan W. Goldman, MD, says he understands the mentality, “If it’s going well, why would I change?”

In his experience, at 2 years of immunotherapy, most patients “say they’re feeling great” and “don’t mind coming in every 4 or 6 weeks, depending on the drug,” said Dr. Goldman, director of clinical trials in thoracic oncology at UCLA Medical Center in Santa Monica, Calif.

Dr. Goldman noted that in the future, instead of continuing immunotherapy indefinitely, clinicians may aim to maintain the patient “in the best response possible,” adding an intervention, such as stereotactic body radiotherapy or radiologic ablation, when needed.

“It may be that many of these long-term disease control patients are not cured in a traditional sense,” Dr. Goldman said, “but have controlled cancer that could potentially last years or even decades with ongoing care.”

Dr. Sun has relationships with Regeneron, GenMab, Seagen, and Bayer and has received institutional funding from Blueprint Research, Seagen Research, and IO Biotech Research. Dr. West has relationships with AstraZeneca, Genentech/Roche, Merck, and Regeneron outside the submitted work. Dr. Reck has relationships with Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Daiichi-Sankyo, GSK, Lilly, Merck, MSD, Mirati, Novartis, Roche Regeneron, and Pfizer.

A version of this article appeared on Medscape.com.

Most patients with non–small cell lung cancer (NSCLC) who are long-term responders to immunotherapy will continue receiving treatment beyond 2 years. However, the best available evidence to date indicates that receiving immunotherapy after this 2-year mark likely offers no survival benefit.

Given the data, why do many clinicians keep having their patients receive immunotherapy beyond 2 years?

Is it an overabundance of caution? A desire for more definitive data? Or is it simply a judgment call oncologists make on the basis of the individual patient?

Lova Sun, MD, MSCE, of the University of Pennsylvania in Philadelphia, believes the general inconsistency between the data and clinical practice “likely reflects significant hesitation on the part of clinicians, patients, or both to stop a treatment that is still ‘working.’ ”

H. Jack West, MD, agreed, adding that “in an ambiguous situation, a U.S.-based population is going to err on the side of overtreatment.”

Without “incontrovertible evidence” that immunotherapy should stop at 2 years, “many, many, many patients and clinicians are going to favor continuing ‘doing what you’re doing’ in the absence of either prohibitive toxicity or clinically significant disease progression,” said Dr. West of the City of Hope Comprehensive Cancer Center, Duarte, Calif.

One factor adding to this ambiguity: Most pivotal studies that examine first-line immunotherapy in NSCLC limit therapy duration to 2 years.

Another key factor is the absence of prospective data as to when to stop treatment for these patients, according to Martin Reck, MD, PhD, head of thoracic oncology at the Lung Clinic Grosshansdorf (Germany).

“We have never prospectively investigated the correlation of the duration of a checkpoint blockade and the efficacy of treatment,” Dr. Reck said. “And this is a big problem.” It means “we really do not know how long we should treat the patient.”

To make matters muddier, some data do suggest that more therapy may be better. The recent Checkmate 153 trial, for instance, found that patients who had no signs of disease progression and who received 1-year fixed-duration nivolumab had significantly shorter progression-free and overall survival than those who received treatment indefinitely.

However, randomized trials with longer-term follow-up suggest durable responses can be maintained for years after immunotherapy is stopped.

Data from the KEYNOTE-024 trial, for instance, showed that more than 45% of patients with metastatic NSCLC and high tumor PD-L1 expression who received pembrolizumab for 2 years remained alive at 5 years without further treatment or disease progression. Another trial, KEYNOTE-407, demonstrated similar 5-year survival outcomes among patients with advanced squamous NSCLC, regardless of PD-L1 status, who completed 2 years of chemotherapy plus pembrolizumab followed by maintenance pembrolizumab.

With these studies, however, “we can only speculate about whether the proportion of patients alive without progression would be substantially higher if treatment with immunotherapy continued longer,” Dr. West wrote in a recent editorial .

Perhaps the most telling data so far come from a recent retrospective analysis from Dr. Sun and colleagues. The researchers directly compared survival outcomes among patients who continued receiving immunotherapy indefinitely with outcomes among patients for whom immunotherapy was discontinued at 2 years.

The JAMA Oncology study, which focused on 706 patients with NSCLC who completed 2 years of therapy, found that only 16% stopped receiving immune checkpoint inhibitor therapy at 2 years, whereas the remaining 84% continued receiving treatment indefinitely.

Among patients who continued receiving immunotherapy for 2 additional years, overall survival was not better than among those who stopped receiving immunotherapy at the 2-year mark. Even among the 11 patients whose condition progressed when therapy was discontinued, most still did well after treatment was resumed.

However, the retrospective design of the study limits its impact.

Without more definitive “data about when the treatment can be stopped,” many continue “indefinitely as long as the patient is tolerating treatment and the disease is not progressing,” Conor E. Steuer, MD, and Suresh S. Ramalingam, MD, of Winship Cancer Institute at Emory University, Atlanta, wrote in a recent review.
 

Impact on practice?

Dr. Sun views her team’s findings not as a recommendation to halt immunotherapy for every patient at 2 years but rather as “one piece of data that may provide reassurance to providers and patients who wish to stop at 2 years.”

Ultimately, however, the decision as to when or whether to stop immunotherapy for long-term responders is “an individualized one that requires shared decision-making and consideration of each patient’s clinical history, preferences, and risk tolerance,” Dr. Sun explained.

Dr. Reck agreed, noting that until prospective trials evaluate a fixed approach, the duration of immunotherapy “has to be determined by the treating physician and the individual patient.”

For a patient with metastatic NSCLC who is having an excellent response to checkpoint blockade, “we are somewhat afraid to stop the immunotherapy,” explained Dr. Reck, “because we are afraid the disease might relapse.” However, he noted, for patients who have a stable response to therapy, it may make sense to consider discontinuing checkpoint blockade.

Outside of survival outcomes, oncologists should also consider quality of life. Stopping treatment at 2 years comes with a “lower risk of toxic effects, less time in treatment for patients, and considerably lower costs for our health care system,” said Dr. West.

But for a fixed strategy to become more standard practice, the burden of proof is high, Dr. West said.

Jonathan W. Goldman, MD, says he understands the mentality, “If it’s going well, why would I change?”

In his experience, at 2 years of immunotherapy, most patients “say they’re feeling great” and “don’t mind coming in every 4 or 6 weeks, depending on the drug,” said Dr. Goldman, director of clinical trials in thoracic oncology at UCLA Medical Center in Santa Monica, Calif.

Dr. Goldman noted that in the future, instead of continuing immunotherapy indefinitely, clinicians may aim to maintain the patient “in the best response possible,” adding an intervention, such as stereotactic body radiotherapy or radiologic ablation, when needed.

“It may be that many of these long-term disease control patients are not cured in a traditional sense,” Dr. Goldman said, “but have controlled cancer that could potentially last years or even decades with ongoing care.”

Dr. Sun has relationships with Regeneron, GenMab, Seagen, and Bayer and has received institutional funding from Blueprint Research, Seagen Research, and IO Biotech Research. Dr. West has relationships with AstraZeneca, Genentech/Roche, Merck, and Regeneron outside the submitted work. Dr. Reck has relationships with Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Daiichi-Sankyo, GSK, Lilly, Merck, MSD, Mirati, Novartis, Roche Regeneron, and Pfizer.

A version of this article appeared on Medscape.com.

The 2022-2023 Term of the Supreme Court illustrates how important the Court has become to health-related matters, including decisions regarding the selection and training of new professionals, the daily practice of medicine, and the future availability of new drugs. The importance of several cases is reinforced by the fact that major medical organizations filed amicus curiae (“friend of the court”) briefs in those cases.

Amicus briefs are filed by individuals or organizations with something significant to say about a case to the court—most often to present a point of view, make an argument, or provide information that the parties to the case may not have communicated. Amicus briefs are burdensome in terms of the time, energy, and cost of preparing and filing. Thus, they are not undertaken lightly. Medical organizations submitted amicus briefs in the first 3 cases we consider.

Admissions, race, and diversity

The case: Students for Fair Admissions v President and Fellows of Harvard College

The American College of Obstetricians and Gynecologists (ACOG) joined an amici curiae brief in Students for Fair Admissions v President and Fellows of Harvard College (and the University of North Carolina [UNC]).¹ This case challenged the use of racial preferences in college admissions. The Association of American Medical Colleges (AAMC) was the lead organization; nearly 40 other health-related organizations joined the brief.

The legal claim. Those filing the suits asserted that racial preferences by public colleges violate the 14th Amendment’s Equal Protection Clause (“no state shall deny to any person … the equal protection of the law”). That is, if a state university gives racial preferences in selective admissions, it denies some other applicant the equal protection of the law. As for private schools (in this case, Harvard), Title VI of the Civil Rights Act of 1964 has the same standards as the Equal Protection Clause. Thus, the Court consolidated the cases and used the same legal standard in considering public and private colleges (with “colleges” including professional and graduate programs as well as undergraduate institutions).

Background. For nearly 50 years, the Supreme Court has allowed limited racial preferences in college admissions. Those preferences could only operate as a plus, however, and not a negative for applicants and be narrowly tailored. The measure was instituted temporarily; in a 2003 case, the Court said, “We expect that 25 years from now, the use of racial preferences will no longer be necessary.”²

Decision. In a 6-3 decision, the Court held (in the UNC case) that racial preferences generally violate the Constitution, and by a 6-2 decision (in the Harvard case) these preferences violate the Civil Rights Act of 1964. (Justice Jackson was recused in the Harvard case because of a conflict.) The opinion covered 237 pages in the US Reports, so any summary is incomplete.

The majority concluded, “The Harvard and UNC admissions programs cannot be reconciled with the guarantees of the Equal Protection Clause. Both programs lack sufficiently focused and measurable objectives warranting the use of race, unavoidably employ race in a negative manner, involve racial stereotyping, and lack meaningful end points. We have never permitted admissions programs to work in that way, and we will not do so today.”³

There were 3 concurring opinions and 2 dissents in the case. The concurrences reviewed the history of the Equal Protection Clause and the Civil Rights Act, the damage racial preferences can do, and the explicit limits the Court said there must be on racial preferences in higher education. The dissents had a different view of the legal history of the 14th Amendment. They said the majority was turning a blind eye to segregation in society and the race-based gap in America.

As a practical matter, this case means that colleges, including professional schools, cannot use racial preferences. The Court said that universities may consider essays and the like in which applicants describe how their own experiences as an individual (including race) have affected their own lives. However, the Court cautioned that “universities may not simply establish through application essays or other means the regime we hold unlawful today.”³

Continue to: The amici brief...

ACOG joined 40 other health-related organizations in filing an amici brief (multiple “friends”) in Students for Fair Admission. The AAMC led the brief, with the others signing as amici.⁴ The brief made 3 essential points: diversity in medical education “markedly improves health outcomes,” and a loss of diversity “threaten[s] patients’ health; medical schools engage in an intense “holistic” review of applicants for admission; and medical schools must consider applicants’ “full background” (including race) to achieve their educational and professional goals.⁴

A powerful part of the brief described the medical school admissions process, particularly the very “holistic” review that is not entirely dependent on admissions scores. The brief effectively weaves the consideration of race into this process, mentioning race (on page 22) only after discussing many other admissions factors.

Child custody decisions related to the Indian Child Welfare Act

The case: Haaland v Brackeen

The American Medical Association (AMA) and the American Academy of Pediatrics filed a brief in Haaland v Brackeen⁵ involving the constitutionality of the 1978 Indian Child Welfare Act (ICWA). The statute followed a terrible history of Indian children being removed from their families inappropriately, as detailed in a concurring opinion by Justice Gorsuch.⁵ The two purposes of the act were to promote raising Native American children in their culture and stem the downward trend in tribal membership.

The legal claim. The Court consolidated several cases. Essentially, a 10-month-old child (A.L.M.) was placed in foster care with the Brackeens in Texas. After more than 1 year, the Brackeens sought adoption; the biological father, mother, and grandparents all supported it. The Navajo and Cherokee Nations objected and informed the Texas court that they had found alternative placement with (nonrelative) tribal members in New Mexico. The “court-appointed guardian and a psychological expert … described the strong emotional bond between A.L.M. and his foster parents.” The court denied the adoption petition based on ICWA’s preference for tribe custody, and the Brackeens filed a lawsuit. The Court noted that the act “requires a state court to place an Indian child with an Indian caretaker, if one is available, even if the child is already living with a non-Indian family and the state court thinks it in the child’s best interest to stay there.” That is, the ICWA may require a placement that the court believes is not in the child’s best interest.⁵

Decision. The constitutional claim in the case was that Congress lacked the authority to impose these substantial rules on states in making child custody decisions. The Supreme Court, in a 7-2 decision, upheld the constitutionality of the ICWA. The Court found the authority primarily in Article 1, Section 8, giving Congress the power to “regulate Commerce with foreign Nations, and among the several States, and with the Indian Tribes.” In addition, the Court suggested that the treaty power and “principles inherent in the Constitution’s structure may empower Congress to act in the field of Indian affairs.”

The amici brief

The joint amici brief of the American Academy of Pediatrics (AAP) and the AMA argued that tribes are “extended families” of Native American children.⁶ It noted the destructive history of removing Native American children from their families and suggested that kinship care improves children’s health. To its credit, the brief also honestly noted the serious mental health and suicide rates in some tribes, which suggest issues that might arise in child custody and adoption cases.

The Court did not, in this case, take up another constitutional issue that the parties raised—whether the strong preference for Native American over non ̶ Native American custody violates the Equal Protection Clause of the 14th Amendment. The Court said the parties to this case did not have standing to raise the issue. Justice Kavanaugh, concurring, said it was a “serious” issue and invited it to be raised in another case.⁵

False Claims Act cases

The case: Costs for SuperValu prescriptions

For physicians and health care organizations, False Claims Act (FCA) cases are an ongoing burden and, some would say, threat. (There are also state FCAs, but here we are discussing the federal act.) The federal government has recovered more than $70 billion since 1986, most from health care entities.⁷The Justice Department identifies “health care fraud” as the largest area of FCA recovery and provides annual details on frauds resulting in liability.⁸

The legal claim. One FCA case this Term involved billings SuperValu made for outpatient prescriptions in Medicare-Medicaid programs. As its “usual and customary” costs, it essentially reported a list price that did not include the substantial discounts it commonly gave.⁹ The charge was that it “knowingly” made a false claim regarding the price of prescriptions. The question was what state of mind, or “scienter,” is required for “knowingly.” Should it be objective (what a reasonable person would know) or subjective (the defendant’s “knowledge and subjective beliefs”)?

Background. Subjective knowledge (what the defendant actually knows) may seem impossible to prove—the defendant could just say, “I did not know I was doing wrong.” Over time the law has developed several ways of demonstrating “knowing.” Justice Thomas, writing for a unanimous Court, held that whistleblowers or the government might prove “knowing” in 3 ways:

1. defendants “actually knew that their reported prices were not their ‘usual and customary’ prices when they reported them”

2. were aware of a substantial risk that their higher, retail prices were not their “usual and customary” prices and intentionally avoided learning whether their reports were accurate

3. were aware of such a substantial and unjustifiable risk but submitted the claims anyway.⁹

Of course, records of the company, information from the whistleblower, and circumstantial evidence may be used to prove any of these; it does not require the company’s admission.

The Court said that if the government or whistleblowers make a showing of any of these 3 things, it is enough.

Decision. The case was returned to the lower court to apply these rules.

The amici brief

The American Hospital Association and America’s Health Insurance Plans filed an amici brief.¹⁰ It reminded the Court that many reimbursement regulations are unclear. Therefore, it is inappropriate to impose FCA liability for guessing incorrectly what the regulations mean. Having to check on every possible ambiguity was unworkable. The Court declined, however, the suggestion that defendants should be able to use any one of many “objectively” reasonable interpretations of regulations.

Continue to: The case: Polansky v Executive Health Resources...

The case: Polansky v Executive Health Resources

Health care providers who dislike the FCA may find solace this Term in this second FCA case.¹¹

The legal claim. Polansky, a physician employed by a medical billing company, became an “intervenor” in a suit claiming the company assisted hospitals in false billing (inpatient claims for outpatient services). The government sought to dismiss the case, but Polansky refused.

Decision. The case eventually reached the Supreme Court, which held that the government may enter an FCA case at any time and move to dismiss the case even over the objection of a whistleblower. The government does not seek to enter a case in order to file dismissal motions often. When it does so, whistleblowers are protected by the fact that the dismissal motion requires a hearing before the federal court.

An important part of this case has escaped much attention. Justices Thomas, Kavanaugh, and Barrett invited litigation to determine if allowing private whistleblowers to represent the government’s interest is consistent with Article II of the Constitution.¹¹ The invitation will likely be accepted. We expect to see cases challenging the place of “intervenors” pursuing claims when the government has declined to take up the case. The private intervenor is a crucial provision of the current FCA, and if such a challenge were successful, it could substantially reduce FCA cases.

Criminal false claims

Another case this Term is cautionary about the consequences of health care misbilling. It resulted in a criminal charge. More importantly, in addition to a basic fraud charge, the government added a charge of aggravated identity theft,¹² which carries a mandatory 2-year prison sentence.

Dubin overbilled Medicaid for psychological testing by saying the testing was done by a licensed psychologist rather than an assistant. The government claimed the “identity theft” was using the patient’s (actual) Medicaid number in submitting the bill.¹² The Court unanimously held the overbilling was not aggravated identity theft as defined in federal law. Dubin could be convicted of fraudulent billing but not aggravated identity theft, thereby avoiding the mandatory prison term.

Patents of “genus” targets

The case: Amgen v Sanofi

This case, which corrected an error of the patent office, received little attention but was likely a turning point in the next generation of pharmaceuticals.¹³

Background. “Genus” patents allow a single pharmaceutical company to patent every antibody that binds to a specific amino acid on a naturally occurring protein. In this case, the patent office had granted a “genus” patent on “all antibodies” that bind to the naturally occurring protein PCSK9 and block it from hindering the body’s mechanism for removing low-density lipoprotein (LDL) cholesterol from the bloodstream,¹³ helping to reduce LDL cholesterol levels. These patents could involve millions of antibodies—and Amgen was claiming a patent on all of them. Amgen and Sanofi marketed their products, each with their own unique amino acid sequence.¹³ Amgen sued Sanofi for violating its patent rights.

Decision. The Court unanimously held that Amgen did not have a valid patent on all antibodies targeting PCSK9, only those that it had explicitly described in its patent application—a ruling based on a 150-year-old technical requirement for receiving a patent. An applicant for a patent must include “a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art…to make and use the same.”¹³ Amgen’s patent provided the description for only a few of the antibodies, but from the description in its application others could not “make and use” all of the antibodies targeting PCSK9.

While the decision was vital for future pharmaceuticals, the patent principle on which it was based has an interesting history. The Court noted that it affected the telegraph (Morse lost part of his patent), electric lights (Edison won his case against other inventors), and the glue for wood veneering (Perkins Glue Company lost).¹³

Continue to: Other notable decisions...

Student loans

The Court struck down the Biden Administration’s student loan forgiveness program, which would have cost approximately $430 billion.¹⁴ The central issue was whether the administration had the authority for such massive loan forgiveness; that is, whether Congress had authorized the broad loan forgiveness. The administration claimed authority from the post ̶ 9/11 HEROES Act, which allows the Secretary of Education to “waive or modify” loan provisions during national emergencies. The temporary hold on loan payments during COVID was based on this provision. However, in a 6-3 decision, the Court held that the act did not allow the secretary to cancel $430 billion in loans. “The Act allows the Secretary to ‘waive or modify’ existing statutory or regulatory provisions applicable to financial assistance programs under the Education Act, not to rewrite that statute from the ground up.”¹⁴

Free speech and the wedding web designer

303 Creative v Elenis involved a creative website designer who did not want to be required to create a website for a gay wedding.¹⁵ The designer had strong beliefs against same-sex marriages, but Colorado sought to force her to do so under the state “public accommodations” law. In a 6-3 decision, the Court held that the designer had a “free speech” right. That is, the state could not compel her to undertake speech expressing things she did not believe. This was because the website design was an expressive, creative activity and therefore was “speech” under the First Amendment.

Wetlands and the Clean Water Act

The essential issue in Sackett v Environmental Protection Agency (EPA) was the definitions of waters of the United States and related wetlands. The broad definition the EPA used meant it had jurisdiction to regulate an extraordinary amount of territory. It had, for example, prevented the Sacketts from building a modest house claiming it was part of the “waters of the United States because they were near a ditch that fed into a creek, which fed into Priest Lake, a navigable, intrastate lake.” The Court held that the EPA exceeded its statutory authority to define “wetlands.”¹⁶

The Court held that under the Clean Water Act, for the EPA to establish jurisdiction over adjacent wetlands, it must demonstrate that¹⁶:

1. “the adjacent body of water constitutes waters of the United States (ie, a relatively permanent body of water connected to traditional interstate navigable waters)…”

2. “…the wetland has a continuous surface connection with that water, making it difficult to determine where the water ends, and the wetland begins.”

Under this definition, the Sacketts could build their house. This was a statutory interpretation case. Therefore, Congress can expand or otherwise change the EPA’s authority under the Clean Water Act and other legislation.

Conclusions: A new justice, “shadow docket,” and ethics rules

SCOTUS’ newest member. When the Marshall called the Court into session on October 3, 2022, it had a new member, Justice Ketanji Brown Jackson. She was sworn in on June 30, 2022, when her predecessor (Justice Breyer) officially retired. She had been a law clerk for Justice Breyer in 1999, as well as a district court judge and court of appeals judge. Those who count such things described her as the “chattiest justice.”¹⁷ She spoke more than any other justice—by one count, a total of 75,632 words (an average of 1,300 words in each of the 58 arguments).

A more balanced Court? Most commentators view the Court as more balanced or less conservative than the previous Term. For example, Justice Sotomayor was in the majority 40% last Term but 65% this Term. Justice Thomas was in the majority 75% last Term but 55% this Term. Put another way, this Term in the divided cases, the liberal justices were in the majority 64% of the time, compared with the conservative justices 73%.¹⁸ Of course, these differences may reflect a different set of cases rather than a change in the direction of the Court. There were 11 (or 12, depending on how 1 case is counted) 6-3 cases, but only 5 were considered ideological. That suggests that, in many cases, the coalitions were somewhat fluid.

“Shadow docket” controversy continues.¹⁹ Shadow docket refers to orders the Court makes that do not follow oral arguments and often do not have written opinions. The orders are all publicly available. This Term a close examination of the approximately 30 shadow docket opinions shows that the overwhelming majority were dissents or explanations about denials of certiorari. The Court ordered only a few stays or injunctions via the shadow docket. One shadow docket stay (that prevented a lower court order from going into effect) is particularly noteworthy. A federal judge had ordered the suspension of the distribution of mifepristone while courts considered claims that the US Food and Drug Administration (FDA) had improperly approved the drug. In a shadow docket order, the Court issued the stay to allow mifepristone to be sold while the case challenging its approval was heard.²⁰ The only opinion was a dissent from Justice Alito. But it also demonstrates the importance of the shadow docket. Without this intervention, in at least part of the country, the distribution of mifepristone would have been interrupted pending the outcome of the FDA cases.

In August, the Court delayed a settlement in the Purdue Pharma liability bankruptcy case.²¹ It also stayed an injunction of a lower court, thereby permitting federal “ghost guns” regulations to go into effect at least temporarily.²²

More ethics rules to come? Another area in which the Court faced criticism was formal ethics rules. The justices make financial disclosures, but these are somewhat ambiguous. There is likely to be increasing pressure for a more complete disclosure of non-financial relationships and more formal ethics rules. ●

The 2022-2023 Term of the Supreme Court illustrates how important the Court has become to health-related matters, including decisions regarding the selection and training of new professionals, the daily practice of medicine, and the future availability of new drugs. The importance of several cases is reinforced by the fact that major medical organizations filed amicus curiae (“friend of the court”) briefs in those cases.

Amicus briefs are filed by individuals or organizations with something significant to say about a case to the court—most often to present a point of view, make an argument, or provide information that the parties to the case may not have communicated. Amicus briefs are burdensome in terms of the time, energy, and cost of preparing and filing. Thus, they are not undertaken lightly. Medical organizations submitted amicus briefs in the first 3 cases we consider.

Admissions, race, and diversity

The case: Students for Fair Admissions v President and Fellows of Harvard College

The American College of Obstetricians and Gynecologists (ACOG) joined an amici curiae brief in Students for Fair Admissions v President and Fellows of Harvard College (and the University of North Carolina [UNC]).¹ This case challenged the use of racial preferences in college admissions. The Association of American Medical Colleges (AAMC) was the lead organization; nearly 40 other health-related organizations joined the brief.

The legal claim. Those filing the suits asserted that racial preferences by public colleges violate the 14th Amendment’s Equal Protection Clause (“no state shall deny to any person … the equal protection of the law”). That is, if a state university gives racial preferences in selective admissions, it denies some other applicant the equal protection of the law. As for private schools (in this case, Harvard), Title VI of the Civil Rights Act of 1964 has the same standards as the Equal Protection Clause. Thus, the Court consolidated the cases and used the same legal standard in considering public and private colleges (with “colleges” including professional and graduate programs as well as undergraduate institutions).

Background. For nearly 50 years, the Supreme Court has allowed limited racial preferences in college admissions. Those preferences could only operate as a plus, however, and not a negative for applicants and be narrowly tailored. The measure was instituted temporarily; in a 2003 case, the Court said, “We expect that 25 years from now, the use of racial preferences will no longer be necessary.”²

Decision. In a 6-3 decision, the Court held (in the UNC case) that racial preferences generally violate the Constitution, and by a 6-2 decision (in the Harvard case) these preferences violate the Civil Rights Act of 1964. (Justice Jackson was recused in the Harvard case because of a conflict.) The opinion covered 237 pages in the US Reports, so any summary is incomplete.

The majority concluded, “The Harvard and UNC admissions programs cannot be reconciled with the guarantees of the Equal Protection Clause. Both programs lack sufficiently focused and measurable objectives warranting the use of race, unavoidably employ race in a negative manner, involve racial stereotyping, and lack meaningful end points. We have never permitted admissions programs to work in that way, and we will not do so today.”³

There were 3 concurring opinions and 2 dissents in the case. The concurrences reviewed the history of the Equal Protection Clause and the Civil Rights Act, the damage racial preferences can do, and the explicit limits the Court said there must be on racial preferences in higher education. The dissents had a different view of the legal history of the 14th Amendment. They said the majority was turning a blind eye to segregation in society and the race-based gap in America.

As a practical matter, this case means that colleges, including professional schools, cannot use racial preferences. The Court said that universities may consider essays and the like in which applicants describe how their own experiences as an individual (including race) have affected their own lives. However, the Court cautioned that “universities may not simply establish through application essays or other means the regime we hold unlawful today.”³

Continue to: The amici brief...

ACOG joined 40 other health-related organizations in filing an amici brief (multiple “friends”) in Students for Fair Admission. The AAMC led the brief, with the others signing as amici.⁴ The brief made 3 essential points: diversity in medical education “markedly improves health outcomes,” and a loss of diversity “threaten[s] patients’ health; medical schools engage in an intense “holistic” review of applicants for admission; and medical schools must consider applicants’ “full background” (including race) to achieve their educational and professional goals.⁴

A powerful part of the brief described the medical school admissions process, particularly the very “holistic” review that is not entirely dependent on admissions scores. The brief effectively weaves the consideration of race into this process, mentioning race (on page 22) only after discussing many other admissions factors.

Child custody decisions related to the Indian Child Welfare Act

The case: Haaland v Brackeen

The American Medical Association (AMA) and the American Academy of Pediatrics filed a brief in Haaland v Brackeen⁵ involving the constitutionality of the 1978 Indian Child Welfare Act (ICWA). The statute followed a terrible history of Indian children being removed from their families inappropriately, as detailed in a concurring opinion by Justice Gorsuch.⁵ The two purposes of the act were to promote raising Native American children in their culture and stem the downward trend in tribal membership.

The legal claim. The Court consolidated several cases. Essentially, a 10-month-old child (A.L.M.) was placed in foster care with the Brackeens in Texas. After more than 1 year, the Brackeens sought adoption; the biological father, mother, and grandparents all supported it. The Navajo and Cherokee Nations objected and informed the Texas court that they had found alternative placement with (nonrelative) tribal members in New Mexico. The “court-appointed guardian and a psychological expert … described the strong emotional bond between A.L.M. and his foster parents.” The court denied the adoption petition based on ICWA’s preference for tribe custody, and the Brackeens filed a lawsuit. The Court noted that the act “requires a state court to place an Indian child with an Indian caretaker, if one is available, even if the child is already living with a non-Indian family and the state court thinks it in the child’s best interest to stay there.” That is, the ICWA may require a placement that the court believes is not in the child’s best interest.⁵

Decision. The constitutional claim in the case was that Congress lacked the authority to impose these substantial rules on states in making child custody decisions. The Supreme Court, in a 7-2 decision, upheld the constitutionality of the ICWA. The Court found the authority primarily in Article 1, Section 8, giving Congress the power to “regulate Commerce with foreign Nations, and among the several States, and with the Indian Tribes.” In addition, the Court suggested that the treaty power and “principles inherent in the Constitution’s structure may empower Congress to act in the field of Indian affairs.”

The amici brief

The joint amici brief of the American Academy of Pediatrics (AAP) and the AMA argued that tribes are “extended families” of Native American children.⁶ It noted the destructive history of removing Native American children from their families and suggested that kinship care improves children’s health. To its credit, the brief also honestly noted the serious mental health and suicide rates in some tribes, which suggest issues that might arise in child custody and adoption cases.

The Court did not, in this case, take up another constitutional issue that the parties raised—whether the strong preference for Native American over non ̶ Native American custody violates the Equal Protection Clause of the 14th Amendment. The Court said the parties to this case did not have standing to raise the issue. Justice Kavanaugh, concurring, said it was a “serious” issue and invited it to be raised in another case.⁵

False Claims Act cases

The case: Costs for SuperValu prescriptions

For physicians and health care organizations, False Claims Act (FCA) cases are an ongoing burden and, some would say, threat. (There are also state FCAs, but here we are discussing the federal act.) The federal government has recovered more than $70 billion since 1986, most from health care entities.⁷The Justice Department identifies “health care fraud” as the largest area of FCA recovery and provides annual details on frauds resulting in liability.⁸

The legal claim. One FCA case this Term involved billings SuperValu made for outpatient prescriptions in Medicare-Medicaid programs. As its “usual and customary” costs, it essentially reported a list price that did not include the substantial discounts it commonly gave.⁹ The charge was that it “knowingly” made a false claim regarding the price of prescriptions. The question was what state of mind, or “scienter,” is required for “knowingly.” Should it be objective (what a reasonable person would know) or subjective (the defendant’s “knowledge and subjective beliefs”)?

Background. Subjective knowledge (what the defendant actually knows) may seem impossible to prove—the defendant could just say, “I did not know I was doing wrong.” Over time the law has developed several ways of demonstrating “knowing.” Justice Thomas, writing for a unanimous Court, held that whistleblowers or the government might prove “knowing” in 3 ways:

1. defendants “actually knew that their reported prices were not their ‘usual and customary’ prices when they reported them”

2. were aware of a substantial risk that their higher, retail prices were not their “usual and customary” prices and intentionally avoided learning whether their reports were accurate

3. were aware of such a substantial and unjustifiable risk but submitted the claims anyway.⁹

Of course, records of the company, information from the whistleblower, and circumstantial evidence may be used to prove any of these; it does not require the company’s admission.

The Court said that if the government or whistleblowers make a showing of any of these 3 things, it is enough.

Decision. The case was returned to the lower court to apply these rules.

The amici brief

The American Hospital Association and America’s Health Insurance Plans filed an amici brief.¹⁰ It reminded the Court that many reimbursement regulations are unclear. Therefore, it is inappropriate to impose FCA liability for guessing incorrectly what the regulations mean. Having to check on every possible ambiguity was unworkable. The Court declined, however, the suggestion that defendants should be able to use any one of many “objectively” reasonable interpretations of regulations.

Continue to: The case: Polansky v Executive Health Resources...

The case: Polansky v Executive Health Resources

Health care providers who dislike the FCA may find solace this Term in this second FCA case.¹¹

The legal claim. Polansky, a physician employed by a medical billing company, became an “intervenor” in a suit claiming the company assisted hospitals in false billing (inpatient claims for outpatient services). The government sought to dismiss the case, but Polansky refused.

Decision. The case eventually reached the Supreme Court, which held that the government may enter an FCA case at any time and move to dismiss the case even over the objection of a whistleblower. The government does not seek to enter a case in order to file dismissal motions often. When it does so, whistleblowers are protected by the fact that the dismissal motion requires a hearing before the federal court.

An important part of this case has escaped much attention. Justices Thomas, Kavanaugh, and Barrett invited litigation to determine if allowing private whistleblowers to represent the government’s interest is consistent with Article II of the Constitution.¹¹ The invitation will likely be accepted. We expect to see cases challenging the place of “intervenors” pursuing claims when the government has declined to take up the case. The private intervenor is a crucial provision of the current FCA, and if such a challenge were successful, it could substantially reduce FCA cases.

Criminal false claims

Another case this Term is cautionary about the consequences of health care misbilling. It resulted in a criminal charge. More importantly, in addition to a basic fraud charge, the government added a charge of aggravated identity theft,¹² which carries a mandatory 2-year prison sentence.

Dubin overbilled Medicaid for psychological testing by saying the testing was done by a licensed psychologist rather than an assistant. The government claimed the “identity theft” was using the patient’s (actual) Medicaid number in submitting the bill.¹² The Court unanimously held the overbilling was not aggravated identity theft as defined in federal law. Dubin could be convicted of fraudulent billing but not aggravated identity theft, thereby avoiding the mandatory prison term.

Patents of “genus” targets

The case: Amgen v Sanofi

This case, which corrected an error of the patent office, received little attention but was likely a turning point in the next generation of pharmaceuticals.¹³

Background. “Genus” patents allow a single pharmaceutical company to patent every antibody that binds to a specific amino acid on a naturally occurring protein. In this case, the patent office had granted a “genus” patent on “all antibodies” that bind to the naturally occurring protein PCSK9 and block it from hindering the body’s mechanism for removing low-density lipoprotein (LDL) cholesterol from the bloodstream,¹³ helping to reduce LDL cholesterol levels. These patents could involve millions of antibodies—and Amgen was claiming a patent on all of them. Amgen and Sanofi marketed their products, each with their own unique amino acid sequence.¹³ Amgen sued Sanofi for violating its patent rights.

Decision. The Court unanimously held that Amgen did not have a valid patent on all antibodies targeting PCSK9, only those that it had explicitly described in its patent application—a ruling based on a 150-year-old technical requirement for receiving a patent. An applicant for a patent must include “a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art…to make and use the same.”¹³ Amgen’s patent provided the description for only a few of the antibodies, but from the description in its application others could not “make and use” all of the antibodies targeting PCSK9.

While the decision was vital for future pharmaceuticals, the patent principle on which it was based has an interesting history. The Court noted that it affected the telegraph (Morse lost part of his patent), electric lights (Edison won his case against other inventors), and the glue for wood veneering (Perkins Glue Company lost).¹³

Continue to: Other notable decisions...

Student loans

The Court struck down the Biden Administration’s student loan forgiveness program, which would have cost approximately $430 billion.¹⁴ The central issue was whether the administration had the authority for such massive loan forgiveness; that is, whether Congress had authorized the broad loan forgiveness. The administration claimed authority from the post ̶ 9/11 HEROES Act, which allows the Secretary of Education to “waive or modify” loan provisions during national emergencies. The temporary hold on loan payments during COVID was based on this provision. However, in a 6-3 decision, the Court held that the act did not allow the secretary to cancel $430 billion in loans. “The Act allows the Secretary to ‘waive or modify’ existing statutory or regulatory provisions applicable to financial assistance programs under the Education Act, not to rewrite that statute from the ground up.”¹⁴

Free speech and the wedding web designer

303 Creative v Elenis involved a creative website designer who did not want to be required to create a website for a gay wedding.¹⁵ The designer had strong beliefs against same-sex marriages, but Colorado sought to force her to do so under the state “public accommodations” law. In a 6-3 decision, the Court held that the designer had a “free speech” right. That is, the state could not compel her to undertake speech expressing things she did not believe. This was because the website design was an expressive, creative activity and therefore was “speech” under the First Amendment.

Wetlands and the Clean Water Act

The essential issue in Sackett v Environmental Protection Agency (EPA) was the definitions of waters of the United States and related wetlands. The broad definition the EPA used meant it had jurisdiction to regulate an extraordinary amount of territory. It had, for example, prevented the Sacketts from building a modest house claiming it was part of the “waters of the United States because they were near a ditch that fed into a creek, which fed into Priest Lake, a navigable, intrastate lake.” The Court held that the EPA exceeded its statutory authority to define “wetlands.”¹⁶

The Court held that under the Clean Water Act, for the EPA to establish jurisdiction over adjacent wetlands, it must demonstrate that¹⁶:

1. “the adjacent body of water constitutes waters of the United States (ie, a relatively permanent body of water connected to traditional interstate navigable waters)…”

2. “…the wetland has a continuous surface connection with that water, making it difficult to determine where the water ends, and the wetland begins.”

Under this definition, the Sacketts could build their house. This was a statutory interpretation case. Therefore, Congress can expand or otherwise change the EPA’s authority under the Clean Water Act and other legislation.

Conclusions: A new justice, “shadow docket,” and ethics rules

SCOTUS’ newest member. When the Marshall called the Court into session on October 3, 2022, it had a new member, Justice Ketanji Brown Jackson. She was sworn in on June 30, 2022, when her predecessor (Justice Breyer) officially retired. She had been a law clerk for Justice Breyer in 1999, as well as a district court judge and court of appeals judge. Those who count such things described her as the “chattiest justice.”¹⁷ She spoke more than any other justice—by one count, a total of 75,632 words (an average of 1,300 words in each of the 58 arguments).

A more balanced Court? Most commentators view the Court as more balanced or less conservative than the previous Term. For example, Justice Sotomayor was in the majority 40% last Term but 65% this Term. Justice Thomas was in the majority 75% last Term but 55% this Term. Put another way, this Term in the divided cases, the liberal justices were in the majority 64% of the time, compared with the conservative justices 73%.¹⁸ Of course, these differences may reflect a different set of cases rather than a change in the direction of the Court. There were 11 (or 12, depending on how 1 case is counted) 6-3 cases, but only 5 were considered ideological. That suggests that, in many cases, the coalitions were somewhat fluid.

“Shadow docket” controversy continues.¹⁹ Shadow docket refers to orders the Court makes that do not follow oral arguments and often do not have written opinions. The orders are all publicly available. This Term a close examination of the approximately 30 shadow docket opinions shows that the overwhelming majority were dissents or explanations about denials of certiorari. The Court ordered only a few stays or injunctions via the shadow docket. One shadow docket stay (that prevented a lower court order from going into effect) is particularly noteworthy. A federal judge had ordered the suspension of the distribution of mifepristone while courts considered claims that the US Food and Drug Administration (FDA) had improperly approved the drug. In a shadow docket order, the Court issued the stay to allow mifepristone to be sold while the case challenging its approval was heard.²⁰ The only opinion was a dissent from Justice Alito. But it also demonstrates the importance of the shadow docket. Without this intervention, in at least part of the country, the distribution of mifepristone would have been interrupted pending the outcome of the FDA cases.

In August, the Court delayed a settlement in the Purdue Pharma liability bankruptcy case.²¹ It also stayed an injunction of a lower court, thereby permitting federal “ghost guns” regulations to go into effect at least temporarily.²²

More ethics rules to come? Another area in which the Court faced criticism was formal ethics rules. The justices make financial disclosures, but these are somewhat ambiguous. There is likely to be increasing pressure for a more complete disclosure of non-financial relationships and more formal ethics rules. ●

The 2022-2023 Term of the Supreme Court illustrates how important the Court has become to health-related matters, including decisions regarding the selection and training of new professionals, the daily practice of medicine, and the future availability of new drugs. The importance of several cases is reinforced by the fact that major medical organizations filed amicus curiae (“friend of the court”) briefs in those cases.

Amicus briefs are filed by individuals or organizations with something significant to say about a case to the court—most often to present a point of view, make an argument, or provide information that the parties to the case may not have communicated. Amicus briefs are burdensome in terms of the time, energy, and cost of preparing and filing. Thus, they are not undertaken lightly. Medical organizations submitted amicus briefs in the first 3 cases we consider.

Admissions, race, and diversity

The case: Students for Fair Admissions v President and Fellows of Harvard College

The American College of Obstetricians and Gynecologists (ACOG) joined an amici curiae brief in Students for Fair Admissions v President and Fellows of Harvard College (and the University of North Carolina [UNC]).¹ This case challenged the use of racial preferences in college admissions. The Association of American Medical Colleges (AAMC) was the lead organization; nearly 40 other health-related organizations joined the brief.

The legal claim. Those filing the suits asserted that racial preferences by public colleges violate the 14th Amendment’s Equal Protection Clause (“no state shall deny to any person … the equal protection of the law”). That is, if a state university gives racial preferences in selective admissions, it denies some other applicant the equal protection of the law. As for private schools (in this case, Harvard), Title VI of the Civil Rights Act of 1964 has the same standards as the Equal Protection Clause. Thus, the Court consolidated the cases and used the same legal standard in considering public and private colleges (with “colleges” including professional and graduate programs as well as undergraduate institutions).

Background. For nearly 50 years, the Supreme Court has allowed limited racial preferences in college admissions. Those preferences could only operate as a plus, however, and not a negative for applicants and be narrowly tailored. The measure was instituted temporarily; in a 2003 case, the Court said, “We expect that 25 years from now, the use of racial preferences will no longer be necessary.”²

Decision. In a 6-3 decision, the Court held (in the UNC case) that racial preferences generally violate the Constitution, and by a 6-2 decision (in the Harvard case) these preferences violate the Civil Rights Act of 1964. (Justice Jackson was recused in the Harvard case because of a conflict.) The opinion covered 237 pages in the US Reports, so any summary is incomplete.

The majority concluded, “The Harvard and UNC admissions programs cannot be reconciled with the guarantees of the Equal Protection Clause. Both programs lack sufficiently focused and measurable objectives warranting the use of race, unavoidably employ race in a negative manner, involve racial stereotyping, and lack meaningful end points. We have never permitted admissions programs to work in that way, and we will not do so today.”³

There were 3 concurring opinions and 2 dissents in the case. The concurrences reviewed the history of the Equal Protection Clause and the Civil Rights Act, the damage racial preferences can do, and the explicit limits the Court said there must be on racial preferences in higher education. The dissents had a different view of the legal history of the 14th Amendment. They said the majority was turning a blind eye to segregation in society and the race-based gap in America.

As a practical matter, this case means that colleges, including professional schools, cannot use racial preferences. The Court said that universities may consider essays and the like in which applicants describe how their own experiences as an individual (including race) have affected their own lives. However, the Court cautioned that “universities may not simply establish through application essays or other means the regime we hold unlawful today.”³

Continue to: The amici brief...

ACOG joined 40 other health-related organizations in filing an amici brief (multiple “friends”) in Students for Fair Admission. The AAMC led the brief, with the others signing as amici.⁴ The brief made 3 essential points: diversity in medical education “markedly improves health outcomes,” and a loss of diversity “threaten[s] patients’ health; medical schools engage in an intense “holistic” review of applicants for admission; and medical schools must consider applicants’ “full background” (including race) to achieve their educational and professional goals.⁴

A powerful part of the brief described the medical school admissions process, particularly the very “holistic” review that is not entirely dependent on admissions scores. The brief effectively weaves the consideration of race into this process, mentioning race (on page 22) only after discussing many other admissions factors.

Child custody decisions related to the Indian Child Welfare Act

The case: Haaland v Brackeen

The American Medical Association (AMA) and the American Academy of Pediatrics filed a brief in Haaland v Brackeen⁵ involving the constitutionality of the 1978 Indian Child Welfare Act (ICWA). The statute followed a terrible history of Indian children being removed from their families inappropriately, as detailed in a concurring opinion by Justice Gorsuch.⁵ The two purposes of the act were to promote raising Native American children in their culture and stem the downward trend in tribal membership.

The legal claim. The Court consolidated several cases. Essentially, a 10-month-old child (A.L.M.) was placed in foster care with the Brackeens in Texas. After more than 1 year, the Brackeens sought adoption; the biological father, mother, and grandparents all supported it. The Navajo and Cherokee Nations objected and informed the Texas court that they had found alternative placement with (nonrelative) tribal members in New Mexico. The “court-appointed guardian and a psychological expert … described the strong emotional bond between A.L.M. and his foster parents.” The court denied the adoption petition based on ICWA’s preference for tribe custody, and the Brackeens filed a lawsuit. The Court noted that the act “requires a state court to place an Indian child with an Indian caretaker, if one is available, even if the child is already living with a non-Indian family and the state court thinks it in the child’s best interest to stay there.” That is, the ICWA may require a placement that the court believes is not in the child’s best interest.⁵

Decision. The constitutional claim in the case was that Congress lacked the authority to impose these substantial rules on states in making child custody decisions. The Supreme Court, in a 7-2 decision, upheld the constitutionality of the ICWA. The Court found the authority primarily in Article 1, Section 8, giving Congress the power to “regulate Commerce with foreign Nations, and among the several States, and with the Indian Tribes.” In addition, the Court suggested that the treaty power and “principles inherent in the Constitution’s structure may empower Congress to act in the field of Indian affairs.”

The amici brief

The joint amici brief of the American Academy of Pediatrics (AAP) and the AMA argued that tribes are “extended families” of Native American children.⁶ It noted the destructive history of removing Native American children from their families and suggested that kinship care improves children’s health. To its credit, the brief also honestly noted the serious mental health and suicide rates in some tribes, which suggest issues that might arise in child custody and adoption cases.

The Court did not, in this case, take up another constitutional issue that the parties raised—whether the strong preference for Native American over non ̶ Native American custody violates the Equal Protection Clause of the 14th Amendment. The Court said the parties to this case did not have standing to raise the issue. Justice Kavanaugh, concurring, said it was a “serious” issue and invited it to be raised in another case.⁵

False Claims Act cases

The case: Costs for SuperValu prescriptions

For physicians and health care organizations, False Claims Act (FCA) cases are an ongoing burden and, some would say, threat. (There are also state FCAs, but here we are discussing the federal act.) The federal government has recovered more than $70 billion since 1986, most from health care entities.⁷The Justice Department identifies “health care fraud” as the largest area of FCA recovery and provides annual details on frauds resulting in liability.⁸

The legal claim. One FCA case this Term involved billings SuperValu made for outpatient prescriptions in Medicare-Medicaid programs. As its “usual and customary” costs, it essentially reported a list price that did not include the substantial discounts it commonly gave.⁹ The charge was that it “knowingly” made a false claim regarding the price of prescriptions. The question was what state of mind, or “scienter,” is required for “knowingly.” Should it be objective (what a reasonable person would know) or subjective (the defendant’s “knowledge and subjective beliefs”)?

Background. Subjective knowledge (what the defendant actually knows) may seem impossible to prove—the defendant could just say, “I did not know I was doing wrong.” Over time the law has developed several ways of demonstrating “knowing.” Justice Thomas, writing for a unanimous Court, held that whistleblowers or the government might prove “knowing” in 3 ways:

1. defendants “actually knew that their reported prices were not their ‘usual and customary’ prices when they reported them”

2. were aware of a substantial risk that their higher, retail prices were not their “usual and customary” prices and intentionally avoided learning whether their reports were accurate

3. were aware of such a substantial and unjustifiable risk but submitted the claims anyway.⁹

Of course, records of the company, information from the whistleblower, and circumstantial evidence may be used to prove any of these; it does not require the company’s admission.

The Court said that if the government or whistleblowers make a showing of any of these 3 things, it is enough.

Decision. The case was returned to the lower court to apply these rules.

The amici brief

The American Hospital Association and America’s Health Insurance Plans filed an amici brief.¹⁰ It reminded the Court that many reimbursement regulations are unclear. Therefore, it is inappropriate to impose FCA liability for guessing incorrectly what the regulations mean. Having to check on every possible ambiguity was unworkable. The Court declined, however, the suggestion that defendants should be able to use any one of many “objectively” reasonable interpretations of regulations.

Continue to: The case: Polansky v Executive Health Resources...

The case: Polansky v Executive Health Resources

Health care providers who dislike the FCA may find solace this Term in this second FCA case.¹¹

The legal claim. Polansky, a physician employed by a medical billing company, became an “intervenor” in a suit claiming the company assisted hospitals in false billing (inpatient claims for outpatient services). The government sought to dismiss the case, but Polansky refused.

Decision. The case eventually reached the Supreme Court, which held that the government may enter an FCA case at any time and move to dismiss the case even over the objection of a whistleblower. The government does not seek to enter a case in order to file dismissal motions often. When it does so, whistleblowers are protected by the fact that the dismissal motion requires a hearing before the federal court.

An important part of this case has escaped much attention. Justices Thomas, Kavanaugh, and Barrett invited litigation to determine if allowing private whistleblowers to represent the government’s interest is consistent with Article II of the Constitution.¹¹ The invitation will likely be accepted. We expect to see cases challenging the place of “intervenors” pursuing claims when the government has declined to take up the case. The private intervenor is a crucial provision of the current FCA, and if such a challenge were successful, it could substantially reduce FCA cases.

Criminal false claims

Another case this Term is cautionary about the consequences of health care misbilling. It resulted in a criminal charge. More importantly, in addition to a basic fraud charge, the government added a charge of aggravated identity theft,¹² which carries a mandatory 2-year prison sentence.

Dubin overbilled Medicaid for psychological testing by saying the testing was done by a licensed psychologist rather than an assistant. The government claimed the “identity theft” was using the patient’s (actual) Medicaid number in submitting the bill.¹² The Court unanimously held the overbilling was not aggravated identity theft as defined in federal law. Dubin could be convicted of fraudulent billing but not aggravated identity theft, thereby avoiding the mandatory prison term.

Patents of “genus” targets

The case: Amgen v Sanofi

This case, which corrected an error of the patent office, received little attention but was likely a turning point in the next generation of pharmaceuticals.¹³

Background. “Genus” patents allow a single pharmaceutical company to patent every antibody that binds to a specific amino acid on a naturally occurring protein. In this case, the patent office had granted a “genus” patent on “all antibodies” that bind to the naturally occurring protein PCSK9 and block it from hindering the body’s mechanism for removing low-density lipoprotein (LDL) cholesterol from the bloodstream,¹³ helping to reduce LDL cholesterol levels. These patents could involve millions of antibodies—and Amgen was claiming a patent on all of them. Amgen and Sanofi marketed their products, each with their own unique amino acid sequence.¹³ Amgen sued Sanofi for violating its patent rights.

Decision. The Court unanimously held that Amgen did not have a valid patent on all antibodies targeting PCSK9, only those that it had explicitly described in its patent application—a ruling based on a 150-year-old technical requirement for receiving a patent. An applicant for a patent must include “a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art…to make and use the same.”¹³ Amgen’s patent provided the description for only a few of the antibodies, but from the description in its application others could not “make and use” all of the antibodies targeting PCSK9.

While the decision was vital for future pharmaceuticals, the patent principle on which it was based has an interesting history. The Court noted that it affected the telegraph (Morse lost part of his patent), electric lights (Edison won his case against other inventors), and the glue for wood veneering (Perkins Glue Company lost).¹³

Continue to: Other notable decisions...

Student loans

The Court struck down the Biden Administration’s student loan forgiveness program, which would have cost approximately $430 billion.¹⁴ The central issue was whether the administration had the authority for such massive loan forgiveness; that is, whether Congress had authorized the broad loan forgiveness. The administration claimed authority from the post ̶ 9/11 HEROES Act, which allows the Secretary of Education to “waive or modify” loan provisions during national emergencies. The temporary hold on loan payments during COVID was based on this provision. However, in a 6-3 decision, the Court held that the act did not allow the secretary to cancel $430 billion in loans. “The Act allows the Secretary to ‘waive or modify’ existing statutory or regulatory provisions applicable to financial assistance programs under the Education Act, not to rewrite that statute from the ground up.”¹⁴

Free speech and the wedding web designer

303 Creative v Elenis involved a creative website designer who did not want to be required to create a website for a gay wedding.¹⁵ The designer had strong beliefs against same-sex marriages, but Colorado sought to force her to do so under the state “public accommodations” law. In a 6-3 decision, the Court held that the designer had a “free speech” right. That is, the state could not compel her to undertake speech expressing things she did not believe. This was because the website design was an expressive, creative activity and therefore was “speech” under the First Amendment.

Wetlands and the Clean Water Act

The essential issue in Sackett v Environmental Protection Agency (EPA) was the definitions of waters of the United States and related wetlands. The broad definition the EPA used meant it had jurisdiction to regulate an extraordinary amount of territory. It had, for example, prevented the Sacketts from building a modest house claiming it was part of the “waters of the United States because they were near a ditch that fed into a creek, which fed into Priest Lake, a navigable, intrastate lake.” The Court held that the EPA exceeded its statutory authority to define “wetlands.”¹⁶

The Court held that under the Clean Water Act, for the EPA to establish jurisdiction over adjacent wetlands, it must demonstrate that¹⁶:

1. “the adjacent body of water constitutes waters of the United States (ie, a relatively permanent body of water connected to traditional interstate navigable waters)…”

2. “…the wetland has a continuous surface connection with that water, making it difficult to determine where the water ends, and the wetland begins.”

Under this definition, the Sacketts could build their house. This was a statutory interpretation case. Therefore, Congress can expand or otherwise change the EPA’s authority under the Clean Water Act and other legislation.

Conclusions: A new justice, “shadow docket,” and ethics rules

SCOTUS’ newest member. When the Marshall called the Court into session on October 3, 2022, it had a new member, Justice Ketanji Brown Jackson. She was sworn in on June 30, 2022, when her predecessor (Justice Breyer) officially retired. She had been a law clerk for Justice Breyer in 1999, as well as a district court judge and court of appeals judge. Those who count such things described her as the “chattiest justice.”¹⁷ She spoke more than any other justice—by one count, a total of 75,632 words (an average of 1,300 words in each of the 58 arguments).

A more balanced Court? Most commentators view the Court as more balanced or less conservative than the previous Term. For example, Justice Sotomayor was in the majority 40% last Term but 65% this Term. Justice Thomas was in the majority 75% last Term but 55% this Term. Put another way, this Term in the divided cases, the liberal justices were in the majority 64% of the time, compared with the conservative justices 73%.¹⁸ Of course, these differences may reflect a different set of cases rather than a change in the direction of the Court. There were 11 (or 12, depending on how 1 case is counted) 6-3 cases, but only 5 were considered ideological. That suggests that, in many cases, the coalitions were somewhat fluid.

“Shadow docket” controversy continues.¹⁹ Shadow docket refers to orders the Court makes that do not follow oral arguments and often do not have written opinions. The orders are all publicly available. This Term a close examination of the approximately 30 shadow docket opinions shows that the overwhelming majority were dissents or explanations about denials of certiorari. The Court ordered only a few stays or injunctions via the shadow docket. One shadow docket stay (that prevented a lower court order from going into effect) is particularly noteworthy. A federal judge had ordered the suspension of the distribution of mifepristone while courts considered claims that the US Food and Drug Administration (FDA) had improperly approved the drug. In a shadow docket order, the Court issued the stay to allow mifepristone to be sold while the case challenging its approval was heard.²⁰ The only opinion was a dissent from Justice Alito. But it also demonstrates the importance of the shadow docket. Without this intervention, in at least part of the country, the distribution of mifepristone would have been interrupted pending the outcome of the FDA cases.

In August, the Court delayed a settlement in the Purdue Pharma liability bankruptcy case.²¹ It also stayed an injunction of a lower court, thereby permitting federal “ghost guns” regulations to go into effect at least temporarily.²²

More ethics rules to come? Another area in which the Court faced criticism was formal ethics rules. The justices make financial disclosures, but these are somewhat ambiguous. There is likely to be increasing pressure for a more complete disclosure of non-financial relationships and more formal ethics rules. ●

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Hepatitis B is one of the more common infections encountered in the daily practice of obstetrics. It is responsible for 40% to 45% of all cases of viral hepatitis.^1,2 Hepatitis B may cause serious complications in both the infected mother and neonate.

In this article, I review the virology, epidemiology, and clinical presentation of hepatitis B and then discuss the key diagnostic tests and, subsequently, the clinical management for both the mother and neonate. I focus particular attention on relatively new information about the value of specific antiviral medication to enhance the protective effect of conventional neonatal immunoprophylaxis.

To set the framework for the discussion, consider the following 2 case studies.

CASE 1 Undetectable level of hepatitis B surface antibody in a pregnant woman

A 25-year-old healthy primigravid woman at 10 weeks’ gestation had a series of laboratory studies that included a test for hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (HBsAb). The test for the surface antigen was negative. The test for the surface antibody was below the level of detection. Upon questioning, the patient indicates that she received the 3-dose hepatitis B vaccine when she was age 13 years.

• What treatment, if any, is indicated for this patient?
• What treatment is indicated for her neonate?

CASE 2 Pregnant woman tests positive for hepatitis B surface antigen

A 31-year-old woman (G3P2002) at 12 weeks’ gestation tested positive for HBsAg. She indicates that she never has had symptomatic hepatitis and that she considers herself to be in excellent health.

• What additional laboratory tests are indicated at this time?
• What additional laboratory test should be performed at the end of the second trimester?
• What treatment is indicated for the mother and neonate?

Virology and epidemiology of hepatitis B

Hepatitis B is caused by a double-stranded, enveloped DNA virus. The virus has 10 genotypes and 24 subtypes.³ The organism contains 3 major antigens. Detection of these antigens and their corresponding antibodies is an essential step in the diagnostic workup of patients who may be infected.

The surface antigen (HBsAg) confers infectivity and is the most valuable serologic marker of infection. The e antigen (HBeAg) is not present in every infected patient. It is secreted from infected cells, but it is not incorporated into the viral particle. When present, it denotes a high level of viral replication and exceptionally high infectivity. The core antigen (HBcAg) is a valuable serologic marker for distinguishing between acute and chronic infection.^1-3

Hepatitis B is highly infectious, much more so than HIV or hepatitis C. The virus has an incubation period of 4 weeks to 6 months, and the duration of incubation is inversely related to the size of the viral inoculum. The virus is transmitted in 3 principal ways: sexual contact with contaminated genital tract secretions, contact with infected blood from sharing contaminated drug-injecting paraphernalia or from receiving a blood transfusion (extremely rare today), and transmission from an infected mother to her neonate. Perinatal transmission occurs primarily during the delivery process as opposed to transplacental infection. Transmission also can occur by more casual household contact, such as sharing eating utensils, kissing, and handling an infant.^1,2,4,5

Worldwide, more than 400 million people have chronic hepatitis B infection. In the United States, approximately 1.25 to 1.5 million individuals are infected. Several groups are at particularly high risk for being infected, including^1-3:

• Asians
• Alaska Natives
• sub-Saharan Africans
• sex workers
• intravenous drug users
• individuals with hemophilia
• international travelers
• staff and residents of long-term care facilities
• tattoo recipients.

Continue to: Clinical presentation...

Approximately 90% of adult patients who contract hepatitis B, either symptomatically or asymptomatically, will develop protective levels of antibody and clear the virus from their system. They will then have lifelong immunity to reinfection. Approximately 10% of patients will fail to develop protective levels of antibody and will become chronically infected, posing a risk to their household members, sexual contacts, and their fetus if they become pregnant. Persistence of the surface antigen in the patient’s serum for more than 6 months denotes chronic infection. A very small number of individuals—less than 1%—will develop acute liver failure and experience a fatal outcome.^1-3,5

In the United States, the prevalence of acute hepatitis B in pregnancy is 1 to 2 per 1,000. Clinical manifestations typically include anorexia, nausea, low-grade fever, right upper quadrant pain and tenderness, passage of clay-colored stools, and jaundice.

The prevalence of chronic infection in pregnancy is significantly higher, approximately 5 to 15 per 1,000. Over the long term, patients with chronic infection are at risk for progressive liver injury, including cirrhosis and even hepatocellular carcinoma. These serious sequelae are particularly likely to occur when the patient is co-infected with hepatitis C, D, or both. The overall risk of progression to chronic cirrhosis is approximately 15% to 30%. In patients who progress to cirrhosis, the annual incidence of hepatocellular carcinoma is 10%.^1-3

Diagnosis of hepatitis B infection

Patients with acute hepatitis B will test positive for HBsAg and immunoglobulin M (IgM) antibody to the core antigen. Some patients will also test positive for HBeAg. Assessment of the patient’s serum by polymerase chain reaction (PCR) allows quantitation of the viral load, which often is expressed as viral copies per milliliter. Alternatively, the quantitative hepatitis B DNA concentration may be expressed as international units per milliliter (IU/mL). The World Health Organization recommends this latter quantitative method. Multiplying the DNA in IU/mL by 5.6 provides the conversion to viral copies per milliliter.

Patients with chronic hepatitis B infection will test positive for the HBsAg and for immunoglobulin G (IgG) antibody to the core antigen. They may also have a positive test for the HBeAg, and PCR may be used to quantify the viral load.^1-3

Managing hepatitis B infection in pregnancy

General supportive measures. All pregnant patients should be tested for the HBsAg and HBsAb at the time of the first prenatal appointment. The tests should be repeated at the beginning of the third trimester in high-risk patients. Seropositive patients should have a hepatitis B genotype, a test for the e antigen, and tests for other sexually transmissible infections (gonorrhea, chlamydia, syphilis, HIV) and for hepatitis C and D. Liver function tests should be performed to assess for elevations in the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Patients with elevated transaminase enzymes should have a coagulation profile to be certain they are not at risk for a coagulopathy.

At the end of the second trimester, patients should have a PCR assessment to determine the viral load. This assessment will be important for deciding if specific antiviral therapy is indicated during the third trimester to enhance the effects of neonatal immunoprophylaxis (see below). Of note, patients who are positive for the e antigen may have a very high viral load and yet have normal or near-normal transaminase levels. This seemingly paradoxical finding reflects the non-cytopathic nature of hepatitis B.

The patient should optimize her nutrition and sleep. She should avoid, or at least minimize, medications such as acetaminophen that could cause further liver injury. Without question, she should refrain from consuming even small amounts of alcohol. She should be tested for immunity to hepatitis A; if found to be susceptible, she should be vaccinated with the hepatitis A vaccine. This agent is an inactivated vaccine and is safe for administration at any time in pregnancy.^1,2,5

Household contacts. In addition to the measures outlined above, the patient’s household contacts, particularly her sexual partner(s), should be tested for immunity to hepatitis B. If they do not have immunity by virtue of natural infection or previous vaccination, they should receive the hepatitis B vaccine series. It is also prudent to provide the sexual partner(s) with an initial dose of hepatitis B immune globulin (HBIG) to provide a temporary level of passive immunity.

Postdelivery care. After delivery, the patient should be referred to an infectious disease specialist or hepatologist for consideration of long-term treatment with antiviral agents, such as interferon alfa, pegylated interferon alfa, lamivudine, adefovir, entecavir, telbivudine, or tenofovir.⁶ The principal candidates for treatment are those who have cirrhosis and detectable levels of hepatitis B DNA. The ultimate goal of treatment is to reduce the serum hepatitis B DNA concentration to an undetectable level. Once the surface antigenemia is cleared, treatment can be stopped. A cure is defined when the absence of hepa-titis B DNA in the serum is sustained.

Neonatal immunoprophylaxis

The Centers for Disease Control and Prevention recommends universal hepatitis B vaccination for all newborns. The first dose of the vaccine should be administered prior to hospital discharge. The second and third doses should be administered 1 and 6 months later.^1,2,5 There are few, if any, medical contraindications to neonatal vaccination. For the vast majority of infants, the immunity induced by vaccination is lifelong. For a small number, immunity may wane over time. Thus, reassessment of the HBsAb concentration is indicated in selected situations, for example, acute high-risk exposure to an infected person, development of an immunosuppressive disorder, or pregnancy.

Infants delivered to mothers who are infected with hepatitis B also should receive HBIG in addition to the vaccine. HBIG provides passive immunization to counteract the high viral inoculum encountered by the neonate during delivery. This preparation should be administered within 12 hours of birth.^1,2,5

In the absence of immunoprophylaxis, a neonate delivered to a mother who is seropositive for HBsAg has a 20% to 30% probability of becoming chronically infected. If the mother is positive for both the surface antigen and the e antigen, the risk of chronic infection increases to almost 90%. Approximately 90% of infants who are infected in the perinatal period subsequently develop chronic infection. However, with appropriate immunoprophylaxis in the neonatal period, the risk of perinatal transmission is reduced by 85% to 95%.^1,2,5

Cesarean delivery offers no additional protection beyond that provided by immunoprophylaxis. Moreover, because immunoprophylaxis is so effective, infected mothers may breastfeed without fear of transmitting infection to their infant. Shi and colleagues published a systematic review and meta-analysis of the risk associated with breastfeeding in hepatitis B–infected mothers.⁷ Infants who breastfed did not have a higher rate of mother-to-child transmission, regardless of whether they received combined immunoprophylaxis or only hepatitis B vaccine and regardless of whether the HBsAg was detected in the mother’s breast milk. The only precaution is the need to avoid breastfeeding if the nipples are cracked or bleeding or if exudative lesions are present on the skin near the nipple.

Continue to: Maternal antiviral therapy...

Maternal antiviral therapy

As noted above, neonatal immunoprophylaxis is 85% to 95% effective in preventing perinatal transmission of hepatitis B infection. Failures of prophylaxis are primarily due to antenatal transmission in patients who have exceptionally high viral loads. Several cutoffs have been used to define “high viral load,” including greater than 1 to 2 million copies/mL and a hepatitis B DNA concentration greater than 200,000 IU/mL. There is not a perfect consensus on the appropriate cutoff.

In essence, 2 different approaches have been tried to further reduce the risk of perinatal transmission in these high-risk patients.⁸ The first major initiative was administration of HBIG (100–200 IU) intramuscularly to the patient at 28, 32, and 36 weeks. The outcomes with this approach have been inconsistent, due, at least in part, to varying doses of the agent and various cutoffs for defining “high risk,” and this intervention is no longer recommended.^1,2

The second major approach is administration of specific antiviral drugs to the mother during the third trimester. The first agent widely used in clinical practice was lamivudine. In a systematic review and meta-analysis, Shi and colleagues reported that, in infants whose mothers received lamivudine plus conventional neonatal immunuprophylaxis, the risk of perinatal infection was significantly reduced compared with infants who received only immunoprophylaxis.⁹

Although lamivudine is effective, there is considerable concern about the rapid development of viral resistance to the medication. Accordingly, most attention today is focused on the use of tenofovir to prevent perinatal transmission.

In an important early investigation, Pan and colleagues reported the results of a randomized controlled trial conducted in China in women with a hepatitis B DNA concentration greater than 200,000 IU/mL (viral load > 1,120,000 copies/mL).¹⁰ Patients also were positive for the e antigen. Ninety-two patients were assigned to tenofovir disoproxil fumarate (TDF), 300 mg daily, from 30 to 32 weeks until postpartum week 4 plus conventional neonatal immunoprophylaxis, and 100 patients were assigned to immunoprophylaxis alone. In the intention-to-treat analysis, 18 neonates in the control group were infected compared with 5 in the treatment group (P = .007). In the per-protocol analysis, 7 neonates in the control group were infected compared with 0 in the treatment group (P = .01). No clinically significant adverse maternal or neonatal effects occurred in the treatment group.

Subsequently, Jourdain and colleagues reported a multicenter, double-blind trial conducted in 17 public health hospitals in Thailand.¹¹ TDF (300 mg daily) or placebo was administered from 28 weeks’ gestation until 8 weeks postpartum. Patients in both arms of the study were positive for the e antigen; 87% to 90% of the patients had a serum hepatitis B DNA concentration greater than 200,000 IU/mL.Following birth, infants in both groups received an injection of HBIG and then 4 doses of hepatitis B vaccine (0, 1, 2, 4, and 6 months). Both the HBIG and hepatitis B vaccine were administered very promptly after birth (median time, 1.2–1.3 hours).

At 6 months after delivery, 2% of infants in the placebo group (3 of 147) were HBsAg-positive compared with none of the infants in the treatment arm.¹¹ No serious adverse effects occurred in infants in the TDF group. This difference in outcome was not statistically significant, but the overall rate of infection was so low in both groups that the sample size was definitely too small to exclude a type 2 statistical error. Moreover, the fourth dose of neonatal hepatitis B vaccine may have contributed to the surprisingly low rate of perinatal transmission. Of note, the serum hepatitis B DNA concentration in the TDF group declined from a mean of 7.6 log₁₀ IU/mL to a mean of 4.0 log₁₀ IU/mL at delivery.

In the most recent report, Wang and colleagues reported the results of a prospective cohort study in patients with a hepatitis B virus DNA concentration greater than 200,000 IU/mL.¹² Beginning at either 24 or 32 weeks, patients were assigned to treatment with either oral TDF (300 mg daily) or oral telbivudine (LdT, 600 mg daily). The medications were continued for 4 weeks postpartum. In the intention-to-treat analysis, the rates of perinatal transmission were comparable, 1.5% versus 1.8%. In the per-protocol analysis, no infants in either group were infected. However, the predelivery decline in hepatitis Bvirus DNA concentration was greater in the TDF group. The ALT elevation rate was also lower in the TDF group. Patients in the LdT group had fewer problems with anorexia but more instances of arthralgia compared with those in the TDF group.

Based primarily on these 3 investigations, I recommend that all infected patients with a hepatitis B DNA concentration greater than 200,000 IU/mL or a viral load greater than 1,120,000 million copies/mL receive oral TDF, 300 mg daily, from 28 weeks until at least 4 to 8 weeks postpartum. The decision about duration of postpartum treatment should be made in consultation with an infectious disease specialist or hepatologist.

Case studies resolved

CASE 1 No protective level of surface antibody

This patient should promptly receive a single booster dose of the hepatitis B vaccine. The vaccine is an inactivated agent and is safe for administration at any time in pregnancy. Following delivery and prior to discharge from the hospital, the neonate should receive the first dose of the hepatitis B vaccine. A second dose should be administered 1 month later, and a third dose should be administered 6 months after the first dose.

CASE 2 Mother is seropositive for HBsAg

This patient should be tested immediately for HIV infection and hepatitis C and D. The hepatitis B viral genotype should be determined. She also should have a panel of liver function tests. If any of these tests are abnormal, a coagulation profile should be obtained to be certain that the patient is not at risk for a coagulopathy. Near the end of the second trimester, a hepatitis B viral load should be obtained. If the viral DNA concentration is greater than 200,000 IU/mLor a viral load greater than 1,120,000 million copies/mL, the patient should be treated with tenofovir, 300 mg daily, from week 28 until at least 4 weeks after delivery. The neonate should receive an injection of HBIG within 12 hours of birth and the first dose of the hepatitis B vaccine prior to discharge from the hospital. Two additional doses of the vaccine should be administered 1 and 6 months later. ●

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Hepatitis B is one of the more common infections encountered in the daily practice of obstetrics. It is responsible for 40% to 45% of all cases of viral hepatitis.^1,2 Hepatitis B may cause serious complications in both the infected mother and neonate.

In this article, I review the virology, epidemiology, and clinical presentation of hepatitis B and then discuss the key diagnostic tests and, subsequently, the clinical management for both the mother and neonate. I focus particular attention on relatively new information about the value of specific antiviral medication to enhance the protective effect of conventional neonatal immunoprophylaxis.

To set the framework for the discussion, consider the following 2 case studies.

CASE 1 Undetectable level of hepatitis B surface antibody in a pregnant woman

A 25-year-old healthy primigravid woman at 10 weeks’ gestation had a series of laboratory studies that included a test for hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (HBsAb). The test for the surface antigen was negative. The test for the surface antibody was below the level of detection. Upon questioning, the patient indicates that she received the 3-dose hepatitis B vaccine when she was age 13 years.

• What treatment, if any, is indicated for this patient?
• What treatment is indicated for her neonate?

CASE 2 Pregnant woman tests positive for hepatitis B surface antigen

A 31-year-old woman (G3P2002) at 12 weeks’ gestation tested positive for HBsAg. She indicates that she never has had symptomatic hepatitis and that she considers herself to be in excellent health.

• What additional laboratory tests are indicated at this time?
• What additional laboratory test should be performed at the end of the second trimester?
• What treatment is indicated for the mother and neonate?

Virology and epidemiology of hepatitis B

Hepatitis B is caused by a double-stranded, enveloped DNA virus. The virus has 10 genotypes and 24 subtypes.³ The organism contains 3 major antigens. Detection of these antigens and their corresponding antibodies is an essential step in the diagnostic workup of patients who may be infected.

The surface antigen (HBsAg) confers infectivity and is the most valuable serologic marker of infection. The e antigen (HBeAg) is not present in every infected patient. It is secreted from infected cells, but it is not incorporated into the viral particle. When present, it denotes a high level of viral replication and exceptionally high infectivity. The core antigen (HBcAg) is a valuable serologic marker for distinguishing between acute and chronic infection.^1-3

Hepatitis B is highly infectious, much more so than HIV or hepatitis C. The virus has an incubation period of 4 weeks to 6 months, and the duration of incubation is inversely related to the size of the viral inoculum. The virus is transmitted in 3 principal ways: sexual contact with contaminated genital tract secretions, contact with infected blood from sharing contaminated drug-injecting paraphernalia or from receiving a blood transfusion (extremely rare today), and transmission from an infected mother to her neonate. Perinatal transmission occurs primarily during the delivery process as opposed to transplacental infection. Transmission also can occur by more casual household contact, such as sharing eating utensils, kissing, and handling an infant.^1,2,4,5

Worldwide, more than 400 million people have chronic hepatitis B infection. In the United States, approximately 1.25 to 1.5 million individuals are infected. Several groups are at particularly high risk for being infected, including^1-3:

• Asians
• Alaska Natives
• sub-Saharan Africans
• sex workers
• intravenous drug users
• individuals with hemophilia
• international travelers
• staff and residents of long-term care facilities
• tattoo recipients.

Continue to: Clinical presentation...

Approximately 90% of adult patients who contract hepatitis B, either symptomatically or asymptomatically, will develop protective levels of antibody and clear the virus from their system. They will then have lifelong immunity to reinfection. Approximately 10% of patients will fail to develop protective levels of antibody and will become chronically infected, posing a risk to their household members, sexual contacts, and their fetus if they become pregnant. Persistence of the surface antigen in the patient’s serum for more than 6 months denotes chronic infection. A very small number of individuals—less than 1%—will develop acute liver failure and experience a fatal outcome.^1-3,5

In the United States, the prevalence of acute hepatitis B in pregnancy is 1 to 2 per 1,000. Clinical manifestations typically include anorexia, nausea, low-grade fever, right upper quadrant pain and tenderness, passage of clay-colored stools, and jaundice.

The prevalence of chronic infection in pregnancy is significantly higher, approximately 5 to 15 per 1,000. Over the long term, patients with chronic infection are at risk for progressive liver injury, including cirrhosis and even hepatocellular carcinoma. These serious sequelae are particularly likely to occur when the patient is co-infected with hepatitis C, D, or both. The overall risk of progression to chronic cirrhosis is approximately 15% to 30%. In patients who progress to cirrhosis, the annual incidence of hepatocellular carcinoma is 10%.^1-3

Diagnosis of hepatitis B infection

Patients with acute hepatitis B will test positive for HBsAg and immunoglobulin M (IgM) antibody to the core antigen. Some patients will also test positive for HBeAg. Assessment of the patient’s serum by polymerase chain reaction (PCR) allows quantitation of the viral load, which often is expressed as viral copies per milliliter. Alternatively, the quantitative hepatitis B DNA concentration may be expressed as international units per milliliter (IU/mL). The World Health Organization recommends this latter quantitative method. Multiplying the DNA in IU/mL by 5.6 provides the conversion to viral copies per milliliter.

Patients with chronic hepatitis B infection will test positive for the HBsAg and for immunoglobulin G (IgG) antibody to the core antigen. They may also have a positive test for the HBeAg, and PCR may be used to quantify the viral load.^1-3

Managing hepatitis B infection in pregnancy

General supportive measures. All pregnant patients should be tested for the HBsAg and HBsAb at the time of the first prenatal appointment. The tests should be repeated at the beginning of the third trimester in high-risk patients. Seropositive patients should have a hepatitis B genotype, a test for the e antigen, and tests for other sexually transmissible infections (gonorrhea, chlamydia, syphilis, HIV) and for hepatitis C and D. Liver function tests should be performed to assess for elevations in the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Patients with elevated transaminase enzymes should have a coagulation profile to be certain they are not at risk for a coagulopathy.

At the end of the second trimester, patients should have a PCR assessment to determine the viral load. This assessment will be important for deciding if specific antiviral therapy is indicated during the third trimester to enhance the effects of neonatal immunoprophylaxis (see below). Of note, patients who are positive for the e antigen may have a very high viral load and yet have normal or near-normal transaminase levels. This seemingly paradoxical finding reflects the non-cytopathic nature of hepatitis B.

The patient should optimize her nutrition and sleep. She should avoid, or at least minimize, medications such as acetaminophen that could cause further liver injury. Without question, she should refrain from consuming even small amounts of alcohol. She should be tested for immunity to hepatitis A; if found to be susceptible, she should be vaccinated with the hepatitis A vaccine. This agent is an inactivated vaccine and is safe for administration at any time in pregnancy.^1,2,5

Household contacts. In addition to the measures outlined above, the patient’s household contacts, particularly her sexual partner(s), should be tested for immunity to hepatitis B. If they do not have immunity by virtue of natural infection or previous vaccination, they should receive the hepatitis B vaccine series. It is also prudent to provide the sexual partner(s) with an initial dose of hepatitis B immune globulin (HBIG) to provide a temporary level of passive immunity.

Postdelivery care. After delivery, the patient should be referred to an infectious disease specialist or hepatologist for consideration of long-term treatment with antiviral agents, such as interferon alfa, pegylated interferon alfa, lamivudine, adefovir, entecavir, telbivudine, or tenofovir.⁶ The principal candidates for treatment are those who have cirrhosis and detectable levels of hepatitis B DNA. The ultimate goal of treatment is to reduce the serum hepatitis B DNA concentration to an undetectable level. Once the surface antigenemia is cleared, treatment can be stopped. A cure is defined when the absence of hepa-titis B DNA in the serum is sustained.

Neonatal immunoprophylaxis

The Centers for Disease Control and Prevention recommends universal hepatitis B vaccination for all newborns. The first dose of the vaccine should be administered prior to hospital discharge. The second and third doses should be administered 1 and 6 months later.^1,2,5 There are few, if any, medical contraindications to neonatal vaccination. For the vast majority of infants, the immunity induced by vaccination is lifelong. For a small number, immunity may wane over time. Thus, reassessment of the HBsAb concentration is indicated in selected situations, for example, acute high-risk exposure to an infected person, development of an immunosuppressive disorder, or pregnancy.

Infants delivered to mothers who are infected with hepatitis B also should receive HBIG in addition to the vaccine. HBIG provides passive immunization to counteract the high viral inoculum encountered by the neonate during delivery. This preparation should be administered within 12 hours of birth.^1,2,5

In the absence of immunoprophylaxis, a neonate delivered to a mother who is seropositive for HBsAg has a 20% to 30% probability of becoming chronically infected. If the mother is positive for both the surface antigen and the e antigen, the risk of chronic infection increases to almost 90%. Approximately 90% of infants who are infected in the perinatal period subsequently develop chronic infection. However, with appropriate immunoprophylaxis in the neonatal period, the risk of perinatal transmission is reduced by 85% to 95%.^1,2,5

Cesarean delivery offers no additional protection beyond that provided by immunoprophylaxis. Moreover, because immunoprophylaxis is so effective, infected mothers may breastfeed without fear of transmitting infection to their infant. Shi and colleagues published a systematic review and meta-analysis of the risk associated with breastfeeding in hepatitis B–infected mothers.⁷ Infants who breastfed did not have a higher rate of mother-to-child transmission, regardless of whether they received combined immunoprophylaxis or only hepatitis B vaccine and regardless of whether the HBsAg was detected in the mother’s breast milk. The only precaution is the need to avoid breastfeeding if the nipples are cracked or bleeding or if exudative lesions are present on the skin near the nipple.

Continue to: Maternal antiviral therapy...

Maternal antiviral therapy

As noted above, neonatal immunoprophylaxis is 85% to 95% effective in preventing perinatal transmission of hepatitis B infection. Failures of prophylaxis are primarily due to antenatal transmission in patients who have exceptionally high viral loads. Several cutoffs have been used to define “high viral load,” including greater than 1 to 2 million copies/mL and a hepatitis B DNA concentration greater than 200,000 IU/mL. There is not a perfect consensus on the appropriate cutoff.

In essence, 2 different approaches have been tried to further reduce the risk of perinatal transmission in these high-risk patients.⁸ The first major initiative was administration of HBIG (100–200 IU) intramuscularly to the patient at 28, 32, and 36 weeks. The outcomes with this approach have been inconsistent, due, at least in part, to varying doses of the agent and various cutoffs for defining “high risk,” and this intervention is no longer recommended.^1,2

The second major approach is administration of specific antiviral drugs to the mother during the third trimester. The first agent widely used in clinical practice was lamivudine. In a systematic review and meta-analysis, Shi and colleagues reported that, in infants whose mothers received lamivudine plus conventional neonatal immunuprophylaxis, the risk of perinatal infection was significantly reduced compared with infants who received only immunoprophylaxis.⁹

Although lamivudine is effective, there is considerable concern about the rapid development of viral resistance to the medication. Accordingly, most attention today is focused on the use of tenofovir to prevent perinatal transmission.

In an important early investigation, Pan and colleagues reported the results of a randomized controlled trial conducted in China in women with a hepatitis B DNA concentration greater than 200,000 IU/mL (viral load > 1,120,000 copies/mL).¹⁰ Patients also were positive for the e antigen. Ninety-two patients were assigned to tenofovir disoproxil fumarate (TDF), 300 mg daily, from 30 to 32 weeks until postpartum week 4 plus conventional neonatal immunoprophylaxis, and 100 patients were assigned to immunoprophylaxis alone. In the intention-to-treat analysis, 18 neonates in the control group were infected compared with 5 in the treatment group (P = .007). In the per-protocol analysis, 7 neonates in the control group were infected compared with 0 in the treatment group (P = .01). No clinically significant adverse maternal or neonatal effects occurred in the treatment group.

Subsequently, Jourdain and colleagues reported a multicenter, double-blind trial conducted in 17 public health hospitals in Thailand.¹¹ TDF (300 mg daily) or placebo was administered from 28 weeks’ gestation until 8 weeks postpartum. Patients in both arms of the study were positive for the e antigen; 87% to 90% of the patients had a serum hepatitis B DNA concentration greater than 200,000 IU/mL.Following birth, infants in both groups received an injection of HBIG and then 4 doses of hepatitis B vaccine (0, 1, 2, 4, and 6 months). Both the HBIG and hepatitis B vaccine were administered very promptly after birth (median time, 1.2–1.3 hours).

At 6 months after delivery, 2% of infants in the placebo group (3 of 147) were HBsAg-positive compared with none of the infants in the treatment arm.¹¹ No serious adverse effects occurred in infants in the TDF group. This difference in outcome was not statistically significant, but the overall rate of infection was so low in both groups that the sample size was definitely too small to exclude a type 2 statistical error. Moreover, the fourth dose of neonatal hepatitis B vaccine may have contributed to the surprisingly low rate of perinatal transmission. Of note, the serum hepatitis B DNA concentration in the TDF group declined from a mean of 7.6 log₁₀ IU/mL to a mean of 4.0 log₁₀ IU/mL at delivery.

In the most recent report, Wang and colleagues reported the results of a prospective cohort study in patients with a hepatitis B virus DNA concentration greater than 200,000 IU/mL.¹² Beginning at either 24 or 32 weeks, patients were assigned to treatment with either oral TDF (300 mg daily) or oral telbivudine (LdT, 600 mg daily). The medications were continued for 4 weeks postpartum. In the intention-to-treat analysis, the rates of perinatal transmission were comparable, 1.5% versus 1.8%. In the per-protocol analysis, no infants in either group were infected. However, the predelivery decline in hepatitis Bvirus DNA concentration was greater in the TDF group. The ALT elevation rate was also lower in the TDF group. Patients in the LdT group had fewer problems with anorexia but more instances of arthralgia compared with those in the TDF group.

Based primarily on these 3 investigations, I recommend that all infected patients with a hepatitis B DNA concentration greater than 200,000 IU/mL or a viral load greater than 1,120,000 million copies/mL receive oral TDF, 300 mg daily, from 28 weeks until at least 4 to 8 weeks postpartum. The decision about duration of postpartum treatment should be made in consultation with an infectious disease specialist or hepatologist.

Case studies resolved

CASE 1 No protective level of surface antibody

This patient should promptly receive a single booster dose of the hepatitis B vaccine. The vaccine is an inactivated agent and is safe for administration at any time in pregnancy. Following delivery and prior to discharge from the hospital, the neonate should receive the first dose of the hepatitis B vaccine. A second dose should be administered 1 month later, and a third dose should be administered 6 months after the first dose.

CASE 2 Mother is seropositive for HBsAg

This patient should be tested immediately for HIV infection and hepatitis C and D. The hepatitis B viral genotype should be determined. She also should have a panel of liver function tests. If any of these tests are abnormal, a coagulation profile should be obtained to be certain that the patient is not at risk for a coagulopathy. Near the end of the second trimester, a hepatitis B viral load should be obtained. If the viral DNA concentration is greater than 200,000 IU/mLor a viral load greater than 1,120,000 million copies/mL, the patient should be treated with tenofovir, 300 mg daily, from week 28 until at least 4 weeks after delivery. The neonate should receive an injection of HBIG within 12 hours of birth and the first dose of the hepatitis B vaccine prior to discharge from the hospital. Two additional doses of the vaccine should be administered 1 and 6 months later. ●

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Hepatitis B is one of the more common infections encountered in the daily practice of obstetrics. It is responsible for 40% to 45% of all cases of viral hepatitis.^1,2 Hepatitis B may cause serious complications in both the infected mother and neonate.

In this article, I review the virology, epidemiology, and clinical presentation of hepatitis B and then discuss the key diagnostic tests and, subsequently, the clinical management for both the mother and neonate. I focus particular attention on relatively new information about the value of specific antiviral medication to enhance the protective effect of conventional neonatal immunoprophylaxis.

To set the framework for the discussion, consider the following 2 case studies.

CASE 1 Undetectable level of hepatitis B surface antibody in a pregnant woman

A 25-year-old healthy primigravid woman at 10 weeks’ gestation had a series of laboratory studies that included a test for hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (HBsAb). The test for the surface antigen was negative. The test for the surface antibody was below the level of detection. Upon questioning, the patient indicates that she received the 3-dose hepatitis B vaccine when she was age 13 years.

• What treatment, if any, is indicated for this patient?
• What treatment is indicated for her neonate?

CASE 2 Pregnant woman tests positive for hepatitis B surface antigen

A 31-year-old woman (G3P2002) at 12 weeks’ gestation tested positive for HBsAg. She indicates that she never has had symptomatic hepatitis and that she considers herself to be in excellent health.

• What additional laboratory tests are indicated at this time?
• What additional laboratory test should be performed at the end of the second trimester?
• What treatment is indicated for the mother and neonate?

Virology and epidemiology of hepatitis B

Hepatitis B is caused by a double-stranded, enveloped DNA virus. The virus has 10 genotypes and 24 subtypes.³ The organism contains 3 major antigens. Detection of these antigens and their corresponding antibodies is an essential step in the diagnostic workup of patients who may be infected.

The surface antigen (HBsAg) confers infectivity and is the most valuable serologic marker of infection. The e antigen (HBeAg) is not present in every infected patient. It is secreted from infected cells, but it is not incorporated into the viral particle. When present, it denotes a high level of viral replication and exceptionally high infectivity. The core antigen (HBcAg) is a valuable serologic marker for distinguishing between acute and chronic infection.^1-3

Hepatitis B is highly infectious, much more so than HIV or hepatitis C. The virus has an incubation period of 4 weeks to 6 months, and the duration of incubation is inversely related to the size of the viral inoculum. The virus is transmitted in 3 principal ways: sexual contact with contaminated genital tract secretions, contact with infected blood from sharing contaminated drug-injecting paraphernalia or from receiving a blood transfusion (extremely rare today), and transmission from an infected mother to her neonate. Perinatal transmission occurs primarily during the delivery process as opposed to transplacental infection. Transmission also can occur by more casual household contact, such as sharing eating utensils, kissing, and handling an infant.^1,2,4,5

Worldwide, more than 400 million people have chronic hepatitis B infection. In the United States, approximately 1.25 to 1.5 million individuals are infected. Several groups are at particularly high risk for being infected, including^1-3:

• Asians
• Alaska Natives
• sub-Saharan Africans
• sex workers
• intravenous drug users
• individuals with hemophilia
• international travelers
• staff and residents of long-term care facilities
• tattoo recipients.

Continue to: Clinical presentation...

Approximately 90% of adult patients who contract hepatitis B, either symptomatically or asymptomatically, will develop protective levels of antibody and clear the virus from their system. They will then have lifelong immunity to reinfection. Approximately 10% of patients will fail to develop protective levels of antibody and will become chronically infected, posing a risk to their household members, sexual contacts, and their fetus if they become pregnant. Persistence of the surface antigen in the patient’s serum for more than 6 months denotes chronic infection. A very small number of individuals—less than 1%—will develop acute liver failure and experience a fatal outcome.^1-3,5

In the United States, the prevalence of acute hepatitis B in pregnancy is 1 to 2 per 1,000. Clinical manifestations typically include anorexia, nausea, low-grade fever, right upper quadrant pain and tenderness, passage of clay-colored stools, and jaundice.

The prevalence of chronic infection in pregnancy is significantly higher, approximately 5 to 15 per 1,000. Over the long term, patients with chronic infection are at risk for progressive liver injury, including cirrhosis and even hepatocellular carcinoma. These serious sequelae are particularly likely to occur when the patient is co-infected with hepatitis C, D, or both. The overall risk of progression to chronic cirrhosis is approximately 15% to 30%. In patients who progress to cirrhosis, the annual incidence of hepatocellular carcinoma is 10%.^1-3

Diagnosis of hepatitis B infection

Patients with acute hepatitis B will test positive for HBsAg and immunoglobulin M (IgM) antibody to the core antigen. Some patients will also test positive for HBeAg. Assessment of the patient’s serum by polymerase chain reaction (PCR) allows quantitation of the viral load, which often is expressed as viral copies per milliliter. Alternatively, the quantitative hepatitis B DNA concentration may be expressed as international units per milliliter (IU/mL). The World Health Organization recommends this latter quantitative method. Multiplying the DNA in IU/mL by 5.6 provides the conversion to viral copies per milliliter.

Patients with chronic hepatitis B infection will test positive for the HBsAg and for immunoglobulin G (IgG) antibody to the core antigen. They may also have a positive test for the HBeAg, and PCR may be used to quantify the viral load.^1-3

Managing hepatitis B infection in pregnancy

General supportive measures. All pregnant patients should be tested for the HBsAg and HBsAb at the time of the first prenatal appointment. The tests should be repeated at the beginning of the third trimester in high-risk patients. Seropositive patients should have a hepatitis B genotype, a test for the e antigen, and tests for other sexually transmissible infections (gonorrhea, chlamydia, syphilis, HIV) and for hepatitis C and D. Liver function tests should be performed to assess for elevations in the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Patients with elevated transaminase enzymes should have a coagulation profile to be certain they are not at risk for a coagulopathy.

At the end of the second trimester, patients should have a PCR assessment to determine the viral load. This assessment will be important for deciding if specific antiviral therapy is indicated during the third trimester to enhance the effects of neonatal immunoprophylaxis (see below). Of note, patients who are positive for the e antigen may have a very high viral load and yet have normal or near-normal transaminase levels. This seemingly paradoxical finding reflects the non-cytopathic nature of hepatitis B.

The patient should optimize her nutrition and sleep. She should avoid, or at least minimize, medications such as acetaminophen that could cause further liver injury. Without question, she should refrain from consuming even small amounts of alcohol. She should be tested for immunity to hepatitis A; if found to be susceptible, she should be vaccinated with the hepatitis A vaccine. This agent is an inactivated vaccine and is safe for administration at any time in pregnancy.^1,2,5

Household contacts. In addition to the measures outlined above, the patient’s household contacts, particularly her sexual partner(s), should be tested for immunity to hepatitis B. If they do not have immunity by virtue of natural infection or previous vaccination, they should receive the hepatitis B vaccine series. It is also prudent to provide the sexual partner(s) with an initial dose of hepatitis B immune globulin (HBIG) to provide a temporary level of passive immunity.

Postdelivery care. After delivery, the patient should be referred to an infectious disease specialist or hepatologist for consideration of long-term treatment with antiviral agents, such as interferon alfa, pegylated interferon alfa, lamivudine, adefovir, entecavir, telbivudine, or tenofovir.⁶ The principal candidates for treatment are those who have cirrhosis and detectable levels of hepatitis B DNA. The ultimate goal of treatment is to reduce the serum hepatitis B DNA concentration to an undetectable level. Once the surface antigenemia is cleared, treatment can be stopped. A cure is defined when the absence of hepa-titis B DNA in the serum is sustained.

Neonatal immunoprophylaxis

The Centers for Disease Control and Prevention recommends universal hepatitis B vaccination for all newborns. The first dose of the vaccine should be administered prior to hospital discharge. The second and third doses should be administered 1 and 6 months later.^1,2,5 There are few, if any, medical contraindications to neonatal vaccination. For the vast majority of infants, the immunity induced by vaccination is lifelong. For a small number, immunity may wane over time. Thus, reassessment of the HBsAb concentration is indicated in selected situations, for example, acute high-risk exposure to an infected person, development of an immunosuppressive disorder, or pregnancy.

Infants delivered to mothers who are infected with hepatitis B also should receive HBIG in addition to the vaccine. HBIG provides passive immunization to counteract the high viral inoculum encountered by the neonate during delivery. This preparation should be administered within 12 hours of birth.^1,2,5

In the absence of immunoprophylaxis, a neonate delivered to a mother who is seropositive for HBsAg has a 20% to 30% probability of becoming chronically infected. If the mother is positive for both the surface antigen and the e antigen, the risk of chronic infection increases to almost 90%. Approximately 90% of infants who are infected in the perinatal period subsequently develop chronic infection. However, with appropriate immunoprophylaxis in the neonatal period, the risk of perinatal transmission is reduced by 85% to 95%.^1,2,5

Cesarean delivery offers no additional protection beyond that provided by immunoprophylaxis. Moreover, because immunoprophylaxis is so effective, infected mothers may breastfeed without fear of transmitting infection to their infant. Shi and colleagues published a systematic review and meta-analysis of the risk associated with breastfeeding in hepatitis B–infected mothers.⁷ Infants who breastfed did not have a higher rate of mother-to-child transmission, regardless of whether they received combined immunoprophylaxis or only hepatitis B vaccine and regardless of whether the HBsAg was detected in the mother’s breast milk. The only precaution is the need to avoid breastfeeding if the nipples are cracked or bleeding or if exudative lesions are present on the skin near the nipple.

Continue to: Maternal antiviral therapy...

Maternal antiviral therapy

As noted above, neonatal immunoprophylaxis is 85% to 95% effective in preventing perinatal transmission of hepatitis B infection. Failures of prophylaxis are primarily due to antenatal transmission in patients who have exceptionally high viral loads. Several cutoffs have been used to define “high viral load,” including greater than 1 to 2 million copies/mL and a hepatitis B DNA concentration greater than 200,000 IU/mL. There is not a perfect consensus on the appropriate cutoff.

In essence, 2 different approaches have been tried to further reduce the risk of perinatal transmission in these high-risk patients.⁸ The first major initiative was administration of HBIG (100–200 IU) intramuscularly to the patient at 28, 32, and 36 weeks. The outcomes with this approach have been inconsistent, due, at least in part, to varying doses of the agent and various cutoffs for defining “high risk,” and this intervention is no longer recommended.^1,2

The second major approach is administration of specific antiviral drugs to the mother during the third trimester. The first agent widely used in clinical practice was lamivudine. In a systematic review and meta-analysis, Shi and colleagues reported that, in infants whose mothers received lamivudine plus conventional neonatal immunuprophylaxis, the risk of perinatal infection was significantly reduced compared with infants who received only immunoprophylaxis.⁹

Although lamivudine is effective, there is considerable concern about the rapid development of viral resistance to the medication. Accordingly, most attention today is focused on the use of tenofovir to prevent perinatal transmission.

In an important early investigation, Pan and colleagues reported the results of a randomized controlled trial conducted in China in women with a hepatitis B DNA concentration greater than 200,000 IU/mL (viral load > 1,120,000 copies/mL).¹⁰ Patients also were positive for the e antigen. Ninety-two patients were assigned to tenofovir disoproxil fumarate (TDF), 300 mg daily, from 30 to 32 weeks until postpartum week 4 plus conventional neonatal immunoprophylaxis, and 100 patients were assigned to immunoprophylaxis alone. In the intention-to-treat analysis, 18 neonates in the control group were infected compared with 5 in the treatment group (P = .007). In the per-protocol analysis, 7 neonates in the control group were infected compared with 0 in the treatment group (P = .01). No clinically significant adverse maternal or neonatal effects occurred in the treatment group.

Subsequently, Jourdain and colleagues reported a multicenter, double-blind trial conducted in 17 public health hospitals in Thailand.¹¹ TDF (300 mg daily) or placebo was administered from 28 weeks’ gestation until 8 weeks postpartum. Patients in both arms of the study were positive for the e antigen; 87% to 90% of the patients had a serum hepatitis B DNA concentration greater than 200,000 IU/mL.Following birth, infants in both groups received an injection of HBIG and then 4 doses of hepatitis B vaccine (0, 1, 2, 4, and 6 months). Both the HBIG and hepatitis B vaccine were administered very promptly after birth (median time, 1.2–1.3 hours).

At 6 months after delivery, 2% of infants in the placebo group (3 of 147) were HBsAg-positive compared with none of the infants in the treatment arm.¹¹ No serious adverse effects occurred in infants in the TDF group. This difference in outcome was not statistically significant, but the overall rate of infection was so low in both groups that the sample size was definitely too small to exclude a type 2 statistical error. Moreover, the fourth dose of neonatal hepatitis B vaccine may have contributed to the surprisingly low rate of perinatal transmission. Of note, the serum hepatitis B DNA concentration in the TDF group declined from a mean of 7.6 log₁₀ IU/mL to a mean of 4.0 log₁₀ IU/mL at delivery.

In the most recent report, Wang and colleagues reported the results of a prospective cohort study in patients with a hepatitis B virus DNA concentration greater than 200,000 IU/mL.¹² Beginning at either 24 or 32 weeks, patients were assigned to treatment with either oral TDF (300 mg daily) or oral telbivudine (LdT, 600 mg daily). The medications were continued for 4 weeks postpartum. In the intention-to-treat analysis, the rates of perinatal transmission were comparable, 1.5% versus 1.8%. In the per-protocol analysis, no infants in either group were infected. However, the predelivery decline in hepatitis Bvirus DNA concentration was greater in the TDF group. The ALT elevation rate was also lower in the TDF group. Patients in the LdT group had fewer problems with anorexia but more instances of arthralgia compared with those in the TDF group.

Based primarily on these 3 investigations, I recommend that all infected patients with a hepatitis B DNA concentration greater than 200,000 IU/mL or a viral load greater than 1,120,000 million copies/mL receive oral TDF, 300 mg daily, from 28 weeks until at least 4 to 8 weeks postpartum. The decision about duration of postpartum treatment should be made in consultation with an infectious disease specialist or hepatologist.

Case studies resolved

CASE 1 No protective level of surface antibody

This patient should promptly receive a single booster dose of the hepatitis B vaccine. The vaccine is an inactivated agent and is safe for administration at any time in pregnancy. Following delivery and prior to discharge from the hospital, the neonate should receive the first dose of the hepatitis B vaccine. A second dose should be administered 1 month later, and a third dose should be administered 6 months after the first dose.

CASE 2 Mother is seropositive for HBsAg

This patient should be tested immediately for HIV infection and hepatitis C and D. The hepatitis B viral genotype should be determined. She also should have a panel of liver function tests. If any of these tests are abnormal, a coagulation profile should be obtained to be certain that the patient is not at risk for a coagulopathy. Near the end of the second trimester, a hepatitis B viral load should be obtained. If the viral DNA concentration is greater than 200,000 IU/mLor a viral load greater than 1,120,000 million copies/mL, the patient should be treated with tenofovir, 300 mg daily, from week 28 until at least 4 weeks after delivery. The neonate should receive an injection of HBIG within 12 hours of birth and the first dose of the hepatitis B vaccine prior to discharge from the hospital. Two additional doses of the vaccine should be administered 1 and 6 months later. ●