Cardiology

There’s abundant evidence linking higher alcohol intake levels to greater stroke risk and, separately, increasing risk for new-onset atrial fibrillation (AFib). Less settled is whether moderate to heavy drinking worsens the risk for stroke in patients already in AFib and whether giving up alcohol can attenuate that risk. A new observational study suggests the answer to both questions is yes.

The risk for ischemic stroke was only around 1% over about 5 years in a Korean nationwide cohort of almost 98,000 patients with new-onset AFib. About half the patients followed were nondrinkers, as they had been before the study, 13% became abstinent soon after their AFib diagnosis, and 36% were currently drinkers.

But stroke risk went up about 30% with “moderate” current alcohol intake, compared with no intake, and by more than 40% for current drinkers reporting “heavy” alcohol intake, researchers found in an adjusted analysis.

However, abstainers who had mild to moderate alcohol-intake levels before their AFib diagnosis “had a similar risk of ischemic stroke as nondrinkers,” write the authors, led by So-Ryoung Lee, MD, PhD, and colleagues, Seoul National University Hospital, Republic of Korea, in their report published June 7 in the European Heart Journal. In a secondary analysis, binge drinking was also independently associated with risk for ischemic stroke.

The findings suggest that “alcohol abstinence after the diagnosis of AFib could reduce the risk of ischemic stroke,” they conclude. “Lifestyle interventions, including attention to alcohol consumption, should be encouraged as part of a comprehensive approach in the management of patients with a new diagnosis of AFib” for lowering the risk for stroke and other clinical outcomes.

“These results are pretty comparable to those obtained in the more general population,” David Conen, MD, MPH, not connected to the analysis, told this news organization.

In the study’s population with new-onset AFib, there is an alcohol-dependent risk for stroke “that goes up with increasing alcohol intake, which is more or less similar to that found without atrial fibrillation in previous studies,” said Dr. Conen, from the Population Health Research Institute, McMaster University, Hamilton, Ont.

The study, “which overall I think is very well done,” he said, is noteworthy for also suggesting that binge drinking, which was scrutinized in a secondary analysis, appeared independently to worsen the risk for stroke in its AFib population.

Dr. Conen said the observed 1% overall risk for stroke was very similar to the rate he and his colleagues saw in a recent combined analysis of two European cohorts with AFib that was usually longer standing; the median was 3 years. That analysis, in contrast, showed no significant association between increasing levels of alcohol intake and risk for stroke or systemic embolism.

However, “our confidence limits did not exclude the possibility of a small to moderate association,” he said. Given that, and the current study from Korea, there might indeed be “a weak association between alcohol consumption and stroke” in patients with AFib.

“Their results are just more precise because of the larger sample size. That’s why they were able to show those associations,” said Dr. Conen, who was senior author on the earlier report, which covered a pooled analysis of 3,852 patients with AFib in the BEAT-AF and SWISS-AF cohort studies. It was published January 25 in CMAJ, with lead author Philipp Reddiess, MD, Cardiovascular Research Institute Basel, Switzerland.

The two published studies contrast in other ways that are worth noting and together suggest the stroke rate might have been 1% in both by chance, Dr. Conen said. “The populations were pretty different.”

In the earlier study, for example, the overwhelmingly European patients had more comorbidities and had been in AFib for much longer; their mean age was 71 years; and 84% were on oral anticoagulation (OAC).

In contrast, the Korean cohort averaged 61 years in age and only about 24% were taking oral anticoagulants. Given their distribution of CHA2DS2-VASc scores and mean score of 2.3, more than twice as many should have been on OAC, Dr. Conen speculated. “Even if you take into account that some patients may have contraindications, this is clearly an underanticoagulated population.”

The European cohort might have been “a little bit more representative because atrial fibrillation is a disease of the elderly,” Dr. Conen said, but “the Korean paper has the advantage of being a population-based study.”

It involved 97,869 patients from a Korean national data base who were newly diagnosed with AFib from 2010 to 2016. Of the total, 49,781 (51%) were continuously nondrinkers before and after their diagnosis; 12,789 (13%) abstained from alcohol only after their AFib diagnosis; and 35,299 (36%) were drinkers during the follow-up, either because they continued to drink or newly started after their diagnosis.

Of the cohort, 3,120 were diagnosed with new ischemic stroke over a follow-up of 310,926 person-years, for a rate of 1 per 100 person-years.

The adjusted hazard ratio (HR) for ischemic stroke over a 5-year follow-up, compared with nondrinkers, was:

• 1.127 (95% confidence interval, 1.003-1.266) among abstainers
• 1.280 (95% CI, 1.166-1.405) for current drinkers

The corresponding HR, compared with current drinkers, was:

• 0.781 (95% CI, 0.712-0.858) for nondrinkers
• 0.880 (95% CI, 0.782-0.990) among abstainers

No significant interactions with ischemic stroke risk were observed in groups by sex, age, CHA2DS2-VASc score, or smoking status. The risk rose consistently with current drinking levels.

The overall stroke rate of 1% per year is “very low,” and “the absolute differences are small, even though there is a clear significant trend from nondrinking to drinking,” Dr. Conen said.

However, “the difference becomes more sizable when you compare heavy drinking to abstinence.”

Dr. Lee reports no conflicts of interest; disclosures for the other authors are in their report. Dr. Conen reports receiving speaker fees from Servier Canada; disclosures for the other authors are in their report.

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

There’s abundant evidence linking higher alcohol intake levels to greater stroke risk and, separately, increasing risk for new-onset atrial fibrillation (AFib). Less settled is whether moderate to heavy drinking worsens the risk for stroke in patients already in AFib and whether giving up alcohol can attenuate that risk. A new observational study suggests the answer to both questions is yes.

The risk for ischemic stroke was only around 1% over about 5 years in a Korean nationwide cohort of almost 98,000 patients with new-onset AFib. About half the patients followed were nondrinkers, as they had been before the study, 13% became abstinent soon after their AFib diagnosis, and 36% were currently drinkers.

But stroke risk went up about 30% with “moderate” current alcohol intake, compared with no intake, and by more than 40% for current drinkers reporting “heavy” alcohol intake, researchers found in an adjusted analysis.

However, abstainers who had mild to moderate alcohol-intake levels before their AFib diagnosis “had a similar risk of ischemic stroke as nondrinkers,” write the authors, led by So-Ryoung Lee, MD, PhD, and colleagues, Seoul National University Hospital, Republic of Korea, in their report published June 7 in the European Heart Journal. In a secondary analysis, binge drinking was also independently associated with risk for ischemic stroke.

The findings suggest that “alcohol abstinence after the diagnosis of AFib could reduce the risk of ischemic stroke,” they conclude. “Lifestyle interventions, including attention to alcohol consumption, should be encouraged as part of a comprehensive approach in the management of patients with a new diagnosis of AFib” for lowering the risk for stroke and other clinical outcomes.

“These results are pretty comparable to those obtained in the more general population,” David Conen, MD, MPH, not connected to the analysis, told this news organization.

In the study’s population with new-onset AFib, there is an alcohol-dependent risk for stroke “that goes up with increasing alcohol intake, which is more or less similar to that found without atrial fibrillation in previous studies,” said Dr. Conen, from the Population Health Research Institute, McMaster University, Hamilton, Ont.

The study, “which overall I think is very well done,” he said, is noteworthy for also suggesting that binge drinking, which was scrutinized in a secondary analysis, appeared independently to worsen the risk for stroke in its AFib population.

Dr. Conen said the observed 1% overall risk for stroke was very similar to the rate he and his colleagues saw in a recent combined analysis of two European cohorts with AFib that was usually longer standing; the median was 3 years. That analysis, in contrast, showed no significant association between increasing levels of alcohol intake and risk for stroke or systemic embolism.

However, “our confidence limits did not exclude the possibility of a small to moderate association,” he said. Given that, and the current study from Korea, there might indeed be “a weak association between alcohol consumption and stroke” in patients with AFib.

“Their results are just more precise because of the larger sample size. That’s why they were able to show those associations,” said Dr. Conen, who was senior author on the earlier report, which covered a pooled analysis of 3,852 patients with AFib in the BEAT-AF and SWISS-AF cohort studies. It was published January 25 in CMAJ, with lead author Philipp Reddiess, MD, Cardiovascular Research Institute Basel, Switzerland.

The two published studies contrast in other ways that are worth noting and together suggest the stroke rate might have been 1% in both by chance, Dr. Conen said. “The populations were pretty different.”

In the earlier study, for example, the overwhelmingly European patients had more comorbidities and had been in AFib for much longer; their mean age was 71 years; and 84% were on oral anticoagulation (OAC).

In contrast, the Korean cohort averaged 61 years in age and only about 24% were taking oral anticoagulants. Given their distribution of CHA2DS2-VASc scores and mean score of 2.3, more than twice as many should have been on OAC, Dr. Conen speculated. “Even if you take into account that some patients may have contraindications, this is clearly an underanticoagulated population.”

The European cohort might have been “a little bit more representative because atrial fibrillation is a disease of the elderly,” Dr. Conen said, but “the Korean paper has the advantage of being a population-based study.”

It involved 97,869 patients from a Korean national data base who were newly diagnosed with AFib from 2010 to 2016. Of the total, 49,781 (51%) were continuously nondrinkers before and after their diagnosis; 12,789 (13%) abstained from alcohol only after their AFib diagnosis; and 35,299 (36%) were drinkers during the follow-up, either because they continued to drink or newly started after their diagnosis.

Of the cohort, 3,120 were diagnosed with new ischemic stroke over a follow-up of 310,926 person-years, for a rate of 1 per 100 person-years.

The adjusted hazard ratio (HR) for ischemic stroke over a 5-year follow-up, compared with nondrinkers, was:

• 1.127 (95% confidence interval, 1.003-1.266) among abstainers
• 1.280 (95% CI, 1.166-1.405) for current drinkers

The corresponding HR, compared with current drinkers, was:

• 0.781 (95% CI, 0.712-0.858) for nondrinkers
• 0.880 (95% CI, 0.782-0.990) among abstainers

No significant interactions with ischemic stroke risk were observed in groups by sex, age, CHA2DS2-VASc score, or smoking status. The risk rose consistently with current drinking levels.

The overall stroke rate of 1% per year is “very low,” and “the absolute differences are small, even though there is a clear significant trend from nondrinking to drinking,” Dr. Conen said.

However, “the difference becomes more sizable when you compare heavy drinking to abstinence.”

Dr. Lee reports no conflicts of interest; disclosures for the other authors are in their report. Dr. Conen reports receiving speaker fees from Servier Canada; disclosures for the other authors are in their report.

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

There’s abundant evidence linking higher alcohol intake levels to greater stroke risk and, separately, increasing risk for new-onset atrial fibrillation (AFib). Less settled is whether moderate to heavy drinking worsens the risk for stroke in patients already in AFib and whether giving up alcohol can attenuate that risk. A new observational study suggests the answer to both questions is yes.

The risk for ischemic stroke was only around 1% over about 5 years in a Korean nationwide cohort of almost 98,000 patients with new-onset AFib. About half the patients followed were nondrinkers, as they had been before the study, 13% became abstinent soon after their AFib diagnosis, and 36% were currently drinkers.

But stroke risk went up about 30% with “moderate” current alcohol intake, compared with no intake, and by more than 40% for current drinkers reporting “heavy” alcohol intake, researchers found in an adjusted analysis.

However, abstainers who had mild to moderate alcohol-intake levels before their AFib diagnosis “had a similar risk of ischemic stroke as nondrinkers,” write the authors, led by So-Ryoung Lee, MD, PhD, and colleagues, Seoul National University Hospital, Republic of Korea, in their report published June 7 in the European Heart Journal. In a secondary analysis, binge drinking was also independently associated with risk for ischemic stroke.

The findings suggest that “alcohol abstinence after the diagnosis of AFib could reduce the risk of ischemic stroke,” they conclude. “Lifestyle interventions, including attention to alcohol consumption, should be encouraged as part of a comprehensive approach in the management of patients with a new diagnosis of AFib” for lowering the risk for stroke and other clinical outcomes.

“These results are pretty comparable to those obtained in the more general population,” David Conen, MD, MPH, not connected to the analysis, told this news organization.

In the study’s population with new-onset AFib, there is an alcohol-dependent risk for stroke “that goes up with increasing alcohol intake, which is more or less similar to that found without atrial fibrillation in previous studies,” said Dr. Conen, from the Population Health Research Institute, McMaster University, Hamilton, Ont.

The study, “which overall I think is very well done,” he said, is noteworthy for also suggesting that binge drinking, which was scrutinized in a secondary analysis, appeared independently to worsen the risk for stroke in its AFib population.

Dr. Conen said the observed 1% overall risk for stroke was very similar to the rate he and his colleagues saw in a recent combined analysis of two European cohorts with AFib that was usually longer standing; the median was 3 years. That analysis, in contrast, showed no significant association between increasing levels of alcohol intake and risk for stroke or systemic embolism.

However, “our confidence limits did not exclude the possibility of a small to moderate association,” he said. Given that, and the current study from Korea, there might indeed be “a weak association between alcohol consumption and stroke” in patients with AFib.

“Their results are just more precise because of the larger sample size. That’s why they were able to show those associations,” said Dr. Conen, who was senior author on the earlier report, which covered a pooled analysis of 3,852 patients with AFib in the BEAT-AF and SWISS-AF cohort studies. It was published January 25 in CMAJ, with lead author Philipp Reddiess, MD, Cardiovascular Research Institute Basel, Switzerland.

The two published studies contrast in other ways that are worth noting and together suggest the stroke rate might have been 1% in both by chance, Dr. Conen said. “The populations were pretty different.”

In the earlier study, for example, the overwhelmingly European patients had more comorbidities and had been in AFib for much longer; their mean age was 71 years; and 84% were on oral anticoagulation (OAC).

In contrast, the Korean cohort averaged 61 years in age and only about 24% were taking oral anticoagulants. Given their distribution of CHA2DS2-VASc scores and mean score of 2.3, more than twice as many should have been on OAC, Dr. Conen speculated. “Even if you take into account that some patients may have contraindications, this is clearly an underanticoagulated population.”

The European cohort might have been “a little bit more representative because atrial fibrillation is a disease of the elderly,” Dr. Conen said, but “the Korean paper has the advantage of being a population-based study.”

It involved 97,869 patients from a Korean national data base who were newly diagnosed with AFib from 2010 to 2016. Of the total, 49,781 (51%) were continuously nondrinkers before and after their diagnosis; 12,789 (13%) abstained from alcohol only after their AFib diagnosis; and 35,299 (36%) were drinkers during the follow-up, either because they continued to drink or newly started after their diagnosis.

Of the cohort, 3,120 were diagnosed with new ischemic stroke over a follow-up of 310,926 person-years, for a rate of 1 per 100 person-years.

The adjusted hazard ratio (HR) for ischemic stroke over a 5-year follow-up, compared with nondrinkers, was:

• 1.127 (95% confidence interval, 1.003-1.266) among abstainers
• 1.280 (95% CI, 1.166-1.405) for current drinkers

The corresponding HR, compared with current drinkers, was:

• 0.781 (95% CI, 0.712-0.858) for nondrinkers
• 0.880 (95% CI, 0.782-0.990) among abstainers

No significant interactions with ischemic stroke risk were observed in groups by sex, age, CHA2DS2-VASc score, or smoking status. The risk rose consistently with current drinking levels.

The overall stroke rate of 1% per year is “very low,” and “the absolute differences are small, even though there is a clear significant trend from nondrinking to drinking,” Dr. Conen said.

However, “the difference becomes more sizable when you compare heavy drinking to abstinence.”

Dr. Lee reports no conflicts of interest; disclosures for the other authors are in their report. Dr. Conen reports receiving speaker fees from Servier Canada; disclosures for the other authors are in their report.

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

Your article, “Is an underlying cardiac condition causing your patient’s palpitations?” (J Fam Pract. 2021;70:60-68), listed a number of causes of palpitations in the table on page 62. However, 1 cause was noticeably missing: underlying genetic disorders, such as amyloidosis. Genetic disorders can affect the cardiac muscle and lead to increased rates of both cardiac arrhythmias and palpitations.

I recently treated a 43-year-old man who presented with shortness of breath and presyncopal episodes; his medical history included anxiety and gastritis. He previously had undergone a cervical spine fusion and was postoperatively given a diagnosis of bigeminy and frequent premature ventricular contractions (PVCs). An echocardiogram was ordered and came back negative, while a Holter monitor showed PVCs > 30%. Genetic testing was performed only after the family history offered some clues. The diagnosis was hereditary transthyretin (ATTR) amyloidosis. Now, he is awaiting cardiac magnetic resonance imaging to determine whether muscle or pericardium has been affected. 
 

Genetic disorders can affect the cardiac muscle and lead to increased rates of both cardiac arrhythmias and palpitations.

When I discussed the findings with the patient, he wisely stated, “Perhaps it is more common than studies show if patients are not normally tested until elderly or hospitalized.” This resonated with me when I considered that routine lab work done in an office would miss amyloidosis. This definitely reinforced my philosophy to always listen to the patient and take symptoms seriously, as sometimes we just haven’t figured out the true diagnosis yet. 

Your article, “Is an underlying cardiac condition causing your patient’s palpitations?” (J Fam Pract. 2021;70:60-68), listed a number of causes of palpitations in the table on page 62. However, 1 cause was noticeably missing: underlying genetic disorders, such as amyloidosis. Genetic disorders can affect the cardiac muscle and lead to increased rates of both cardiac arrhythmias and palpitations.

I recently treated a 43-year-old man who presented with shortness of breath and presyncopal episodes; his medical history included anxiety and gastritis. He previously had undergone a cervical spine fusion and was postoperatively given a diagnosis of bigeminy and frequent premature ventricular contractions (PVCs). An echocardiogram was ordered and came back negative, while a Holter monitor showed PVCs > 30%. Genetic testing was performed only after the family history offered some clues. The diagnosis was hereditary transthyretin (ATTR) amyloidosis. Now, he is awaiting cardiac magnetic resonance imaging to determine whether muscle or pericardium has been affected. 
 

Genetic disorders can affect the cardiac muscle and lead to increased rates of both cardiac arrhythmias and palpitations.

When I discussed the findings with the patient, he wisely stated, “Perhaps it is more common than studies show if patients are not normally tested until elderly or hospitalized.” This resonated with me when I considered that routine lab work done in an office would miss amyloidosis. This definitely reinforced my philosophy to always listen to the patient and take symptoms seriously, as sometimes we just haven’t figured out the true diagnosis yet. 

Your article, “Is an underlying cardiac condition causing your patient’s palpitations?” (J Fam Pract. 2021;70:60-68), listed a number of causes of palpitations in the table on page 62. However, 1 cause was noticeably missing: underlying genetic disorders, such as amyloidosis. Genetic disorders can affect the cardiac muscle and lead to increased rates of both cardiac arrhythmias and palpitations.

I recently treated a 43-year-old man who presented with shortness of breath and presyncopal episodes; his medical history included anxiety and gastritis. He previously had undergone a cervical spine fusion and was postoperatively given a diagnosis of bigeminy and frequent premature ventricular contractions (PVCs). An echocardiogram was ordered and came back negative, while a Holter monitor showed PVCs > 30%. Genetic testing was performed only after the family history offered some clues. The diagnosis was hereditary transthyretin (ATTR) amyloidosis. Now, he is awaiting cardiac magnetic resonance imaging to determine whether muscle or pericardium has been affected. 
 

Genetic disorders can affect the cardiac muscle and lead to increased rates of both cardiac arrhythmias and palpitations.

When I discussed the findings with the patient, he wisely stated, “Perhaps it is more common than studies show if patients are not normally tested until elderly or hospitalized.” This resonated with me when I considered that routine lab work done in an office would miss amyloidosis. This definitely reinforced my philosophy to always listen to the patient and take symptoms seriously, as sometimes we just haven’t figured out the true diagnosis yet. 

In this issue of JFP, Smith et al recommend following guidelines from the American Academy of Pediatrics to annually screen children for hypertension (see page 220). This recommendation appears to be at odds with the recent US Preventive Services Task Force (USPSTF) statement that concluded there is insufficient evidence for screening children and adolescents for hypertension. But an “I” recommendation from the USPSTF is not the same as a “D” recommendation. “D” means don’t do it, because the evidence indicates that the harms outweigh the benefits. “I” means we don’t have enough evidence to weigh the harms and benefits, so it is up to you and your patients to decide what to do.

So whose recommendations should we follow?

Our decision should be based on a thorough understanding of the evidence, and that evidence is well summarized in the recent USPSTF report.¹ The reviewers found no studies that evaluated the benefits and harms of screening children and adolescents for hypertension and no studies evaluating disease outcomes from treating hypertension in these patients.

What we can all agree on is that, when hypertension is identified in a child or adolescent, it is important to determine if there is a treatable cause.

There is, however, an association between elevated blood pressure in childhood and outcomes such as left ventricular hypertrophy and carotid intimal thickness.² Some physicians contend that these “disease-oriented outcomes” are sufficient reason to identify and treat hypertension in children and adolescents.³ The USPSTF, however, requires a higher level of evidence that includes patient-oriented outcomes, such as a lower risk of congestive heart failure, renal failure, or death, before recommending treatment. Physicians and patients have to choose what level of evidence is sufficient to take action.

Dr. Smith comments: “As noted in their report, the USPSTF acknowledges that observational studies indicate an association between hypertension in childhood and hypertension in adulthood, but there have been no randomized trials to determine if treating hypertension in children and adolescents reduces risk of cardiovascular events. Although it is a cohort study, not a randomized trial, the ongoing i3C Consortium Outcomes Study⁴ may provide better information to guide decision-making for children and adolescents with elevated blood pressure.”

What we can all agree on is that, when hypertension is identified in a child or adolescent, it is important to determine if there is a treatable cause of elevated blood pressure such as coarctation of the aorta or renal disease. It is also important to address risk factors for elevated blood pressure and cardiovascular disease, such as obesity, poor dietary habits, and smoking. The treatment is lifestyle modification with diet, exercise, and smoking cessation. 

In this issue of JFP, Smith et al recommend following guidelines from the American Academy of Pediatrics to annually screen children for hypertension (see page 220). This recommendation appears to be at odds with the recent US Preventive Services Task Force (USPSTF) statement that concluded there is insufficient evidence for screening children and adolescents for hypertension. But an “I” recommendation from the USPSTF is not the same as a “D” recommendation. “D” means don’t do it, because the evidence indicates that the harms outweigh the benefits. “I” means we don’t have enough evidence to weigh the harms and benefits, so it is up to you and your patients to decide what to do.

So whose recommendations should we follow?

Our decision should be based on a thorough understanding of the evidence, and that evidence is well summarized in the recent USPSTF report.¹ The reviewers found no studies that evaluated the benefits and harms of screening children and adolescents for hypertension and no studies evaluating disease outcomes from treating hypertension in these patients.

What we can all agree on is that, when hypertension is identified in a child or adolescent, it is important to determine if there is a treatable cause.

There is, however, an association between elevated blood pressure in childhood and outcomes such as left ventricular hypertrophy and carotid intimal thickness.² Some physicians contend that these “disease-oriented outcomes” are sufficient reason to identify and treat hypertension in children and adolescents.³ The USPSTF, however, requires a higher level of evidence that includes patient-oriented outcomes, such as a lower risk of congestive heart failure, renal failure, or death, before recommending treatment. Physicians and patients have to choose what level of evidence is sufficient to take action.

Dr. Smith comments: “As noted in their report, the USPSTF acknowledges that observational studies indicate an association between hypertension in childhood and hypertension in adulthood, but there have been no randomized trials to determine if treating hypertension in children and adolescents reduces risk of cardiovascular events. Although it is a cohort study, not a randomized trial, the ongoing i3C Consortium Outcomes Study⁴ may provide better information to guide decision-making for children and adolescents with elevated blood pressure.”

What we can all agree on is that, when hypertension is identified in a child or adolescent, it is important to determine if there is a treatable cause of elevated blood pressure such as coarctation of the aorta or renal disease. It is also important to address risk factors for elevated blood pressure and cardiovascular disease, such as obesity, poor dietary habits, and smoking. The treatment is lifestyle modification with diet, exercise, and smoking cessation. 

In this issue of JFP, Smith et al recommend following guidelines from the American Academy of Pediatrics to annually screen children for hypertension (see page 220). This recommendation appears to be at odds with the recent US Preventive Services Task Force (USPSTF) statement that concluded there is insufficient evidence for screening children and adolescents for hypertension. But an “I” recommendation from the USPSTF is not the same as a “D” recommendation. “D” means don’t do it, because the evidence indicates that the harms outweigh the benefits. “I” means we don’t have enough evidence to weigh the harms and benefits, so it is up to you and your patients to decide what to do.

So whose recommendations should we follow?

Our decision should be based on a thorough understanding of the evidence, and that evidence is well summarized in the recent USPSTF report.¹ The reviewers found no studies that evaluated the benefits and harms of screening children and adolescents for hypertension and no studies evaluating disease outcomes from treating hypertension in these patients.

What we can all agree on is that, when hypertension is identified in a child or adolescent, it is important to determine if there is a treatable cause.

There is, however, an association between elevated blood pressure in childhood and outcomes such as left ventricular hypertrophy and carotid intimal thickness.² Some physicians contend that these “disease-oriented outcomes” are sufficient reason to identify and treat hypertension in children and adolescents.³ The USPSTF, however, requires a higher level of evidence that includes patient-oriented outcomes, such as a lower risk of congestive heart failure, renal failure, or death, before recommending treatment. Physicians and patients have to choose what level of evidence is sufficient to take action.

Dr. Smith comments: “As noted in their report, the USPSTF acknowledges that observational studies indicate an association between hypertension in childhood and hypertension in adulthood, but there have been no randomized trials to determine if treating hypertension in children and adolescents reduces risk of cardiovascular events. Although it is a cohort study, not a randomized trial, the ongoing i3C Consortium Outcomes Study⁴ may provide better information to guide decision-making for children and adolescents with elevated blood pressure.”

What we can all agree on is that, when hypertension is identified in a child or adolescent, it is important to determine if there is a treatable cause of elevated blood pressure such as coarctation of the aorta or renal disease. It is also important to address risk factors for elevated blood pressure and cardiovascular disease, such as obesity, poor dietary habits, and smoking. The treatment is lifestyle modification with diet, exercise, and smoking cessation. 

Treating obstructive sleep apnea with continuous positive airway pressure therapy protects against myocardial infarction, stroke, and other cardiovascular (CV) events, particularly for patients with moderate to severe OSA and those who are more adherent to CPAP therapy, a new study suggests.

“Most clinical trials on the effect of CPAP on CV diseases to date have focused on secondary CV prevention. This study contributes another piece of evidence about the role of CPAP therapy to prevent CV diseases,” said Diego R. Mazzotti, PhD, an assistant professor at the University of Kansas Medical Center, Kansas City.

“Our study, while observational, suggests that clinical trials focused on understanding how to sustain long-term CPAP adherence in obstructive sleep apnea patients are necessary and could be critical for optimizing comorbidity risk reduction,” Dr. Mazzotti said.

The study was presented at the virtual annual meeting of the Associated Professional Sleep Societies.
 

Good adherence important

The researchers analyzed the electronic health records of adults referred for a sleep study through the Kaiser Permanente Southern California health system. The sample included 11,145 adults without OSA, 13,898 with OSA who used CPAP, and 20,884 adults with OSA who did not use CPAP. None of them had CV disease at baseline. Median follow-up was 262 days.

The primary outcome was first occurrence of myocardial infarction, stroke, unstable angina, heart failure, or death caused by CV disease.

In adjusted models, adults with moderate to severe OSA (apnea-hypopnea index ≥15) who did not use CPAP were 71% more likely than those without OSA to have a first CV event (hazard ratio, 1.71; 95% CI, 1.11-2.64). However, the risk for a CV event during follow-up was 32% lower among OSA patients with any CPAP use (HR, 0.68; 95% CI, 0.50-0.93; P = .016).

The effect was mostly driven by those who used CPAP for at least 4 hours per night (HR, 0.60; 95% CI, 0.39-0.95). This association was stronger for those with moderate to severe OSA (HR, 0.56; 95% CI, 0.39-0.81).

“This study highlights the importance of long-term management of CPAP therapy in patients with moderate-severe OSA,” Dr. Mazzotti said in an interview.

“It suggests that maintaining good CPAP adherence might be beneficial for cardiovascular health, besides the already established benefits on quality of life, sleepiness, and other cardiometabolic functions,” he said.

Dr. Mazzotti said several mechanisms might explain the association between CPAP use and lower risk for CV events. “CPAP treats OSA by preventing respiratory pauses that occur during sleep, therefore preventing arousals, sleep fragmentation, and decreases in blood oxygen. These improved cardiorespiratory functions can be beneficial to avoid certain molecular changes that are known to contribute to cardiovascular risk, such as oxidative stress and inflammation,” he explained.

“However, specific studies fully understanding these mechanisms are necessary,” Dr. Mazzotti added.

In a comment, Nitun Verma, MD, a spokesperson for the American Academy of Sleep Medicine, said that “the frequent decreases in oxygen levels and fragmented sleep from apnea are associated with cardiovascular disorders. We know this from multiple studies. This, however, was a large study and strengthens the association between improving apnea and reduced serious cardiovascular events.”

Funding for the study was provided by the American Academy of Sleep Medicine Foundation and the American Heart Association. Dr. Mazzotti and Dr. Verma disclosed no relevant financial relationships.

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

Treating obstructive sleep apnea with continuous positive airway pressure therapy protects against myocardial infarction, stroke, and other cardiovascular (CV) events, particularly for patients with moderate to severe OSA and those who are more adherent to CPAP therapy, a new study suggests.

“Most clinical trials on the effect of CPAP on CV diseases to date have focused on secondary CV prevention. This study contributes another piece of evidence about the role of CPAP therapy to prevent CV diseases,” said Diego R. Mazzotti, PhD, an assistant professor at the University of Kansas Medical Center, Kansas City.

“Our study, while observational, suggests that clinical trials focused on understanding how to sustain long-term CPAP adherence in obstructive sleep apnea patients are necessary and could be critical for optimizing comorbidity risk reduction,” Dr. Mazzotti said.

The study was presented at the virtual annual meeting of the Associated Professional Sleep Societies.
 

Good adherence important

The researchers analyzed the electronic health records of adults referred for a sleep study through the Kaiser Permanente Southern California health system. The sample included 11,145 adults without OSA, 13,898 with OSA who used CPAP, and 20,884 adults with OSA who did not use CPAP. None of them had CV disease at baseline. Median follow-up was 262 days.

The primary outcome was first occurrence of myocardial infarction, stroke, unstable angina, heart failure, or death caused by CV disease.

In adjusted models, adults with moderate to severe OSA (apnea-hypopnea index ≥15) who did not use CPAP were 71% more likely than those without OSA to have a first CV event (hazard ratio, 1.71; 95% CI, 1.11-2.64). However, the risk for a CV event during follow-up was 32% lower among OSA patients with any CPAP use (HR, 0.68; 95% CI, 0.50-0.93; P = .016).

The effect was mostly driven by those who used CPAP for at least 4 hours per night (HR, 0.60; 95% CI, 0.39-0.95). This association was stronger for those with moderate to severe OSA (HR, 0.56; 95% CI, 0.39-0.81).

“This study highlights the importance of long-term management of CPAP therapy in patients with moderate-severe OSA,” Dr. Mazzotti said in an interview.

“It suggests that maintaining good CPAP adherence might be beneficial for cardiovascular health, besides the already established benefits on quality of life, sleepiness, and other cardiometabolic functions,” he said.

Dr. Mazzotti said several mechanisms might explain the association between CPAP use and lower risk for CV events. “CPAP treats OSA by preventing respiratory pauses that occur during sleep, therefore preventing arousals, sleep fragmentation, and decreases in blood oxygen. These improved cardiorespiratory functions can be beneficial to avoid certain molecular changes that are known to contribute to cardiovascular risk, such as oxidative stress and inflammation,” he explained.

“However, specific studies fully understanding these mechanisms are necessary,” Dr. Mazzotti added.

In a comment, Nitun Verma, MD, a spokesperson for the American Academy of Sleep Medicine, said that “the frequent decreases in oxygen levels and fragmented sleep from apnea are associated with cardiovascular disorders. We know this from multiple studies. This, however, was a large study and strengthens the association between improving apnea and reduced serious cardiovascular events.”

Funding for the study was provided by the American Academy of Sleep Medicine Foundation and the American Heart Association. Dr. Mazzotti and Dr. Verma disclosed no relevant financial relationships.

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

Treating obstructive sleep apnea with continuous positive airway pressure therapy protects against myocardial infarction, stroke, and other cardiovascular (CV) events, particularly for patients with moderate to severe OSA and those who are more adherent to CPAP therapy, a new study suggests.

“Most clinical trials on the effect of CPAP on CV diseases to date have focused on secondary CV prevention. This study contributes another piece of evidence about the role of CPAP therapy to prevent CV diseases,” said Diego R. Mazzotti, PhD, an assistant professor at the University of Kansas Medical Center, Kansas City.

“Our study, while observational, suggests that clinical trials focused on understanding how to sustain long-term CPAP adherence in obstructive sleep apnea patients are necessary and could be critical for optimizing comorbidity risk reduction,” Dr. Mazzotti said.

The study was presented at the virtual annual meeting of the Associated Professional Sleep Societies.
 

Good adherence important

The researchers analyzed the electronic health records of adults referred for a sleep study through the Kaiser Permanente Southern California health system. The sample included 11,145 adults without OSA, 13,898 with OSA who used CPAP, and 20,884 adults with OSA who did not use CPAP. None of them had CV disease at baseline. Median follow-up was 262 days.

The primary outcome was first occurrence of myocardial infarction, stroke, unstable angina, heart failure, or death caused by CV disease.

In adjusted models, adults with moderate to severe OSA (apnea-hypopnea index ≥15) who did not use CPAP were 71% more likely than those without OSA to have a first CV event (hazard ratio, 1.71; 95% CI, 1.11-2.64). However, the risk for a CV event during follow-up was 32% lower among OSA patients with any CPAP use (HR, 0.68; 95% CI, 0.50-0.93; P = .016).

The effect was mostly driven by those who used CPAP for at least 4 hours per night (HR, 0.60; 95% CI, 0.39-0.95). This association was stronger for those with moderate to severe OSA (HR, 0.56; 95% CI, 0.39-0.81).

“This study highlights the importance of long-term management of CPAP therapy in patients with moderate-severe OSA,” Dr. Mazzotti said in an interview.

“It suggests that maintaining good CPAP adherence might be beneficial for cardiovascular health, besides the already established benefits on quality of life, sleepiness, and other cardiometabolic functions,” he said.

Dr. Mazzotti said several mechanisms might explain the association between CPAP use and lower risk for CV events. “CPAP treats OSA by preventing respiratory pauses that occur during sleep, therefore preventing arousals, sleep fragmentation, and decreases in blood oxygen. These improved cardiorespiratory functions can be beneficial to avoid certain molecular changes that are known to contribute to cardiovascular risk, such as oxidative stress and inflammation,” he explained.

“However, specific studies fully understanding these mechanisms are necessary,” Dr. Mazzotti added.

In a comment, Nitun Verma, MD, a spokesperson for the American Academy of Sleep Medicine, said that “the frequent decreases in oxygen levels and fragmented sleep from apnea are associated with cardiovascular disorders. We know this from multiple studies. This, however, was a large study and strengthens the association between improving apnea and reduced serious cardiovascular events.”

Funding for the study was provided by the American Academy of Sleep Medicine Foundation and the American Heart Association. Dr. Mazzotti and Dr. Verma disclosed no relevant financial relationships.

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

Antihypertensive medications that cross the blood-brain barrier (BBB) may be linked with less memory decline, compared with other drugs for high blood pressure, suggest the findings of a meta-analysis.

Over a 3-year period, cognitively normal older adults taking BBB-crossing antihypertensives demonstrated superior verbal memory, compared with similar individuals receiving non–BBB-crossing antihypertensives, reported lead author Jean K. Ho, PhD, of the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine, and colleagues.

According to the investigators, the findings add color to a known link between hypertension and neurologic degeneration, and may aid the search for new therapeutic targets.

“Hypertension is a well-established risk factor for cognitive decline and dementia, possibly through its effects on both cerebrovascular disease and Alzheimer’s disease,” Dr. Ho and colleagues wrote in Hypertension. “Studies of antihypertensive treatments have reported possible salutary effects on cognition and cerebrovascular disease, as well as Alzheimer’s disease neuropathology.”

In a previous study, individuals younger than 75 years exposed to antihypertensives had an 8% decreased risk of dementia per year of use, while another trial showed that intensive blood pressure–lowering therapy reduced mild cognitive impairment by 19%.

“Despite these encouraging findings ... larger meta-analytic studies have been hampered by the fact that pharmacokinetic properties are typically not considered in existing studies or routine clinical practice,” wrote Dr. Ho and colleagues. “The present study sought to fill this gap [in that it was] a large and longitudinal meta-analytic study of existing data recoded to assess the effects of BBB-crossing potential in renin-angiotensin system [RAS] treatments among hypertensive adults.”
 

Methods and results

The meta-analysis included randomized clinical trials, prospective cohort studies, and retrospective observational studies. The researchers assessed data on 12,849 individuals from 14 cohorts that received either BBB-crossing or non–BBB-crossing antihypertensives.

The BBB-crossing properties of RAS treatments were identified by a literature review. Of ACE inhibitors, captopril, fosinopril, lisinopril, perindopril, ramipril, and trandolapril were classified as BBB crossing, and benazepril, enalapril, moexipril, and quinapril were classified as non–BBB-crossing. Of ARBs, telmisartan and candesartan were considered BBB-crossing, and olmesartan, eprosartan, irbesartan, and losartan were tagged as non–BBB-crossing.

Cognition was assessed via the following seven domains: executive function, attention, verbal memory learning, language, mental status, recall, and processing speed.

Compared with individuals taking non–BBB-crossing antihypertensives, those taking BBB-crossing agents had significantly superior verbal memory (recall), with a maximum effect size of 0.07 (P = .03).

According to the investigators, this finding was particularly noteworthy, as the BBB-crossing group had relatively higher vascular risk burden and lower mean education level.

“These differences make it all the more remarkable that the BBB-crossing group displayed better memory ability over time despite these cognitive disadvantages,” the investigators wrote.

Still, not all the findings favored BBB-crossing agents. Individuals in the BBB-crossing group had relatively inferior attention ability, with a minimum effect size of –0.17 (P = .02).

The other cognitive measures were not significantly different between groups.
 

Clinicians may consider findings after accounting for other factors

Principal investigator Daniel A. Nation, PhD, associate professor of psychological science and a faculty member of the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine, suggested that the small difference in verbal memory between groups could be clinically significant over a longer period of time.

“Although the overall effect size was pretty small, if you look at how long it would take for someone [with dementia] to progress over many years of decline, it would actually end up being a pretty big effect,” Dr. Nation said in an interview. “Small effect sizes could actually end up preventing a lot of cases of dementia,” he added.

The conflicting results in the BBB-crossing group – better verbal memory but worse attention ability – were “surprising,” he noted.

“I sort of didn’t believe it at first,” Dr. Nation said, “because the memory finding is sort of replication – we’d observed the same exact effect on memory in a smaller sample in another study. ... The attention [finding], going another way, was a new thing.”

Dr. Nation suggested that the intergroup differences in attention ability may stem from idiosyncrasies of the tests used to measure that domain, which can be impacted by cardiovascular or brain vascular disease. Or it could be caused by something else entirely, he said, noting that further investigation is needed.

He added that the improvements in verbal memory within the BBB-crossing group could be caused by direct effects on the brain. He pointed out that certain ACE polymorphisms have been linked with Alzheimer’s disease risk, and those same polymorphisms, in animal models, lead to neurodegeneration, with reversal possible through administration of ACE inhibitors.

“It could be that what we’re observing has nothing really to do with blood pressure,” Dr. Nation explained. “This could be a neuronal effect on learning memory systems.”

He went on to suggest that clinicians may consider these findings when selecting antihypertensive agents for their patients, with the caveat that all other prescribing factors have already been taking to account.

“In the event that you’re going to give an ACE inhibitor or an angiotensin receptor blocker anyway, and it ends up being a somewhat arbitrary decision in terms of which specific drug you’re going to give, then perhaps this is a piece of information you would take into account – that one gets in the brain and one doesn’t – in somebody at risk for cognitive decline,” Dr. Nation said.
 

Exact mechanisms of action unknown

Hélène Girouard, PhD, assistant professor of pharmacology and physiology at the University of Montreal, said in an interview that the findings are “of considerable importance, knowing that brain alterations could begin as much as 30 years before manifestation of dementia.”

Since 2003, Dr. Girouard has been studying the cognitive effects of antihypertensive medications. She noted that previous studies involving rodents “have shown beneficial effects [of BBB-crossing antihypertensive drugs] on cognition independent of their effects on blood pressure.”

The drugs’ exact mechanisms of action, however, remain elusive, according to Dr. Girouard, who offered several possible explanations, including amelioration of BBB disruption, brain inflammation, cerebral blood flow dysregulation, cholinergic dysfunction, and neurologic deficits. “Whether these mechanisms may explain Ho and colleagues’ observations remains to be established,” she added.

Andrea L. Schneider, MD, PhD, assistant professor of neurology at the University of Pennsylvania, Philadelphia, applauded the study, but ultimately suggested that more research is needed to impact clinical decision-making.

“The results of this important and well-done study suggest that further investigation into targeted mechanism-based approaches to selecting hypertension treatment agents, with a specific focus on cognitive outcomes, is warranted,” Dr. Schneider said in an interview. “Before changing clinical practice, further work is necessary to disentangle contributions of medication mechanism, comorbid vascular risk factors, and achieved blood pressure reduction, among others.”

The investigators disclosed support from the National Institutes of Health, the Alzheimer’s Association, the Waksman Foundation of Japan, and others. The interviewees reported no relevant conflicts of interest.

Antihypertensive medications that cross the blood-brain barrier (BBB) may be linked with less memory decline, compared with other drugs for high blood pressure, suggest the findings of a meta-analysis.

Over a 3-year period, cognitively normal older adults taking BBB-crossing antihypertensives demonstrated superior verbal memory, compared with similar individuals receiving non–BBB-crossing antihypertensives, reported lead author Jean K. Ho, PhD, of the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine, and colleagues.

According to the investigators, the findings add color to a known link between hypertension and neurologic degeneration, and may aid the search for new therapeutic targets.

“Hypertension is a well-established risk factor for cognitive decline and dementia, possibly through its effects on both cerebrovascular disease and Alzheimer’s disease,” Dr. Ho and colleagues wrote in Hypertension. “Studies of antihypertensive treatments have reported possible salutary effects on cognition and cerebrovascular disease, as well as Alzheimer’s disease neuropathology.”

In a previous study, individuals younger than 75 years exposed to antihypertensives had an 8% decreased risk of dementia per year of use, while another trial showed that intensive blood pressure–lowering therapy reduced mild cognitive impairment by 19%.

“Despite these encouraging findings ... larger meta-analytic studies have been hampered by the fact that pharmacokinetic properties are typically not considered in existing studies or routine clinical practice,” wrote Dr. Ho and colleagues. “The present study sought to fill this gap [in that it was] a large and longitudinal meta-analytic study of existing data recoded to assess the effects of BBB-crossing potential in renin-angiotensin system [RAS] treatments among hypertensive adults.”
 

Methods and results

The meta-analysis included randomized clinical trials, prospective cohort studies, and retrospective observational studies. The researchers assessed data on 12,849 individuals from 14 cohorts that received either BBB-crossing or non–BBB-crossing antihypertensives.

The BBB-crossing properties of RAS treatments were identified by a literature review. Of ACE inhibitors, captopril, fosinopril, lisinopril, perindopril, ramipril, and trandolapril were classified as BBB crossing, and benazepril, enalapril, moexipril, and quinapril were classified as non–BBB-crossing. Of ARBs, telmisartan and candesartan were considered BBB-crossing, and olmesartan, eprosartan, irbesartan, and losartan were tagged as non–BBB-crossing.

Cognition was assessed via the following seven domains: executive function, attention, verbal memory learning, language, mental status, recall, and processing speed.

Compared with individuals taking non–BBB-crossing antihypertensives, those taking BBB-crossing agents had significantly superior verbal memory (recall), with a maximum effect size of 0.07 (P = .03).

According to the investigators, this finding was particularly noteworthy, as the BBB-crossing group had relatively higher vascular risk burden and lower mean education level.

“These differences make it all the more remarkable that the BBB-crossing group displayed better memory ability over time despite these cognitive disadvantages,” the investigators wrote.

Still, not all the findings favored BBB-crossing agents. Individuals in the BBB-crossing group had relatively inferior attention ability, with a minimum effect size of –0.17 (P = .02).

The other cognitive measures were not significantly different between groups.
 

Clinicians may consider findings after accounting for other factors

Principal investigator Daniel A. Nation, PhD, associate professor of psychological science and a faculty member of the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine, suggested that the small difference in verbal memory between groups could be clinically significant over a longer period of time.

“Although the overall effect size was pretty small, if you look at how long it would take for someone [with dementia] to progress over many years of decline, it would actually end up being a pretty big effect,” Dr. Nation said in an interview. “Small effect sizes could actually end up preventing a lot of cases of dementia,” he added.

The conflicting results in the BBB-crossing group – better verbal memory but worse attention ability – were “surprising,” he noted.

“I sort of didn’t believe it at first,” Dr. Nation said, “because the memory finding is sort of replication – we’d observed the same exact effect on memory in a smaller sample in another study. ... The attention [finding], going another way, was a new thing.”

Dr. Nation suggested that the intergroup differences in attention ability may stem from idiosyncrasies of the tests used to measure that domain, which can be impacted by cardiovascular or brain vascular disease. Or it could be caused by something else entirely, he said, noting that further investigation is needed.

He added that the improvements in verbal memory within the BBB-crossing group could be caused by direct effects on the brain. He pointed out that certain ACE polymorphisms have been linked with Alzheimer’s disease risk, and those same polymorphisms, in animal models, lead to neurodegeneration, with reversal possible through administration of ACE inhibitors.

“It could be that what we’re observing has nothing really to do with blood pressure,” Dr. Nation explained. “This could be a neuronal effect on learning memory systems.”

He went on to suggest that clinicians may consider these findings when selecting antihypertensive agents for their patients, with the caveat that all other prescribing factors have already been taking to account.

“In the event that you’re going to give an ACE inhibitor or an angiotensin receptor blocker anyway, and it ends up being a somewhat arbitrary decision in terms of which specific drug you’re going to give, then perhaps this is a piece of information you would take into account – that one gets in the brain and one doesn’t – in somebody at risk for cognitive decline,” Dr. Nation said.
 

Exact mechanisms of action unknown

Hélène Girouard, PhD, assistant professor of pharmacology and physiology at the University of Montreal, said in an interview that the findings are “of considerable importance, knowing that brain alterations could begin as much as 30 years before manifestation of dementia.”

Since 2003, Dr. Girouard has been studying the cognitive effects of antihypertensive medications. She noted that previous studies involving rodents “have shown beneficial effects [of BBB-crossing antihypertensive drugs] on cognition independent of their effects on blood pressure.”

The drugs’ exact mechanisms of action, however, remain elusive, according to Dr. Girouard, who offered several possible explanations, including amelioration of BBB disruption, brain inflammation, cerebral blood flow dysregulation, cholinergic dysfunction, and neurologic deficits. “Whether these mechanisms may explain Ho and colleagues’ observations remains to be established,” she added.

Andrea L. Schneider, MD, PhD, assistant professor of neurology at the University of Pennsylvania, Philadelphia, applauded the study, but ultimately suggested that more research is needed to impact clinical decision-making.

“The results of this important and well-done study suggest that further investigation into targeted mechanism-based approaches to selecting hypertension treatment agents, with a specific focus on cognitive outcomes, is warranted,” Dr. Schneider said in an interview. “Before changing clinical practice, further work is necessary to disentangle contributions of medication mechanism, comorbid vascular risk factors, and achieved blood pressure reduction, among others.”

The investigators disclosed support from the National Institutes of Health, the Alzheimer’s Association, the Waksman Foundation of Japan, and others. The interviewees reported no relevant conflicts of interest.

Antihypertensive medications that cross the blood-brain barrier (BBB) may be linked with less memory decline, compared with other drugs for high blood pressure, suggest the findings of a meta-analysis.

Over a 3-year period, cognitively normal older adults taking BBB-crossing antihypertensives demonstrated superior verbal memory, compared with similar individuals receiving non–BBB-crossing antihypertensives, reported lead author Jean K. Ho, PhD, of the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine, and colleagues.

According to the investigators, the findings add color to a known link between hypertension and neurologic degeneration, and may aid the search for new therapeutic targets.

“Hypertension is a well-established risk factor for cognitive decline and dementia, possibly through its effects on both cerebrovascular disease and Alzheimer’s disease,” Dr. Ho and colleagues wrote in Hypertension. “Studies of antihypertensive treatments have reported possible salutary effects on cognition and cerebrovascular disease, as well as Alzheimer’s disease neuropathology.”

In a previous study, individuals younger than 75 years exposed to antihypertensives had an 8% decreased risk of dementia per year of use, while another trial showed that intensive blood pressure–lowering therapy reduced mild cognitive impairment by 19%.

“Despite these encouraging findings ... larger meta-analytic studies have been hampered by the fact that pharmacokinetic properties are typically not considered in existing studies or routine clinical practice,” wrote Dr. Ho and colleagues. “The present study sought to fill this gap [in that it was] a large and longitudinal meta-analytic study of existing data recoded to assess the effects of BBB-crossing potential in renin-angiotensin system [RAS] treatments among hypertensive adults.”
 

Methods and results

The meta-analysis included randomized clinical trials, prospective cohort studies, and retrospective observational studies. The researchers assessed data on 12,849 individuals from 14 cohorts that received either BBB-crossing or non–BBB-crossing antihypertensives.

The BBB-crossing properties of RAS treatments were identified by a literature review. Of ACE inhibitors, captopril, fosinopril, lisinopril, perindopril, ramipril, and trandolapril were classified as BBB crossing, and benazepril, enalapril, moexipril, and quinapril were classified as non–BBB-crossing. Of ARBs, telmisartan and candesartan were considered BBB-crossing, and olmesartan, eprosartan, irbesartan, and losartan were tagged as non–BBB-crossing.

Cognition was assessed via the following seven domains: executive function, attention, verbal memory learning, language, mental status, recall, and processing speed.

Compared with individuals taking non–BBB-crossing antihypertensives, those taking BBB-crossing agents had significantly superior verbal memory (recall), with a maximum effect size of 0.07 (P = .03).

According to the investigators, this finding was particularly noteworthy, as the BBB-crossing group had relatively higher vascular risk burden and lower mean education level.

“These differences make it all the more remarkable that the BBB-crossing group displayed better memory ability over time despite these cognitive disadvantages,” the investigators wrote.

Still, not all the findings favored BBB-crossing agents. Individuals in the BBB-crossing group had relatively inferior attention ability, with a minimum effect size of –0.17 (P = .02).

The other cognitive measures were not significantly different between groups.
 

Clinicians may consider findings after accounting for other factors

Principal investigator Daniel A. Nation, PhD, associate professor of psychological science and a faculty member of the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine, suggested that the small difference in verbal memory between groups could be clinically significant over a longer period of time.

“Although the overall effect size was pretty small, if you look at how long it would take for someone [with dementia] to progress over many years of decline, it would actually end up being a pretty big effect,” Dr. Nation said in an interview. “Small effect sizes could actually end up preventing a lot of cases of dementia,” he added.

The conflicting results in the BBB-crossing group – better verbal memory but worse attention ability – were “surprising,” he noted.

“I sort of didn’t believe it at first,” Dr. Nation said, “because the memory finding is sort of replication – we’d observed the same exact effect on memory in a smaller sample in another study. ... The attention [finding], going another way, was a new thing.”

Dr. Nation suggested that the intergroup differences in attention ability may stem from idiosyncrasies of the tests used to measure that domain, which can be impacted by cardiovascular or brain vascular disease. Or it could be caused by something else entirely, he said, noting that further investigation is needed.

He added that the improvements in verbal memory within the BBB-crossing group could be caused by direct effects on the brain. He pointed out that certain ACE polymorphisms have been linked with Alzheimer’s disease risk, and those same polymorphisms, in animal models, lead to neurodegeneration, with reversal possible through administration of ACE inhibitors.

“It could be that what we’re observing has nothing really to do with blood pressure,” Dr. Nation explained. “This could be a neuronal effect on learning memory systems.”

He went on to suggest that clinicians may consider these findings when selecting antihypertensive agents for their patients, with the caveat that all other prescribing factors have already been taking to account.

“In the event that you’re going to give an ACE inhibitor or an angiotensin receptor blocker anyway, and it ends up being a somewhat arbitrary decision in terms of which specific drug you’re going to give, then perhaps this is a piece of information you would take into account – that one gets in the brain and one doesn’t – in somebody at risk for cognitive decline,” Dr. Nation said.
 

Exact mechanisms of action unknown

Hélène Girouard, PhD, assistant professor of pharmacology and physiology at the University of Montreal, said in an interview that the findings are “of considerable importance, knowing that brain alterations could begin as much as 30 years before manifestation of dementia.”

Since 2003, Dr. Girouard has been studying the cognitive effects of antihypertensive medications. She noted that previous studies involving rodents “have shown beneficial effects [of BBB-crossing antihypertensive drugs] on cognition independent of their effects on blood pressure.”

The drugs’ exact mechanisms of action, however, remain elusive, according to Dr. Girouard, who offered several possible explanations, including amelioration of BBB disruption, brain inflammation, cerebral blood flow dysregulation, cholinergic dysfunction, and neurologic deficits. “Whether these mechanisms may explain Ho and colleagues’ observations remains to be established,” she added.

Andrea L. Schneider, MD, PhD, assistant professor of neurology at the University of Pennsylvania, Philadelphia, applauded the study, but ultimately suggested that more research is needed to impact clinical decision-making.

“The results of this important and well-done study suggest that further investigation into targeted mechanism-based approaches to selecting hypertension treatment agents, with a specific focus on cognitive outcomes, is warranted,” Dr. Schneider said in an interview. “Before changing clinical practice, further work is necessary to disentangle contributions of medication mechanism, comorbid vascular risk factors, and achieved blood pressure reduction, among others.”

The investigators disclosed support from the National Institutes of Health, the Alzheimer’s Association, the Waksman Foundation of Japan, and others. The interviewees reported no relevant conflicts of interest.

About 40% of patients with heart failure (HF) also have type 2 diabetes mellitus (T2DM).¹ Certain sodium-glucose cotransporter-2 (SGLT2) inhibitors have benefited patients with HF.² We report a case of a patient with T2DM who had signs and symptoms of hypervolemia after discontinuing the SGLT2 inhibitor empagliflozin. The patient was found to have previously undiagnosed HF. This case highlights the relationship between T2DM and HF and the benefits of treatment with SGLT2 inhibitors.

Case Presentation

A 58-year-old male presented for care at Malcolm Randall Veterans Affairs Medical Center in Gainseville, Florida, diabetes clinic. The patient was diagnosed with T2DM at age 32 years. At 36 years, he was started on subcutaneous insulin injections, and was switched to insulin pump therapy in his early 40s. At the time of evaluation, the T2DM was managed using an insulin pump, metformin, and acarbose. He had been prescribed empagliflozin 10 mg several months before presentation, but the medication ran out about 1 month prior to evaluation, and additional refills were unavailable.

The patient reported a 1-month history of worsening exertional shortness of breath, decreased exercise tolerance, and lower extremity swelling. Vitals signs, including respiratory rate and oxygen saturation were within normal limits. Bibasilar crackles and bilateral 2+ pitting pedal edema were noted. The remaining examination was unrevealing. His most recent glycated hemoglobin A_1c level from 1 month prior to the presentation was 6.4%.

Given the patient’s shortness of breath and evidence of fluid overload on examination, brain natriuretic peptide was obtained and was significantly elevated at 5,895 pg/mL. A transthoracic echocardiogram revealed left ventricular ejection fraction < 20%. The patient was started on furosemide 40 mg, pending receipt of empagliflozin. A cardiology evaluation also was recommended.

Cardiac catheterization identified significant obstructions to the left anterior descending and left circumflex arteries. The patient underwent successful percutaneous coronary intervention to these areas. Following initiation of medications and coronary revascularization, the patient reported significant symptom improvement. At the follow-up evaluation 8 weeks later, he was symptom free, and his physical examination was consistent with euvolemia.

Discussion

T2DM has been associated with adverse cardiovascular outcomes, including atherosclerotic heart disease and HF. There are several theories about the relationship between T2DM and HF, though the exact pathophysiology of this relationship is unknown.^3,4 One theory suggests diabetic cardiomyopathy as the cause. In patients with diabetic cardiomyopathy, there is early development of diastolic dysfunction, which eventually progresses to ventricular dysfunction. There is continued stimulation of the renin-angiotensin-aldosterone system that leads to death of cardiomyocytes, fibrosis, and remodeling, which worsens pump failure.⁵

SGLT2 inhibitors decrease hyperglycemia and hyperinsulinemia, potentially reducing HF risk. SGLT2 inhibitors decrease blood glucose levels by inhibiting SGLT2 in the proximal tubule, leading to a decrease of glucose reabsorption and an increase in excretion.^6,7 The EMPA-REG OUTCOME trial looked at cardiovascular outcomes in patients with T2DM at high risk for adverse cardiac events. There was a significant risk reduction in deaths and hospitalizations for HF in patients treated with empagliflozin.⁸

Conclusions

SGLT2 inhibitors have been shown to have a role in the management of HF in patients with T2DM. There is a risk of exacerbation or unmasking of HF when discontinuing SGLT2 inhibitors. To our knowledge, this is the first paper describing the discovery of HF following interruption of SGLT2 inhibitor treatment. The clinician and patient should monitor for signs and symptoms of fluid overload when stopping therapy. Further research into the benefits of a more comprehensive evaluation is needed.

About 40% of patients with heart failure (HF) also have type 2 diabetes mellitus (T2DM).¹ Certain sodium-glucose cotransporter-2 (SGLT2) inhibitors have benefited patients with HF.² We report a case of a patient with T2DM who had signs and symptoms of hypervolemia after discontinuing the SGLT2 inhibitor empagliflozin. The patient was found to have previously undiagnosed HF. This case highlights the relationship between T2DM and HF and the benefits of treatment with SGLT2 inhibitors.

Case Presentation

A 58-year-old male presented for care at Malcolm Randall Veterans Affairs Medical Center in Gainseville, Florida, diabetes clinic. The patient was diagnosed with T2DM at age 32 years. At 36 years, he was started on subcutaneous insulin injections, and was switched to insulin pump therapy in his early 40s. At the time of evaluation, the T2DM was managed using an insulin pump, metformin, and acarbose. He had been prescribed empagliflozin 10 mg several months before presentation, but the medication ran out about 1 month prior to evaluation, and additional refills were unavailable.

The patient reported a 1-month history of worsening exertional shortness of breath, decreased exercise tolerance, and lower extremity swelling. Vitals signs, including respiratory rate and oxygen saturation were within normal limits. Bibasilar crackles and bilateral 2+ pitting pedal edema were noted. The remaining examination was unrevealing. His most recent glycated hemoglobin A_1c level from 1 month prior to the presentation was 6.4%.

Given the patient’s shortness of breath and evidence of fluid overload on examination, brain natriuretic peptide was obtained and was significantly elevated at 5,895 pg/mL. A transthoracic echocardiogram revealed left ventricular ejection fraction < 20%. The patient was started on furosemide 40 mg, pending receipt of empagliflozin. A cardiology evaluation also was recommended.

Cardiac catheterization identified significant obstructions to the left anterior descending and left circumflex arteries. The patient underwent successful percutaneous coronary intervention to these areas. Following initiation of medications and coronary revascularization, the patient reported significant symptom improvement. At the follow-up evaluation 8 weeks later, he was symptom free, and his physical examination was consistent with euvolemia.

Discussion

T2DM has been associated with adverse cardiovascular outcomes, including atherosclerotic heart disease and HF. There are several theories about the relationship between T2DM and HF, though the exact pathophysiology of this relationship is unknown.^3,4 One theory suggests diabetic cardiomyopathy as the cause. In patients with diabetic cardiomyopathy, there is early development of diastolic dysfunction, which eventually progresses to ventricular dysfunction. There is continued stimulation of the renin-angiotensin-aldosterone system that leads to death of cardiomyocytes, fibrosis, and remodeling, which worsens pump failure.⁵

SGLT2 inhibitors decrease hyperglycemia and hyperinsulinemia, potentially reducing HF risk. SGLT2 inhibitors decrease blood glucose levels by inhibiting SGLT2 in the proximal tubule, leading to a decrease of glucose reabsorption and an increase in excretion.^6,7 The EMPA-REG OUTCOME trial looked at cardiovascular outcomes in patients with T2DM at high risk for adverse cardiac events. There was a significant risk reduction in deaths and hospitalizations for HF in patients treated with empagliflozin.⁸

Conclusions

SGLT2 inhibitors have been shown to have a role in the management of HF in patients with T2DM. There is a risk of exacerbation or unmasking of HF when discontinuing SGLT2 inhibitors. To our knowledge, this is the first paper describing the discovery of HF following interruption of SGLT2 inhibitor treatment. The clinician and patient should monitor for signs and symptoms of fluid overload when stopping therapy. Further research into the benefits of a more comprehensive evaluation is needed.

About 40% of patients with heart failure (HF) also have type 2 diabetes mellitus (T2DM).¹ Certain sodium-glucose cotransporter-2 (SGLT2) inhibitors have benefited patients with HF.² We report a case of a patient with T2DM who had signs and symptoms of hypervolemia after discontinuing the SGLT2 inhibitor empagliflozin. The patient was found to have previously undiagnosed HF. This case highlights the relationship between T2DM and HF and the benefits of treatment with SGLT2 inhibitors.

Case Presentation

A 58-year-old male presented for care at Malcolm Randall Veterans Affairs Medical Center in Gainseville, Florida, diabetes clinic. The patient was diagnosed with T2DM at age 32 years. At 36 years, he was started on subcutaneous insulin injections, and was switched to insulin pump therapy in his early 40s. At the time of evaluation, the T2DM was managed using an insulin pump, metformin, and acarbose. He had been prescribed empagliflozin 10 mg several months before presentation, but the medication ran out about 1 month prior to evaluation, and additional refills were unavailable.

The patient reported a 1-month history of worsening exertional shortness of breath, decreased exercise tolerance, and lower extremity swelling. Vitals signs, including respiratory rate and oxygen saturation were within normal limits. Bibasilar crackles and bilateral 2+ pitting pedal edema were noted. The remaining examination was unrevealing. His most recent glycated hemoglobin A_1c level from 1 month prior to the presentation was 6.4%.

Given the patient’s shortness of breath and evidence of fluid overload on examination, brain natriuretic peptide was obtained and was significantly elevated at 5,895 pg/mL. A transthoracic echocardiogram revealed left ventricular ejection fraction < 20%. The patient was started on furosemide 40 mg, pending receipt of empagliflozin. A cardiology evaluation also was recommended.

Cardiac catheterization identified significant obstructions to the left anterior descending and left circumflex arteries. The patient underwent successful percutaneous coronary intervention to these areas. Following initiation of medications and coronary revascularization, the patient reported significant symptom improvement. At the follow-up evaluation 8 weeks later, he was symptom free, and his physical examination was consistent with euvolemia.

Discussion

T2DM has been associated with adverse cardiovascular outcomes, including atherosclerotic heart disease and HF. There are several theories about the relationship between T2DM and HF, though the exact pathophysiology of this relationship is unknown.^3,4 One theory suggests diabetic cardiomyopathy as the cause. In patients with diabetic cardiomyopathy, there is early development of diastolic dysfunction, which eventually progresses to ventricular dysfunction. There is continued stimulation of the renin-angiotensin-aldosterone system that leads to death of cardiomyocytes, fibrosis, and remodeling, which worsens pump failure.⁵

SGLT2 inhibitors decrease hyperglycemia and hyperinsulinemia, potentially reducing HF risk. SGLT2 inhibitors decrease blood glucose levels by inhibiting SGLT2 in the proximal tubule, leading to a decrease of glucose reabsorption and an increase in excretion.^6,7 The EMPA-REG OUTCOME trial looked at cardiovascular outcomes in patients with T2DM at high risk for adverse cardiac events. There was a significant risk reduction in deaths and hospitalizations for HF in patients treated with empagliflozin.⁸

Conclusions

SGLT2 inhibitors have been shown to have a role in the management of HF in patients with T2DM. There is a risk of exacerbation or unmasking of HF when discontinuing SGLT2 inhibitors. To our knowledge, this is the first paper describing the discovery of HF following interruption of SGLT2 inhibitor treatment. The clinician and patient should monitor for signs and symptoms of fluid overload when stopping therapy. Further research into the benefits of a more comprehensive evaluation is needed.

Patients with obesity who underwent bariatric surgery had 46% lower odds of stroke 1 year later, similar odds of stroke 3 years later, and 22% lower odds of stroke 5 years later, compared with matched control patients, in new research.

purestock/Thinkstock

Michael D. Williams, MD, presented the study findings (abstract A002) at the annual meeting of the American Society for Metabolic & Bariatric Surgery.

The findings are “very good news,” even though the protection against stroke declined further out from the surgery, John D. Scott, MD, scientific program chair of the ASMBS meeting, told this news organization.

The investigators matched more than 56,000 patients with obesity who had bariatric surgery with an equal number of similar patients who did not have this surgery, from a large national insurance database, in what they believe is the largest study of this to date.

“Any intervention that decreases your risk of [cardiovascular] events is good news,” said Dr. Scott, a clinical professor of surgery at the University of South Carolina, Greenville, and metabolic and bariatric surgery director at Prisma Health in Greenville, S.C. “And having a 22%-45% chance of reduction in stroke risk is a very worthwhile intervention.”

Asked how this would change the way clinicians inform patients of what to expect from bariatric surgery, he said: “I would advise patients that studies like this show that surgery would not increase your risk of having a stroke.

“This is consistent with many studies that show that the risks of all macrovascular events decrease after the comorbidity reductions seen after surgery.”

According to Dr. Scott, “the next steps might include a prospective randomized trial of medical treatment versus surgery alone for [cardiovascular]/stroke outcomes, but this is unlikely.”

Similarly, Dr. Williams told this news organization that “I would tell [patients] that surgery is an effective and durable method for weight loss. It also can improve comorbid conditions, particularly diabetes and hypertension.”

Even with this study, “I’m not sure it’s appropriate to say that bariatric surgery will reduce the risk of stroke,” he cautioned.

“However, as we continue to investigate the effects of bariatric surgery, this study contributes to the greater body of knowledge that suggests that reduction in ischemic stroke risk is yet another benefit of bariatric surgery.”

The assigned discussant, Corrigan L. McBride, MD, MBA wanted to know if the lower odds ratio at 1 year might be because preoperative patient selection might eliminate patients at high risk of poor cardiovascular outcomes.

Dr. Williams, a resident at Rush Medical College, Chicago, replied that it is difficult to eliminate potential selection bias, despite best efforts, but this study shows that he can tell patients: “Having surgery is not going to increases your risk of stroke.”

“This is an important study,” Dr. McBride, professor and chief of minimally invasive surgery and bariatric surgery, University of Nebraska Medical Center, Omaha, told this news organization.

“It is the first large study to show a decreased [or no increased] risk of stroke 1, 3, and 5 years after bariatric surgery compared to matched patients, and it had enough data to look at stroke as a standalone endpoint,” Dr. McBride said. “It is important too, for patients and their physicians to understand that there is a lower chance of them having a stroke if they have surgery than if they do not.”
 

‘Important,’ ‘good news’ for stroke risk after bariatric surgery

The impact of bariatric surgery on remission of type 2 diabetes is well known, Dr. Williams noted, and other studies have reported how bariatric surgery affects the risk of major adverse cardiovascular events – a composite of stroke, myocardial infarction, coronary artery disease, and all-cause death – including a study presented in the same meeting session.

However, a very large sample size is needed to be able to demonstrate the effect of bariatric surgery on stroke, since stroke is a rare event.

The researchers analyzed data from the Mariner (PearlDiver.) all-payer insurance national claims database of patients in the United States.

They matched 56,514 patients with a body mass index over 35 kg/m² and comorbidities or a BMI of more than 40 who underwent sleeve gastrectomy or Roux-en-Y gastric bypass during 2010-2019 with 56,514 control patients who did not undergo bariatric surgery.

A year after bariatric surgery, patients in that group had a lower stroke rate than patients in the control group (0.6% vs. 1.2%), and they had close to 50% lower odds of having a stroke (odds ratio, 0.54; 95% CI, 0.47-0.61).

Three years after bariatric surgery, there were 44,948 patients in each group; the rate of stroke was 2.1% in the surgery group and 2.2% in the control group, and there was no significant difference in the odds of having a stroke (OR, 0.96; 95% CI, 0.91-1.00).

Five years after bariatric surgery, there were 27,619 patients in each group; the stroke rate was lower in the bariatric surgery group than in the control group (2.8% vs 3.6%), but reduced odds of stroke was not as great as after 1 year (OR, 0.78; 95% CI, 0.65-0.90).

Dr. Williams has no relevant financial disclosures. Dr. McBride and Dr. Scott disclosed that they are speakers/trainers/faculty advisers for Gore. Dr. Scott is also a consultant for C-SATS (part of Johnson & Johnson).

Patients with obesity who underwent bariatric surgery had 46% lower odds of stroke 1 year later, similar odds of stroke 3 years later, and 22% lower odds of stroke 5 years later, compared with matched control patients, in new research.

purestock/Thinkstock

Michael D. Williams, MD, presented the study findings (abstract A002) at the annual meeting of the American Society for Metabolic & Bariatric Surgery.

The findings are “very good news,” even though the protection against stroke declined further out from the surgery, John D. Scott, MD, scientific program chair of the ASMBS meeting, told this news organization.

The investigators matched more than 56,000 patients with obesity who had bariatric surgery with an equal number of similar patients who did not have this surgery, from a large national insurance database, in what they believe is the largest study of this to date.

“Any intervention that decreases your risk of [cardiovascular] events is good news,” said Dr. Scott, a clinical professor of surgery at the University of South Carolina, Greenville, and metabolic and bariatric surgery director at Prisma Health in Greenville, S.C. “And having a 22%-45% chance of reduction in stroke risk is a very worthwhile intervention.”

Asked how this would change the way clinicians inform patients of what to expect from bariatric surgery, he said: “I would advise patients that studies like this show that surgery would not increase your risk of having a stroke.

“This is consistent with many studies that show that the risks of all macrovascular events decrease after the comorbidity reductions seen after surgery.”

According to Dr. Scott, “the next steps might include a prospective randomized trial of medical treatment versus surgery alone for [cardiovascular]/stroke outcomes, but this is unlikely.”

Similarly, Dr. Williams told this news organization that “I would tell [patients] that surgery is an effective and durable method for weight loss. It also can improve comorbid conditions, particularly diabetes and hypertension.”

Even with this study, “I’m not sure it’s appropriate to say that bariatric surgery will reduce the risk of stroke,” he cautioned.

“However, as we continue to investigate the effects of bariatric surgery, this study contributes to the greater body of knowledge that suggests that reduction in ischemic stroke risk is yet another benefit of bariatric surgery.”

The assigned discussant, Corrigan L. McBride, MD, MBA wanted to know if the lower odds ratio at 1 year might be because preoperative patient selection might eliminate patients at high risk of poor cardiovascular outcomes.

Dr. Williams, a resident at Rush Medical College, Chicago, replied that it is difficult to eliminate potential selection bias, despite best efforts, but this study shows that he can tell patients: “Having surgery is not going to increases your risk of stroke.”

“This is an important study,” Dr. McBride, professor and chief of minimally invasive surgery and bariatric surgery, University of Nebraska Medical Center, Omaha, told this news organization.

“It is the first large study to show a decreased [or no increased] risk of stroke 1, 3, and 5 years after bariatric surgery compared to matched patients, and it had enough data to look at stroke as a standalone endpoint,” Dr. McBride said. “It is important too, for patients and their physicians to understand that there is a lower chance of them having a stroke if they have surgery than if they do not.”
 

‘Important,’ ‘good news’ for stroke risk after bariatric surgery

The impact of bariatric surgery on remission of type 2 diabetes is well known, Dr. Williams noted, and other studies have reported how bariatric surgery affects the risk of major adverse cardiovascular events – a composite of stroke, myocardial infarction, coronary artery disease, and all-cause death – including a study presented in the same meeting session.

However, a very large sample size is needed to be able to demonstrate the effect of bariatric surgery on stroke, since stroke is a rare event.

The researchers analyzed data from the Mariner (PearlDiver.) all-payer insurance national claims database of patients in the United States.

They matched 56,514 patients with a body mass index over 35 kg/m² and comorbidities or a BMI of more than 40 who underwent sleeve gastrectomy or Roux-en-Y gastric bypass during 2010-2019 with 56,514 control patients who did not undergo bariatric surgery.

A year after bariatric surgery, patients in that group had a lower stroke rate than patients in the control group (0.6% vs. 1.2%), and they had close to 50% lower odds of having a stroke (odds ratio, 0.54; 95% CI, 0.47-0.61).

Three years after bariatric surgery, there were 44,948 patients in each group; the rate of stroke was 2.1% in the surgery group and 2.2% in the control group, and there was no significant difference in the odds of having a stroke (OR, 0.96; 95% CI, 0.91-1.00).

Five years after bariatric surgery, there were 27,619 patients in each group; the stroke rate was lower in the bariatric surgery group than in the control group (2.8% vs 3.6%), but reduced odds of stroke was not as great as after 1 year (OR, 0.78; 95% CI, 0.65-0.90).

Dr. Williams has no relevant financial disclosures. Dr. McBride and Dr. Scott disclosed that they are speakers/trainers/faculty advisers for Gore. Dr. Scott is also a consultant for C-SATS (part of Johnson & Johnson).

Patients with obesity who underwent bariatric surgery had 46% lower odds of stroke 1 year later, similar odds of stroke 3 years later, and 22% lower odds of stroke 5 years later, compared with matched control patients, in new research.

purestock/Thinkstock

Michael D. Williams, MD, presented the study findings (abstract A002) at the annual meeting of the American Society for Metabolic & Bariatric Surgery.

The findings are “very good news,” even though the protection against stroke declined further out from the surgery, John D. Scott, MD, scientific program chair of the ASMBS meeting, told this news organization.

The investigators matched more than 56,000 patients with obesity who had bariatric surgery with an equal number of similar patients who did not have this surgery, from a large national insurance database, in what they believe is the largest study of this to date.

“Any intervention that decreases your risk of [cardiovascular] events is good news,” said Dr. Scott, a clinical professor of surgery at the University of South Carolina, Greenville, and metabolic and bariatric surgery director at Prisma Health in Greenville, S.C. “And having a 22%-45% chance of reduction in stroke risk is a very worthwhile intervention.”

Asked how this would change the way clinicians inform patients of what to expect from bariatric surgery, he said: “I would advise patients that studies like this show that surgery would not increase your risk of having a stroke.

“This is consistent with many studies that show that the risks of all macrovascular events decrease after the comorbidity reductions seen after surgery.”

According to Dr. Scott, “the next steps might include a prospective randomized trial of medical treatment versus surgery alone for [cardiovascular]/stroke outcomes, but this is unlikely.”

Similarly, Dr. Williams told this news organization that “I would tell [patients] that surgery is an effective and durable method for weight loss. It also can improve comorbid conditions, particularly diabetes and hypertension.”

Even with this study, “I’m not sure it’s appropriate to say that bariatric surgery will reduce the risk of stroke,” he cautioned.

“However, as we continue to investigate the effects of bariatric surgery, this study contributes to the greater body of knowledge that suggests that reduction in ischemic stroke risk is yet another benefit of bariatric surgery.”

The assigned discussant, Corrigan L. McBride, MD, MBA wanted to know if the lower odds ratio at 1 year might be because preoperative patient selection might eliminate patients at high risk of poor cardiovascular outcomes.

Dr. Williams, a resident at Rush Medical College, Chicago, replied that it is difficult to eliminate potential selection bias, despite best efforts, but this study shows that he can tell patients: “Having surgery is not going to increases your risk of stroke.”

“This is an important study,” Dr. McBride, professor and chief of minimally invasive surgery and bariatric surgery, University of Nebraska Medical Center, Omaha, told this news organization.

“It is the first large study to show a decreased [or no increased] risk of stroke 1, 3, and 5 years after bariatric surgery compared to matched patients, and it had enough data to look at stroke as a standalone endpoint,” Dr. McBride said. “It is important too, for patients and their physicians to understand that there is a lower chance of them having a stroke if they have surgery than if they do not.”
 

‘Important,’ ‘good news’ for stroke risk after bariatric surgery

The impact of bariatric surgery on remission of type 2 diabetes is well known, Dr. Williams noted, and other studies have reported how bariatric surgery affects the risk of major adverse cardiovascular events – a composite of stroke, myocardial infarction, coronary artery disease, and all-cause death – including a study presented in the same meeting session.

However, a very large sample size is needed to be able to demonstrate the effect of bariatric surgery on stroke, since stroke is a rare event.

The researchers analyzed data from the Mariner (PearlDiver.) all-payer insurance national claims database of patients in the United States.

They matched 56,514 patients with a body mass index over 35 kg/m² and comorbidities or a BMI of more than 40 who underwent sleeve gastrectomy or Roux-en-Y gastric bypass during 2010-2019 with 56,514 control patients who did not undergo bariatric surgery.

A year after bariatric surgery, patients in that group had a lower stroke rate than patients in the control group (0.6% vs. 1.2%), and they had close to 50% lower odds of having a stroke (odds ratio, 0.54; 95% CI, 0.47-0.61).

Three years after bariatric surgery, there were 44,948 patients in each group; the rate of stroke was 2.1% in the surgery group and 2.2% in the control group, and there was no significant difference in the odds of having a stroke (OR, 0.96; 95% CI, 0.91-1.00).

Five years after bariatric surgery, there were 27,619 patients in each group; the stroke rate was lower in the bariatric surgery group than in the control group (2.8% vs 3.6%), but reduced odds of stroke was not as great as after 1 year (OR, 0.78; 95% CI, 0.65-0.90).

Dr. Williams has no relevant financial disclosures. Dr. McBride and Dr. Scott disclosed that they are speakers/trainers/faculty advisers for Gore. Dr. Scott is also a consultant for C-SATS (part of Johnson & Johnson).

Prophylactic anticoagulation to prevent venous thromboembolism (VTE) was associated with reduced 60-day mortality in patients with COVID-19 who were ill enough to require hospitalization, a new report shows.

In a cohort study of more than 1,300 hospitalized patients with COVID-19 infection across 30 hospitals in Michigan, both prophylactic- and therapeutic-dose anticoagulation were associated with reduced in-hospital mortality; however, at 60 days, only prophylactic-dose anticoagulation remained associated with lower mortality.

And adherence was key; nonadherence, or missing 2 days or more of anticoagulation, was linked to more deaths at 60 days.

The findings, which were published online June 11 in JAMA Network Open, are final proof that a prophylactic anticoagulation strategy for the hospitalized COVID population is, indeed, the right one, Valerie M. Vaughn, MD, director of hospital medicine research at the University of Utah, Salt Lake City, said in an interview.

“We’ve probably always known that patients with COVID need prophylaxis for VTE, but we found that early on, unfortunately, that wasn’t being done,” Dr. Vaughn said.

“Now, we see that prophylactic rates have increased. We always knew to use anticoagulation prophylactically in patients who were hospitalized with infection because of their risk for VTE, so this study just drives home that proper adherence to an anticoagulation protocol improves mortality,” she said.

Dr. Vaughn was on the front lines when COVID-19 came to Michigan, where the research was conducted.

“We probably should have been anticoagulating from the get-go, but you have to remember that in the early days of COVID, the hospitals in Michigan were being overwhelmed. They didn’t have PPE. They were taking care of patients outside of their typical hospital beds or setting up field hospitals,” she said. “It was not quite as bad as New York, but at the University of Michigan, we set up four or five ICUs outside of our normal care.”

They also converted the top floor of their pediatric hospital into an ICU to take care of patients with COVID during the first surge, she added. “We didn’t know much about this disease, but faced with this influx of patients, many of whom were dying with blood clots, we had to do something.”  

Some hospitals began prophylactically anticoagulating their patients, but others hesitated before adopting the strategy. “But now we feel confident that prophylactic anticoagulation, done according to the right protocol, with no interruptions in the treatment, is beneficial,” Dr. Vaughn said.

The best medication choice is enoxaparin (Lovenox), which can be given once a day, as opposed to heparin, which needs to be given via injection three times a day, she said.

“Prophylactic dose anticoagulation is typically given by an injection under the skin, but a lot of times, I’ve had patients tell me they feel like a human pin cushion and have all these bruises from being stuck with needles every day, which I can totally relate to,” she said.

“It is important for us as clinicians to explain that we’re having to poke our patients because it is good for them and will help them fight COVID,” she added. “Also having the once-a-day option is going to be a lot better for adherence, and adherence to the protocol, not missing any days, is key to the better outcome.”

Dr. Vaughn and her team reviewed the charts of 1,351 patients (48% women, 49% Black, median age 64 [range 52-75]) who were hospitalized throughout Michigan during the first several months of the COVID-19 pandemic, from March to June 2020.

Only 18 patients (1.3%) had a confirmed VTE and 219 patients (16.2%) received treatment-dose anticoagulation.

The researchers noted that use of treatment-dose anticoagulation without imaging ranged from 0% to 29% across hospitals and increased significantly over time.

Of the 1,127 patients who received anticoagulation, 392 (34.8%) missed 2 days or more of prophylaxis.

In addition, there were varying rates of missed prophylaxis among the hospitals, from 11% to 61%, but these rates decreased markedly over time.

Missed doses were associated with a higher 60-day mortality (adjusted hazard ratio, 1.31; 95% confidence interval, 1.03-1.67), but not in-hospital mortality (aHR, 0.97; 95% CI, 0.91-1.03).

Compared with no anticoagulation, receiving any dose of anticoagulation was associated with lower in-hospital mortality.

However, only prophylactic-dose anticoagulation remained associated with lower mortality at 60 days. The adjusted hazard ratio for prophylactic-dose anticoagulation was 0.71 (95% CI, 0.51-0.90), compared with 0.92 (95% CI, 0.63-1.35) for treatment-dose anticoagulation.
 

Study boosts confidence

Despite its limitations, the study should make clinicians more confident that the use of prophylactic anticoagulation is warranted for hospitalized patients with COVID-19, write Andrew B. Dicks, MD, and Ido Weinberg, MD, from Massachusetts General Hospital, Boston, in an invited commentary.

“Practically, we still lack the granular data we need to help guide us in patient-by-patient decision-making – such as anticoagulation agent choice, dosage, and duration of therapy – especially as dictated by acuity of patient illness,” Dr. Dicks and Dr. Weinberg note.

“While we still await the data from randomized controlled trials to guide the optimal anticoagulation dose and duration, this study adds significant merit to the previously published recommendations from several different medical organizations regarding the use of prophylactic anticoagulation in hospitalized patients with COVID-19,” Dr. Dicks told this news organization.

The study was supported by Blue Cross and Blue Shield of Michigan and Blue Care Network as part of their Value Partnerships program. Dr. Vaughn has reported receiving speaking fees from Thermo Fisher Scientific. Dr. Dicks and Dr. Weinberg have reported no relevant financial relationships.

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

Prophylactic anticoagulation to prevent venous thromboembolism (VTE) was associated with reduced 60-day mortality in patients with COVID-19 who were ill enough to require hospitalization, a new report shows.

In a cohort study of more than 1,300 hospitalized patients with COVID-19 infection across 30 hospitals in Michigan, both prophylactic- and therapeutic-dose anticoagulation were associated with reduced in-hospital mortality; however, at 60 days, only prophylactic-dose anticoagulation remained associated with lower mortality.

And adherence was key; nonadherence, or missing 2 days or more of anticoagulation, was linked to more deaths at 60 days.

The findings, which were published online June 11 in JAMA Network Open, are final proof that a prophylactic anticoagulation strategy for the hospitalized COVID population is, indeed, the right one, Valerie M. Vaughn, MD, director of hospital medicine research at the University of Utah, Salt Lake City, said in an interview.

“We’ve probably always known that patients with COVID need prophylaxis for VTE, but we found that early on, unfortunately, that wasn’t being done,” Dr. Vaughn said.

“Now, we see that prophylactic rates have increased. We always knew to use anticoagulation prophylactically in patients who were hospitalized with infection because of their risk for VTE, so this study just drives home that proper adherence to an anticoagulation protocol improves mortality,” she said.

Dr. Vaughn was on the front lines when COVID-19 came to Michigan, where the research was conducted.

“We probably should have been anticoagulating from the get-go, but you have to remember that in the early days of COVID, the hospitals in Michigan were being overwhelmed. They didn’t have PPE. They were taking care of patients outside of their typical hospital beds or setting up field hospitals,” she said. “It was not quite as bad as New York, but at the University of Michigan, we set up four or five ICUs outside of our normal care.”

They also converted the top floor of their pediatric hospital into an ICU to take care of patients with COVID during the first surge, she added. “We didn’t know much about this disease, but faced with this influx of patients, many of whom were dying with blood clots, we had to do something.”  

Some hospitals began prophylactically anticoagulating their patients, but others hesitated before adopting the strategy. “But now we feel confident that prophylactic anticoagulation, done according to the right protocol, with no interruptions in the treatment, is beneficial,” Dr. Vaughn said.

The best medication choice is enoxaparin (Lovenox), which can be given once a day, as opposed to heparin, which needs to be given via injection three times a day, she said.

“Prophylactic dose anticoagulation is typically given by an injection under the skin, but a lot of times, I’ve had patients tell me they feel like a human pin cushion and have all these bruises from being stuck with needles every day, which I can totally relate to,” she said.

“It is important for us as clinicians to explain that we’re having to poke our patients because it is good for them and will help them fight COVID,” she added. “Also having the once-a-day option is going to be a lot better for adherence, and adherence to the protocol, not missing any days, is key to the better outcome.”

Dr. Vaughn and her team reviewed the charts of 1,351 patients (48% women, 49% Black, median age 64 [range 52-75]) who were hospitalized throughout Michigan during the first several months of the COVID-19 pandemic, from March to June 2020.

Only 18 patients (1.3%) had a confirmed VTE and 219 patients (16.2%) received treatment-dose anticoagulation.

The researchers noted that use of treatment-dose anticoagulation without imaging ranged from 0% to 29% across hospitals and increased significantly over time.

Of the 1,127 patients who received anticoagulation, 392 (34.8%) missed 2 days or more of prophylaxis.

In addition, there were varying rates of missed prophylaxis among the hospitals, from 11% to 61%, but these rates decreased markedly over time.

Missed doses were associated with a higher 60-day mortality (adjusted hazard ratio, 1.31; 95% confidence interval, 1.03-1.67), but not in-hospital mortality (aHR, 0.97; 95% CI, 0.91-1.03).

Compared with no anticoagulation, receiving any dose of anticoagulation was associated with lower in-hospital mortality.

However, only prophylactic-dose anticoagulation remained associated with lower mortality at 60 days. The adjusted hazard ratio for prophylactic-dose anticoagulation was 0.71 (95% CI, 0.51-0.90), compared with 0.92 (95% CI, 0.63-1.35) for treatment-dose anticoagulation.
 

Study boosts confidence

Despite its limitations, the study should make clinicians more confident that the use of prophylactic anticoagulation is warranted for hospitalized patients with COVID-19, write Andrew B. Dicks, MD, and Ido Weinberg, MD, from Massachusetts General Hospital, Boston, in an invited commentary.

“Practically, we still lack the granular data we need to help guide us in patient-by-patient decision-making – such as anticoagulation agent choice, dosage, and duration of therapy – especially as dictated by acuity of patient illness,” Dr. Dicks and Dr. Weinberg note.

“While we still await the data from randomized controlled trials to guide the optimal anticoagulation dose and duration, this study adds significant merit to the previously published recommendations from several different medical organizations regarding the use of prophylactic anticoagulation in hospitalized patients with COVID-19,” Dr. Dicks told this news organization.

The study was supported by Blue Cross and Blue Shield of Michigan and Blue Care Network as part of their Value Partnerships program. Dr. Vaughn has reported receiving speaking fees from Thermo Fisher Scientific. Dr. Dicks and Dr. Weinberg have reported no relevant financial relationships.

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

Prophylactic anticoagulation to prevent venous thromboembolism (VTE) was associated with reduced 60-day mortality in patients with COVID-19 who were ill enough to require hospitalization, a new report shows.

In a cohort study of more than 1,300 hospitalized patients with COVID-19 infection across 30 hospitals in Michigan, both prophylactic- and therapeutic-dose anticoagulation were associated with reduced in-hospital mortality; however, at 60 days, only prophylactic-dose anticoagulation remained associated with lower mortality.

And adherence was key; nonadherence, or missing 2 days or more of anticoagulation, was linked to more deaths at 60 days.

The findings, which were published online June 11 in JAMA Network Open, are final proof that a prophylactic anticoagulation strategy for the hospitalized COVID population is, indeed, the right one, Valerie M. Vaughn, MD, director of hospital medicine research at the University of Utah, Salt Lake City, said in an interview.

“We’ve probably always known that patients with COVID need prophylaxis for VTE, but we found that early on, unfortunately, that wasn’t being done,” Dr. Vaughn said.

“Now, we see that prophylactic rates have increased. We always knew to use anticoagulation prophylactically in patients who were hospitalized with infection because of their risk for VTE, so this study just drives home that proper adherence to an anticoagulation protocol improves mortality,” she said.

Dr. Vaughn was on the front lines when COVID-19 came to Michigan, where the research was conducted.

“We probably should have been anticoagulating from the get-go, but you have to remember that in the early days of COVID, the hospitals in Michigan were being overwhelmed. They didn’t have PPE. They were taking care of patients outside of their typical hospital beds or setting up field hospitals,” she said. “It was not quite as bad as New York, but at the University of Michigan, we set up four or five ICUs outside of our normal care.”

They also converted the top floor of their pediatric hospital into an ICU to take care of patients with COVID during the first surge, she added. “We didn’t know much about this disease, but faced with this influx of patients, many of whom were dying with blood clots, we had to do something.”  

Some hospitals began prophylactically anticoagulating their patients, but others hesitated before adopting the strategy. “But now we feel confident that prophylactic anticoagulation, done according to the right protocol, with no interruptions in the treatment, is beneficial,” Dr. Vaughn said.

The best medication choice is enoxaparin (Lovenox), which can be given once a day, as opposed to heparin, which needs to be given via injection three times a day, she said.

“Prophylactic dose anticoagulation is typically given by an injection under the skin, but a lot of times, I’ve had patients tell me they feel like a human pin cushion and have all these bruises from being stuck with needles every day, which I can totally relate to,” she said.

“It is important for us as clinicians to explain that we’re having to poke our patients because it is good for them and will help them fight COVID,” she added. “Also having the once-a-day option is going to be a lot better for adherence, and adherence to the protocol, not missing any days, is key to the better outcome.”

Dr. Vaughn and her team reviewed the charts of 1,351 patients (48% women, 49% Black, median age 64 [range 52-75]) who were hospitalized throughout Michigan during the first several months of the COVID-19 pandemic, from March to June 2020.

Only 18 patients (1.3%) had a confirmed VTE and 219 patients (16.2%) received treatment-dose anticoagulation.

The researchers noted that use of treatment-dose anticoagulation without imaging ranged from 0% to 29% across hospitals and increased significantly over time.

Of the 1,127 patients who received anticoagulation, 392 (34.8%) missed 2 days or more of prophylaxis.

In addition, there were varying rates of missed prophylaxis among the hospitals, from 11% to 61%, but these rates decreased markedly over time.

Missed doses were associated with a higher 60-day mortality (adjusted hazard ratio, 1.31; 95% confidence interval, 1.03-1.67), but not in-hospital mortality (aHR, 0.97; 95% CI, 0.91-1.03).

Compared with no anticoagulation, receiving any dose of anticoagulation was associated with lower in-hospital mortality.

However, only prophylactic-dose anticoagulation remained associated with lower mortality at 60 days. The adjusted hazard ratio for prophylactic-dose anticoagulation was 0.71 (95% CI, 0.51-0.90), compared with 0.92 (95% CI, 0.63-1.35) for treatment-dose anticoagulation.
 

Study boosts confidence

Despite its limitations, the study should make clinicians more confident that the use of prophylactic anticoagulation is warranted for hospitalized patients with COVID-19, write Andrew B. Dicks, MD, and Ido Weinberg, MD, from Massachusetts General Hospital, Boston, in an invited commentary.

“Practically, we still lack the granular data we need to help guide us in patient-by-patient decision-making – such as anticoagulation agent choice, dosage, and duration of therapy – especially as dictated by acuity of patient illness,” Dr. Dicks and Dr. Weinberg note.

“While we still await the data from randomized controlled trials to guide the optimal anticoagulation dose and duration, this study adds significant merit to the previously published recommendations from several different medical organizations regarding the use of prophylactic anticoagulation in hospitalized patients with COVID-19,” Dr. Dicks told this news organization.

The study was supported by Blue Cross and Blue Shield of Michigan and Blue Care Network as part of their Value Partnerships program. Dr. Vaughn has reported receiving speaking fees from Thermo Fisher Scientific. Dr. Dicks and Dr. Weinberg have reported no relevant financial relationships.

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

In the absence of formal clinical trials, pediatricians are racing to determine the efficacy and risks of currently used therapies for the SARS-CoV-2–linked multisystem inflammatory syndrome in children (MIS-C).

That requires rapid pragmatic evaluation of therapies. Two real-world observational studies published online June 16 in The New England Journal of Medicine do that, with differing results.

In the Overcoming COVID-19 study, investigators assessed initial therapy and outcomes for patients with MIS-C using surveillance data from 58 pediatric hospitals nationwide.

The results suggest that patients with MIS-C who were younger than 21 years of age and who were initially treated with intravenous immunoglobulin (IVIG) plus glucocorticoids fared better in terms of cardiovascular function.

The study included 518 children (median age, 8.7 years) who were admitted to the hospital between March and October 2020 and who received at least one immunomodulatory therapy. In a propensity score–matched analysis, those given IVIG plus glucocorticoids (n = 103) had a lower risk for the primary outcome of cardiovascular dysfunction on or after day 2 than those given IVIG alone (n = 103), at 17% versus 31% (risk ratio, 0.56; 95% confidence interval, 0.34-0.94).

Risks for individual aspects of the study’s composite outcome were also lower with IVIG plus glucocorticoids. Left ventricular dysfunction occurred in 8% and 17%, respectively (RR, 0.46; 95% CI, 0.19-1.15). Shock requiring vasopressor use emerged in 13% and 24%, respectively (RR, 0.54; 95% CI, 0.29-1.00).

In addition, there were fewer cases in which adjunctive therapy was given on day one among those who received combination therapy than among those who received IVIG alone, at 34% versus 70% (RR, 0.49; 95% CI, 0.36-0.65), but the risk for fever was not lower on or after day two (31% and 40%, respectively; RR, 0.78; 95% CI, 0.53-1.13).

Lead author Mary Beth F. Son, MD, director of the rheumatology program at Boston Children’s Hospital, who is also associate professor of pediatrics at Harvard Medical School, stressed that the study did not assess which MIS-C patients should receive treatment. “Rather, we studied children who had been treated with one of two initial regimens and then assessed short-term outcomes,” she told this news organization.

Going forward, it will be important to study which children should receive immunomodulatory treatment, Dr. Son said. “Specifically, can the less ill children receive IVIG alone or no treatment? This is an unanswered question at the moment, which could be addressed with a randomized controlled trial.”

Future directions, she added, will include assessing long-term cardiac outcomes for patients with MIS-C as well as studying outpatient regimens, especially those that involve steroids.

Earlier this year, French investigators found better outcomes with combined corticosteroids and IVIG than with IVIG alone. They suggested that combination therapy should be the standard of care, given the present state of therapeutic knowledge.
 

Maybe not so standard

Different results emerged, however, from an international study of MIS-C that compared three, rather than two, treatment approaches. Collaborators from the Best Available Treatment Study for MIS-C (BATS) evaluated data for 614 children with suspected MIS-C between June 2020 and February 2021 in 32 countries and found no substantial differences in recovery among children whose primary treatment was IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone.

The study by Andrew J. McArdle, MB BChir, MSC, a clinical research fellow at Imperial College London, and colleagues was published June 16 in The New England Journal of Medicine.

In the BATS cohort, 246 received IVIG alone, 208 received IVIG plus glucocorticoids, and 99 received glucocorticoids alone. Twenty-two patients received other combinations, including biologics, and 39 received no immunomodulatory therapy.

Among patients who were included in the primary analysis, death occurred or inotropic or ventilatory support was employed in 56 of 180 of the patients who received IVIG plus glucocorticoids, compared with 44 of 211 patients treated with IVIG alone, for an adjusted odds ratio (aOR) of 0.77 (95% CI, 0.33-1.82). Among those who received glucocorticoids alone, 17 of 83 met the primary endpoint of death or inotropic or ventilatory support, for an aOR relative to IVIG alone of 0.54 (95% CI, 0.22-1.33).

After adjustments, the likelihood for reduced disease severity was similar in the two groups relative to IVIG alone, at 0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone. Time to reduction in disease severity was also comparable across all groups.

Some of the differences between the U.S. study and the global studies could be the result of the larger size of the international cohort and possibly a difference in the strains of virus in the United States and abroad, according to S. Sexson Tejtel, MD, PhD, MPH, a pediatric cardiologist at Texas Children’s Hospital and an assistant professor at Baylor College of Medicine, Houston, Texas. “Some strains make children sicker than others, and they’re going to need more treatment,” said Dr. Sexson Tejtel, who was not involved in either study.

Dr. Sexson Tejtel also noted that the U.S. researchers did not assess outcomes among children treated with steroids alone. “It would be interesting to know what steroids alone look like in the U.S. MIS-C population,” she said in an interview.

BATS corresponding author Michael Levin, MBE, PhD, FRCPCH, an Imperial College professor of pediatrics and international child health, told this news organization that the differing results may have arisen because of the international study’s three-treatment focus, its wider spectrum of patients, and its different endpoints: Death and inotropic support on or after day 2, versus echocardiographic left ventricular dysfunction or inotropic usage.

Regardless of the differences between the two studies, neither establishes the most effective single or combination treatment, writes Roberta L. DeBiasi, MD, of the Division of Pediatric Infectious Diseases at Children’s National Hospital and Research Institute and George Washington University, Washington, in an accompanying editorial. “Specifically, neither study was powered to include an evaluation of approaches that steer away from broad immunosuppression with glucocorticoids and that focus on more targeted and titratable treatments with biologic agents, such as anakinra and infliximab,” she writes.

Dr. DeBiasi adds that long-term follow-up studies of cardiac and noncardiac outcomes in these patients will launch soon. “Meanwhile, continued collaboration across centers is essential to decreasing the short-term incidence of death and complications,” she writes.

“It will be interesting as we apply results from these studies as they come out to see how they change our practice,” Dr. Sexson Tejtel said. “And it would be good to have some randomized clinical trials.”

For Dr. Levin, the bottom line is that all three treatments are associated with recovery for a majority of children. “This is good news for clinicians who have been guessing which treatment to use,” he said. “Both studies are attempts to provide doctors with some evidence on which to base treatment decisions and are not the final answer. Our study is ongoing, and with larger numbers of patients it may give clearer answers.”

The Overcoming COVID-19 study was funded by the U.S. Centers for Disease Control and Prevention. Several coauthors have reported support from industry outside of the submitted work. BATS was funded by the European Union’s Horizons 2020 Program. The study authors have disclosed no relevant financial relationships. One coauthor’s spouse is employed by GlaxoSmithKline. Dr. DeBiasi and Dr. Sexson Tejtel have disclosed no relevant financial relationships.

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

In the absence of formal clinical trials, pediatricians are racing to determine the efficacy and risks of currently used therapies for the SARS-CoV-2–linked multisystem inflammatory syndrome in children (MIS-C).

That requires rapid pragmatic evaluation of therapies. Two real-world observational studies published online June 16 in The New England Journal of Medicine do that, with differing results.

In the Overcoming COVID-19 study, investigators assessed initial therapy and outcomes for patients with MIS-C using surveillance data from 58 pediatric hospitals nationwide.

The results suggest that patients with MIS-C who were younger than 21 years of age and who were initially treated with intravenous immunoglobulin (IVIG) plus glucocorticoids fared better in terms of cardiovascular function.

The study included 518 children (median age, 8.7 years) who were admitted to the hospital between March and October 2020 and who received at least one immunomodulatory therapy. In a propensity score–matched analysis, those given IVIG plus glucocorticoids (n = 103) had a lower risk for the primary outcome of cardiovascular dysfunction on or after day 2 than those given IVIG alone (n = 103), at 17% versus 31% (risk ratio, 0.56; 95% confidence interval, 0.34-0.94).

Risks for individual aspects of the study’s composite outcome were also lower with IVIG plus glucocorticoids. Left ventricular dysfunction occurred in 8% and 17%, respectively (RR, 0.46; 95% CI, 0.19-1.15). Shock requiring vasopressor use emerged in 13% and 24%, respectively (RR, 0.54; 95% CI, 0.29-1.00).

In addition, there were fewer cases in which adjunctive therapy was given on day one among those who received combination therapy than among those who received IVIG alone, at 34% versus 70% (RR, 0.49; 95% CI, 0.36-0.65), but the risk for fever was not lower on or after day two (31% and 40%, respectively; RR, 0.78; 95% CI, 0.53-1.13).

Lead author Mary Beth F. Son, MD, director of the rheumatology program at Boston Children’s Hospital, who is also associate professor of pediatrics at Harvard Medical School, stressed that the study did not assess which MIS-C patients should receive treatment. “Rather, we studied children who had been treated with one of two initial regimens and then assessed short-term outcomes,” she told this news organization.

Going forward, it will be important to study which children should receive immunomodulatory treatment, Dr. Son said. “Specifically, can the less ill children receive IVIG alone or no treatment? This is an unanswered question at the moment, which could be addressed with a randomized controlled trial.”

Future directions, she added, will include assessing long-term cardiac outcomes for patients with MIS-C as well as studying outpatient regimens, especially those that involve steroids.

Earlier this year, French investigators found better outcomes with combined corticosteroids and IVIG than with IVIG alone. They suggested that combination therapy should be the standard of care, given the present state of therapeutic knowledge.
 

Maybe not so standard

Different results emerged, however, from an international study of MIS-C that compared three, rather than two, treatment approaches. Collaborators from the Best Available Treatment Study for MIS-C (BATS) evaluated data for 614 children with suspected MIS-C between June 2020 and February 2021 in 32 countries and found no substantial differences in recovery among children whose primary treatment was IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone.

The study by Andrew J. McArdle, MB BChir, MSC, a clinical research fellow at Imperial College London, and colleagues was published June 16 in The New England Journal of Medicine.

In the BATS cohort, 246 received IVIG alone, 208 received IVIG plus glucocorticoids, and 99 received glucocorticoids alone. Twenty-two patients received other combinations, including biologics, and 39 received no immunomodulatory therapy.

Among patients who were included in the primary analysis, death occurred or inotropic or ventilatory support was employed in 56 of 180 of the patients who received IVIG plus glucocorticoids, compared with 44 of 211 patients treated with IVIG alone, for an adjusted odds ratio (aOR) of 0.77 (95% CI, 0.33-1.82). Among those who received glucocorticoids alone, 17 of 83 met the primary endpoint of death or inotropic or ventilatory support, for an aOR relative to IVIG alone of 0.54 (95% CI, 0.22-1.33).

After adjustments, the likelihood for reduced disease severity was similar in the two groups relative to IVIG alone, at 0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone. Time to reduction in disease severity was also comparable across all groups.

Some of the differences between the U.S. study and the global studies could be the result of the larger size of the international cohort and possibly a difference in the strains of virus in the United States and abroad, according to S. Sexson Tejtel, MD, PhD, MPH, a pediatric cardiologist at Texas Children’s Hospital and an assistant professor at Baylor College of Medicine, Houston, Texas. “Some strains make children sicker than others, and they’re going to need more treatment,” said Dr. Sexson Tejtel, who was not involved in either study.

Dr. Sexson Tejtel also noted that the U.S. researchers did not assess outcomes among children treated with steroids alone. “It would be interesting to know what steroids alone look like in the U.S. MIS-C population,” she said in an interview.

BATS corresponding author Michael Levin, MBE, PhD, FRCPCH, an Imperial College professor of pediatrics and international child health, told this news organization that the differing results may have arisen because of the international study’s three-treatment focus, its wider spectrum of patients, and its different endpoints: Death and inotropic support on or after day 2, versus echocardiographic left ventricular dysfunction or inotropic usage.

Regardless of the differences between the two studies, neither establishes the most effective single or combination treatment, writes Roberta L. DeBiasi, MD, of the Division of Pediatric Infectious Diseases at Children’s National Hospital and Research Institute and George Washington University, Washington, in an accompanying editorial. “Specifically, neither study was powered to include an evaluation of approaches that steer away from broad immunosuppression with glucocorticoids and that focus on more targeted and titratable treatments with biologic agents, such as anakinra and infliximab,” she writes.

Dr. DeBiasi adds that long-term follow-up studies of cardiac and noncardiac outcomes in these patients will launch soon. “Meanwhile, continued collaboration across centers is essential to decreasing the short-term incidence of death and complications,” she writes.

“It will be interesting as we apply results from these studies as they come out to see how they change our practice,” Dr. Sexson Tejtel said. “And it would be good to have some randomized clinical trials.”

For Dr. Levin, the bottom line is that all three treatments are associated with recovery for a majority of children. “This is good news for clinicians who have been guessing which treatment to use,” he said. “Both studies are attempts to provide doctors with some evidence on which to base treatment decisions and are not the final answer. Our study is ongoing, and with larger numbers of patients it may give clearer answers.”

The Overcoming COVID-19 study was funded by the U.S. Centers for Disease Control and Prevention. Several coauthors have reported support from industry outside of the submitted work. BATS was funded by the European Union’s Horizons 2020 Program. The study authors have disclosed no relevant financial relationships. One coauthor’s spouse is employed by GlaxoSmithKline. Dr. DeBiasi and Dr. Sexson Tejtel have disclosed no relevant financial relationships.

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

In the absence of formal clinical trials, pediatricians are racing to determine the efficacy and risks of currently used therapies for the SARS-CoV-2–linked multisystem inflammatory syndrome in children (MIS-C).

That requires rapid pragmatic evaluation of therapies. Two real-world observational studies published online June 16 in The New England Journal of Medicine do that, with differing results.

In the Overcoming COVID-19 study, investigators assessed initial therapy and outcomes for patients with MIS-C using surveillance data from 58 pediatric hospitals nationwide.

The results suggest that patients with MIS-C who were younger than 21 years of age and who were initially treated with intravenous immunoglobulin (IVIG) plus glucocorticoids fared better in terms of cardiovascular function.

The study included 518 children (median age, 8.7 years) who were admitted to the hospital between March and October 2020 and who received at least one immunomodulatory therapy. In a propensity score–matched analysis, those given IVIG plus glucocorticoids (n = 103) had a lower risk for the primary outcome of cardiovascular dysfunction on or after day 2 than those given IVIG alone (n = 103), at 17% versus 31% (risk ratio, 0.56; 95% confidence interval, 0.34-0.94).

Risks for individual aspects of the study’s composite outcome were also lower with IVIG plus glucocorticoids. Left ventricular dysfunction occurred in 8% and 17%, respectively (RR, 0.46; 95% CI, 0.19-1.15). Shock requiring vasopressor use emerged in 13% and 24%, respectively (RR, 0.54; 95% CI, 0.29-1.00).

In addition, there were fewer cases in which adjunctive therapy was given on day one among those who received combination therapy than among those who received IVIG alone, at 34% versus 70% (RR, 0.49; 95% CI, 0.36-0.65), but the risk for fever was not lower on or after day two (31% and 40%, respectively; RR, 0.78; 95% CI, 0.53-1.13).

Lead author Mary Beth F. Son, MD, director of the rheumatology program at Boston Children’s Hospital, who is also associate professor of pediatrics at Harvard Medical School, stressed that the study did not assess which MIS-C patients should receive treatment. “Rather, we studied children who had been treated with one of two initial regimens and then assessed short-term outcomes,” she told this news organization.

Going forward, it will be important to study which children should receive immunomodulatory treatment, Dr. Son said. “Specifically, can the less ill children receive IVIG alone or no treatment? This is an unanswered question at the moment, which could be addressed with a randomized controlled trial.”

Future directions, she added, will include assessing long-term cardiac outcomes for patients with MIS-C as well as studying outpatient regimens, especially those that involve steroids.

Earlier this year, French investigators found better outcomes with combined corticosteroids and IVIG than with IVIG alone. They suggested that combination therapy should be the standard of care, given the present state of therapeutic knowledge.
 

Maybe not so standard

Different results emerged, however, from an international study of MIS-C that compared three, rather than two, treatment approaches. Collaborators from the Best Available Treatment Study for MIS-C (BATS) evaluated data for 614 children with suspected MIS-C between June 2020 and February 2021 in 32 countries and found no substantial differences in recovery among children whose primary treatment was IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone.

The study by Andrew J. McArdle, MB BChir, MSC, a clinical research fellow at Imperial College London, and colleagues was published June 16 in The New England Journal of Medicine.

In the BATS cohort, 246 received IVIG alone, 208 received IVIG plus glucocorticoids, and 99 received glucocorticoids alone. Twenty-two patients received other combinations, including biologics, and 39 received no immunomodulatory therapy.

Among patients who were included in the primary analysis, death occurred or inotropic or ventilatory support was employed in 56 of 180 of the patients who received IVIG plus glucocorticoids, compared with 44 of 211 patients treated with IVIG alone, for an adjusted odds ratio (aOR) of 0.77 (95% CI, 0.33-1.82). Among those who received glucocorticoids alone, 17 of 83 met the primary endpoint of death or inotropic or ventilatory support, for an aOR relative to IVIG alone of 0.54 (95% CI, 0.22-1.33).

After adjustments, the likelihood for reduced disease severity was similar in the two groups relative to IVIG alone, at 0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone. Time to reduction in disease severity was also comparable across all groups.

Some of the differences between the U.S. study and the global studies could be the result of the larger size of the international cohort and possibly a difference in the strains of virus in the United States and abroad, according to S. Sexson Tejtel, MD, PhD, MPH, a pediatric cardiologist at Texas Children’s Hospital and an assistant professor at Baylor College of Medicine, Houston, Texas. “Some strains make children sicker than others, and they’re going to need more treatment,” said Dr. Sexson Tejtel, who was not involved in either study.

Dr. Sexson Tejtel also noted that the U.S. researchers did not assess outcomes among children treated with steroids alone. “It would be interesting to know what steroids alone look like in the U.S. MIS-C population,” she said in an interview.

BATS corresponding author Michael Levin, MBE, PhD, FRCPCH, an Imperial College professor of pediatrics and international child health, told this news organization that the differing results may have arisen because of the international study’s three-treatment focus, its wider spectrum of patients, and its different endpoints: Death and inotropic support on or after day 2, versus echocardiographic left ventricular dysfunction or inotropic usage.

Regardless of the differences between the two studies, neither establishes the most effective single or combination treatment, writes Roberta L. DeBiasi, MD, of the Division of Pediatric Infectious Diseases at Children’s National Hospital and Research Institute and George Washington University, Washington, in an accompanying editorial. “Specifically, neither study was powered to include an evaluation of approaches that steer away from broad immunosuppression with glucocorticoids and that focus on more targeted and titratable treatments with biologic agents, such as anakinra and infliximab,” she writes.

Dr. DeBiasi adds that long-term follow-up studies of cardiac and noncardiac outcomes in these patients will launch soon. “Meanwhile, continued collaboration across centers is essential to decreasing the short-term incidence of death and complications,” she writes.

“It will be interesting as we apply results from these studies as they come out to see how they change our practice,” Dr. Sexson Tejtel said. “And it would be good to have some randomized clinical trials.”

For Dr. Levin, the bottom line is that all three treatments are associated with recovery for a majority of children. “This is good news for clinicians who have been guessing which treatment to use,” he said. “Both studies are attempts to provide doctors with some evidence on which to base treatment decisions and are not the final answer. Our study is ongoing, and with larger numbers of patients it may give clearer answers.”

The Overcoming COVID-19 study was funded by the U.S. Centers for Disease Control and Prevention. Several coauthors have reported support from industry outside of the submitted work. BATS was funded by the European Union’s Horizons 2020 Program. The study authors have disclosed no relevant financial relationships. One coauthor’s spouse is employed by GlaxoSmithKline. Dr. DeBiasi and Dr. Sexson Tejtel have disclosed no relevant financial relationships.

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

Agents that reverse the effect of direct oral anticoagulants (DOACs) are highly effective in patients with severe bleeding, but mortality rates remain high despite their use, a meta-analysis shows.

Effective hemostasis was achieved in 78.5% of patients treated with a reversal agent, whereas failure to achieve hemostasis was associated with more than a threefold higher relative risk for death (relative risk, 3.63; 95% confidence interval, 2.56-5.16).

“This has implications in practice because it emphasizes the need for achieving effective hemostasis, if not with only one agent, trying other agents or treatment modalities, because it is a strong predictor of survival,” lead author Antonio Gómez-Outes, MD, PhD, said in an interview.

The bad news, he said, is that the mortality rate was still significant, at 17.7%, and approximately half of patients with DOAC-related severe intracranial bleeding survived with long-term moderate/severe disability.

“The lesson is to prevent these bleeding events because once they appear, even if you give an antidote, the outcome is poor, particularly for intracranial bleeding,” said Dr. Gómez-Outes, division of pharmacology and clinical drug evaluation, Spanish Agency for Medicines and Medical Devices, Madrid.

To put this in context, mortality rates were close to 50% after intracranial bleeding a decade ago when there were no antidotes or reversal agents, he observed. “So to some extent, patient care has improved, and the outcome has improved, but there is a long road to improve regarding disability.”

More than 100,000 DOAC-related major bleeding cases occur each year in the United States and European Union, Dr. Gómez-Outes said, and about half are severe enough to require hospitalization and potentially the use of a reversal agent. These include idarucizumab (Praxbind) for dabigatran reversal and prothombin complex concentrates (4CCC) or andexanet alpha (Andexxa) for reversal of direct factor Xa inhibitors like rivaroxaban, apixaban, and edoxaban.

As reported in the June 22 issue of the Journal of the American College of Cardiology, the meta-analysis comprised 4,735 patients (mean age, 77 years; 57% male) with severe DOAC-related bleeding who received 4PCC (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936) in 60 studies between January 2010 and December 2020.

Atrial fibrillation (AFib) was the most common reason for use of a DOAC (82%), followed by venous thromboembolism (14%). Rivaroxaban was used in 36%, apixaban in 32%, dabigatran in 31%, and edoxaban in 1%.

The index bleeding event was intracranial hemorrhage (ICH) in 55%. Anticoagulation was restarted in 57% of patients an average of 11 days after admission.

Mortality rates were 20.2% in patients with ICH and 15.4% in those with extracranial bleeding. There were no differences in death rates by reversal agent used, type of study, risk for bias, or study sponsorship in meta-regression analysis.

Rebleeding occurred in 13.2% of patients; 82.0% of these events were described as an ICH, and 78.0% occurred after anticoagulation was restarted.

The overall rate of thromboembolism was 4.6%. The risk was particularly high with andexanet, at 10.7%, and relatively low with idarucizumab (3.8%) and 4PCC (4.3%), the authors note.

“Our meta-analysis suggests specific reversal with andexanet is not superior to unspecific reversal with 4PCC, and that’s good news because many centers, in many countries, have no access to specific antidotes that are more costly,” Dr. Gómez-Outes said. “4PCC is an effective and relatively safe drug, so it’s still a good option for these patients.”

Labeling for andexanet includes a warning for thromboembolic events, but in the absence of direct comparisons, the findings should be interpreted with caution, he added. Further insights are expected from an ongoing randomized trial of andexanet and standard of care in 900 patients who present with acute ICH less than 15 hours after taking an oral factor Xa inhibitor. The preliminary completion date is set for 2023.

“The meta-analysis raises awareness about the rates of mortality and thromboembolism after reversal agent administration, although understanding the implications of these data is challenging,” Christopher Granger, MD, and Sean P. Pokomey, MD, MBA, Duke University Medical Center, Durham, N.C., say in an accompanying editorial.

The fact that failure to achieve hemostasis was associated with death is expected and might be related to the way hemostasis was defined, rather than the actual failure of the hemostatic treatments, they suggest. “The prothrombotic effects of each agent, including andexanet, need to be better understood, as clinicians work toward including reversal agents into algorithms for bleeding management.”

Effective hemostasis was defined in the studies through various methods as: “Excellent/good” using the Sarode and ANNEXA-4 scales; “yes” in the International Society on Thrombosis and Hemostasis Scale; and with other scales and through clinical judgment.

Although the size of the meta-analysis dwarfs previous reviews, the editorialists and authors point out that 47 of the 60 studies were retrospective, only two had control groups, and 45 had a high risk for bias.

In general, there was also poor reporting of key clinical data, such as postbleeding anticoagulation management, and a limitation of the mortality analysis is that it was based in selected patients with effective hemostasis assessed within 48 hours, which may not capture early deaths, the authors note.

“The morbidity and mortality from ischemic strokes as a result of undertreatment of stroke prevention in patients with AFib continue to dwarf the bleeding related mortality among patients with AFib and on DOACs, and thus the number one priority is to treat nearly all patients with AFib with a DOAC,” Dr. Granger and Dr. Pokomey conclude. “The availability of reversal agents for DOACs should provide reassurance, with another tool in our armamentarium, to providers to prescribe OACs for stroke prevention.”

No funding/grant support was received to conduct the study. Coauthor Ramón Lecumberri has received personal fees from Boehringer Ingelheim and Bristol Myers Squibb outside the submitted work. All other authors report no relevant financial relationships. Dr. Granger has received research and consulting fees from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer, Janssen, Boston Scientific, Apple, AstraZeneca, Novartis, AbbVie, Biomed, CeleCor, GSK, Novartis, Medtronic, Merck, Novo Nordisk, Philips, Rho, and the U.S. Food and Drug Administration. Dr. Pokomey has received modest consulting support from Bristol Myers Squibb, Pfizer, Boston Scientific, Medtronic, Janssen, and Zoll; modest research support from Gilead, Boston Scientific, Bristol Myers Squibb, Pfizer, and Janssen; and significant research support from the FDA.

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

Agents that reverse the effect of direct oral anticoagulants (DOACs) are highly effective in patients with severe bleeding, but mortality rates remain high despite their use, a meta-analysis shows.

Effective hemostasis was achieved in 78.5% of patients treated with a reversal agent, whereas failure to achieve hemostasis was associated with more than a threefold higher relative risk for death (relative risk, 3.63; 95% confidence interval, 2.56-5.16).

“This has implications in practice because it emphasizes the need for achieving effective hemostasis, if not with only one agent, trying other agents or treatment modalities, because it is a strong predictor of survival,” lead author Antonio Gómez-Outes, MD, PhD, said in an interview.

The bad news, he said, is that the mortality rate was still significant, at 17.7%, and approximately half of patients with DOAC-related severe intracranial bleeding survived with long-term moderate/severe disability.

“The lesson is to prevent these bleeding events because once they appear, even if you give an antidote, the outcome is poor, particularly for intracranial bleeding,” said Dr. Gómez-Outes, division of pharmacology and clinical drug evaluation, Spanish Agency for Medicines and Medical Devices, Madrid.

To put this in context, mortality rates were close to 50% after intracranial bleeding a decade ago when there were no antidotes or reversal agents, he observed. “So to some extent, patient care has improved, and the outcome has improved, but there is a long road to improve regarding disability.”

More than 100,000 DOAC-related major bleeding cases occur each year in the United States and European Union, Dr. Gómez-Outes said, and about half are severe enough to require hospitalization and potentially the use of a reversal agent. These include idarucizumab (Praxbind) for dabigatran reversal and prothombin complex concentrates (4CCC) or andexanet alpha (Andexxa) for reversal of direct factor Xa inhibitors like rivaroxaban, apixaban, and edoxaban.

As reported in the June 22 issue of the Journal of the American College of Cardiology, the meta-analysis comprised 4,735 patients (mean age, 77 years; 57% male) with severe DOAC-related bleeding who received 4PCC (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936) in 60 studies between January 2010 and December 2020.

Atrial fibrillation (AFib) was the most common reason for use of a DOAC (82%), followed by venous thromboembolism (14%). Rivaroxaban was used in 36%, apixaban in 32%, dabigatran in 31%, and edoxaban in 1%.

The index bleeding event was intracranial hemorrhage (ICH) in 55%. Anticoagulation was restarted in 57% of patients an average of 11 days after admission.

Mortality rates were 20.2% in patients with ICH and 15.4% in those with extracranial bleeding. There were no differences in death rates by reversal agent used, type of study, risk for bias, or study sponsorship in meta-regression analysis.

Rebleeding occurred in 13.2% of patients; 82.0% of these events were described as an ICH, and 78.0% occurred after anticoagulation was restarted.

The overall rate of thromboembolism was 4.6%. The risk was particularly high with andexanet, at 10.7%, and relatively low with idarucizumab (3.8%) and 4PCC (4.3%), the authors note.

“Our meta-analysis suggests specific reversal with andexanet is not superior to unspecific reversal with 4PCC, and that’s good news because many centers, in many countries, have no access to specific antidotes that are more costly,” Dr. Gómez-Outes said. “4PCC is an effective and relatively safe drug, so it’s still a good option for these patients.”

Labeling for andexanet includes a warning for thromboembolic events, but in the absence of direct comparisons, the findings should be interpreted with caution, he added. Further insights are expected from an ongoing randomized trial of andexanet and standard of care in 900 patients who present with acute ICH less than 15 hours after taking an oral factor Xa inhibitor. The preliminary completion date is set for 2023.

“The meta-analysis raises awareness about the rates of mortality and thromboembolism after reversal agent administration, although understanding the implications of these data is challenging,” Christopher Granger, MD, and Sean P. Pokomey, MD, MBA, Duke University Medical Center, Durham, N.C., say in an accompanying editorial.

The fact that failure to achieve hemostasis was associated with death is expected and might be related to the way hemostasis was defined, rather than the actual failure of the hemostatic treatments, they suggest. “The prothrombotic effects of each agent, including andexanet, need to be better understood, as clinicians work toward including reversal agents into algorithms for bleeding management.”

Effective hemostasis was defined in the studies through various methods as: “Excellent/good” using the Sarode and ANNEXA-4 scales; “yes” in the International Society on Thrombosis and Hemostasis Scale; and with other scales and through clinical judgment.

Although the size of the meta-analysis dwarfs previous reviews, the editorialists and authors point out that 47 of the 60 studies were retrospective, only two had control groups, and 45 had a high risk for bias.

In general, there was also poor reporting of key clinical data, such as postbleeding anticoagulation management, and a limitation of the mortality analysis is that it was based in selected patients with effective hemostasis assessed within 48 hours, which may not capture early deaths, the authors note.

“The morbidity and mortality from ischemic strokes as a result of undertreatment of stroke prevention in patients with AFib continue to dwarf the bleeding related mortality among patients with AFib and on DOACs, and thus the number one priority is to treat nearly all patients with AFib with a DOAC,” Dr. Granger and Dr. Pokomey conclude. “The availability of reversal agents for DOACs should provide reassurance, with another tool in our armamentarium, to providers to prescribe OACs for stroke prevention.”

No funding/grant support was received to conduct the study. Coauthor Ramón Lecumberri has received personal fees from Boehringer Ingelheim and Bristol Myers Squibb outside the submitted work. All other authors report no relevant financial relationships. Dr. Granger has received research and consulting fees from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer, Janssen, Boston Scientific, Apple, AstraZeneca, Novartis, AbbVie, Biomed, CeleCor, GSK, Novartis, Medtronic, Merck, Novo Nordisk, Philips, Rho, and the U.S. Food and Drug Administration. Dr. Pokomey has received modest consulting support from Bristol Myers Squibb, Pfizer, Boston Scientific, Medtronic, Janssen, and Zoll; modest research support from Gilead, Boston Scientific, Bristol Myers Squibb, Pfizer, and Janssen; and significant research support from the FDA.

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

Agents that reverse the effect of direct oral anticoagulants (DOACs) are highly effective in patients with severe bleeding, but mortality rates remain high despite their use, a meta-analysis shows.

Effective hemostasis was achieved in 78.5% of patients treated with a reversal agent, whereas failure to achieve hemostasis was associated with more than a threefold higher relative risk for death (relative risk, 3.63; 95% confidence interval, 2.56-5.16).

“This has implications in practice because it emphasizes the need for achieving effective hemostasis, if not with only one agent, trying other agents or treatment modalities, because it is a strong predictor of survival,” lead author Antonio Gómez-Outes, MD, PhD, said in an interview.

The bad news, he said, is that the mortality rate was still significant, at 17.7%, and approximately half of patients with DOAC-related severe intracranial bleeding survived with long-term moderate/severe disability.

“The lesson is to prevent these bleeding events because once they appear, even if you give an antidote, the outcome is poor, particularly for intracranial bleeding,” said Dr. Gómez-Outes, division of pharmacology and clinical drug evaluation, Spanish Agency for Medicines and Medical Devices, Madrid.

To put this in context, mortality rates were close to 50% after intracranial bleeding a decade ago when there were no antidotes or reversal agents, he observed. “So to some extent, patient care has improved, and the outcome has improved, but there is a long road to improve regarding disability.”

More than 100,000 DOAC-related major bleeding cases occur each year in the United States and European Union, Dr. Gómez-Outes said, and about half are severe enough to require hospitalization and potentially the use of a reversal agent. These include idarucizumab (Praxbind) for dabigatran reversal and prothombin complex concentrates (4CCC) or andexanet alpha (Andexxa) for reversal of direct factor Xa inhibitors like rivaroxaban, apixaban, and edoxaban.

As reported in the June 22 issue of the Journal of the American College of Cardiology, the meta-analysis comprised 4,735 patients (mean age, 77 years; 57% male) with severe DOAC-related bleeding who received 4PCC (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936) in 60 studies between January 2010 and December 2020.

Atrial fibrillation (AFib) was the most common reason for use of a DOAC (82%), followed by venous thromboembolism (14%). Rivaroxaban was used in 36%, apixaban in 32%, dabigatran in 31%, and edoxaban in 1%.

The index bleeding event was intracranial hemorrhage (ICH) in 55%. Anticoagulation was restarted in 57% of patients an average of 11 days after admission.

Mortality rates were 20.2% in patients with ICH and 15.4% in those with extracranial bleeding. There were no differences in death rates by reversal agent used, type of study, risk for bias, or study sponsorship in meta-regression analysis.

Rebleeding occurred in 13.2% of patients; 82.0% of these events were described as an ICH, and 78.0% occurred after anticoagulation was restarted.

The overall rate of thromboembolism was 4.6%. The risk was particularly high with andexanet, at 10.7%, and relatively low with idarucizumab (3.8%) and 4PCC (4.3%), the authors note.

“Our meta-analysis suggests specific reversal with andexanet is not superior to unspecific reversal with 4PCC, and that’s good news because many centers, in many countries, have no access to specific antidotes that are more costly,” Dr. Gómez-Outes said. “4PCC is an effective and relatively safe drug, so it’s still a good option for these patients.”

Labeling for andexanet includes a warning for thromboembolic events, but in the absence of direct comparisons, the findings should be interpreted with caution, he added. Further insights are expected from an ongoing randomized trial of andexanet and standard of care in 900 patients who present with acute ICH less than 15 hours after taking an oral factor Xa inhibitor. The preliminary completion date is set for 2023.

“The meta-analysis raises awareness about the rates of mortality and thromboembolism after reversal agent administration, although understanding the implications of these data is challenging,” Christopher Granger, MD, and Sean P. Pokomey, MD, MBA, Duke University Medical Center, Durham, N.C., say in an accompanying editorial.

The fact that failure to achieve hemostasis was associated with death is expected and might be related to the way hemostasis was defined, rather than the actual failure of the hemostatic treatments, they suggest. “The prothrombotic effects of each agent, including andexanet, need to be better understood, as clinicians work toward including reversal agents into algorithms for bleeding management.”

Effective hemostasis was defined in the studies through various methods as: “Excellent/good” using the Sarode and ANNEXA-4 scales; “yes” in the International Society on Thrombosis and Hemostasis Scale; and with other scales and through clinical judgment.

Although the size of the meta-analysis dwarfs previous reviews, the editorialists and authors point out that 47 of the 60 studies were retrospective, only two had control groups, and 45 had a high risk for bias.

In general, there was also poor reporting of key clinical data, such as postbleeding anticoagulation management, and a limitation of the mortality analysis is that it was based in selected patients with effective hemostasis assessed within 48 hours, which may not capture early deaths, the authors note.

“The morbidity and mortality from ischemic strokes as a result of undertreatment of stroke prevention in patients with AFib continue to dwarf the bleeding related mortality among patients with AFib and on DOACs, and thus the number one priority is to treat nearly all patients with AFib with a DOAC,” Dr. Granger and Dr. Pokomey conclude. “The availability of reversal agents for DOACs should provide reassurance, with another tool in our armamentarium, to providers to prescribe OACs for stroke prevention.”

No funding/grant support was received to conduct the study. Coauthor Ramón Lecumberri has received personal fees from Boehringer Ingelheim and Bristol Myers Squibb outside the submitted work. All other authors report no relevant financial relationships. Dr. Granger has received research and consulting fees from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer, Janssen, Boston Scientific, Apple, AstraZeneca, Novartis, AbbVie, Biomed, CeleCor, GSK, Novartis, Medtronic, Merck, Novo Nordisk, Philips, Rho, and the U.S. Food and Drug Administration. Dr. Pokomey has received modest consulting support from Bristol Myers Squibb, Pfizer, Boston Scientific, Medtronic, Janssen, and Zoll; modest research support from Gilead, Boston Scientific, Bristol Myers Squibb, Pfizer, and Janssen; and significant research support from the FDA.

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