Cardiology

A sleep burden index that considers multiple sleep-wake disturbances (SWDs) predicts subsequent cardiocerebrovascular events during the 2 years after a stroke, preliminary results on an ongoing study suggest.

The index, which combines sleep duration, sleep disordered breathing, restless leg syndrome (RLS), insomnia, and sleep duration, is a better predictor of new events than a single sleep disorder alone.

With further evidence of its usefulness, “the sleep burden index could be integrated into clinical routine,” Simone B. Duss, PhD, of the department of neurology at Bern (Switzerland) University Hospital, told a press briefing.

The findings were presented online at the Congress of the European Academy of Neurology 2020, which transitioned to a virtual meeting because of the COVID-19 pandemic.

Sleep-wake disorders are very common in stroke patients and may preexist or appear de novo as a consequence of brain damage, said Dr. Duss. “They may also be a result of medical, psychological, or environmental challenges these patients face after a stroke.”
 

Clear Evidence

There’s “clear evidence” that sleep disordered breathing is a risk factor for stroke, and negatively affects stroke outcome if left untreated, said Dr. Duss.

But for other SWDs, such as insomnia, RLS, and long and short sleep duration, “the evidence is less compelling,” she said. “However, some studies still suggest they influence stroke risk and outcome.”

Experts believe that sleep disturbances after a stroke lead to sleep fragmentation, as well as decreased slow wave sleep and REM sleep.

“This negatively affects inflammatory neuroprotective and synaptic plasticity processes during the recovery process of a stroke,” said Dr. Duss. “In the end, this results in worse outcomes with regard to recurrent events but also in activities of daily living and mood.”

The new analysis aimed to assess the impact of sleep-wake disturbances on recurrent events and outcomes following a stroke or transient ischemic attack (TIA). It included 438 patients with acute stroke (85%) or TIA (15%). The mean age of the study population was 65 years, and 64% were male.

Researchers used the National Institutes of Health Stroke Scale (NIHSS) to assess stroke severity. At admission, the mean NIHSS score was 4. Most strokes (77.2%) were supratentorial.

About one-fifth of stroke patients and one-third of TIA patients had experienced a previous event.

Researchers used functional outcome scores to assess the clinical course of the stroke or TIA. In addition, they regularly asked patients about recurrence of cardiocerebrovascular events.

Investigators assessed sleep disordered breathing during the acute phase of stroke, so within the first few days, using respirography. They collected information on the presence of other sleep-wake disturbances from questionnaires and clinical interviews at 1 month, 3 months, 1 year, and 2 years after the event.

About 26% of subjects showed severe sleep disordered breathing, “meaning that they had more than 20 apnea-hypopnea events per hour,” said Dr. Duss.

More than a quarter of patients reported subclinical symptoms of insomnia (measured using the Insomnia Severity Index), and up to 10% reported severe insomnia symptoms corresponding to the clinical diagnosis of insomnia, she said.

About 9% of patients in the acute phase of stroke, and 6% in the more chronic phase, fulfilled the diagnostic criteria of RLS.
 

More ‘skewed’

The results for sleep duration were relatively “skewed,” said Dr. Duss. More patients reported longer sleep duration (more than 9 hours) at 1 month than at month 3, and more reported shorter sleep duration (4.0 hours or less) at month 3 than at month 1.

The researchers built a sleep burden index for the combined impact of the various sleep-wake disturbances.

They used this index as a predictor of subsequent cardiocerebrovascular events within 3 months after an event. They used a composite outcome that included recurrent stroke or TIA, MI, heart failure, and urgent revascularization, as well as new cardiocerebrovascular events, from 3 to 24 months.

The analysis showed that the mean sleep burden index was higher for stroke patients with a recurrent event, compared with stroke or TIA patients without a recurrent event (P = .0002).

A multiple logistical regression model with the presence or absence of a recurrent event as an outcome showed that the sleep burden index is a significant predictor of recurrent events (odds ratio, 2.10; P = .001). This was true even after controlling for age, gender, and baseline stroke severity.

The baseline apnea/hypopnea index and sleep duration were also significant predictors of new events. Importantly, though, the sleep burden index remained a significant predictor of recurrent events even after excluding the apnea/hypopnea index component, said Dr. Duss. “So the predictive power of the sleep burden index is not only driven by the apnea-hypopnea index at the beginning of a stroke.”

Sleep-wake disturbances “should be more carefully assessed and considered in comprehensive treatment approaches,” not only in stroke patients, but in neurologic patients in general, said Dr. Duss

She noted that these are preliminary observations from an ongoing study. The results need to be confirmed and should be when the study is finalized, she said.

Researchers are also analyzing MRI data to assess whether certain brain lesions are associated with sleep disturbances.

Jesse Dawson, MD, professor of stroke medicine at the University of Glasgow, said the clinical scoring system the study included “will be a big help in design and conduct of clinical trials.”

Although he and other stroke experts are aware of the high prevalence of sleep disorders after stroke, “we don’t routinely look for them as we’re uncertain whether intervention is of benefit,” said Dr. Dawson.

This new study “suggests there is an association with adverse outcome,” he said.

The research was supported by grants from the Swiss National Science Foundation and the Swiss Heart Foundation. Dr. Duss and Dr. Dawson disclosed no relevant financial relationships.

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

A sleep burden index that considers multiple sleep-wake disturbances (SWDs) predicts subsequent cardiocerebrovascular events during the 2 years after a stroke, preliminary results on an ongoing study suggest.

The index, which combines sleep duration, sleep disordered breathing, restless leg syndrome (RLS), insomnia, and sleep duration, is a better predictor of new events than a single sleep disorder alone.

With further evidence of its usefulness, “the sleep burden index could be integrated into clinical routine,” Simone B. Duss, PhD, of the department of neurology at Bern (Switzerland) University Hospital, told a press briefing.

The findings were presented online at the Congress of the European Academy of Neurology 2020, which transitioned to a virtual meeting because of the COVID-19 pandemic.

Sleep-wake disorders are very common in stroke patients and may preexist or appear de novo as a consequence of brain damage, said Dr. Duss. “They may also be a result of medical, psychological, or environmental challenges these patients face after a stroke.”
 

Clear Evidence

There’s “clear evidence” that sleep disordered breathing is a risk factor for stroke, and negatively affects stroke outcome if left untreated, said Dr. Duss.

But for other SWDs, such as insomnia, RLS, and long and short sleep duration, “the evidence is less compelling,” she said. “However, some studies still suggest they influence stroke risk and outcome.”

Experts believe that sleep disturbances after a stroke lead to sleep fragmentation, as well as decreased slow wave sleep and REM sleep.

“This negatively affects inflammatory neuroprotective and synaptic plasticity processes during the recovery process of a stroke,” said Dr. Duss. “In the end, this results in worse outcomes with regard to recurrent events but also in activities of daily living and mood.”

The new analysis aimed to assess the impact of sleep-wake disturbances on recurrent events and outcomes following a stroke or transient ischemic attack (TIA). It included 438 patients with acute stroke (85%) or TIA (15%). The mean age of the study population was 65 years, and 64% were male.

Researchers used the National Institutes of Health Stroke Scale (NIHSS) to assess stroke severity. At admission, the mean NIHSS score was 4. Most strokes (77.2%) were supratentorial.

About one-fifth of stroke patients and one-third of TIA patients had experienced a previous event.

Researchers used functional outcome scores to assess the clinical course of the stroke or TIA. In addition, they regularly asked patients about recurrence of cardiocerebrovascular events.

Investigators assessed sleep disordered breathing during the acute phase of stroke, so within the first few days, using respirography. They collected information on the presence of other sleep-wake disturbances from questionnaires and clinical interviews at 1 month, 3 months, 1 year, and 2 years after the event.

About 26% of subjects showed severe sleep disordered breathing, “meaning that they had more than 20 apnea-hypopnea events per hour,” said Dr. Duss.

More than a quarter of patients reported subclinical symptoms of insomnia (measured using the Insomnia Severity Index), and up to 10% reported severe insomnia symptoms corresponding to the clinical diagnosis of insomnia, she said.

About 9% of patients in the acute phase of stroke, and 6% in the more chronic phase, fulfilled the diagnostic criteria of RLS.
 

More ‘skewed’

The results for sleep duration were relatively “skewed,” said Dr. Duss. More patients reported longer sleep duration (more than 9 hours) at 1 month than at month 3, and more reported shorter sleep duration (4.0 hours or less) at month 3 than at month 1.

The researchers built a sleep burden index for the combined impact of the various sleep-wake disturbances.

They used this index as a predictor of subsequent cardiocerebrovascular events within 3 months after an event. They used a composite outcome that included recurrent stroke or TIA, MI, heart failure, and urgent revascularization, as well as new cardiocerebrovascular events, from 3 to 24 months.

The analysis showed that the mean sleep burden index was higher for stroke patients with a recurrent event, compared with stroke or TIA patients without a recurrent event (P = .0002).

A multiple logistical regression model with the presence or absence of a recurrent event as an outcome showed that the sleep burden index is a significant predictor of recurrent events (odds ratio, 2.10; P = .001). This was true even after controlling for age, gender, and baseline stroke severity.

The baseline apnea/hypopnea index and sleep duration were also significant predictors of new events. Importantly, though, the sleep burden index remained a significant predictor of recurrent events even after excluding the apnea/hypopnea index component, said Dr. Duss. “So the predictive power of the sleep burden index is not only driven by the apnea-hypopnea index at the beginning of a stroke.”

Sleep-wake disturbances “should be more carefully assessed and considered in comprehensive treatment approaches,” not only in stroke patients, but in neurologic patients in general, said Dr. Duss

She noted that these are preliminary observations from an ongoing study. The results need to be confirmed and should be when the study is finalized, she said.

Researchers are also analyzing MRI data to assess whether certain brain lesions are associated with sleep disturbances.

Jesse Dawson, MD, professor of stroke medicine at the University of Glasgow, said the clinical scoring system the study included “will be a big help in design and conduct of clinical trials.”

Although he and other stroke experts are aware of the high prevalence of sleep disorders after stroke, “we don’t routinely look for them as we’re uncertain whether intervention is of benefit,” said Dr. Dawson.

This new study “suggests there is an association with adverse outcome,” he said.

The research was supported by grants from the Swiss National Science Foundation and the Swiss Heart Foundation. Dr. Duss and Dr. Dawson disclosed no relevant financial relationships.

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

A sleep burden index that considers multiple sleep-wake disturbances (SWDs) predicts subsequent cardiocerebrovascular events during the 2 years after a stroke, preliminary results on an ongoing study suggest.

The index, which combines sleep duration, sleep disordered breathing, restless leg syndrome (RLS), insomnia, and sleep duration, is a better predictor of new events than a single sleep disorder alone.

With further evidence of its usefulness, “the sleep burden index could be integrated into clinical routine,” Simone B. Duss, PhD, of the department of neurology at Bern (Switzerland) University Hospital, told a press briefing.

The findings were presented online at the Congress of the European Academy of Neurology 2020, which transitioned to a virtual meeting because of the COVID-19 pandemic.

Sleep-wake disorders are very common in stroke patients and may preexist or appear de novo as a consequence of brain damage, said Dr. Duss. “They may also be a result of medical, psychological, or environmental challenges these patients face after a stroke.”
 

Clear Evidence

There’s “clear evidence” that sleep disordered breathing is a risk factor for stroke, and negatively affects stroke outcome if left untreated, said Dr. Duss.

But for other SWDs, such as insomnia, RLS, and long and short sleep duration, “the evidence is less compelling,” she said. “However, some studies still suggest they influence stroke risk and outcome.”

Experts believe that sleep disturbances after a stroke lead to sleep fragmentation, as well as decreased slow wave sleep and REM sleep.

“This negatively affects inflammatory neuroprotective and synaptic plasticity processes during the recovery process of a stroke,” said Dr. Duss. “In the end, this results in worse outcomes with regard to recurrent events but also in activities of daily living and mood.”

The new analysis aimed to assess the impact of sleep-wake disturbances on recurrent events and outcomes following a stroke or transient ischemic attack (TIA). It included 438 patients with acute stroke (85%) or TIA (15%). The mean age of the study population was 65 years, and 64% were male.

Researchers used the National Institutes of Health Stroke Scale (NIHSS) to assess stroke severity. At admission, the mean NIHSS score was 4. Most strokes (77.2%) were supratentorial.

About one-fifth of stroke patients and one-third of TIA patients had experienced a previous event.

Researchers used functional outcome scores to assess the clinical course of the stroke or TIA. In addition, they regularly asked patients about recurrence of cardiocerebrovascular events.

Investigators assessed sleep disordered breathing during the acute phase of stroke, so within the first few days, using respirography. They collected information on the presence of other sleep-wake disturbances from questionnaires and clinical interviews at 1 month, 3 months, 1 year, and 2 years after the event.

About 26% of subjects showed severe sleep disordered breathing, “meaning that they had more than 20 apnea-hypopnea events per hour,” said Dr. Duss.

More than a quarter of patients reported subclinical symptoms of insomnia (measured using the Insomnia Severity Index), and up to 10% reported severe insomnia symptoms corresponding to the clinical diagnosis of insomnia, she said.

About 9% of patients in the acute phase of stroke, and 6% in the more chronic phase, fulfilled the diagnostic criteria of RLS.
 

More ‘skewed’

The results for sleep duration were relatively “skewed,” said Dr. Duss. More patients reported longer sleep duration (more than 9 hours) at 1 month than at month 3, and more reported shorter sleep duration (4.0 hours or less) at month 3 than at month 1.

The researchers built a sleep burden index for the combined impact of the various sleep-wake disturbances.

They used this index as a predictor of subsequent cardiocerebrovascular events within 3 months after an event. They used a composite outcome that included recurrent stroke or TIA, MI, heart failure, and urgent revascularization, as well as new cardiocerebrovascular events, from 3 to 24 months.

The analysis showed that the mean sleep burden index was higher for stroke patients with a recurrent event, compared with stroke or TIA patients without a recurrent event (P = .0002).

A multiple logistical regression model with the presence or absence of a recurrent event as an outcome showed that the sleep burden index is a significant predictor of recurrent events (odds ratio, 2.10; P = .001). This was true even after controlling for age, gender, and baseline stroke severity.

The baseline apnea/hypopnea index and sleep duration were also significant predictors of new events. Importantly, though, the sleep burden index remained a significant predictor of recurrent events even after excluding the apnea/hypopnea index component, said Dr. Duss. “So the predictive power of the sleep burden index is not only driven by the apnea-hypopnea index at the beginning of a stroke.”

Sleep-wake disturbances “should be more carefully assessed and considered in comprehensive treatment approaches,” not only in stroke patients, but in neurologic patients in general, said Dr. Duss

She noted that these are preliminary observations from an ongoing study. The results need to be confirmed and should be when the study is finalized, she said.

Researchers are also analyzing MRI data to assess whether certain brain lesions are associated with sleep disturbances.

Jesse Dawson, MD, professor of stroke medicine at the University of Glasgow, said the clinical scoring system the study included “will be a big help in design and conduct of clinical trials.”

Although he and other stroke experts are aware of the high prevalence of sleep disorders after stroke, “we don’t routinely look for them as we’re uncertain whether intervention is of benefit,” said Dr. Dawson.

This new study “suggests there is an association with adverse outcome,” he said.

The research was supported by grants from the Swiss National Science Foundation and the Swiss Heart Foundation. Dr. Duss and Dr. Dawson disclosed no relevant financial relationships.

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

Patients in the landmark ISCHEMIA trial with intermediate left main disease had a greater extent of coronary artery disease on invasive angiography, indicating greater atherosclerotic burden. They also had worse prognosis with a higher risk of cardiovascular events.

“Many times, we are looking at results as to whether patients have left main disease or not,” Sripal Bangalore, MD, said during the Society for Cardiovascular Angiography & Interventions virtual annual scientific sessions. “Here, we are showing that it’s not black and white; there are shades of gray. If a patient has intermediate left main disease, the prognosis is worse. That’s very important information we need to convey to our referrals also, because many times they may just look at the bottom line and say, ‘there is no left main disease.’ But here, we’re seeing that even having intermediate left main disease has significantly worse prognosis. We need to take that seriously.”

Prior studies show that patients with significant left main disease (LMD; defined as 50% or greater stenosis on coronary CT angiography [CCTA]) have a high risk of cardiovascular events and guidelines recommend revascularization to improve survival, said Dr. Bangalore, an interventional cardiologist at New York University Langone Health. However, the impact of intermediate LMD (defined as 25%-49% stenosis on CCTA) on outcomes is unclear.

Members of the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) research group randomized 5,179 participants to an initial invasive or conservative strategy. The main results showed that immediate revascularization in patients with stable ischemic heart disease provided no reduction in cardiovascular endpoints through 4 years of follow-up, compared with initial optimal medical therapy alone.
 

‘Discordance’ revealed in imaging modalities

For the current analysis, named the ISCHEMIA Intermediate LM Substudy, those who underwent coronary CCTA comprise the LMD substudy cohort. The objective was to evaluate clinical and quality of life outcomes in patients with and without intermediate left main disease on coronary CT and to evaluate the impact of treatment strategy on those outcomes across subgroups.

At baseline, these patients were categorized into those with and without intermediate LMD as determined by a core lab. Patients with LMD of 50% or greater, those with prior coronary artery bypass graft surgery, and those with nonevaluable or missing data on LM stenosis were excluded.

Among the 3,913 ISCHEMIA participants who underwent CCTA, 3,699 satisfied the inclusion criteria. Of these patients, 962 (26%) had intermediate LMD and 2,737 (74%) did not.

The researchers observed no significant differences in baseline characteristics between patients with and without LMD. However, patients with intermediate LMD tended to be older, and a greater proportion had hypertension and diabetes. Stress test characteristics were also similar between patients with and without LMD. However, patients with intermediate LMD tended toward a greater severity of severe ischemia.

This was also true for anatomic disease on CCTA. A higher proportion of patients with intermediate LMD had triple-vessel disease (61%-62%, compared with 36%-40% along those without intermediate LMD). In addition, a higher proportion of patients with intermediate LMD had stenosis in the proximal left anterior artery descending (LAD) artery (65% vs. 39% among those without intermediate LMD).

On analysis limited to 1,846 patients who underwent invasive angiography treatment in the main ISCHEMIA trial, 7% of those who were categorized into the intermediate LMD group were found to have LMD disease of 50% or greater, compared with 1.4% of patients who were categorized as not having intermediate LMD. “This goes to show this discordance between the two modalities [CCTA and coronary angiography], and I think we have to be careful,” said Dr. Bangalore, who also directs NYU Langone’s Cardiac Catheterization Laboratory. “There may be patients with left main disease, even if the CCTA says it’s not at 25%-29% [stenosis].”

The researchers found that, among patients who underwent invasive angiography, a greater proportion of those who were categorized into the LMD group had proximal LAD disease (43% vs. 33% among those who were categorized into the nonintermediate LMD group), triple-vessel disease (47% vs. 35%), a greater extent of coronary artery disease as denoted by a higher SYNTAX score (21 vs. 15), and a higher proportion underwent coronary artery bypass graft surgery (32% vs. 18%).
 

Intermediate LMD linked to worse outcomes

After the researchers adjusted for baseline differences between the two groups in overall substudy cohort, they found that intermediate LMD severity was an independent predictor of the primary composite endpoint of cardiovascular death, MI, hospitalization for unstable angina, heart failure, and resuscitated cardiac arrest (hazard ratio, 1.31; P = .0123); cardiovascular death/MI/stroke (HR, 1.30; P = .0143); procedural primary MI (HR, 1.64; P = .0487); heart failure (HR, 2.06; P = .0239); and stroke (HR, 1.82, P = .0362).

“We then looked to see if there is a treatment difference, a treatment effect based on whether patients had intermediate LMD,” Dr. Bangalore said. “Most of the P values were not significant. The results are very consistent with what we saw in the main analysis: not a significant difference between invasive and conservative strategy. We do see some differences, though. An invasive strategy was associated with a significantly higher risk of procedural MI [2.9% vs. 1.5%], but a significantly lower risk of nonprocedural MI [–6.4% vs. –2%].”

Dr. Bangalore added that there was significant benefit of the invasive strategy in reducing angina and improving quality of life based on the Seattle Angina Questionnaire-7. “This result was durable up to 48 months of follow-up, whether the patient had intermediate left main disease or not. These results were dependent on baseline angina status. The benefit of invasive strategy was mainly in patients who had daily, weekly, and monthly angina, and no benefit in patients with no angina; there was no interaction based on intermediate left main status.”

Dr. Bangalore emphasized that the original ISCHEMIA trial excluded patients with severe left main disease by design. “But patients with intermediate left main disease in ISCHEMIA tended to have a greater extent of coronary artery disease, indicating greater atherosclerotic burden. I don’t think that’s any surprise. They had a worse prognosis with higher risk of cardiovascular events but similar quality of life, including angina-specific quality of life.”

The key clinical message, he said, is that patients with intermediate LMD face an increased risk of cardiovascular events. “I think we have to be aggressive in trying to reduce their risk with medical therapy, etc.,” he said. “If they are symptomatic, ISCHEMIA tells us that patients have two options. They can choose an invasive strategy, because clearly there is a benefit. You have a significant benefit at making you feel better and potentially reducing the risk of spontaneous MI over a period of time. Or, you can try medical therapy first. If you do see some left main disease, it’s showing the general burden of atherosclerosis disease in those patients. I think that’s the critical message, that we have to be very aggressive with these patients.”
 

A call for more imaging studies

An invited panelist, Timothy D. Henry, MD, said that the results of the ISCHEMIA substudy should stimulate further research. “With an intermediate lesion, clearly the interventional group did better, and it wasn’t symptom related,” said Dr. Henry, medical director of the Carl and Edyth Lindner Center for Research and Education at the Christ Hospital in Cincinnati. “So even if you do medical therapy, you’re not going to really find it out. In my mind, this should stimulate us to do more imaging of the left main that are moderate lesions, and follow this up as an independent study. I think this is a really important finding.”

ISCHEMIA was supported by grants from the National Heart, Lung, and Blood Institute. Dr. Bangalore disclosed that he is a member of the advisory board and/or a board member for Meril, SMT, Pfizer, Amgen, Biotronik, and Abbott. He also is a consultant for Reata Pharmaceuticals.

dbrunk@mdedge.com

SOURCE: Bangalore S et al. SCAI 2020, Abstract 11656.

Patients in the landmark ISCHEMIA trial with intermediate left main disease had a greater extent of coronary artery disease on invasive angiography, indicating greater atherosclerotic burden. They also had worse prognosis with a higher risk of cardiovascular events.

“Many times, we are looking at results as to whether patients have left main disease or not,” Sripal Bangalore, MD, said during the Society for Cardiovascular Angiography & Interventions virtual annual scientific sessions. “Here, we are showing that it’s not black and white; there are shades of gray. If a patient has intermediate left main disease, the prognosis is worse. That’s very important information we need to convey to our referrals also, because many times they may just look at the bottom line and say, ‘there is no left main disease.’ But here, we’re seeing that even having intermediate left main disease has significantly worse prognosis. We need to take that seriously.”

Prior studies show that patients with significant left main disease (LMD; defined as 50% or greater stenosis on coronary CT angiography [CCTA]) have a high risk of cardiovascular events and guidelines recommend revascularization to improve survival, said Dr. Bangalore, an interventional cardiologist at New York University Langone Health. However, the impact of intermediate LMD (defined as 25%-49% stenosis on CCTA) on outcomes is unclear.

Members of the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) research group randomized 5,179 participants to an initial invasive or conservative strategy. The main results showed that immediate revascularization in patients with stable ischemic heart disease provided no reduction in cardiovascular endpoints through 4 years of follow-up, compared with initial optimal medical therapy alone.
 

‘Discordance’ revealed in imaging modalities

For the current analysis, named the ISCHEMIA Intermediate LM Substudy, those who underwent coronary CCTA comprise the LMD substudy cohort. The objective was to evaluate clinical and quality of life outcomes in patients with and without intermediate left main disease on coronary CT and to evaluate the impact of treatment strategy on those outcomes across subgroups.

At baseline, these patients were categorized into those with and without intermediate LMD as determined by a core lab. Patients with LMD of 50% or greater, those with prior coronary artery bypass graft surgery, and those with nonevaluable or missing data on LM stenosis were excluded.

Among the 3,913 ISCHEMIA participants who underwent CCTA, 3,699 satisfied the inclusion criteria. Of these patients, 962 (26%) had intermediate LMD and 2,737 (74%) did not.

The researchers observed no significant differences in baseline characteristics between patients with and without LMD. However, patients with intermediate LMD tended to be older, and a greater proportion had hypertension and diabetes. Stress test characteristics were also similar between patients with and without LMD. However, patients with intermediate LMD tended toward a greater severity of severe ischemia.

This was also true for anatomic disease on CCTA. A higher proportion of patients with intermediate LMD had triple-vessel disease (61%-62%, compared with 36%-40% along those without intermediate LMD). In addition, a higher proportion of patients with intermediate LMD had stenosis in the proximal left anterior artery descending (LAD) artery (65% vs. 39% among those without intermediate LMD).

On analysis limited to 1,846 patients who underwent invasive angiography treatment in the main ISCHEMIA trial, 7% of those who were categorized into the intermediate LMD group were found to have LMD disease of 50% or greater, compared with 1.4% of patients who were categorized as not having intermediate LMD. “This goes to show this discordance between the two modalities [CCTA and coronary angiography], and I think we have to be careful,” said Dr. Bangalore, who also directs NYU Langone’s Cardiac Catheterization Laboratory. “There may be patients with left main disease, even if the CCTA says it’s not at 25%-29% [stenosis].”

The researchers found that, among patients who underwent invasive angiography, a greater proportion of those who were categorized into the LMD group had proximal LAD disease (43% vs. 33% among those who were categorized into the nonintermediate LMD group), triple-vessel disease (47% vs. 35%), a greater extent of coronary artery disease as denoted by a higher SYNTAX score (21 vs. 15), and a higher proportion underwent coronary artery bypass graft surgery (32% vs. 18%).
 

Intermediate LMD linked to worse outcomes

After the researchers adjusted for baseline differences between the two groups in overall substudy cohort, they found that intermediate LMD severity was an independent predictor of the primary composite endpoint of cardiovascular death, MI, hospitalization for unstable angina, heart failure, and resuscitated cardiac arrest (hazard ratio, 1.31; P = .0123); cardiovascular death/MI/stroke (HR, 1.30; P = .0143); procedural primary MI (HR, 1.64; P = .0487); heart failure (HR, 2.06; P = .0239); and stroke (HR, 1.82, P = .0362).

“We then looked to see if there is a treatment difference, a treatment effect based on whether patients had intermediate LMD,” Dr. Bangalore said. “Most of the P values were not significant. The results are very consistent with what we saw in the main analysis: not a significant difference between invasive and conservative strategy. We do see some differences, though. An invasive strategy was associated with a significantly higher risk of procedural MI [2.9% vs. 1.5%], but a significantly lower risk of nonprocedural MI [–6.4% vs. –2%].”

Dr. Bangalore added that there was significant benefit of the invasive strategy in reducing angina and improving quality of life based on the Seattle Angina Questionnaire-7. “This result was durable up to 48 months of follow-up, whether the patient had intermediate left main disease or not. These results were dependent on baseline angina status. The benefit of invasive strategy was mainly in patients who had daily, weekly, and monthly angina, and no benefit in patients with no angina; there was no interaction based on intermediate left main status.”

Dr. Bangalore emphasized that the original ISCHEMIA trial excluded patients with severe left main disease by design. “But patients with intermediate left main disease in ISCHEMIA tended to have a greater extent of coronary artery disease, indicating greater atherosclerotic burden. I don’t think that’s any surprise. They had a worse prognosis with higher risk of cardiovascular events but similar quality of life, including angina-specific quality of life.”

The key clinical message, he said, is that patients with intermediate LMD face an increased risk of cardiovascular events. “I think we have to be aggressive in trying to reduce their risk with medical therapy, etc.,” he said. “If they are symptomatic, ISCHEMIA tells us that patients have two options. They can choose an invasive strategy, because clearly there is a benefit. You have a significant benefit at making you feel better and potentially reducing the risk of spontaneous MI over a period of time. Or, you can try medical therapy first. If you do see some left main disease, it’s showing the general burden of atherosclerosis disease in those patients. I think that’s the critical message, that we have to be very aggressive with these patients.”
 

A call for more imaging studies

An invited panelist, Timothy D. Henry, MD, said that the results of the ISCHEMIA substudy should stimulate further research. “With an intermediate lesion, clearly the interventional group did better, and it wasn’t symptom related,” said Dr. Henry, medical director of the Carl and Edyth Lindner Center for Research and Education at the Christ Hospital in Cincinnati. “So even if you do medical therapy, you’re not going to really find it out. In my mind, this should stimulate us to do more imaging of the left main that are moderate lesions, and follow this up as an independent study. I think this is a really important finding.”

ISCHEMIA was supported by grants from the National Heart, Lung, and Blood Institute. Dr. Bangalore disclosed that he is a member of the advisory board and/or a board member for Meril, SMT, Pfizer, Amgen, Biotronik, and Abbott. He also is a consultant for Reata Pharmaceuticals.

dbrunk@mdedge.com

SOURCE: Bangalore S et al. SCAI 2020, Abstract 11656.

Patients in the landmark ISCHEMIA trial with intermediate left main disease had a greater extent of coronary artery disease on invasive angiography, indicating greater atherosclerotic burden. They also had worse prognosis with a higher risk of cardiovascular events.

“Many times, we are looking at results as to whether patients have left main disease or not,” Sripal Bangalore, MD, said during the Society for Cardiovascular Angiography & Interventions virtual annual scientific sessions. “Here, we are showing that it’s not black and white; there are shades of gray. If a patient has intermediate left main disease, the prognosis is worse. That’s very important information we need to convey to our referrals also, because many times they may just look at the bottom line and say, ‘there is no left main disease.’ But here, we’re seeing that even having intermediate left main disease has significantly worse prognosis. We need to take that seriously.”

Prior studies show that patients with significant left main disease (LMD; defined as 50% or greater stenosis on coronary CT angiography [CCTA]) have a high risk of cardiovascular events and guidelines recommend revascularization to improve survival, said Dr. Bangalore, an interventional cardiologist at New York University Langone Health. However, the impact of intermediate LMD (defined as 25%-49% stenosis on CCTA) on outcomes is unclear.

Members of the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) research group randomized 5,179 participants to an initial invasive or conservative strategy. The main results showed that immediate revascularization in patients with stable ischemic heart disease provided no reduction in cardiovascular endpoints through 4 years of follow-up, compared with initial optimal medical therapy alone.
 

‘Discordance’ revealed in imaging modalities

For the current analysis, named the ISCHEMIA Intermediate LM Substudy, those who underwent coronary CCTA comprise the LMD substudy cohort. The objective was to evaluate clinical and quality of life outcomes in patients with and without intermediate left main disease on coronary CT and to evaluate the impact of treatment strategy on those outcomes across subgroups.

At baseline, these patients were categorized into those with and without intermediate LMD as determined by a core lab. Patients with LMD of 50% or greater, those with prior coronary artery bypass graft surgery, and those with nonevaluable or missing data on LM stenosis were excluded.

Among the 3,913 ISCHEMIA participants who underwent CCTA, 3,699 satisfied the inclusion criteria. Of these patients, 962 (26%) had intermediate LMD and 2,737 (74%) did not.

The researchers observed no significant differences in baseline characteristics between patients with and without LMD. However, patients with intermediate LMD tended to be older, and a greater proportion had hypertension and diabetes. Stress test characteristics were also similar between patients with and without LMD. However, patients with intermediate LMD tended toward a greater severity of severe ischemia.

This was also true for anatomic disease on CCTA. A higher proportion of patients with intermediate LMD had triple-vessel disease (61%-62%, compared with 36%-40% along those without intermediate LMD). In addition, a higher proportion of patients with intermediate LMD had stenosis in the proximal left anterior artery descending (LAD) artery (65% vs. 39% among those without intermediate LMD).

On analysis limited to 1,846 patients who underwent invasive angiography treatment in the main ISCHEMIA trial, 7% of those who were categorized into the intermediate LMD group were found to have LMD disease of 50% or greater, compared with 1.4% of patients who were categorized as not having intermediate LMD. “This goes to show this discordance between the two modalities [CCTA and coronary angiography], and I think we have to be careful,” said Dr. Bangalore, who also directs NYU Langone’s Cardiac Catheterization Laboratory. “There may be patients with left main disease, even if the CCTA says it’s not at 25%-29% [stenosis].”

The researchers found that, among patients who underwent invasive angiography, a greater proportion of those who were categorized into the LMD group had proximal LAD disease (43% vs. 33% among those who were categorized into the nonintermediate LMD group), triple-vessel disease (47% vs. 35%), a greater extent of coronary artery disease as denoted by a higher SYNTAX score (21 vs. 15), and a higher proportion underwent coronary artery bypass graft surgery (32% vs. 18%).
 

Intermediate LMD linked to worse outcomes

After the researchers adjusted for baseline differences between the two groups in overall substudy cohort, they found that intermediate LMD severity was an independent predictor of the primary composite endpoint of cardiovascular death, MI, hospitalization for unstable angina, heart failure, and resuscitated cardiac arrest (hazard ratio, 1.31; P = .0123); cardiovascular death/MI/stroke (HR, 1.30; P = .0143); procedural primary MI (HR, 1.64; P = .0487); heart failure (HR, 2.06; P = .0239); and stroke (HR, 1.82, P = .0362).

“We then looked to see if there is a treatment difference, a treatment effect based on whether patients had intermediate LMD,” Dr. Bangalore said. “Most of the P values were not significant. The results are very consistent with what we saw in the main analysis: not a significant difference between invasive and conservative strategy. We do see some differences, though. An invasive strategy was associated with a significantly higher risk of procedural MI [2.9% vs. 1.5%], but a significantly lower risk of nonprocedural MI [–6.4% vs. –2%].”

Dr. Bangalore added that there was significant benefit of the invasive strategy in reducing angina and improving quality of life based on the Seattle Angina Questionnaire-7. “This result was durable up to 48 months of follow-up, whether the patient had intermediate left main disease or not. These results were dependent on baseline angina status. The benefit of invasive strategy was mainly in patients who had daily, weekly, and monthly angina, and no benefit in patients with no angina; there was no interaction based on intermediate left main status.”

Dr. Bangalore emphasized that the original ISCHEMIA trial excluded patients with severe left main disease by design. “But patients with intermediate left main disease in ISCHEMIA tended to have a greater extent of coronary artery disease, indicating greater atherosclerotic burden. I don’t think that’s any surprise. They had a worse prognosis with higher risk of cardiovascular events but similar quality of life, including angina-specific quality of life.”

The key clinical message, he said, is that patients with intermediate LMD face an increased risk of cardiovascular events. “I think we have to be aggressive in trying to reduce their risk with medical therapy, etc.,” he said. “If they are symptomatic, ISCHEMIA tells us that patients have two options. They can choose an invasive strategy, because clearly there is a benefit. You have a significant benefit at making you feel better and potentially reducing the risk of spontaneous MI over a period of time. Or, you can try medical therapy first. If you do see some left main disease, it’s showing the general burden of atherosclerosis disease in those patients. I think that’s the critical message, that we have to be very aggressive with these patients.”
 

A call for more imaging studies

An invited panelist, Timothy D. Henry, MD, said that the results of the ISCHEMIA substudy should stimulate further research. “With an intermediate lesion, clearly the interventional group did better, and it wasn’t symptom related,” said Dr. Henry, medical director of the Carl and Edyth Lindner Center for Research and Education at the Christ Hospital in Cincinnati. “So even if you do medical therapy, you’re not going to really find it out. In my mind, this should stimulate us to do more imaging of the left main that are moderate lesions, and follow this up as an independent study. I think this is a really important finding.”

ISCHEMIA was supported by grants from the National Heart, Lung, and Blood Institute. Dr. Bangalore disclosed that he is a member of the advisory board and/or a board member for Meril, SMT, Pfizer, Amgen, Biotronik, and Abbott. He also is a consultant for Reata Pharmaceuticals.

dbrunk@mdedge.com

SOURCE: Bangalore S et al. SCAI 2020, Abstract 11656.

Background: Often atrial fibrillation terminates spontaneously and occasionally recurs; therefore, the advantage of immediate electric or pharmacologic cardioversion over watchful waiting and subsequent delayed cardioversion is not clear.

This was a noninferiority, open-label study that was not powered enough to study harm between the two strategies. It showed a 30% incidence of recurrence of AFib regardless of study assignment. Hospitalists should not feel pressured to initiate early cardioversion for new-onset AFib. Rate control, anticoagulation (if applicable), prompt follow-up, and early discharge (even from the ED) seem to be a safe and practical approach.

Bottom line: In patients presenting with symptomatic recent-onset AFib, delayed cardioversion in a wait-and-see approach was noninferior to early cardioversion in achieving sinus rhythm at 4 weeks’ follow-up.

Citation: Pluymaekers NA et al. Early or delayed cardioversion in recent-onset atrial fibrillation. N Engl J Med.

2019 Apr 18;380(16):1499-508.

Dr. Abdo is a hospitalist at Duke University Health System.

Background: Often atrial fibrillation terminates spontaneously and occasionally recurs; therefore, the advantage of immediate electric or pharmacologic cardioversion over watchful waiting and subsequent delayed cardioversion is not clear.

This was a noninferiority, open-label study that was not powered enough to study harm between the two strategies. It showed a 30% incidence of recurrence of AFib regardless of study assignment. Hospitalists should not feel pressured to initiate early cardioversion for new-onset AFib. Rate control, anticoagulation (if applicable), prompt follow-up, and early discharge (even from the ED) seem to be a safe and practical approach.

Bottom line: In patients presenting with symptomatic recent-onset AFib, delayed cardioversion in a wait-and-see approach was noninferior to early cardioversion in achieving sinus rhythm at 4 weeks’ follow-up.

Citation: Pluymaekers NA et al. Early or delayed cardioversion in recent-onset atrial fibrillation. N Engl J Med.

2019 Apr 18;380(16):1499-508.

Dr. Abdo is a hospitalist at Duke University Health System.

Background: Often atrial fibrillation terminates spontaneously and occasionally recurs; therefore, the advantage of immediate electric or pharmacologic cardioversion over watchful waiting and subsequent delayed cardioversion is not clear.

This was a noninferiority, open-label study that was not powered enough to study harm between the two strategies. It showed a 30% incidence of recurrence of AFib regardless of study assignment. Hospitalists should not feel pressured to initiate early cardioversion for new-onset AFib. Rate control, anticoagulation (if applicable), prompt follow-up, and early discharge (even from the ED) seem to be a safe and practical approach.

Bottom line: In patients presenting with symptomatic recent-onset AFib, delayed cardioversion in a wait-and-see approach was noninferior to early cardioversion in achieving sinus rhythm at 4 weeks’ follow-up.

Citation: Pluymaekers NA et al. Early or delayed cardioversion in recent-onset atrial fibrillation. N Engl J Med.

2019 Apr 18;380(16):1499-508.

Dr. Abdo is a hospitalist at Duke University Health System.

Patients who received a protocol-driven recommendation to initiate statin therapy for primary prevention of cardiovascular disease based upon their CT angiography coronary artery calcium score were twice as likely to actually start on the drug than those whose recommendation was guided by the American College of Cardiology/American Heart Association Pooled Cohort Equations Risk Calculator, according to the results of the randomized CorCal Vanguard study.

Bruce Jancin/MDedge News

These results suggest that patients – and their primary care physicians – find the conventional method of screening for cardiovascular risk using the Pooled Cohort Equations to estimate the 10-year risk of MI or stroke, as recommended in ACC/AHA guidelines, to be less persuasive than screening for the presence or absence of actual disease as captured by CT angiography images and the associated coronary artery calcium (CAC) score, Joseph B. Muhlestein, MD, said at the joint scientific sessions of the ACC and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

The CorCal Vanguard study included 601 patients with an average baseline LDL cholesterol of 120 mg/dL, an average age of 60 years, and no history of cardiovascular disease, diabetes, or prior statin therapy. They were randomized to decision-making regarding statin therapy based on either the ACC/AHA guideline–endorsed Pooled Cohort Equations, which use an estimated 10-year risk of 7.5% or more as the threshold for statin initiation, or their CAC score.

If a patient’s CAC score was 0, the recommendation was against starting a statin. Everyone with a CAC greater than 100 received a recommendation for high-intensity statin therapy. And for those with a CAC of 1-100, the decision defaulted to the results of the Pooled Cohort Equations. The screening results were provided to a patient’s primary physician so they could engage in joint decision-making regarding initiation of statin therapy. Adherence to a screening-based recommendation to start on a statin was assessed at 3 and 12 months of follow-up, explained Dr. Muhlestein, a cardiologist at the Intermountain Medical Center Heart Institute in Salt Lake City.

He noted that CorCal Vanguard was merely a feasibility study. Based on the study results he presented at ACC 2020, the full 9,000-patient CorCal primary prevention trial is now enrolling participants. CorCal is the first randomized trial to pit the Pooled Cohort Equations against the CAC score in a large study looking for differences in downstream clinical outcomes.

The rationale for this line of clinical research lies in the known limitations of the ACC/AHA risk calculator. “It may overestimate risk in some populations, patients aren’t always adherent to Pooled Cohort Equations Risk Calculator recommendations, and it doesn’t include novel risk markers such as C-reactive protein that some consider important for risk assessment. And the big question: Should we continue risk screening to determine potential benefit from drug therapy, or should we switch to disease screening?” the cardiologist commented.
 

The CorCal Vanguard results

A recommendation to start statin therapy was made in 48% of patients in the Pooled Cohort Equations group, versus 36% of the group randomized to CAC. However, only 17% of patients in the Pooled Cohort Equations group actually initiated a statin, a significantly lower rate than the 26% figure in the CAC arm. Fully 70% of patients who received a recommendation to start taking a statin on the basis of their CAC score actually did so, compared to just 36% of those whose recommendation was based upon their Pooled Cohort Equations Risk Calculator.

At 3 months of follow-up, 61% of patients who received an initial recommendation to start statin therapy based upon their CAC screening were actually taking a statin, compared with 41% of those whose recommendation was based upon the Pooled Cohort Equations. At 12 months, the figures were 64% and 49%.

In both groups, at 12 months of follow-up, the No. 1 reason patients weren’t taking a statin as recommended was that their personal physician had advised against it or never prescribed it. That accounted for roughly half of the nonadherence. Another quarter was because of a preference to try lifestyle change first. Fear of drug side effects was a less common reason.

Putting the CorCal Vanguard study results in perspective, Dr. Muhlestein observed that, prior to the screening study, none of the participants had ever been on a statin, yet 37% of them were found by one screening method or the other to be at high cardiovascular risk. Of those high-risk patients, 51% actually initiated statin therapy and the majority of them were still taking their medication 12 months later.

“That has to be a good thing. It emphasizes what can be done when proactive primary prevention is practiced,” the cardiologist said.

He reported having no financial conflicts regarding the CorCal study, which was funded by a grant from the Dell Loy Hansen Cardiovascular Research Fund.

bjancin@mdedge.com

SOURCE: Muhlestein JB et al. ACC 2020, Abstract 909-12.

Patients who received a protocol-driven recommendation to initiate statin therapy for primary prevention of cardiovascular disease based upon their CT angiography coronary artery calcium score were twice as likely to actually start on the drug than those whose recommendation was guided by the American College of Cardiology/American Heart Association Pooled Cohort Equations Risk Calculator, according to the results of the randomized CorCal Vanguard study.

Bruce Jancin/MDedge News

These results suggest that patients – and their primary care physicians – find the conventional method of screening for cardiovascular risk using the Pooled Cohort Equations to estimate the 10-year risk of MI or stroke, as recommended in ACC/AHA guidelines, to be less persuasive than screening for the presence or absence of actual disease as captured by CT angiography images and the associated coronary artery calcium (CAC) score, Joseph B. Muhlestein, MD, said at the joint scientific sessions of the ACC and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

The CorCal Vanguard study included 601 patients with an average baseline LDL cholesterol of 120 mg/dL, an average age of 60 years, and no history of cardiovascular disease, diabetes, or prior statin therapy. They were randomized to decision-making regarding statin therapy based on either the ACC/AHA guideline–endorsed Pooled Cohort Equations, which use an estimated 10-year risk of 7.5% or more as the threshold for statin initiation, or their CAC score.

If a patient’s CAC score was 0, the recommendation was against starting a statin. Everyone with a CAC greater than 100 received a recommendation for high-intensity statin therapy. And for those with a CAC of 1-100, the decision defaulted to the results of the Pooled Cohort Equations. The screening results were provided to a patient’s primary physician so they could engage in joint decision-making regarding initiation of statin therapy. Adherence to a screening-based recommendation to start on a statin was assessed at 3 and 12 months of follow-up, explained Dr. Muhlestein, a cardiologist at the Intermountain Medical Center Heart Institute in Salt Lake City.

He noted that CorCal Vanguard was merely a feasibility study. Based on the study results he presented at ACC 2020, the full 9,000-patient CorCal primary prevention trial is now enrolling participants. CorCal is the first randomized trial to pit the Pooled Cohort Equations against the CAC score in a large study looking for differences in downstream clinical outcomes.

The rationale for this line of clinical research lies in the known limitations of the ACC/AHA risk calculator. “It may overestimate risk in some populations, patients aren’t always adherent to Pooled Cohort Equations Risk Calculator recommendations, and it doesn’t include novel risk markers such as C-reactive protein that some consider important for risk assessment. And the big question: Should we continue risk screening to determine potential benefit from drug therapy, or should we switch to disease screening?” the cardiologist commented.
 

The CorCal Vanguard results

A recommendation to start statin therapy was made in 48% of patients in the Pooled Cohort Equations group, versus 36% of the group randomized to CAC. However, only 17% of patients in the Pooled Cohort Equations group actually initiated a statin, a significantly lower rate than the 26% figure in the CAC arm. Fully 70% of patients who received a recommendation to start taking a statin on the basis of their CAC score actually did so, compared to just 36% of those whose recommendation was based upon their Pooled Cohort Equations Risk Calculator.

At 3 months of follow-up, 61% of patients who received an initial recommendation to start statin therapy based upon their CAC screening were actually taking a statin, compared with 41% of those whose recommendation was based upon the Pooled Cohort Equations. At 12 months, the figures were 64% and 49%.

In both groups, at 12 months of follow-up, the No. 1 reason patients weren’t taking a statin as recommended was that their personal physician had advised against it or never prescribed it. That accounted for roughly half of the nonadherence. Another quarter was because of a preference to try lifestyle change first. Fear of drug side effects was a less common reason.

Putting the CorCal Vanguard study results in perspective, Dr. Muhlestein observed that, prior to the screening study, none of the participants had ever been on a statin, yet 37% of them were found by one screening method or the other to be at high cardiovascular risk. Of those high-risk patients, 51% actually initiated statin therapy and the majority of them were still taking their medication 12 months later.

“That has to be a good thing. It emphasizes what can be done when proactive primary prevention is practiced,” the cardiologist said.

He reported having no financial conflicts regarding the CorCal study, which was funded by a grant from the Dell Loy Hansen Cardiovascular Research Fund.

bjancin@mdedge.com

SOURCE: Muhlestein JB et al. ACC 2020, Abstract 909-12.

Patients who received a protocol-driven recommendation to initiate statin therapy for primary prevention of cardiovascular disease based upon their CT angiography coronary artery calcium score were twice as likely to actually start on the drug than those whose recommendation was guided by the American College of Cardiology/American Heart Association Pooled Cohort Equations Risk Calculator, according to the results of the randomized CorCal Vanguard study.

Bruce Jancin/MDedge News

These results suggest that patients – and their primary care physicians – find the conventional method of screening for cardiovascular risk using the Pooled Cohort Equations to estimate the 10-year risk of MI or stroke, as recommended in ACC/AHA guidelines, to be less persuasive than screening for the presence or absence of actual disease as captured by CT angiography images and the associated coronary artery calcium (CAC) score, Joseph B. Muhlestein, MD, said at the joint scientific sessions of the ACC and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

The CorCal Vanguard study included 601 patients with an average baseline LDL cholesterol of 120 mg/dL, an average age of 60 years, and no history of cardiovascular disease, diabetes, or prior statin therapy. They were randomized to decision-making regarding statin therapy based on either the ACC/AHA guideline–endorsed Pooled Cohort Equations, which use an estimated 10-year risk of 7.5% or more as the threshold for statin initiation, or their CAC score.

If a patient’s CAC score was 0, the recommendation was against starting a statin. Everyone with a CAC greater than 100 received a recommendation for high-intensity statin therapy. And for those with a CAC of 1-100, the decision defaulted to the results of the Pooled Cohort Equations. The screening results were provided to a patient’s primary physician so they could engage in joint decision-making regarding initiation of statin therapy. Adherence to a screening-based recommendation to start on a statin was assessed at 3 and 12 months of follow-up, explained Dr. Muhlestein, a cardiologist at the Intermountain Medical Center Heart Institute in Salt Lake City.

He noted that CorCal Vanguard was merely a feasibility study. Based on the study results he presented at ACC 2020, the full 9,000-patient CorCal primary prevention trial is now enrolling participants. CorCal is the first randomized trial to pit the Pooled Cohort Equations against the CAC score in a large study looking for differences in downstream clinical outcomes.

The rationale for this line of clinical research lies in the known limitations of the ACC/AHA risk calculator. “It may overestimate risk in some populations, patients aren’t always adherent to Pooled Cohort Equations Risk Calculator recommendations, and it doesn’t include novel risk markers such as C-reactive protein that some consider important for risk assessment. And the big question: Should we continue risk screening to determine potential benefit from drug therapy, or should we switch to disease screening?” the cardiologist commented.
 

The CorCal Vanguard results

A recommendation to start statin therapy was made in 48% of patients in the Pooled Cohort Equations group, versus 36% of the group randomized to CAC. However, only 17% of patients in the Pooled Cohort Equations group actually initiated a statin, a significantly lower rate than the 26% figure in the CAC arm. Fully 70% of patients who received a recommendation to start taking a statin on the basis of their CAC score actually did so, compared to just 36% of those whose recommendation was based upon their Pooled Cohort Equations Risk Calculator.

At 3 months of follow-up, 61% of patients who received an initial recommendation to start statin therapy based upon their CAC screening were actually taking a statin, compared with 41% of those whose recommendation was based upon the Pooled Cohort Equations. At 12 months, the figures were 64% and 49%.

In both groups, at 12 months of follow-up, the No. 1 reason patients weren’t taking a statin as recommended was that their personal physician had advised against it or never prescribed it. That accounted for roughly half of the nonadherence. Another quarter was because of a preference to try lifestyle change first. Fear of drug side effects was a less common reason.

Putting the CorCal Vanguard study results in perspective, Dr. Muhlestein observed that, prior to the screening study, none of the participants had ever been on a statin, yet 37% of them were found by one screening method or the other to be at high cardiovascular risk. Of those high-risk patients, 51% actually initiated statin therapy and the majority of them were still taking their medication 12 months later.

“That has to be a good thing. It emphasizes what can be done when proactive primary prevention is practiced,” the cardiologist said.

He reported having no financial conflicts regarding the CorCal study, which was funded by a grant from the Dell Loy Hansen Cardiovascular Research Fund.

bjancin@mdedge.com

SOURCE: Muhlestein JB et al. ACC 2020, Abstract 909-12.

A new analysis from the REDUCE-IT trial has shown that the high-strength eicosapentaenoic acid product icosapent ethyl (Vascepa; Amarin) reduced the number of revascularization procedures by more than one-third in statin-treated patients whose triglyceride levels were elevated and who were at increased cardiovascular risk.

The new data were presented at the Society for Cardiovascular Angiography & Interventions virtual annual scientific sessions.

REDUCE-IT, a multicenter, double-blind, placebo-controlled trial, randomly assigned statin-treated patients whose triglyceride levels were elevated (135-499 mg/dL), whose LDL cholesterol levels were controlled (41-100 mg/dL), and who had established cardiovascular disease or diabetes plus risk factors to receive either icosapent ethyl 4 g daily or placebo.

The primary composite and other cardiovascular endpoints were substantially reduced. Prespecified analyses examined all coronary revascularizations, recurrent revascularizations, and revascularization subtypes.

“Compared with placebo, icosapent ethyl 4 g/day significantly reduced first and total revascularization events by 34% and 36%, respectively,” REDUCE-IT investigator Benjamin Peterson, MD, of Brigham and Women’s Hospital, Boston, concluded during his presentation.

This reduction was consistent with respect to urgent, emergent, and elective revascularization procedures overall, as well as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) individually, he reported.

“Prior therapies aimed at patients with elevated triglycerides have not demonstrated a consistent benefit in reducing coronary revascularization, and to the best of our knowledge, this is the first non–LDL cholesterol intervention in a major randomized trial in which statin-treated patients underwent fewer CABG surgeries,” Dr. Peterson stated.

“These data highlight the substantial impact of icosapent ethyl on the underlying atherothrombotic burden in the at-risk REDUCE-IT population,” he added.

Detailed results showed that the percentage of patients who underwent first revascularizations was 9.2% with icosapent ethyl versus 13.3% with placebo (hazard ratio, 0.66; P < .0001; number needed to treat, 25).

Similar reductions were observed in total (first and subsequent) revascularizations (risk ratio, 0.64; P < .0001) and across urgent, emergent, and elective revascularizations. Icosapent ethyl significantly reduced the need for PCI (HR, 0.68; P < .0001) and CABG (HR, 0.61; P = .0005).

The moderator of a SCAI press conference, Kirk Garratt, MD, of the Center for Heart and Vascular Health at Christiana Care Health System in Wilmington, Del., said that “this is an impressive impact. I couldn’t count the number of zeros in the P value.”

Timothy Henry, MD, of Christ Hospital in Cincinnati, said that REDUCE-IT was an important trial. “It showed a very impressive effect on revascularizations along with all the other benefits.” But he suggested that the uptake in usage of icosapent ethyl in the United States has been slow, and he asked what could be done to enhance this.

REDUCE-IT senior investigator Deepak Bhatt, MD, replied that the product was only approved for the REDUCE-IT indication in December 2019, and he suggested that initial uptake may have been affected by the current COVID-19 pandemic.

“This new REDUCE-IT indication ― patients with established cardiovascular disease or diabetes plus risk factors who have moderately elevated triglycerides and controlled LDL ― includes a lot of patients, between 15% and 50% of all cardiovascular patients,” he said.

“We wanted to present this revascularization data at the SCAI meeting, as it is superimportant that interventional cardiologists know about this. Interventionalists have now taken ownership of LDL and make sure patients are on statins, and we hope they will now do the same thing for triglycerides,” Dr. Bhatt commented.

Dr. Henry agreed. “It should be a simple thing to take all secondary prevention patients with eligible triglycerides and be aggressive with this new therapy.”

Dr. Bhatt noted that a cost-effectiveness analysis of the REDUCE-IT trial that was presented at last year’s American Heart Association meeting “has shown the drug to be highly cost effective and actually cost saving at the current list price.”

Asked what the mechanism of benefit is, Dr. Bhatt said that “there has been good basic science showing that EPA [eicosapentaenoic acid] stabilizes cell membranes and reduces plaque vulnerability and progression.”

REDUCE-IT was sponsored by Amarin. Brigham and Women’s Hospital receives research funding from Amarin for Dr. Bhatt’s role as chair of the trial.

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

A new analysis from the REDUCE-IT trial has shown that the high-strength eicosapentaenoic acid product icosapent ethyl (Vascepa; Amarin) reduced the number of revascularization procedures by more than one-third in statin-treated patients whose triglyceride levels were elevated and who were at increased cardiovascular risk.

The new data were presented at the Society for Cardiovascular Angiography & Interventions virtual annual scientific sessions.

REDUCE-IT, a multicenter, double-blind, placebo-controlled trial, randomly assigned statin-treated patients whose triglyceride levels were elevated (135-499 mg/dL), whose LDL cholesterol levels were controlled (41-100 mg/dL), and who had established cardiovascular disease or diabetes plus risk factors to receive either icosapent ethyl 4 g daily or placebo.

The primary composite and other cardiovascular endpoints were substantially reduced. Prespecified analyses examined all coronary revascularizations, recurrent revascularizations, and revascularization subtypes.

“Compared with placebo, icosapent ethyl 4 g/day significantly reduced first and total revascularization events by 34% and 36%, respectively,” REDUCE-IT investigator Benjamin Peterson, MD, of Brigham and Women’s Hospital, Boston, concluded during his presentation.

This reduction was consistent with respect to urgent, emergent, and elective revascularization procedures overall, as well as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) individually, he reported.

“Prior therapies aimed at patients with elevated triglycerides have not demonstrated a consistent benefit in reducing coronary revascularization, and to the best of our knowledge, this is the first non–LDL cholesterol intervention in a major randomized trial in which statin-treated patients underwent fewer CABG surgeries,” Dr. Peterson stated.

“These data highlight the substantial impact of icosapent ethyl on the underlying atherothrombotic burden in the at-risk REDUCE-IT population,” he added.

Detailed results showed that the percentage of patients who underwent first revascularizations was 9.2% with icosapent ethyl versus 13.3% with placebo (hazard ratio, 0.66; P < .0001; number needed to treat, 25).

Similar reductions were observed in total (first and subsequent) revascularizations (risk ratio, 0.64; P < .0001) and across urgent, emergent, and elective revascularizations. Icosapent ethyl significantly reduced the need for PCI (HR, 0.68; P < .0001) and CABG (HR, 0.61; P = .0005).

The moderator of a SCAI press conference, Kirk Garratt, MD, of the Center for Heart and Vascular Health at Christiana Care Health System in Wilmington, Del., said that “this is an impressive impact. I couldn’t count the number of zeros in the P value.”

Timothy Henry, MD, of Christ Hospital in Cincinnati, said that REDUCE-IT was an important trial. “It showed a very impressive effect on revascularizations along with all the other benefits.” But he suggested that the uptake in usage of icosapent ethyl in the United States has been slow, and he asked what could be done to enhance this.

REDUCE-IT senior investigator Deepak Bhatt, MD, replied that the product was only approved for the REDUCE-IT indication in December 2019, and he suggested that initial uptake may have been affected by the current COVID-19 pandemic.

“This new REDUCE-IT indication ― patients with established cardiovascular disease or diabetes plus risk factors who have moderately elevated triglycerides and controlled LDL ― includes a lot of patients, between 15% and 50% of all cardiovascular patients,” he said.

“We wanted to present this revascularization data at the SCAI meeting, as it is superimportant that interventional cardiologists know about this. Interventionalists have now taken ownership of LDL and make sure patients are on statins, and we hope they will now do the same thing for triglycerides,” Dr. Bhatt commented.

Dr. Henry agreed. “It should be a simple thing to take all secondary prevention patients with eligible triglycerides and be aggressive with this new therapy.”

Dr. Bhatt noted that a cost-effectiveness analysis of the REDUCE-IT trial that was presented at last year’s American Heart Association meeting “has shown the drug to be highly cost effective and actually cost saving at the current list price.”

Asked what the mechanism of benefit is, Dr. Bhatt said that “there has been good basic science showing that EPA [eicosapentaenoic acid] stabilizes cell membranes and reduces plaque vulnerability and progression.”

REDUCE-IT was sponsored by Amarin. Brigham and Women’s Hospital receives research funding from Amarin for Dr. Bhatt’s role as chair of the trial.

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

A new analysis from the REDUCE-IT trial has shown that the high-strength eicosapentaenoic acid product icosapent ethyl (Vascepa; Amarin) reduced the number of revascularization procedures by more than one-third in statin-treated patients whose triglyceride levels were elevated and who were at increased cardiovascular risk.

The new data were presented at the Society for Cardiovascular Angiography & Interventions virtual annual scientific sessions.

REDUCE-IT, a multicenter, double-blind, placebo-controlled trial, randomly assigned statin-treated patients whose triglyceride levels were elevated (135-499 mg/dL), whose LDL cholesterol levels were controlled (41-100 mg/dL), and who had established cardiovascular disease or diabetes plus risk factors to receive either icosapent ethyl 4 g daily or placebo.

The primary composite and other cardiovascular endpoints were substantially reduced. Prespecified analyses examined all coronary revascularizations, recurrent revascularizations, and revascularization subtypes.

“Compared with placebo, icosapent ethyl 4 g/day significantly reduced first and total revascularization events by 34% and 36%, respectively,” REDUCE-IT investigator Benjamin Peterson, MD, of Brigham and Women’s Hospital, Boston, concluded during his presentation.

This reduction was consistent with respect to urgent, emergent, and elective revascularization procedures overall, as well as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) individually, he reported.

“Prior therapies aimed at patients with elevated triglycerides have not demonstrated a consistent benefit in reducing coronary revascularization, and to the best of our knowledge, this is the first non–LDL cholesterol intervention in a major randomized trial in which statin-treated patients underwent fewer CABG surgeries,” Dr. Peterson stated.

“These data highlight the substantial impact of icosapent ethyl on the underlying atherothrombotic burden in the at-risk REDUCE-IT population,” he added.

Detailed results showed that the percentage of patients who underwent first revascularizations was 9.2% with icosapent ethyl versus 13.3% with placebo (hazard ratio, 0.66; P < .0001; number needed to treat, 25).

Similar reductions were observed in total (first and subsequent) revascularizations (risk ratio, 0.64; P < .0001) and across urgent, emergent, and elective revascularizations. Icosapent ethyl significantly reduced the need for PCI (HR, 0.68; P < .0001) and CABG (HR, 0.61; P = .0005).

The moderator of a SCAI press conference, Kirk Garratt, MD, of the Center for Heart and Vascular Health at Christiana Care Health System in Wilmington, Del., said that “this is an impressive impact. I couldn’t count the number of zeros in the P value.”

Timothy Henry, MD, of Christ Hospital in Cincinnati, said that REDUCE-IT was an important trial. “It showed a very impressive effect on revascularizations along with all the other benefits.” But he suggested that the uptake in usage of icosapent ethyl in the United States has been slow, and he asked what could be done to enhance this.

REDUCE-IT senior investigator Deepak Bhatt, MD, replied that the product was only approved for the REDUCE-IT indication in December 2019, and he suggested that initial uptake may have been affected by the current COVID-19 pandemic.

“This new REDUCE-IT indication ― patients with established cardiovascular disease or diabetes plus risk factors who have moderately elevated triglycerides and controlled LDL ― includes a lot of patients, between 15% and 50% of all cardiovascular patients,” he said.

“We wanted to present this revascularization data at the SCAI meeting, as it is superimportant that interventional cardiologists know about this. Interventionalists have now taken ownership of LDL and make sure patients are on statins, and we hope they will now do the same thing for triglycerides,” Dr. Bhatt commented.

Dr. Henry agreed. “It should be a simple thing to take all secondary prevention patients with eligible triglycerides and be aggressive with this new therapy.”

Dr. Bhatt noted that a cost-effectiveness analysis of the REDUCE-IT trial that was presented at last year’s American Heart Association meeting “has shown the drug to be highly cost effective and actually cost saving at the current list price.”

Asked what the mechanism of benefit is, Dr. Bhatt said that “there has been good basic science showing that EPA [eicosapentaenoic acid] stabilizes cell membranes and reduces plaque vulnerability and progression.”

REDUCE-IT was sponsored by Amarin. Brigham and Women’s Hospital receives research funding from Amarin for Dr. Bhatt’s role as chair of the trial.

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

Roughly 16%-22% of patients with hypertension appeared to have primary aldosteronism as the likely major cause of their elevated blood pressure, in an analysis of about 1,000 Americans, which is a much higher prevalence than previously appreciated and a finding that could potentially reorient both screening for aldosteronism and management for this subset of patients.

“Our findings show a high prevalence of unrecognized yet biochemically overt primary aldosteronism [PA] using current confirmatory diagnostic thresholds. They highlight the inadequacy of the current diagnostic approach that heavily relies on the ARR [aldosterone renin ratio] and, most important, show the existence of a pathologic continuum of nonsuppressible renin-independent aldosterone production that parallels the severity of hypertension,” wrote Jennifer M. Brown, MD, and coinvestigators in a report published in Annals of Internal Medicine on May 25. “These findings support the need to redefine primary aldosteronism from a rare and categorical disease to, instead, a common syndrome that manifests across a broad severity spectrum and may be a primary contributor to hypertension pathogenesis,” they wrote in the report.

The results, showing an underappreciated prevalence of both overt and subtler forms of aldosteronism that link with hypertension, won praise from several experts for the potential of these findings to boost the profile of excess aldosterone as a common and treatable cause of high blood pressure, but opinions on the role for the ARR as a screen to identify affected patients were more mixed.

“ARR is still the best screening approach we have” for identifying people who likely have PA, especially when the ratio threshold for finding patients who need further investigation is reduced from the traditional level of 30 ng/dL to 20 ng/dL, commented Michael Stowasser, MBBS, professor of medicine at the University of Queensland in Brisbane, Australia, and director of the Endocrine Hypertension Research Centre at Greenslopes and Princess Alexandra Hospitals in Brisbane. “I strongly recommend ARR testing in all newly diagnosed hypertensives.”

The study results “showed that PA is much more common than previously perceived, and suggest that perhaps PA in milder forms than we typically recognize contributes more to ‘essential’ hypertension than we previously thought,” said Anand Vaidya, MD, senior author of the report and director of the Center for Adrenal Disorders at Brigham and Women’s Hospital in Boston. The researchers found adjusted PA prevalence rates of 16% among 115 untreated patients with stage 1 hypertension (130-139/80-89 mm Hg), 22% among 203 patients with untreated stage 2 hypertension (at least 140/90 mm Hg), and 22% among 408 patients with treatment-resistant hypertension. All three prevalence rates were based on relatively conservative criteria that included all 726 patients with hypertension in the analysis (which also included 289 normotensive subjects) regardless of whether or not they also had low levels of serum renin. These PA prevalence rates were also based on a “conservative” definition of PA, a level of at least 12 mcg excreted in a 24-hour urine specimen.

When the researchers applied less stringent diagnostic criteria for PA or focused on the types of patients usually at highest risk for PA because of a suppressed renin level, the prevalence rates rose substantially and, in some subgroups, more than doubled. Of the 726 people with hypertension included in the analysis, 452 (62%) had suppressed renin (seated plasma renin activity < 1.0 mcg/L per hour or supine plasma renin activity < 0.6 mcg/L per hour). Within this subgroup of patients with suppressed renin, the adjusted prevalence of PA by the threshold of 24-hour urine aldosterone secretion of at least 12 mcg was 52% in those with treatment-resistant hypertension; among patients with stage 1 or 2 hypertension the adjusted prevalence rates were just slightly above the rates in the entire study group. But among patients with suppressed renin who were judged to have PA by a more liberal definition of at least 10 mcg in a 24-hour urine sample, the adjusted prevalence rates were 27% among untreated stage 1 hypertensives, 40% among untreated stage 2 patients, and 58% among treatment-resistant patients, the report showed.
 

A role for subtler forms of aldosteronism

Defining PA as at least 12 mcg secreted in a 24-hour urine collection “is relatively arbitrary, and our findings show that it bisects a continuous distribution. How we should redefine PA is also arbitrary, but step one is to recognize that many people have milder forms of PA” that could have an important effect on blood pressure, Dr. Vaidya said in an interview.

“This is the very first study to show that aldosterone may be contributing to the hypertensive process even though it is not severe enough to be diagnosed as PA according to current criteria,” said Robert M. Carey, MD, a cardiovascular endocrinologist and professor of medicine at the University of Virginia in Charlottesville and a coauthor on the new report. “More patients than we have ever known have an aldosterone component to their hypertension,” Dr. Carey said in an interview.

The new report on the prevalence of unrecognized PA in hypertensive patients “is a game changer,” wrote John W. Funder, MD, professor of medicine at Monash University in Clayton, Australia, in an editorial published along with the new report. In the editorial, he synthesized the new findings with results from prior reports to estimate that excess aldosteronism could play a clinically meaningful role in close to half of patients with hypertension, although Dr. Stowasser called this an “overestimate.” The new results also showed that “the single spot measurement of plasma aldosterone concentration, which clinicians have used for decades to screen for primary aldosteronism, is not merely useless but actually misleading. The authors cautioned readers about the uncertain representativeness of the study population to the U.S. population, but I believe that the findings are generalizable to the United States and elsewhere,” Dr. Funder wrote. “The central problem is that plasma aldosterone concentration is a very poor index of total daily aldosterone secretion. A single morning spot measurement of plasma aldosterone cannot take into account ultradian variation in aldosterone secretion.”
 

The importance of finding excess aldosterone

Identifying patients with hypertension and PA, as well as hypertensives with excess aldosterone production that may not meet the traditional definition of PA, is especially important because they are excellent candidates for two forms of targeted and very effective treatments that have a reliable and substantial impact on lowering blood pressure in these patients. One treatment is unilateral adrenal gland removal in patients who produce excess aldosterone because of benign adenomas in one adrenal gland, which accounts for “approximately 30%” of patients with PA. “Patients with suspected PA should have an opportunity to find out whether they have a unilateral variety and chance for surgical cure,” said Dr. Stowasser in an interview. “Patients with PA do far better in terms of blood pressure control, prevention of cardiovascular complications, and quality of life if they are treated specifically, either medically or particularly by surgery.”

The specific medical treatment he cited refers to one of the mineralocorticoid receptor antagonist (MRA) drugs, spironolactone and eplerenone (Inspra), because mineralocorticoid receptor blockade directly short-circuits the path by which aldosterone increases blood pressure. “We’re advocating earlier use of MRAs” for hypertensive patients identified with excess aldosterone production, said Dr. Carey. He noted that alternative, nonsteroidal MRAs, such as finerenone, have shown promise for efficacy levels similar to what spironolactone provides but without as many adverse effects because of greater receptor specificity. Finerenone and other nonsteroidal MRAs are all currently investigational. Spironolactone and eplerenone both cause hyperkalemia, although treatment with potassium binding agents can blunt the risk this poses. Spironolactone also causes bothersome adverse effects in men, including impotence and gynecomastia because of its action on androgen receptors, effects that diminished with eplerenone, but eplerenone is not as effective as spironolactone, Dr. Carey said.
 

Study details

The new study ran a post hoc analysis on data collected in five independent studies run at centers in four U.S. locations: Birmingham, Ala.; Boston; Charlottesville, Va.; and Salt Lake City. The studies included a total of 1,846 adults, mostly patients with hypertension of varying severity but also several hundred normotensive people. Data on 24-hour sodium excretion during an oral sodium suppression test were available for all participants, and the researchers excluded 831 people with an “inadequate” sodium balance of less than 190 mmol based on this metric, leaving a study population of 1,015. The researchers acknowledged the limitation that the study participants were not representative of the U.S. population.

The analysis included 289 normotensive people not on any blood pressure–lowering medications, and 239 fit the definition of having suppressed renin. The adjusted prevalence of aldosteronism at the level of at least 12 mcg excreted in a 24-hour urine specimen was 11% among all 289 normotensive subjects and 12% among the 239 with suppressed renin. When the definition of aldosteronism loosened to at least 10 mcg excreted during 24 hours the adjusted prevalence of excess aldosterone among normotensives increased to 19% among the entire group and 20% among those with suppressed renin. This finding may have identified a primordial phase of nascent hypertension that needs further study but may eventually provide a new scenario for intervention. “If a normotensive person has compliant arteries and healthy kidneys they can handle the excess salt and volume load of PA,” but when compensatory mechanisms start falling short through aging or other deteriorations, then blood pressure starts to rise, suggested Dr. Vaidya.
 

Whom to screen for aldosteronism and how

While several experts agreed these findings added to an existing and growing literature showing that PA is common and needs greater diagnostic attention, they differed on what this may mean for the specifics of screening and diagnosis, especially at the primary care level.

“Our results showed more explicitly that excess aldosterone exists on a broad severity spectrum and can’t be regarded as a categorical diagnosis that a patient either has or does not have. The hard part is figuring out where we should begin interventions,” said Dr. Vaidya.

In his editorial, Dr. Funder wrote that “much of the present guideline needs to be jettisoned, and radically reconstructed recommendations should be developed.”

One answer may be to apply a less stringent ARR threshold for further work-up. Dr. Stowasser’s program in Brisbane, as well as some other groups worldwide, use an ARR of at least 20 ng/dL as an indication of possible PA. “If you lower the cutoff to 20 [ng/dL], and ignore the plasma aldosterone level, then the ARR should pick up the great majority of patients with PA,” he said.

Another controversial aspect is whether aldosterone detection should be screened by 24-hour urine collection or by spot testing. In his editorial, Dr. Funder called spot testing “useless” and “misleading,” but Dr. Vaidya acknowledged that the 24-hour collection used in his current study is “not practical” for widespread use. Despite that, the Mayo Clinic in Rochester has focused on 24-hour urine collected “for more than 4 decades,” said Dr. Young, even though “a morning blood sample remains a simple screening test” that will catch “more than 95% of patients with PA” when combined with a plasma aldosterone threshold of 10 ng/dL. Dr. Stowasser noted that “patients don’t like” 24-hour collection, and not infrequently muck up collection” by forgetting to collect their entire 1-day output. Regardless of its shortcomings, 24-hour urine has the advantage of greater precision and accuracy than spot measurement, and using it on newly diagnosed hypertensive patients who also show renin suppression may be a viable approach, Dr. Carey suggested.

Regardless of exactly how guidelines for assessing aldosterone in hypertensive patients change, prospects seem ripe for some sort of revision and for greater participation and buy-in by primary care physicians than in the past. Dr. Carey, who also served as vice-chair of the American College of Cardiology and American Heart Association Task Force that wrote the most current U.S. guideline for managing hypertension, said it was too soon to revise that document, but the time had come to revise the Endocrine Society’s 2016 guideline for diagnosing and treating PA and to hash out the revision “in partnership” with one or more primary care societies. He also highlighted that publishing the current study in a high-profile primary care journal was an intentional effort to reach a large segment of the primary care community.

The new report “has the potential to change the current state of inertia” over wider PA diagnosis and targeted treatment “by being published in a widely read, major international journal,” commented Dr. Stowasser.

Dr. Vaidya has been a consultant to Catalys Pacific, Corcept Therapeutics, HRA Pharma, Orphagen, and Selenity Therapeutics. None of the other report coauthors had commercial disclosures, including Dr. Carey. Dr. Funder, Dr. Stowasser, and Dr. Young had no disclosures.

mzoler@mdedge.com

SOURCE: Brown JM et al. Ann Int Med. 2020 May 25. doi: 10.7326/M20-0065.
 

Roughly 16%-22% of patients with hypertension appeared to have primary aldosteronism as the likely major cause of their elevated blood pressure, in an analysis of about 1,000 Americans, which is a much higher prevalence than previously appreciated and a finding that could potentially reorient both screening for aldosteronism and management for this subset of patients.

“Our findings show a high prevalence of unrecognized yet biochemically overt primary aldosteronism [PA] using current confirmatory diagnostic thresholds. They highlight the inadequacy of the current diagnostic approach that heavily relies on the ARR [aldosterone renin ratio] and, most important, show the existence of a pathologic continuum of nonsuppressible renin-independent aldosterone production that parallels the severity of hypertension,” wrote Jennifer M. Brown, MD, and coinvestigators in a report published in Annals of Internal Medicine on May 25. “These findings support the need to redefine primary aldosteronism from a rare and categorical disease to, instead, a common syndrome that manifests across a broad severity spectrum and may be a primary contributor to hypertension pathogenesis,” they wrote in the report.

The results, showing an underappreciated prevalence of both overt and subtler forms of aldosteronism that link with hypertension, won praise from several experts for the potential of these findings to boost the profile of excess aldosterone as a common and treatable cause of high blood pressure, but opinions on the role for the ARR as a screen to identify affected patients were more mixed.

“ARR is still the best screening approach we have” for identifying people who likely have PA, especially when the ratio threshold for finding patients who need further investigation is reduced from the traditional level of 30 ng/dL to 20 ng/dL, commented Michael Stowasser, MBBS, professor of medicine at the University of Queensland in Brisbane, Australia, and director of the Endocrine Hypertension Research Centre at Greenslopes and Princess Alexandra Hospitals in Brisbane. “I strongly recommend ARR testing in all newly diagnosed hypertensives.”

The study results “showed that PA is much more common than previously perceived, and suggest that perhaps PA in milder forms than we typically recognize contributes more to ‘essential’ hypertension than we previously thought,” said Anand Vaidya, MD, senior author of the report and director of the Center for Adrenal Disorders at Brigham and Women’s Hospital in Boston. The researchers found adjusted PA prevalence rates of 16% among 115 untreated patients with stage 1 hypertension (130-139/80-89 mm Hg), 22% among 203 patients with untreated stage 2 hypertension (at least 140/90 mm Hg), and 22% among 408 patients with treatment-resistant hypertension. All three prevalence rates were based on relatively conservative criteria that included all 726 patients with hypertension in the analysis (which also included 289 normotensive subjects) regardless of whether or not they also had low levels of serum renin. These PA prevalence rates were also based on a “conservative” definition of PA, a level of at least 12 mcg excreted in a 24-hour urine specimen.

When the researchers applied less stringent diagnostic criteria for PA or focused on the types of patients usually at highest risk for PA because of a suppressed renin level, the prevalence rates rose substantially and, in some subgroups, more than doubled. Of the 726 people with hypertension included in the analysis, 452 (62%) had suppressed renin (seated plasma renin activity < 1.0 mcg/L per hour or supine plasma renin activity < 0.6 mcg/L per hour). Within this subgroup of patients with suppressed renin, the adjusted prevalence of PA by the threshold of 24-hour urine aldosterone secretion of at least 12 mcg was 52% in those with treatment-resistant hypertension; among patients with stage 1 or 2 hypertension the adjusted prevalence rates were just slightly above the rates in the entire study group. But among patients with suppressed renin who were judged to have PA by a more liberal definition of at least 10 mcg in a 24-hour urine sample, the adjusted prevalence rates were 27% among untreated stage 1 hypertensives, 40% among untreated stage 2 patients, and 58% among treatment-resistant patients, the report showed.
 

A role for subtler forms of aldosteronism

Defining PA as at least 12 mcg secreted in a 24-hour urine collection “is relatively arbitrary, and our findings show that it bisects a continuous distribution. How we should redefine PA is also arbitrary, but step one is to recognize that many people have milder forms of PA” that could have an important effect on blood pressure, Dr. Vaidya said in an interview.

“This is the very first study to show that aldosterone may be contributing to the hypertensive process even though it is not severe enough to be diagnosed as PA according to current criteria,” said Robert M. Carey, MD, a cardiovascular endocrinologist and professor of medicine at the University of Virginia in Charlottesville and a coauthor on the new report. “More patients than we have ever known have an aldosterone component to their hypertension,” Dr. Carey said in an interview.

The new report on the prevalence of unrecognized PA in hypertensive patients “is a game changer,” wrote John W. Funder, MD, professor of medicine at Monash University in Clayton, Australia, in an editorial published along with the new report. In the editorial, he synthesized the new findings with results from prior reports to estimate that excess aldosteronism could play a clinically meaningful role in close to half of patients with hypertension, although Dr. Stowasser called this an “overestimate.” The new results also showed that “the single spot measurement of plasma aldosterone concentration, which clinicians have used for decades to screen for primary aldosteronism, is not merely useless but actually misleading. The authors cautioned readers about the uncertain representativeness of the study population to the U.S. population, but I believe that the findings are generalizable to the United States and elsewhere,” Dr. Funder wrote. “The central problem is that plasma aldosterone concentration is a very poor index of total daily aldosterone secretion. A single morning spot measurement of plasma aldosterone cannot take into account ultradian variation in aldosterone secretion.”
 

The importance of finding excess aldosterone

Identifying patients with hypertension and PA, as well as hypertensives with excess aldosterone production that may not meet the traditional definition of PA, is especially important because they are excellent candidates for two forms of targeted and very effective treatments that have a reliable and substantial impact on lowering blood pressure in these patients. One treatment is unilateral adrenal gland removal in patients who produce excess aldosterone because of benign adenomas in one adrenal gland, which accounts for “approximately 30%” of patients with PA. “Patients with suspected PA should have an opportunity to find out whether they have a unilateral variety and chance for surgical cure,” said Dr. Stowasser in an interview. “Patients with PA do far better in terms of blood pressure control, prevention of cardiovascular complications, and quality of life if they are treated specifically, either medically or particularly by surgery.”

The specific medical treatment he cited refers to one of the mineralocorticoid receptor antagonist (MRA) drugs, spironolactone and eplerenone (Inspra), because mineralocorticoid receptor blockade directly short-circuits the path by which aldosterone increases blood pressure. “We’re advocating earlier use of MRAs” for hypertensive patients identified with excess aldosterone production, said Dr. Carey. He noted that alternative, nonsteroidal MRAs, such as finerenone, have shown promise for efficacy levels similar to what spironolactone provides but without as many adverse effects because of greater receptor specificity. Finerenone and other nonsteroidal MRAs are all currently investigational. Spironolactone and eplerenone both cause hyperkalemia, although treatment with potassium binding agents can blunt the risk this poses. Spironolactone also causes bothersome adverse effects in men, including impotence and gynecomastia because of its action on androgen receptors, effects that diminished with eplerenone, but eplerenone is not as effective as spironolactone, Dr. Carey said.
 

Study details

The new study ran a post hoc analysis on data collected in five independent studies run at centers in four U.S. locations: Birmingham, Ala.; Boston; Charlottesville, Va.; and Salt Lake City. The studies included a total of 1,846 adults, mostly patients with hypertension of varying severity but also several hundred normotensive people. Data on 24-hour sodium excretion during an oral sodium suppression test were available for all participants, and the researchers excluded 831 people with an “inadequate” sodium balance of less than 190 mmol based on this metric, leaving a study population of 1,015. The researchers acknowledged the limitation that the study participants were not representative of the U.S. population.

The analysis included 289 normotensive people not on any blood pressure–lowering medications, and 239 fit the definition of having suppressed renin. The adjusted prevalence of aldosteronism at the level of at least 12 mcg excreted in a 24-hour urine specimen was 11% among all 289 normotensive subjects and 12% among the 239 with suppressed renin. When the definition of aldosteronism loosened to at least 10 mcg excreted during 24 hours the adjusted prevalence of excess aldosterone among normotensives increased to 19% among the entire group and 20% among those with suppressed renin. This finding may have identified a primordial phase of nascent hypertension that needs further study but may eventually provide a new scenario for intervention. “If a normotensive person has compliant arteries and healthy kidneys they can handle the excess salt and volume load of PA,” but when compensatory mechanisms start falling short through aging or other deteriorations, then blood pressure starts to rise, suggested Dr. Vaidya.
 

Whom to screen for aldosteronism and how

While several experts agreed these findings added to an existing and growing literature showing that PA is common and needs greater diagnostic attention, they differed on what this may mean for the specifics of screening and diagnosis, especially at the primary care level.

“Our results showed more explicitly that excess aldosterone exists on a broad severity spectrum and can’t be regarded as a categorical diagnosis that a patient either has or does not have. The hard part is figuring out where we should begin interventions,” said Dr. Vaidya.

In his editorial, Dr. Funder wrote that “much of the present guideline needs to be jettisoned, and radically reconstructed recommendations should be developed.”

One answer may be to apply a less stringent ARR threshold for further work-up. Dr. Stowasser’s program in Brisbane, as well as some other groups worldwide, use an ARR of at least 20 ng/dL as an indication of possible PA. “If you lower the cutoff to 20 [ng/dL], and ignore the plasma aldosterone level, then the ARR should pick up the great majority of patients with PA,” he said.

Another controversial aspect is whether aldosterone detection should be screened by 24-hour urine collection or by spot testing. In his editorial, Dr. Funder called spot testing “useless” and “misleading,” but Dr. Vaidya acknowledged that the 24-hour collection used in his current study is “not practical” for widespread use. Despite that, the Mayo Clinic in Rochester has focused on 24-hour urine collected “for more than 4 decades,” said Dr. Young, even though “a morning blood sample remains a simple screening test” that will catch “more than 95% of patients with PA” when combined with a plasma aldosterone threshold of 10 ng/dL. Dr. Stowasser noted that “patients don’t like” 24-hour collection, and not infrequently muck up collection” by forgetting to collect their entire 1-day output. Regardless of its shortcomings, 24-hour urine has the advantage of greater precision and accuracy than spot measurement, and using it on newly diagnosed hypertensive patients who also show renin suppression may be a viable approach, Dr. Carey suggested.

Regardless of exactly how guidelines for assessing aldosterone in hypertensive patients change, prospects seem ripe for some sort of revision and for greater participation and buy-in by primary care physicians than in the past. Dr. Carey, who also served as vice-chair of the American College of Cardiology and American Heart Association Task Force that wrote the most current U.S. guideline for managing hypertension, said it was too soon to revise that document, but the time had come to revise the Endocrine Society’s 2016 guideline for diagnosing and treating PA and to hash out the revision “in partnership” with one or more primary care societies. He also highlighted that publishing the current study in a high-profile primary care journal was an intentional effort to reach a large segment of the primary care community.

The new report “has the potential to change the current state of inertia” over wider PA diagnosis and targeted treatment “by being published in a widely read, major international journal,” commented Dr. Stowasser.

Dr. Vaidya has been a consultant to Catalys Pacific, Corcept Therapeutics, HRA Pharma, Orphagen, and Selenity Therapeutics. None of the other report coauthors had commercial disclosures, including Dr. Carey. Dr. Funder, Dr. Stowasser, and Dr. Young had no disclosures.

mzoler@mdedge.com

SOURCE: Brown JM et al. Ann Int Med. 2020 May 25. doi: 10.7326/M20-0065.
 

Roughly 16%-22% of patients with hypertension appeared to have primary aldosteronism as the likely major cause of their elevated blood pressure, in an analysis of about 1,000 Americans, which is a much higher prevalence than previously appreciated and a finding that could potentially reorient both screening for aldosteronism and management for this subset of patients.

“Our findings show a high prevalence of unrecognized yet biochemically overt primary aldosteronism [PA] using current confirmatory diagnostic thresholds. They highlight the inadequacy of the current diagnostic approach that heavily relies on the ARR [aldosterone renin ratio] and, most important, show the existence of a pathologic continuum of nonsuppressible renin-independent aldosterone production that parallels the severity of hypertension,” wrote Jennifer M. Brown, MD, and coinvestigators in a report published in Annals of Internal Medicine on May 25. “These findings support the need to redefine primary aldosteronism from a rare and categorical disease to, instead, a common syndrome that manifests across a broad severity spectrum and may be a primary contributor to hypertension pathogenesis,” they wrote in the report.

The results, showing an underappreciated prevalence of both overt and subtler forms of aldosteronism that link with hypertension, won praise from several experts for the potential of these findings to boost the profile of excess aldosterone as a common and treatable cause of high blood pressure, but opinions on the role for the ARR as a screen to identify affected patients were more mixed.

“ARR is still the best screening approach we have” for identifying people who likely have PA, especially when the ratio threshold for finding patients who need further investigation is reduced from the traditional level of 30 ng/dL to 20 ng/dL, commented Michael Stowasser, MBBS, professor of medicine at the University of Queensland in Brisbane, Australia, and director of the Endocrine Hypertension Research Centre at Greenslopes and Princess Alexandra Hospitals in Brisbane. “I strongly recommend ARR testing in all newly diagnosed hypertensives.”

The study results “showed that PA is much more common than previously perceived, and suggest that perhaps PA in milder forms than we typically recognize contributes more to ‘essential’ hypertension than we previously thought,” said Anand Vaidya, MD, senior author of the report and director of the Center for Adrenal Disorders at Brigham and Women’s Hospital in Boston. The researchers found adjusted PA prevalence rates of 16% among 115 untreated patients with stage 1 hypertension (130-139/80-89 mm Hg), 22% among 203 patients with untreated stage 2 hypertension (at least 140/90 mm Hg), and 22% among 408 patients with treatment-resistant hypertension. All three prevalence rates were based on relatively conservative criteria that included all 726 patients with hypertension in the analysis (which also included 289 normotensive subjects) regardless of whether or not they also had low levels of serum renin. These PA prevalence rates were also based on a “conservative” definition of PA, a level of at least 12 mcg excreted in a 24-hour urine specimen.

When the researchers applied less stringent diagnostic criteria for PA or focused on the types of patients usually at highest risk for PA because of a suppressed renin level, the prevalence rates rose substantially and, in some subgroups, more than doubled. Of the 726 people with hypertension included in the analysis, 452 (62%) had suppressed renin (seated plasma renin activity < 1.0 mcg/L per hour or supine plasma renin activity < 0.6 mcg/L per hour). Within this subgroup of patients with suppressed renin, the adjusted prevalence of PA by the threshold of 24-hour urine aldosterone secretion of at least 12 mcg was 52% in those with treatment-resistant hypertension; among patients with stage 1 or 2 hypertension the adjusted prevalence rates were just slightly above the rates in the entire study group. But among patients with suppressed renin who were judged to have PA by a more liberal definition of at least 10 mcg in a 24-hour urine sample, the adjusted prevalence rates were 27% among untreated stage 1 hypertensives, 40% among untreated stage 2 patients, and 58% among treatment-resistant patients, the report showed.
 

A role for subtler forms of aldosteronism

Defining PA as at least 12 mcg secreted in a 24-hour urine collection “is relatively arbitrary, and our findings show that it bisects a continuous distribution. How we should redefine PA is also arbitrary, but step one is to recognize that many people have milder forms of PA” that could have an important effect on blood pressure, Dr. Vaidya said in an interview.

“This is the very first study to show that aldosterone may be contributing to the hypertensive process even though it is not severe enough to be diagnosed as PA according to current criteria,” said Robert M. Carey, MD, a cardiovascular endocrinologist and professor of medicine at the University of Virginia in Charlottesville and a coauthor on the new report. “More patients than we have ever known have an aldosterone component to their hypertension,” Dr. Carey said in an interview.

The new report on the prevalence of unrecognized PA in hypertensive patients “is a game changer,” wrote John W. Funder, MD, professor of medicine at Monash University in Clayton, Australia, in an editorial published along with the new report. In the editorial, he synthesized the new findings with results from prior reports to estimate that excess aldosteronism could play a clinically meaningful role in close to half of patients with hypertension, although Dr. Stowasser called this an “overestimate.” The new results also showed that “the single spot measurement of plasma aldosterone concentration, which clinicians have used for decades to screen for primary aldosteronism, is not merely useless but actually misleading. The authors cautioned readers about the uncertain representativeness of the study population to the U.S. population, but I believe that the findings are generalizable to the United States and elsewhere,” Dr. Funder wrote. “The central problem is that plasma aldosterone concentration is a very poor index of total daily aldosterone secretion. A single morning spot measurement of plasma aldosterone cannot take into account ultradian variation in aldosterone secretion.”
 

The importance of finding excess aldosterone

Identifying patients with hypertension and PA, as well as hypertensives with excess aldosterone production that may not meet the traditional definition of PA, is especially important because they are excellent candidates for two forms of targeted and very effective treatments that have a reliable and substantial impact on lowering blood pressure in these patients. One treatment is unilateral adrenal gland removal in patients who produce excess aldosterone because of benign adenomas in one adrenal gland, which accounts for “approximately 30%” of patients with PA. “Patients with suspected PA should have an opportunity to find out whether they have a unilateral variety and chance for surgical cure,” said Dr. Stowasser in an interview. “Patients with PA do far better in terms of blood pressure control, prevention of cardiovascular complications, and quality of life if they are treated specifically, either medically or particularly by surgery.”

The specific medical treatment he cited refers to one of the mineralocorticoid receptor antagonist (MRA) drugs, spironolactone and eplerenone (Inspra), because mineralocorticoid receptor blockade directly short-circuits the path by which aldosterone increases blood pressure. “We’re advocating earlier use of MRAs” for hypertensive patients identified with excess aldosterone production, said Dr. Carey. He noted that alternative, nonsteroidal MRAs, such as finerenone, have shown promise for efficacy levels similar to what spironolactone provides but without as many adverse effects because of greater receptor specificity. Finerenone and other nonsteroidal MRAs are all currently investigational. Spironolactone and eplerenone both cause hyperkalemia, although treatment with potassium binding agents can blunt the risk this poses. Spironolactone also causes bothersome adverse effects in men, including impotence and gynecomastia because of its action on androgen receptors, effects that diminished with eplerenone, but eplerenone is not as effective as spironolactone, Dr. Carey said.
 

Study details

The new study ran a post hoc analysis on data collected in five independent studies run at centers in four U.S. locations: Birmingham, Ala.; Boston; Charlottesville, Va.; and Salt Lake City. The studies included a total of 1,846 adults, mostly patients with hypertension of varying severity but also several hundred normotensive people. Data on 24-hour sodium excretion during an oral sodium suppression test were available for all participants, and the researchers excluded 831 people with an “inadequate” sodium balance of less than 190 mmol based on this metric, leaving a study population of 1,015. The researchers acknowledged the limitation that the study participants were not representative of the U.S. population.

The analysis included 289 normotensive people not on any blood pressure–lowering medications, and 239 fit the definition of having suppressed renin. The adjusted prevalence of aldosteronism at the level of at least 12 mcg excreted in a 24-hour urine specimen was 11% among all 289 normotensive subjects and 12% among the 239 with suppressed renin. When the definition of aldosteronism loosened to at least 10 mcg excreted during 24 hours the adjusted prevalence of excess aldosterone among normotensives increased to 19% among the entire group and 20% among those with suppressed renin. This finding may have identified a primordial phase of nascent hypertension that needs further study but may eventually provide a new scenario for intervention. “If a normotensive person has compliant arteries and healthy kidneys they can handle the excess salt and volume load of PA,” but when compensatory mechanisms start falling short through aging or other deteriorations, then blood pressure starts to rise, suggested Dr. Vaidya.
 

Whom to screen for aldosteronism and how

While several experts agreed these findings added to an existing and growing literature showing that PA is common and needs greater diagnostic attention, they differed on what this may mean for the specifics of screening and diagnosis, especially at the primary care level.

“Our results showed more explicitly that excess aldosterone exists on a broad severity spectrum and can’t be regarded as a categorical diagnosis that a patient either has or does not have. The hard part is figuring out where we should begin interventions,” said Dr. Vaidya.

In his editorial, Dr. Funder wrote that “much of the present guideline needs to be jettisoned, and radically reconstructed recommendations should be developed.”

One answer may be to apply a less stringent ARR threshold for further work-up. Dr. Stowasser’s program in Brisbane, as well as some other groups worldwide, use an ARR of at least 20 ng/dL as an indication of possible PA. “If you lower the cutoff to 20 [ng/dL], and ignore the plasma aldosterone level, then the ARR should pick up the great majority of patients with PA,” he said.

Another controversial aspect is whether aldosterone detection should be screened by 24-hour urine collection or by spot testing. In his editorial, Dr. Funder called spot testing “useless” and “misleading,” but Dr. Vaidya acknowledged that the 24-hour collection used in his current study is “not practical” for widespread use. Despite that, the Mayo Clinic in Rochester has focused on 24-hour urine collected “for more than 4 decades,” said Dr. Young, even though “a morning blood sample remains a simple screening test” that will catch “more than 95% of patients with PA” when combined with a plasma aldosterone threshold of 10 ng/dL. Dr. Stowasser noted that “patients don’t like” 24-hour collection, and not infrequently muck up collection” by forgetting to collect their entire 1-day output. Regardless of its shortcomings, 24-hour urine has the advantage of greater precision and accuracy than spot measurement, and using it on newly diagnosed hypertensive patients who also show renin suppression may be a viable approach, Dr. Carey suggested.

Regardless of exactly how guidelines for assessing aldosterone in hypertensive patients change, prospects seem ripe for some sort of revision and for greater participation and buy-in by primary care physicians than in the past. Dr. Carey, who also served as vice-chair of the American College of Cardiology and American Heart Association Task Force that wrote the most current U.S. guideline for managing hypertension, said it was too soon to revise that document, but the time had come to revise the Endocrine Society’s 2016 guideline for diagnosing and treating PA and to hash out the revision “in partnership” with one or more primary care societies. He also highlighted that publishing the current study in a high-profile primary care journal was an intentional effort to reach a large segment of the primary care community.

The new report “has the potential to change the current state of inertia” over wider PA diagnosis and targeted treatment “by being published in a widely read, major international journal,” commented Dr. Stowasser.

Dr. Vaidya has been a consultant to Catalys Pacific, Corcept Therapeutics, HRA Pharma, Orphagen, and Selenity Therapeutics. None of the other report coauthors had commercial disclosures, including Dr. Carey. Dr. Funder, Dr. Stowasser, and Dr. Young had no disclosures.

mzoler@mdedge.com

SOURCE: Brown JM et al. Ann Int Med. 2020 May 25. doi: 10.7326/M20-0065.
 

Social isolation is associated with an increased risk of a cardiovascular event of more than 40%, and of all-cause mortality approaching 50%, new research suggests. “These results are especially important in the current times of social isolation during the coronavirus crisis,” Janine Gronewold, PhD, University Hospital in Essen, Germany, told a press briefing.

The mechanism by which social isolation may boost risk for stroke, MI, or death is not clear, but other research has shown that loneliness or lack of contact with close friends and family can affect physical health, said Dr. Gronewold.

The findings were presented at the sixth Congress of the European Academy of Neurology (EAN) 2020, which transitioned to a virtual/online meeting because of the COVID-19 pandemic.

For this new study, researchers analyzed data from 4,139 participants, ranging in age from 45 to 75 years (mean 59.1 years), who were recruited into the large community-based Heinz Nixdorf Recall study. The randomly selected study group was representative of an industrial rural area of Germany, said Dr. Gronewold.

Study participants entered the study with no known cardiovascular disease and were followed for a mean of 13.4 years.
 

Social supports

Investigators collected information on three types of social support: instrumental (getting help with everyday activities such as buying food), emotional (provided with comfort), and financial (receiving monetary assistance when needed). They also looked at social integration (or social isolation) using an index with scores for marital status, number of contacts with family and friends, and membership in political, religious, community, sports, or professional associations.

Of the total, 501 participants reported a lack of instrumental support, 659 a lack of emotional support, and 907 a lack of financial support. A total of 309 lacked social integration, defined by the lowest level on the social integration index.

Participants were asked annually about new cardiovascular events, including stroke and MI. Over the follow-up period, there were 339 such events and 530 deaths.

After adjustment for age, sex, and social support, the analysis showed that social isolation was significantly associated with an increased risk of cardiovascular events (hazard ratio, 1.44; 95% confidence interval, 0.97-2.14) and all-cause mortality (HR, 1.47; 95% CI, 1.09-1.97).

The new research also showed that lack of financial support was significantly associated with increased risk for a cardiovascular event (HR, 1.30; 95% CI, 1.01-1.67).
 

Direct effect

Additional models that also adjusted for cardiovascular risk factors, health behaviors, depression, and socioeconomic factors, did not significantly change effect estimates.

“Social relationships protect us from cardiovascular events and mortality, not only via good mood, healthy behavior, and lower cardiovascular risk profile,” Dr. Gronewold said. “They seem to have a direct effect on these outcomes.”

Having strong social relationships is as important to cardiovascular health as classic protective factors such as controlling blood pressure and cholesterol levels, and maintaining a normal weight, said Dr. Gronewold.

The new results are worrying and are particularly important during the current COVID-19 pandemic, as social contact has been restricted in many areas, said Dr. Gronewold.

It is not yet clear why people who are socially isolated have such poor health outcomes, she added.

Dr. Gronewold has reported no relevant financial relationships.

This article first appeared on Medscape.com.

Social isolation is associated with an increased risk of a cardiovascular event of more than 40%, and of all-cause mortality approaching 50%, new research suggests. “These results are especially important in the current times of social isolation during the coronavirus crisis,” Janine Gronewold, PhD, University Hospital in Essen, Germany, told a press briefing.

The mechanism by which social isolation may boost risk for stroke, MI, or death is not clear, but other research has shown that loneliness or lack of contact with close friends and family can affect physical health, said Dr. Gronewold.

The findings were presented at the sixth Congress of the European Academy of Neurology (EAN) 2020, which transitioned to a virtual/online meeting because of the COVID-19 pandemic.

For this new study, researchers analyzed data from 4,139 participants, ranging in age from 45 to 75 years (mean 59.1 years), who were recruited into the large community-based Heinz Nixdorf Recall study. The randomly selected study group was representative of an industrial rural area of Germany, said Dr. Gronewold.

Study participants entered the study with no known cardiovascular disease and were followed for a mean of 13.4 years.
 

Social supports

Investigators collected information on three types of social support: instrumental (getting help with everyday activities such as buying food), emotional (provided with comfort), and financial (receiving monetary assistance when needed). They also looked at social integration (or social isolation) using an index with scores for marital status, number of contacts with family and friends, and membership in political, religious, community, sports, or professional associations.

Of the total, 501 participants reported a lack of instrumental support, 659 a lack of emotional support, and 907 a lack of financial support. A total of 309 lacked social integration, defined by the lowest level on the social integration index.

Participants were asked annually about new cardiovascular events, including stroke and MI. Over the follow-up period, there were 339 such events and 530 deaths.

After adjustment for age, sex, and social support, the analysis showed that social isolation was significantly associated with an increased risk of cardiovascular events (hazard ratio, 1.44; 95% confidence interval, 0.97-2.14) and all-cause mortality (HR, 1.47; 95% CI, 1.09-1.97).

The new research also showed that lack of financial support was significantly associated with increased risk for a cardiovascular event (HR, 1.30; 95% CI, 1.01-1.67).
 

Direct effect

Additional models that also adjusted for cardiovascular risk factors, health behaviors, depression, and socioeconomic factors, did not significantly change effect estimates.

“Social relationships protect us from cardiovascular events and mortality, not only via good mood, healthy behavior, and lower cardiovascular risk profile,” Dr. Gronewold said. “They seem to have a direct effect on these outcomes.”

Having strong social relationships is as important to cardiovascular health as classic protective factors such as controlling blood pressure and cholesterol levels, and maintaining a normal weight, said Dr. Gronewold.

The new results are worrying and are particularly important during the current COVID-19 pandemic, as social contact has been restricted in many areas, said Dr. Gronewold.

It is not yet clear why people who are socially isolated have such poor health outcomes, she added.

Dr. Gronewold has reported no relevant financial relationships.

This article first appeared on Medscape.com.

Social isolation is associated with an increased risk of a cardiovascular event of more than 40%, and of all-cause mortality approaching 50%, new research suggests. “These results are especially important in the current times of social isolation during the coronavirus crisis,” Janine Gronewold, PhD, University Hospital in Essen, Germany, told a press briefing.

The mechanism by which social isolation may boost risk for stroke, MI, or death is not clear, but other research has shown that loneliness or lack of contact with close friends and family can affect physical health, said Dr. Gronewold.

The findings were presented at the sixth Congress of the European Academy of Neurology (EAN) 2020, which transitioned to a virtual/online meeting because of the COVID-19 pandemic.

For this new study, researchers analyzed data from 4,139 participants, ranging in age from 45 to 75 years (mean 59.1 years), who were recruited into the large community-based Heinz Nixdorf Recall study. The randomly selected study group was representative of an industrial rural area of Germany, said Dr. Gronewold.

Study participants entered the study with no known cardiovascular disease and were followed for a mean of 13.4 years.
 

Social supports

Investigators collected information on three types of social support: instrumental (getting help with everyday activities such as buying food), emotional (provided with comfort), and financial (receiving monetary assistance when needed). They also looked at social integration (or social isolation) using an index with scores for marital status, number of contacts with family and friends, and membership in political, religious, community, sports, or professional associations.

Of the total, 501 participants reported a lack of instrumental support, 659 a lack of emotional support, and 907 a lack of financial support. A total of 309 lacked social integration, defined by the lowest level on the social integration index.

Participants were asked annually about new cardiovascular events, including stroke and MI. Over the follow-up period, there were 339 such events and 530 deaths.

After adjustment for age, sex, and social support, the analysis showed that social isolation was significantly associated with an increased risk of cardiovascular events (hazard ratio, 1.44; 95% confidence interval, 0.97-2.14) and all-cause mortality (HR, 1.47; 95% CI, 1.09-1.97).

The new research also showed that lack of financial support was significantly associated with increased risk for a cardiovascular event (HR, 1.30; 95% CI, 1.01-1.67).
 

Direct effect

Additional models that also adjusted for cardiovascular risk factors, health behaviors, depression, and socioeconomic factors, did not significantly change effect estimates.

“Social relationships protect us from cardiovascular events and mortality, not only via good mood, healthy behavior, and lower cardiovascular risk profile,” Dr. Gronewold said. “They seem to have a direct effect on these outcomes.”

Having strong social relationships is as important to cardiovascular health as classic protective factors such as controlling blood pressure and cholesterol levels, and maintaining a normal weight, said Dr. Gronewold.

The new results are worrying and are particularly important during the current COVID-19 pandemic, as social contact has been restricted in many areas, said Dr. Gronewold.

It is not yet clear why people who are socially isolated have such poor health outcomes, she added.

Dr. Gronewold has reported no relevant financial relationships.

This article first appeared on Medscape.com.

Hydroxychloroquine and chloroquine, with or without azithromycin or clarithromycin, offer no benefit in treating patients with COVID-19 and, instead, are associated with ventricular arrhythmias and higher rates of mortality, according to a major new international study.

Bruce Jancin/MDedge News

In the largest observational study of its kind, including close to 100,000 people in 671 hospitals on six continents, investigators compared outcomes in 15,000 patients with COVID-19 treated with hydroxychloroquine and chloroquine alone or in combination with a macrolide with 80,000 control patients with COVID-19 not receiving these agents.

Treatment with any of these medications, either alone or in combination, was associated with increased death during hospitalization; compared with about 10% in control group patients, mortality rates ranged from more than 16% to almost 24% in the treated groups.

Patients treated with hydroxychloroquine plus a macrolide showed the highest rates of serious cardiac arrhythmias, and, even after accounting for demographic factors and comorbidities, this combination was found to be associated with a more than 5-fold increase in the risk of developing a serious arrhythmia while in the hospital.

“In this real-world study, the biggest yet, we looked at 100,000 patients [with COVID-19] across six continents and found not the slightest hint of benefits and only risks, and the data is pretty straightforward,” study coauthor Frank Ruschitzka, MD, director of the Heart Center at University Hospital, Zürich, said in an interview. The study was published online May 22 in The Lancet.
 

‘Inconclusive’ evidence

The absence of an effective treatment for COVID-19 has led to the “repurposing” of the antimalarial drug chloroquine and its analogue hydroxychloroquine, which is used for treating autoimmune disease, but this approach is based on anecdotal evidence or open-label randomized trials that have been “largely inconclusive,” the authors wrote.

Additional agents used to treat COVID-19 are second-generation macrolides (azithromycin or clarithromycin), in combination with chloroquine or hydroxychloroquine, “despite limited evidence” and the risk for ventricular arrhythmias, the authors noted.

“Our primary question was whether there was any associated benefits of the use of hydroxychloroquine, chloroquine, or a combined regimen with macrolides in treating COVID-19, and — if there was no benefit — would there be harm?” lead author Mandeep R. Mehra, MD, MSc, William Harvey Distinguished Chair in Advanced Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, said in an interview.

The investigators used data from a multinational registry comprising 671 hospitals that included patients (n = 96,032; mean age 53.8 years; 46.3% female) who had been hospitalized between Dec. 20, 2019, and April 14, 2020, with confirmed COVID-19 infection.

They also collected data about demographics, underlying comorbidities, and medical history, and medications that patients were taking at baseline.

Patients receiving treatment (n = 14,888) were divided into four groups: those receiving chloroquine alone (n = 1,868), those receiving chloroquine with a macrolide (n = 3,783), those receiving hydroxychloroquine alone (n = 3,016) and those receiving hydroxychloroquine with a macrolide (n = 6,221).

The remaining patients not treated with these regimens (n = 81,144) were regarded as the control group.

Most patients (65.9%) came from North America, followed by Europe (17.39%), Asia (7.9%), Africa (4.6%), South America (3.7%), and Australia (0.6%). Most (66.9%) were white, followed by patients of Asian origin (14.1%), black patients (9.4%), and Hispanic patients (6.2%).

Comorbidities and underlying conditions included obesity, hyperlipidemia, and hypertension in about 30%.
 

Comorbidities and underlying conditions

The investigators conducted multiple analyses to control for confounding variables, including Cox proportional hazards regression and propensity score matching analyses.

“In an observational study, there is always a chance of residual confounding, which is why we did propensity score based matched analyses,” Dr. Ruschitzka explained.

No significant differences were found in distribution of demographics and comorbidities between the groups.
 

As good as it gets

“We found no benefit in any of the four treatment regimens for hospitalized patients with COVID-19, but we did notice higher rates of death and serious ventricular arrhythmias in these patients, compared to the controls,” Dr. Mehra reported.

Of the patients in the control group, roughly 9.3% died during their hospitalization, compared with 16.4% of patients treated with chloroquine alone, 18.0% of those treated with hydroxychloroquine alone, 22.2% of those treated with chloroquine and a macrolide, and 23.8% of those treated with hydroxychloroquine and a macrolide.

After accounting for confounding variables, the researchers estimated that the excess mortality risk attributable to use of the drug regimen ranged from 34% to 45%.

Patients treated with any of the four regimens sustained more serious arrhythmias, compared with those in the control group (0.35), with the biggest increase seen in the group treated with the combination of hydroxychloroquine plus a macrolide (8.1%), followed by chloroquine with a macrolide (6.5%), hydroxychloroquine alone (6.1%), and chloroquine alone (4.3%).

“We were fairly reassured that, although the study was observational, the signals were robust and consistent across all regions of the world in diverse populations, and we did not see any muting of that signal, depending on region,” Dr. Mehra said.

“Two months ago, we were all scratching our heads about how to treat patients with COVID-19, and then came a drug [hydroxychloroquine] with some anecdotal evidence, but now we have 2 months more experience, and we looked to science to provide some answer,” Dr. Ruschitzka said.

“Although this was not a randomized, controlled trial, so we do not have a definite answer, the data provided in this [large, multinational] real-world study is as good as it gets and the best data we have,” he concluded.

“Let the science speak for itself”

Commenting on the study in an interview, Christian Funck-Brentano, MD, from the Hospital Pitié-Salpêtrière and Sorbonne University, both in Paris, said that, although the study is observational and therefore not as reliable as a randomized controlled trial, it is “nevertheless well-documented, studied a huge amount of people, and utilized several sensitivity methods, all of which showed the same results.”

Dr. Funck-Brentano, who is the coauthor of an accompanying editorial in The Lancet and was not involved with the study, said that “we now have no evidence that hydroxychloroquine and chloroquine alone or in combination with a macrolide do any good and we have potential evidence that they do harm and kill people.”

Also commenting on the study in an interview, David Holtgrave, PhD, dean of the School of Public Health at the State University of New York at Albany, said that, “while no one observational study alone would lead to a firm clinical recommendation, I think it is helpful for physicians and public health officials to be aware of the findings of the peer-reviewed observational studies to date and the National Institutes of Health COVID-19 treatment guidelines and the Food and Drug Administration’s statement of drug safety concern about hydroxychloroquine to inform their decision-making as we await the results of randomized clinical trials of these drugs for the treatment of COVID-19,” said Dr. Holtgrave, who was not involved with the study.

He added that, to his knowledge, there are “still no published studies of prophylactic use of these drugs to prevent COVID-19.”

Dr. Mehra emphasized that a cardinal principle of practicing medicine is “first do no harm” and “even in situations where you believe a desperate disease calls for desperate measures, responsible physicians should take a step back and ask if we are doing harm, and until we can say we aren’t, I don’t think it’s wise to push something like this in the absence of good efficacy data.”

Dr. Ruschitzka added that those who are encouraging the use of these agents “should review their decision based on today’s data and let the science speak for itself.”

The study was supported by the William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women’s Hospital, Boston. Dr. Mehra reported personal fees from Abbott, Medtronic, Janssen, Mesoblast, Portola, Bayer, Baim Institute for Clinical Research, NuPulseCV, FineHeart, Leviticus, Roivant, and Triple Gene. Dr. Ruschitzka was paid for time spent as a committee member for clinical trials, advisory boards, other forms of consulting, and lectures or presentations; these payments were made directly to the University of Zürich and no personal payments were received in relation to these trials or other activities. Dr. Funck-Brentano, his coauthor, and Dr. Holtgrave declared no relevant financial relationships.

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

Hydroxychloroquine and chloroquine, with or without azithromycin or clarithromycin, offer no benefit in treating patients with COVID-19 and, instead, are associated with ventricular arrhythmias and higher rates of mortality, according to a major new international study.

Bruce Jancin/MDedge News

In the largest observational study of its kind, including close to 100,000 people in 671 hospitals on six continents, investigators compared outcomes in 15,000 patients with COVID-19 treated with hydroxychloroquine and chloroquine alone or in combination with a macrolide with 80,000 control patients with COVID-19 not receiving these agents.

Treatment with any of these medications, either alone or in combination, was associated with increased death during hospitalization; compared with about 10% in control group patients, mortality rates ranged from more than 16% to almost 24% in the treated groups.

Patients treated with hydroxychloroquine plus a macrolide showed the highest rates of serious cardiac arrhythmias, and, even after accounting for demographic factors and comorbidities, this combination was found to be associated with a more than 5-fold increase in the risk of developing a serious arrhythmia while in the hospital.

“In this real-world study, the biggest yet, we looked at 100,000 patients [with COVID-19] across six continents and found not the slightest hint of benefits and only risks, and the data is pretty straightforward,” study coauthor Frank Ruschitzka, MD, director of the Heart Center at University Hospital, Zürich, said in an interview. The study was published online May 22 in The Lancet.
 

‘Inconclusive’ evidence

The absence of an effective treatment for COVID-19 has led to the “repurposing” of the antimalarial drug chloroquine and its analogue hydroxychloroquine, which is used for treating autoimmune disease, but this approach is based on anecdotal evidence or open-label randomized trials that have been “largely inconclusive,” the authors wrote.

Additional agents used to treat COVID-19 are second-generation macrolides (azithromycin or clarithromycin), in combination with chloroquine or hydroxychloroquine, “despite limited evidence” and the risk for ventricular arrhythmias, the authors noted.

“Our primary question was whether there was any associated benefits of the use of hydroxychloroquine, chloroquine, or a combined regimen with macrolides in treating COVID-19, and — if there was no benefit — would there be harm?” lead author Mandeep R. Mehra, MD, MSc, William Harvey Distinguished Chair in Advanced Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, said in an interview.

The investigators used data from a multinational registry comprising 671 hospitals that included patients (n = 96,032; mean age 53.8 years; 46.3% female) who had been hospitalized between Dec. 20, 2019, and April 14, 2020, with confirmed COVID-19 infection.

They also collected data about demographics, underlying comorbidities, and medical history, and medications that patients were taking at baseline.

Patients receiving treatment (n = 14,888) were divided into four groups: those receiving chloroquine alone (n = 1,868), those receiving chloroquine with a macrolide (n = 3,783), those receiving hydroxychloroquine alone (n = 3,016) and those receiving hydroxychloroquine with a macrolide (n = 6,221).

The remaining patients not treated with these regimens (n = 81,144) were regarded as the control group.

Most patients (65.9%) came from North America, followed by Europe (17.39%), Asia (7.9%), Africa (4.6%), South America (3.7%), and Australia (0.6%). Most (66.9%) were white, followed by patients of Asian origin (14.1%), black patients (9.4%), and Hispanic patients (6.2%).

Comorbidities and underlying conditions included obesity, hyperlipidemia, and hypertension in about 30%.
 

Comorbidities and underlying conditions

The investigators conducted multiple analyses to control for confounding variables, including Cox proportional hazards regression and propensity score matching analyses.

“In an observational study, there is always a chance of residual confounding, which is why we did propensity score based matched analyses,” Dr. Ruschitzka explained.

No significant differences were found in distribution of demographics and comorbidities between the groups.
 

As good as it gets

“We found no benefit in any of the four treatment regimens for hospitalized patients with COVID-19, but we did notice higher rates of death and serious ventricular arrhythmias in these patients, compared to the controls,” Dr. Mehra reported.

Of the patients in the control group, roughly 9.3% died during their hospitalization, compared with 16.4% of patients treated with chloroquine alone, 18.0% of those treated with hydroxychloroquine alone, 22.2% of those treated with chloroquine and a macrolide, and 23.8% of those treated with hydroxychloroquine and a macrolide.

After accounting for confounding variables, the researchers estimated that the excess mortality risk attributable to use of the drug regimen ranged from 34% to 45%.

Patients treated with any of the four regimens sustained more serious arrhythmias, compared with those in the control group (0.35), with the biggest increase seen in the group treated with the combination of hydroxychloroquine plus a macrolide (8.1%), followed by chloroquine with a macrolide (6.5%), hydroxychloroquine alone (6.1%), and chloroquine alone (4.3%).

“We were fairly reassured that, although the study was observational, the signals were robust and consistent across all regions of the world in diverse populations, and we did not see any muting of that signal, depending on region,” Dr. Mehra said.

“Two months ago, we were all scratching our heads about how to treat patients with COVID-19, and then came a drug [hydroxychloroquine] with some anecdotal evidence, but now we have 2 months more experience, and we looked to science to provide some answer,” Dr. Ruschitzka said.

“Although this was not a randomized, controlled trial, so we do not have a definite answer, the data provided in this [large, multinational] real-world study is as good as it gets and the best data we have,” he concluded.

“Let the science speak for itself”

Commenting on the study in an interview, Christian Funck-Brentano, MD, from the Hospital Pitié-Salpêtrière and Sorbonne University, both in Paris, said that, although the study is observational and therefore not as reliable as a randomized controlled trial, it is “nevertheless well-documented, studied a huge amount of people, and utilized several sensitivity methods, all of which showed the same results.”

Dr. Funck-Brentano, who is the coauthor of an accompanying editorial in The Lancet and was not involved with the study, said that “we now have no evidence that hydroxychloroquine and chloroquine alone or in combination with a macrolide do any good and we have potential evidence that they do harm and kill people.”

Also commenting on the study in an interview, David Holtgrave, PhD, dean of the School of Public Health at the State University of New York at Albany, said that, “while no one observational study alone would lead to a firm clinical recommendation, I think it is helpful for physicians and public health officials to be aware of the findings of the peer-reviewed observational studies to date and the National Institutes of Health COVID-19 treatment guidelines and the Food and Drug Administration’s statement of drug safety concern about hydroxychloroquine to inform their decision-making as we await the results of randomized clinical trials of these drugs for the treatment of COVID-19,” said Dr. Holtgrave, who was not involved with the study.

He added that, to his knowledge, there are “still no published studies of prophylactic use of these drugs to prevent COVID-19.”

Dr. Mehra emphasized that a cardinal principle of practicing medicine is “first do no harm” and “even in situations where you believe a desperate disease calls for desperate measures, responsible physicians should take a step back and ask if we are doing harm, and until we can say we aren’t, I don’t think it’s wise to push something like this in the absence of good efficacy data.”

Dr. Ruschitzka added that those who are encouraging the use of these agents “should review their decision based on today’s data and let the science speak for itself.”

The study was supported by the William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women’s Hospital, Boston. Dr. Mehra reported personal fees from Abbott, Medtronic, Janssen, Mesoblast, Portola, Bayer, Baim Institute for Clinical Research, NuPulseCV, FineHeart, Leviticus, Roivant, and Triple Gene. Dr. Ruschitzka was paid for time spent as a committee member for clinical trials, advisory boards, other forms of consulting, and lectures or presentations; these payments were made directly to the University of Zürich and no personal payments were received in relation to these trials or other activities. Dr. Funck-Brentano, his coauthor, and Dr. Holtgrave declared no relevant financial relationships.

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

Hydroxychloroquine and chloroquine, with or without azithromycin or clarithromycin, offer no benefit in treating patients with COVID-19 and, instead, are associated with ventricular arrhythmias and higher rates of mortality, according to a major new international study.

Bruce Jancin/MDedge News

In the largest observational study of its kind, including close to 100,000 people in 671 hospitals on six continents, investigators compared outcomes in 15,000 patients with COVID-19 treated with hydroxychloroquine and chloroquine alone or in combination with a macrolide with 80,000 control patients with COVID-19 not receiving these agents.

Treatment with any of these medications, either alone or in combination, was associated with increased death during hospitalization; compared with about 10% in control group patients, mortality rates ranged from more than 16% to almost 24% in the treated groups.

Patients treated with hydroxychloroquine plus a macrolide showed the highest rates of serious cardiac arrhythmias, and, even after accounting for demographic factors and comorbidities, this combination was found to be associated with a more than 5-fold increase in the risk of developing a serious arrhythmia while in the hospital.

“In this real-world study, the biggest yet, we looked at 100,000 patients [with COVID-19] across six continents and found not the slightest hint of benefits and only risks, and the data is pretty straightforward,” study coauthor Frank Ruschitzka, MD, director of the Heart Center at University Hospital, Zürich, said in an interview. The study was published online May 22 in The Lancet.
 

‘Inconclusive’ evidence

The absence of an effective treatment for COVID-19 has led to the “repurposing” of the antimalarial drug chloroquine and its analogue hydroxychloroquine, which is used for treating autoimmune disease, but this approach is based on anecdotal evidence or open-label randomized trials that have been “largely inconclusive,” the authors wrote.

Additional agents used to treat COVID-19 are second-generation macrolides (azithromycin or clarithromycin), in combination with chloroquine or hydroxychloroquine, “despite limited evidence” and the risk for ventricular arrhythmias, the authors noted.

“Our primary question was whether there was any associated benefits of the use of hydroxychloroquine, chloroquine, or a combined regimen with macrolides in treating COVID-19, and — if there was no benefit — would there be harm?” lead author Mandeep R. Mehra, MD, MSc, William Harvey Distinguished Chair in Advanced Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, said in an interview.

The investigators used data from a multinational registry comprising 671 hospitals that included patients (n = 96,032; mean age 53.8 years; 46.3% female) who had been hospitalized between Dec. 20, 2019, and April 14, 2020, with confirmed COVID-19 infection.

They also collected data about demographics, underlying comorbidities, and medical history, and medications that patients were taking at baseline.

Patients receiving treatment (n = 14,888) were divided into four groups: those receiving chloroquine alone (n = 1,868), those receiving chloroquine with a macrolide (n = 3,783), those receiving hydroxychloroquine alone (n = 3,016) and those receiving hydroxychloroquine with a macrolide (n = 6,221).

The remaining patients not treated with these regimens (n = 81,144) were regarded as the control group.

Most patients (65.9%) came from North America, followed by Europe (17.39%), Asia (7.9%), Africa (4.6%), South America (3.7%), and Australia (0.6%). Most (66.9%) were white, followed by patients of Asian origin (14.1%), black patients (9.4%), and Hispanic patients (6.2%).

Comorbidities and underlying conditions included obesity, hyperlipidemia, and hypertension in about 30%.
 

Comorbidities and underlying conditions

The investigators conducted multiple analyses to control for confounding variables, including Cox proportional hazards regression and propensity score matching analyses.

“In an observational study, there is always a chance of residual confounding, which is why we did propensity score based matched analyses,” Dr. Ruschitzka explained.

No significant differences were found in distribution of demographics and comorbidities between the groups.
 

As good as it gets

“We found no benefit in any of the four treatment regimens for hospitalized patients with COVID-19, but we did notice higher rates of death and serious ventricular arrhythmias in these patients, compared to the controls,” Dr. Mehra reported.

Of the patients in the control group, roughly 9.3% died during their hospitalization, compared with 16.4% of patients treated with chloroquine alone, 18.0% of those treated with hydroxychloroquine alone, 22.2% of those treated with chloroquine and a macrolide, and 23.8% of those treated with hydroxychloroquine and a macrolide.

After accounting for confounding variables, the researchers estimated that the excess mortality risk attributable to use of the drug regimen ranged from 34% to 45%.

Patients treated with any of the four regimens sustained more serious arrhythmias, compared with those in the control group (0.35), with the biggest increase seen in the group treated with the combination of hydroxychloroquine plus a macrolide (8.1%), followed by chloroquine with a macrolide (6.5%), hydroxychloroquine alone (6.1%), and chloroquine alone (4.3%).

“We were fairly reassured that, although the study was observational, the signals were robust and consistent across all regions of the world in diverse populations, and we did not see any muting of that signal, depending on region,” Dr. Mehra said.

“Two months ago, we were all scratching our heads about how to treat patients with COVID-19, and then came a drug [hydroxychloroquine] with some anecdotal evidence, but now we have 2 months more experience, and we looked to science to provide some answer,” Dr. Ruschitzka said.

“Although this was not a randomized, controlled trial, so we do not have a definite answer, the data provided in this [large, multinational] real-world study is as good as it gets and the best data we have,” he concluded.

“Let the science speak for itself”

Commenting on the study in an interview, Christian Funck-Brentano, MD, from the Hospital Pitié-Salpêtrière and Sorbonne University, both in Paris, said that, although the study is observational and therefore not as reliable as a randomized controlled trial, it is “nevertheless well-documented, studied a huge amount of people, and utilized several sensitivity methods, all of which showed the same results.”

Dr. Funck-Brentano, who is the coauthor of an accompanying editorial in The Lancet and was not involved with the study, said that “we now have no evidence that hydroxychloroquine and chloroquine alone or in combination with a macrolide do any good and we have potential evidence that they do harm and kill people.”

Also commenting on the study in an interview, David Holtgrave, PhD, dean of the School of Public Health at the State University of New York at Albany, said that, “while no one observational study alone would lead to a firm clinical recommendation, I think it is helpful for physicians and public health officials to be aware of the findings of the peer-reviewed observational studies to date and the National Institutes of Health COVID-19 treatment guidelines and the Food and Drug Administration’s statement of drug safety concern about hydroxychloroquine to inform their decision-making as we await the results of randomized clinical trials of these drugs for the treatment of COVID-19,” said Dr. Holtgrave, who was not involved with the study.

He added that, to his knowledge, there are “still no published studies of prophylactic use of these drugs to prevent COVID-19.”

Dr. Mehra emphasized that a cardinal principle of practicing medicine is “first do no harm” and “even in situations where you believe a desperate disease calls for desperate measures, responsible physicians should take a step back and ask if we are doing harm, and until we can say we aren’t, I don’t think it’s wise to push something like this in the absence of good efficacy data.”

Dr. Ruschitzka added that those who are encouraging the use of these agents “should review their decision based on today’s data and let the science speak for itself.”

The study was supported by the William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women’s Hospital, Boston. Dr. Mehra reported personal fees from Abbott, Medtronic, Janssen, Mesoblast, Portola, Bayer, Baim Institute for Clinical Research, NuPulseCV, FineHeart, Leviticus, Roivant, and Triple Gene. Dr. Ruschitzka was paid for time spent as a committee member for clinical trials, advisory boards, other forms of consulting, and lectures or presentations; these payments were made directly to the University of Zürich and no personal payments were received in relation to these trials or other activities. Dr. Funck-Brentano, his coauthor, and Dr. Holtgrave declared no relevant financial relationships.

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

According to study of a cluster of patients in France and Switzerland, children may experience an acute cardiac decompensation from the severe inflammatory state following SARS-CoV-2 infection, termed multisystem inflammatory syndrome in children (MIS-C). Treatment with immunoglobulin appears to be associated with recovery of left ventricular systolic function.

“The pediatric and cardiology communities should be acutely aware of this new disease probably related to SARS-CoV-2 infection (MIS-C), that shares similarities with Kawasaki disease but has specificities in its presentation,” researchers led by Zahra Belhadjer, MD, of Necker-Enfants Malades Hospital in Paris, wrote in a cases series report published online in Circulation “Early diagnosis and management appear to lead to favorable outcome using classical therapies. Elucidating the immune mechanisms of this disease will afford further insights for treatment and potential global prevention of severe forms.”

Over a 2-month period that coincided with the SARS-CoV-2 pandemic in France and Switzerland, the researchers retrospectively collected clinical, biological, therapeutic, and early-outcomes data in 35 children who were admitted to pediatric ICUs in 14 centers for cardiogenic shock, left ventricular dysfunction, and severe inflammatory state. Their median age was 10 years, all presented with a fever, 80% had gastrointestinal symptoms of abdominal pain, vomiting, or diarrhea, and 28% had comorbidities that included body mass index of greater than 25 kg/m² (17%), asthma (9%), and lupus (3%), and overweight. Only 17% presented with chest pain. The researchers observed that left ventricular ejection fraction was less than 30% in 28% of patients, and 80% required inotropic support with 28% treated with extracorporeal membrane oxygenation (ECMO). All patients presented with a severe inflammatory state evidenced by elevated C-reactive protein and d-dimer. Interleukin 6 was elevated to a median of 135 pg/mL in 13 of the patients. Elevation of troponin I was constant but mild to moderate, and NT-proBNP or BNP elevation was present in all children.

Nearly all patients 35 (88%) patients tested positive for SARS-CoV-2 infection by polymerase chain reaction of nasopharyngeal swab or serology. Most patients (80%) received IV inotropic support, 71% received first-line IV immunoglobulin, 65% received anticoagulation with heparin, 34% received IV steroids having been considered high-risk patients with symptoms similar to an incomplete form of Kawasaki disease, and 8% received treatment with an interleukin-1 receptor antagonist because of a persistent severe inflammatory state. Left ventricular function was restored in 71% of those discharged from the intensive care unit. No patient died, and all patients treated with ECMO were successfully weaned after a median of 4.5 days.

“Some aspects of this emerging pediatric disease (MIS-C) are similar to those of Kawasaki disease: prolonged fever, multisystem inflammation with skin rash, lymphadenopathy, diarrhea, meningism, and high levels of inflammatory biomarkers,” the researchers wrote. “But differences are important and raise the question as to whether this syndrome is Kawasaki disease with SARS-CoV-2 as the triggering agent, or represents a different syndrome (MIS-C). Kawasaki disease predominantly affects young children younger than 5 years, whereas the median age in our series is 10 years. Incomplete forms of Kawasaki disease occur in infants who may have fever as the sole clinical finding, whereas older patients are more prone to exhibit the complete form.”

They went on to note that the overlapping features between MIS-C and Kawasaki disease “may be due to similar pathophysiology. The etiologic agent of Kawasaki disease is unknown but likely to be ubiquitous, causing asymptomatic childhood infection but triggering the immunologic cascade of Kawasaki disease in genetically susceptible individuals. Please note that infection with a novel RNA virus that enters through the upper respiratory tract has been proposed to be the cause of the disease (see PLoS One. 2008 Feb 13;3:e1582 and J Infect Dis. 2011 Apr 1;203:1021-30).”

Based on the work of authors, it appears that a high index of suspicion for MIS-C is important for children who develop Kawasaki-like symptoms, David J. Goldberg, MD, said in an interview. “Although children have largely been spared from the acute respiratory presentation of the SARS-CoV-2 pandemic, the recognition and understanding of what appears to be a postviral inflammatory response is a critical first step in developing treatment algorithms for this disease process,” said Dr. Goldberg, a board-certified attending cardiologist in the cardiac center and fetal heart program at Children’s Hospital of Philadelphia. “If inflammatory markers are elevated, particularly if there are accompanying gastrointestinal symptoms, the possibility of cardiac involvement suggests the utility of screening echocardiography. Given the potential need for inotropic or mechanical circulatory support, the presence of myocardial dysfunction dictates care in an intensive care unit capable of providing advanced therapies. While the evidence from Dr. Belhadjer’s cohort suggests that full recovery is probable, there is still much to be learned about this unique inflammatory syndrome and the alarm has rightly been sounded.”

The researchers and Dr. Goldberg reported having no disclosures.

dbrunk@mdedge.com

SOURCE: Belhadjer Z et al. Circulation 2020 May 17; doi: 10.1161/circulationaha.120.048360.

According to study of a cluster of patients in France and Switzerland, children may experience an acute cardiac decompensation from the severe inflammatory state following SARS-CoV-2 infection, termed multisystem inflammatory syndrome in children (MIS-C). Treatment with immunoglobulin appears to be associated with recovery of left ventricular systolic function.

“The pediatric and cardiology communities should be acutely aware of this new disease probably related to SARS-CoV-2 infection (MIS-C), that shares similarities with Kawasaki disease but has specificities in its presentation,” researchers led by Zahra Belhadjer, MD, of Necker-Enfants Malades Hospital in Paris, wrote in a cases series report published online in Circulation “Early diagnosis and management appear to lead to favorable outcome using classical therapies. Elucidating the immune mechanisms of this disease will afford further insights for treatment and potential global prevention of severe forms.”

Over a 2-month period that coincided with the SARS-CoV-2 pandemic in France and Switzerland, the researchers retrospectively collected clinical, biological, therapeutic, and early-outcomes data in 35 children who were admitted to pediatric ICUs in 14 centers for cardiogenic shock, left ventricular dysfunction, and severe inflammatory state. Their median age was 10 years, all presented with a fever, 80% had gastrointestinal symptoms of abdominal pain, vomiting, or diarrhea, and 28% had comorbidities that included body mass index of greater than 25 kg/m² (17%), asthma (9%), and lupus (3%), and overweight. Only 17% presented with chest pain. The researchers observed that left ventricular ejection fraction was less than 30% in 28% of patients, and 80% required inotropic support with 28% treated with extracorporeal membrane oxygenation (ECMO). All patients presented with a severe inflammatory state evidenced by elevated C-reactive protein and d-dimer. Interleukin 6 was elevated to a median of 135 pg/mL in 13 of the patients. Elevation of troponin I was constant but mild to moderate, and NT-proBNP or BNP elevation was present in all children.

Nearly all patients 35 (88%) patients tested positive for SARS-CoV-2 infection by polymerase chain reaction of nasopharyngeal swab or serology. Most patients (80%) received IV inotropic support, 71% received first-line IV immunoglobulin, 65% received anticoagulation with heparin, 34% received IV steroids having been considered high-risk patients with symptoms similar to an incomplete form of Kawasaki disease, and 8% received treatment with an interleukin-1 receptor antagonist because of a persistent severe inflammatory state. Left ventricular function was restored in 71% of those discharged from the intensive care unit. No patient died, and all patients treated with ECMO were successfully weaned after a median of 4.5 days.

“Some aspects of this emerging pediatric disease (MIS-C) are similar to those of Kawasaki disease: prolonged fever, multisystem inflammation with skin rash, lymphadenopathy, diarrhea, meningism, and high levels of inflammatory biomarkers,” the researchers wrote. “But differences are important and raise the question as to whether this syndrome is Kawasaki disease with SARS-CoV-2 as the triggering agent, or represents a different syndrome (MIS-C). Kawasaki disease predominantly affects young children younger than 5 years, whereas the median age in our series is 10 years. Incomplete forms of Kawasaki disease occur in infants who may have fever as the sole clinical finding, whereas older patients are more prone to exhibit the complete form.”

They went on to note that the overlapping features between MIS-C and Kawasaki disease “may be due to similar pathophysiology. The etiologic agent of Kawasaki disease is unknown but likely to be ubiquitous, causing asymptomatic childhood infection but triggering the immunologic cascade of Kawasaki disease in genetically susceptible individuals. Please note that infection with a novel RNA virus that enters through the upper respiratory tract has been proposed to be the cause of the disease (see PLoS One. 2008 Feb 13;3:e1582 and J Infect Dis. 2011 Apr 1;203:1021-30).”

Based on the work of authors, it appears that a high index of suspicion for MIS-C is important for children who develop Kawasaki-like symptoms, David J. Goldberg, MD, said in an interview. “Although children have largely been spared from the acute respiratory presentation of the SARS-CoV-2 pandemic, the recognition and understanding of what appears to be a postviral inflammatory response is a critical first step in developing treatment algorithms for this disease process,” said Dr. Goldberg, a board-certified attending cardiologist in the cardiac center and fetal heart program at Children’s Hospital of Philadelphia. “If inflammatory markers are elevated, particularly if there are accompanying gastrointestinal symptoms, the possibility of cardiac involvement suggests the utility of screening echocardiography. Given the potential need for inotropic or mechanical circulatory support, the presence of myocardial dysfunction dictates care in an intensive care unit capable of providing advanced therapies. While the evidence from Dr. Belhadjer’s cohort suggests that full recovery is probable, there is still much to be learned about this unique inflammatory syndrome and the alarm has rightly been sounded.”

The researchers and Dr. Goldberg reported having no disclosures.

dbrunk@mdedge.com

SOURCE: Belhadjer Z et al. Circulation 2020 May 17; doi: 10.1161/circulationaha.120.048360.

According to study of a cluster of patients in France and Switzerland, children may experience an acute cardiac decompensation from the severe inflammatory state following SARS-CoV-2 infection, termed multisystem inflammatory syndrome in children (MIS-C). Treatment with immunoglobulin appears to be associated with recovery of left ventricular systolic function.

“The pediatric and cardiology communities should be acutely aware of this new disease probably related to SARS-CoV-2 infection (MIS-C), that shares similarities with Kawasaki disease but has specificities in its presentation,” researchers led by Zahra Belhadjer, MD, of Necker-Enfants Malades Hospital in Paris, wrote in a cases series report published online in Circulation “Early diagnosis and management appear to lead to favorable outcome using classical therapies. Elucidating the immune mechanisms of this disease will afford further insights for treatment and potential global prevention of severe forms.”

Over a 2-month period that coincided with the SARS-CoV-2 pandemic in France and Switzerland, the researchers retrospectively collected clinical, biological, therapeutic, and early-outcomes data in 35 children who were admitted to pediatric ICUs in 14 centers for cardiogenic shock, left ventricular dysfunction, and severe inflammatory state. Their median age was 10 years, all presented with a fever, 80% had gastrointestinal symptoms of abdominal pain, vomiting, or diarrhea, and 28% had comorbidities that included body mass index of greater than 25 kg/m² (17%), asthma (9%), and lupus (3%), and overweight. Only 17% presented with chest pain. The researchers observed that left ventricular ejection fraction was less than 30% in 28% of patients, and 80% required inotropic support with 28% treated with extracorporeal membrane oxygenation (ECMO). All patients presented with a severe inflammatory state evidenced by elevated C-reactive protein and d-dimer. Interleukin 6 was elevated to a median of 135 pg/mL in 13 of the patients. Elevation of troponin I was constant but mild to moderate, and NT-proBNP or BNP elevation was present in all children.

Nearly all patients 35 (88%) patients tested positive for SARS-CoV-2 infection by polymerase chain reaction of nasopharyngeal swab or serology. Most patients (80%) received IV inotropic support, 71% received first-line IV immunoglobulin, 65% received anticoagulation with heparin, 34% received IV steroids having been considered high-risk patients with symptoms similar to an incomplete form of Kawasaki disease, and 8% received treatment with an interleukin-1 receptor antagonist because of a persistent severe inflammatory state. Left ventricular function was restored in 71% of those discharged from the intensive care unit. No patient died, and all patients treated with ECMO were successfully weaned after a median of 4.5 days.

“Some aspects of this emerging pediatric disease (MIS-C) are similar to those of Kawasaki disease: prolonged fever, multisystem inflammation with skin rash, lymphadenopathy, diarrhea, meningism, and high levels of inflammatory biomarkers,” the researchers wrote. “But differences are important and raise the question as to whether this syndrome is Kawasaki disease with SARS-CoV-2 as the triggering agent, or represents a different syndrome (MIS-C). Kawasaki disease predominantly affects young children younger than 5 years, whereas the median age in our series is 10 years. Incomplete forms of Kawasaki disease occur in infants who may have fever as the sole clinical finding, whereas older patients are more prone to exhibit the complete form.”

They went on to note that the overlapping features between MIS-C and Kawasaki disease “may be due to similar pathophysiology. The etiologic agent of Kawasaki disease is unknown but likely to be ubiquitous, causing asymptomatic childhood infection but triggering the immunologic cascade of Kawasaki disease in genetically susceptible individuals. Please note that infection with a novel RNA virus that enters through the upper respiratory tract has been proposed to be the cause of the disease (see PLoS One. 2008 Feb 13;3:e1582 and J Infect Dis. 2011 Apr 1;203:1021-30).”

Based on the work of authors, it appears that a high index of suspicion for MIS-C is important for children who develop Kawasaki-like symptoms, David J. Goldberg, MD, said in an interview. “Although children have largely been spared from the acute respiratory presentation of the SARS-CoV-2 pandemic, the recognition and understanding of what appears to be a postviral inflammatory response is a critical first step in developing treatment algorithms for this disease process,” said Dr. Goldberg, a board-certified attending cardiologist in the cardiac center and fetal heart program at Children’s Hospital of Philadelphia. “If inflammatory markers are elevated, particularly if there are accompanying gastrointestinal symptoms, the possibility of cardiac involvement suggests the utility of screening echocardiography. Given the potential need for inotropic or mechanical circulatory support, the presence of myocardial dysfunction dictates care in an intensive care unit capable of providing advanced therapies. While the evidence from Dr. Belhadjer’s cohort suggests that full recovery is probable, there is still much to be learned about this unique inflammatory syndrome and the alarm has rightly been sounded.”

The researchers and Dr. Goldberg reported having no disclosures.

dbrunk@mdedge.com

SOURCE: Belhadjer Z et al. Circulation 2020 May 17; doi: 10.1161/circulationaha.120.048360.

The direct oral anticoagulant (DOAC) drugs apixaban, dabigatran, and rivaroxaban are associated with a lower risk of osteoporotic fracture than is warfarin in patients with atrial fibrillation (AFib), according to a new retrospective analysis.

There was no difference in risk between individual DOAC medications.

The study drew from an EHR database of the Hong Kong Hospital Authority. It was led by Wallis C.Y. Lau, PhD, of the University of Hong Kong and appeared online May 19 in Annals of Internal Medicine.

Warfarin is suspected to contribute to osteoporotic fracturing in AFib patients, but previous studies returned mixed results. The more recently introduced DOACs were not tested for fracture risks, and it hasn’t been determined if individual DOACs have different risks. The question is even more important in AFib, in which patients are older and often have comorbidities that could predispose them to fractures.

The study included 23,515 patients with AFib who used anticoagulants. 3,241 used apixaban, 6,867 dabigatran, 3,866 rivaroxaban, and 9,541 used warfarin. The median follow-up was 423 days.

According to Cox proportional hazards model analyses, DOAC use was associated with fewer fractures than was warfarin (hazard ratio for apixaban vs. warfarin, 0.62; 95% confidence interval, 0.41-0.94; HR for dabigatran, 0.65; 95% CI, 0.49-0.86; HR for rivaroxaban, 0.52; 95% CI, 0.37-0.73). Subanalyses in men and women showed similar results (P for interaction >.05).

Head-to-head comparisons between individual DOACs yielded no statistically significant differences in osteoporotic fracture risk.

Although the findings couldn’t absolutely rule out a difference in osteoporotic fracture risk between different DOACs, the authors argue that any clinical significance would likely be small.

“Given the supportive evidence from experimental settings, findings from our study using clinical data, and the indirect evidence provided by the previous meta-analysis of randomized, controlled trials, there exists a compelling case for evaluating whether the risk for osteoporotic fractures should be considered at the point of prescribing an oral anticoagulant to minimize fracture risk,” the authors wrote.

The study is limited by the potential for residual confounding, the investigators noted.

The study was funded by the University of Hong Kong and University College London Strategic Partnership Fund.

SOURCE: Lau WCY et al. Ann Intern Med. 2020 May 19. doi: 10.7326/M19-3671.

The direct oral anticoagulant (DOAC) drugs apixaban, dabigatran, and rivaroxaban are associated with a lower risk of osteoporotic fracture than is warfarin in patients with atrial fibrillation (AFib), according to a new retrospective analysis.

There was no difference in risk between individual DOAC medications.

The study drew from an EHR database of the Hong Kong Hospital Authority. It was led by Wallis C.Y. Lau, PhD, of the University of Hong Kong and appeared online May 19 in Annals of Internal Medicine.

Warfarin is suspected to contribute to osteoporotic fracturing in AFib patients, but previous studies returned mixed results. The more recently introduced DOACs were not tested for fracture risks, and it hasn’t been determined if individual DOACs have different risks. The question is even more important in AFib, in which patients are older and often have comorbidities that could predispose them to fractures.

The study included 23,515 patients with AFib who used anticoagulants. 3,241 used apixaban, 6,867 dabigatran, 3,866 rivaroxaban, and 9,541 used warfarin. The median follow-up was 423 days.

According to Cox proportional hazards model analyses, DOAC use was associated with fewer fractures than was warfarin (hazard ratio for apixaban vs. warfarin, 0.62; 95% confidence interval, 0.41-0.94; HR for dabigatran, 0.65; 95% CI, 0.49-0.86; HR for rivaroxaban, 0.52; 95% CI, 0.37-0.73). Subanalyses in men and women showed similar results (P for interaction >.05).

Head-to-head comparisons between individual DOACs yielded no statistically significant differences in osteoporotic fracture risk.

Although the findings couldn’t absolutely rule out a difference in osteoporotic fracture risk between different DOACs, the authors argue that any clinical significance would likely be small.

“Given the supportive evidence from experimental settings, findings from our study using clinical data, and the indirect evidence provided by the previous meta-analysis of randomized, controlled trials, there exists a compelling case for evaluating whether the risk for osteoporotic fractures should be considered at the point of prescribing an oral anticoagulant to minimize fracture risk,” the authors wrote.

The study is limited by the potential for residual confounding, the investigators noted.

The study was funded by the University of Hong Kong and University College London Strategic Partnership Fund.

SOURCE: Lau WCY et al. Ann Intern Med. 2020 May 19. doi: 10.7326/M19-3671.

The direct oral anticoagulant (DOAC) drugs apixaban, dabigatran, and rivaroxaban are associated with a lower risk of osteoporotic fracture than is warfarin in patients with atrial fibrillation (AFib), according to a new retrospective analysis.

There was no difference in risk between individual DOAC medications.

The study drew from an EHR database of the Hong Kong Hospital Authority. It was led by Wallis C.Y. Lau, PhD, of the University of Hong Kong and appeared online May 19 in Annals of Internal Medicine.

Warfarin is suspected to contribute to osteoporotic fracturing in AFib patients, but previous studies returned mixed results. The more recently introduced DOACs were not tested for fracture risks, and it hasn’t been determined if individual DOACs have different risks. The question is even more important in AFib, in which patients are older and often have comorbidities that could predispose them to fractures.

The study included 23,515 patients with AFib who used anticoagulants. 3,241 used apixaban, 6,867 dabigatran, 3,866 rivaroxaban, and 9,541 used warfarin. The median follow-up was 423 days.

According to Cox proportional hazards model analyses, DOAC use was associated with fewer fractures than was warfarin (hazard ratio for apixaban vs. warfarin, 0.62; 95% confidence interval, 0.41-0.94; HR for dabigatran, 0.65; 95% CI, 0.49-0.86; HR for rivaroxaban, 0.52; 95% CI, 0.37-0.73). Subanalyses in men and women showed similar results (P for interaction >.05).

Head-to-head comparisons between individual DOACs yielded no statistically significant differences in osteoporotic fracture risk.

Although the findings couldn’t absolutely rule out a difference in osteoporotic fracture risk between different DOACs, the authors argue that any clinical significance would likely be small.

“Given the supportive evidence from experimental settings, findings from our study using clinical data, and the indirect evidence provided by the previous meta-analysis of randomized, controlled trials, there exists a compelling case for evaluating whether the risk for osteoporotic fractures should be considered at the point of prescribing an oral anticoagulant to minimize fracture risk,” the authors wrote.

The study is limited by the potential for residual confounding, the investigators noted.

The study was funded by the University of Hong Kong and University College London Strategic Partnership Fund.

SOURCE: Lau WCY et al. Ann Intern Med. 2020 May 19. doi: 10.7326/M19-3671.