Cardiology

A Food and Drug Administration advisory committee has voted 11 to 2 against a recommendation that the agency approve a long-studied antiarrhythmic agent for cardioversion of recent-onset atrial fibrillation (AFib).

It was the second time before an FDA advisory panel for vernakalant (Brinavess, Correvio International Sàrl), which the agency had declined to approve in 2008 due to safety concerns. That time, however, its advisors had given the agency a decidedly positive recommendation.

Since then, registry data collected for the drug’s resubmission seemed only to raise further safety issues, especially evidence that a single infusion may cause severe hypotension and suppress left ventricular function.

Some members of the Cardiovascular and Renal Drugs Advisory Committee (CRDAC), including a number who voted against approval, expressed hopes for further research aimed at identifying specific AFib patient groups who might safely benefit from vernakalant.

Of note, the drug has long been available for AFib cardioversion in Europe, where there are a number of other pharmacologic options, and was recently approved in Canada.

“We do recognize there’s a significant clinical need here,” observed Paul M. Ridker, MD, MPH, of Harvard Medical School and Brigham and Women’s Hospital Boston, a CRDAC panelist.

The results of the safety study that Correvio presented to the panel were “pretty marginal,” Dr. Ridker said. Given the negative safety signals and the available cardioversion alternatives, he questioned whether vernakalant represented a “substantial advance versus just another option. Right now, I’m not convinced it’s a substantial advance.”

FDA representatives were skeptical about vernakalant when they walked into the meeting room, as noted in briefing documents they had circulated beforehand. The drug’s safety experience under consideration included one case of ventricular arrhythmia and cardiogenic shock in a treated patient without apparent structural heart disease, who subsequently died. That case was much discussed throughout the meeting.

In its resubmission of vernakalant to regulators, Correvio also pointed to a significant unmet need for AFib cardioversion options in the United States, given the few alternatives.

For example, ibutilide is FDA-approved for recent-onset AFib or atrial flutter; but as the company and panelists noted, the drug isn’t often used for that indication. Patients with recent-onset AFib are often put on rate-control meds without cardioversion. Or clinicians may resort to electrical cardioversion, which can be logistically cumbersome and require anesthesia and generally a hospital stay.

Oral or intravenous amiodarone and oral dofetilide, flecainide, and propafenone are guideline-recommended but not actually FDA-approved for recent-onset AFib, the company noted.

Correvio made its “pre-infusion checklist” a core feature of its case. It was designed to guide selection of patients for vernakalant cardioversion based on contraindications such as a systolic blood pressure under 100 mm Hg, severe heart failure, aortic stenosis, severe bradycardia or heart block, or a prolonged QT interval.

In his presentation to the panel, FDA medical officer Preston Dunnmon, MD, said the safety results from the SPECTRUM registry, another main pillar of support for the vernakalant resubmission, “are not reassuring.”

As reasons, Dr. Dunnmon cited likely patient-selection bias and its high proportion of patients who were not prospectively enrolled; 21% were retrospectively entered from records.

Moreover, “the proposed preinfusion checklist will not reliably predict which subjects will experience serious cardiovascular adverse events with vernakalant,” he said.

“Vernakalant has induced harm that cannot be reliably predicted, prevented, or in some cases, treated. In contrast to vernakalant, electrical cardioversion and ibutilide pharmacologic cardioversion can cause adverse events, but these are transient and treatable,” he said.

Many on the panel agreed. “I thought the totality of evidence supported the hypothesis that this drug has a potential for a fatal side effect in a disease that you can live with, potentially, and that there are other treatments for,” said Julia B. Lewis, MD, Vanderbilt Medical Center, Nashville, Tenn., who chaired the CRDAC panel.

“The drug clearly converts atrial fibrillation, although it’s only transient,” observed John H. Alexander, MD, MHSc, Duke University, Durham, N.C., one of the two panelists who voted to recommend approval of vernakalant.

“And, there clearly is a serious safety signal in some populations of patients,” he agreed. “However, I was more reassured by the SPECTRUM data.” There is likely to be a low-risk group of patients for whom vernakalant could represent an important option that “outweighs the relatively low risk of serious complications,” Dr. Alexander said.

“So more work needs to be done to clarify who are the low risk patients where it would be favorable.”

Panelist Matthew Needleman, MD, Walter Reed National Military Medical Center, Bethesda, Md., also voted in favor of approval.

“We’ve all known patients with normal ejection fractions who keep coming in with symptomatic atrial fib, want to get out of it quickly, and get back to their lives. So having an option like this I think would be good for a very select group of patients,” Dr. Needleman said.

But the preinfusion checklist and other potential ways to select low-risk patients for vernakalant could potentially backfire, warned John M. Mandrola, MD, Baptist Medical Associates, Louisville, Ky., from the panel.

The FDA representatives had presented evidence that the drug can seriously depress ventricular function, and that the lower cardiac output is what leads to hypotension, he elaborated in an interview after the meeting.

If the checklist is used to exclude hemodynamically unstable patients from receiving vernakalant, he said, “Then you’re really giving this drug to relatively healthy patients for convenience, to decrease hospitalization or the hospital stay.”

The signal for substantial harm, Dr. Mandrola said, has to be balanced against that modest benefit.

Moreover, those in whom the drug doesn’t work may be left in a worse situation, he proposed. Only about half of patients are successfully converted on vernakalant, the company and FDA data suggested. The other half of patients who don’t achieve sinus rhythm on the drug still must face the significant hazards of depressed ejection fraction and hypotension, a high price to pay for an unsuccessful treatment.

Dr. Mandrola is Chief Cardiology Correspondent for theheart.org | Medscape Cardiology; his disclosure statement states no relevant financial relationships.

This article first appeared on Medscape.com.

A Food and Drug Administration advisory committee has voted 11 to 2 against a recommendation that the agency approve a long-studied antiarrhythmic agent for cardioversion of recent-onset atrial fibrillation (AFib).

It was the second time before an FDA advisory panel for vernakalant (Brinavess, Correvio International Sàrl), which the agency had declined to approve in 2008 due to safety concerns. That time, however, its advisors had given the agency a decidedly positive recommendation.

Since then, registry data collected for the drug’s resubmission seemed only to raise further safety issues, especially evidence that a single infusion may cause severe hypotension and suppress left ventricular function.

Some members of the Cardiovascular and Renal Drugs Advisory Committee (CRDAC), including a number who voted against approval, expressed hopes for further research aimed at identifying specific AFib patient groups who might safely benefit from vernakalant.

Of note, the drug has long been available for AFib cardioversion in Europe, where there are a number of other pharmacologic options, and was recently approved in Canada.

“We do recognize there’s a significant clinical need here,” observed Paul M. Ridker, MD, MPH, of Harvard Medical School and Brigham and Women’s Hospital Boston, a CRDAC panelist.

The results of the safety study that Correvio presented to the panel were “pretty marginal,” Dr. Ridker said. Given the negative safety signals and the available cardioversion alternatives, he questioned whether vernakalant represented a “substantial advance versus just another option. Right now, I’m not convinced it’s a substantial advance.”

FDA representatives were skeptical about vernakalant when they walked into the meeting room, as noted in briefing documents they had circulated beforehand. The drug’s safety experience under consideration included one case of ventricular arrhythmia and cardiogenic shock in a treated patient without apparent structural heart disease, who subsequently died. That case was much discussed throughout the meeting.

In its resubmission of vernakalant to regulators, Correvio also pointed to a significant unmet need for AFib cardioversion options in the United States, given the few alternatives.

For example, ibutilide is FDA-approved for recent-onset AFib or atrial flutter; but as the company and panelists noted, the drug isn’t often used for that indication. Patients with recent-onset AFib are often put on rate-control meds without cardioversion. Or clinicians may resort to electrical cardioversion, which can be logistically cumbersome and require anesthesia and generally a hospital stay.

Oral or intravenous amiodarone and oral dofetilide, flecainide, and propafenone are guideline-recommended but not actually FDA-approved for recent-onset AFib, the company noted.

Correvio made its “pre-infusion checklist” a core feature of its case. It was designed to guide selection of patients for vernakalant cardioversion based on contraindications such as a systolic blood pressure under 100 mm Hg, severe heart failure, aortic stenosis, severe bradycardia or heart block, or a prolonged QT interval.

In his presentation to the panel, FDA medical officer Preston Dunnmon, MD, said the safety results from the SPECTRUM registry, another main pillar of support for the vernakalant resubmission, “are not reassuring.”

As reasons, Dr. Dunnmon cited likely patient-selection bias and its high proportion of patients who were not prospectively enrolled; 21% were retrospectively entered from records.

Moreover, “the proposed preinfusion checklist will not reliably predict which subjects will experience serious cardiovascular adverse events with vernakalant,” he said.

“Vernakalant has induced harm that cannot be reliably predicted, prevented, or in some cases, treated. In contrast to vernakalant, electrical cardioversion and ibutilide pharmacologic cardioversion can cause adverse events, but these are transient and treatable,” he said.

Many on the panel agreed. “I thought the totality of evidence supported the hypothesis that this drug has a potential for a fatal side effect in a disease that you can live with, potentially, and that there are other treatments for,” said Julia B. Lewis, MD, Vanderbilt Medical Center, Nashville, Tenn., who chaired the CRDAC panel.

“The drug clearly converts atrial fibrillation, although it’s only transient,” observed John H. Alexander, MD, MHSc, Duke University, Durham, N.C., one of the two panelists who voted to recommend approval of vernakalant.

“And, there clearly is a serious safety signal in some populations of patients,” he agreed. “However, I was more reassured by the SPECTRUM data.” There is likely to be a low-risk group of patients for whom vernakalant could represent an important option that “outweighs the relatively low risk of serious complications,” Dr. Alexander said.

“So more work needs to be done to clarify who are the low risk patients where it would be favorable.”

Panelist Matthew Needleman, MD, Walter Reed National Military Medical Center, Bethesda, Md., also voted in favor of approval.

“We’ve all known patients with normal ejection fractions who keep coming in with symptomatic atrial fib, want to get out of it quickly, and get back to their lives. So having an option like this I think would be good for a very select group of patients,” Dr. Needleman said.

But the preinfusion checklist and other potential ways to select low-risk patients for vernakalant could potentially backfire, warned John M. Mandrola, MD, Baptist Medical Associates, Louisville, Ky., from the panel.

The FDA representatives had presented evidence that the drug can seriously depress ventricular function, and that the lower cardiac output is what leads to hypotension, he elaborated in an interview after the meeting.

If the checklist is used to exclude hemodynamically unstable patients from receiving vernakalant, he said, “Then you’re really giving this drug to relatively healthy patients for convenience, to decrease hospitalization or the hospital stay.”

The signal for substantial harm, Dr. Mandrola said, has to be balanced against that modest benefit.

Moreover, those in whom the drug doesn’t work may be left in a worse situation, he proposed. Only about half of patients are successfully converted on vernakalant, the company and FDA data suggested. The other half of patients who don’t achieve sinus rhythm on the drug still must face the significant hazards of depressed ejection fraction and hypotension, a high price to pay for an unsuccessful treatment.

Dr. Mandrola is Chief Cardiology Correspondent for theheart.org | Medscape Cardiology; his disclosure statement states no relevant financial relationships.

This article first appeared on Medscape.com.

A Food and Drug Administration advisory committee has voted 11 to 2 against a recommendation that the agency approve a long-studied antiarrhythmic agent for cardioversion of recent-onset atrial fibrillation (AFib).

It was the second time before an FDA advisory panel for vernakalant (Brinavess, Correvio International Sàrl), which the agency had declined to approve in 2008 due to safety concerns. That time, however, its advisors had given the agency a decidedly positive recommendation.

Since then, registry data collected for the drug’s resubmission seemed only to raise further safety issues, especially evidence that a single infusion may cause severe hypotension and suppress left ventricular function.

Some members of the Cardiovascular and Renal Drugs Advisory Committee (CRDAC), including a number who voted against approval, expressed hopes for further research aimed at identifying specific AFib patient groups who might safely benefit from vernakalant.

Of note, the drug has long been available for AFib cardioversion in Europe, where there are a number of other pharmacologic options, and was recently approved in Canada.

“We do recognize there’s a significant clinical need here,” observed Paul M. Ridker, MD, MPH, of Harvard Medical School and Brigham and Women’s Hospital Boston, a CRDAC panelist.

The results of the safety study that Correvio presented to the panel were “pretty marginal,” Dr. Ridker said. Given the negative safety signals and the available cardioversion alternatives, he questioned whether vernakalant represented a “substantial advance versus just another option. Right now, I’m not convinced it’s a substantial advance.”

FDA representatives were skeptical about vernakalant when they walked into the meeting room, as noted in briefing documents they had circulated beforehand. The drug’s safety experience under consideration included one case of ventricular arrhythmia and cardiogenic shock in a treated patient without apparent structural heart disease, who subsequently died. That case was much discussed throughout the meeting.

In its resubmission of vernakalant to regulators, Correvio also pointed to a significant unmet need for AFib cardioversion options in the United States, given the few alternatives.

For example, ibutilide is FDA-approved for recent-onset AFib or atrial flutter; but as the company and panelists noted, the drug isn’t often used for that indication. Patients with recent-onset AFib are often put on rate-control meds without cardioversion. Or clinicians may resort to electrical cardioversion, which can be logistically cumbersome and require anesthesia and generally a hospital stay.

Oral or intravenous amiodarone and oral dofetilide, flecainide, and propafenone are guideline-recommended but not actually FDA-approved for recent-onset AFib, the company noted.

Correvio made its “pre-infusion checklist” a core feature of its case. It was designed to guide selection of patients for vernakalant cardioversion based on contraindications such as a systolic blood pressure under 100 mm Hg, severe heart failure, aortic stenosis, severe bradycardia or heart block, or a prolonged QT interval.

In his presentation to the panel, FDA medical officer Preston Dunnmon, MD, said the safety results from the SPECTRUM registry, another main pillar of support for the vernakalant resubmission, “are not reassuring.”

As reasons, Dr. Dunnmon cited likely patient-selection bias and its high proportion of patients who were not prospectively enrolled; 21% were retrospectively entered from records.

Moreover, “the proposed preinfusion checklist will not reliably predict which subjects will experience serious cardiovascular adverse events with vernakalant,” he said.

“Vernakalant has induced harm that cannot be reliably predicted, prevented, or in some cases, treated. In contrast to vernakalant, electrical cardioversion and ibutilide pharmacologic cardioversion can cause adverse events, but these are transient and treatable,” he said.

Many on the panel agreed. “I thought the totality of evidence supported the hypothesis that this drug has a potential for a fatal side effect in a disease that you can live with, potentially, and that there are other treatments for,” said Julia B. Lewis, MD, Vanderbilt Medical Center, Nashville, Tenn., who chaired the CRDAC panel.

“The drug clearly converts atrial fibrillation, although it’s only transient,” observed John H. Alexander, MD, MHSc, Duke University, Durham, N.C., one of the two panelists who voted to recommend approval of vernakalant.

“And, there clearly is a serious safety signal in some populations of patients,” he agreed. “However, I was more reassured by the SPECTRUM data.” There is likely to be a low-risk group of patients for whom vernakalant could represent an important option that “outweighs the relatively low risk of serious complications,” Dr. Alexander said.

“So more work needs to be done to clarify who are the low risk patients where it would be favorable.”

Panelist Matthew Needleman, MD, Walter Reed National Military Medical Center, Bethesda, Md., also voted in favor of approval.

“We’ve all known patients with normal ejection fractions who keep coming in with symptomatic atrial fib, want to get out of it quickly, and get back to their lives. So having an option like this I think would be good for a very select group of patients,” Dr. Needleman said.

But the preinfusion checklist and other potential ways to select low-risk patients for vernakalant could potentially backfire, warned John M. Mandrola, MD, Baptist Medical Associates, Louisville, Ky., from the panel.

The FDA representatives had presented evidence that the drug can seriously depress ventricular function, and that the lower cardiac output is what leads to hypotension, he elaborated in an interview after the meeting.

If the checklist is used to exclude hemodynamically unstable patients from receiving vernakalant, he said, “Then you’re really giving this drug to relatively healthy patients for convenience, to decrease hospitalization or the hospital stay.”

The signal for substantial harm, Dr. Mandrola said, has to be balanced against that modest benefit.

Moreover, those in whom the drug doesn’t work may be left in a worse situation, he proposed. Only about half of patients are successfully converted on vernakalant, the company and FDA data suggested. The other half of patients who don’t achieve sinus rhythm on the drug still must face the significant hazards of depressed ejection fraction and hypotension, a high price to pay for an unsuccessful treatment.

Dr. Mandrola is Chief Cardiology Correspondent for theheart.org | Medscape Cardiology; his disclosure statement states no relevant financial relationships.

This article first appeared on Medscape.com.

BALTIMORE – Patients hospitalized for epilepsy may have higher odds of death if they have a secondary diagnosis of arrhythmia, whereas the presence of apnea alone may not significantly increase mortality, according to an analysis of data from the Nationwide Inpatient Sample presented at the annual meeting of the American Epilepsy Society.

Jake Remaly/MDedge News

“If you have someone with arrhythmia and epilepsy, you have to be more concerned about possible SUDEP [sudden unexpected death in epilepsy],” relative to someone with apnea and epilepsy, said senior study author Sanjay P. Singh, MD, professor of neurology at Creighton University, Omaha, Neb.

Research indicates that apnea and cardiac arrhythmias may contribute to SUDEP, and the incidence of SUDEP is higher in patients with intractable epilepsy.

To identify the prevalence of apnea, arrhythmia, and both conditions in epilepsy hospitalizations, as well as the prevalence of intractable epilepsy and mortality, Dr. Singh and colleagues performed a retrospective, cross-sectional analysis of pediatric and adult epilepsy hospitalizations between 2003 and 2014 in the Nationwide Inpatient Sample. They determined apnea and arrhythmia diagnoses using ICD-9-CM codes.

Among more than 2.6 million epilepsy hospitalizations, the prevalence of apnea was 2.75%, the prevalence of arrhythmia was 8.91%, and the prevalence of both was 0.49%. The proportion of patients with intractable epilepsy was 7.7%. Among the more than 207,000 hospitalizations with intractable epilepsy, the prevalence of apnea was 3.62%, the prevalence of arrhythmia was 3.34%, and the prevalence of both was 0.36%. The prevalence trend of apnea, arrhythmia, and both together increased between 2003 and 2014.

“In univariate analysis, prevalence of mortality was highest among patients with arrhythmia,” the researchers reported, at – 3.1% in patients with arrhythmia versus 0.48% in patients with apnea, 2.91% in patients with both, and 0.46% in patients without apnea or arrhythmia.

In a multivariable regression analysis, significant and independent predictors of death included intractable epilepsy (odds ratio, 1.17), apnea (OR, 0.84), arrhythmia (OR, 3.29), and the presence of both apnea and arrhythmia (OR, 3.24). When hospitalization was complicated by intractable epilepsy, the odds of death rose with the presence of apnea (OR, 2.07), arrhythmia (OR, 8.39), and with both apnea and arrhythmia (OR, 11.64).

The results highlight the importance of effective epilepsy management, said first author Urvish K. Patel, MBBS, also with Creighton University. “If we can stop [conversion to intractable epilepsy], then this odds ratio can go down.”

Attention to arrhythmias, as well as the combination of arrhythmias and apnea, may “be important in identifying patients at risk for SUDEP,” the authors concluded.

The researchers had no disclosures and reported receiving no outside funding for their work.

jremaly@mdedge.com

SOURCE: Patel UK et al. AES 2019, Abstract 2.140.

BALTIMORE – Patients hospitalized for epilepsy may have higher odds of death if they have a secondary diagnosis of arrhythmia, whereas the presence of apnea alone may not significantly increase mortality, according to an analysis of data from the Nationwide Inpatient Sample presented at the annual meeting of the American Epilepsy Society.

Jake Remaly/MDedge News

“If you have someone with arrhythmia and epilepsy, you have to be more concerned about possible SUDEP [sudden unexpected death in epilepsy],” relative to someone with apnea and epilepsy, said senior study author Sanjay P. Singh, MD, professor of neurology at Creighton University, Omaha, Neb.

Research indicates that apnea and cardiac arrhythmias may contribute to SUDEP, and the incidence of SUDEP is higher in patients with intractable epilepsy.

To identify the prevalence of apnea, arrhythmia, and both conditions in epilepsy hospitalizations, as well as the prevalence of intractable epilepsy and mortality, Dr. Singh and colleagues performed a retrospective, cross-sectional analysis of pediatric and adult epilepsy hospitalizations between 2003 and 2014 in the Nationwide Inpatient Sample. They determined apnea and arrhythmia diagnoses using ICD-9-CM codes.

Among more than 2.6 million epilepsy hospitalizations, the prevalence of apnea was 2.75%, the prevalence of arrhythmia was 8.91%, and the prevalence of both was 0.49%. The proportion of patients with intractable epilepsy was 7.7%. Among the more than 207,000 hospitalizations with intractable epilepsy, the prevalence of apnea was 3.62%, the prevalence of arrhythmia was 3.34%, and the prevalence of both was 0.36%. The prevalence trend of apnea, arrhythmia, and both together increased between 2003 and 2014.

“In univariate analysis, prevalence of mortality was highest among patients with arrhythmia,” the researchers reported, at – 3.1% in patients with arrhythmia versus 0.48% in patients with apnea, 2.91% in patients with both, and 0.46% in patients without apnea or arrhythmia.

In a multivariable regression analysis, significant and independent predictors of death included intractable epilepsy (odds ratio, 1.17), apnea (OR, 0.84), arrhythmia (OR, 3.29), and the presence of both apnea and arrhythmia (OR, 3.24). When hospitalization was complicated by intractable epilepsy, the odds of death rose with the presence of apnea (OR, 2.07), arrhythmia (OR, 8.39), and with both apnea and arrhythmia (OR, 11.64).

The results highlight the importance of effective epilepsy management, said first author Urvish K. Patel, MBBS, also with Creighton University. “If we can stop [conversion to intractable epilepsy], then this odds ratio can go down.”

Attention to arrhythmias, as well as the combination of arrhythmias and apnea, may “be important in identifying patients at risk for SUDEP,” the authors concluded.

The researchers had no disclosures and reported receiving no outside funding for their work.

jremaly@mdedge.com

SOURCE: Patel UK et al. AES 2019, Abstract 2.140.

BALTIMORE – Patients hospitalized for epilepsy may have higher odds of death if they have a secondary diagnosis of arrhythmia, whereas the presence of apnea alone may not significantly increase mortality, according to an analysis of data from the Nationwide Inpatient Sample presented at the annual meeting of the American Epilepsy Society.

Jake Remaly/MDedge News

“If you have someone with arrhythmia and epilepsy, you have to be more concerned about possible SUDEP [sudden unexpected death in epilepsy],” relative to someone with apnea and epilepsy, said senior study author Sanjay P. Singh, MD, professor of neurology at Creighton University, Omaha, Neb.

Research indicates that apnea and cardiac arrhythmias may contribute to SUDEP, and the incidence of SUDEP is higher in patients with intractable epilepsy.

To identify the prevalence of apnea, arrhythmia, and both conditions in epilepsy hospitalizations, as well as the prevalence of intractable epilepsy and mortality, Dr. Singh and colleagues performed a retrospective, cross-sectional analysis of pediatric and adult epilepsy hospitalizations between 2003 and 2014 in the Nationwide Inpatient Sample. They determined apnea and arrhythmia diagnoses using ICD-9-CM codes.

Among more than 2.6 million epilepsy hospitalizations, the prevalence of apnea was 2.75%, the prevalence of arrhythmia was 8.91%, and the prevalence of both was 0.49%. The proportion of patients with intractable epilepsy was 7.7%. Among the more than 207,000 hospitalizations with intractable epilepsy, the prevalence of apnea was 3.62%, the prevalence of arrhythmia was 3.34%, and the prevalence of both was 0.36%. The prevalence trend of apnea, arrhythmia, and both together increased between 2003 and 2014.

“In univariate analysis, prevalence of mortality was highest among patients with arrhythmia,” the researchers reported, at – 3.1% in patients with arrhythmia versus 0.48% in patients with apnea, 2.91% in patients with both, and 0.46% in patients without apnea or arrhythmia.

In a multivariable regression analysis, significant and independent predictors of death included intractable epilepsy (odds ratio, 1.17), apnea (OR, 0.84), arrhythmia (OR, 3.29), and the presence of both apnea and arrhythmia (OR, 3.24). When hospitalization was complicated by intractable epilepsy, the odds of death rose with the presence of apnea (OR, 2.07), arrhythmia (OR, 8.39), and with both apnea and arrhythmia (OR, 11.64).

The results highlight the importance of effective epilepsy management, said first author Urvish K. Patel, MBBS, also with Creighton University. “If we can stop [conversion to intractable epilepsy], then this odds ratio can go down.”

Attention to arrhythmias, as well as the combination of arrhythmias and apnea, may “be important in identifying patients at risk for SUDEP,” the authors concluded.

The researchers had no disclosures and reported receiving no outside funding for their work.

jremaly@mdedge.com

SOURCE: Patel UK et al. AES 2019, Abstract 2.140.

SAN FRANCISCO – Among patients with severe aortic stenosis at low surgical risk, both transcatheter and surgical aortic valve replacement resulted in substantial health status benefits at 1 year despite most patients having New York Heart Association class I or II symptoms at baseline.

Doug Brunk/MDedge News

However, when compared with surgical replacement, transcatheter replacement was linked with significantly improved disease-specific health status not only at 1 month, but also at 6 months and 1 year.

The findings come from an analysis of patients enrolled in the randomized PARTNER 3 trial, which showed that transcatheter aortic valve replacement (TAVR) with the SAPIEN 3 valve. At 1 year post procedure, the rate of the primary composite endpoint comprising death, stroke, or cardiovascular rehospitalization was 8.5% in the TAVR group and 15.1% with surgical aortic valve replacement (SAVR), for a highly significant 46% relative risk reduction (N Engl J Med 2019 May 2;380:1695-705).

“The PARTNER 3 and Evolut Low Risk trials have demonstrated that transfemoral TAVR is both safe and effective when compared with SAVR in patients with severe aortic stenosis at low surgical risk,” Suzanne J. Baron, MD, MSc, said at the Transcatheter Cardiovascular Therapeutics annual meeting. “While prior studies have demonstrated improved early health status with transfemoral TAVR, compared with SAVR in intermediate and high-risk patients, there is little evidence of any late health status benefit with TAVR.”

To address this gap in knowledge, Dr. Baron, director of interventional cardiology research at Lahey Hospital and Medical Center in Burlington, Mass., and associates performed a prospective study alongside the PARTNER 3 randomized trial to understand the impact of valve replacement strategy on early and late health status in aortic stenosis patients at low surgical risk. She reported results from 449 low-risk patients with severe aortic stenosis who were assigned to transfemoral TAVR using a balloon-expandable valve, and 449 who were assigned to surgery in PARTNER 3. At baseline, the mean age of patients was 73 years, 69% were male, and the average STS (Society of Thoracic Surgeons) Risk Score was 1.9%. Rates of other comorbidities were generally low.

Patients in both groups reported a mild baseline impairment in health status. The mean Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ-OS) score was 70, “which corresponds to only New York Heart Association Class II symptoms,” Dr. Baron said. “The SF-36 [Short Form 36] physical summary score was 44 for both groups, which is approximately half of a standard deviation below the population mean.”

As expected, patients who underwent TAVR showed substantially improved health status at 1 month based on the KCCQ-OS (mean difference,16 points; P less than .001). However, in contrast to prior studies, the researchers observed a persistent, although attenuated, benefit of TAVR over SAVR in disease-specific health status at 6 and 12 months (mean difference in KCCQ-OS of 2.6 and 1.8 points respectively; P less than .04 for both).

Dr. Baron said that a sustained benefit of TAVR over SAVR at 6 months and 1 year was observed on several KCCQ subscales, but a similar benefit was not noted on the generic health status measures such as the SF-36 physical summary score. “That’s likely reflective of the fact that, as a disease-specific measure, the KCCQ is much more sensitive in detecting meaningful differences in this population,” she explained. When change in health status was analyzed as an ordinal variable, with death as the worst outcome and large clinical improvement, which was defined as a 20-point or greater increase in the KCCQ-OS score, TAVR showed a significant benefit, compared with surgery at all time points (P less than .05).

In an effort to better understand the mechanism underlying this persistent albeit small late benefit in disease-specific health status with TAVR, the researchers generated cumulative distribution curves to display the proportion of patients who achieved a given change on the KCCQ-OS. A clear separation of the curves emerged, with 5.2% more patients in the TAVR group experiencing a change of at least 20 points, compared with the surgery group. “This suggests that the difference in late health status between the two groups is driven by this 5.2% absolute risk difference in the proportion of patients who experienced a large clinical improvement,” Dr. Baron said at the meeting, which was sponsored by the Cardiovascular Research Foundation.

Next, the researchers performed subgroup analyses to examine the interaction between the 1-year health status benefit of TAVR over surgery and prespecified baseline characteristics including age, gender, STS risk score, ejection fraction, atrial fibrillation, and New York Heart Association (NYHA) class. They observed a significant interaction between NYHA class and treatment effect such that patients who had NYHA class III or IV symptoms at baseline derived greater benefit from TAVR, compared with those who had NYHA class I or II symptoms at baseline.

“This finding suggests that it’s the patients with worse functional impairment at baseline who may be that subset of patients on the cumulative responder curves who gained better health status outcomes with TAVR, compared with surgery in the low-risk population,” Dr. Baron said.

Suzanne V. Arnold, MD, a cardiologist at Saint Luke’s Mid America Heart Institute, Kansas City, Mo., who was an invited discussant, said that it was “remarkable” that patients in the substudy were not particularly symptomatic and yet they still experienced close to a 20-point improvement in the KCCQ-OS score following TAVR, and asked whether frailty may have played a role in the 1.8-point adjusted difference in the KCCQ-OS score between TAVR and surgery at 1 year. Dr. Baron responded that she and her colleagues performed a subgroup analysis of patients who had two or more markers of frailty versus those who had one or less. Noting that there were only 20 patients in that subgroup, she said there was a significant signal that patients who were considered have two or more frail measures were considered to do much better with TAVR.

Dr. Baron concluded that the study’s overall findings, taken together with the clinical outcomes of the PARTNER 3 trial, “further support the use of TAVR in patients with severe [aortic stenosis] at low surgical risk. Longer-term follow up is needed (and ongoing) to determine whether the health status benefits of TAVR at 1 year are durable.”
The content of the study was published online at the time of presentation (J Am Coll Cardiol 2019 Sep 29. doi: 10.1016/j.jacc.2019.09.007). The PARTNER 3 quality of life substudy was funded by Edwards Lifesciences. Dr. Baron disclosed research funding and advisory board compensation from Boston Scientific Corp and consulting fees from Edwards Lifesciences.

dbrunk@mdedge.com

SAN FRANCISCO – Among patients with severe aortic stenosis at low surgical risk, both transcatheter and surgical aortic valve replacement resulted in substantial health status benefits at 1 year despite most patients having New York Heart Association class I or II symptoms at baseline.

Doug Brunk/MDedge News

However, when compared with surgical replacement, transcatheter replacement was linked with significantly improved disease-specific health status not only at 1 month, but also at 6 months and 1 year.

The findings come from an analysis of patients enrolled in the randomized PARTNER 3 trial, which showed that transcatheter aortic valve replacement (TAVR) with the SAPIEN 3 valve. At 1 year post procedure, the rate of the primary composite endpoint comprising death, stroke, or cardiovascular rehospitalization was 8.5% in the TAVR group and 15.1% with surgical aortic valve replacement (SAVR), for a highly significant 46% relative risk reduction (N Engl J Med 2019 May 2;380:1695-705).

“The PARTNER 3 and Evolut Low Risk trials have demonstrated that transfemoral TAVR is both safe and effective when compared with SAVR in patients with severe aortic stenosis at low surgical risk,” Suzanne J. Baron, MD, MSc, said at the Transcatheter Cardiovascular Therapeutics annual meeting. “While prior studies have demonstrated improved early health status with transfemoral TAVR, compared with SAVR in intermediate and high-risk patients, there is little evidence of any late health status benefit with TAVR.”

To address this gap in knowledge, Dr. Baron, director of interventional cardiology research at Lahey Hospital and Medical Center in Burlington, Mass., and associates performed a prospective study alongside the PARTNER 3 randomized trial to understand the impact of valve replacement strategy on early and late health status in aortic stenosis patients at low surgical risk. She reported results from 449 low-risk patients with severe aortic stenosis who were assigned to transfemoral TAVR using a balloon-expandable valve, and 449 who were assigned to surgery in PARTNER 3. At baseline, the mean age of patients was 73 years, 69% were male, and the average STS (Society of Thoracic Surgeons) Risk Score was 1.9%. Rates of other comorbidities were generally low.

Patients in both groups reported a mild baseline impairment in health status. The mean Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ-OS) score was 70, “which corresponds to only New York Heart Association Class II symptoms,” Dr. Baron said. “The SF-36 [Short Form 36] physical summary score was 44 for both groups, which is approximately half of a standard deviation below the population mean.”

As expected, patients who underwent TAVR showed substantially improved health status at 1 month based on the KCCQ-OS (mean difference,16 points; P less than .001). However, in contrast to prior studies, the researchers observed a persistent, although attenuated, benefit of TAVR over SAVR in disease-specific health status at 6 and 12 months (mean difference in KCCQ-OS of 2.6 and 1.8 points respectively; P less than .04 for both).

Dr. Baron said that a sustained benefit of TAVR over SAVR at 6 months and 1 year was observed on several KCCQ subscales, but a similar benefit was not noted on the generic health status measures such as the SF-36 physical summary score. “That’s likely reflective of the fact that, as a disease-specific measure, the KCCQ is much more sensitive in detecting meaningful differences in this population,” she explained. When change in health status was analyzed as an ordinal variable, with death as the worst outcome and large clinical improvement, which was defined as a 20-point or greater increase in the KCCQ-OS score, TAVR showed a significant benefit, compared with surgery at all time points (P less than .05).

In an effort to better understand the mechanism underlying this persistent albeit small late benefit in disease-specific health status with TAVR, the researchers generated cumulative distribution curves to display the proportion of patients who achieved a given change on the KCCQ-OS. A clear separation of the curves emerged, with 5.2% more patients in the TAVR group experiencing a change of at least 20 points, compared with the surgery group. “This suggests that the difference in late health status between the two groups is driven by this 5.2% absolute risk difference in the proportion of patients who experienced a large clinical improvement,” Dr. Baron said at the meeting, which was sponsored by the Cardiovascular Research Foundation.

Next, the researchers performed subgroup analyses to examine the interaction between the 1-year health status benefit of TAVR over surgery and prespecified baseline characteristics including age, gender, STS risk score, ejection fraction, atrial fibrillation, and New York Heart Association (NYHA) class. They observed a significant interaction between NYHA class and treatment effect such that patients who had NYHA class III or IV symptoms at baseline derived greater benefit from TAVR, compared with those who had NYHA class I or II symptoms at baseline.

“This finding suggests that it’s the patients with worse functional impairment at baseline who may be that subset of patients on the cumulative responder curves who gained better health status outcomes with TAVR, compared with surgery in the low-risk population,” Dr. Baron said.

Suzanne V. Arnold, MD, a cardiologist at Saint Luke’s Mid America Heart Institute, Kansas City, Mo., who was an invited discussant, said that it was “remarkable” that patients in the substudy were not particularly symptomatic and yet they still experienced close to a 20-point improvement in the KCCQ-OS score following TAVR, and asked whether frailty may have played a role in the 1.8-point adjusted difference in the KCCQ-OS score between TAVR and surgery at 1 year. Dr. Baron responded that she and her colleagues performed a subgroup analysis of patients who had two or more markers of frailty versus those who had one or less. Noting that there were only 20 patients in that subgroup, she said there was a significant signal that patients who were considered have two or more frail measures were considered to do much better with TAVR.

Dr. Baron concluded that the study’s overall findings, taken together with the clinical outcomes of the PARTNER 3 trial, “further support the use of TAVR in patients with severe [aortic stenosis] at low surgical risk. Longer-term follow up is needed (and ongoing) to determine whether the health status benefits of TAVR at 1 year are durable.”
The content of the study was published online at the time of presentation (J Am Coll Cardiol 2019 Sep 29. doi: 10.1016/j.jacc.2019.09.007). The PARTNER 3 quality of life substudy was funded by Edwards Lifesciences. Dr. Baron disclosed research funding and advisory board compensation from Boston Scientific Corp and consulting fees from Edwards Lifesciences.

dbrunk@mdedge.com

SAN FRANCISCO – Among patients with severe aortic stenosis at low surgical risk, both transcatheter and surgical aortic valve replacement resulted in substantial health status benefits at 1 year despite most patients having New York Heart Association class I or II symptoms at baseline.

Doug Brunk/MDedge News

However, when compared with surgical replacement, transcatheter replacement was linked with significantly improved disease-specific health status not only at 1 month, but also at 6 months and 1 year.

The findings come from an analysis of patients enrolled in the randomized PARTNER 3 trial, which showed that transcatheter aortic valve replacement (TAVR) with the SAPIEN 3 valve. At 1 year post procedure, the rate of the primary composite endpoint comprising death, stroke, or cardiovascular rehospitalization was 8.5% in the TAVR group and 15.1% with surgical aortic valve replacement (SAVR), for a highly significant 46% relative risk reduction (N Engl J Med 2019 May 2;380:1695-705).

“The PARTNER 3 and Evolut Low Risk trials have demonstrated that transfemoral TAVR is both safe and effective when compared with SAVR in patients with severe aortic stenosis at low surgical risk,” Suzanne J. Baron, MD, MSc, said at the Transcatheter Cardiovascular Therapeutics annual meeting. “While prior studies have demonstrated improved early health status with transfemoral TAVR, compared with SAVR in intermediate and high-risk patients, there is little evidence of any late health status benefit with TAVR.”

To address this gap in knowledge, Dr. Baron, director of interventional cardiology research at Lahey Hospital and Medical Center in Burlington, Mass., and associates performed a prospective study alongside the PARTNER 3 randomized trial to understand the impact of valve replacement strategy on early and late health status in aortic stenosis patients at low surgical risk. She reported results from 449 low-risk patients with severe aortic stenosis who were assigned to transfemoral TAVR using a balloon-expandable valve, and 449 who were assigned to surgery in PARTNER 3. At baseline, the mean age of patients was 73 years, 69% were male, and the average STS (Society of Thoracic Surgeons) Risk Score was 1.9%. Rates of other comorbidities were generally low.

Patients in both groups reported a mild baseline impairment in health status. The mean Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ-OS) score was 70, “which corresponds to only New York Heart Association Class II symptoms,” Dr. Baron said. “The SF-36 [Short Form 36] physical summary score was 44 for both groups, which is approximately half of a standard deviation below the population mean.”

As expected, patients who underwent TAVR showed substantially improved health status at 1 month based on the KCCQ-OS (mean difference,16 points; P less than .001). However, in contrast to prior studies, the researchers observed a persistent, although attenuated, benefit of TAVR over SAVR in disease-specific health status at 6 and 12 months (mean difference in KCCQ-OS of 2.6 and 1.8 points respectively; P less than .04 for both).

Dr. Baron said that a sustained benefit of TAVR over SAVR at 6 months and 1 year was observed on several KCCQ subscales, but a similar benefit was not noted on the generic health status measures such as the SF-36 physical summary score. “That’s likely reflective of the fact that, as a disease-specific measure, the KCCQ is much more sensitive in detecting meaningful differences in this population,” she explained. When change in health status was analyzed as an ordinal variable, with death as the worst outcome and large clinical improvement, which was defined as a 20-point or greater increase in the KCCQ-OS score, TAVR showed a significant benefit, compared with surgery at all time points (P less than .05).

In an effort to better understand the mechanism underlying this persistent albeit small late benefit in disease-specific health status with TAVR, the researchers generated cumulative distribution curves to display the proportion of patients who achieved a given change on the KCCQ-OS. A clear separation of the curves emerged, with 5.2% more patients in the TAVR group experiencing a change of at least 20 points, compared with the surgery group. “This suggests that the difference in late health status between the two groups is driven by this 5.2% absolute risk difference in the proportion of patients who experienced a large clinical improvement,” Dr. Baron said at the meeting, which was sponsored by the Cardiovascular Research Foundation.

Next, the researchers performed subgroup analyses to examine the interaction between the 1-year health status benefit of TAVR over surgery and prespecified baseline characteristics including age, gender, STS risk score, ejection fraction, atrial fibrillation, and New York Heart Association (NYHA) class. They observed a significant interaction between NYHA class and treatment effect such that patients who had NYHA class III or IV symptoms at baseline derived greater benefit from TAVR, compared with those who had NYHA class I or II symptoms at baseline.

“This finding suggests that it’s the patients with worse functional impairment at baseline who may be that subset of patients on the cumulative responder curves who gained better health status outcomes with TAVR, compared with surgery in the low-risk population,” Dr. Baron said.

Suzanne V. Arnold, MD, a cardiologist at Saint Luke’s Mid America Heart Institute, Kansas City, Mo., who was an invited discussant, said that it was “remarkable” that patients in the substudy were not particularly symptomatic and yet they still experienced close to a 20-point improvement in the KCCQ-OS score following TAVR, and asked whether frailty may have played a role in the 1.8-point adjusted difference in the KCCQ-OS score between TAVR and surgery at 1 year. Dr. Baron responded that she and her colleagues performed a subgroup analysis of patients who had two or more markers of frailty versus those who had one or less. Noting that there were only 20 patients in that subgroup, she said there was a significant signal that patients who were considered have two or more frail measures were considered to do much better with TAVR.

Dr. Baron concluded that the study’s overall findings, taken together with the clinical outcomes of the PARTNER 3 trial, “further support the use of TAVR in patients with severe [aortic stenosis] at low surgical risk. Longer-term follow up is needed (and ongoing) to determine whether the health status benefits of TAVR at 1 year are durable.”
The content of the study was published online at the time of presentation (J Am Coll Cardiol 2019 Sep 29. doi: 10.1016/j.jacc.2019.09.007). The PARTNER 3 quality of life substudy was funded by Edwards Lifesciences. Dr. Baron disclosed research funding and advisory board compensation from Boston Scientific Corp and consulting fees from Edwards Lifesciences.

dbrunk@mdedge.com

PHILADELPHIA – Obese people living in the United Kingdom who underwent bariatric surgery had a two-thirds lower rate of major cerebrovascular events than that of a matched group of obese residents who did not undergo bariatric surgery, in a retrospective study of 8,424 people followed for a mean of just over 11 years.

Mitchel L. Zoler/MDedge News

Although the cut in cerebrovascular events that linked with bariatric surgery shown by the analysis was mostly driven by a reduced rate of transient ischemic attacks, a potentially unreliable diagnosis, the results showed consistent reductions in the rates of acute ischemic strokes as well as in acute, nontraumatic intracranial hemorrhages, two other components of the combined primary endpoint, Maddalena Ardissino, MBBS, said at the American Heart Association scientific sessions.

This finding of an apparent benefit from bariatric surgery in obese patients in a large U.K. database confirms other findings from a “fast-growing” evidence base showing benefits from bariatric surgery for reducing other types of cardiovascular disease events, said Dr. Ardissino, a researcher at Imperial College, London. However, the impact of bariatric surgery specifically on cerebrovascular events had not received much attention in published studies, she noted.

Her study used data collected by the Clinical Practice Research Datalink, which has primary and secondary care health records for about 42 million U.K. residents. The researchers focused on more than 251,000 obese U.K. adults (body mass index of 30 kg/m² or greater) without a history of a cerebrovascular event who had at least 1 year of follow-up, a data file that included 4,212 adults who had undergone bariatric surgery. Their analysis matched these surgical patients with an equal number of obese adults who did not have surgery, pairing the cases and controls based on age, sex, and BMI. The resulting matched cohorts each averaged 50 years old, with a mean BMI of 40.5 kg/m².

During just over 11 years of average follow-up, the incidence of acute ischemic stroke, acute intracranial hemorrhage, subarachnoid hemorrhage, or transient ischemic attack was about 1.3% in those without bariatric surgery and about 0.4% in those who had surgery, an absolute risk reduction of 0.9 linked with surgery and a relative risk reduction of 65% that was statistically significant, Dr. Ardissino reported. All-cause mortality was about 70% lower in the group that underwent bariatric surgery compared with those who did not have surgery, a finding that confirmed prior reports. She cautioned that the analysis was limited by a relatively low number of total events, and by the small number of criteria used for cohort matching that might have left unadjusted certain potential confounders such as the level of engagement people had with their medical care.

mzoler@mdedge.com

SOURCE: Ardissino M. AHA 2019, Abstract 335.

PHILADELPHIA – Obese people living in the United Kingdom who underwent bariatric surgery had a two-thirds lower rate of major cerebrovascular events than that of a matched group of obese residents who did not undergo bariatric surgery, in a retrospective study of 8,424 people followed for a mean of just over 11 years.

Mitchel L. Zoler/MDedge News

Although the cut in cerebrovascular events that linked with bariatric surgery shown by the analysis was mostly driven by a reduced rate of transient ischemic attacks, a potentially unreliable diagnosis, the results showed consistent reductions in the rates of acute ischemic strokes as well as in acute, nontraumatic intracranial hemorrhages, two other components of the combined primary endpoint, Maddalena Ardissino, MBBS, said at the American Heart Association scientific sessions.

This finding of an apparent benefit from bariatric surgery in obese patients in a large U.K. database confirms other findings from a “fast-growing” evidence base showing benefits from bariatric surgery for reducing other types of cardiovascular disease events, said Dr. Ardissino, a researcher at Imperial College, London. However, the impact of bariatric surgery specifically on cerebrovascular events had not received much attention in published studies, she noted.

Her study used data collected by the Clinical Practice Research Datalink, which has primary and secondary care health records for about 42 million U.K. residents. The researchers focused on more than 251,000 obese U.K. adults (body mass index of 30 kg/m² or greater) without a history of a cerebrovascular event who had at least 1 year of follow-up, a data file that included 4,212 adults who had undergone bariatric surgery. Their analysis matched these surgical patients with an equal number of obese adults who did not have surgery, pairing the cases and controls based on age, sex, and BMI. The resulting matched cohorts each averaged 50 years old, with a mean BMI of 40.5 kg/m².

During just over 11 years of average follow-up, the incidence of acute ischemic stroke, acute intracranial hemorrhage, subarachnoid hemorrhage, or transient ischemic attack was about 1.3% in those without bariatric surgery and about 0.4% in those who had surgery, an absolute risk reduction of 0.9 linked with surgery and a relative risk reduction of 65% that was statistically significant, Dr. Ardissino reported. All-cause mortality was about 70% lower in the group that underwent bariatric surgery compared with those who did not have surgery, a finding that confirmed prior reports. She cautioned that the analysis was limited by a relatively low number of total events, and by the small number of criteria used for cohort matching that might have left unadjusted certain potential confounders such as the level of engagement people had with their medical care.

mzoler@mdedge.com

SOURCE: Ardissino M. AHA 2019, Abstract 335.

PHILADELPHIA – Obese people living in the United Kingdom who underwent bariatric surgery had a two-thirds lower rate of major cerebrovascular events than that of a matched group of obese residents who did not undergo bariatric surgery, in a retrospective study of 8,424 people followed for a mean of just over 11 years.

Mitchel L. Zoler/MDedge News

Although the cut in cerebrovascular events that linked with bariatric surgery shown by the analysis was mostly driven by a reduced rate of transient ischemic attacks, a potentially unreliable diagnosis, the results showed consistent reductions in the rates of acute ischemic strokes as well as in acute, nontraumatic intracranial hemorrhages, two other components of the combined primary endpoint, Maddalena Ardissino, MBBS, said at the American Heart Association scientific sessions.

This finding of an apparent benefit from bariatric surgery in obese patients in a large U.K. database confirms other findings from a “fast-growing” evidence base showing benefits from bariatric surgery for reducing other types of cardiovascular disease events, said Dr. Ardissino, a researcher at Imperial College, London. However, the impact of bariatric surgery specifically on cerebrovascular events had not received much attention in published studies, she noted.

Her study used data collected by the Clinical Practice Research Datalink, which has primary and secondary care health records for about 42 million U.K. residents. The researchers focused on more than 251,000 obese U.K. adults (body mass index of 30 kg/m² or greater) without a history of a cerebrovascular event who had at least 1 year of follow-up, a data file that included 4,212 adults who had undergone bariatric surgery. Their analysis matched these surgical patients with an equal number of obese adults who did not have surgery, pairing the cases and controls based on age, sex, and BMI. The resulting matched cohorts each averaged 50 years old, with a mean BMI of 40.5 kg/m².

During just over 11 years of average follow-up, the incidence of acute ischemic stroke, acute intracranial hemorrhage, subarachnoid hemorrhage, or transient ischemic attack was about 1.3% in those without bariatric surgery and about 0.4% in those who had surgery, an absolute risk reduction of 0.9 linked with surgery and a relative risk reduction of 65% that was statistically significant, Dr. Ardissino reported. All-cause mortality was about 70% lower in the group that underwent bariatric surgery compared with those who did not have surgery, a finding that confirmed prior reports. She cautioned that the analysis was limited by a relatively low number of total events, and by the small number of criteria used for cohort matching that might have left unadjusted certain potential confounders such as the level of engagement people had with their medical care.

mzoler@mdedge.com

SOURCE: Ardissino M. AHA 2019, Abstract 335.

Lipoprotein(a) molar concentration, rather than apolipoprotein(a) size, appears to be the factor that drives lipoprotein(a)-based cardiovascular disease, according to research published in the Journal of the American College of Cardiology.

The causal association between lipoprotein(a), or Lp(a), and cardiovascular disease has been previously established, but exactly what attribute of Lp(a) is related to cardiovascular risk is not known, Daniel F. Gudbjartsson, PhD, of deCODE genetics and the University of Iceland in Reykjavik, and colleagues wrote in their study. The researchers set out to determine whether Lp(a) molar concentration or apolipoprotein(a), or apo(a), size affects cardiovascular risk. In addition, Dr. Gudbjartsson and colleagues examined the relationship between Lp(a) and type 2 diabetes. While low levels of Lp(a) have been linked to type 2 diabetes, the researchers sought to examine whether low Lp(a) molar concentration levels were also associated with type 2 diabetes risk.

“With Lp(a)-lowering drugs being developed, it is important to understand which attributes of Lp(a) best capture the cardiovascular risk and the consequences of Lp(a) lowering,” noted Dr. Gudbjartsson and colleagues.

Using Mendelian randomization, the researchers assessed Lp(a) molar concentration and kringle IV type 2 (KIV-2) repeat sequence variants to determine a causal relationship between both variants and disease risk. Lp(a) molar concentration serum samples were measured using particle-enhanced turbidimetric immunoassay, while KIV-2 repeats were genotyped with real-time polymerase chain reaction.

Overall, 143,087 participants from Iceland had their genetic information analyzed; of these, 17,715 participants had coronary artery disease, and 8,734 had type 2 diabetes. Lp(a) molecular concentration was analyzed in 12,137 participants and genetically imputed into 130,950 Icelanders, and KIV-2 repeats were estimated in 22,771 Icelanders and genetically imputed into 120,316 Icelanders.

Dr. Gudbjartsson and colleagues found there was a dose-dependent association between Lp(a) molar concentration and risk of coronary artery disease (CAD), peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. In participants in whom Lp(a) molar concentration was at the 79th percentile (50 units of molarity [nM]), the odds ratio was 1.11, and for those in the 99th percentile (250 nM), there was an odds ratio of 2.01 when compared with participants with a median Lp(a) molar concentration of 14 nM. “Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size,” the researchers said.

Participants who were not at increased risk for CAD included those with few KIV-2 repeats and participants with the splice variant G4925A. “This suggested that risk prediction based on Lp(a) should only depend on molar concentration and that treatment of Lp(a) should focus on lowering the molar concentration in subjects with high Lp(a) levels, regardless of the apo(a) size distribution,” Dr. Gudbjartsson and colleagues wrote.

Among participants with type 2 diabetes examined, the 10% of participants with Lp(a) molar concentrations of less than 3.5 nM were at the highest risk of developing type 2 diabetes.

In an accompanying editorial, Benoit J. Arsenault, PhD, of the Quebec Heart and Lung Institute, said that the findings of an association between Lp(a) concentration and atherosclerotic cardiovascular diseases (ASCVD) from Gudbjartsson et al. are important, particularly if they can be replicated in more diverse populations (doi: 10.1016/j.jacc.2019.06.083). “Investigating the association between Lp(a) levels, apo(a) isoform size, and ASCVD risk in different populations is important because the distribution of Lp(a) levels appears to be different across ethnic groups,” he said.

Despite the link between absolute Lp(a) concentrations and cardiovascular disease, cardiovascular outcome trials will need be conducted, Dr. Arsenault noted.

“In the post-statin and post-genomic era, finding much needed therapeutic targets for residual cardiovascular risk can be compared to a gold-digging expedition. Like a map to the location of the gold, GWAS [genome-wide association studies] and Mendelian randomization studies are consistently pointing us in the direction of Lp(a),” he said. “It is time to coordinate our efforts to dig where the map told us, to see once and for all if we will find the golden target of residual cardiovascular risk that we are hoping for and to give hope to high-risk patients with elevated Lp(a) levels.”

Dr. Gudbjartsson and 19 other authors reported being employees of deCODE genetics, owned by Amgen, which is developing Lp(a)-lowering drugs related to the study findings. The other authors reported no relevant conflict of interest. Dr. Arsenault reported being supported by the Fonds de recherche du Québec: Santé and the Canadian Institutes of Health Research; has received research funding from Pfizer, Merck, and Ionis; and was a former consultant for Pfizer and Novartis.

SOURCE: Gudbjartsson DF et al. J Am Coll Cardiol. 2019. doi: 10.1016/j.jacc.2019.10.019.

Lipoprotein(a) molar concentration, rather than apolipoprotein(a) size, appears to be the factor that drives lipoprotein(a)-based cardiovascular disease, according to research published in the Journal of the American College of Cardiology.

The causal association between lipoprotein(a), or Lp(a), and cardiovascular disease has been previously established, but exactly what attribute of Lp(a) is related to cardiovascular risk is not known, Daniel F. Gudbjartsson, PhD, of deCODE genetics and the University of Iceland in Reykjavik, and colleagues wrote in their study. The researchers set out to determine whether Lp(a) molar concentration or apolipoprotein(a), or apo(a), size affects cardiovascular risk. In addition, Dr. Gudbjartsson and colleagues examined the relationship between Lp(a) and type 2 diabetes. While low levels of Lp(a) have been linked to type 2 diabetes, the researchers sought to examine whether low Lp(a) molar concentration levels were also associated with type 2 diabetes risk.

“With Lp(a)-lowering drugs being developed, it is important to understand which attributes of Lp(a) best capture the cardiovascular risk and the consequences of Lp(a) lowering,” noted Dr. Gudbjartsson and colleagues.

Using Mendelian randomization, the researchers assessed Lp(a) molar concentration and kringle IV type 2 (KIV-2) repeat sequence variants to determine a causal relationship between both variants and disease risk. Lp(a) molar concentration serum samples were measured using particle-enhanced turbidimetric immunoassay, while KIV-2 repeats were genotyped with real-time polymerase chain reaction.

Overall, 143,087 participants from Iceland had their genetic information analyzed; of these, 17,715 participants had coronary artery disease, and 8,734 had type 2 diabetes. Lp(a) molecular concentration was analyzed in 12,137 participants and genetically imputed into 130,950 Icelanders, and KIV-2 repeats were estimated in 22,771 Icelanders and genetically imputed into 120,316 Icelanders.

Dr. Gudbjartsson and colleagues found there was a dose-dependent association between Lp(a) molar concentration and risk of coronary artery disease (CAD), peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. In participants in whom Lp(a) molar concentration was at the 79th percentile (50 units of molarity [nM]), the odds ratio was 1.11, and for those in the 99th percentile (250 nM), there was an odds ratio of 2.01 when compared with participants with a median Lp(a) molar concentration of 14 nM. “Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size,” the researchers said.

Participants who were not at increased risk for CAD included those with few KIV-2 repeats and participants with the splice variant G4925A. “This suggested that risk prediction based on Lp(a) should only depend on molar concentration and that treatment of Lp(a) should focus on lowering the molar concentration in subjects with high Lp(a) levels, regardless of the apo(a) size distribution,” Dr. Gudbjartsson and colleagues wrote.

Among participants with type 2 diabetes examined, the 10% of participants with Lp(a) molar concentrations of less than 3.5 nM were at the highest risk of developing type 2 diabetes.

In an accompanying editorial, Benoit J. Arsenault, PhD, of the Quebec Heart and Lung Institute, said that the findings of an association between Lp(a) concentration and atherosclerotic cardiovascular diseases (ASCVD) from Gudbjartsson et al. are important, particularly if they can be replicated in more diverse populations (doi: 10.1016/j.jacc.2019.06.083). “Investigating the association between Lp(a) levels, apo(a) isoform size, and ASCVD risk in different populations is important because the distribution of Lp(a) levels appears to be different across ethnic groups,” he said.

Despite the link between absolute Lp(a) concentrations and cardiovascular disease, cardiovascular outcome trials will need be conducted, Dr. Arsenault noted.

“In the post-statin and post-genomic era, finding much needed therapeutic targets for residual cardiovascular risk can be compared to a gold-digging expedition. Like a map to the location of the gold, GWAS [genome-wide association studies] and Mendelian randomization studies are consistently pointing us in the direction of Lp(a),” he said. “It is time to coordinate our efforts to dig where the map told us, to see once and for all if we will find the golden target of residual cardiovascular risk that we are hoping for and to give hope to high-risk patients with elevated Lp(a) levels.”

Dr. Gudbjartsson and 19 other authors reported being employees of deCODE genetics, owned by Amgen, which is developing Lp(a)-lowering drugs related to the study findings. The other authors reported no relevant conflict of interest. Dr. Arsenault reported being supported by the Fonds de recherche du Québec: Santé and the Canadian Institutes of Health Research; has received research funding from Pfizer, Merck, and Ionis; and was a former consultant for Pfizer and Novartis.

SOURCE: Gudbjartsson DF et al. J Am Coll Cardiol. 2019. doi: 10.1016/j.jacc.2019.10.019.

Lipoprotein(a) molar concentration, rather than apolipoprotein(a) size, appears to be the factor that drives lipoprotein(a)-based cardiovascular disease, according to research published in the Journal of the American College of Cardiology.

The causal association between lipoprotein(a), or Lp(a), and cardiovascular disease has been previously established, but exactly what attribute of Lp(a) is related to cardiovascular risk is not known, Daniel F. Gudbjartsson, PhD, of deCODE genetics and the University of Iceland in Reykjavik, and colleagues wrote in their study. The researchers set out to determine whether Lp(a) molar concentration or apolipoprotein(a), or apo(a), size affects cardiovascular risk. In addition, Dr. Gudbjartsson and colleagues examined the relationship between Lp(a) and type 2 diabetes. While low levels of Lp(a) have been linked to type 2 diabetes, the researchers sought to examine whether low Lp(a) molar concentration levels were also associated with type 2 diabetes risk.

“With Lp(a)-lowering drugs being developed, it is important to understand which attributes of Lp(a) best capture the cardiovascular risk and the consequences of Lp(a) lowering,” noted Dr. Gudbjartsson and colleagues.

Using Mendelian randomization, the researchers assessed Lp(a) molar concentration and kringle IV type 2 (KIV-2) repeat sequence variants to determine a causal relationship between both variants and disease risk. Lp(a) molar concentration serum samples were measured using particle-enhanced turbidimetric immunoassay, while KIV-2 repeats were genotyped with real-time polymerase chain reaction.

Overall, 143,087 participants from Iceland had their genetic information analyzed; of these, 17,715 participants had coronary artery disease, and 8,734 had type 2 diabetes. Lp(a) molecular concentration was analyzed in 12,137 participants and genetically imputed into 130,950 Icelanders, and KIV-2 repeats were estimated in 22,771 Icelanders and genetically imputed into 120,316 Icelanders.

Dr. Gudbjartsson and colleagues found there was a dose-dependent association between Lp(a) molar concentration and risk of coronary artery disease (CAD), peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. In participants in whom Lp(a) molar concentration was at the 79th percentile (50 units of molarity [nM]), the odds ratio was 1.11, and for those in the 99th percentile (250 nM), there was an odds ratio of 2.01 when compared with participants with a median Lp(a) molar concentration of 14 nM. “Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size,” the researchers said.

Participants who were not at increased risk for CAD included those with few KIV-2 repeats and participants with the splice variant G4925A. “This suggested that risk prediction based on Lp(a) should only depend on molar concentration and that treatment of Lp(a) should focus on lowering the molar concentration in subjects with high Lp(a) levels, regardless of the apo(a) size distribution,” Dr. Gudbjartsson and colleagues wrote.

Among participants with type 2 diabetes examined, the 10% of participants with Lp(a) molar concentrations of less than 3.5 nM were at the highest risk of developing type 2 diabetes.

In an accompanying editorial, Benoit J. Arsenault, PhD, of the Quebec Heart and Lung Institute, said that the findings of an association between Lp(a) concentration and atherosclerotic cardiovascular diseases (ASCVD) from Gudbjartsson et al. are important, particularly if they can be replicated in more diverse populations (doi: 10.1016/j.jacc.2019.06.083). “Investigating the association between Lp(a) levels, apo(a) isoform size, and ASCVD risk in different populations is important because the distribution of Lp(a) levels appears to be different across ethnic groups,” he said.

Despite the link between absolute Lp(a) concentrations and cardiovascular disease, cardiovascular outcome trials will need be conducted, Dr. Arsenault noted.

“In the post-statin and post-genomic era, finding much needed therapeutic targets for residual cardiovascular risk can be compared to a gold-digging expedition. Like a map to the location of the gold, GWAS [genome-wide association studies] and Mendelian randomization studies are consistently pointing us in the direction of Lp(a),” he said. “It is time to coordinate our efforts to dig where the map told us, to see once and for all if we will find the golden target of residual cardiovascular risk that we are hoping for and to give hope to high-risk patients with elevated Lp(a) levels.”

Dr. Gudbjartsson and 19 other authors reported being employees of deCODE genetics, owned by Amgen, which is developing Lp(a)-lowering drugs related to the study findings. The other authors reported no relevant conflict of interest. Dr. Arsenault reported being supported by the Fonds de recherche du Québec: Santé and the Canadian Institutes of Health Research; has received research funding from Pfizer, Merck, and Ionis; and was a former consultant for Pfizer and Novartis.

SOURCE: Gudbjartsson DF et al. J Am Coll Cardiol. 2019. doi: 10.1016/j.jacc.2019.10.019.

While women were found to be at lower risk of major cardiovascular events than men after non–ST-segment elevation acute coronary syndromes (NSTEACS), a new study has also shown that they remain undertreated with guideline-directed therapies.

©Thinkstock

“These findings underscore the fact that efforts to modify risk factors and implement appropriate treatment strategies in women and men may be a powerful means to further improve outcomes among patients with NSTEACS,” wrote Amy A. Sarma, MD, of Massachusetts General Hospital in Boston and coauthors. The study was published in the Journal of the American College of Cardiology.

To determine if outcomes differed between men and women after NSTEACS, the researchers analyzed 68,730 patients from 10 different clinical trials as part of the Thrombolysis In Myocardial Infarction (TIMI) Study Group. All trials enrolled patients with NSTEACS within 30 days of hospitalization. Across the 10 trials, there were a total of 19,827 women (29%).

Female patients had an average age of 67 years, compared with a mean age of 62 years for men. Women were also more likely to have had hypertension, diabetes, or prior heart failure, though less likely to have had a prior MI. In regard to treatment strategies for NSTEACS, women were less likely to receive aspirin, P2Y12 inhibitors, or statins. Women at high risk were also less likely to receive aspirin, P2Y12 inhibitors, or statins.

Before adjusted analysis, women and men had a similar risk of major adverse cardiovascular events (MACE) – defined as cardiovascular death, MI, or stroke – after NSTEACS (hazard ratio, 1.04; 95% confidence interval, 0.99-1.09; P = .16). However, women were found to be at increased risk of cardiovascular death (HR, 1.16; 95% CI, 1.02-1.32; P = .03), all-cause mortality (HR, 1.12; 95% CI, 1.01-1.24; P = .03), and stroke (HR, 1.19; 95% CI, 1.03-1.37; P = .02).

After adjusting for baseline risk predictors, women were found to have a 7% lower risk of MACE (adjusted HR, 0.93; 95% CI, 0.89-0.98; P = .005), along with a 15% lower risk of cardiovascular death (aHR, 0.85; 95% CI, 0.76-0.96; P = .008) and a 16% lower risk of all-cause death (aHR, 0.84; 95% CI, 0.78-0.90; P less than .0001). Additional adjustments for guideline-based therapies did not significantly alter the risk estimates.

In an accompanying editorial, Michael E. Farkouh, MD, and Wendy Tsang, MD, of the University of Toronto noted that this study from Sarma et al. underlines the “lack of progress made in addressing sex inequality in the care for women with ACS” (J Am Coll Cardiol. 2019 Dec 9. doi: 10.1016/j.jacc.2019.10.017).

Though Dr. Farkouh and Dr. Tsang were not surprised that the women in the study were older than the men, as women typically develop cardiovascular disease later, they noted that the women also presented with higher baseline risk. Could this be because of the “persistent perception that coronary disease is a male disease?” They cited the treatment-risk paradox and an emphasis on diagnosing obstructive coronary disease – typically seen in men – as potential contributors to underdiagnosis and undertreatment in at-risk women.

“That this care gap for women with cardiovascular diseases continues to persist, even in well-run contemporary landmark ACS trials, highlights how challenging it is to address,” they wrote.

Dr. Sarma and coauthors acknowledged their study’s potential limitations, including the 10 trials differing in study design, enrollment timing, treatments tested, and follow-up duration. They also noted that the cohort of patients were all at moderate to high risk, which may not make the findings generalizable to the broader NSTEACS patient population.

The study authors reported numerous potential conflicts of interest, including receiving research grants from – and serving as a consultant or on the advisory board of – various pharmaceutical and medical companies. Dr. Farkouh reported receiving research support from Amgen and Novo Nordisk, and Dr. Tsang is supported by a National New Investigator Award from the Heart and Stroke Foundation of Canada.

SOURCE: Sarma AA et al. J Am Coll Cardiol. 2019 Dec 9. doi: 10.1016/j.jacc.2019.09.065.

While women were found to be at lower risk of major cardiovascular events than men after non–ST-segment elevation acute coronary syndromes (NSTEACS), a new study has also shown that they remain undertreated with guideline-directed therapies.

©Thinkstock

“These findings underscore the fact that efforts to modify risk factors and implement appropriate treatment strategies in women and men may be a powerful means to further improve outcomes among patients with NSTEACS,” wrote Amy A. Sarma, MD, of Massachusetts General Hospital in Boston and coauthors. The study was published in the Journal of the American College of Cardiology.

To determine if outcomes differed between men and women after NSTEACS, the researchers analyzed 68,730 patients from 10 different clinical trials as part of the Thrombolysis In Myocardial Infarction (TIMI) Study Group. All trials enrolled patients with NSTEACS within 30 days of hospitalization. Across the 10 trials, there were a total of 19,827 women (29%).

Female patients had an average age of 67 years, compared with a mean age of 62 years for men. Women were also more likely to have had hypertension, diabetes, or prior heart failure, though less likely to have had a prior MI. In regard to treatment strategies for NSTEACS, women were less likely to receive aspirin, P2Y12 inhibitors, or statins. Women at high risk were also less likely to receive aspirin, P2Y12 inhibitors, or statins.

Before adjusted analysis, women and men had a similar risk of major adverse cardiovascular events (MACE) – defined as cardiovascular death, MI, or stroke – after NSTEACS (hazard ratio, 1.04; 95% confidence interval, 0.99-1.09; P = .16). However, women were found to be at increased risk of cardiovascular death (HR, 1.16; 95% CI, 1.02-1.32; P = .03), all-cause mortality (HR, 1.12; 95% CI, 1.01-1.24; P = .03), and stroke (HR, 1.19; 95% CI, 1.03-1.37; P = .02).

After adjusting for baseline risk predictors, women were found to have a 7% lower risk of MACE (adjusted HR, 0.93; 95% CI, 0.89-0.98; P = .005), along with a 15% lower risk of cardiovascular death (aHR, 0.85; 95% CI, 0.76-0.96; P = .008) and a 16% lower risk of all-cause death (aHR, 0.84; 95% CI, 0.78-0.90; P less than .0001). Additional adjustments for guideline-based therapies did not significantly alter the risk estimates.

In an accompanying editorial, Michael E. Farkouh, MD, and Wendy Tsang, MD, of the University of Toronto noted that this study from Sarma et al. underlines the “lack of progress made in addressing sex inequality in the care for women with ACS” (J Am Coll Cardiol. 2019 Dec 9. doi: 10.1016/j.jacc.2019.10.017).

Though Dr. Farkouh and Dr. Tsang were not surprised that the women in the study were older than the men, as women typically develop cardiovascular disease later, they noted that the women also presented with higher baseline risk. Could this be because of the “persistent perception that coronary disease is a male disease?” They cited the treatment-risk paradox and an emphasis on diagnosing obstructive coronary disease – typically seen in men – as potential contributors to underdiagnosis and undertreatment in at-risk women.

“That this care gap for women with cardiovascular diseases continues to persist, even in well-run contemporary landmark ACS trials, highlights how challenging it is to address,” they wrote.

Dr. Sarma and coauthors acknowledged their study’s potential limitations, including the 10 trials differing in study design, enrollment timing, treatments tested, and follow-up duration. They also noted that the cohort of patients were all at moderate to high risk, which may not make the findings generalizable to the broader NSTEACS patient population.

The study authors reported numerous potential conflicts of interest, including receiving research grants from – and serving as a consultant or on the advisory board of – various pharmaceutical and medical companies. Dr. Farkouh reported receiving research support from Amgen and Novo Nordisk, and Dr. Tsang is supported by a National New Investigator Award from the Heart and Stroke Foundation of Canada.

SOURCE: Sarma AA et al. J Am Coll Cardiol. 2019 Dec 9. doi: 10.1016/j.jacc.2019.09.065.

While women were found to be at lower risk of major cardiovascular events than men after non–ST-segment elevation acute coronary syndromes (NSTEACS), a new study has also shown that they remain undertreated with guideline-directed therapies.

©Thinkstock

“These findings underscore the fact that efforts to modify risk factors and implement appropriate treatment strategies in women and men may be a powerful means to further improve outcomes among patients with NSTEACS,” wrote Amy A. Sarma, MD, of Massachusetts General Hospital in Boston and coauthors. The study was published in the Journal of the American College of Cardiology.

To determine if outcomes differed between men and women after NSTEACS, the researchers analyzed 68,730 patients from 10 different clinical trials as part of the Thrombolysis In Myocardial Infarction (TIMI) Study Group. All trials enrolled patients with NSTEACS within 30 days of hospitalization. Across the 10 trials, there were a total of 19,827 women (29%).

Female patients had an average age of 67 years, compared with a mean age of 62 years for men. Women were also more likely to have had hypertension, diabetes, or prior heart failure, though less likely to have had a prior MI. In regard to treatment strategies for NSTEACS, women were less likely to receive aspirin, P2Y12 inhibitors, or statins. Women at high risk were also less likely to receive aspirin, P2Y12 inhibitors, or statins.

Before adjusted analysis, women and men had a similar risk of major adverse cardiovascular events (MACE) – defined as cardiovascular death, MI, or stroke – after NSTEACS (hazard ratio, 1.04; 95% confidence interval, 0.99-1.09; P = .16). However, women were found to be at increased risk of cardiovascular death (HR, 1.16; 95% CI, 1.02-1.32; P = .03), all-cause mortality (HR, 1.12; 95% CI, 1.01-1.24; P = .03), and stroke (HR, 1.19; 95% CI, 1.03-1.37; P = .02).

After adjusting for baseline risk predictors, women were found to have a 7% lower risk of MACE (adjusted HR, 0.93; 95% CI, 0.89-0.98; P = .005), along with a 15% lower risk of cardiovascular death (aHR, 0.85; 95% CI, 0.76-0.96; P = .008) and a 16% lower risk of all-cause death (aHR, 0.84; 95% CI, 0.78-0.90; P less than .0001). Additional adjustments for guideline-based therapies did not significantly alter the risk estimates.

In an accompanying editorial, Michael E. Farkouh, MD, and Wendy Tsang, MD, of the University of Toronto noted that this study from Sarma et al. underlines the “lack of progress made in addressing sex inequality in the care for women with ACS” (J Am Coll Cardiol. 2019 Dec 9. doi: 10.1016/j.jacc.2019.10.017).

Though Dr. Farkouh and Dr. Tsang were not surprised that the women in the study were older than the men, as women typically develop cardiovascular disease later, they noted that the women also presented with higher baseline risk. Could this be because of the “persistent perception that coronary disease is a male disease?” They cited the treatment-risk paradox and an emphasis on diagnosing obstructive coronary disease – typically seen in men – as potential contributors to underdiagnosis and undertreatment in at-risk women.

“That this care gap for women with cardiovascular diseases continues to persist, even in well-run contemporary landmark ACS trials, highlights how challenging it is to address,” they wrote.

Dr. Sarma and coauthors acknowledged their study’s potential limitations, including the 10 trials differing in study design, enrollment timing, treatments tested, and follow-up duration. They also noted that the cohort of patients were all at moderate to high risk, which may not make the findings generalizable to the broader NSTEACS patient population.

The study authors reported numerous potential conflicts of interest, including receiving research grants from – and serving as a consultant or on the advisory board of – various pharmaceutical and medical companies. Dr. Farkouh reported receiving research support from Amgen and Novo Nordisk, and Dr. Tsang is supported by a National New Investigator Award from the Heart and Stroke Foundation of Canada.

SOURCE: Sarma AA et al. J Am Coll Cardiol. 2019 Dec 9. doi: 10.1016/j.jacc.2019.09.065.

PHILADELPHIA – A 32-gene screening test for stroke risk identified a subgroup of atrial fibrillation (AFib) patients with an elevated rate of ischemic strokes despite having a low stroke risk by conventional criteria by their CHA2DS2-VASc score in a post-hoc analysis of more than 11,000 patients enrolled in a recent drug trial.

Mitchel L. Zoler/MDedge News

Overall, AFib patients in the highest tertile for genetic risk based on a 32 gene-loci test had a 31% increase rate of ischemic stroke during a median 2.8 years of follow-up compared with patients in the tertile with the lowest risk based on the 32-loci screen, Nicholas A. Marston, MD, said at the American Heart Association scientific sessions. This suggested that the genetic test had roughly the same association with an increased stroke risk as several components of the CHA2DS2-VASc score, such as female sex, an age of 65-74 years old, or having heart failure as a comorbidity, each of which links with an increased risk for ischemic stroke of about 31%-38%, Dr. Marston noted.

The genetic test produced even sharper discrimination among the patients with the lowest stroke risk as measured by their CHA2DS2-VASc score (Circulation. 2012 Aug 14;126[7]: 860-5). Among the slightly more than 3,000 patients in the study with a CHA2DS2-VASc score of three or less, those in the subgroup with the highest risk by the 32-loci screen had a stroke rate during follow-up that was 76% higher than those in the low or intermediate tertile for their genetic score. Among the 796 patients with a CHA2DS2-VASc score of just 1 or 2, those who also fell into the highest level of risk on the 32-loci screen had a stroke rate 3.5-fold higher than those with a similar CHA2DS2-VASc score but in the low and intermediate tertiles by the 32-loci screen.

The additional risk prediction provided by the 32-loci test was statistically significant in the analysis of the 3,071 patients with a CHA2DS2-VASc score of 3 or less after adjustment for age, sex, ancestry, and the individual components of the CHA2DS2-VASc score, which includes factors such as hypertension, diabetes, and heart failure, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. The 3.5-fold elevation among patients with a high genetic-risk score in the cohort of 796 patients with a CHA2DS2-VASc score of 1 or 2 just missed statistical significance (P = .06), possibly because the number of patients in the analysis was relatively low. Future research should explore the predictive value of the genetic risk score in patients with a CHA2DS2-VASc score of 0 or 1, the “group where therapeutic decisions could be altered” depending on the genetic risk score, he explained.

Dr. Marston and his associates used data collected in the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48) trial, which was designed to assess the safety and efficacy of the direct-acting oral anticoagulant edoxaban in patients with AFib (New Engl J Med. 2013 Nov 28; 369[21]: 2091-2104). The 32-loci panel to measure a person’s genetic risk for stroke came from a 2018 report by a multinational team of researchers (Nature Genetics. 2018 Apr;50[4]: 524-37). The new analysis applied this 32-loci genetic test panel to 11.164 unrelated AFib patients with European ancestry from the ENGAGE AF-TIMIT 48 database. They divided this cohort into tertiles based on having a low, intermediate, or high stroke risk as assessed by the 32-loci genetic test. The analysis focused on patients enrolled in the trial who had European ancestry because the 32-loci screening test relied predominantly on data collected from people with this genetic background, Dr. Marston said.

mzoler@mdedge.com

SOURCE: Marston NA et al. AHA 2019, Abstract 336.

PHILADELPHIA – A 32-gene screening test for stroke risk identified a subgroup of atrial fibrillation (AFib) patients with an elevated rate of ischemic strokes despite having a low stroke risk by conventional criteria by their CHA2DS2-VASc score in a post-hoc analysis of more than 11,000 patients enrolled in a recent drug trial.

Mitchel L. Zoler/MDedge News

Overall, AFib patients in the highest tertile for genetic risk based on a 32 gene-loci test had a 31% increase rate of ischemic stroke during a median 2.8 years of follow-up compared with patients in the tertile with the lowest risk based on the 32-loci screen, Nicholas A. Marston, MD, said at the American Heart Association scientific sessions. This suggested that the genetic test had roughly the same association with an increased stroke risk as several components of the CHA2DS2-VASc score, such as female sex, an age of 65-74 years old, or having heart failure as a comorbidity, each of which links with an increased risk for ischemic stroke of about 31%-38%, Dr. Marston noted.

The genetic test produced even sharper discrimination among the patients with the lowest stroke risk as measured by their CHA2DS2-VASc score (Circulation. 2012 Aug 14;126[7]: 860-5). Among the slightly more than 3,000 patients in the study with a CHA2DS2-VASc score of three or less, those in the subgroup with the highest risk by the 32-loci screen had a stroke rate during follow-up that was 76% higher than those in the low or intermediate tertile for their genetic score. Among the 796 patients with a CHA2DS2-VASc score of just 1 or 2, those who also fell into the highest level of risk on the 32-loci screen had a stroke rate 3.5-fold higher than those with a similar CHA2DS2-VASc score but in the low and intermediate tertiles by the 32-loci screen.

The additional risk prediction provided by the 32-loci test was statistically significant in the analysis of the 3,071 patients with a CHA2DS2-VASc score of 3 or less after adjustment for age, sex, ancestry, and the individual components of the CHA2DS2-VASc score, which includes factors such as hypertension, diabetes, and heart failure, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. The 3.5-fold elevation among patients with a high genetic-risk score in the cohort of 796 patients with a CHA2DS2-VASc score of 1 or 2 just missed statistical significance (P = .06), possibly because the number of patients in the analysis was relatively low. Future research should explore the predictive value of the genetic risk score in patients with a CHA2DS2-VASc score of 0 or 1, the “group where therapeutic decisions could be altered” depending on the genetic risk score, he explained.

Dr. Marston and his associates used data collected in the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48) trial, which was designed to assess the safety and efficacy of the direct-acting oral anticoagulant edoxaban in patients with AFib (New Engl J Med. 2013 Nov 28; 369[21]: 2091-2104). The 32-loci panel to measure a person’s genetic risk for stroke came from a 2018 report by a multinational team of researchers (Nature Genetics. 2018 Apr;50[4]: 524-37). The new analysis applied this 32-loci genetic test panel to 11.164 unrelated AFib patients with European ancestry from the ENGAGE AF-TIMIT 48 database. They divided this cohort into tertiles based on having a low, intermediate, or high stroke risk as assessed by the 32-loci genetic test. The analysis focused on patients enrolled in the trial who had European ancestry because the 32-loci screening test relied predominantly on data collected from people with this genetic background, Dr. Marston said.

mzoler@mdedge.com

SOURCE: Marston NA et al. AHA 2019, Abstract 336.

PHILADELPHIA – A 32-gene screening test for stroke risk identified a subgroup of atrial fibrillation (AFib) patients with an elevated rate of ischemic strokes despite having a low stroke risk by conventional criteria by their CHA2DS2-VASc score in a post-hoc analysis of more than 11,000 patients enrolled in a recent drug trial.

Mitchel L. Zoler/MDedge News

Overall, AFib patients in the highest tertile for genetic risk based on a 32 gene-loci test had a 31% increase rate of ischemic stroke during a median 2.8 years of follow-up compared with patients in the tertile with the lowest risk based on the 32-loci screen, Nicholas A. Marston, MD, said at the American Heart Association scientific sessions. This suggested that the genetic test had roughly the same association with an increased stroke risk as several components of the CHA2DS2-VASc score, such as female sex, an age of 65-74 years old, or having heart failure as a comorbidity, each of which links with an increased risk for ischemic stroke of about 31%-38%, Dr. Marston noted.

The genetic test produced even sharper discrimination among the patients with the lowest stroke risk as measured by their CHA2DS2-VASc score (Circulation. 2012 Aug 14;126[7]: 860-5). Among the slightly more than 3,000 patients in the study with a CHA2DS2-VASc score of three or less, those in the subgroup with the highest risk by the 32-loci screen had a stroke rate during follow-up that was 76% higher than those in the low or intermediate tertile for their genetic score. Among the 796 patients with a CHA2DS2-VASc score of just 1 or 2, those who also fell into the highest level of risk on the 32-loci screen had a stroke rate 3.5-fold higher than those with a similar CHA2DS2-VASc score but in the low and intermediate tertiles by the 32-loci screen.

The additional risk prediction provided by the 32-loci test was statistically significant in the analysis of the 3,071 patients with a CHA2DS2-VASc score of 3 or less after adjustment for age, sex, ancestry, and the individual components of the CHA2DS2-VASc score, which includes factors such as hypertension, diabetes, and heart failure, said Dr. Marston, a cardiologist at Brigham and Women’s Hospital in Boston. The 3.5-fold elevation among patients with a high genetic-risk score in the cohort of 796 patients with a CHA2DS2-VASc score of 1 or 2 just missed statistical significance (P = .06), possibly because the number of patients in the analysis was relatively low. Future research should explore the predictive value of the genetic risk score in patients with a CHA2DS2-VASc score of 0 or 1, the “group where therapeutic decisions could be altered” depending on the genetic risk score, he explained.

Dr. Marston and his associates used data collected in the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48) trial, which was designed to assess the safety and efficacy of the direct-acting oral anticoagulant edoxaban in patients with AFib (New Engl J Med. 2013 Nov 28; 369[21]: 2091-2104). The 32-loci panel to measure a person’s genetic risk for stroke came from a 2018 report by a multinational team of researchers (Nature Genetics. 2018 Apr;50[4]: 524-37). The new analysis applied this 32-loci genetic test panel to 11.164 unrelated AFib patients with European ancestry from the ENGAGE AF-TIMIT 48 database. They divided this cohort into tertiles based on having a low, intermediate, or high stroke risk as assessed by the 32-loci genetic test. The analysis focused on patients enrolled in the trial who had European ancestry because the 32-loci screening test relied predominantly on data collected from people with this genetic background, Dr. Marston said.

mzoler@mdedge.com

SOURCE: Marston NA et al. AHA 2019, Abstract 336.

Despite several reports of dramatic efficacy and reasonable safety using catheter ablation of atrial fibrillation (AFib) in patients with heart failure, many clinicians, including many heart failure specialists, remain skeptical about whether existing evidence supports using ablation routinely in selected heart failure patients.

Mitchel L. Zoler/MDedge News

Though concerns vary, one core stumbling block is inadequate confidence that the ablation outcomes reported from studies represent the benefit that the average American heart failure patient might expect to receive from ablation done outside of a study. A related issue is whether atrial fibrillation ablation in patients with heart failure is cost effective, especially at sites that did not participate in the published studies.

The first part of this article discussed the building evidence that radiofrequency catheter ablation of atrial fibrillation (AFib) can produce striking reductions in all-cause mortality of nearly 50%, and a greater than one-third cut in cardiovascular hospitalizations in patients with heart failure with reduced ejection fraction (HFrEF), according to one recent meta-analysis (Circ Arrhythm Electrophysiol. 2019 Sep;12[9]:e007414). A key question about the implications of these findings is their generalizability.

“Experience is an issue, and I agree that not every operator should do it. A common perception is that ablation doesn’t work, but that mindset is changing,” said Luigi Di Biase, MD, director of arrhythmia services at Montefiore Medical Center and professor of medicine at Albert Einstein College of Medicine in New York. He noted that some apparent ablations failures happen because the treatment is used too late. “Ablation will fail if it is done too late. Think about using ablation earlier,” he advised. “The earlier you ablate, the earlier you reduce the AFib burden and the sooner the patient benefits. Ablation is a cost-effective, first-line strategy for younger patients with paroxysmal AFib. The unanswered question is whether it is cost effective for patients who have both AFib and heart failure. It may be, because in addition to the mortality benefit, there are likely savings from a lower rate of hospitalizations. A clearer picture should emerge from the cost-effectiveness analysis of CASTLE-AF.”

CASTLE-AF (Catheter Ablation Versus Standard Conventional Therapy in Patients With Left Ventricular Dysfunction and Atrial Fibrillation), which randomized patients with heart failure and AFib to ablation or medical management (N Engl J Med. 2018 Feb 1;378[5]:417-27), is one of the highest-profile studies reported so far showing AFib ablation’s efficacy in patients with heart failure. However, it has drawn skepticism over its generalizability because of its long enrollment period of 8 years despite running at 33 worldwide sites, and by its winnowing of 3,013 patients assessed down to the 398 actually enrolled and 363 randomized and included in the efficacy analysis.

“CASTLE-HF showed a remarkable benefit. The problem was that it took years and years to enroll the patients,” commented Mariell Jessup, MD, a heart failure specialist and chief science and medical officer of the American Heart Association in Dallas.

At the annual congress of the European Society of Cardiology in September 2019, French researchers reported data that supported the generalizability of the CASTLE-AF findings. The study used data collected from 252,395 patients in the French national hospital-discharge database during 2010-2018 who had diagnoses of both heart failure and AFib. Among these patients, 1,384 underwent catheter ablation and the remaining 251,011 were managed without ablation.

During a median follow-up of 537 days (about 1.5 years), the incidence of both all-cause death and heart failure hospitalization were both significantly lower in the ablated patients. The ablated patients were also much younger and were more often men, but both groups had several prevalent comorbidities at roughly similar rates. To better match the groups, the French researchers ran both a multivariate analysis, and then an even more intensively adjusting propensity-score analysis that compared the ablated patients with 1,384 closely matched patients from the nonablated group. Both analyses showed substantial incremental benefit from ablation. In the propensity score–matched analysis, ablation was linked with a relative 66% cut in all-cause death, and a relative 71% reduction in heart failure hospitalizations, compared with the patients who did not undergo ablation, reported Arnaud Bisson, MD, a cardiologist at the University of Tours (France).

Another recent assessment of the generalizability of the AFib ablation trial findings used data from nearly 184,000 U.S. patients treated for AFib during 2009-2016 in an administrative database, including more than 12,000 treated with ablation. This analysis did not take into account the coexistence of heart failure. After propensity-score matching of the ablated patients with a similar subgroup of those managed medically, the results showed a 25% relative cut in the combined primary endpoint used in the CABANA (Catheter Ablation vs. Anti-Arrhythmic Drug Therapy for Atrial Fibrillation Trial) study (JAMA. 2019 Mar 15;321[134]:1261-74). Among the 74% of ablated patients who met the enrollment criteria for CABANA, the primary endpoint reduction was even greater, a 30% drop relative to matched patients who did not undergo ablation (Eur Heart J. 2019 Apr 21;40[16]:1257-64).

Mitchel L. Zoler/MDedge News

“Professional societies are working to clarify best practices for procedural volume, outcomes, etc.,” said Jonathan P. Piccini, MD, a cardiac electrophysiologist at Duke University, Durham, N.C., and a CABANA coinvestigator. “There are some data on ablation cost effectiveness, and they generally favor” positive cost efficacy, with more analyses now in progress,” he noted in an interview.

Many unanswered questions remain about AFib in heart failure patients and how aggressively to use ablation to treat it. Most of the data so far have come from patients with HFrEF, and so most experts consider AFib ablation in patients with heart failure with preserved ejection fraction (HFpEF) a big unknown, although nearly 80% of the heart failure patients enrolled in CABANA (the largest randomized trial of AFib ablation with more than 2,200 patients) had left ventricular ejection fraction of 50% or greater, which translates into HFpEF. Another gray area is how to think about asymptomatic (also called subclinical) AFib and whether that warrants ablation in heart failure patients. The presence or absence of symptoms is a major consideration because the traditional indication for ablation has been to reduce or eliminate symptoms like palpitations, a step that can substantially improve patients’ quality of life as well as their left ventricular function. The indication to ablate asymptomatic AFib for the purpose of improving survival and reducing hospitalizations is the new and controversial concept. Yet it has been embraced by some heart failure physicians.

“Whether or not AFib is symptomatic doesn’t matter” in a heart failure patient, said Maria Rosa Costanzo, MD, a heart failure physician at Edward Heart Hospital in Naperville, Ill. “A patient with AFib doesn’t get the atrial contribution to cardiac output. When we look deeper, a patient with ‘asymptomatic’ AFib often has symptoms, such as new fatigue or obstructive sleep apnea, so when you see a patient with asymptomatic AFib look for sleep apnea, a trigger for AFib,” Dr. Costanzo advised. “Sleep apnea, AFib, and heart failure form a triad” that often clusters in patients, and the three conditions interact in a vicious circle of reinforcing comorbidities, she said in an interview.

The cardiac electrophysiology and arrhythmia community clearly realizes that catheter ablation of AFib, in patients with or without heart failure, has many unaddressed questions about who should administer it and who should undergo it. In March 2019, the National Heart, Lung, and Blood Institute held a workshop on AFib ablation. “Numerous knowledge gaps remain” about the best way to use ablation, said a summary of the workshop (Circulation. 2019 Nov 20;doi: 10.1161/CIRCULATIONAHA.119.042706). Among the research needs highlighted by the workshop was “more definitive studies ... to delineate the impact of AFib ablation on outcomes in patients with heart failure with preserved ejection fraction.” The workshop recommended establishing a national U.S. registry for AFib ablations with a reliable source of funding, as well as “establishing the cause-effect relationship between ventricular dysfunction and AFib, and the potential moderating role of atrial structure and function.” The workshop also raised the possibility of sham-controlled assessments of AFib ablation, while conceding that enrollment into such trials would probably be very challenging.

The upshot is that, even while ablation advocates agree on the need for more study, clinicians are using AFib ablation on a growing number of heart failure patients (as well as on growing numbers of patients with AFib but without heart failure), with a focus on treating those who “have refractory symptoms or evidence of tachycardia-induced cardiomyopathy,” said Dr. Piccini. Extending that to a first-line, class I indication for heart failure patients seems to need more data, and also needs clinicians to collectively raise their comfort level with the ablation concept. If results from additional studies now underway support the dramatic efficacy and reasonable safety that’s already been seen with ablation, then increased comfort should follow.

CABANA received funding from Biosense Webster, Boston Scientific, Medtronic, and St. Jude. CASTLE-AF was funded by Biotronik. Dr. Di Biase, Dr. Jessup, and Dr. Bisson had no disclosures. Dr. Piccini has been a consultant to Allergan, Biotronik, Medtronic, Phillips, and Sanofi Aventis; he has received research funding from Abbott, ARCA, Boston Scientific, Gilead, and Johnson & Johnson; and he had a financial relationship with GlaxoSmithKline. Dr. Costanzo has been a consultant to Abbott.

This is part 2 of a 2-part story. See part 1 here.

mzoler@mdedge.com

Despite several reports of dramatic efficacy and reasonable safety using catheter ablation of atrial fibrillation (AFib) in patients with heart failure, many clinicians, including many heart failure specialists, remain skeptical about whether existing evidence supports using ablation routinely in selected heart failure patients.

Mitchel L. Zoler/MDedge News

Though concerns vary, one core stumbling block is inadequate confidence that the ablation outcomes reported from studies represent the benefit that the average American heart failure patient might expect to receive from ablation done outside of a study. A related issue is whether atrial fibrillation ablation in patients with heart failure is cost effective, especially at sites that did not participate in the published studies.

The first part of this article discussed the building evidence that radiofrequency catheter ablation of atrial fibrillation (AFib) can produce striking reductions in all-cause mortality of nearly 50%, and a greater than one-third cut in cardiovascular hospitalizations in patients with heart failure with reduced ejection fraction (HFrEF), according to one recent meta-analysis (Circ Arrhythm Electrophysiol. 2019 Sep;12[9]:e007414). A key question about the implications of these findings is their generalizability.

“Experience is an issue, and I agree that not every operator should do it. A common perception is that ablation doesn’t work, but that mindset is changing,” said Luigi Di Biase, MD, director of arrhythmia services at Montefiore Medical Center and professor of medicine at Albert Einstein College of Medicine in New York. He noted that some apparent ablations failures happen because the treatment is used too late. “Ablation will fail if it is done too late. Think about using ablation earlier,” he advised. “The earlier you ablate, the earlier you reduce the AFib burden and the sooner the patient benefits. Ablation is a cost-effective, first-line strategy for younger patients with paroxysmal AFib. The unanswered question is whether it is cost effective for patients who have both AFib and heart failure. It may be, because in addition to the mortality benefit, there are likely savings from a lower rate of hospitalizations. A clearer picture should emerge from the cost-effectiveness analysis of CASTLE-AF.”

CASTLE-AF (Catheter Ablation Versus Standard Conventional Therapy in Patients With Left Ventricular Dysfunction and Atrial Fibrillation), which randomized patients with heart failure and AFib to ablation or medical management (N Engl J Med. 2018 Feb 1;378[5]:417-27), is one of the highest-profile studies reported so far showing AFib ablation’s efficacy in patients with heart failure. However, it has drawn skepticism over its generalizability because of its long enrollment period of 8 years despite running at 33 worldwide sites, and by its winnowing of 3,013 patients assessed down to the 398 actually enrolled and 363 randomized and included in the efficacy analysis.

“CASTLE-HF showed a remarkable benefit. The problem was that it took years and years to enroll the patients,” commented Mariell Jessup, MD, a heart failure specialist and chief science and medical officer of the American Heart Association in Dallas.

At the annual congress of the European Society of Cardiology in September 2019, French researchers reported data that supported the generalizability of the CASTLE-AF findings. The study used data collected from 252,395 patients in the French national hospital-discharge database during 2010-2018 who had diagnoses of both heart failure and AFib. Among these patients, 1,384 underwent catheter ablation and the remaining 251,011 were managed without ablation.

During a median follow-up of 537 days (about 1.5 years), the incidence of both all-cause death and heart failure hospitalization were both significantly lower in the ablated patients. The ablated patients were also much younger and were more often men, but both groups had several prevalent comorbidities at roughly similar rates. To better match the groups, the French researchers ran both a multivariate analysis, and then an even more intensively adjusting propensity-score analysis that compared the ablated patients with 1,384 closely matched patients from the nonablated group. Both analyses showed substantial incremental benefit from ablation. In the propensity score–matched analysis, ablation was linked with a relative 66% cut in all-cause death, and a relative 71% reduction in heart failure hospitalizations, compared with the patients who did not undergo ablation, reported Arnaud Bisson, MD, a cardiologist at the University of Tours (France).

Another recent assessment of the generalizability of the AFib ablation trial findings used data from nearly 184,000 U.S. patients treated for AFib during 2009-2016 in an administrative database, including more than 12,000 treated with ablation. This analysis did not take into account the coexistence of heart failure. After propensity-score matching of the ablated patients with a similar subgroup of those managed medically, the results showed a 25% relative cut in the combined primary endpoint used in the CABANA (Catheter Ablation vs. Anti-Arrhythmic Drug Therapy for Atrial Fibrillation Trial) study (JAMA. 2019 Mar 15;321[134]:1261-74). Among the 74% of ablated patients who met the enrollment criteria for CABANA, the primary endpoint reduction was even greater, a 30% drop relative to matched patients who did not undergo ablation (Eur Heart J. 2019 Apr 21;40[16]:1257-64).

Mitchel L. Zoler/MDedge News

“Professional societies are working to clarify best practices for procedural volume, outcomes, etc.,” said Jonathan P. Piccini, MD, a cardiac electrophysiologist at Duke University, Durham, N.C., and a CABANA coinvestigator. “There are some data on ablation cost effectiveness, and they generally favor” positive cost efficacy, with more analyses now in progress,” he noted in an interview.

Many unanswered questions remain about AFib in heart failure patients and how aggressively to use ablation to treat it. Most of the data so far have come from patients with HFrEF, and so most experts consider AFib ablation in patients with heart failure with preserved ejection fraction (HFpEF) a big unknown, although nearly 80% of the heart failure patients enrolled in CABANA (the largest randomized trial of AFib ablation with more than 2,200 patients) had left ventricular ejection fraction of 50% or greater, which translates into HFpEF. Another gray area is how to think about asymptomatic (also called subclinical) AFib and whether that warrants ablation in heart failure patients. The presence or absence of symptoms is a major consideration because the traditional indication for ablation has been to reduce or eliminate symptoms like palpitations, a step that can substantially improve patients’ quality of life as well as their left ventricular function. The indication to ablate asymptomatic AFib for the purpose of improving survival and reducing hospitalizations is the new and controversial concept. Yet it has been embraced by some heart failure physicians.

“Whether or not AFib is symptomatic doesn’t matter” in a heart failure patient, said Maria Rosa Costanzo, MD, a heart failure physician at Edward Heart Hospital in Naperville, Ill. “A patient with AFib doesn’t get the atrial contribution to cardiac output. When we look deeper, a patient with ‘asymptomatic’ AFib often has symptoms, such as new fatigue or obstructive sleep apnea, so when you see a patient with asymptomatic AFib look for sleep apnea, a trigger for AFib,” Dr. Costanzo advised. “Sleep apnea, AFib, and heart failure form a triad” that often clusters in patients, and the three conditions interact in a vicious circle of reinforcing comorbidities, she said in an interview.

The cardiac electrophysiology and arrhythmia community clearly realizes that catheter ablation of AFib, in patients with or without heart failure, has many unaddressed questions about who should administer it and who should undergo it. In March 2019, the National Heart, Lung, and Blood Institute held a workshop on AFib ablation. “Numerous knowledge gaps remain” about the best way to use ablation, said a summary of the workshop (Circulation. 2019 Nov 20;doi: 10.1161/CIRCULATIONAHA.119.042706). Among the research needs highlighted by the workshop was “more definitive studies ... to delineate the impact of AFib ablation on outcomes in patients with heart failure with preserved ejection fraction.” The workshop recommended establishing a national U.S. registry for AFib ablations with a reliable source of funding, as well as “establishing the cause-effect relationship between ventricular dysfunction and AFib, and the potential moderating role of atrial structure and function.” The workshop also raised the possibility of sham-controlled assessments of AFib ablation, while conceding that enrollment into such trials would probably be very challenging.

The upshot is that, even while ablation advocates agree on the need for more study, clinicians are using AFib ablation on a growing number of heart failure patients (as well as on growing numbers of patients with AFib but without heart failure), with a focus on treating those who “have refractory symptoms or evidence of tachycardia-induced cardiomyopathy,” said Dr. Piccini. Extending that to a first-line, class I indication for heart failure patients seems to need more data, and also needs clinicians to collectively raise their comfort level with the ablation concept. If results from additional studies now underway support the dramatic efficacy and reasonable safety that’s already been seen with ablation, then increased comfort should follow.

CABANA received funding from Biosense Webster, Boston Scientific, Medtronic, and St. Jude. CASTLE-AF was funded by Biotronik. Dr. Di Biase, Dr. Jessup, and Dr. Bisson had no disclosures. Dr. Piccini has been a consultant to Allergan, Biotronik, Medtronic, Phillips, and Sanofi Aventis; he has received research funding from Abbott, ARCA, Boston Scientific, Gilead, and Johnson & Johnson; and he had a financial relationship with GlaxoSmithKline. Dr. Costanzo has been a consultant to Abbott.

This is part 2 of a 2-part story. See part 1 here.

mzoler@mdedge.com

Despite several reports of dramatic efficacy and reasonable safety using catheter ablation of atrial fibrillation (AFib) in patients with heart failure, many clinicians, including many heart failure specialists, remain skeptical about whether existing evidence supports using ablation routinely in selected heart failure patients.

Mitchel L. Zoler/MDedge News

Though concerns vary, one core stumbling block is inadequate confidence that the ablation outcomes reported from studies represent the benefit that the average American heart failure patient might expect to receive from ablation done outside of a study. A related issue is whether atrial fibrillation ablation in patients with heart failure is cost effective, especially at sites that did not participate in the published studies.

The first part of this article discussed the building evidence that radiofrequency catheter ablation of atrial fibrillation (AFib) can produce striking reductions in all-cause mortality of nearly 50%, and a greater than one-third cut in cardiovascular hospitalizations in patients with heart failure with reduced ejection fraction (HFrEF), according to one recent meta-analysis (Circ Arrhythm Electrophysiol. 2019 Sep;12[9]:e007414). A key question about the implications of these findings is their generalizability.

“Experience is an issue, and I agree that not every operator should do it. A common perception is that ablation doesn’t work, but that mindset is changing,” said Luigi Di Biase, MD, director of arrhythmia services at Montefiore Medical Center and professor of medicine at Albert Einstein College of Medicine in New York. He noted that some apparent ablations failures happen because the treatment is used too late. “Ablation will fail if it is done too late. Think about using ablation earlier,” he advised. “The earlier you ablate, the earlier you reduce the AFib burden and the sooner the patient benefits. Ablation is a cost-effective, first-line strategy for younger patients with paroxysmal AFib. The unanswered question is whether it is cost effective for patients who have both AFib and heart failure. It may be, because in addition to the mortality benefit, there are likely savings from a lower rate of hospitalizations. A clearer picture should emerge from the cost-effectiveness analysis of CASTLE-AF.”

CASTLE-AF (Catheter Ablation Versus Standard Conventional Therapy in Patients With Left Ventricular Dysfunction and Atrial Fibrillation), which randomized patients with heart failure and AFib to ablation or medical management (N Engl J Med. 2018 Feb 1;378[5]:417-27), is one of the highest-profile studies reported so far showing AFib ablation’s efficacy in patients with heart failure. However, it has drawn skepticism over its generalizability because of its long enrollment period of 8 years despite running at 33 worldwide sites, and by its winnowing of 3,013 patients assessed down to the 398 actually enrolled and 363 randomized and included in the efficacy analysis.

“CASTLE-HF showed a remarkable benefit. The problem was that it took years and years to enroll the patients,” commented Mariell Jessup, MD, a heart failure specialist and chief science and medical officer of the American Heart Association in Dallas.

At the annual congress of the European Society of Cardiology in September 2019, French researchers reported data that supported the generalizability of the CASTLE-AF findings. The study used data collected from 252,395 patients in the French national hospital-discharge database during 2010-2018 who had diagnoses of both heart failure and AFib. Among these patients, 1,384 underwent catheter ablation and the remaining 251,011 were managed without ablation.

During a median follow-up of 537 days (about 1.5 years), the incidence of both all-cause death and heart failure hospitalization were both significantly lower in the ablated patients. The ablated patients were also much younger and were more often men, but both groups had several prevalent comorbidities at roughly similar rates. To better match the groups, the French researchers ran both a multivariate analysis, and then an even more intensively adjusting propensity-score analysis that compared the ablated patients with 1,384 closely matched patients from the nonablated group. Both analyses showed substantial incremental benefit from ablation. In the propensity score–matched analysis, ablation was linked with a relative 66% cut in all-cause death, and a relative 71% reduction in heart failure hospitalizations, compared with the patients who did not undergo ablation, reported Arnaud Bisson, MD, a cardiologist at the University of Tours (France).

Another recent assessment of the generalizability of the AFib ablation trial findings used data from nearly 184,000 U.S. patients treated for AFib during 2009-2016 in an administrative database, including more than 12,000 treated with ablation. This analysis did not take into account the coexistence of heart failure. After propensity-score matching of the ablated patients with a similar subgroup of those managed medically, the results showed a 25% relative cut in the combined primary endpoint used in the CABANA (Catheter Ablation vs. Anti-Arrhythmic Drug Therapy for Atrial Fibrillation Trial) study (JAMA. 2019 Mar 15;321[134]:1261-74). Among the 74% of ablated patients who met the enrollment criteria for CABANA, the primary endpoint reduction was even greater, a 30% drop relative to matched patients who did not undergo ablation (Eur Heart J. 2019 Apr 21;40[16]:1257-64).

Mitchel L. Zoler/MDedge News

“Professional societies are working to clarify best practices for procedural volume, outcomes, etc.,” said Jonathan P. Piccini, MD, a cardiac electrophysiologist at Duke University, Durham, N.C., and a CABANA coinvestigator. “There are some data on ablation cost effectiveness, and they generally favor” positive cost efficacy, with more analyses now in progress,” he noted in an interview.

Many unanswered questions remain about AFib in heart failure patients and how aggressively to use ablation to treat it. Most of the data so far have come from patients with HFrEF, and so most experts consider AFib ablation in patients with heart failure with preserved ejection fraction (HFpEF) a big unknown, although nearly 80% of the heart failure patients enrolled in CABANA (the largest randomized trial of AFib ablation with more than 2,200 patients) had left ventricular ejection fraction of 50% or greater, which translates into HFpEF. Another gray area is how to think about asymptomatic (also called subclinical) AFib and whether that warrants ablation in heart failure patients. The presence or absence of symptoms is a major consideration because the traditional indication for ablation has been to reduce or eliminate symptoms like palpitations, a step that can substantially improve patients’ quality of life as well as their left ventricular function. The indication to ablate asymptomatic AFib for the purpose of improving survival and reducing hospitalizations is the new and controversial concept. Yet it has been embraced by some heart failure physicians.

“Whether or not AFib is symptomatic doesn’t matter” in a heart failure patient, said Maria Rosa Costanzo, MD, a heart failure physician at Edward Heart Hospital in Naperville, Ill. “A patient with AFib doesn’t get the atrial contribution to cardiac output. When we look deeper, a patient with ‘asymptomatic’ AFib often has symptoms, such as new fatigue or obstructive sleep apnea, so when you see a patient with asymptomatic AFib look for sleep apnea, a trigger for AFib,” Dr. Costanzo advised. “Sleep apnea, AFib, and heart failure form a triad” that often clusters in patients, and the three conditions interact in a vicious circle of reinforcing comorbidities, she said in an interview.

The cardiac electrophysiology and arrhythmia community clearly realizes that catheter ablation of AFib, in patients with or without heart failure, has many unaddressed questions about who should administer it and who should undergo it. In March 2019, the National Heart, Lung, and Blood Institute held a workshop on AFib ablation. “Numerous knowledge gaps remain” about the best way to use ablation, said a summary of the workshop (Circulation. 2019 Nov 20;doi: 10.1161/CIRCULATIONAHA.119.042706). Among the research needs highlighted by the workshop was “more definitive studies ... to delineate the impact of AFib ablation on outcomes in patients with heart failure with preserved ejection fraction.” The workshop recommended establishing a national U.S. registry for AFib ablations with a reliable source of funding, as well as “establishing the cause-effect relationship between ventricular dysfunction and AFib, and the potential moderating role of atrial structure and function.” The workshop also raised the possibility of sham-controlled assessments of AFib ablation, while conceding that enrollment into such trials would probably be very challenging.

The upshot is that, even while ablation advocates agree on the need for more study, clinicians are using AFib ablation on a growing number of heart failure patients (as well as on growing numbers of patients with AFib but without heart failure), with a focus on treating those who “have refractory symptoms or evidence of tachycardia-induced cardiomyopathy,” said Dr. Piccini. Extending that to a first-line, class I indication for heart failure patients seems to need more data, and also needs clinicians to collectively raise their comfort level with the ablation concept. If results from additional studies now underway support the dramatic efficacy and reasonable safety that’s already been seen with ablation, then increased comfort should follow.

CABANA received funding from Biosense Webster, Boston Scientific, Medtronic, and St. Jude. CASTLE-AF was funded by Biotronik. Dr. Di Biase, Dr. Jessup, and Dr. Bisson had no disclosures. Dr. Piccini has been a consultant to Allergan, Biotronik, Medtronic, Phillips, and Sanofi Aventis; he has received research funding from Abbott, ARCA, Boston Scientific, Gilead, and Johnson & Johnson; and he had a financial relationship with GlaxoSmithKline. Dr. Costanzo has been a consultant to Abbott.

This is part 2 of a 2-part story. See part 1 here.

mzoler@mdedge.com

PHILADELPHIA – The definition and treatment of heart failure with reduced ejection fraction should change based on recent findings and analyses from major trials, said a key heart failure leader at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The people charged with writing U.S. guidelines for heart failure management already have enough evidence to change the recommended way of using sacubitril/valsartan (Entresto) in patients with heart failure with reduced ejection fraction (HFrEF), said Clyde W. Yancy, MD, professor of medicine and chief of cardiology at Northwestern University, Chicago. Accumulated evidence from studies and more than 5 years of experience in routine practice with the angiotensin receptor neprilysin inhibitor (ARNI) combination sacubitril/valsartan for treating HFrEF patients justifies striking the existing recommendation to first start patients on an ACE inhibitor or angiotensin receptor blocker and only after that switching to sacubitril/valsartan, a sequence that has rankled some clinicians as an unnecessary delay and barrier to starting patients on the ARNI regimen.

U.S. guidelines should now suggest that ARNI treatment start immediately, suggested Dr. Yancy, who chaired the AHA/American College of Cardiology panel that updated U.S. guidelines for heart failure management in 2013 (Circulation. 2013 Oct 15;128[16]:e240-327), 2016 (J Am Coll Cardiol. 2016 Sep;68[13]:1476-88), and 2017 (Circulation. 2017 Aug 8; 136[6]:e137-61).

Expanding the heart failure group for sacubitril/valsartan

Dr. Yancy also proposed a second major and immediate change to the existing heart failure guideline based on a new appreciation of a heart failure population that could benefit from ARNI treatment: patients with “mid-range” heart failure, defined by a left ventricular ejection fraction (LVEF) of 41%-49% that places them between patients with HFrEF with an ejection fraction of 40% or less, and those with heart failure with preserved ejection fraction (HFpEF) of 50% or more. As yet unchanged in the 2013 AHA/ACC heart failure guideline is the proposition that patients with heart failure and an ejection fraction of 41%-49% have “borderline” heart failure with characteristics, treatment patterns, and outcomes “similar to patients with HFpEF.”

That premise should now go out the window, urged Dr. Yancy, based on a new analysis of data collected from both the recent PARAGON-HF trial of sacubitril/valsartan in patients with HFpEF and ejection fractions of 45% or higher (N Engl J Med. 2019 Oct 24;381[17]:1609-20) and the landmark PARADIGM-HF trial that established sacubitril/valsartan as a treatment for patients with HFrEF (N Engl J Med. 2014 Sep 11;371[11]:993-1004). A combined analysis of the more than 13,000 total patients in both studies suggested that “patients with ejection fraction lower than normal, which includes those with so-called heart failure with mid-range ejection fraction or borderline ejection fraction, would likely benefit from sacubitril/valsartan, compared with RAS inhibition,” concluded the authors of the new analysis (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044586).

Dr. Yancy argued that, based on this new analysis, a further revision to the 2013 guideline should say that patients with heart failure with a LVEF of 41%-49% have characteristics, treatment responses, and outcomes that “appear similar to those of patient with HFrEF,” a sharp departure from the existing text that lumps these patients with the HFpEF subgroup. “There appears to be a signal that extends the benefit of ARNI to patients with ejection fractions above the current threshold for HFrEF but below what is typically HFpEF,” he said.

Bringing SGLT2 inhibitors into heart failure management

Dr. Yancy also cited recently reported data from another landmark trial, DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), as an impetus for both another immediate change to the guideline and for a potential second change pending a report of confirmatory evidence that may arrive in 2020.

The DAPA-HF results showed that the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) was just as effective for preventing all-cause death and heart failure hospitalizations and urgent visits in patients without type 2 diabetes as it is in patients with type 2 diabetes (N Engl J Med. 2019 Nov 21;381[21]:1995-2008), a remarkable finding for an agent that came onto the U.S. market as a diabetes drug specifically aimed at reducing levels of glycosylated hemoglobin.

Dr. Yancy proposed an immediate guideline change to acknowledge the proven protection against incident heart failure that treatment with a SGLT2 inhibitor gives patients with type 2 diabetes. There is now “a strong opportunity to use an SGLT2 inhibitor in patients with type 2 diabetes to reduce the incidence of heart failure,” he said.

And he added that, if results from EMPEROR REDUCED (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), studying the SGLT2 inhibitor empagliflozin (Jardiance) in HFrEF patients with and without type 2 diabetes, can confirm the efficacy of a second drug from this class in preventing heart failure events in patients with HFrEF but without diabetes, then the time will have arrived for another guideline change to establish the SGLT2 inhibitors as a new “foundational” drug for the management of all HFrEF patients, regardless of their level of glycemic control. The SGLT2 inhibitors are a particularly attractive additional drug because they are taken once daily orally with no need for dosage adjustment, so far they have shown excellent safety in patients without diabetes with no episodes of hypoglycemia or ketoacidosis, and they have even shown evidence for heart failure benefit in patients older than 75 years, Dr. Yancy noted.

Dr. Yancy had no relevant disclosures.

mzoler@mdedge.com

PHILADELPHIA – The definition and treatment of heart failure with reduced ejection fraction should change based on recent findings and analyses from major trials, said a key heart failure leader at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The people charged with writing U.S. guidelines for heart failure management already have enough evidence to change the recommended way of using sacubitril/valsartan (Entresto) in patients with heart failure with reduced ejection fraction (HFrEF), said Clyde W. Yancy, MD, professor of medicine and chief of cardiology at Northwestern University, Chicago. Accumulated evidence from studies and more than 5 years of experience in routine practice with the angiotensin receptor neprilysin inhibitor (ARNI) combination sacubitril/valsartan for treating HFrEF patients justifies striking the existing recommendation to first start patients on an ACE inhibitor or angiotensin receptor blocker and only after that switching to sacubitril/valsartan, a sequence that has rankled some clinicians as an unnecessary delay and barrier to starting patients on the ARNI regimen.

U.S. guidelines should now suggest that ARNI treatment start immediately, suggested Dr. Yancy, who chaired the AHA/American College of Cardiology panel that updated U.S. guidelines for heart failure management in 2013 (Circulation. 2013 Oct 15;128[16]:e240-327), 2016 (J Am Coll Cardiol. 2016 Sep;68[13]:1476-88), and 2017 (Circulation. 2017 Aug 8; 136[6]:e137-61).

Expanding the heart failure group for sacubitril/valsartan

Dr. Yancy also proposed a second major and immediate change to the existing heart failure guideline based on a new appreciation of a heart failure population that could benefit from ARNI treatment: patients with “mid-range” heart failure, defined by a left ventricular ejection fraction (LVEF) of 41%-49% that places them between patients with HFrEF with an ejection fraction of 40% or less, and those with heart failure with preserved ejection fraction (HFpEF) of 50% or more. As yet unchanged in the 2013 AHA/ACC heart failure guideline is the proposition that patients with heart failure and an ejection fraction of 41%-49% have “borderline” heart failure with characteristics, treatment patterns, and outcomes “similar to patients with HFpEF.”

That premise should now go out the window, urged Dr. Yancy, based on a new analysis of data collected from both the recent PARAGON-HF trial of sacubitril/valsartan in patients with HFpEF and ejection fractions of 45% or higher (N Engl J Med. 2019 Oct 24;381[17]:1609-20) and the landmark PARADIGM-HF trial that established sacubitril/valsartan as a treatment for patients with HFrEF (N Engl J Med. 2014 Sep 11;371[11]:993-1004). A combined analysis of the more than 13,000 total patients in both studies suggested that “patients with ejection fraction lower than normal, which includes those with so-called heart failure with mid-range ejection fraction or borderline ejection fraction, would likely benefit from sacubitril/valsartan, compared with RAS inhibition,” concluded the authors of the new analysis (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044586).

Dr. Yancy argued that, based on this new analysis, a further revision to the 2013 guideline should say that patients with heart failure with a LVEF of 41%-49% have characteristics, treatment responses, and outcomes that “appear similar to those of patient with HFrEF,” a sharp departure from the existing text that lumps these patients with the HFpEF subgroup. “There appears to be a signal that extends the benefit of ARNI to patients with ejection fractions above the current threshold for HFrEF but below what is typically HFpEF,” he said.

Bringing SGLT2 inhibitors into heart failure management

Dr. Yancy also cited recently reported data from another landmark trial, DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), as an impetus for both another immediate change to the guideline and for a potential second change pending a report of confirmatory evidence that may arrive in 2020.

The DAPA-HF results showed that the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) was just as effective for preventing all-cause death and heart failure hospitalizations and urgent visits in patients without type 2 diabetes as it is in patients with type 2 diabetes (N Engl J Med. 2019 Nov 21;381[21]:1995-2008), a remarkable finding for an agent that came onto the U.S. market as a diabetes drug specifically aimed at reducing levels of glycosylated hemoglobin.

Dr. Yancy proposed an immediate guideline change to acknowledge the proven protection against incident heart failure that treatment with a SGLT2 inhibitor gives patients with type 2 diabetes. There is now “a strong opportunity to use an SGLT2 inhibitor in patients with type 2 diabetes to reduce the incidence of heart failure,” he said.

And he added that, if results from EMPEROR REDUCED (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), studying the SGLT2 inhibitor empagliflozin (Jardiance) in HFrEF patients with and without type 2 diabetes, can confirm the efficacy of a second drug from this class in preventing heart failure events in patients with HFrEF but without diabetes, then the time will have arrived for another guideline change to establish the SGLT2 inhibitors as a new “foundational” drug for the management of all HFrEF patients, regardless of their level of glycemic control. The SGLT2 inhibitors are a particularly attractive additional drug because they are taken once daily orally with no need for dosage adjustment, so far they have shown excellent safety in patients without diabetes with no episodes of hypoglycemia or ketoacidosis, and they have even shown evidence for heart failure benefit in patients older than 75 years, Dr. Yancy noted.

Dr. Yancy had no relevant disclosures.

mzoler@mdedge.com

PHILADELPHIA – The definition and treatment of heart failure with reduced ejection fraction should change based on recent findings and analyses from major trials, said a key heart failure leader at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The people charged with writing U.S. guidelines for heart failure management already have enough evidence to change the recommended way of using sacubitril/valsartan (Entresto) in patients with heart failure with reduced ejection fraction (HFrEF), said Clyde W. Yancy, MD, professor of medicine and chief of cardiology at Northwestern University, Chicago. Accumulated evidence from studies and more than 5 years of experience in routine practice with the angiotensin receptor neprilysin inhibitor (ARNI) combination sacubitril/valsartan for treating HFrEF patients justifies striking the existing recommendation to first start patients on an ACE inhibitor or angiotensin receptor blocker and only after that switching to sacubitril/valsartan, a sequence that has rankled some clinicians as an unnecessary delay and barrier to starting patients on the ARNI regimen.

U.S. guidelines should now suggest that ARNI treatment start immediately, suggested Dr. Yancy, who chaired the AHA/American College of Cardiology panel that updated U.S. guidelines for heart failure management in 2013 (Circulation. 2013 Oct 15;128[16]:e240-327), 2016 (J Am Coll Cardiol. 2016 Sep;68[13]:1476-88), and 2017 (Circulation. 2017 Aug 8; 136[6]:e137-61).

Expanding the heart failure group for sacubitril/valsartan

Dr. Yancy also proposed a second major and immediate change to the existing heart failure guideline based on a new appreciation of a heart failure population that could benefit from ARNI treatment: patients with “mid-range” heart failure, defined by a left ventricular ejection fraction (LVEF) of 41%-49% that places them between patients with HFrEF with an ejection fraction of 40% or less, and those with heart failure with preserved ejection fraction (HFpEF) of 50% or more. As yet unchanged in the 2013 AHA/ACC heart failure guideline is the proposition that patients with heart failure and an ejection fraction of 41%-49% have “borderline” heart failure with characteristics, treatment patterns, and outcomes “similar to patients with HFpEF.”

That premise should now go out the window, urged Dr. Yancy, based on a new analysis of data collected from both the recent PARAGON-HF trial of sacubitril/valsartan in patients with HFpEF and ejection fractions of 45% or higher (N Engl J Med. 2019 Oct 24;381[17]:1609-20) and the landmark PARADIGM-HF trial that established sacubitril/valsartan as a treatment for patients with HFrEF (N Engl J Med. 2014 Sep 11;371[11]:993-1004). A combined analysis of the more than 13,000 total patients in both studies suggested that “patients with ejection fraction lower than normal, which includes those with so-called heart failure with mid-range ejection fraction or borderline ejection fraction, would likely benefit from sacubitril/valsartan, compared with RAS inhibition,” concluded the authors of the new analysis (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044586).

Dr. Yancy argued that, based on this new analysis, a further revision to the 2013 guideline should say that patients with heart failure with a LVEF of 41%-49% have characteristics, treatment responses, and outcomes that “appear similar to those of patient with HFrEF,” a sharp departure from the existing text that lumps these patients with the HFpEF subgroup. “There appears to be a signal that extends the benefit of ARNI to patients with ejection fractions above the current threshold for HFrEF but below what is typically HFpEF,” he said.

Bringing SGLT2 inhibitors into heart failure management

Dr. Yancy also cited recently reported data from another landmark trial, DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), as an impetus for both another immediate change to the guideline and for a potential second change pending a report of confirmatory evidence that may arrive in 2020.

The DAPA-HF results showed that the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) was just as effective for preventing all-cause death and heart failure hospitalizations and urgent visits in patients without type 2 diabetes as it is in patients with type 2 diabetes (N Engl J Med. 2019 Nov 21;381[21]:1995-2008), a remarkable finding for an agent that came onto the U.S. market as a diabetes drug specifically aimed at reducing levels of glycosylated hemoglobin.

Dr. Yancy proposed an immediate guideline change to acknowledge the proven protection against incident heart failure that treatment with a SGLT2 inhibitor gives patients with type 2 diabetes. There is now “a strong opportunity to use an SGLT2 inhibitor in patients with type 2 diabetes to reduce the incidence of heart failure,” he said.

And he added that, if results from EMPEROR REDUCED (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), studying the SGLT2 inhibitor empagliflozin (Jardiance) in HFrEF patients with and without type 2 diabetes, can confirm the efficacy of a second drug from this class in preventing heart failure events in patients with HFrEF but without diabetes, then the time will have arrived for another guideline change to establish the SGLT2 inhibitors as a new “foundational” drug for the management of all HFrEF patients, regardless of their level of glycemic control. The SGLT2 inhibitors are a particularly attractive additional drug because they are taken once daily orally with no need for dosage adjustment, so far they have shown excellent safety in patients without diabetes with no episodes of hypoglycemia or ketoacidosis, and they have even shown evidence for heart failure benefit in patients older than 75 years, Dr. Yancy noted.

Dr. Yancy had no relevant disclosures.

mzoler@mdedge.com

ORLANDO – Combining aspirin and direct oral anticoagulant (DOAC) therapy for the secondary prevention of venous thromboembolism (VTE) or the prevention of stroke associated with nonvalvular atrial fibrillation (NVAF) without a clear indication was associated with increased bleeding risks in a large registry-based cohort.

Sharon Worcester/MDedge News

The study, which involved a cohort of 2,045 patients who were followed at 6 anticoagulation clinics in Michigan during January 2009–June 2019, also found no apparent improvement in thrombosis incidence with the addition of aspirin, Jordan K. Schaefer, MD, reported during a press briefing at the annual meeting of the American Society of Hematology.

Of the cohort patients, 639 adults who received a DOAC plus aspirin after VTE or for NVAF without a clear indication were compared with 639 propensity-matched controls. The bleeding event rate per 100 patient years was 39.50 vs. 32.32 at an average of 15.2 months of follow-up in the combination therapy and DOAC monotherapy groups, respectively, said Dr. Schaefer of the division of hematology/oncology, department of internal medicine, University of Michigan, Ann Arbor.

“This result was statistically significant for clinically relevant non-major bleeding, with an 18.7 rate per 100 patient years, compared with 13.5 for DOAC monotherapy,” (P = .02), he said. “We also saw a significant increase in non-major bleeding with combination therapy, compared with direct oral anticoagulant monotherapy” (rate, 32.82 vs. 25.88; P =.04).

No significant difference was seen overall (P =.07) or for other specific types of bleeding, he noted.

The observed rates of thrombosis in the groups, respectively, were 2.35 and 2.23 per 100 patient years (P =.95), he said, noting that patients on combination therapy also had more emergency department visits and hospitalizations, but those differences were not statistically significant.

“Direct-acting oral anticoagulants, which include apixaban, dabigatran, edoxaban, and rivaroxaban, are increasingly used in clinical practice for indications that include the prevention of strokes for patients with nonvalvular atrial fibrillation, and the treatment and secondary prevention of venous thromboembolic disease,” Dr. Schaefer said.

Aspirin is commonly used in clinical practice for various indications, including primary prevention of heart attacks, strokes, and colorectal cancer, as well as for thromboprophylaxis in patients with certain blood disorders or with certain cardiac devices, he added.

“Aspirin is used for the secondary prevention of thrombosis for patients with known coronary artery disease, peripheral artery disease, or carotid artery disease,” he said. “And while adding aspirin to a DOAC is often appropriate after acute coronary syndromes or percutaneous coronary intervention, many patients receive the combination therapy without a clear indication, he said, noting that increasing evidence in recent years, largely from patients treated with warfarin and aspirin, suggest that the approach may do more harm than good for certain patients.

Specifically, there’s a question of whether aspirin is increasing the rates of bleeding without protecting patients from adverse thrombotic outcomes.

“This has specifically been a concern for patients who are on full-dose anticoagulation,” he said.

In the current study, patient demographics, comorbidities, and concurrent medications were well balanced in the treatment and control groups after propensity score matching, he said, noting that patients with a history of heart valve replacement, recent MI, or less than 3 months of follow-up were excluded.

“These findings need to be confirmed in larger studies, but until such data [are] available, clinicians and patients should continue to balance the relative risks and benefits of adding aspirin to their direct oral anticoagulant therapy,” Dr. Schaefer said. “Further research needs to evaluate key subgroups to see if any particular population may benefit from combination therapy compared to DOAC therapy alone.”

Dr. Schaefer reported having no disclosures.

sworcester@mdedge.com

SOURCE: Schaeffer J et al. ASH 2019. Abstract 787.

ORLANDO – Combining aspirin and direct oral anticoagulant (DOAC) therapy for the secondary prevention of venous thromboembolism (VTE) or the prevention of stroke associated with nonvalvular atrial fibrillation (NVAF) without a clear indication was associated with increased bleeding risks in a large registry-based cohort.

Sharon Worcester/MDedge News

The study, which involved a cohort of 2,045 patients who were followed at 6 anticoagulation clinics in Michigan during January 2009–June 2019, also found no apparent improvement in thrombosis incidence with the addition of aspirin, Jordan K. Schaefer, MD, reported during a press briefing at the annual meeting of the American Society of Hematology.

Of the cohort patients, 639 adults who received a DOAC plus aspirin after VTE or for NVAF without a clear indication were compared with 639 propensity-matched controls. The bleeding event rate per 100 patient years was 39.50 vs. 32.32 at an average of 15.2 months of follow-up in the combination therapy and DOAC monotherapy groups, respectively, said Dr. Schaefer of the division of hematology/oncology, department of internal medicine, University of Michigan, Ann Arbor.

“This result was statistically significant for clinically relevant non-major bleeding, with an 18.7 rate per 100 patient years, compared with 13.5 for DOAC monotherapy,” (P = .02), he said. “We also saw a significant increase in non-major bleeding with combination therapy, compared with direct oral anticoagulant monotherapy” (rate, 32.82 vs. 25.88; P =.04).

No significant difference was seen overall (P =.07) or for other specific types of bleeding, he noted.

The observed rates of thrombosis in the groups, respectively, were 2.35 and 2.23 per 100 patient years (P =.95), he said, noting that patients on combination therapy also had more emergency department visits and hospitalizations, but those differences were not statistically significant.

“Direct-acting oral anticoagulants, which include apixaban, dabigatran, edoxaban, and rivaroxaban, are increasingly used in clinical practice for indications that include the prevention of strokes for patients with nonvalvular atrial fibrillation, and the treatment and secondary prevention of venous thromboembolic disease,” Dr. Schaefer said.

Aspirin is commonly used in clinical practice for various indications, including primary prevention of heart attacks, strokes, and colorectal cancer, as well as for thromboprophylaxis in patients with certain blood disorders or with certain cardiac devices, he added.

“Aspirin is used for the secondary prevention of thrombosis for patients with known coronary artery disease, peripheral artery disease, or carotid artery disease,” he said. “And while adding aspirin to a DOAC is often appropriate after acute coronary syndromes or percutaneous coronary intervention, many patients receive the combination therapy without a clear indication, he said, noting that increasing evidence in recent years, largely from patients treated with warfarin and aspirin, suggest that the approach may do more harm than good for certain patients.

Specifically, there’s a question of whether aspirin is increasing the rates of bleeding without protecting patients from adverse thrombotic outcomes.

“This has specifically been a concern for patients who are on full-dose anticoagulation,” he said.

In the current study, patient demographics, comorbidities, and concurrent medications were well balanced in the treatment and control groups after propensity score matching, he said, noting that patients with a history of heart valve replacement, recent MI, or less than 3 months of follow-up were excluded.

“These findings need to be confirmed in larger studies, but until such data [are] available, clinicians and patients should continue to balance the relative risks and benefits of adding aspirin to their direct oral anticoagulant therapy,” Dr. Schaefer said. “Further research needs to evaluate key subgroups to see if any particular population may benefit from combination therapy compared to DOAC therapy alone.”

Dr. Schaefer reported having no disclosures.

sworcester@mdedge.com

SOURCE: Schaeffer J et al. ASH 2019. Abstract 787.

ORLANDO – Combining aspirin and direct oral anticoagulant (DOAC) therapy for the secondary prevention of venous thromboembolism (VTE) or the prevention of stroke associated with nonvalvular atrial fibrillation (NVAF) without a clear indication was associated with increased bleeding risks in a large registry-based cohort.

Sharon Worcester/MDedge News

The study, which involved a cohort of 2,045 patients who were followed at 6 anticoagulation clinics in Michigan during January 2009–June 2019, also found no apparent improvement in thrombosis incidence with the addition of aspirin, Jordan K. Schaefer, MD, reported during a press briefing at the annual meeting of the American Society of Hematology.

Of the cohort patients, 639 adults who received a DOAC plus aspirin after VTE or for NVAF without a clear indication were compared with 639 propensity-matched controls. The bleeding event rate per 100 patient years was 39.50 vs. 32.32 at an average of 15.2 months of follow-up in the combination therapy and DOAC monotherapy groups, respectively, said Dr. Schaefer of the division of hematology/oncology, department of internal medicine, University of Michigan, Ann Arbor.

“This result was statistically significant for clinically relevant non-major bleeding, with an 18.7 rate per 100 patient years, compared with 13.5 for DOAC monotherapy,” (P = .02), he said. “We also saw a significant increase in non-major bleeding with combination therapy, compared with direct oral anticoagulant monotherapy” (rate, 32.82 vs. 25.88; P =.04).

No significant difference was seen overall (P =.07) or for other specific types of bleeding, he noted.

The observed rates of thrombosis in the groups, respectively, were 2.35 and 2.23 per 100 patient years (P =.95), he said, noting that patients on combination therapy also had more emergency department visits and hospitalizations, but those differences were not statistically significant.

“Direct-acting oral anticoagulants, which include apixaban, dabigatran, edoxaban, and rivaroxaban, are increasingly used in clinical practice for indications that include the prevention of strokes for patients with nonvalvular atrial fibrillation, and the treatment and secondary prevention of venous thromboembolic disease,” Dr. Schaefer said.

Aspirin is commonly used in clinical practice for various indications, including primary prevention of heart attacks, strokes, and colorectal cancer, as well as for thromboprophylaxis in patients with certain blood disorders or with certain cardiac devices, he added.

“Aspirin is used for the secondary prevention of thrombosis for patients with known coronary artery disease, peripheral artery disease, or carotid artery disease,” he said. “And while adding aspirin to a DOAC is often appropriate after acute coronary syndromes or percutaneous coronary intervention, many patients receive the combination therapy without a clear indication, he said, noting that increasing evidence in recent years, largely from patients treated with warfarin and aspirin, suggest that the approach may do more harm than good for certain patients.

Specifically, there’s a question of whether aspirin is increasing the rates of bleeding without protecting patients from adverse thrombotic outcomes.

“This has specifically been a concern for patients who are on full-dose anticoagulation,” he said.

In the current study, patient demographics, comorbidities, and concurrent medications were well balanced in the treatment and control groups after propensity score matching, he said, noting that patients with a history of heart valve replacement, recent MI, or less than 3 months of follow-up were excluded.

“These findings need to be confirmed in larger studies, but until such data [are] available, clinicians and patients should continue to balance the relative risks and benefits of adding aspirin to their direct oral anticoagulant therapy,” Dr. Schaefer said. “Further research needs to evaluate key subgroups to see if any particular population may benefit from combination therapy compared to DOAC therapy alone.”

Dr. Schaefer reported having no disclosures.

sworcester@mdedge.com

SOURCE: Schaeffer J et al. ASH 2019. Abstract 787.