Heart Failure

When possible, diagnostic tests to determine the cause of a first stroke or transient ischemic attack (TIA) should be completed within 48 hours after symptom onset, the American Heart Association/American Stroke Association said in an updated clinical practice guideline.

“It is critically important to understand the best ways to prevent another stroke once someone has had a stroke or a TIA,” Dawn O. Kleindorfer, MD, chair of the guideline writing group, said in a news release.

“If we can pinpoint the cause of the first stroke or TIA, we can tailor strategies to prevent a second stroke,” said Dr. Kleindorfer, professor and chair, department of neurology, University of Michigan, Ann Arbor.

The updated guideline was published online May 24, 2021, in Stroke.

“The secondary prevention of stroke guideline is one of the ASA’s ‘flagship’ guidelines, last updated in 2014,” Dr. Kleindorfer said.

The update includes “a number of changes to the writing and formatting of this guideline to make it easier for professionals to understand and locate information more quickly, ultimately greatly improving patient care and preventing more strokes in our patients,” she noted.
 

Let pathogenic subtype guide prevention

For patients who have survived a stroke or TIA, management of vascular risk factors, particularly hypertension, diabetes, cholesterol/triglyceride levels, and smoking cessation, are key secondary prevention tactics, the guideline said.

Limiting salt intake and/or following a heart-healthy Mediterranean diet is also advised, as is engaging in at least moderate-intensity aerobic activity for at least 10 minutes four times a week or vigorous-intensity aerobic activity for at least 20 minutes twice a week.

“Approximately 80% of strokes can be prevented by controlling blood pressure, eating a healthy diet, engaging in regular physical activity, not smoking and maintaining a healthy weight,” Amytis Towfighi, MD, vice chair of the guideline writing group and director of neurologic services, Los Angeles County Department of Health Services, noted in the release.

For health care professionals, the guideline said specific recommendations for secondary prevention often depend on the ischemic stroke/TIA subtype. “Therefore, new in this guideline is a section describing recommendations for the diagnostic workup after ischemic stroke, to define ischemic stroke pathogenesis (when possible), and to identify targets for treatment to reduce the risk of recurrent ischemic stroke. Recommendations are now segregated by pathogenetic subtype,” the guideline stated.

Among the recommendations:

• Use multidisciplinary care teams to personalize care for patients and employ shared decision-making with the patient to develop care plans that incorporate a patient’s wishes, goals, and concerns.
• Screen for  and initiate anticoagulant drug therapy to reduce recurrent events.
• Prescribe antithrombotic therapy, including antiplatelets or anticoagulants, in the absence of contraindications. The guideline noted that the combination of antiplatelets and anticoagulation is typically not recommended for preventing second strokes and that dual antiplatelet therapy (DAPT) – taking  along with a second medication to prevent blood clotting – is recommended in the short term and only for specific patients: those with early arriving minor stroke and high-risk TIA or severe symptomatic stenosis.
• Consider  or carotid artery stenting for select patients with narrowing of carotid arteries.
• Aggressive medical management of risk factors and short-term DAPT are preferred for patients with severe intracranial stenosis thought to be the cause of first stroke or TIA.
• In some patients, it’s reasonable to consider percutaneous closure of .

The guideline is accompanied by a systematic review and meta-analysis regarding the benefits and risks of dual antiplatelet versus single antiplatelet therapy for secondary stroke prevention. The authors conclude that DAPT may be appropriate for select patients.

“Additional research is needed to determine: the optimal timing of starting treatment relative to the clinical event; the optimal duration of DAPT to maximize the risk-benefit ratio; whether additional populations excluded from POINT and CHANCE [two of the trials examined], such as those with major stroke, may also benefit from early DAPT; and whether certain genetic profiles eliminate the benefit of early DAPT,” concluded the reviewers, led by Devin Brown, MD, University of Michigan.

The guideline was prepared on behalf of and approved by the AHA Stroke Council’s Scientific Statements Oversight Committee on Clinical Practice Guidelines. The writing group included representatives from the AHA/ASA and the American Academy of Neurology. The guideline has been endorsed by the American Association of Neurological Surgeons/Congress of Neurological Surgeons and the Society of Vascular and Interventional Neurology. It has also been affirmed by the AAN as an educational tool for neurologists.

The research had no commercial funding.

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

When possible, diagnostic tests to determine the cause of a first stroke or transient ischemic attack (TIA) should be completed within 48 hours after symptom onset, the American Heart Association/American Stroke Association said in an updated clinical practice guideline.

“It is critically important to understand the best ways to prevent another stroke once someone has had a stroke or a TIA,” Dawn O. Kleindorfer, MD, chair of the guideline writing group, said in a news release.

“If we can pinpoint the cause of the first stroke or TIA, we can tailor strategies to prevent a second stroke,” said Dr. Kleindorfer, professor and chair, department of neurology, University of Michigan, Ann Arbor.

The updated guideline was published online May 24, 2021, in Stroke.

“The secondary prevention of stroke guideline is one of the ASA’s ‘flagship’ guidelines, last updated in 2014,” Dr. Kleindorfer said.

The update includes “a number of changes to the writing and formatting of this guideline to make it easier for professionals to understand and locate information more quickly, ultimately greatly improving patient care and preventing more strokes in our patients,” she noted.
 

Let pathogenic subtype guide prevention

For patients who have survived a stroke or TIA, management of vascular risk factors, particularly hypertension, diabetes, cholesterol/triglyceride levels, and smoking cessation, are key secondary prevention tactics, the guideline said.

Limiting salt intake and/or following a heart-healthy Mediterranean diet is also advised, as is engaging in at least moderate-intensity aerobic activity for at least 10 minutes four times a week or vigorous-intensity aerobic activity for at least 20 minutes twice a week.

“Approximately 80% of strokes can be prevented by controlling blood pressure, eating a healthy diet, engaging in regular physical activity, not smoking and maintaining a healthy weight,” Amytis Towfighi, MD, vice chair of the guideline writing group and director of neurologic services, Los Angeles County Department of Health Services, noted in the release.

For health care professionals, the guideline said specific recommendations for secondary prevention often depend on the ischemic stroke/TIA subtype. “Therefore, new in this guideline is a section describing recommendations for the diagnostic workup after ischemic stroke, to define ischemic stroke pathogenesis (when possible), and to identify targets for treatment to reduce the risk of recurrent ischemic stroke. Recommendations are now segregated by pathogenetic subtype,” the guideline stated.

Among the recommendations:

• Use multidisciplinary care teams to personalize care for patients and employ shared decision-making with the patient to develop care plans that incorporate a patient’s wishes, goals, and concerns.
• Screen for  and initiate anticoagulant drug therapy to reduce recurrent events.
• Prescribe antithrombotic therapy, including antiplatelets or anticoagulants, in the absence of contraindications. The guideline noted that the combination of antiplatelets and anticoagulation is typically not recommended for preventing second strokes and that dual antiplatelet therapy (DAPT) – taking  along with a second medication to prevent blood clotting – is recommended in the short term and only for specific patients: those with early arriving minor stroke and high-risk TIA or severe symptomatic stenosis.
• Consider  or carotid artery stenting for select patients with narrowing of carotid arteries.
• Aggressive medical management of risk factors and short-term DAPT are preferred for patients with severe intracranial stenosis thought to be the cause of first stroke or TIA.
• In some patients, it’s reasonable to consider percutaneous closure of .

The guideline is accompanied by a systematic review and meta-analysis regarding the benefits and risks of dual antiplatelet versus single antiplatelet therapy for secondary stroke prevention. The authors conclude that DAPT may be appropriate for select patients.

“Additional research is needed to determine: the optimal timing of starting treatment relative to the clinical event; the optimal duration of DAPT to maximize the risk-benefit ratio; whether additional populations excluded from POINT and CHANCE [two of the trials examined], such as those with major stroke, may also benefit from early DAPT; and whether certain genetic profiles eliminate the benefit of early DAPT,” concluded the reviewers, led by Devin Brown, MD, University of Michigan.

The guideline was prepared on behalf of and approved by the AHA Stroke Council’s Scientific Statements Oversight Committee on Clinical Practice Guidelines. The writing group included representatives from the AHA/ASA and the American Academy of Neurology. The guideline has been endorsed by the American Association of Neurological Surgeons/Congress of Neurological Surgeons and the Society of Vascular and Interventional Neurology. It has also been affirmed by the AAN as an educational tool for neurologists.

The research had no commercial funding.

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

When possible, diagnostic tests to determine the cause of a first stroke or transient ischemic attack (TIA) should be completed within 48 hours after symptom onset, the American Heart Association/American Stroke Association said in an updated clinical practice guideline.

“It is critically important to understand the best ways to prevent another stroke once someone has had a stroke or a TIA,” Dawn O. Kleindorfer, MD, chair of the guideline writing group, said in a news release.

“If we can pinpoint the cause of the first stroke or TIA, we can tailor strategies to prevent a second stroke,” said Dr. Kleindorfer, professor and chair, department of neurology, University of Michigan, Ann Arbor.

The updated guideline was published online May 24, 2021, in Stroke.

“The secondary prevention of stroke guideline is one of the ASA’s ‘flagship’ guidelines, last updated in 2014,” Dr. Kleindorfer said.

The update includes “a number of changes to the writing and formatting of this guideline to make it easier for professionals to understand and locate information more quickly, ultimately greatly improving patient care and preventing more strokes in our patients,” she noted.
 

Let pathogenic subtype guide prevention

For patients who have survived a stroke or TIA, management of vascular risk factors, particularly hypertension, diabetes, cholesterol/triglyceride levels, and smoking cessation, are key secondary prevention tactics, the guideline said.

Limiting salt intake and/or following a heart-healthy Mediterranean diet is also advised, as is engaging in at least moderate-intensity aerobic activity for at least 10 minutes four times a week or vigorous-intensity aerobic activity for at least 20 minutes twice a week.

“Approximately 80% of strokes can be prevented by controlling blood pressure, eating a healthy diet, engaging in regular physical activity, not smoking and maintaining a healthy weight,” Amytis Towfighi, MD, vice chair of the guideline writing group and director of neurologic services, Los Angeles County Department of Health Services, noted in the release.

For health care professionals, the guideline said specific recommendations for secondary prevention often depend on the ischemic stroke/TIA subtype. “Therefore, new in this guideline is a section describing recommendations for the diagnostic workup after ischemic stroke, to define ischemic stroke pathogenesis (when possible), and to identify targets for treatment to reduce the risk of recurrent ischemic stroke. Recommendations are now segregated by pathogenetic subtype,” the guideline stated.

Among the recommendations:

• Use multidisciplinary care teams to personalize care for patients and employ shared decision-making with the patient to develop care plans that incorporate a patient’s wishes, goals, and concerns.
• Screen for  and initiate anticoagulant drug therapy to reduce recurrent events.
• Prescribe antithrombotic therapy, including antiplatelets or anticoagulants, in the absence of contraindications. The guideline noted that the combination of antiplatelets and anticoagulation is typically not recommended for preventing second strokes and that dual antiplatelet therapy (DAPT) – taking  along with a second medication to prevent blood clotting – is recommended in the short term and only for specific patients: those with early arriving minor stroke and high-risk TIA or severe symptomatic stenosis.
• Consider  or carotid artery stenting for select patients with narrowing of carotid arteries.
• Aggressive medical management of risk factors and short-term DAPT are preferred for patients with severe intracranial stenosis thought to be the cause of first stroke or TIA.
• In some patients, it’s reasonable to consider percutaneous closure of .

The guideline is accompanied by a systematic review and meta-analysis regarding the benefits and risks of dual antiplatelet versus single antiplatelet therapy for secondary stroke prevention. The authors conclude that DAPT may be appropriate for select patients.

“Additional research is needed to determine: the optimal timing of starting treatment relative to the clinical event; the optimal duration of DAPT to maximize the risk-benefit ratio; whether additional populations excluded from POINT and CHANCE [two of the trials examined], such as those with major stroke, may also benefit from early DAPT; and whether certain genetic profiles eliminate the benefit of early DAPT,” concluded the reviewers, led by Devin Brown, MD, University of Michigan.

The guideline was prepared on behalf of and approved by the AHA Stroke Council’s Scientific Statements Oversight Committee on Clinical Practice Guidelines. The writing group included representatives from the AHA/ASA and the American Academy of Neurology. The guideline has been endorsed by the American Association of Neurological Surgeons/Congress of Neurological Surgeons and the Society of Vascular and Interventional Neurology. It has also been affirmed by the AAN as an educational tool for neurologists.

The research had no commercial funding.

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

The benefits of COVID-19 vaccination “enormously outweigh” the rare possible risk for heart-related complications, including myocarditis, the American Heart Association/American Stroke Association (ASA) says in new statement.

The message follows a Centers for Disease Control and Prevention report that the agency is monitoring the Vaccine Adverse Events Reporting System (VAERS) and the Vaccine Safety Datalink (VSD) for cases of myocarditis that have been associated with the mRNA vaccines against SARS-CoV-2 from Pfizer and Moderna.

The “relatively few” reported cases myocarditis in adolescents or young adults have involved males more often than females, more often followed the second dose rather than the first, and were usually seen in the 4 days after vaccination, the CDC’s COVID-19 Vaccine Safety Technical Work Group (VaST) found.

“Most cases appear to be mild, and follow-up of cases is ongoing,” the CDC says. “Within CDC safety monitoring systems, rates of myocarditis reports in the window following COVID-19 vaccination have not differed from expected baseline rates.”

In their statement, the AHA/ASA “strongly urge” all adults and children 12 years and older to receive a COVID-19 vaccine as soon as possible.

“The evidence continues to indicate that the COVID-19 vaccines are nearly 100% effective at preventing death and hospitalization due to COVID-19 infection,” the groups say.

Although the investigation of cases of myocarditis related to COVID-19 vaccination is ongoing, the AHA/ASA notes that myocarditis is typically the result of an actual viral infection, “and it is yet to be determined if these cases have any correlation to receiving a COVID-19 vaccine.”

“We’ve lost hundreds of children, and there have been thousands who have been hospitalized, thousands who developed an inflammatory syndrome, and one of the pieces of that can be myocarditis,” Richard Besser, MD, president and CEO of the Robert Wood Johnson Foundation (RWJF), said today on ABC’s Good Morning America.

Still, “from my perspective, the risk of COVID is so much greater than any theoretical risk from the vaccine,” said Dr. Besser, former acting director of the CDC.

The symptoms that can occur after COVID-19 vaccination include tiredness, headache, muscle pain, chills, fever, and nausea, reminds the AHA/ASA statement. Such symptoms would “typically appear within 24-48 hours and usually pass within 36-48 hours after receiving the vaccine.”

All health care providers should be aware of the “very rare” adverse events that could be related to a COVID-19 vaccine, including myocarditis, blood clots, low platelets, and symptoms of severe inflammation, it says.

“Health care professionals should strongly consider inquiring about the timing of any recent COVID vaccination among patients presenting with these conditions, as needed, in order to provide appropriate treatment quickly,” the statement advises.

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

The benefits of COVID-19 vaccination “enormously outweigh” the rare possible risk for heart-related complications, including myocarditis, the American Heart Association/American Stroke Association (ASA) says in new statement.

The message follows a Centers for Disease Control and Prevention report that the agency is monitoring the Vaccine Adverse Events Reporting System (VAERS) and the Vaccine Safety Datalink (VSD) for cases of myocarditis that have been associated with the mRNA vaccines against SARS-CoV-2 from Pfizer and Moderna.

The “relatively few” reported cases myocarditis in adolescents or young adults have involved males more often than females, more often followed the second dose rather than the first, and were usually seen in the 4 days after vaccination, the CDC’s COVID-19 Vaccine Safety Technical Work Group (VaST) found.

“Most cases appear to be mild, and follow-up of cases is ongoing,” the CDC says. “Within CDC safety monitoring systems, rates of myocarditis reports in the window following COVID-19 vaccination have not differed from expected baseline rates.”

In their statement, the AHA/ASA “strongly urge” all adults and children 12 years and older to receive a COVID-19 vaccine as soon as possible.

“The evidence continues to indicate that the COVID-19 vaccines are nearly 100% effective at preventing death and hospitalization due to COVID-19 infection,” the groups say.

Although the investigation of cases of myocarditis related to COVID-19 vaccination is ongoing, the AHA/ASA notes that myocarditis is typically the result of an actual viral infection, “and it is yet to be determined if these cases have any correlation to receiving a COVID-19 vaccine.”

“We’ve lost hundreds of children, and there have been thousands who have been hospitalized, thousands who developed an inflammatory syndrome, and one of the pieces of that can be myocarditis,” Richard Besser, MD, president and CEO of the Robert Wood Johnson Foundation (RWJF), said today on ABC’s Good Morning America.

Still, “from my perspective, the risk of COVID is so much greater than any theoretical risk from the vaccine,” said Dr. Besser, former acting director of the CDC.

The symptoms that can occur after COVID-19 vaccination include tiredness, headache, muscle pain, chills, fever, and nausea, reminds the AHA/ASA statement. Such symptoms would “typically appear within 24-48 hours and usually pass within 36-48 hours after receiving the vaccine.”

All health care providers should be aware of the “very rare” adverse events that could be related to a COVID-19 vaccine, including myocarditis, blood clots, low platelets, and symptoms of severe inflammation, it says.

“Health care professionals should strongly consider inquiring about the timing of any recent COVID vaccination among patients presenting with these conditions, as needed, in order to provide appropriate treatment quickly,” the statement advises.

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

The benefits of COVID-19 vaccination “enormously outweigh” the rare possible risk for heart-related complications, including myocarditis, the American Heart Association/American Stroke Association (ASA) says in new statement.

The message follows a Centers for Disease Control and Prevention report that the agency is monitoring the Vaccine Adverse Events Reporting System (VAERS) and the Vaccine Safety Datalink (VSD) for cases of myocarditis that have been associated with the mRNA vaccines against SARS-CoV-2 from Pfizer and Moderna.

The “relatively few” reported cases myocarditis in adolescents or young adults have involved males more often than females, more often followed the second dose rather than the first, and were usually seen in the 4 days after vaccination, the CDC’s COVID-19 Vaccine Safety Technical Work Group (VaST) found.

“Most cases appear to be mild, and follow-up of cases is ongoing,” the CDC says. “Within CDC safety monitoring systems, rates of myocarditis reports in the window following COVID-19 vaccination have not differed from expected baseline rates.”

In their statement, the AHA/ASA “strongly urge” all adults and children 12 years and older to receive a COVID-19 vaccine as soon as possible.

“The evidence continues to indicate that the COVID-19 vaccines are nearly 100% effective at preventing death and hospitalization due to COVID-19 infection,” the groups say.

Although the investigation of cases of myocarditis related to COVID-19 vaccination is ongoing, the AHA/ASA notes that myocarditis is typically the result of an actual viral infection, “and it is yet to be determined if these cases have any correlation to receiving a COVID-19 vaccine.”

“We’ve lost hundreds of children, and there have been thousands who have been hospitalized, thousands who developed an inflammatory syndrome, and one of the pieces of that can be myocarditis,” Richard Besser, MD, president and CEO of the Robert Wood Johnson Foundation (RWJF), said today on ABC’s Good Morning America.

Still, “from my perspective, the risk of COVID is so much greater than any theoretical risk from the vaccine,” said Dr. Besser, former acting director of the CDC.

The symptoms that can occur after COVID-19 vaccination include tiredness, headache, muscle pain, chills, fever, and nausea, reminds the AHA/ASA statement. Such symptoms would “typically appear within 24-48 hours and usually pass within 36-48 hours after receiving the vaccine.”

All health care providers should be aware of the “very rare” adverse events that could be related to a COVID-19 vaccine, including myocarditis, blood clots, low platelets, and symptoms of severe inflammation, it says.

“Health care professionals should strongly consider inquiring about the timing of any recent COVID vaccination among patients presenting with these conditions, as needed, in order to provide appropriate treatment quickly,” the statement advises.

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

The greatest relative benefit from omecamtiv mecarbil, a member of the novel myotropic drug class that improves cardiac performance, is produced in heart failure patients with the lowest left ventricular ejection fraction (LVEF), a new analysis of the recently published phase 3 GALACTIC-HF trial has found.

The findings reinforce the potential for this drug to be helpful in the management of the most advanced stages of heart failure with reduced ejection fraction (HFrEF), reported John R. Teerlink, MD, director of heart failure at San Francisco Veterans Affairs Medical Center, at the annual scientific sessions of the American College of Cardiology.

The phase 3 multinational GALACTIC-HF trial, published earlier this year, linked omecamtiv mecarbil with an 8% reduction in the risk of a heart failure–related events or cardiovascular death, relative to placebo, which was the primary outcome. For entry, HFrEF patients were required to have a LVEF of 35% or less.

Drilling down on ejection fraction

The new analysis divided participants into quartiles of baseline LVEF and then compared relative outcomes and safety.

In the lowest quartile, defined by a LVEF of 22% or lower, the reduction in risk of events reached 17% (hazard ratio, 0.83; 95% confidence interval, 0.73-0.95) for omecamtiv mecarbil relative to placebo. In the highest, defined by a LVEF of 33% or greater, the benefit fell short of significance (HR 0.99; 95% CI, 0.84-1.16). Across quartiles, LVEF was the “strongest modifier of the treatment effect,” emerging in this analysis as a statistically significant (P = .004) continuous variable.

The comparison by LVEF quartiles also provided an opportunity to show that omecamtiv mecarbil was as safe and well tolerated in those with the most advanced disease as in those less sick. At the lowest levels of LVEF, like the higher levels, omecamtiv mecarbil did not produce any adverse effects on blood pressure, heart rate, potassium homeostasis, or renal function.

In GALACTIC-HF, 8,256 HFrEF patients with LVEF 35% or less were randomized to omecamtiv mecarbil or placebo. The primary composite outcome of hospitalization or urgent visit for heart failure or death from cardiovascular causes was evaluated after a median of 21.8 months on therapy.

When incidence rate per 100 patient years was graphed against the range of LVEF, the relative advantage of omecamtiv mecarbil became visible just below an LVEF of 30%, climbing steadily even to the lowest LVEF, which reached 10%.

Perhaps relevant to the reduction in events, there were also greater relative reductions in NT-proBNP (NT-proB-type natriuretic peptide) for omecamtiv mecarbil at lower relative to higher LVEF. Although omecamtiv mecarbil is not associated with any direct vascular, electrophysiologic, or neurohormonal effects, according to Dr. Teerlink, the indirect effects of selective binding to cardiac myosin has been associated with lower NT-proBNP and other biomarkers of cardiac remodeling in prior clinical studies.

Although Dr. Teerlink acknowledged that relatively few patients in GALACTIC-HF received an angiotensin-receptor neprilysin inhibitor (ARNI) or a sodium glucose cotransporter-2 (SGLT2) inhibitor, he said there is “every reason to believe that omecamtiv mecarbil would be complementary to these therapies.” He said the mechanism of action of omecamtiv mecarbil, which improves systolic function, has no overlap with these drugs.

Importantly, there is a particular need for new treatment options in patients with advanced LVEF, according to Dr. Teerlink, who cited evidence, for example, that “the beneficial effect of [the ARNI] sacubitril valsartan, while still significant, decreases in patients with LVEF less than 35%.”

Overall, based on these results, “we believe that omecamtiv mecarbil represents a novel therapy that holds the promise of improving clinical outcomes in patients with severely reduced ejection fraction, which are the very patients that are most challenging for us to treat,” Dr. Teerlink said.
 

Omecamtiv mecarbil may ‘buy you some time’

Ileana Piña, MD, clinical professor of medicine, Central Michigan University, Mount Pleasant, Mich., agreed. She said that omecamtiv mecarbil, if approved, will be an option for the type of HFrEF patients who are being considered for heart transplant or mechanical-assist devices.

“We are very loath to use inotropes in this population, because we know that ultimately the inotrope is not going to do well,” said Dr. Piña, calling these therapies a “Band-Aid.” Based on the evidence from GALACTIC-HF, she thinks that omecamtiv mecarbil will be more versatile.

“This drug does not increase myocardial oxygen demand as do the inotropes, and it can be given in the outpatient setting if need be, so I see this as a real advance,” Dr. Piña said. Although Dr. Piña acknowledged that omecamtiv mecarbil did not reduce mortality in the GALACTIC-HF trial, “at least it will buy you some time.”

Dr. Teerlink has financial relationships with multiple pharmaceutical companies, including Amgen, Cytogenetics, and Servier, which provided funding for the GALACTIC-HF trial. Dr. Piña reports no potential conflicts of interest.

The greatest relative benefit from omecamtiv mecarbil, a member of the novel myotropic drug class that improves cardiac performance, is produced in heart failure patients with the lowest left ventricular ejection fraction (LVEF), a new analysis of the recently published phase 3 GALACTIC-HF trial has found.

The findings reinforce the potential for this drug to be helpful in the management of the most advanced stages of heart failure with reduced ejection fraction (HFrEF), reported John R. Teerlink, MD, director of heart failure at San Francisco Veterans Affairs Medical Center, at the annual scientific sessions of the American College of Cardiology.

The phase 3 multinational GALACTIC-HF trial, published earlier this year, linked omecamtiv mecarbil with an 8% reduction in the risk of a heart failure–related events or cardiovascular death, relative to placebo, which was the primary outcome. For entry, HFrEF patients were required to have a LVEF of 35% or less.

Drilling down on ejection fraction

The new analysis divided participants into quartiles of baseline LVEF and then compared relative outcomes and safety.

In the lowest quartile, defined by a LVEF of 22% or lower, the reduction in risk of events reached 17% (hazard ratio, 0.83; 95% confidence interval, 0.73-0.95) for omecamtiv mecarbil relative to placebo. In the highest, defined by a LVEF of 33% or greater, the benefit fell short of significance (HR 0.99; 95% CI, 0.84-1.16). Across quartiles, LVEF was the “strongest modifier of the treatment effect,” emerging in this analysis as a statistically significant (P = .004) continuous variable.

The comparison by LVEF quartiles also provided an opportunity to show that omecamtiv mecarbil was as safe and well tolerated in those with the most advanced disease as in those less sick. At the lowest levels of LVEF, like the higher levels, omecamtiv mecarbil did not produce any adverse effects on blood pressure, heart rate, potassium homeostasis, or renal function.

In GALACTIC-HF, 8,256 HFrEF patients with LVEF 35% or less were randomized to omecamtiv mecarbil or placebo. The primary composite outcome of hospitalization or urgent visit for heart failure or death from cardiovascular causes was evaluated after a median of 21.8 months on therapy.

When incidence rate per 100 patient years was graphed against the range of LVEF, the relative advantage of omecamtiv mecarbil became visible just below an LVEF of 30%, climbing steadily even to the lowest LVEF, which reached 10%.

Perhaps relevant to the reduction in events, there were also greater relative reductions in NT-proBNP (NT-proB-type natriuretic peptide) for omecamtiv mecarbil at lower relative to higher LVEF. Although omecamtiv mecarbil is not associated with any direct vascular, electrophysiologic, or neurohormonal effects, according to Dr. Teerlink, the indirect effects of selective binding to cardiac myosin has been associated with lower NT-proBNP and other biomarkers of cardiac remodeling in prior clinical studies.

Although Dr. Teerlink acknowledged that relatively few patients in GALACTIC-HF received an angiotensin-receptor neprilysin inhibitor (ARNI) or a sodium glucose cotransporter-2 (SGLT2) inhibitor, he said there is “every reason to believe that omecamtiv mecarbil would be complementary to these therapies.” He said the mechanism of action of omecamtiv mecarbil, which improves systolic function, has no overlap with these drugs.

Importantly, there is a particular need for new treatment options in patients with advanced LVEF, according to Dr. Teerlink, who cited evidence, for example, that “the beneficial effect of [the ARNI] sacubitril valsartan, while still significant, decreases in patients with LVEF less than 35%.”

Overall, based on these results, “we believe that omecamtiv mecarbil represents a novel therapy that holds the promise of improving clinical outcomes in patients with severely reduced ejection fraction, which are the very patients that are most challenging for us to treat,” Dr. Teerlink said.
 

Omecamtiv mecarbil may ‘buy you some time’

Ileana Piña, MD, clinical professor of medicine, Central Michigan University, Mount Pleasant, Mich., agreed. She said that omecamtiv mecarbil, if approved, will be an option for the type of HFrEF patients who are being considered for heart transplant or mechanical-assist devices.

“We are very loath to use inotropes in this population, because we know that ultimately the inotrope is not going to do well,” said Dr. Piña, calling these therapies a “Band-Aid.” Based on the evidence from GALACTIC-HF, she thinks that omecamtiv mecarbil will be more versatile.

“This drug does not increase myocardial oxygen demand as do the inotropes, and it can be given in the outpatient setting if need be, so I see this as a real advance,” Dr. Piña said. Although Dr. Piña acknowledged that omecamtiv mecarbil did not reduce mortality in the GALACTIC-HF trial, “at least it will buy you some time.”

Dr. Teerlink has financial relationships with multiple pharmaceutical companies, including Amgen, Cytogenetics, and Servier, which provided funding for the GALACTIC-HF trial. Dr. Piña reports no potential conflicts of interest.

The greatest relative benefit from omecamtiv mecarbil, a member of the novel myotropic drug class that improves cardiac performance, is produced in heart failure patients with the lowest left ventricular ejection fraction (LVEF), a new analysis of the recently published phase 3 GALACTIC-HF trial has found.

The findings reinforce the potential for this drug to be helpful in the management of the most advanced stages of heart failure with reduced ejection fraction (HFrEF), reported John R. Teerlink, MD, director of heart failure at San Francisco Veterans Affairs Medical Center, at the annual scientific sessions of the American College of Cardiology.

The phase 3 multinational GALACTIC-HF trial, published earlier this year, linked omecamtiv mecarbil with an 8% reduction in the risk of a heart failure–related events or cardiovascular death, relative to placebo, which was the primary outcome. For entry, HFrEF patients were required to have a LVEF of 35% or less.

Drilling down on ejection fraction

The new analysis divided participants into quartiles of baseline LVEF and then compared relative outcomes and safety.

In the lowest quartile, defined by a LVEF of 22% or lower, the reduction in risk of events reached 17% (hazard ratio, 0.83; 95% confidence interval, 0.73-0.95) for omecamtiv mecarbil relative to placebo. In the highest, defined by a LVEF of 33% or greater, the benefit fell short of significance (HR 0.99; 95% CI, 0.84-1.16). Across quartiles, LVEF was the “strongest modifier of the treatment effect,” emerging in this analysis as a statistically significant (P = .004) continuous variable.

The comparison by LVEF quartiles also provided an opportunity to show that omecamtiv mecarbil was as safe and well tolerated in those with the most advanced disease as in those less sick. At the lowest levels of LVEF, like the higher levels, omecamtiv mecarbil did not produce any adverse effects on blood pressure, heart rate, potassium homeostasis, or renal function.

In GALACTIC-HF, 8,256 HFrEF patients with LVEF 35% or less were randomized to omecamtiv mecarbil or placebo. The primary composite outcome of hospitalization or urgent visit for heart failure or death from cardiovascular causes was evaluated after a median of 21.8 months on therapy.

When incidence rate per 100 patient years was graphed against the range of LVEF, the relative advantage of omecamtiv mecarbil became visible just below an LVEF of 30%, climbing steadily even to the lowest LVEF, which reached 10%.

Perhaps relevant to the reduction in events, there were also greater relative reductions in NT-proBNP (NT-proB-type natriuretic peptide) for omecamtiv mecarbil at lower relative to higher LVEF. Although omecamtiv mecarbil is not associated with any direct vascular, electrophysiologic, or neurohormonal effects, according to Dr. Teerlink, the indirect effects of selective binding to cardiac myosin has been associated with lower NT-proBNP and other biomarkers of cardiac remodeling in prior clinical studies.

Although Dr. Teerlink acknowledged that relatively few patients in GALACTIC-HF received an angiotensin-receptor neprilysin inhibitor (ARNI) or a sodium glucose cotransporter-2 (SGLT2) inhibitor, he said there is “every reason to believe that omecamtiv mecarbil would be complementary to these therapies.” He said the mechanism of action of omecamtiv mecarbil, which improves systolic function, has no overlap with these drugs.

Importantly, there is a particular need for new treatment options in patients with advanced LVEF, according to Dr. Teerlink, who cited evidence, for example, that “the beneficial effect of [the ARNI] sacubitril valsartan, while still significant, decreases in patients with LVEF less than 35%.”

Overall, based on these results, “we believe that omecamtiv mecarbil represents a novel therapy that holds the promise of improving clinical outcomes in patients with severely reduced ejection fraction, which are the very patients that are most challenging for us to treat,” Dr. Teerlink said.
 

Omecamtiv mecarbil may ‘buy you some time’

Ileana Piña, MD, clinical professor of medicine, Central Michigan University, Mount Pleasant, Mich., agreed. She said that omecamtiv mecarbil, if approved, will be an option for the type of HFrEF patients who are being considered for heart transplant or mechanical-assist devices.

“We are very loath to use inotropes in this population, because we know that ultimately the inotrope is not going to do well,” said Dr. Piña, calling these therapies a “Band-Aid.” Based on the evidence from GALACTIC-HF, she thinks that omecamtiv mecarbil will be more versatile.

“This drug does not increase myocardial oxygen demand as do the inotropes, and it can be given in the outpatient setting if need be, so I see this as a real advance,” Dr. Piña said. Although Dr. Piña acknowledged that omecamtiv mecarbil did not reduce mortality in the GALACTIC-HF trial, “at least it will buy you some time.”

Dr. Teerlink has financial relationships with multiple pharmaceutical companies, including Amgen, Cytogenetics, and Servier, which provided funding for the GALACTIC-HF trial. Dr. Piña reports no potential conflicts of interest.

It’s now official: The investigational sodium-glucose cotransporter (SGLT) 1/2 inhibitor sotagliflozin is the first agent clearly shown in a prespecified analysis of randomized trials to improve clinical outcomes in patients with heart failure with reduced ejection fraction (HFpEF).

Researchers who ran the SCORED and SOLOIST-WHF pivotal trials for sotagliflozin first made that claim in November 2020 when reporting top-line results from a prespecified meta-analysis of the two trials during the American Heart Association annual scientific sessions. A follow-up report during the annual scientific sessions of the American College of Cardiology fleshed out the evidence and firmed up their landmark conclusion.

The meta-analysis (Abstract 410-08) included 4,500 patients with type 2 diabetes and diagnosed heart failure at entry; its primary endpoint, which was the same in both trials, was the combined incidence of cardiovascular death and the total number of either hospitalization for heart failure or urgent outpatient visits for heart failure.

Compared with placebo, treatment with sotagliflozin for a median of about 15 months dropped this composite endpoint by a relative 33% among the 1,931 who began the study with a left ventricular ejection fraction (LVEF) of at least 50% (HFpEF), by a relative 22% in the 1,758 patients who entered with an LVEF of less than 40% (patients with heart failure with reduced ejection fraction), and by a relative 43% among the 811 patients who began with an LVEF of 40%-49% (patients with heart failure with mid-range ejection fraction). The relative risk reductions were significant for all three subgroups, Deepak L. Bhatt, MD, reported at the meeting.
 

Equally effective ‘across the full range of LVEFs.’

Perhaps as notable and unprecedented was the further finding that the clinical benefits seen with treatment of patients with type 2 diabetes with sotagliflozin was consistent regardless of the ejection fraction they had at entry. Enrolled patients with baseline LVEFs in the range of 25% received a relative benefit from sotagliflozin treatment that was statistically no different from the benefit seen in patients who entered with an LVEF in the neighborhood of 45%, 65%, or at any other level across the LVEF spectrum, a finding that Dr. Bhatt called “remarkable” during a press briefing. “The results show the benefit of sotagliflozin across the full range of LVEFs.”

“We are very excited in the heart failure world by the SGLT2 inhibitors; we’ve been impressed by their reduction in heart failure hospitalizations, but we wonder about the patients with HFpEF, where we haven’t had a blockbuster drug to give,” said Ileana L. Piña, MD, a heart failure specialist and medical officer with the Food and Drug Administration.

The new findings “look like they could pose a regulatory indication [for sotagliflozin] for patients with type 2 diabetes and heart failure across the entire spectrum of heart failure,” said Christopher M. O’Connor, MD, a heart failure specialist and president of the Inova Heart & Vascular institute in Falls Church, Va., and designated discussant for Dr. Bhatt’s report.

A significant on-treatment reduction in CV death

Other new, notable findings from the meta-analysis included the observation that while treatment with sotagliflozin failed to produce a significant reduction in cardiovascular death, compared with placebo, in the intent-to-treat analysis of all patients and of those with heart failure at baseline (it produced nonsignificant point-estimate reductions of 11% compared with placebo for all patients, and of 23% for patients who began the study with heart failure), it did result in a significant 23% relative risk reduction when the researchers focused on patients while they remained adherent to their sotagliflozin regimen (the on-treatment analysis). This 23% relative reduction appeared among all enrolled patients, as well as in the subgroup that started with diagnosed heart failure.

“Given the totality of data from the SGLT2 inhibitors, I think this is a real finding,” Dr. Bhatt said.

Additional analyses also showed that, among women, treatment with sotagliflozin was linked with significant relative reductions in the primary endpoint of roughly 30% compared with placebo among all patients, and also among those with heart failure at baseline. “HFpEF is a problem particularly in older women, and we showed that the benefit was consistent in men and women,” Dr. Bhatt said.

He acknowledged that results are expected soon from two pivotal trials that are examining two different SGLT2 inhibitors, dapagliflozin and empagliflozin, in patients with HFpEF. “I think there will be a class effect for both SGLT2 inhibitors and sotagliflozin for reducing heart failure events in patients with HFpEF, and I predict that the dapagliflozin and empagliflozin trials will have positive results,” Dr. Bhatt said.

Sotagliflozin differs from the SGLT2 inhibitors by also inhibiting SGLT1, an enzyme found in the gastrointestinal system that, when inhibited, results in increased glucose excretion from the gut and a cut in bloodstream levels of postprandial glucose levels. The Food and Drug Administration accepted data from SCORED and SOLOIST-WHF as part of the evidence the agency is now considering for granting a new drug approval to sotagliflozin.

SCORED and SOLOIST-WHF were initially sponsored by Sanofi, and later by Lexicon Pharmaceuticals. Dr. Bhatt’s institution, Brigham and Women’s Hospital, has received funding from Sanofi and Lexicon Pharmaceuticals. He has been a consultant to and received honoraria from K₂P, Level Ex, and MJH Life Sciences; he has been an adviser to Cardax, Cereno Scientific, Myokardia, Novo Nordisk, Phase Bio, and PLx Pharma; and he has received research funding from numerous companies. Dr. Piña has no relevant disclosures. Dr. O’Connor has been a consultant to Arena, Bayer, Bristol-Myers Squibb, Merck, and Windtree, and he has an ownership interest in Biscardia.

[email protected]

It’s now official: The investigational sodium-glucose cotransporter (SGLT) 1/2 inhibitor sotagliflozin is the first agent clearly shown in a prespecified analysis of randomized trials to improve clinical outcomes in patients with heart failure with reduced ejection fraction (HFpEF).

Researchers who ran the SCORED and SOLOIST-WHF pivotal trials for sotagliflozin first made that claim in November 2020 when reporting top-line results from a prespecified meta-analysis of the two trials during the American Heart Association annual scientific sessions. A follow-up report during the annual scientific sessions of the American College of Cardiology fleshed out the evidence and firmed up their landmark conclusion.

The meta-analysis (Abstract 410-08) included 4,500 patients with type 2 diabetes and diagnosed heart failure at entry; its primary endpoint, which was the same in both trials, was the combined incidence of cardiovascular death and the total number of either hospitalization for heart failure or urgent outpatient visits for heart failure.

Compared with placebo, treatment with sotagliflozin for a median of about 15 months dropped this composite endpoint by a relative 33% among the 1,931 who began the study with a left ventricular ejection fraction (LVEF) of at least 50% (HFpEF), by a relative 22% in the 1,758 patients who entered with an LVEF of less than 40% (patients with heart failure with reduced ejection fraction), and by a relative 43% among the 811 patients who began with an LVEF of 40%-49% (patients with heart failure with mid-range ejection fraction). The relative risk reductions were significant for all three subgroups, Deepak L. Bhatt, MD, reported at the meeting.
 

Equally effective ‘across the full range of LVEFs.’

Perhaps as notable and unprecedented was the further finding that the clinical benefits seen with treatment of patients with type 2 diabetes with sotagliflozin was consistent regardless of the ejection fraction they had at entry. Enrolled patients with baseline LVEFs in the range of 25% received a relative benefit from sotagliflozin treatment that was statistically no different from the benefit seen in patients who entered with an LVEF in the neighborhood of 45%, 65%, or at any other level across the LVEF spectrum, a finding that Dr. Bhatt called “remarkable” during a press briefing. “The results show the benefit of sotagliflozin across the full range of LVEFs.”

“We are very excited in the heart failure world by the SGLT2 inhibitors; we’ve been impressed by their reduction in heart failure hospitalizations, but we wonder about the patients with HFpEF, where we haven’t had a blockbuster drug to give,” said Ileana L. Piña, MD, a heart failure specialist and medical officer with the Food and Drug Administration.

The new findings “look like they could pose a regulatory indication [for sotagliflozin] for patients with type 2 diabetes and heart failure across the entire spectrum of heart failure,” said Christopher M. O’Connor, MD, a heart failure specialist and president of the Inova Heart & Vascular institute in Falls Church, Va., and designated discussant for Dr. Bhatt’s report.

A significant on-treatment reduction in CV death

Other new, notable findings from the meta-analysis included the observation that while treatment with sotagliflozin failed to produce a significant reduction in cardiovascular death, compared with placebo, in the intent-to-treat analysis of all patients and of those with heart failure at baseline (it produced nonsignificant point-estimate reductions of 11% compared with placebo for all patients, and of 23% for patients who began the study with heart failure), it did result in a significant 23% relative risk reduction when the researchers focused on patients while they remained adherent to their sotagliflozin regimen (the on-treatment analysis). This 23% relative reduction appeared among all enrolled patients, as well as in the subgroup that started with diagnosed heart failure.

“Given the totality of data from the SGLT2 inhibitors, I think this is a real finding,” Dr. Bhatt said.

Additional analyses also showed that, among women, treatment with sotagliflozin was linked with significant relative reductions in the primary endpoint of roughly 30% compared with placebo among all patients, and also among those with heart failure at baseline. “HFpEF is a problem particularly in older women, and we showed that the benefit was consistent in men and women,” Dr. Bhatt said.

He acknowledged that results are expected soon from two pivotal trials that are examining two different SGLT2 inhibitors, dapagliflozin and empagliflozin, in patients with HFpEF. “I think there will be a class effect for both SGLT2 inhibitors and sotagliflozin for reducing heart failure events in patients with HFpEF, and I predict that the dapagliflozin and empagliflozin trials will have positive results,” Dr. Bhatt said.

Sotagliflozin differs from the SGLT2 inhibitors by also inhibiting SGLT1, an enzyme found in the gastrointestinal system that, when inhibited, results in increased glucose excretion from the gut and a cut in bloodstream levels of postprandial glucose levels. The Food and Drug Administration accepted data from SCORED and SOLOIST-WHF as part of the evidence the agency is now considering for granting a new drug approval to sotagliflozin.

SCORED and SOLOIST-WHF were initially sponsored by Sanofi, and later by Lexicon Pharmaceuticals. Dr. Bhatt’s institution, Brigham and Women’s Hospital, has received funding from Sanofi and Lexicon Pharmaceuticals. He has been a consultant to and received honoraria from K₂P, Level Ex, and MJH Life Sciences; he has been an adviser to Cardax, Cereno Scientific, Myokardia, Novo Nordisk, Phase Bio, and PLx Pharma; and he has received research funding from numerous companies. Dr. Piña has no relevant disclosures. Dr. O’Connor has been a consultant to Arena, Bayer, Bristol-Myers Squibb, Merck, and Windtree, and he has an ownership interest in Biscardia.

[email protected]

It’s now official: The investigational sodium-glucose cotransporter (SGLT) 1/2 inhibitor sotagliflozin is the first agent clearly shown in a prespecified analysis of randomized trials to improve clinical outcomes in patients with heart failure with reduced ejection fraction (HFpEF).

Researchers who ran the SCORED and SOLOIST-WHF pivotal trials for sotagliflozin first made that claim in November 2020 when reporting top-line results from a prespecified meta-analysis of the two trials during the American Heart Association annual scientific sessions. A follow-up report during the annual scientific sessions of the American College of Cardiology fleshed out the evidence and firmed up their landmark conclusion.

The meta-analysis (Abstract 410-08) included 4,500 patients with type 2 diabetes and diagnosed heart failure at entry; its primary endpoint, which was the same in both trials, was the combined incidence of cardiovascular death and the total number of either hospitalization for heart failure or urgent outpatient visits for heart failure.

Compared with placebo, treatment with sotagliflozin for a median of about 15 months dropped this composite endpoint by a relative 33% among the 1,931 who began the study with a left ventricular ejection fraction (LVEF) of at least 50% (HFpEF), by a relative 22% in the 1,758 patients who entered with an LVEF of less than 40% (patients with heart failure with reduced ejection fraction), and by a relative 43% among the 811 patients who began with an LVEF of 40%-49% (patients with heart failure with mid-range ejection fraction). The relative risk reductions were significant for all three subgroups, Deepak L. Bhatt, MD, reported at the meeting.
 

Equally effective ‘across the full range of LVEFs.’

Perhaps as notable and unprecedented was the further finding that the clinical benefits seen with treatment of patients with type 2 diabetes with sotagliflozin was consistent regardless of the ejection fraction they had at entry. Enrolled patients with baseline LVEFs in the range of 25% received a relative benefit from sotagliflozin treatment that was statistically no different from the benefit seen in patients who entered with an LVEF in the neighborhood of 45%, 65%, or at any other level across the LVEF spectrum, a finding that Dr. Bhatt called “remarkable” during a press briefing. “The results show the benefit of sotagliflozin across the full range of LVEFs.”

“We are very excited in the heart failure world by the SGLT2 inhibitors; we’ve been impressed by their reduction in heart failure hospitalizations, but we wonder about the patients with HFpEF, where we haven’t had a blockbuster drug to give,” said Ileana L. Piña, MD, a heart failure specialist and medical officer with the Food and Drug Administration.

The new findings “look like they could pose a regulatory indication [for sotagliflozin] for patients with type 2 diabetes and heart failure across the entire spectrum of heart failure,” said Christopher M. O’Connor, MD, a heart failure specialist and president of the Inova Heart & Vascular institute in Falls Church, Va., and designated discussant for Dr. Bhatt’s report.

A significant on-treatment reduction in CV death

Other new, notable findings from the meta-analysis included the observation that while treatment with sotagliflozin failed to produce a significant reduction in cardiovascular death, compared with placebo, in the intent-to-treat analysis of all patients and of those with heart failure at baseline (it produced nonsignificant point-estimate reductions of 11% compared with placebo for all patients, and of 23% for patients who began the study with heart failure), it did result in a significant 23% relative risk reduction when the researchers focused on patients while they remained adherent to their sotagliflozin regimen (the on-treatment analysis). This 23% relative reduction appeared among all enrolled patients, as well as in the subgroup that started with diagnosed heart failure.

“Given the totality of data from the SGLT2 inhibitors, I think this is a real finding,” Dr. Bhatt said.

Additional analyses also showed that, among women, treatment with sotagliflozin was linked with significant relative reductions in the primary endpoint of roughly 30% compared with placebo among all patients, and also among those with heart failure at baseline. “HFpEF is a problem particularly in older women, and we showed that the benefit was consistent in men and women,” Dr. Bhatt said.

He acknowledged that results are expected soon from two pivotal trials that are examining two different SGLT2 inhibitors, dapagliflozin and empagliflozin, in patients with HFpEF. “I think there will be a class effect for both SGLT2 inhibitors and sotagliflozin for reducing heart failure events in patients with HFpEF, and I predict that the dapagliflozin and empagliflozin trials will have positive results,” Dr. Bhatt said.

Sotagliflozin differs from the SGLT2 inhibitors by also inhibiting SGLT1, an enzyme found in the gastrointestinal system that, when inhibited, results in increased glucose excretion from the gut and a cut in bloodstream levels of postprandial glucose levels. The Food and Drug Administration accepted data from SCORED and SOLOIST-WHF as part of the evidence the agency is now considering for granting a new drug approval to sotagliflozin.

SCORED and SOLOIST-WHF were initially sponsored by Sanofi, and later by Lexicon Pharmaceuticals. Dr. Bhatt’s institution, Brigham and Women’s Hospital, has received funding from Sanofi and Lexicon Pharmaceuticals. He has been a consultant to and received honoraria from K₂P, Level Ex, and MJH Life Sciences; he has been an adviser to Cardax, Cereno Scientific, Myokardia, Novo Nordisk, Phase Bio, and PLx Pharma; and he has received research funding from numerous companies. Dr. Piña has no relevant disclosures. Dr. O’Connor has been a consultant to Arena, Bayer, Bristol-Myers Squibb, Merck, and Windtree, and he has an ownership interest in Biscardia.

[email protected]

Combined data from five implantable cardioverter-defibrillator (ICD) trials suggest that it is the underlying arrhythmic disorder, rather than the ICD therapy itself, that affects mortality in these patients.

Analysis of the MADIT II, MADIT-RISK, MADIT-CRT, MADIT-RIT, and RAID trials showed that the major determinant of mortality in patients receiving a primary prevention ICD was the arrhythmic substrate that leads to occurrence of fast ventricular tachycardia (VT), defined as ≥ 200 bpm, or ventricular fibrillation (VF), not adverse effects of the ICD shock therapy itself.

Patients experiencing an episode of VT had more than a twofold increased risk for death during a follow-up of 2½ years; however, ICD therapies for VT less than 200 bpm and inappropriate ICD shocks were not associated with a higher risk for death.

The findings were published online in the Journal of the American College of Cardiology.

“We know that patients receiving an ICD shock have increased mortality during subsequent follow-up,” first author Mehmet K. Aktas, MD, MBA, University of Rochester (N.Y.), said in an interview.

“There are conflicting data on the impact of ICD shocks on subsequent mortality, and in this study, we aimed to determine whether shocks per se increase subsequent mortality risk or whether the arrhythmic substrate that leads to ICD therapy results in subsequent risk of death,” Dr. Aktas said.

He and his team evaluated the association of ICD therapy with subsequent mortality according to the type of ICD therapy (model I), type of arrhythmia for which ICD therapy was delivered (model II), combined assessment of all arrhythmia and therapy types during follow-up (model III), and incremental risk associated with repeated ICD shocks (model IV).

The study cohort included 5,516 patients. Of these, 1,001 patients (18%) received appropriate ICD therapy and 561 (10%) received inappropriate ICD therapy during an average of 2.4 years.

Patients receiving an appropriate ICD therapy were more likely to be male and to have prior atrial arrhythmia and nonsustained VT compared with those without ICD therapy.

Patients receiving an inappropriate shock were more likely to be younger, to be African American, and to be less likely to have prior nonsustained VT, compared with those without ICD therapy.

Most patients (90%) were receiving beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers regardless of device therapy during follow-up, and 10% of patients were treated with amiodarone.

In model I, at 3 years, the cumulative probability of death following an appropriate ICD shock was 38% compared with no appropriate ICD shock (P < .001). Inappropriate shock alone was not associated with mortality risk.

In model II, which looked at the type of arrhythmia for which ICD therapy was delivered, the cumulative death rate at 3 years following the first occurrence of ICD therapy for VT ≥ 200 beats/min or VF was 27%, compared with 10% in patients not experiencing VT ≥ 200 beats/min or VF (P < .001).

In model III, the highest risk for death was observed following shocks delivered after a failed antitachycardia pacing (ATP) for fast VT (hazard ratio [HR], 3.05), followed by ICD shock for VF (HR, 2.86), ICD shock for fast VT without a prior ATP (HR, 2.83), and ICD shock for slower VT (< 200 beats/min) without a prior ATP (HR, 2.39).

In contrast, other types of appropriate and inappropriate shock or ATP therapies were not associated with a significant risk increase.

In model IV, which assessed the association of shock therapy counts with the risk for death, two or more ICD appropriate shocks were not associated with increased risk after the first appropriate ICD shock.

“Our findings shed light on the mechanisms associated with increased mortality risk in primary prevention ICD recipients,” Dr. Aktas said.

“Studies that evaluate interventions focused on treating and stabilizing the myocardial substrate, which promotes ventricular tachyarrhythmias, such as catheter ablation, are needed to improve survival in heart failure patients,” he added.
 

Thoughtful study design

In an accompanying editorial, Rajat Deo, MD, and Naga Venkata K. Pothineni, MD, both from the University of Pennsylvania, Philadelphia, praised the researchers for their “thoughtful study design.”

“The take-home message that is most relevant to our clinical practice is clear: Sustained ventricular arrhythmias are a prognostic marker of death and heart failure hospitalization,” they wrote.

The editorialists also commented on the higher rate of inappropriate ICD therapies in African Americans.

“It is concerning to observe that Black patients had a markedly higher rate of inappropriate ICD therapies compared with White patients – and this was in the setting of some of the most respectable, established, and well-funded clinical trials,” they wrote.

Reasons for disparities in outcomes include access to appropriate and affordable medical therapies, access to specialty clinics and caregivers, remote ICD monitoring, and compliance issues.

“Future work will need to understand how the social determinants of health including race affect the treatment and outcomes of our primary prevention ICD population,” they wrote.

Identifying and characterizing the arrhythmic substrate will become a key component of sudden cardiac death risk stratification, the editorialists predicted.

“Concurrently, we must continue to partner with industry colleagues and work with our professional societies to ensure health equity across our patient population,” they concluded.

Dr. Aktas has received research grants from Boston Scientific and Medtronic. Dr. Deo and his coeditorialists report no relevant financial relationships. The MADIT trials were funded by an unrestricted research grant from Boston Scientific to the University of Rochester Medical Center. The RAID trial was funded by the National Institutes of Health.

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

Combined data from five implantable cardioverter-defibrillator (ICD) trials suggest that it is the underlying arrhythmic disorder, rather than the ICD therapy itself, that affects mortality in these patients.

Analysis of the MADIT II, MADIT-RISK, MADIT-CRT, MADIT-RIT, and RAID trials showed that the major determinant of mortality in patients receiving a primary prevention ICD was the arrhythmic substrate that leads to occurrence of fast ventricular tachycardia (VT), defined as ≥ 200 bpm, or ventricular fibrillation (VF), not adverse effects of the ICD shock therapy itself.

Patients experiencing an episode of VT had more than a twofold increased risk for death during a follow-up of 2½ years; however, ICD therapies for VT less than 200 bpm and inappropriate ICD shocks were not associated with a higher risk for death.

The findings were published online in the Journal of the American College of Cardiology.

“We know that patients receiving an ICD shock have increased mortality during subsequent follow-up,” first author Mehmet K. Aktas, MD, MBA, University of Rochester (N.Y.), said in an interview.

“There are conflicting data on the impact of ICD shocks on subsequent mortality, and in this study, we aimed to determine whether shocks per se increase subsequent mortality risk or whether the arrhythmic substrate that leads to ICD therapy results in subsequent risk of death,” Dr. Aktas said.

He and his team evaluated the association of ICD therapy with subsequent mortality according to the type of ICD therapy (model I), type of arrhythmia for which ICD therapy was delivered (model II), combined assessment of all arrhythmia and therapy types during follow-up (model III), and incremental risk associated with repeated ICD shocks (model IV).

The study cohort included 5,516 patients. Of these, 1,001 patients (18%) received appropriate ICD therapy and 561 (10%) received inappropriate ICD therapy during an average of 2.4 years.

Patients receiving an appropriate ICD therapy were more likely to be male and to have prior atrial arrhythmia and nonsustained VT compared with those without ICD therapy.

Patients receiving an inappropriate shock were more likely to be younger, to be African American, and to be less likely to have prior nonsustained VT, compared with those without ICD therapy.

Most patients (90%) were receiving beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers regardless of device therapy during follow-up, and 10% of patients were treated with amiodarone.

In model I, at 3 years, the cumulative probability of death following an appropriate ICD shock was 38% compared with no appropriate ICD shock (P < .001). Inappropriate shock alone was not associated with mortality risk.

In model II, which looked at the type of arrhythmia for which ICD therapy was delivered, the cumulative death rate at 3 years following the first occurrence of ICD therapy for VT ≥ 200 beats/min or VF was 27%, compared with 10% in patients not experiencing VT ≥ 200 beats/min or VF (P < .001).

In model III, the highest risk for death was observed following shocks delivered after a failed antitachycardia pacing (ATP) for fast VT (hazard ratio [HR], 3.05), followed by ICD shock for VF (HR, 2.86), ICD shock for fast VT without a prior ATP (HR, 2.83), and ICD shock for slower VT (< 200 beats/min) without a prior ATP (HR, 2.39).

In contrast, other types of appropriate and inappropriate shock or ATP therapies were not associated with a significant risk increase.

In model IV, which assessed the association of shock therapy counts with the risk for death, two or more ICD appropriate shocks were not associated with increased risk after the first appropriate ICD shock.

“Our findings shed light on the mechanisms associated with increased mortality risk in primary prevention ICD recipients,” Dr. Aktas said.

“Studies that evaluate interventions focused on treating and stabilizing the myocardial substrate, which promotes ventricular tachyarrhythmias, such as catheter ablation, are needed to improve survival in heart failure patients,” he added.
 

Thoughtful study design

In an accompanying editorial, Rajat Deo, MD, and Naga Venkata K. Pothineni, MD, both from the University of Pennsylvania, Philadelphia, praised the researchers for their “thoughtful study design.”

“The take-home message that is most relevant to our clinical practice is clear: Sustained ventricular arrhythmias are a prognostic marker of death and heart failure hospitalization,” they wrote.

The editorialists also commented on the higher rate of inappropriate ICD therapies in African Americans.

“It is concerning to observe that Black patients had a markedly higher rate of inappropriate ICD therapies compared with White patients – and this was in the setting of some of the most respectable, established, and well-funded clinical trials,” they wrote.

Reasons for disparities in outcomes include access to appropriate and affordable medical therapies, access to specialty clinics and caregivers, remote ICD monitoring, and compliance issues.

“Future work will need to understand how the social determinants of health including race affect the treatment and outcomes of our primary prevention ICD population,” they wrote.

Identifying and characterizing the arrhythmic substrate will become a key component of sudden cardiac death risk stratification, the editorialists predicted.

“Concurrently, we must continue to partner with industry colleagues and work with our professional societies to ensure health equity across our patient population,” they concluded.

Dr. Aktas has received research grants from Boston Scientific and Medtronic. Dr. Deo and his coeditorialists report no relevant financial relationships. The MADIT trials were funded by an unrestricted research grant from Boston Scientific to the University of Rochester Medical Center. The RAID trial was funded by the National Institutes of Health.

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

Combined data from five implantable cardioverter-defibrillator (ICD) trials suggest that it is the underlying arrhythmic disorder, rather than the ICD therapy itself, that affects mortality in these patients.

Analysis of the MADIT II, MADIT-RISK, MADIT-CRT, MADIT-RIT, and RAID trials showed that the major determinant of mortality in patients receiving a primary prevention ICD was the arrhythmic substrate that leads to occurrence of fast ventricular tachycardia (VT), defined as ≥ 200 bpm, or ventricular fibrillation (VF), not adverse effects of the ICD shock therapy itself.

Patients experiencing an episode of VT had more than a twofold increased risk for death during a follow-up of 2½ years; however, ICD therapies for VT less than 200 bpm and inappropriate ICD shocks were not associated with a higher risk for death.

The findings were published online in the Journal of the American College of Cardiology.

“We know that patients receiving an ICD shock have increased mortality during subsequent follow-up,” first author Mehmet K. Aktas, MD, MBA, University of Rochester (N.Y.), said in an interview.

“There are conflicting data on the impact of ICD shocks on subsequent mortality, and in this study, we aimed to determine whether shocks per se increase subsequent mortality risk or whether the arrhythmic substrate that leads to ICD therapy results in subsequent risk of death,” Dr. Aktas said.

He and his team evaluated the association of ICD therapy with subsequent mortality according to the type of ICD therapy (model I), type of arrhythmia for which ICD therapy was delivered (model II), combined assessment of all arrhythmia and therapy types during follow-up (model III), and incremental risk associated with repeated ICD shocks (model IV).

The study cohort included 5,516 patients. Of these, 1,001 patients (18%) received appropriate ICD therapy and 561 (10%) received inappropriate ICD therapy during an average of 2.4 years.

Patients receiving an appropriate ICD therapy were more likely to be male and to have prior atrial arrhythmia and nonsustained VT compared with those without ICD therapy.

Patients receiving an inappropriate shock were more likely to be younger, to be African American, and to be less likely to have prior nonsustained VT, compared with those without ICD therapy.

Most patients (90%) were receiving beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers regardless of device therapy during follow-up, and 10% of patients were treated with amiodarone.

In model I, at 3 years, the cumulative probability of death following an appropriate ICD shock was 38% compared with no appropriate ICD shock (P < .001). Inappropriate shock alone was not associated with mortality risk.

In model II, which looked at the type of arrhythmia for which ICD therapy was delivered, the cumulative death rate at 3 years following the first occurrence of ICD therapy for VT ≥ 200 beats/min or VF was 27%, compared with 10% in patients not experiencing VT ≥ 200 beats/min or VF (P < .001).

In model III, the highest risk for death was observed following shocks delivered after a failed antitachycardia pacing (ATP) for fast VT (hazard ratio [HR], 3.05), followed by ICD shock for VF (HR, 2.86), ICD shock for fast VT without a prior ATP (HR, 2.83), and ICD shock for slower VT (< 200 beats/min) without a prior ATP (HR, 2.39).

In contrast, other types of appropriate and inappropriate shock or ATP therapies were not associated with a significant risk increase.

In model IV, which assessed the association of shock therapy counts with the risk for death, two or more ICD appropriate shocks were not associated with increased risk after the first appropriate ICD shock.

“Our findings shed light on the mechanisms associated with increased mortality risk in primary prevention ICD recipients,” Dr. Aktas said.

“Studies that evaluate interventions focused on treating and stabilizing the myocardial substrate, which promotes ventricular tachyarrhythmias, such as catheter ablation, are needed to improve survival in heart failure patients,” he added.
 

Thoughtful study design

In an accompanying editorial, Rajat Deo, MD, and Naga Venkata K. Pothineni, MD, both from the University of Pennsylvania, Philadelphia, praised the researchers for their “thoughtful study design.”

“The take-home message that is most relevant to our clinical practice is clear: Sustained ventricular arrhythmias are a prognostic marker of death and heart failure hospitalization,” they wrote.

The editorialists also commented on the higher rate of inappropriate ICD therapies in African Americans.

“It is concerning to observe that Black patients had a markedly higher rate of inappropriate ICD therapies compared with White patients – and this was in the setting of some of the most respectable, established, and well-funded clinical trials,” they wrote.

Reasons for disparities in outcomes include access to appropriate and affordable medical therapies, access to specialty clinics and caregivers, remote ICD monitoring, and compliance issues.

“Future work will need to understand how the social determinants of health including race affect the treatment and outcomes of our primary prevention ICD population,” they wrote.

Identifying and characterizing the arrhythmic substrate will become a key component of sudden cardiac death risk stratification, the editorialists predicted.

“Concurrently, we must continue to partner with industry colleagues and work with our professional societies to ensure health equity across our patient population,” they concluded.

Dr. Aktas has received research grants from Boston Scientific and Medtronic. Dr. Deo and his coeditorialists report no relevant financial relationships. The MADIT trials were funded by an unrestricted research grant from Boston Scientific to the University of Rochester Medical Center. The RAID trial was funded by the National Institutes of Health.

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

Finerenone treatment of patients with type 2 diabetes and diabetic kidney disease was linked to a significant drop in the incidence of new-onset atrial fibrillation as a prespecified, exploratory endpoint of the FIDELIO-DKD pivotal trial that randomized more than 5,700 patients.

Treatment with finerenone linked with a 29% relative reduction compared with placebo in incident cases of atrial fibrillation (AFib), Gerasimos Filippatos, MD, reported at the annual scientific sessions of the American College of Cardiology.

The absolute reduction was modest, a 1.3% reduction from the 4.5% incidence rate on placebo to a 3.2% rate on finerenone during a median 2.6 years of follow-up. Concurrently with the report, the results appeared online (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.079).

The analyses Dr. Filippatos presented also showed that whether or not patients had a history of AFib, there was no impact on either the primary benefit from finerenone treatment seen in FIDELIO-DKD, which was a significant 18% relative risk reduction compared with placebo in the combined rate of kidney failure, a 40% or greater decline from baseline in estimated glomerular filtration rate, or renal death.

Likewise, prior AFib status had no effect on the study’s key secondary endpoint, a significant 14% relative risk reduction in the combined rate of cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure.

The primary results from FIDELIO-DKD (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease) appeared in a 2020 report (N Engl J Med. 2020 Dec 3;383[23];2219-29).
 

‘Side benefits can be very helpful’

“It’s important to know of finerenone’s benefits beyond the primary outcome of a trial because side benefits can be very helpful,” said Anne B. Curtis, MD, an electrophysiologist and professor and chair of medicine at the University of Buffalo (N.Y.) School of Medicine and Biomedical Sciences. “It’s not a huge benefit, but this could be an added benefit for selected patients,” she said during a press briefing. “Background studies had shown favorable remodeling of the heart [by finerenone] that could affect AFib.”

Possible mitigating effects by finerenone on inflammation and fibrosis might also mediate the drug’s apparent effect on AFib, said Dr. Filippatos, professor of cardiology and director of the Heart Failure and Cardio-Oncology Clinic at Attikon University Hospital and the University of Athens.

He noted that additional data addressing a possible AFib effect of finerenone will emerge soon from the FIGARO-DKD trial, which enrolled patients similar to those in FIDELIO-DKD but with more moderate stages of kidney disease, and from the FINEARTS-HF trial, which is examining the effect of finerenone in patients with heart failure with an ejection fraction of at least 40%.

“Heart failure and AFib go together tightly. It’s worth studying this specifically, so we can see whether there is an impact of finerenone on patients with heart failure who may not necessarily have kidney disease or diabetes,” Dr. Curtis said.
 

Hypothesis-generating findings

The new findings reported by Dr. Filippatos “should be considered hypothesis generating. Until we have more information, upstream therapies, including mineralocorticoid receptor antagonists [MRAs, the umbrella drug class that includes finerenone], should be used in appropriate patient populations based on defined benefits with the hope they will also reduce the development of AFib and atrial flutter over time,” Gerald V. Naccarelli, MD, and coauthors wrote in an editorial that accompanied the report (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.080).

The FIDELIO-DKD trial randomized 5,734 patients at 913 sites in 48 countries, including 461 patients with a history of AFib. The observed link of finerenone treatment with a reduced incidence of AFib appeared consistent regardless of patients’ age, sex, race, their kidney characteristics at baseline, baseline levels of systolic blood pressure, serum potassium, body mass index, A1c, or use of glucose-lowering medications.

Finerenone belongs to a new class of MRAs that have a nonsteroidal structure, in contrast with the MRAs spironolactone and eplerenone. This means that finerenone does not produce steroidal-associated adverse effects linked with certain other MRAs, such as gynecomastia, and may also differ in other actions.

FIDELIO-DKD was sponsored by Bayer, the company developing finerenone. Dr. Filippatos has received lecture fees from or participated in the direction of trials on behalf of Bayer, as well as for Amgen, Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor. Dr. Curtis is an adviser to and receives honoraria from St. Jude Medical, and receives honoraria from Medtronic. Dr. Naccarelli has been a consultant to Acesion, ARCA, GlaxoSmithKline, Janssen, Milestone, Omeicos, and Sanofi. His coauthors had no disclosures.

[email protected]

Finerenone treatment of patients with type 2 diabetes and diabetic kidney disease was linked to a significant drop in the incidence of new-onset atrial fibrillation as a prespecified, exploratory endpoint of the FIDELIO-DKD pivotal trial that randomized more than 5,700 patients.

Treatment with finerenone linked with a 29% relative reduction compared with placebo in incident cases of atrial fibrillation (AFib), Gerasimos Filippatos, MD, reported at the annual scientific sessions of the American College of Cardiology.

The absolute reduction was modest, a 1.3% reduction from the 4.5% incidence rate on placebo to a 3.2% rate on finerenone during a median 2.6 years of follow-up. Concurrently with the report, the results appeared online (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.079).

The analyses Dr. Filippatos presented also showed that whether or not patients had a history of AFib, there was no impact on either the primary benefit from finerenone treatment seen in FIDELIO-DKD, which was a significant 18% relative risk reduction compared with placebo in the combined rate of kidney failure, a 40% or greater decline from baseline in estimated glomerular filtration rate, or renal death.

Likewise, prior AFib status had no effect on the study’s key secondary endpoint, a significant 14% relative risk reduction in the combined rate of cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure.

The primary results from FIDELIO-DKD (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease) appeared in a 2020 report (N Engl J Med. 2020 Dec 3;383[23];2219-29).
 

‘Side benefits can be very helpful’

“It’s important to know of finerenone’s benefits beyond the primary outcome of a trial because side benefits can be very helpful,” said Anne B. Curtis, MD, an electrophysiologist and professor and chair of medicine at the University of Buffalo (N.Y.) School of Medicine and Biomedical Sciences. “It’s not a huge benefit, but this could be an added benefit for selected patients,” she said during a press briefing. “Background studies had shown favorable remodeling of the heart [by finerenone] that could affect AFib.”

Possible mitigating effects by finerenone on inflammation and fibrosis might also mediate the drug’s apparent effect on AFib, said Dr. Filippatos, professor of cardiology and director of the Heart Failure and Cardio-Oncology Clinic at Attikon University Hospital and the University of Athens.

He noted that additional data addressing a possible AFib effect of finerenone will emerge soon from the FIGARO-DKD trial, which enrolled patients similar to those in FIDELIO-DKD but with more moderate stages of kidney disease, and from the FINEARTS-HF trial, which is examining the effect of finerenone in patients with heart failure with an ejection fraction of at least 40%.

“Heart failure and AFib go together tightly. It’s worth studying this specifically, so we can see whether there is an impact of finerenone on patients with heart failure who may not necessarily have kidney disease or diabetes,” Dr. Curtis said.
 

Hypothesis-generating findings

The new findings reported by Dr. Filippatos “should be considered hypothesis generating. Until we have more information, upstream therapies, including mineralocorticoid receptor antagonists [MRAs, the umbrella drug class that includes finerenone], should be used in appropriate patient populations based on defined benefits with the hope they will also reduce the development of AFib and atrial flutter over time,” Gerald V. Naccarelli, MD, and coauthors wrote in an editorial that accompanied the report (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.080).

The FIDELIO-DKD trial randomized 5,734 patients at 913 sites in 48 countries, including 461 patients with a history of AFib. The observed link of finerenone treatment with a reduced incidence of AFib appeared consistent regardless of patients’ age, sex, race, their kidney characteristics at baseline, baseline levels of systolic blood pressure, serum potassium, body mass index, A1c, or use of glucose-lowering medications.

Finerenone belongs to a new class of MRAs that have a nonsteroidal structure, in contrast with the MRAs spironolactone and eplerenone. This means that finerenone does not produce steroidal-associated adverse effects linked with certain other MRAs, such as gynecomastia, and may also differ in other actions.

FIDELIO-DKD was sponsored by Bayer, the company developing finerenone. Dr. Filippatos has received lecture fees from or participated in the direction of trials on behalf of Bayer, as well as for Amgen, Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor. Dr. Curtis is an adviser to and receives honoraria from St. Jude Medical, and receives honoraria from Medtronic. Dr. Naccarelli has been a consultant to Acesion, ARCA, GlaxoSmithKline, Janssen, Milestone, Omeicos, and Sanofi. His coauthors had no disclosures.

[email protected]

Finerenone treatment of patients with type 2 diabetes and diabetic kidney disease was linked to a significant drop in the incidence of new-onset atrial fibrillation as a prespecified, exploratory endpoint of the FIDELIO-DKD pivotal trial that randomized more than 5,700 patients.

Treatment with finerenone linked with a 29% relative reduction compared with placebo in incident cases of atrial fibrillation (AFib), Gerasimos Filippatos, MD, reported at the annual scientific sessions of the American College of Cardiology.

The absolute reduction was modest, a 1.3% reduction from the 4.5% incidence rate on placebo to a 3.2% rate on finerenone during a median 2.6 years of follow-up. Concurrently with the report, the results appeared online (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.079).

The analyses Dr. Filippatos presented also showed that whether or not patients had a history of AFib, there was no impact on either the primary benefit from finerenone treatment seen in FIDELIO-DKD, which was a significant 18% relative risk reduction compared with placebo in the combined rate of kidney failure, a 40% or greater decline from baseline in estimated glomerular filtration rate, or renal death.

Likewise, prior AFib status had no effect on the study’s key secondary endpoint, a significant 14% relative risk reduction in the combined rate of cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure.

The primary results from FIDELIO-DKD (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease) appeared in a 2020 report (N Engl J Med. 2020 Dec 3;383[23];2219-29).
 

‘Side benefits can be very helpful’

“It’s important to know of finerenone’s benefits beyond the primary outcome of a trial because side benefits can be very helpful,” said Anne B. Curtis, MD, an electrophysiologist and professor and chair of medicine at the University of Buffalo (N.Y.) School of Medicine and Biomedical Sciences. “It’s not a huge benefit, but this could be an added benefit for selected patients,” she said during a press briefing. “Background studies had shown favorable remodeling of the heart [by finerenone] that could affect AFib.”

Possible mitigating effects by finerenone on inflammation and fibrosis might also mediate the drug’s apparent effect on AFib, said Dr. Filippatos, professor of cardiology and director of the Heart Failure and Cardio-Oncology Clinic at Attikon University Hospital and the University of Athens.

He noted that additional data addressing a possible AFib effect of finerenone will emerge soon from the FIGARO-DKD trial, which enrolled patients similar to those in FIDELIO-DKD but with more moderate stages of kidney disease, and from the FINEARTS-HF trial, which is examining the effect of finerenone in patients with heart failure with an ejection fraction of at least 40%.

“Heart failure and AFib go together tightly. It’s worth studying this specifically, so we can see whether there is an impact of finerenone on patients with heart failure who may not necessarily have kidney disease or diabetes,” Dr. Curtis said.
 

Hypothesis-generating findings

The new findings reported by Dr. Filippatos “should be considered hypothesis generating. Until we have more information, upstream therapies, including mineralocorticoid receptor antagonists [MRAs, the umbrella drug class that includes finerenone], should be used in appropriate patient populations based on defined benefits with the hope they will also reduce the development of AFib and atrial flutter over time,” Gerald V. Naccarelli, MD, and coauthors wrote in an editorial that accompanied the report (J Am Coll Cardiol. 2021 May 17. doi: 10.1016/j.jacc.2021.04.080).

The FIDELIO-DKD trial randomized 5,734 patients at 913 sites in 48 countries, including 461 patients with a history of AFib. The observed link of finerenone treatment with a reduced incidence of AFib appeared consistent regardless of patients’ age, sex, race, their kidney characteristics at baseline, baseline levels of systolic blood pressure, serum potassium, body mass index, A1c, or use of glucose-lowering medications.

Finerenone belongs to a new class of MRAs that have a nonsteroidal structure, in contrast with the MRAs spironolactone and eplerenone. This means that finerenone does not produce steroidal-associated adverse effects linked with certain other MRAs, such as gynecomastia, and may also differ in other actions.

FIDELIO-DKD was sponsored by Bayer, the company developing finerenone. Dr. Filippatos has received lecture fees from or participated in the direction of trials on behalf of Bayer, as well as for Amgen, Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor. Dr. Curtis is an adviser to and receives honoraria from St. Jude Medical, and receives honoraria from Medtronic. Dr. Naccarelli has been a consultant to Acesion, ARCA, GlaxoSmithKline, Janssen, Milestone, Omeicos, and Sanofi. His coauthors had no disclosures.

[email protected]

In patients hospitalized with COVID-19 infection, the sodium-glucose transporter 2 inhibitor dapagliflozin showed a trend for benefit relative to placebo on multiple outcomes, including the primary outcome of time to organ failure or death, according to results from the randomized DARE-19 trial.

Because of the failure to reach statistical significance, these results have no immediate relevance, but the trends support interest in further testing SGLT2 inhibitors in acute diseases posing a high risk for organ failure, according to Mikhail Kosiborod, MD.

In a trial that did not meet its primary endpoint, Dr. Kosiborod acknowledged that positive interpretations are speculative, but he does believe that there is one immediate take-home message.

“Our results do not support discontinuation of SGLT2 inhibitors in the setting of COVID-19 as long as patients are monitored,” said Dr. Kosiborod, director of cardiometabolic research at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo.

At many institutions, it has been common to discontinue SGLT2 inhibitors in patients admitted with COVID-19. One reason was the concern that drugs in this class could exacerbate organ damage, particularly if they were to induced ketoacidosis. However, only 2 (0.003%) of 613 patients treated with dapagliflozin developed ketoacidosis, and the signal for organ protection overall, although not significant, was consistent.

“Numerically, fewer patients treated with dapagliflozin experienced organ failure and death, and this was consistent across systems, including the kidney,” Dr. Kosiborod said in presenting the study at the annual scientific sessions of the American College of Cardiology.

Overall, the study suggests that, in the context of COVID-19, dapagliflozin did not show harm and might have potential benefit, he added.

DARE-19 was rapidly conceived, designed, and implemented during the early stages of the COVID-19 pandemic. Based on prior evidence that SGLT2 inhibitors “favorably affect a number of pathophysiologic pathways disrupted during acute illness” and that drugs in this class have provided organ protection in the context of heart failure, chronic kidney disease, and other cardiometabolic conditions, the study was designed to test the hypothesis that this mechanism might improve outcomes in patients hospitalized with COVID-19, Dr. Kosiborod said.

The entry criteria included confirmed or suspected COVID-19 with an onset of 4 days of fewer and one additional risk factor, such as atherosclerotic cardiovascular disease, hypertension, or type 2 diabetes. Patients with significant renal impairment or a history of diabetic ketoacidosis were excluded.

On top of standard treatments for COVID-19, patients were randomized to 10 mg dapagliflozin or placebo once daily. There were two primary endpoints. That of prevention was time to criteria for respiratory, cardiovascular, or renal organ failure or death. The second primary outcome, for recovery, was a hierarchical composite for four endpoints: death, organ failure, status at 30 days if hospitalized, and time to discharge if this occurred before day 30.

Of the 1,250 patients randomized at 95 sites in seven countries, 617 in the dapagliflozin group and 620 patients in the placebo group completed the study. Baseline characteristics, which included a mean of age of 62 years; types of comorbidities; and types of treatments were similar.
 

Results for two primary endpoints

The curves for the primary outcome of prevention had already separated by day 3 and continued to widen over the 30 days in which outcomes were compared. At the end of 30 days, 11.2% of the dapagliflozin group and 13.8% of the placebo group had an event. By hazard ratio, dapagliflozin was linked to 20% nonsignificant relative protection from events (hazard ratio, 0.80; 95% confidence interval, 0.58-1.10).

The trend (P = .168) for the primary endpoint for prevention was reflected in the individual components. For dapagliflozin related to placebo, there were generally similar or greater reductions in new or worsening organ failure (HR, 0.80), cardiac decompensation (HR, 0.81), respiratory decompensation (HR, 0.85), and kidney decompensation (HR, 0.65). None were statistically significant, but the confidence intervals were tight with the upper end never exceeding 1.20.

Moreover, the relative risk reduction for all-cause mortality moved in the same direction (HR, 0.77; 95% CI, 0.52-1.16).

In the hierarchical composite endpoint of recovery, there was no significant difference in the time to discharge, but again many recovery metrics numerically favored dapagliflozin with an overall difference producing a statistical trend (P = .14) similar to organ failure events and death.

In safety analyses, dapagliflozin consistently outperformed placebo across a broad array of safety measure, including any severe adverse event (65% vs. 82%), any adverse event with an outcome of death (32% vs. 48%), discontinuation caused by an adverse event (44% vs. 55%), and acute kidney injury (21% vs. 34%).
 

Data could fuel related studies

According to Ana Barac, MD, PhD, director of the cardio-oncology program in the Medstar Heart and Vascular Institute, Washington, these data are “thought provoking.” Although this was a negative trial, she said that it generates an “exciting hypothesis” about the potential of SGLT2 inhibitors to provide organ protection. She called for studies to pursue this path of research.

More immediately, Dr. Barac agreed that these data argue against stopping SGLT2 inhibitors in patients admitted to a hospital for COVID-19 infection.

“These data show that these drugs are not going to lead to harm, but they might lead to benefit,” she said.

For James Januzzi, MD, a cardiologist at Massachusetts General Hospital and professor of medicine at Harvard Medical School, both in Boston, DARE-19 was perhaps most impressive because of its rigorous design and execution in the midst of a pandemic.

Over the past year, “the medical literature was flooded with grossly underpowered, poorly designed, single-center studies” yielding results that have been hard to interpret, Dr. Januzzi said. Despite the fact that this study failed to confirm its hypothesis, he said the investigators deserve praise for the quality of the work.

Courtesy Massachusetts General Hospital

Dr. Januzzi also believes the study is not without clinically relevant findings, particularly the fact that dapagliflozin was associated with a lower rate of adverse events than placebo. This, at least, provides reassurance about the safety of this drug in the setting of COVID-19 infection.

Dr. Kosiborod reported financial relationships with more than 10 pharmaceutical companies, including AstraZeneca, which provided funding for DARE-19. Dr. Barac reported financial relationships with Bristol-Myers Squibb and CTI BioPharma. Dr. Januzzi reported financial relationships with Boehringer Ingelheim, GE Healthcare, Johnson & Johnson, Merck, Novartis, Pfizer, and Roche.

In patients hospitalized with COVID-19 infection, the sodium-glucose transporter 2 inhibitor dapagliflozin showed a trend for benefit relative to placebo on multiple outcomes, including the primary outcome of time to organ failure or death, according to results from the randomized DARE-19 trial.

Because of the failure to reach statistical significance, these results have no immediate relevance, but the trends support interest in further testing SGLT2 inhibitors in acute diseases posing a high risk for organ failure, according to Mikhail Kosiborod, MD.

In a trial that did not meet its primary endpoint, Dr. Kosiborod acknowledged that positive interpretations are speculative, but he does believe that there is one immediate take-home message.

“Our results do not support discontinuation of SGLT2 inhibitors in the setting of COVID-19 as long as patients are monitored,” said Dr. Kosiborod, director of cardiometabolic research at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo.

At many institutions, it has been common to discontinue SGLT2 inhibitors in patients admitted with COVID-19. One reason was the concern that drugs in this class could exacerbate organ damage, particularly if they were to induced ketoacidosis. However, only 2 (0.003%) of 613 patients treated with dapagliflozin developed ketoacidosis, and the signal for organ protection overall, although not significant, was consistent.

“Numerically, fewer patients treated with dapagliflozin experienced organ failure and death, and this was consistent across systems, including the kidney,” Dr. Kosiborod said in presenting the study at the annual scientific sessions of the American College of Cardiology.

Overall, the study suggests that, in the context of COVID-19, dapagliflozin did not show harm and might have potential benefit, he added.

DARE-19 was rapidly conceived, designed, and implemented during the early stages of the COVID-19 pandemic. Based on prior evidence that SGLT2 inhibitors “favorably affect a number of pathophysiologic pathways disrupted during acute illness” and that drugs in this class have provided organ protection in the context of heart failure, chronic kidney disease, and other cardiometabolic conditions, the study was designed to test the hypothesis that this mechanism might improve outcomes in patients hospitalized with COVID-19, Dr. Kosiborod said.

The entry criteria included confirmed or suspected COVID-19 with an onset of 4 days of fewer and one additional risk factor, such as atherosclerotic cardiovascular disease, hypertension, or type 2 diabetes. Patients with significant renal impairment or a history of diabetic ketoacidosis were excluded.

On top of standard treatments for COVID-19, patients were randomized to 10 mg dapagliflozin or placebo once daily. There were two primary endpoints. That of prevention was time to criteria for respiratory, cardiovascular, or renal organ failure or death. The second primary outcome, for recovery, was a hierarchical composite for four endpoints: death, organ failure, status at 30 days if hospitalized, and time to discharge if this occurred before day 30.

Of the 1,250 patients randomized at 95 sites in seven countries, 617 in the dapagliflozin group and 620 patients in the placebo group completed the study. Baseline characteristics, which included a mean of age of 62 years; types of comorbidities; and types of treatments were similar.
 

Results for two primary endpoints

The curves for the primary outcome of prevention had already separated by day 3 and continued to widen over the 30 days in which outcomes were compared. At the end of 30 days, 11.2% of the dapagliflozin group and 13.8% of the placebo group had an event. By hazard ratio, dapagliflozin was linked to 20% nonsignificant relative protection from events (hazard ratio, 0.80; 95% confidence interval, 0.58-1.10).

The trend (P = .168) for the primary endpoint for prevention was reflected in the individual components. For dapagliflozin related to placebo, there were generally similar or greater reductions in new or worsening organ failure (HR, 0.80), cardiac decompensation (HR, 0.81), respiratory decompensation (HR, 0.85), and kidney decompensation (HR, 0.65). None were statistically significant, but the confidence intervals were tight with the upper end never exceeding 1.20.

Moreover, the relative risk reduction for all-cause mortality moved in the same direction (HR, 0.77; 95% CI, 0.52-1.16).

In the hierarchical composite endpoint of recovery, there was no significant difference in the time to discharge, but again many recovery metrics numerically favored dapagliflozin with an overall difference producing a statistical trend (P = .14) similar to organ failure events and death.

In safety analyses, dapagliflozin consistently outperformed placebo across a broad array of safety measure, including any severe adverse event (65% vs. 82%), any adverse event with an outcome of death (32% vs. 48%), discontinuation caused by an adverse event (44% vs. 55%), and acute kidney injury (21% vs. 34%).
 

Data could fuel related studies

According to Ana Barac, MD, PhD, director of the cardio-oncology program in the Medstar Heart and Vascular Institute, Washington, these data are “thought provoking.” Although this was a negative trial, she said that it generates an “exciting hypothesis” about the potential of SGLT2 inhibitors to provide organ protection. She called for studies to pursue this path of research.

More immediately, Dr. Barac agreed that these data argue against stopping SGLT2 inhibitors in patients admitted to a hospital for COVID-19 infection.

“These data show that these drugs are not going to lead to harm, but they might lead to benefit,” she said.

For James Januzzi, MD, a cardiologist at Massachusetts General Hospital and professor of medicine at Harvard Medical School, both in Boston, DARE-19 was perhaps most impressive because of its rigorous design and execution in the midst of a pandemic.

Over the past year, “the medical literature was flooded with grossly underpowered, poorly designed, single-center studies” yielding results that have been hard to interpret, Dr. Januzzi said. Despite the fact that this study failed to confirm its hypothesis, he said the investigators deserve praise for the quality of the work.

Courtesy Massachusetts General Hospital

Dr. Januzzi also believes the study is not without clinically relevant findings, particularly the fact that dapagliflozin was associated with a lower rate of adverse events than placebo. This, at least, provides reassurance about the safety of this drug in the setting of COVID-19 infection.

Dr. Kosiborod reported financial relationships with more than 10 pharmaceutical companies, including AstraZeneca, which provided funding for DARE-19. Dr. Barac reported financial relationships with Bristol-Myers Squibb and CTI BioPharma. Dr. Januzzi reported financial relationships with Boehringer Ingelheim, GE Healthcare, Johnson & Johnson, Merck, Novartis, Pfizer, and Roche.

In patients hospitalized with COVID-19 infection, the sodium-glucose transporter 2 inhibitor dapagliflozin showed a trend for benefit relative to placebo on multiple outcomes, including the primary outcome of time to organ failure or death, according to results from the randomized DARE-19 trial.

Because of the failure to reach statistical significance, these results have no immediate relevance, but the trends support interest in further testing SGLT2 inhibitors in acute diseases posing a high risk for organ failure, according to Mikhail Kosiborod, MD.

In a trial that did not meet its primary endpoint, Dr. Kosiborod acknowledged that positive interpretations are speculative, but he does believe that there is one immediate take-home message.

“Our results do not support discontinuation of SGLT2 inhibitors in the setting of COVID-19 as long as patients are monitored,” said Dr. Kosiborod, director of cardiometabolic research at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo.

At many institutions, it has been common to discontinue SGLT2 inhibitors in patients admitted with COVID-19. One reason was the concern that drugs in this class could exacerbate organ damage, particularly if they were to induced ketoacidosis. However, only 2 (0.003%) of 613 patients treated with dapagliflozin developed ketoacidosis, and the signal for organ protection overall, although not significant, was consistent.

“Numerically, fewer patients treated with dapagliflozin experienced organ failure and death, and this was consistent across systems, including the kidney,” Dr. Kosiborod said in presenting the study at the annual scientific sessions of the American College of Cardiology.

Overall, the study suggests that, in the context of COVID-19, dapagliflozin did not show harm and might have potential benefit, he added.

DARE-19 was rapidly conceived, designed, and implemented during the early stages of the COVID-19 pandemic. Based on prior evidence that SGLT2 inhibitors “favorably affect a number of pathophysiologic pathways disrupted during acute illness” and that drugs in this class have provided organ protection in the context of heart failure, chronic kidney disease, and other cardiometabolic conditions, the study was designed to test the hypothesis that this mechanism might improve outcomes in patients hospitalized with COVID-19, Dr. Kosiborod said.

The entry criteria included confirmed or suspected COVID-19 with an onset of 4 days of fewer and one additional risk factor, such as atherosclerotic cardiovascular disease, hypertension, or type 2 diabetes. Patients with significant renal impairment or a history of diabetic ketoacidosis were excluded.

On top of standard treatments for COVID-19, patients were randomized to 10 mg dapagliflozin or placebo once daily. There were two primary endpoints. That of prevention was time to criteria for respiratory, cardiovascular, or renal organ failure or death. The second primary outcome, for recovery, was a hierarchical composite for four endpoints: death, organ failure, status at 30 days if hospitalized, and time to discharge if this occurred before day 30.

Of the 1,250 patients randomized at 95 sites in seven countries, 617 in the dapagliflozin group and 620 patients in the placebo group completed the study. Baseline characteristics, which included a mean of age of 62 years; types of comorbidities; and types of treatments were similar.
 

Results for two primary endpoints

The curves for the primary outcome of prevention had already separated by day 3 and continued to widen over the 30 days in which outcomes were compared. At the end of 30 days, 11.2% of the dapagliflozin group and 13.8% of the placebo group had an event. By hazard ratio, dapagliflozin was linked to 20% nonsignificant relative protection from events (hazard ratio, 0.80; 95% confidence interval, 0.58-1.10).

The trend (P = .168) for the primary endpoint for prevention was reflected in the individual components. For dapagliflozin related to placebo, there were generally similar or greater reductions in new or worsening organ failure (HR, 0.80), cardiac decompensation (HR, 0.81), respiratory decompensation (HR, 0.85), and kidney decompensation (HR, 0.65). None were statistically significant, but the confidence intervals were tight with the upper end never exceeding 1.20.

Moreover, the relative risk reduction for all-cause mortality moved in the same direction (HR, 0.77; 95% CI, 0.52-1.16).

In the hierarchical composite endpoint of recovery, there was no significant difference in the time to discharge, but again many recovery metrics numerically favored dapagliflozin with an overall difference producing a statistical trend (P = .14) similar to organ failure events and death.

In safety analyses, dapagliflozin consistently outperformed placebo across a broad array of safety measure, including any severe adverse event (65% vs. 82%), any adverse event with an outcome of death (32% vs. 48%), discontinuation caused by an adverse event (44% vs. 55%), and acute kidney injury (21% vs. 34%).
 

Data could fuel related studies

According to Ana Barac, MD, PhD, director of the cardio-oncology program in the Medstar Heart and Vascular Institute, Washington, these data are “thought provoking.” Although this was a negative trial, she said that it generates an “exciting hypothesis” about the potential of SGLT2 inhibitors to provide organ protection. She called for studies to pursue this path of research.

More immediately, Dr. Barac agreed that these data argue against stopping SGLT2 inhibitors in patients admitted to a hospital for COVID-19 infection.

“These data show that these drugs are not going to lead to harm, but they might lead to benefit,” she said.

For James Januzzi, MD, a cardiologist at Massachusetts General Hospital and professor of medicine at Harvard Medical School, both in Boston, DARE-19 was perhaps most impressive because of its rigorous design and execution in the midst of a pandemic.

Over the past year, “the medical literature was flooded with grossly underpowered, poorly designed, single-center studies” yielding results that have been hard to interpret, Dr. Januzzi said. Despite the fact that this study failed to confirm its hypothesis, he said the investigators deserve praise for the quality of the work.

Courtesy Massachusetts General Hospital

Dr. Januzzi also believes the study is not without clinically relevant findings, particularly the fact that dapagliflozin was associated with a lower rate of adverse events than placebo. This, at least, provides reassurance about the safety of this drug in the setting of COVID-19 infection.

Dr. Kosiborod reported financial relationships with more than 10 pharmaceutical companies, including AstraZeneca, which provided funding for DARE-19. Dr. Barac reported financial relationships with Bristol-Myers Squibb and CTI BioPharma. Dr. Januzzi reported financial relationships with Boehringer Ingelheim, GE Healthcare, Johnson & Johnson, Merck, Novartis, Pfizer, and Roche.

A novel physical rehabilitation program for patients with advanced heart failure that aimed to improve their ability to exercise before focusing on endurance was successful in a randomized trial in ways that seem to have eluded some earlier exercise-training studies in the setting of HF.

The often-frail patients following the training regimen, initiated before discharge from hospitalization for acute decompensation, worked on capabilities such as mobility, balance, and strength deemed necessary if exercises meant to build exercise capacity were to succeed.

A huge percentage stayed with the 12-week program, which featured personalized, one-on-one training from a physical therapist. The patients benefited, with improvements in balance, walking ability, and strength, which were followed by significant gains in 6-minute walk distance (6MWD) and measures of physical functioning, frailty, and quality of life. The patients then continued elements of the program at home out to 6 months.

At that time, death and rehospitalizations did not differ between those assigned to the regimen and similar patients who had not participated in the program, although the trial wasn’t powered for clinical events.

The rehab strategy seemed to work across a wide range of patient subgroups. In particular, there was evidence that the benefits were more pronounced in patients with HF and preserved ejection fraction (HFpEF) than in those with HF and reduced ejection fraction (HFrEF), observed Dalane W. Kitzman, MD, Wake Forest University, Winston-Salem, N.C.

Dr. Kitzman presented results from the REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) trial at the annual scientific sessions of the American College of Cardiology and is lead author on its same-day publication in the New England Journal of Medicine.

An earlier pilot program unexpectedly showed that such patients recently hospitalized with HF “have significant impairments in mobility and balance,” he explained. If so, “it would be hazardous to subject them to traditional endurance training, such as walking-based treadmill or even bicycle.”

The unusual program, said Dr. Kitzman, looks to those issues before engaging the patients in endurance exercise by addressing mobility, balance, and basic strength – enough to repeatedly stand up from a sitting position, for example. “If you’re not able to stand with confidence, then you’re not able to walk on a treadmill.”

This model of exercise rehab “is used in geriatrics research, and enables them to safely increase endurance. It’s well known from geriatric studies that if you go directly to endurance in these, frail, older patients, you have little improvement and often have injuries and falls,” he added.
 

Guidance from telemedicine?

The functional outcomes examined in REHAB-HF “are the ones that matter to patients the most,” observed Eileen M. Handberg, PhD, of Shands Hospital at the University of Florida, Gainesville, at a presentation on the trial for the media.

“This is about being able to get out of a chair without assistance, not falling, walking farther, and feeling better as opposed to the more traditional outcome measure that has been used in cardiac rehab trials, which has been the exercise treadmill test – which most patients don’t have the capacity to do very well anyway,” said Dr. Handberg, who is not a part of REHAB-HF.

“This opens up rehab, potentially, to the more sick, who also need a better quality of life,” she said.

However, many patients invited to participate in the trial could not because they lived too far from the program, Dr. Handberg observed. “It would be nice to see if the lessons from COVID-19 might apply to this population” by making participation possible remotely, “perhaps using family members as rehab assistance,” she said.

“I was really very impressed that you had 83% adherence to a home exercise 6 months down the road, which far eclipses what we had in HF-ACTION,” said Vera Bittner, MD, University of Alabama at Birmingham, as the invited discussant following Dr. Kitzman’s formal presentation of the trial. “And it certainly eclipses what we see in the typical cardiac rehab program.”

Both Dr. Bittner and Dr. Kitzman participated in HF-ACTION, a randomized exercise-training trial for patients with chronic, stable HFrEF who were all-around less sick than those in REHAB-HF.
 

Four functional domains

Historically, HF exercise or rehab trials have excluded patients hospitalized with acute decompensation, and third-party reimbursement often has not covered such programs because of a lack of supporting evidence and a supposed potential for harm, Dr. Kitzman said.

Entry to REHAB-HF required the patients to be fit enough to walk 4 meters, with or without a walker or other assistant device, and to have been in the hospital for at least 24 hours with a primary diagnosis of acute decompensated HF.

The intervention relied on exercises aimed at improving the four functional domains of strength, balance, mobility, and – when those three were sufficiently developed – endurance, Dr. Kitzman and associates wrote in their published report.

“The intervention was initiated in the hospital when feasible and was subsequently transitioned to an outpatient facility as soon as possible after discharge,” they wrote. Afterward, “a key goal of the intervention during the first 3 months [the outpatient phase] was to prepare the patient to transition to the independent maintenance phase (months 4-6).”

The study’s control patients “received frequent calls from study staff to try to approximate the increased attention received by the intervention group,” Dr. Kitzman said in an interview. “They were allowed to receive all usual care as ordered by their treating physicians. This included, if ordered, standard physical therapy or cardiac rehabilitation” in 43% of the control cohort. Of the trial’s 349 patients, those assigned to the intervention scored significantly higher on the three-component Short Physical Performance Battery (SPPB) at 12 weeks than those assigned to a usual care approach that included, for some, more conventional cardiac rehabilitation (8.3 vs. 6.9; P < .001).

The SPPB, validated in trials as a proxy for clinical outcomes includes tests of balance while standing, gait speed during a 4-minute walk, and strength. The latter is the test that measures time needed to rise from a chair five times.

They also showed consistent gains in other measures of physical functioning and quality of life by 12 weeks months.

The observed SPPB treatment effect is “impressive” and “compares very favorably with previously reported estimates,” observed an accompanying editorial from Stefan D. Anker, MD, PhD, of the German Center for Cardiovascular Research and Charité Universitätsmedizin, Berlin, and Andrew J.S. Coats, DM, of the University of Warwick, Coventry, England.

“Similarly, the between-group differences seen in 6-minute walk distance (34 m) and gait speed (0.12 m/s) are clinically meaningful and sizable.”

They propose that some of the substantial quality-of-life benefit in the intervention group “may be due to better physical performance, and that part may be due to improvements in psychosocial factors and mood. It appears that exercise also resulted in patients becoming happier, or at least less depressed, as evidenced by the positive results on the Geriatric Depression Scale.”
 

Similar results across most subgroups

In subgroup analyses, the intervention was successful against the standard-care approach in both men and women at all ages and regardless of ejection fraction; symptom status; and whether the patient had diabetes, ischemic heart disease, or atrial fibrillation, or was obese.

Clinical outcomes were not significantly different at 6 months. The rate of death from any cause was 13% for the intervention group and 10% for the control group. There were 194 and 213 hospitalizations from any cause, respectively.

Not included in the trial’s current publication but soon to be published, Dr. Kitzman said when interviewed, is a comparison of outcomes in patients with HFpEF and HFrEF. “We found at baseline that those with HFpEF had worse impairment in physical function, quality of life, and frailty. After the intervention, there appeared to be consistently larger improvements in all outcomes, including SPPB, 6-minute walk, qualify of life, and frailty, in HFpEF versus HFrEF.”

The signals of potential benefit in HFpEF extended to clinical endpoints, he said. In contrast to similar rates of all-cause rehospitalization in HFrEF, “in patients with HFpEF, rehospitalizations were 17% lower in the intervention group, compared to the control group.” Still, he noted, the interaction P value wasn’t significant.

However, Dr. Kitzman added, mortality in the intervention group, compared with the control group, was reduced by 35% among patients with HFpEF, “but was 250% higher in HFrEF,” with a significant interaction P value.

He was careful to note that, as a phase 2 trial, REHAB-HF was underpowered for clinical events, “and even the results in the HFpEF group should not be seen as adequate evidence to change clinical care.” They were from an exploratory analysis that included relatively few events.

“Because definitive demonstration of improvement in clinical events is critical for altering clinical care guidelines and for third-party payer reimbursement decisions, we believe that a subsequent phase 3 trial is needed and are currently planning toward that,” Dr. Kitzman said.

The study was supported by research grants from the National Institutes of Health, the Kermit Glenn Phillips II Chair in Cardiovascular Medicine, and the Oristano Family Fund at Wake Forest. Dr. Kitzman disclosed receiving consulting fees or honoraria from AbbVie, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, CinRx, Corviamedical, GlaxoSmithKline, and Merck; and having an unspecified relationship with Gilead. Dr. Handberg disclosed receiving grants from Aastom Biosciences, Abbott Laboratories, Amgen, Amorcyte, AstraZeneca, Biocardia, Boehringer Ingelheim, Capricor, Cytori Therapeutics, Department of Defense, Direct Flow Medical, Everyfit, Gilead, Ionis, Medtronic, Merck, Mesoblast, Relypsa, and Sanofi-Aventis. Dr. Bittner discloses receiving consulting fees or honoraria from Pfizer and Sanofi; receiving research grants from Amgen and The Medicines Company; and having unspecified relationships with AstraZeneca, DalCor, Esperion, and Sanofi-Aventis. Dr. Anker reported receiving grants and personal fees from Abbott Vascular and Vifor; personal fees from Bayer, Boehringer Ingelheim, Novartis, Servier, Cardiac Dimensions, Thermo Fisher Scientific, AstraZeneca, Occlutech, Actimed, and Respicardia. Dr. Coats disclosed receiving personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Menarini, Novartis, Nutricia, Servier, Vifor, Abbott, Actimed, Arena, Cardiac Dimensions, Corvia, CVRx, Enopace, ESN Cleer, Faraday, WL Gore, Impulse Dynamics, and Respicardia.

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

A novel physical rehabilitation program for patients with advanced heart failure that aimed to improve their ability to exercise before focusing on endurance was successful in a randomized trial in ways that seem to have eluded some earlier exercise-training studies in the setting of HF.

The often-frail patients following the training regimen, initiated before discharge from hospitalization for acute decompensation, worked on capabilities such as mobility, balance, and strength deemed necessary if exercises meant to build exercise capacity were to succeed.

A huge percentage stayed with the 12-week program, which featured personalized, one-on-one training from a physical therapist. The patients benefited, with improvements in balance, walking ability, and strength, which were followed by significant gains in 6-minute walk distance (6MWD) and measures of physical functioning, frailty, and quality of life. The patients then continued elements of the program at home out to 6 months.

At that time, death and rehospitalizations did not differ between those assigned to the regimen and similar patients who had not participated in the program, although the trial wasn’t powered for clinical events.

The rehab strategy seemed to work across a wide range of patient subgroups. In particular, there was evidence that the benefits were more pronounced in patients with HF and preserved ejection fraction (HFpEF) than in those with HF and reduced ejection fraction (HFrEF), observed Dalane W. Kitzman, MD, Wake Forest University, Winston-Salem, N.C.

Dr. Kitzman presented results from the REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) trial at the annual scientific sessions of the American College of Cardiology and is lead author on its same-day publication in the New England Journal of Medicine.

An earlier pilot program unexpectedly showed that such patients recently hospitalized with HF “have significant impairments in mobility and balance,” he explained. If so, “it would be hazardous to subject them to traditional endurance training, such as walking-based treadmill or even bicycle.”

The unusual program, said Dr. Kitzman, looks to those issues before engaging the patients in endurance exercise by addressing mobility, balance, and basic strength – enough to repeatedly stand up from a sitting position, for example. “If you’re not able to stand with confidence, then you’re not able to walk on a treadmill.”

This model of exercise rehab “is used in geriatrics research, and enables them to safely increase endurance. It’s well known from geriatric studies that if you go directly to endurance in these, frail, older patients, you have little improvement and often have injuries and falls,” he added.
 

Guidance from telemedicine?

The functional outcomes examined in REHAB-HF “are the ones that matter to patients the most,” observed Eileen M. Handberg, PhD, of Shands Hospital at the University of Florida, Gainesville, at a presentation on the trial for the media.

“This is about being able to get out of a chair without assistance, not falling, walking farther, and feeling better as opposed to the more traditional outcome measure that has been used in cardiac rehab trials, which has been the exercise treadmill test – which most patients don’t have the capacity to do very well anyway,” said Dr. Handberg, who is not a part of REHAB-HF.

“This opens up rehab, potentially, to the more sick, who also need a better quality of life,” she said.

However, many patients invited to participate in the trial could not because they lived too far from the program, Dr. Handberg observed. “It would be nice to see if the lessons from COVID-19 might apply to this population” by making participation possible remotely, “perhaps using family members as rehab assistance,” she said.

“I was really very impressed that you had 83% adherence to a home exercise 6 months down the road, which far eclipses what we had in HF-ACTION,” said Vera Bittner, MD, University of Alabama at Birmingham, as the invited discussant following Dr. Kitzman’s formal presentation of the trial. “And it certainly eclipses what we see in the typical cardiac rehab program.”

Both Dr. Bittner and Dr. Kitzman participated in HF-ACTION, a randomized exercise-training trial for patients with chronic, stable HFrEF who were all-around less sick than those in REHAB-HF.
 

Four functional domains

Historically, HF exercise or rehab trials have excluded patients hospitalized with acute decompensation, and third-party reimbursement often has not covered such programs because of a lack of supporting evidence and a supposed potential for harm, Dr. Kitzman said.

Entry to REHAB-HF required the patients to be fit enough to walk 4 meters, with or without a walker or other assistant device, and to have been in the hospital for at least 24 hours with a primary diagnosis of acute decompensated HF.

The intervention relied on exercises aimed at improving the four functional domains of strength, balance, mobility, and – when those three were sufficiently developed – endurance, Dr. Kitzman and associates wrote in their published report.

“The intervention was initiated in the hospital when feasible and was subsequently transitioned to an outpatient facility as soon as possible after discharge,” they wrote. Afterward, “a key goal of the intervention during the first 3 months [the outpatient phase] was to prepare the patient to transition to the independent maintenance phase (months 4-6).”

The study’s control patients “received frequent calls from study staff to try to approximate the increased attention received by the intervention group,” Dr. Kitzman said in an interview. “They were allowed to receive all usual care as ordered by their treating physicians. This included, if ordered, standard physical therapy or cardiac rehabilitation” in 43% of the control cohort. Of the trial’s 349 patients, those assigned to the intervention scored significantly higher on the three-component Short Physical Performance Battery (SPPB) at 12 weeks than those assigned to a usual care approach that included, for some, more conventional cardiac rehabilitation (8.3 vs. 6.9; P < .001).

The SPPB, validated in trials as a proxy for clinical outcomes includes tests of balance while standing, gait speed during a 4-minute walk, and strength. The latter is the test that measures time needed to rise from a chair five times.

They also showed consistent gains in other measures of physical functioning and quality of life by 12 weeks months.

The observed SPPB treatment effect is “impressive” and “compares very favorably with previously reported estimates,” observed an accompanying editorial from Stefan D. Anker, MD, PhD, of the German Center for Cardiovascular Research and Charité Universitätsmedizin, Berlin, and Andrew J.S. Coats, DM, of the University of Warwick, Coventry, England.

“Similarly, the between-group differences seen in 6-minute walk distance (34 m) and gait speed (0.12 m/s) are clinically meaningful and sizable.”

They propose that some of the substantial quality-of-life benefit in the intervention group “may be due to better physical performance, and that part may be due to improvements in psychosocial factors and mood. It appears that exercise also resulted in patients becoming happier, or at least less depressed, as evidenced by the positive results on the Geriatric Depression Scale.”
 

Similar results across most subgroups

In subgroup analyses, the intervention was successful against the standard-care approach in both men and women at all ages and regardless of ejection fraction; symptom status; and whether the patient had diabetes, ischemic heart disease, or atrial fibrillation, or was obese.

Clinical outcomes were not significantly different at 6 months. The rate of death from any cause was 13% for the intervention group and 10% for the control group. There were 194 and 213 hospitalizations from any cause, respectively.

Not included in the trial’s current publication but soon to be published, Dr. Kitzman said when interviewed, is a comparison of outcomes in patients with HFpEF and HFrEF. “We found at baseline that those with HFpEF had worse impairment in physical function, quality of life, and frailty. After the intervention, there appeared to be consistently larger improvements in all outcomes, including SPPB, 6-minute walk, qualify of life, and frailty, in HFpEF versus HFrEF.”

The signals of potential benefit in HFpEF extended to clinical endpoints, he said. In contrast to similar rates of all-cause rehospitalization in HFrEF, “in patients with HFpEF, rehospitalizations were 17% lower in the intervention group, compared to the control group.” Still, he noted, the interaction P value wasn’t significant.

However, Dr. Kitzman added, mortality in the intervention group, compared with the control group, was reduced by 35% among patients with HFpEF, “but was 250% higher in HFrEF,” with a significant interaction P value.

He was careful to note that, as a phase 2 trial, REHAB-HF was underpowered for clinical events, “and even the results in the HFpEF group should not be seen as adequate evidence to change clinical care.” They were from an exploratory analysis that included relatively few events.

“Because definitive demonstration of improvement in clinical events is critical for altering clinical care guidelines and for third-party payer reimbursement decisions, we believe that a subsequent phase 3 trial is needed and are currently planning toward that,” Dr. Kitzman said.

The study was supported by research grants from the National Institutes of Health, the Kermit Glenn Phillips II Chair in Cardiovascular Medicine, and the Oristano Family Fund at Wake Forest. Dr. Kitzman disclosed receiving consulting fees or honoraria from AbbVie, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, CinRx, Corviamedical, GlaxoSmithKline, and Merck; and having an unspecified relationship with Gilead. Dr. Handberg disclosed receiving grants from Aastom Biosciences, Abbott Laboratories, Amgen, Amorcyte, AstraZeneca, Biocardia, Boehringer Ingelheim, Capricor, Cytori Therapeutics, Department of Defense, Direct Flow Medical, Everyfit, Gilead, Ionis, Medtronic, Merck, Mesoblast, Relypsa, and Sanofi-Aventis. Dr. Bittner discloses receiving consulting fees or honoraria from Pfizer and Sanofi; receiving research grants from Amgen and The Medicines Company; and having unspecified relationships with AstraZeneca, DalCor, Esperion, and Sanofi-Aventis. Dr. Anker reported receiving grants and personal fees from Abbott Vascular and Vifor; personal fees from Bayer, Boehringer Ingelheim, Novartis, Servier, Cardiac Dimensions, Thermo Fisher Scientific, AstraZeneca, Occlutech, Actimed, and Respicardia. Dr. Coats disclosed receiving personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Menarini, Novartis, Nutricia, Servier, Vifor, Abbott, Actimed, Arena, Cardiac Dimensions, Corvia, CVRx, Enopace, ESN Cleer, Faraday, WL Gore, Impulse Dynamics, and Respicardia.

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

A novel physical rehabilitation program for patients with advanced heart failure that aimed to improve their ability to exercise before focusing on endurance was successful in a randomized trial in ways that seem to have eluded some earlier exercise-training studies in the setting of HF.

The often-frail patients following the training regimen, initiated before discharge from hospitalization for acute decompensation, worked on capabilities such as mobility, balance, and strength deemed necessary if exercises meant to build exercise capacity were to succeed.

A huge percentage stayed with the 12-week program, which featured personalized, one-on-one training from a physical therapist. The patients benefited, with improvements in balance, walking ability, and strength, which were followed by significant gains in 6-minute walk distance (6MWD) and measures of physical functioning, frailty, and quality of life. The patients then continued elements of the program at home out to 6 months.

At that time, death and rehospitalizations did not differ between those assigned to the regimen and similar patients who had not participated in the program, although the trial wasn’t powered for clinical events.

The rehab strategy seemed to work across a wide range of patient subgroups. In particular, there was evidence that the benefits were more pronounced in patients with HF and preserved ejection fraction (HFpEF) than in those with HF and reduced ejection fraction (HFrEF), observed Dalane W. Kitzman, MD, Wake Forest University, Winston-Salem, N.C.

Dr. Kitzman presented results from the REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) trial at the annual scientific sessions of the American College of Cardiology and is lead author on its same-day publication in the New England Journal of Medicine.

An earlier pilot program unexpectedly showed that such patients recently hospitalized with HF “have significant impairments in mobility and balance,” he explained. If so, “it would be hazardous to subject them to traditional endurance training, such as walking-based treadmill or even bicycle.”

The unusual program, said Dr. Kitzman, looks to those issues before engaging the patients in endurance exercise by addressing mobility, balance, and basic strength – enough to repeatedly stand up from a sitting position, for example. “If you’re not able to stand with confidence, then you’re not able to walk on a treadmill.”

This model of exercise rehab “is used in geriatrics research, and enables them to safely increase endurance. It’s well known from geriatric studies that if you go directly to endurance in these, frail, older patients, you have little improvement and often have injuries and falls,” he added.
 

Guidance from telemedicine?

The functional outcomes examined in REHAB-HF “are the ones that matter to patients the most,” observed Eileen M. Handberg, PhD, of Shands Hospital at the University of Florida, Gainesville, at a presentation on the trial for the media.

“This is about being able to get out of a chair without assistance, not falling, walking farther, and feeling better as opposed to the more traditional outcome measure that has been used in cardiac rehab trials, which has been the exercise treadmill test – which most patients don’t have the capacity to do very well anyway,” said Dr. Handberg, who is not a part of REHAB-HF.

“This opens up rehab, potentially, to the more sick, who also need a better quality of life,” she said.

However, many patients invited to participate in the trial could not because they lived too far from the program, Dr. Handberg observed. “It would be nice to see if the lessons from COVID-19 might apply to this population” by making participation possible remotely, “perhaps using family members as rehab assistance,” she said.

“I was really very impressed that you had 83% adherence to a home exercise 6 months down the road, which far eclipses what we had in HF-ACTION,” said Vera Bittner, MD, University of Alabama at Birmingham, as the invited discussant following Dr. Kitzman’s formal presentation of the trial. “And it certainly eclipses what we see in the typical cardiac rehab program.”

Both Dr. Bittner and Dr. Kitzman participated in HF-ACTION, a randomized exercise-training trial for patients with chronic, stable HFrEF who were all-around less sick than those in REHAB-HF.
 

Four functional domains

Historically, HF exercise or rehab trials have excluded patients hospitalized with acute decompensation, and third-party reimbursement often has not covered such programs because of a lack of supporting evidence and a supposed potential for harm, Dr. Kitzman said.

Entry to REHAB-HF required the patients to be fit enough to walk 4 meters, with or without a walker or other assistant device, and to have been in the hospital for at least 24 hours with a primary diagnosis of acute decompensated HF.

The intervention relied on exercises aimed at improving the four functional domains of strength, balance, mobility, and – when those three were sufficiently developed – endurance, Dr. Kitzman and associates wrote in their published report.

“The intervention was initiated in the hospital when feasible and was subsequently transitioned to an outpatient facility as soon as possible after discharge,” they wrote. Afterward, “a key goal of the intervention during the first 3 months [the outpatient phase] was to prepare the patient to transition to the independent maintenance phase (months 4-6).”

The study’s control patients “received frequent calls from study staff to try to approximate the increased attention received by the intervention group,” Dr. Kitzman said in an interview. “They were allowed to receive all usual care as ordered by their treating physicians. This included, if ordered, standard physical therapy or cardiac rehabilitation” in 43% of the control cohort. Of the trial’s 349 patients, those assigned to the intervention scored significantly higher on the three-component Short Physical Performance Battery (SPPB) at 12 weeks than those assigned to a usual care approach that included, for some, more conventional cardiac rehabilitation (8.3 vs. 6.9; P < .001).

The SPPB, validated in trials as a proxy for clinical outcomes includes tests of balance while standing, gait speed during a 4-minute walk, and strength. The latter is the test that measures time needed to rise from a chair five times.

They also showed consistent gains in other measures of physical functioning and quality of life by 12 weeks months.

The observed SPPB treatment effect is “impressive” and “compares very favorably with previously reported estimates,” observed an accompanying editorial from Stefan D. Anker, MD, PhD, of the German Center for Cardiovascular Research and Charité Universitätsmedizin, Berlin, and Andrew J.S. Coats, DM, of the University of Warwick, Coventry, England.

“Similarly, the between-group differences seen in 6-minute walk distance (34 m) and gait speed (0.12 m/s) are clinically meaningful and sizable.”

They propose that some of the substantial quality-of-life benefit in the intervention group “may be due to better physical performance, and that part may be due to improvements in psychosocial factors and mood. It appears that exercise also resulted in patients becoming happier, or at least less depressed, as evidenced by the positive results on the Geriatric Depression Scale.”
 

Similar results across most subgroups

In subgroup analyses, the intervention was successful against the standard-care approach in both men and women at all ages and regardless of ejection fraction; symptom status; and whether the patient had diabetes, ischemic heart disease, or atrial fibrillation, or was obese.

Clinical outcomes were not significantly different at 6 months. The rate of death from any cause was 13% for the intervention group and 10% for the control group. There were 194 and 213 hospitalizations from any cause, respectively.

Not included in the trial’s current publication but soon to be published, Dr. Kitzman said when interviewed, is a comparison of outcomes in patients with HFpEF and HFrEF. “We found at baseline that those with HFpEF had worse impairment in physical function, quality of life, and frailty. After the intervention, there appeared to be consistently larger improvements in all outcomes, including SPPB, 6-minute walk, qualify of life, and frailty, in HFpEF versus HFrEF.”

The signals of potential benefit in HFpEF extended to clinical endpoints, he said. In contrast to similar rates of all-cause rehospitalization in HFrEF, “in patients with HFpEF, rehospitalizations were 17% lower in the intervention group, compared to the control group.” Still, he noted, the interaction P value wasn’t significant.

However, Dr. Kitzman added, mortality in the intervention group, compared with the control group, was reduced by 35% among patients with HFpEF, “but was 250% higher in HFrEF,” with a significant interaction P value.

He was careful to note that, as a phase 2 trial, REHAB-HF was underpowered for clinical events, “and even the results in the HFpEF group should not be seen as adequate evidence to change clinical care.” They were from an exploratory analysis that included relatively few events.

“Because definitive demonstration of improvement in clinical events is critical for altering clinical care guidelines and for third-party payer reimbursement decisions, we believe that a subsequent phase 3 trial is needed and are currently planning toward that,” Dr. Kitzman said.

The study was supported by research grants from the National Institutes of Health, the Kermit Glenn Phillips II Chair in Cardiovascular Medicine, and the Oristano Family Fund at Wake Forest. Dr. Kitzman disclosed receiving consulting fees or honoraria from AbbVie, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, CinRx, Corviamedical, GlaxoSmithKline, and Merck; and having an unspecified relationship with Gilead. Dr. Handberg disclosed receiving grants from Aastom Biosciences, Abbott Laboratories, Amgen, Amorcyte, AstraZeneca, Biocardia, Boehringer Ingelheim, Capricor, Cytori Therapeutics, Department of Defense, Direct Flow Medical, Everyfit, Gilead, Ionis, Medtronic, Merck, Mesoblast, Relypsa, and Sanofi-Aventis. Dr. Bittner discloses receiving consulting fees or honoraria from Pfizer and Sanofi; receiving research grants from Amgen and The Medicines Company; and having unspecified relationships with AstraZeneca, DalCor, Esperion, and Sanofi-Aventis. Dr. Anker reported receiving grants and personal fees from Abbott Vascular and Vifor; personal fees from Bayer, Boehringer Ingelheim, Novartis, Servier, Cardiac Dimensions, Thermo Fisher Scientific, AstraZeneca, Occlutech, Actimed, and Respicardia. Dr. Coats disclosed receiving personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Menarini, Novartis, Nutricia, Servier, Vifor, Abbott, Actimed, Arena, Cardiac Dimensions, Corvia, CVRx, Enopace, ESN Cleer, Faraday, WL Gore, Impulse Dynamics, and Respicardia.

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

Significant improvement in the control of symptoms related to paroxysmal supraventricular tachycardia (PSVT) is resurrecting etripamil as a self-administered nasal spray a year after it failed to meet the primary endpoint in a phase 3 trial, according to a new analysis from this same study presented at the annual scientific sessions of the American College of Cardiology.

Thinkstock

In the phase 3 NODE-301 trial, presented at the 2020 Heart Rhythm Society annual meeting, etripamil did not show an advantage over placebo at 5 hours for achieving sinus rhythm. Nevertheless, a new presentation of the secondary outcomes suggests substantial clinical benefit.

These advantages include significant reductions in PSVT symptoms, a trend for fewer emergency room visits, and a degree of patient satisfaction that appears meaningful, according to Bruce S. Stambler, MD, an electrophysiologist affiliated with Piedmont Heart Institute, Atlanta.

The data, despite the phase 3 trial results, “support continued development of etripamil nasal spray acute treatment of PSVT,” Dr. Stambler said.
Etripamil is an L-type calcium channel blocker. When administered by nasal spray, it reaches peak effects within about 10 minutes. But the action is short, with a decline in antiarrhythmia effects beginning about 30 minutes after the peak effect. 

In the NODE-301 trial, which employed a 2:1 randomization ratio, 138 patients self-administered 70 mg of etripamil or placebo immediately upon experiencing a suspected episode of PSVT.

Up until 45 minutes, the proportion of episodes that converted to sinus rhythm was about 66% greater (hazard ratio, 1.66; P = .02) on etripamil than placebo, but the advantage was then lost. By predefined primary endpoint of 5 hours, when 100% of placebo patients but not all etripamil patients had converted, there was a slight but nonstatistical advantage for placebo (HR 1.08; P = .1212).

However, because of the rapid onset and then the rapid offset of this agent, the 5-hour time point for comparing effects might not have been the optimal duration to compare effects, according to Dr. Stambler.

On the basis of safety of etripamil, which was not associated with any significant adverse events in NODE-301, and the early clinical effect, the investigators have looked again at the data.

For relief of patient-reported symptoms and patient-reported satisfaction, which were secondary endpoints of the study, the data support a clinical role, according to this new analysis. 

Specifically, there were large differences on a 7-point scale for all of the measured symptoms of PSVT in favor of etripamil, including rapid pulse (P = .002), palpitations (P = .0001), dizziness (P = 0.01), shortness of breath (P = 0.008), and anxiety (P = 0.006). A numerical advantage for chest pain did not reach significance.

“In general, patients reported scores of 4 to 5 on this scale, which corresponds to ‘not satisfied’ to ‘satisfied,’ while the placebo-treated patients reported scores of 2 to 3, which corresponds to ‘dissatisfied’ or ‘very dissatisfied,’ ” Dr. Stambler reported.

The favorable patient experience is also reflected in the Treatment Satisfaction with Questionnaire for Medication (TSQM-9), which was another NODE-301 endpoint. Evaluated when patients were still blinded to their assigned therapy, the advantage of etripamil over placebo for both global satisfaction (P = .007) and treatment effectiveness (P = .002) were also highly statistically significant.

The subjective experience of patients appeared to be reflected in objective measures. When the two groups were compared for interventions in an emergency room, the need was reduced by about half (12.1% vs. 24.5%; P = .051) among those treated with etripamil. Although this just missed the conventional measure of statistical significance, it was close. Similarly, patients randomized to etripamil required numerically fewer rescue medications (14.0% vs. 26.5%; P = .059). 

Adenosine was the most common of the rescue medications, according to Dr. Stambler. He said there was no difference between the groups in use of rescue oral therapies.

When comparing etripamil and placebo in the subgroup that did visit an emergency room for PSVT, there was a delay in ER visits among those randomized to etripamil (116 vs. 79 minutes; P < 0.05), suggesting that this agent reduced the sense of urgency when PSVT symptoms develop, according to Dr. Stambler.

On average, the patients who enrolled in this trial had a PSVT history of about 1.5 years. In the year prior to enrollment, the mean number of ER visits was about nine. 

In the trial design, patients were required to take a test dose of etripamil under observation by a physician before being sent home with their assigned therapy, but Dr. Stambler does not believe that the requirement, if the drug is approved, will be in the label. 

Unexpectedly, many patients had symptom relief even without converting to sinus rhythm, Dr. Stambler acknowledged. He speculated that the reduction in heart rate associated with etripamil might have provided a relief of symptoms sufficient to relieve anxiety, producing the relative advantage for patient satisfaction.

Jodie L. Hurwitz, MD, director of the electrophysiology lab at Medical City Hospital, Dallas, indicated that there is a need for new options for PSVT. An expert panelist during the session where these data were presented, she was particularly interested in rapid symptom relief. 

“It would be great to have a therapy that could be self-administered at home. Patients would like it, too,” she said. 

Mary N. Walsh, MD, a heart failure specialist affiliated with Indiana University, Indianapolis, sees a potential role of a self-administered therapy like etripamil in conjunction with wearable devices. She noted that the proportion of patients using these devices to monitor arrhythmias is increasing, providing a role for an easily transportable therapy that could be used quickly when symptoms develop. 

However, after the negative phase 3 trial, more data must now be collected to satisfy the regulatory authorities that this agent is safe and effective. Dr. Stambler said that the developer is now committed to pursue these studies.

Dr. Stambler has a financial relationship with Milestone Pharmaceuticals, which is developing etripamil nasal spray and was the sponsor of this trial. Dr. Walsh and Dr. Hurwitz have no potential relevant conflicts of interest.
 

Significant improvement in the control of symptoms related to paroxysmal supraventricular tachycardia (PSVT) is resurrecting etripamil as a self-administered nasal spray a year after it failed to meet the primary endpoint in a phase 3 trial, according to a new analysis from this same study presented at the annual scientific sessions of the American College of Cardiology.

Thinkstock

In the phase 3 NODE-301 trial, presented at the 2020 Heart Rhythm Society annual meeting, etripamil did not show an advantage over placebo at 5 hours for achieving sinus rhythm. Nevertheless, a new presentation of the secondary outcomes suggests substantial clinical benefit.

These advantages include significant reductions in PSVT symptoms, a trend for fewer emergency room visits, and a degree of patient satisfaction that appears meaningful, according to Bruce S. Stambler, MD, an electrophysiologist affiliated with Piedmont Heart Institute, Atlanta.

The data, despite the phase 3 trial results, “support continued development of etripamil nasal spray acute treatment of PSVT,” Dr. Stambler said.
Etripamil is an L-type calcium channel blocker. When administered by nasal spray, it reaches peak effects within about 10 minutes. But the action is short, with a decline in antiarrhythmia effects beginning about 30 minutes after the peak effect. 

In the NODE-301 trial, which employed a 2:1 randomization ratio, 138 patients self-administered 70 mg of etripamil or placebo immediately upon experiencing a suspected episode of PSVT.

Up until 45 minutes, the proportion of episodes that converted to sinus rhythm was about 66% greater (hazard ratio, 1.66; P = .02) on etripamil than placebo, but the advantage was then lost. By predefined primary endpoint of 5 hours, when 100% of placebo patients but not all etripamil patients had converted, there was a slight but nonstatistical advantage for placebo (HR 1.08; P = .1212).

However, because of the rapid onset and then the rapid offset of this agent, the 5-hour time point for comparing effects might not have been the optimal duration to compare effects, according to Dr. Stambler.

On the basis of safety of etripamil, which was not associated with any significant adverse events in NODE-301, and the early clinical effect, the investigators have looked again at the data.

For relief of patient-reported symptoms and patient-reported satisfaction, which were secondary endpoints of the study, the data support a clinical role, according to this new analysis. 

Specifically, there were large differences on a 7-point scale for all of the measured symptoms of PSVT in favor of etripamil, including rapid pulse (P = .002), palpitations (P = .0001), dizziness (P = 0.01), shortness of breath (P = 0.008), and anxiety (P = 0.006). A numerical advantage for chest pain did not reach significance.

“In general, patients reported scores of 4 to 5 on this scale, which corresponds to ‘not satisfied’ to ‘satisfied,’ while the placebo-treated patients reported scores of 2 to 3, which corresponds to ‘dissatisfied’ or ‘very dissatisfied,’ ” Dr. Stambler reported.

The favorable patient experience is also reflected in the Treatment Satisfaction with Questionnaire for Medication (TSQM-9), which was another NODE-301 endpoint. Evaluated when patients were still blinded to their assigned therapy, the advantage of etripamil over placebo for both global satisfaction (P = .007) and treatment effectiveness (P = .002) were also highly statistically significant.

The subjective experience of patients appeared to be reflected in objective measures. When the two groups were compared for interventions in an emergency room, the need was reduced by about half (12.1% vs. 24.5%; P = .051) among those treated with etripamil. Although this just missed the conventional measure of statistical significance, it was close. Similarly, patients randomized to etripamil required numerically fewer rescue medications (14.0% vs. 26.5%; P = .059). 

Adenosine was the most common of the rescue medications, according to Dr. Stambler. He said there was no difference between the groups in use of rescue oral therapies.

When comparing etripamil and placebo in the subgroup that did visit an emergency room for PSVT, there was a delay in ER visits among those randomized to etripamil (116 vs. 79 minutes; P < 0.05), suggesting that this agent reduced the sense of urgency when PSVT symptoms develop, according to Dr. Stambler.

On average, the patients who enrolled in this trial had a PSVT history of about 1.5 years. In the year prior to enrollment, the mean number of ER visits was about nine. 

In the trial design, patients were required to take a test dose of etripamil under observation by a physician before being sent home with their assigned therapy, but Dr. Stambler does not believe that the requirement, if the drug is approved, will be in the label. 

Unexpectedly, many patients had symptom relief even without converting to sinus rhythm, Dr. Stambler acknowledged. He speculated that the reduction in heart rate associated with etripamil might have provided a relief of symptoms sufficient to relieve anxiety, producing the relative advantage for patient satisfaction.

Jodie L. Hurwitz, MD, director of the electrophysiology lab at Medical City Hospital, Dallas, indicated that there is a need for new options for PSVT. An expert panelist during the session where these data were presented, she was particularly interested in rapid symptom relief. 

“It would be great to have a therapy that could be self-administered at home. Patients would like it, too,” she said. 

Mary N. Walsh, MD, a heart failure specialist affiliated with Indiana University, Indianapolis, sees a potential role of a self-administered therapy like etripamil in conjunction with wearable devices. She noted that the proportion of patients using these devices to monitor arrhythmias is increasing, providing a role for an easily transportable therapy that could be used quickly when symptoms develop. 

However, after the negative phase 3 trial, more data must now be collected to satisfy the regulatory authorities that this agent is safe and effective. Dr. Stambler said that the developer is now committed to pursue these studies.

Dr. Stambler has a financial relationship with Milestone Pharmaceuticals, which is developing etripamil nasal spray and was the sponsor of this trial. Dr. Walsh and Dr. Hurwitz have no potential relevant conflicts of interest.
 

Significant improvement in the control of symptoms related to paroxysmal supraventricular tachycardia (PSVT) is resurrecting etripamil as a self-administered nasal spray a year after it failed to meet the primary endpoint in a phase 3 trial, according to a new analysis from this same study presented at the annual scientific sessions of the American College of Cardiology.

Thinkstock

In the phase 3 NODE-301 trial, presented at the 2020 Heart Rhythm Society annual meeting, etripamil did not show an advantage over placebo at 5 hours for achieving sinus rhythm. Nevertheless, a new presentation of the secondary outcomes suggests substantial clinical benefit.

These advantages include significant reductions in PSVT symptoms, a trend for fewer emergency room visits, and a degree of patient satisfaction that appears meaningful, according to Bruce S. Stambler, MD, an electrophysiologist affiliated with Piedmont Heart Institute, Atlanta.

The data, despite the phase 3 trial results, “support continued development of etripamil nasal spray acute treatment of PSVT,” Dr. Stambler said.
Etripamil is an L-type calcium channel blocker. When administered by nasal spray, it reaches peak effects within about 10 minutes. But the action is short, with a decline in antiarrhythmia effects beginning about 30 minutes after the peak effect. 

In the NODE-301 trial, which employed a 2:1 randomization ratio, 138 patients self-administered 70 mg of etripamil or placebo immediately upon experiencing a suspected episode of PSVT.

Up until 45 minutes, the proportion of episodes that converted to sinus rhythm was about 66% greater (hazard ratio, 1.66; P = .02) on etripamil than placebo, but the advantage was then lost. By predefined primary endpoint of 5 hours, when 100% of placebo patients but not all etripamil patients had converted, there was a slight but nonstatistical advantage for placebo (HR 1.08; P = .1212).

However, because of the rapid onset and then the rapid offset of this agent, the 5-hour time point for comparing effects might not have been the optimal duration to compare effects, according to Dr. Stambler.

On the basis of safety of etripamil, which was not associated with any significant adverse events in NODE-301, and the early clinical effect, the investigators have looked again at the data.

For relief of patient-reported symptoms and patient-reported satisfaction, which were secondary endpoints of the study, the data support a clinical role, according to this new analysis. 

Specifically, there were large differences on a 7-point scale for all of the measured symptoms of PSVT in favor of etripamil, including rapid pulse (P = .002), palpitations (P = .0001), dizziness (P = 0.01), shortness of breath (P = 0.008), and anxiety (P = 0.006). A numerical advantage for chest pain did not reach significance.

“In general, patients reported scores of 4 to 5 on this scale, which corresponds to ‘not satisfied’ to ‘satisfied,’ while the placebo-treated patients reported scores of 2 to 3, which corresponds to ‘dissatisfied’ or ‘very dissatisfied,’ ” Dr. Stambler reported.

The favorable patient experience is also reflected in the Treatment Satisfaction with Questionnaire for Medication (TSQM-9), which was another NODE-301 endpoint. Evaluated when patients were still blinded to their assigned therapy, the advantage of etripamil over placebo for both global satisfaction (P = .007) and treatment effectiveness (P = .002) were also highly statistically significant.

The subjective experience of patients appeared to be reflected in objective measures. When the two groups were compared for interventions in an emergency room, the need was reduced by about half (12.1% vs. 24.5%; P = .051) among those treated with etripamil. Although this just missed the conventional measure of statistical significance, it was close. Similarly, patients randomized to etripamil required numerically fewer rescue medications (14.0% vs. 26.5%; P = .059). 

Adenosine was the most common of the rescue medications, according to Dr. Stambler. He said there was no difference between the groups in use of rescue oral therapies.

When comparing etripamil and placebo in the subgroup that did visit an emergency room for PSVT, there was a delay in ER visits among those randomized to etripamil (116 vs. 79 minutes; P < 0.05), suggesting that this agent reduced the sense of urgency when PSVT symptoms develop, according to Dr. Stambler.

On average, the patients who enrolled in this trial had a PSVT history of about 1.5 years. In the year prior to enrollment, the mean number of ER visits was about nine. 

In the trial design, patients were required to take a test dose of etripamil under observation by a physician before being sent home with their assigned therapy, but Dr. Stambler does not believe that the requirement, if the drug is approved, will be in the label. 

Unexpectedly, many patients had symptom relief even without converting to sinus rhythm, Dr. Stambler acknowledged. He speculated that the reduction in heart rate associated with etripamil might have provided a relief of symptoms sufficient to relieve anxiety, producing the relative advantage for patient satisfaction.

Jodie L. Hurwitz, MD, director of the electrophysiology lab at Medical City Hospital, Dallas, indicated that there is a need for new options for PSVT. An expert panelist during the session where these data were presented, she was particularly interested in rapid symptom relief. 

“It would be great to have a therapy that could be self-administered at home. Patients would like it, too,” she said. 

Mary N. Walsh, MD, a heart failure specialist affiliated with Indiana University, Indianapolis, sees a potential role of a self-administered therapy like etripamil in conjunction with wearable devices. She noted that the proportion of patients using these devices to monitor arrhythmias is increasing, providing a role for an easily transportable therapy that could be used quickly when symptoms develop. 

However, after the negative phase 3 trial, more data must now be collected to satisfy the regulatory authorities that this agent is safe and effective. Dr. Stambler said that the developer is now committed to pursue these studies.

Dr. Stambler has a financial relationship with Milestone Pharmaceuticals, which is developing etripamil nasal spray and was the sponsor of this trial. Dr. Walsh and Dr. Hurwitz have no potential relevant conflicts of interest.
 

Left atrial appendage occlusion performed at the time of other heart surgery reduces the risk for stroke by about one-third in high-risk patients with atrial fibrillation (AFib), according to results of the Left Atrial Appendage Occlusion Study III (LAAOS III).

At 3.8 years’ follow-up, the primary endpoint of ischemic stroke or systemic embolism occurred in 4.8% of patients randomly assigned to left atrial appendage occlusion (LAAO) and 7.0% of those with no occlusion. This translated into a 33% relative risk reduction (hazard ratio, 0.67; 95% confidence interval, 0.53-0.85; P = .001).

In a landmark analysis, the effect was present early on but was more pronounced after the first 30 days, reducing the relative risk by 42% (HR, 0.58; 95% CI, 0.42-0.80), the researchers report.

The reduction in ongoing stroke risk was on top of oral anticoagulation (OAC) and consistent across all subgroups, Richard Whitlock, MD, PhD, professor of surgery, McMaster University, Hamilton, Ont., reported in a late-breaking trial session at the annual scientific sessions of the American College of Cardiology.

The procedure was safe and added, on average, just 6 minutes to cardiopulmonary bypass time, according to the results, simultaneously published in the New England Journal of Medicine.

“Any patient who comes to the operating room who fits the profile of a LAAOS III patient – so has atrial fibrillation and an elevated stroke risk based on their CHA₂DS₂-VASc score – the appendage should come off,” he said in an interview.

Commenting during the formal discussion, panelist Michael J. Mack, MD, of Baylor Health Care System in Houston, said, “This is potentially a game-changing, practice-changing study” but asked if there are any patients who shouldn’t undergo LAAO, such as those with heart failure (HF).

Dr. Whitlock said about 10%-15% of patients coming for heart surgery have a history of AFib and “as surgeons, you do need to individualize therapy. If you have a very frail patient, have concerns about tissue quality, you really need to think about how you would occlude the left atrial appendage or if you would occlude.”

Reassuringly, he noted, the data show no increase in HF hospitalizations and a beneficial effect on stroke among patients with HF and those with low ejection fractions, below 50%.

Observational data on surgical occlusion have been inconsistent, and current guidelines offer a weak recommendation in patients with AFib who have a contraindication to long-term anticoagulation. This is the first study to definitively prove that ischemic stroke is reduced by managing the left atrial appendage, he said in an interview.

“The previous percutaneous trials failed to demonstrate that; they demonstrated noninferiority but it was driven primarily by the avoidance of hemorrhagic events or strokes through taking patients off oral anticoagulation,” he said.

The results should translate into a class I guideline recommendation, he added. “This opens up a new paradigm of treatment for atrial fibrillation and stroke prevention in that it is really the first study that has looked at the additive effects of managing the left atrial appendage in addition to oral anticoagulation, and it’s protective on top of oral anticoagulation. That is a paradigm shift.”

In an accompanying editorial, Richard L. Page, MD, University of Vermont in Burlington, said the trial provides no insight on the possible benefit of surgical occlusion in patients unable to receive anticoagulation or with a lower CHA2DS2-VASc score, but he agreed a class I recommendation is likely for the population studied.

“I hope and anticipate that the results of this paper will strengthen the guideline indications for surgical left atrial appendage occlusion and will increase the number of cardiac surgeons who routinely perform this add-on procedure,” he said. “While many already perform this procedure, cardiac surgeons should now feel more comfortable that surgical left atrial appendage occlusion is indicated and supported by high-quality randomized data.”

Unfortunately, LAAOS III does not answer the question of whether patients can come off anticoagulation, but it does show surgical occlusion provides added protection from strokes, which can be huge with atrial fibrillation, Dr. Whitlock said.

“I spoke with a patient today who is an active 66-year-old individual on a [direct oral anticoagulant], and his stroke risk has been further reduced by 30%-40%, so he was ecstatic to hear the results,” Dr. Whitlock said. “I think it’s peace of mind.”

Global, nonindustry effort

LAAOS III investigators at 105 centers in 27 countries enrolled 4,811 patients undergoing cardiac surgery (mean age, 71 years; 68% male) who had a CHA₂DS₂-VASc score of at least 2.

In all, 4,770 were randomly assigned to no LAAO or occlusion via the preferred technique of amputation with suture closure of the stump as well as stapler occlusion, or epicardial device closure with the AtriClip (AtriCure) or TigerPaw (Maquet Medical). The treating team, researchers, and patients were blinded to assignment.

Patients were followed every 6 months with a validated stroke questionnaire. The trial was stopped early by the data safety monitoring board after the second interim analysis.

The mean CHA₂DS₂-VASc score was 4.2, one-third of patients had permanent AFib, 9% had a history of stroke, and more than two-thirds underwent a valve procedure, which makes LAAOS III unique, as many previous trials excluded valvular AFib, Dr. Whitlock pointed out.

Operative outcomes in the LAAO and no-LAAO groups were as follows:

• Bypass time: mean, 119 minutes vs. 113 minutes.  
• Cross-clamp time: mean, 86 minutes vs. 82 minutes.
• Chest tube output: median, 520 mL vs. 500 mL.
• Reoperation for bleeding: both, 4.0%.
• Prolonged hospitalization due to HF: 5 vs. 14 events.
• 30-day mortality: 3.7% vs 4.0%.

The primary safety outcome of HF hospitalization at 3.8 years occurred in 7.7% of patients with LAAO and 6.8% without occlusion (HR, 1.13; 95% CI, 0.92-1.40), despite concerns that taking off the appendage could worsen HF risk by impairing renal clearance of salt and water.

“There’s observational data on either side of the fence, so it was an important endpoint that people were concerned about,” Dr. Whitlock told this news organization. “We had a data collection firm dedicated to admission for heart failure to really tease that out and, in the end, we saw no adverse effect.”

Although rates of ischemic stroke at 3.8 years were lower with LAAO than without (4.2% vs. 6.6%; HR, 0.62; 95% CI, 0.48-0.80), there was no difference in systemic embolism (0.3% for both) or death (22.6% vs. 22.5%).

In LAAOS III, fewer than 2% of the deaths were attributed to stroke, which is consistent with large stroke registries, Dr. Whitlock said. “Stroke is not what causes people with atrial fibrillation to die; it’s actually the progression on to heart failure.”

The positive effect on stroke was consistent across all subgroups, including sex, age, rheumatic heart disease, type of OAC at baseline, CHA₂DS₂-VASc score (≤4 vs. >4), type of surgery, history of heart failure or hypertension, and prior stroke/transient ischemic attack/systemic embolism.

Panelist Anne B. Curtis, MD, State University of New York at Buffalo, expressed surprise that about half of patients at baseline were not receiving anticoagulation and questioned whether event rates varied among those who did and didn’t stay on OAC.

Dr. Whitlock noted that OAC is often underused in AFib and that analyses showed the effects were consistent whether patients were on or off anticoagulants.

The study was sponsored by the Population Health Research Institute, McMaster University. Dr. Whitlock reported no relevant disclosures. Dr. Curtis reported consultant fees/honoraria from Abbott, Janssen, Medtronic, Milestone Pharmaceuticals, and Sanofi Aventis, and data safety monitoring board participation for Medtronic.
 

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

Left atrial appendage occlusion performed at the time of other heart surgery reduces the risk for stroke by about one-third in high-risk patients with atrial fibrillation (AFib), according to results of the Left Atrial Appendage Occlusion Study III (LAAOS III).

At 3.8 years’ follow-up, the primary endpoint of ischemic stroke or systemic embolism occurred in 4.8% of patients randomly assigned to left atrial appendage occlusion (LAAO) and 7.0% of those with no occlusion. This translated into a 33% relative risk reduction (hazard ratio, 0.67; 95% confidence interval, 0.53-0.85; P = .001).

In a landmark analysis, the effect was present early on but was more pronounced after the first 30 days, reducing the relative risk by 42% (HR, 0.58; 95% CI, 0.42-0.80), the researchers report.

The reduction in ongoing stroke risk was on top of oral anticoagulation (OAC) and consistent across all subgroups, Richard Whitlock, MD, PhD, professor of surgery, McMaster University, Hamilton, Ont., reported in a late-breaking trial session at the annual scientific sessions of the American College of Cardiology.

The procedure was safe and added, on average, just 6 minutes to cardiopulmonary bypass time, according to the results, simultaneously published in the New England Journal of Medicine.

“Any patient who comes to the operating room who fits the profile of a LAAOS III patient – so has atrial fibrillation and an elevated stroke risk based on their CHA₂DS₂-VASc score – the appendage should come off,” he said in an interview.

Commenting during the formal discussion, panelist Michael J. Mack, MD, of Baylor Health Care System in Houston, said, “This is potentially a game-changing, practice-changing study” but asked if there are any patients who shouldn’t undergo LAAO, such as those with heart failure (HF).

Dr. Whitlock said about 10%-15% of patients coming for heart surgery have a history of AFib and “as surgeons, you do need to individualize therapy. If you have a very frail patient, have concerns about tissue quality, you really need to think about how you would occlude the left atrial appendage or if you would occlude.”

Reassuringly, he noted, the data show no increase in HF hospitalizations and a beneficial effect on stroke among patients with HF and those with low ejection fractions, below 50%.

Observational data on surgical occlusion have been inconsistent, and current guidelines offer a weak recommendation in patients with AFib who have a contraindication to long-term anticoagulation. This is the first study to definitively prove that ischemic stroke is reduced by managing the left atrial appendage, he said in an interview.

“The previous percutaneous trials failed to demonstrate that; they demonstrated noninferiority but it was driven primarily by the avoidance of hemorrhagic events or strokes through taking patients off oral anticoagulation,” he said.

The results should translate into a class I guideline recommendation, he added. “This opens up a new paradigm of treatment for atrial fibrillation and stroke prevention in that it is really the first study that has looked at the additive effects of managing the left atrial appendage in addition to oral anticoagulation, and it’s protective on top of oral anticoagulation. That is a paradigm shift.”

In an accompanying editorial, Richard L. Page, MD, University of Vermont in Burlington, said the trial provides no insight on the possible benefit of surgical occlusion in patients unable to receive anticoagulation or with a lower CHA2DS2-VASc score, but he agreed a class I recommendation is likely for the population studied.

“I hope and anticipate that the results of this paper will strengthen the guideline indications for surgical left atrial appendage occlusion and will increase the number of cardiac surgeons who routinely perform this add-on procedure,” he said. “While many already perform this procedure, cardiac surgeons should now feel more comfortable that surgical left atrial appendage occlusion is indicated and supported by high-quality randomized data.”

Unfortunately, LAAOS III does not answer the question of whether patients can come off anticoagulation, but it does show surgical occlusion provides added protection from strokes, which can be huge with atrial fibrillation, Dr. Whitlock said.

“I spoke with a patient today who is an active 66-year-old individual on a [direct oral anticoagulant], and his stroke risk has been further reduced by 30%-40%, so he was ecstatic to hear the results,” Dr. Whitlock said. “I think it’s peace of mind.”

Global, nonindustry effort

LAAOS III investigators at 105 centers in 27 countries enrolled 4,811 patients undergoing cardiac surgery (mean age, 71 years; 68% male) who had a CHA₂DS₂-VASc score of at least 2.

In all, 4,770 were randomly assigned to no LAAO or occlusion via the preferred technique of amputation with suture closure of the stump as well as stapler occlusion, or epicardial device closure with the AtriClip (AtriCure) or TigerPaw (Maquet Medical). The treating team, researchers, and patients were blinded to assignment.

Patients were followed every 6 months with a validated stroke questionnaire. The trial was stopped early by the data safety monitoring board after the second interim analysis.

The mean CHA₂DS₂-VASc score was 4.2, one-third of patients had permanent AFib, 9% had a history of stroke, and more than two-thirds underwent a valve procedure, which makes LAAOS III unique, as many previous trials excluded valvular AFib, Dr. Whitlock pointed out.

Operative outcomes in the LAAO and no-LAAO groups were as follows:

• Bypass time: mean, 119 minutes vs. 113 minutes.  
• Cross-clamp time: mean, 86 minutes vs. 82 minutes.
• Chest tube output: median, 520 mL vs. 500 mL.
• Reoperation for bleeding: both, 4.0%.
• Prolonged hospitalization due to HF: 5 vs. 14 events.
• 30-day mortality: 3.7% vs 4.0%.

The primary safety outcome of HF hospitalization at 3.8 years occurred in 7.7% of patients with LAAO and 6.8% without occlusion (HR, 1.13; 95% CI, 0.92-1.40), despite concerns that taking off the appendage could worsen HF risk by impairing renal clearance of salt and water.

“There’s observational data on either side of the fence, so it was an important endpoint that people were concerned about,” Dr. Whitlock told this news organization. “We had a data collection firm dedicated to admission for heart failure to really tease that out and, in the end, we saw no adverse effect.”

Although rates of ischemic stroke at 3.8 years were lower with LAAO than without (4.2% vs. 6.6%; HR, 0.62; 95% CI, 0.48-0.80), there was no difference in systemic embolism (0.3% for both) or death (22.6% vs. 22.5%).

In LAAOS III, fewer than 2% of the deaths were attributed to stroke, which is consistent with large stroke registries, Dr. Whitlock said. “Stroke is not what causes people with atrial fibrillation to die; it’s actually the progression on to heart failure.”

The positive effect on stroke was consistent across all subgroups, including sex, age, rheumatic heart disease, type of OAC at baseline, CHA₂DS₂-VASc score (≤4 vs. >4), type of surgery, history of heart failure or hypertension, and prior stroke/transient ischemic attack/systemic embolism.

Panelist Anne B. Curtis, MD, State University of New York at Buffalo, expressed surprise that about half of patients at baseline were not receiving anticoagulation and questioned whether event rates varied among those who did and didn’t stay on OAC.

Dr. Whitlock noted that OAC is often underused in AFib and that analyses showed the effects were consistent whether patients were on or off anticoagulants.

The study was sponsored by the Population Health Research Institute, McMaster University. Dr. Whitlock reported no relevant disclosures. Dr. Curtis reported consultant fees/honoraria from Abbott, Janssen, Medtronic, Milestone Pharmaceuticals, and Sanofi Aventis, and data safety monitoring board participation for Medtronic.
 

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

Left atrial appendage occlusion performed at the time of other heart surgery reduces the risk for stroke by about one-third in high-risk patients with atrial fibrillation (AFib), according to results of the Left Atrial Appendage Occlusion Study III (LAAOS III).

At 3.8 years’ follow-up, the primary endpoint of ischemic stroke or systemic embolism occurred in 4.8% of patients randomly assigned to left atrial appendage occlusion (LAAO) and 7.0% of those with no occlusion. This translated into a 33% relative risk reduction (hazard ratio, 0.67; 95% confidence interval, 0.53-0.85; P = .001).

In a landmark analysis, the effect was present early on but was more pronounced after the first 30 days, reducing the relative risk by 42% (HR, 0.58; 95% CI, 0.42-0.80), the researchers report.

The reduction in ongoing stroke risk was on top of oral anticoagulation (OAC) and consistent across all subgroups, Richard Whitlock, MD, PhD, professor of surgery, McMaster University, Hamilton, Ont., reported in a late-breaking trial session at the annual scientific sessions of the American College of Cardiology.

The procedure was safe and added, on average, just 6 minutes to cardiopulmonary bypass time, according to the results, simultaneously published in the New England Journal of Medicine.

“Any patient who comes to the operating room who fits the profile of a LAAOS III patient – so has atrial fibrillation and an elevated stroke risk based on their CHA₂DS₂-VASc score – the appendage should come off,” he said in an interview.

Commenting during the formal discussion, panelist Michael J. Mack, MD, of Baylor Health Care System in Houston, said, “This is potentially a game-changing, practice-changing study” but asked if there are any patients who shouldn’t undergo LAAO, such as those with heart failure (HF).

Dr. Whitlock said about 10%-15% of patients coming for heart surgery have a history of AFib and “as surgeons, you do need to individualize therapy. If you have a very frail patient, have concerns about tissue quality, you really need to think about how you would occlude the left atrial appendage or if you would occlude.”

Reassuringly, he noted, the data show no increase in HF hospitalizations and a beneficial effect on stroke among patients with HF and those with low ejection fractions, below 50%.

Observational data on surgical occlusion have been inconsistent, and current guidelines offer a weak recommendation in patients with AFib who have a contraindication to long-term anticoagulation. This is the first study to definitively prove that ischemic stroke is reduced by managing the left atrial appendage, he said in an interview.

“The previous percutaneous trials failed to demonstrate that; they demonstrated noninferiority but it was driven primarily by the avoidance of hemorrhagic events or strokes through taking patients off oral anticoagulation,” he said.

The results should translate into a class I guideline recommendation, he added. “This opens up a new paradigm of treatment for atrial fibrillation and stroke prevention in that it is really the first study that has looked at the additive effects of managing the left atrial appendage in addition to oral anticoagulation, and it’s protective on top of oral anticoagulation. That is a paradigm shift.”

In an accompanying editorial, Richard L. Page, MD, University of Vermont in Burlington, said the trial provides no insight on the possible benefit of surgical occlusion in patients unable to receive anticoagulation or with a lower CHA2DS2-VASc score, but he agreed a class I recommendation is likely for the population studied.

“I hope and anticipate that the results of this paper will strengthen the guideline indications for surgical left atrial appendage occlusion and will increase the number of cardiac surgeons who routinely perform this add-on procedure,” he said. “While many already perform this procedure, cardiac surgeons should now feel more comfortable that surgical left atrial appendage occlusion is indicated and supported by high-quality randomized data.”

Unfortunately, LAAOS III does not answer the question of whether patients can come off anticoagulation, but it does show surgical occlusion provides added protection from strokes, which can be huge with atrial fibrillation, Dr. Whitlock said.

“I spoke with a patient today who is an active 66-year-old individual on a [direct oral anticoagulant], and his stroke risk has been further reduced by 30%-40%, so he was ecstatic to hear the results,” Dr. Whitlock said. “I think it’s peace of mind.”

Global, nonindustry effort

LAAOS III investigators at 105 centers in 27 countries enrolled 4,811 patients undergoing cardiac surgery (mean age, 71 years; 68% male) who had a CHA₂DS₂-VASc score of at least 2.

In all, 4,770 were randomly assigned to no LAAO or occlusion via the preferred technique of amputation with suture closure of the stump as well as stapler occlusion, or epicardial device closure with the AtriClip (AtriCure) or TigerPaw (Maquet Medical). The treating team, researchers, and patients were blinded to assignment.

Patients were followed every 6 months with a validated stroke questionnaire. The trial was stopped early by the data safety monitoring board after the second interim analysis.

The mean CHA₂DS₂-VASc score was 4.2, one-third of patients had permanent AFib, 9% had a history of stroke, and more than two-thirds underwent a valve procedure, which makes LAAOS III unique, as many previous trials excluded valvular AFib, Dr. Whitlock pointed out.

Operative outcomes in the LAAO and no-LAAO groups were as follows:

• Bypass time: mean, 119 minutes vs. 113 minutes.  
• Cross-clamp time: mean, 86 minutes vs. 82 minutes.
• Chest tube output: median, 520 mL vs. 500 mL.
• Reoperation for bleeding: both, 4.0%.
• Prolonged hospitalization due to HF: 5 vs. 14 events.
• 30-day mortality: 3.7% vs 4.0%.

The primary safety outcome of HF hospitalization at 3.8 years occurred in 7.7% of patients with LAAO and 6.8% without occlusion (HR, 1.13; 95% CI, 0.92-1.40), despite concerns that taking off the appendage could worsen HF risk by impairing renal clearance of salt and water.

“There’s observational data on either side of the fence, so it was an important endpoint that people were concerned about,” Dr. Whitlock told this news organization. “We had a data collection firm dedicated to admission for heart failure to really tease that out and, in the end, we saw no adverse effect.”

Although rates of ischemic stroke at 3.8 years were lower with LAAO than without (4.2% vs. 6.6%; HR, 0.62; 95% CI, 0.48-0.80), there was no difference in systemic embolism (0.3% for both) or death (22.6% vs. 22.5%).

In LAAOS III, fewer than 2% of the deaths were attributed to stroke, which is consistent with large stroke registries, Dr. Whitlock said. “Stroke is not what causes people with atrial fibrillation to die; it’s actually the progression on to heart failure.”

The positive effect on stroke was consistent across all subgroups, including sex, age, rheumatic heart disease, type of OAC at baseline, CHA₂DS₂-VASc score (≤4 vs. >4), type of surgery, history of heart failure or hypertension, and prior stroke/transient ischemic attack/systemic embolism.

Panelist Anne B. Curtis, MD, State University of New York at Buffalo, expressed surprise that about half of patients at baseline were not receiving anticoagulation and questioned whether event rates varied among those who did and didn’t stay on OAC.

Dr. Whitlock noted that OAC is often underused in AFib and that analyses showed the effects were consistent whether patients were on or off anticoagulants.

The study was sponsored by the Population Health Research Institute, McMaster University. Dr. Whitlock reported no relevant disclosures. Dr. Curtis reported consultant fees/honoraria from Abbott, Janssen, Medtronic, Milestone Pharmaceuticals, and Sanofi Aventis, and data safety monitoring board participation for Medtronic.
 

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