Steve Stiles

CLEVELAND – Patients with heart failure (HF) who are started on sacubitril-valsartan (Entresto) in the hospital or soon after discharge will see a sharp drop in clinical risk whether their ejection fraction is “reduced” or merely “below normal,” suggests a combined analysis of two major studies.

Short-term risk for cardiovascular (CV) death or HF hospitalization fell 30% for such patients put on the angiotensin-receptor/neprilysin inhibitor (ARNI) at that early stage, compared with those assigned to receive an ACE inhibitor or angiotensin receptor blocker (ARB).

Of note, the risk-reduction benefit reached 41% among the overwhelming majority of patients with a left ventricular ejection fraction (LVEF) of 60% or lower across the two trials, PIONEER-HF and PARAGLIDE-HF. No such significant benefit was seen in patients with higher LVEF.

The prespecified analysis of 1,347 patients medically stabilized after a “worsening-HF event” was reported by Robert J. Mentz, MD, Duke Clinical Research Institute, Durham, N.C., at the annual scientific meeting of the Heart Failure Society of America.

Across both studies, levels of the prognostically telling biomarker NT-proBNP dropped further in the ARNI group, by almost a fourth, compared with those getting an ACE inhibitor or ARB. The difference emerged within a week and was “similar and consistent” throughout at least 8 weeks of follow-up, Dr. Mentz said.

Sacubitril-valsartan is approved in the United States for chronic HF, broadly but with labeling suggesting clearer efficacy at lower LVEF levels, based on the PARADIGM-HF and PARAGON-HF trials.

The PIONEER-HF and PARAGLIDE-HF trials lending patients to the current analysis demonstrated superiority for the drug vs. an ACE inhibitor or ARB when started in hospital in stabilized patients with HF.
 

Cautions about starting sacubitril-valsartan

In the pooled analysis, patients on sacubitril-valsartan were more likely to experience symptomatic hypotension, with a relative risk for drug’s known potential side effect reaching 1.35 (95% confidence interval, 1.05-1.72), compared with ACE inhibitor or ARB recipients.

But the hypotension risk when starting the drug is manageable to some extent, observed Dr. Mentz. “We can safely start sacubitril-valsartan in the hospital or early post discharge, but we need to make sure their volume status is okay” and keep track of their blood pressure trajectory, he told this news organization.

Those with initially low BP, unsurprisingly, seem more susceptible to the problem, Dr. Mentz said. In such patients “on antihypertensives or other therapies that aren’t going to give them a clinical outcome benefit,” those meds can be withdrawn or their dosages reduced before sacubitril-valsartan is added.

Such cautions are an “important take-home message” of the analysis, observed invited discussant Carolyn S. P. Lam, MBBS, PhD, National Heart Centre, Singapore, after the Dr. Mentz presentation.

Sacubitril-valsartan should be started only in stabilized patients, she emphasized. It should be delayed in those “with ongoing adjustments of antihypertensives, diuretics, and so on,” in whom premature initiation of the drug may promote symptomatic hypotension. Should that happen, Dr. Lam cautioned, there’s a risk that such patients would be “mislabeled as intolerant” of the ARNI and so wouldn’t be started on it later.

The pooled PIONEER-HF and PARAGLIDE-HF analysis, Dr. Lam proposed, might also help overcome the “clinical inertia and fear” that is slowing the uptake of early guideline-directed drug therapy initiation in patients hospitalized with HF.
 

LVEF spectrum across two studies

As Dr. Mentz reported, the analysis included 881 and 466 patients from PIONEER-HF and PARAGLIDE-HF, respectively. Of the total, 673 were assigned to receive valsartan and 674 to receive either enalapril or valsartan. Overall, 36% of the population were women.

Patients in PIONEER-HF, with an LVEF 40% or lower, were started on their assigned drug during an acute-HF hospitalization and followed a median of 8 weeks. PARAGLIDE-HF patients, with LVEF higher than 40%, started therapy either in hospital (in 70% of cases) or within 30 days of their HF event; they were followed a median of 6 months.

Hazard ratios for outcomes in the sacubitril-valsartan group vs. those on ACE inhibitors or ARBs were 0.76; 95% CI, 0.69-0.83; P < .0001 for change in NT-proBNP levels. For the composite of CV death or HF hospitalization, HRs were as follows:

• 0.70 (95% CI, 0.54-0.91; P = .0077) overall.
• 0.59 (95% CI, 0.44-0.79) for LVEF < 60%.
• 1.53 (95% CI, 0.80-2.91) for LVEF > 60%.

Current guidelines, Dr. Mentz noted, recommend that sacubitril-valsartan “be initiated de novo” predischarge in patients without contraindications who are hospitalized with acute HF with reduced LVEF. The combined analysis of PIONEER-HF and PARAGLIDE-HF, he said, potentially extends the recommendation “across the ejection fraction spectrum.”

Dr. Mentz has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Eli Lilly, Medtronic, Medable, Merck, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Relypsa, Respicardia, Roche, Sanofi, Vifor, Windtree Therapeutics, and Zoll. Dr. Lam has reported financial relationships “with more than 25 pharmaceutical or device manufacturers, many of which produce therapies for heart failure,” as well as with Medscape/WebMD Global LLC.

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

CLEVELAND – Patients with heart failure (HF) who are started on sacubitril-valsartan (Entresto) in the hospital or soon after discharge will see a sharp drop in clinical risk whether their ejection fraction is “reduced” or merely “below normal,” suggests a combined analysis of two major studies.

Short-term risk for cardiovascular (CV) death or HF hospitalization fell 30% for such patients put on the angiotensin-receptor/neprilysin inhibitor (ARNI) at that early stage, compared with those assigned to receive an ACE inhibitor or angiotensin receptor blocker (ARB).

Of note, the risk-reduction benefit reached 41% among the overwhelming majority of patients with a left ventricular ejection fraction (LVEF) of 60% or lower across the two trials, PIONEER-HF and PARAGLIDE-HF. No such significant benefit was seen in patients with higher LVEF.

The prespecified analysis of 1,347 patients medically stabilized after a “worsening-HF event” was reported by Robert J. Mentz, MD, Duke Clinical Research Institute, Durham, N.C., at the annual scientific meeting of the Heart Failure Society of America.

Across both studies, levels of the prognostically telling biomarker NT-proBNP dropped further in the ARNI group, by almost a fourth, compared with those getting an ACE inhibitor or ARB. The difference emerged within a week and was “similar and consistent” throughout at least 8 weeks of follow-up, Dr. Mentz said.

Sacubitril-valsartan is approved in the United States for chronic HF, broadly but with labeling suggesting clearer efficacy at lower LVEF levels, based on the PARADIGM-HF and PARAGON-HF trials.

The PIONEER-HF and PARAGLIDE-HF trials lending patients to the current analysis demonstrated superiority for the drug vs. an ACE inhibitor or ARB when started in hospital in stabilized patients with HF.
 

Cautions about starting sacubitril-valsartan

In the pooled analysis, patients on sacubitril-valsartan were more likely to experience symptomatic hypotension, with a relative risk for drug’s known potential side effect reaching 1.35 (95% confidence interval, 1.05-1.72), compared with ACE inhibitor or ARB recipients.

But the hypotension risk when starting the drug is manageable to some extent, observed Dr. Mentz. “We can safely start sacubitril-valsartan in the hospital or early post discharge, but we need to make sure their volume status is okay” and keep track of their blood pressure trajectory, he told this news organization.

Those with initially low BP, unsurprisingly, seem more susceptible to the problem, Dr. Mentz said. In such patients “on antihypertensives or other therapies that aren’t going to give them a clinical outcome benefit,” those meds can be withdrawn or their dosages reduced before sacubitril-valsartan is added.

Such cautions are an “important take-home message” of the analysis, observed invited discussant Carolyn S. P. Lam, MBBS, PhD, National Heart Centre, Singapore, after the Dr. Mentz presentation.

Sacubitril-valsartan should be started only in stabilized patients, she emphasized. It should be delayed in those “with ongoing adjustments of antihypertensives, diuretics, and so on,” in whom premature initiation of the drug may promote symptomatic hypotension. Should that happen, Dr. Lam cautioned, there’s a risk that such patients would be “mislabeled as intolerant” of the ARNI and so wouldn’t be started on it later.

The pooled PIONEER-HF and PARAGLIDE-HF analysis, Dr. Lam proposed, might also help overcome the “clinical inertia and fear” that is slowing the uptake of early guideline-directed drug therapy initiation in patients hospitalized with HF.
 

LVEF spectrum across two studies

As Dr. Mentz reported, the analysis included 881 and 466 patients from PIONEER-HF and PARAGLIDE-HF, respectively. Of the total, 673 were assigned to receive valsartan and 674 to receive either enalapril or valsartan. Overall, 36% of the population were women.

Patients in PIONEER-HF, with an LVEF 40% or lower, were started on their assigned drug during an acute-HF hospitalization and followed a median of 8 weeks. PARAGLIDE-HF patients, with LVEF higher than 40%, started therapy either in hospital (in 70% of cases) or within 30 days of their HF event; they were followed a median of 6 months.

Hazard ratios for outcomes in the sacubitril-valsartan group vs. those on ACE inhibitors or ARBs were 0.76; 95% CI, 0.69-0.83; P < .0001 for change in NT-proBNP levels. For the composite of CV death or HF hospitalization, HRs were as follows:

• 0.70 (95% CI, 0.54-0.91; P = .0077) overall.
• 0.59 (95% CI, 0.44-0.79) for LVEF < 60%.
• 1.53 (95% CI, 0.80-2.91) for LVEF > 60%.

Current guidelines, Dr. Mentz noted, recommend that sacubitril-valsartan “be initiated de novo” predischarge in patients without contraindications who are hospitalized with acute HF with reduced LVEF. The combined analysis of PIONEER-HF and PARAGLIDE-HF, he said, potentially extends the recommendation “across the ejection fraction spectrum.”

Dr. Mentz has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Eli Lilly, Medtronic, Medable, Merck, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Relypsa, Respicardia, Roche, Sanofi, Vifor, Windtree Therapeutics, and Zoll. Dr. Lam has reported financial relationships “with more than 25 pharmaceutical or device manufacturers, many of which produce therapies for heart failure,” as well as with Medscape/WebMD Global LLC.

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

CLEVELAND – Patients with heart failure (HF) who are started on sacubitril-valsartan (Entresto) in the hospital or soon after discharge will see a sharp drop in clinical risk whether their ejection fraction is “reduced” or merely “below normal,” suggests a combined analysis of two major studies.

Short-term risk for cardiovascular (CV) death or HF hospitalization fell 30% for such patients put on the angiotensin-receptor/neprilysin inhibitor (ARNI) at that early stage, compared with those assigned to receive an ACE inhibitor or angiotensin receptor blocker (ARB).

Of note, the risk-reduction benefit reached 41% among the overwhelming majority of patients with a left ventricular ejection fraction (LVEF) of 60% or lower across the two trials, PIONEER-HF and PARAGLIDE-HF. No such significant benefit was seen in patients with higher LVEF.

The prespecified analysis of 1,347 patients medically stabilized after a “worsening-HF event” was reported by Robert J. Mentz, MD, Duke Clinical Research Institute, Durham, N.C., at the annual scientific meeting of the Heart Failure Society of America.

Across both studies, levels of the prognostically telling biomarker NT-proBNP dropped further in the ARNI group, by almost a fourth, compared with those getting an ACE inhibitor or ARB. The difference emerged within a week and was “similar and consistent” throughout at least 8 weeks of follow-up, Dr. Mentz said.

Sacubitril-valsartan is approved in the United States for chronic HF, broadly but with labeling suggesting clearer efficacy at lower LVEF levels, based on the PARADIGM-HF and PARAGON-HF trials.

The PIONEER-HF and PARAGLIDE-HF trials lending patients to the current analysis demonstrated superiority for the drug vs. an ACE inhibitor or ARB when started in hospital in stabilized patients with HF.
 

Cautions about starting sacubitril-valsartan

In the pooled analysis, patients on sacubitril-valsartan were more likely to experience symptomatic hypotension, with a relative risk for drug’s known potential side effect reaching 1.35 (95% confidence interval, 1.05-1.72), compared with ACE inhibitor or ARB recipients.

But the hypotension risk when starting the drug is manageable to some extent, observed Dr. Mentz. “We can safely start sacubitril-valsartan in the hospital or early post discharge, but we need to make sure their volume status is okay” and keep track of their blood pressure trajectory, he told this news organization.

Those with initially low BP, unsurprisingly, seem more susceptible to the problem, Dr. Mentz said. In such patients “on antihypertensives or other therapies that aren’t going to give them a clinical outcome benefit,” those meds can be withdrawn or their dosages reduced before sacubitril-valsartan is added.

Such cautions are an “important take-home message” of the analysis, observed invited discussant Carolyn S. P. Lam, MBBS, PhD, National Heart Centre, Singapore, after the Dr. Mentz presentation.

Sacubitril-valsartan should be started only in stabilized patients, she emphasized. It should be delayed in those “with ongoing adjustments of antihypertensives, diuretics, and so on,” in whom premature initiation of the drug may promote symptomatic hypotension. Should that happen, Dr. Lam cautioned, there’s a risk that such patients would be “mislabeled as intolerant” of the ARNI and so wouldn’t be started on it later.

The pooled PIONEER-HF and PARAGLIDE-HF analysis, Dr. Lam proposed, might also help overcome the “clinical inertia and fear” that is slowing the uptake of early guideline-directed drug therapy initiation in patients hospitalized with HF.
 

LVEF spectrum across two studies

As Dr. Mentz reported, the analysis included 881 and 466 patients from PIONEER-HF and PARAGLIDE-HF, respectively. Of the total, 673 were assigned to receive valsartan and 674 to receive either enalapril or valsartan. Overall, 36% of the population were women.

Patients in PIONEER-HF, with an LVEF 40% or lower, were started on their assigned drug during an acute-HF hospitalization and followed a median of 8 weeks. PARAGLIDE-HF patients, with LVEF higher than 40%, started therapy either in hospital (in 70% of cases) or within 30 days of their HF event; they were followed a median of 6 months.

Hazard ratios for outcomes in the sacubitril-valsartan group vs. those on ACE inhibitors or ARBs were 0.76; 95% CI, 0.69-0.83; P < .0001 for change in NT-proBNP levels. For the composite of CV death or HF hospitalization, HRs were as follows:

• 0.70 (95% CI, 0.54-0.91; P = .0077) overall.
• 0.59 (95% CI, 0.44-0.79) for LVEF < 60%.
• 1.53 (95% CI, 0.80-2.91) for LVEF > 60%.

Current guidelines, Dr. Mentz noted, recommend that sacubitril-valsartan “be initiated de novo” predischarge in patients without contraindications who are hospitalized with acute HF with reduced LVEF. The combined analysis of PIONEER-HF and PARAGLIDE-HF, he said, potentially extends the recommendation “across the ejection fraction spectrum.”

Dr. Mentz has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Eli Lilly, Medtronic, Medable, Merck, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Relypsa, Respicardia, Roche, Sanofi, Vifor, Windtree Therapeutics, and Zoll. Dr. Lam has reported financial relationships “with more than 25 pharmaceutical or device manufacturers, many of which produce therapies for heart failure,” as well as with Medscape/WebMD Global LLC.

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

It’s still early days for a potential transcatheter technique that tones down sympathetic activation mediating blood volume shifts to the heart and lungs. Such volume transfers can contribute to congestion and acute decompensation in some patients with heart failure. But a randomized trial with negative overall results still may have moved the novel procedure a modest step forward.

The procedure, right-sided splanchnic-nerve ablation for volume management (SAVM), failed to show significant effects on hemodynamics, exercise capacity, natriuretic peptides, or quality of life in a trial covering a broad population of patients with heart failure with preserved ejection fraction (HFpEF).

The study, called REBALANCE-HF, compared ablation of the right greater splanchnic nerve with a sham version of the procedure for any effects on hemodynamic or functional outcomes.

But a secondary analysis identified a subgroup of patients, more than half the total, with a profile of features characterizing them, researchers say, as a group likely to respond favorably to SAVM.

Among such “potential responders,” those undergoing SAVM trended better than patients receiving the sham procedure with respect to hemodynamic, functional, natriuretic peptide, and quality of life endpoints.

The potential predictors of SAVM success included elevated or preserved cardiac output and pulse pressure with exercise or on standing up; appropriate heart-rate exercise responses; and little or no echocardiographic evidence of diastolic dysfunction.

The panel of features might potentially identify patients more likely to respond to the procedure and perhaps sharpen entry criteria in future clinical trials, Marat Fudim, MD, MHS, Duke University Medical Center, Durham, N.C., said in an interview.

Dr. Fudim presented the REBALANCE-HF findings at the annual meeting of the Heart Failure Society of America.
 

How SAVM works

Sympathetic activation can lead to acute or chronic constriction of vessels in the splanchnic bed within the upper and lower abdomen, one of the body’s largest blood reservoirs, Dr. Fudim explained. Resulting volume shifts to the general circulation, and therefore the heart and lungs, are a normal exercise response that, in HF, can fall out of balance and excessively raise cardiac filling pressure.

Lessened sympathetic tone after unilateral GNS ablation can promote splanchnic venous dilation that reduces intrathoracic blood volume, potentially averting congestion, and decompensation, observed Kavita Sharma, MD, invited discussant for Dr. Fudim’s presentation.

The trial’s potential-responder cohort “seemed able to augment cardiac output in response to stress” and to “maintain or augment their orthostatic pulse pressure,” more effectively than the other participants, said Dr. Sharma, of Johns Hopkins University, Baltimore.

Although the trial was overall negative for 1-month change in pulmonary capillary wedge pressure (PCWP), the primary efficacy endpoint, Dr. Sharma said, it confirmed SAVM as a safe procedure in HFpEF and “ensured its replicability and technical success.”

Future studies should explore ways to characterize unlikely SAVM responders, she proposed. “I would argue these patients are probably more important than even the responders.”

Yet it’s unknown why, for example, cardiac output wouldn’t increase with exercise in a patient with HFpEF. “Is it related to preload insufficiency, right ventricular failure, atrial myopathy, perhaps more restrictive physiology, chronotropic incompetence, or medications – or a combination of the above?”

REBALANCE-HF assigned 90 patients with HFpEF to either the active or sham SAVM groups, 44 and 46 patients, respectively. To be eligible, patients were stable on HF meds and had either elevated natriuretic peptides or, within the past year, at least one HF hospitalization or escalation of intravenous diuretics for worsening HF.

The active and sham control groups fared similarly for the primary PCWP endpoint and for the secondary endpoints of Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score, 6-minute walk distance (6MWD), and natriuretic peptide levels at 6 and 12 months.
 

Predicting SAVM response

In analysis limited to potential responders, PCWP, KCCQ, 6MWD, and natriuretic peptide outcomes for patients were combined into z scores, a single metric that reflects multiple outcomes, Dr. Fudim explained.

The z scores were derived for tertiles of patients in subgroups defined by a range of parameters that included demographics, medical history, and hemodynamic and echocardiographic variables.

Four such variables were found to interact across tertiles in a way that suggested their value as SAVM outcome predictors and were then used to select the cohort of potential responders. The variables were exertion-related changes in cardiac index, pulse pressure, and heart rate, and mitral E/A ratio – the latter a measure of diastolic dysfunction.

Among potential responders, those who underwent SAVM showed a 2.9–mm Hg steeper drop in peak PCWP at 1 month (P = .02), compared with patients getting the sham procedure.

They also bested control patients at both 6 and 12 months for KCCQ score, 6MWD, and natriuretic peptide levels, the latter of which fell in the SAVM group and climbed in control patients at both follow-ups.

“Hypothetically, it makes sense” to target the splanchnic nerve in HFpEF, and indeed in HF with reduced ejection fraction, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, said in an interview.

And should SAVM enter the mainstream, it would definitely be important to identify “the right” patients for such an invasive procedure, those likely to show “efficacy with a good safety margin,” said Dr. Bozkurt, who was not associated with REBALANCE-HF.

But the trial, she said, “unfortunately did not give real signals of outcome benefit.”

REBALANCE-HF was supported by Axon Therapies. Dr. Fudim disclosed consulting, receiving royalties, or having ownership or equity in Axon Therapies. Dr. Sharma disclosed receiving honoraria for speaking from Novartis and Janssen and serving on an advisory board or consulting for Novartis, Janssen, and Bayer. Dr. Bozkurt disclosed receiving honoraria from AstraZeneca, Baxter Health Care, and Sanofi Aventis and having other relationships with Renovacor, Respicardia, Abbott Vascular, Liva Nova, Vifor, and Cardurion.

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

It’s still early days for a potential transcatheter technique that tones down sympathetic activation mediating blood volume shifts to the heart and lungs. Such volume transfers can contribute to congestion and acute decompensation in some patients with heart failure. But a randomized trial with negative overall results still may have moved the novel procedure a modest step forward.

The procedure, right-sided splanchnic-nerve ablation for volume management (SAVM), failed to show significant effects on hemodynamics, exercise capacity, natriuretic peptides, or quality of life in a trial covering a broad population of patients with heart failure with preserved ejection fraction (HFpEF).

The study, called REBALANCE-HF, compared ablation of the right greater splanchnic nerve with a sham version of the procedure for any effects on hemodynamic or functional outcomes.

But a secondary analysis identified a subgroup of patients, more than half the total, with a profile of features characterizing them, researchers say, as a group likely to respond favorably to SAVM.

Among such “potential responders,” those undergoing SAVM trended better than patients receiving the sham procedure with respect to hemodynamic, functional, natriuretic peptide, and quality of life endpoints.

The potential predictors of SAVM success included elevated or preserved cardiac output and pulse pressure with exercise or on standing up; appropriate heart-rate exercise responses; and little or no echocardiographic evidence of diastolic dysfunction.

The panel of features might potentially identify patients more likely to respond to the procedure and perhaps sharpen entry criteria in future clinical trials, Marat Fudim, MD, MHS, Duke University Medical Center, Durham, N.C., said in an interview.

Dr. Fudim presented the REBALANCE-HF findings at the annual meeting of the Heart Failure Society of America.
 

How SAVM works

Sympathetic activation can lead to acute or chronic constriction of vessels in the splanchnic bed within the upper and lower abdomen, one of the body’s largest blood reservoirs, Dr. Fudim explained. Resulting volume shifts to the general circulation, and therefore the heart and lungs, are a normal exercise response that, in HF, can fall out of balance and excessively raise cardiac filling pressure.

Lessened sympathetic tone after unilateral GNS ablation can promote splanchnic venous dilation that reduces intrathoracic blood volume, potentially averting congestion, and decompensation, observed Kavita Sharma, MD, invited discussant for Dr. Fudim’s presentation.

The trial’s potential-responder cohort “seemed able to augment cardiac output in response to stress” and to “maintain or augment their orthostatic pulse pressure,” more effectively than the other participants, said Dr. Sharma, of Johns Hopkins University, Baltimore.

Although the trial was overall negative for 1-month change in pulmonary capillary wedge pressure (PCWP), the primary efficacy endpoint, Dr. Sharma said, it confirmed SAVM as a safe procedure in HFpEF and “ensured its replicability and technical success.”

Future studies should explore ways to characterize unlikely SAVM responders, she proposed. “I would argue these patients are probably more important than even the responders.”

Yet it’s unknown why, for example, cardiac output wouldn’t increase with exercise in a patient with HFpEF. “Is it related to preload insufficiency, right ventricular failure, atrial myopathy, perhaps more restrictive physiology, chronotropic incompetence, or medications – or a combination of the above?”

REBALANCE-HF assigned 90 patients with HFpEF to either the active or sham SAVM groups, 44 and 46 patients, respectively. To be eligible, patients were stable on HF meds and had either elevated natriuretic peptides or, within the past year, at least one HF hospitalization or escalation of intravenous diuretics for worsening HF.

The active and sham control groups fared similarly for the primary PCWP endpoint and for the secondary endpoints of Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score, 6-minute walk distance (6MWD), and natriuretic peptide levels at 6 and 12 months.
 

Predicting SAVM response

In analysis limited to potential responders, PCWP, KCCQ, 6MWD, and natriuretic peptide outcomes for patients were combined into z scores, a single metric that reflects multiple outcomes, Dr. Fudim explained.

The z scores were derived for tertiles of patients in subgroups defined by a range of parameters that included demographics, medical history, and hemodynamic and echocardiographic variables.

Four such variables were found to interact across tertiles in a way that suggested their value as SAVM outcome predictors and were then used to select the cohort of potential responders. The variables were exertion-related changes in cardiac index, pulse pressure, and heart rate, and mitral E/A ratio – the latter a measure of diastolic dysfunction.

Among potential responders, those who underwent SAVM showed a 2.9–mm Hg steeper drop in peak PCWP at 1 month (P = .02), compared with patients getting the sham procedure.

They also bested control patients at both 6 and 12 months for KCCQ score, 6MWD, and natriuretic peptide levels, the latter of which fell in the SAVM group and climbed in control patients at both follow-ups.

“Hypothetically, it makes sense” to target the splanchnic nerve in HFpEF, and indeed in HF with reduced ejection fraction, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, said in an interview.

And should SAVM enter the mainstream, it would definitely be important to identify “the right” patients for such an invasive procedure, those likely to show “efficacy with a good safety margin,” said Dr. Bozkurt, who was not associated with REBALANCE-HF.

But the trial, she said, “unfortunately did not give real signals of outcome benefit.”

REBALANCE-HF was supported by Axon Therapies. Dr. Fudim disclosed consulting, receiving royalties, or having ownership or equity in Axon Therapies. Dr. Sharma disclosed receiving honoraria for speaking from Novartis and Janssen and serving on an advisory board or consulting for Novartis, Janssen, and Bayer. Dr. Bozkurt disclosed receiving honoraria from AstraZeneca, Baxter Health Care, and Sanofi Aventis and having other relationships with Renovacor, Respicardia, Abbott Vascular, Liva Nova, Vifor, and Cardurion.

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

It’s still early days for a potential transcatheter technique that tones down sympathetic activation mediating blood volume shifts to the heart and lungs. Such volume transfers can contribute to congestion and acute decompensation in some patients with heart failure. But a randomized trial with negative overall results still may have moved the novel procedure a modest step forward.

The procedure, right-sided splanchnic-nerve ablation for volume management (SAVM), failed to show significant effects on hemodynamics, exercise capacity, natriuretic peptides, or quality of life in a trial covering a broad population of patients with heart failure with preserved ejection fraction (HFpEF).

The study, called REBALANCE-HF, compared ablation of the right greater splanchnic nerve with a sham version of the procedure for any effects on hemodynamic or functional outcomes.

But a secondary analysis identified a subgroup of patients, more than half the total, with a profile of features characterizing them, researchers say, as a group likely to respond favorably to SAVM.

Among such “potential responders,” those undergoing SAVM trended better than patients receiving the sham procedure with respect to hemodynamic, functional, natriuretic peptide, and quality of life endpoints.

The potential predictors of SAVM success included elevated or preserved cardiac output and pulse pressure with exercise or on standing up; appropriate heart-rate exercise responses; and little or no echocardiographic evidence of diastolic dysfunction.

The panel of features might potentially identify patients more likely to respond to the procedure and perhaps sharpen entry criteria in future clinical trials, Marat Fudim, MD, MHS, Duke University Medical Center, Durham, N.C., said in an interview.

Dr. Fudim presented the REBALANCE-HF findings at the annual meeting of the Heart Failure Society of America.
 

How SAVM works

Sympathetic activation can lead to acute or chronic constriction of vessels in the splanchnic bed within the upper and lower abdomen, one of the body’s largest blood reservoirs, Dr. Fudim explained. Resulting volume shifts to the general circulation, and therefore the heart and lungs, are a normal exercise response that, in HF, can fall out of balance and excessively raise cardiac filling pressure.

Lessened sympathetic tone after unilateral GNS ablation can promote splanchnic venous dilation that reduces intrathoracic blood volume, potentially averting congestion, and decompensation, observed Kavita Sharma, MD, invited discussant for Dr. Fudim’s presentation.

The trial’s potential-responder cohort “seemed able to augment cardiac output in response to stress” and to “maintain or augment their orthostatic pulse pressure,” more effectively than the other participants, said Dr. Sharma, of Johns Hopkins University, Baltimore.

Although the trial was overall negative for 1-month change in pulmonary capillary wedge pressure (PCWP), the primary efficacy endpoint, Dr. Sharma said, it confirmed SAVM as a safe procedure in HFpEF and “ensured its replicability and technical success.”

Future studies should explore ways to characterize unlikely SAVM responders, she proposed. “I would argue these patients are probably more important than even the responders.”

Yet it’s unknown why, for example, cardiac output wouldn’t increase with exercise in a patient with HFpEF. “Is it related to preload insufficiency, right ventricular failure, atrial myopathy, perhaps more restrictive physiology, chronotropic incompetence, or medications – or a combination of the above?”

REBALANCE-HF assigned 90 patients with HFpEF to either the active or sham SAVM groups, 44 and 46 patients, respectively. To be eligible, patients were stable on HF meds and had either elevated natriuretic peptides or, within the past year, at least one HF hospitalization or escalation of intravenous diuretics for worsening HF.

The active and sham control groups fared similarly for the primary PCWP endpoint and for the secondary endpoints of Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score, 6-minute walk distance (6MWD), and natriuretic peptide levels at 6 and 12 months.
 

Predicting SAVM response

In analysis limited to potential responders, PCWP, KCCQ, 6MWD, and natriuretic peptide outcomes for patients were combined into z scores, a single metric that reflects multiple outcomes, Dr. Fudim explained.

The z scores were derived for tertiles of patients in subgroups defined by a range of parameters that included demographics, medical history, and hemodynamic and echocardiographic variables.

Four such variables were found to interact across tertiles in a way that suggested their value as SAVM outcome predictors and were then used to select the cohort of potential responders. The variables were exertion-related changes in cardiac index, pulse pressure, and heart rate, and mitral E/A ratio – the latter a measure of diastolic dysfunction.

Among potential responders, those who underwent SAVM showed a 2.9–mm Hg steeper drop in peak PCWP at 1 month (P = .02), compared with patients getting the sham procedure.

They also bested control patients at both 6 and 12 months for KCCQ score, 6MWD, and natriuretic peptide levels, the latter of which fell in the SAVM group and climbed in control patients at both follow-ups.

“Hypothetically, it makes sense” to target the splanchnic nerve in HFpEF, and indeed in HF with reduced ejection fraction, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, said in an interview.

And should SAVM enter the mainstream, it would definitely be important to identify “the right” patients for such an invasive procedure, those likely to show “efficacy with a good safety margin,” said Dr. Bozkurt, who was not associated with REBALANCE-HF.

But the trial, she said, “unfortunately did not give real signals of outcome benefit.”

REBALANCE-HF was supported by Axon Therapies. Dr. Fudim disclosed consulting, receiving royalties, or having ownership or equity in Axon Therapies. Dr. Sharma disclosed receiving honoraria for speaking from Novartis and Janssen and serving on an advisory board or consulting for Novartis, Janssen, and Bayer. Dr. Bozkurt disclosed receiving honoraria from AstraZeneca, Baxter Health Care, and Sanofi Aventis and having other relationships with Renovacor, Respicardia, Abbott Vascular, Liva Nova, Vifor, and Cardurion.

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

CLEVELAND – Patients with heart failure (HF) who spread out the time between their first and last meal or snack of the day, regardless of daily caloric intake, may benefit with reduced risk for cardiovascular (CV) death, an observational study suggests.

The new findings, based primarily on 15 years of data from the National Health and Nutrition Examination Survey (NHANES), may argue against time-restricted diet interventions like intermittent fasting for patients with HF, researchers say.

The study’s nearly 1,000 participants on medical therapy for HF reported a mean daily eating window of 11 hours and daily average of four “eating occasions,” defined as meals or snacks of at least 50 kcal.

A daily eating window of 11 or more hours, compared with less than 11 hours, corresponded to a greater than 40% drop in risk for CV mortality (P = .013) over 5-6 years, reported Hayley E. Billingsley, RD, CEP, Virginia Commonwealth University, Richmond, Va,, at the annual scientific meeting of the Heart Failure Society of America.

The analysis adjusted for caloric intake, daily number of eating occasions, body mass index (BMI), history of CV disease and cancer, diabetes, and a slew of other potential confounders.

Prior evidence, mostly from healthy people, has suggested that extended fasting during the day is associated with less physical activity, Ms. Billingsley said in an interview. So it may be that people with HF who spread out their calorie intake are more active throughout the day.

A longer time window for eating, therefore, may have indirect metabolic benefits and help preserve their lean body mass, possibly reducing CV risk in a patient group at risk for muscle wasting.

The findings add to earlier evidence from Ms. Billingsley’s center that suggests that expanded daily time windows for eating, especially later final food rather than earlier first food, may help boost CV fitness for patients with obesity and HF with preserved ejection fraction.

Intermittent fasting and other practices involving the timing of food intake have been studied for weight loss and metabolic health in mostly healthy people and patients with diabetes, she noted. “But it’s really underexplored in people with established cardiovascular disease.”

On the basis of admittedly “very preliminary” findings, it may be that some patients should not shorten their daily time windows for eating or engage in intermittent fasting, Ms. Billingsley said. It’s probably worth considering, before the approach is recommended, “what their risk is for malnutrition or sarcopenia.”

The current study included 991 persons who entered the NHANES database from 2003 to 2018. The patients self-identified as having HF, reported taking medications commonly prescribed in HF, and provided at least two “reliable” dietary recalls.

The average age of the patients was 68 years, and they had had HF for a mean of 9.5 years; 47% were women, three-fourths were White persons, two thirds had dyslipidemia, and a quarter had a history of cancer.

On average, their first eating occasion of the day was at about 8:30 a.m., and the last occasion was at about 7:30 p.m., for a time window of about 11 hours; daily calorie consumption averaged about 1,830 kcal.

About 52% died over the mean follow-up of 69 months; about 44% of deaths were from CV causes.

In a model adjusted for demographics, BMI, smoking status, times of eating occasions, CV disease, diabetes, and cancer history, the all-cause mortality hazard ratio for time windows ≥ 11 hours vs. < 11 hours was 0.236 (95% confidence interval, 0.07-0.715; P = .011).

The reduction was no longer significant on further adjustment for duration of HF, a score reflecting difficulty walking, nightly hours of sleep (which averaged 7.2 hours), daily number of eating occasions, and caloric intake, Ms. Billingsley reported.

But in the fully adjusted analysis, the HR for CV mortality for the longer vs. shorter time window was 0.368 (95% CI, 0.169-0.803; P = .013).

The issue deserves further exploration in a randomized trial, Ms. Billingsley proposed, perhaps one in which patients with HF wear accelerometers to track daily activity levels. “We’d love to do a pilot study of extending their eating window that really digs into what the mechanism of any benefit might be if we assign them to a longer time window and whether it’s related to physical activity.”

Ms. Billingsley reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

CLEVELAND – Patients with heart failure (HF) who spread out the time between their first and last meal or snack of the day, regardless of daily caloric intake, may benefit with reduced risk for cardiovascular (CV) death, an observational study suggests.

The new findings, based primarily on 15 years of data from the National Health and Nutrition Examination Survey (NHANES), may argue against time-restricted diet interventions like intermittent fasting for patients with HF, researchers say.

The study’s nearly 1,000 participants on medical therapy for HF reported a mean daily eating window of 11 hours and daily average of four “eating occasions,” defined as meals or snacks of at least 50 kcal.

A daily eating window of 11 or more hours, compared with less than 11 hours, corresponded to a greater than 40% drop in risk for CV mortality (P = .013) over 5-6 years, reported Hayley E. Billingsley, RD, CEP, Virginia Commonwealth University, Richmond, Va,, at the annual scientific meeting of the Heart Failure Society of America.

The analysis adjusted for caloric intake, daily number of eating occasions, body mass index (BMI), history of CV disease and cancer, diabetes, and a slew of other potential confounders.

Prior evidence, mostly from healthy people, has suggested that extended fasting during the day is associated with less physical activity, Ms. Billingsley said in an interview. So it may be that people with HF who spread out their calorie intake are more active throughout the day.

A longer time window for eating, therefore, may have indirect metabolic benefits and help preserve their lean body mass, possibly reducing CV risk in a patient group at risk for muscle wasting.

The findings add to earlier evidence from Ms. Billingsley’s center that suggests that expanded daily time windows for eating, especially later final food rather than earlier first food, may help boost CV fitness for patients with obesity and HF with preserved ejection fraction.

Intermittent fasting and other practices involving the timing of food intake have been studied for weight loss and metabolic health in mostly healthy people and patients with diabetes, she noted. “But it’s really underexplored in people with established cardiovascular disease.”

On the basis of admittedly “very preliminary” findings, it may be that some patients should not shorten their daily time windows for eating or engage in intermittent fasting, Ms. Billingsley said. It’s probably worth considering, before the approach is recommended, “what their risk is for malnutrition or sarcopenia.”

The current study included 991 persons who entered the NHANES database from 2003 to 2018. The patients self-identified as having HF, reported taking medications commonly prescribed in HF, and provided at least two “reliable” dietary recalls.

The average age of the patients was 68 years, and they had had HF for a mean of 9.5 years; 47% were women, three-fourths were White persons, two thirds had dyslipidemia, and a quarter had a history of cancer.

On average, their first eating occasion of the day was at about 8:30 a.m., and the last occasion was at about 7:30 p.m., for a time window of about 11 hours; daily calorie consumption averaged about 1,830 kcal.

About 52% died over the mean follow-up of 69 months; about 44% of deaths were from CV causes.

In a model adjusted for demographics, BMI, smoking status, times of eating occasions, CV disease, diabetes, and cancer history, the all-cause mortality hazard ratio for time windows ≥ 11 hours vs. < 11 hours was 0.236 (95% confidence interval, 0.07-0.715; P = .011).

The reduction was no longer significant on further adjustment for duration of HF, a score reflecting difficulty walking, nightly hours of sleep (which averaged 7.2 hours), daily number of eating occasions, and caloric intake, Ms. Billingsley reported.

But in the fully adjusted analysis, the HR for CV mortality for the longer vs. shorter time window was 0.368 (95% CI, 0.169-0.803; P = .013).

The issue deserves further exploration in a randomized trial, Ms. Billingsley proposed, perhaps one in which patients with HF wear accelerometers to track daily activity levels. “We’d love to do a pilot study of extending their eating window that really digs into what the mechanism of any benefit might be if we assign them to a longer time window and whether it’s related to physical activity.”

Ms. Billingsley reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

CLEVELAND – Patients with heart failure (HF) who spread out the time between their first and last meal or snack of the day, regardless of daily caloric intake, may benefit with reduced risk for cardiovascular (CV) death, an observational study suggests.

The new findings, based primarily on 15 years of data from the National Health and Nutrition Examination Survey (NHANES), may argue against time-restricted diet interventions like intermittent fasting for patients with HF, researchers say.

The study’s nearly 1,000 participants on medical therapy for HF reported a mean daily eating window of 11 hours and daily average of four “eating occasions,” defined as meals or snacks of at least 50 kcal.

A daily eating window of 11 or more hours, compared with less than 11 hours, corresponded to a greater than 40% drop in risk for CV mortality (P = .013) over 5-6 years, reported Hayley E. Billingsley, RD, CEP, Virginia Commonwealth University, Richmond, Va,, at the annual scientific meeting of the Heart Failure Society of America.

The analysis adjusted for caloric intake, daily number of eating occasions, body mass index (BMI), history of CV disease and cancer, diabetes, and a slew of other potential confounders.

Prior evidence, mostly from healthy people, has suggested that extended fasting during the day is associated with less physical activity, Ms. Billingsley said in an interview. So it may be that people with HF who spread out their calorie intake are more active throughout the day.

A longer time window for eating, therefore, may have indirect metabolic benefits and help preserve their lean body mass, possibly reducing CV risk in a patient group at risk for muscle wasting.

The findings add to earlier evidence from Ms. Billingsley’s center that suggests that expanded daily time windows for eating, especially later final food rather than earlier first food, may help boost CV fitness for patients with obesity and HF with preserved ejection fraction.

Intermittent fasting and other practices involving the timing of food intake have been studied for weight loss and metabolic health in mostly healthy people and patients with diabetes, she noted. “But it’s really underexplored in people with established cardiovascular disease.”

On the basis of admittedly “very preliminary” findings, it may be that some patients should not shorten their daily time windows for eating or engage in intermittent fasting, Ms. Billingsley said. It’s probably worth considering, before the approach is recommended, “what their risk is for malnutrition or sarcopenia.”

The current study included 991 persons who entered the NHANES database from 2003 to 2018. The patients self-identified as having HF, reported taking medications commonly prescribed in HF, and provided at least two “reliable” dietary recalls.

The average age of the patients was 68 years, and they had had HF for a mean of 9.5 years; 47% were women, three-fourths were White persons, two thirds had dyslipidemia, and a quarter had a history of cancer.

On average, their first eating occasion of the day was at about 8:30 a.m., and the last occasion was at about 7:30 p.m., for a time window of about 11 hours; daily calorie consumption averaged about 1,830 kcal.

About 52% died over the mean follow-up of 69 months; about 44% of deaths were from CV causes.

In a model adjusted for demographics, BMI, smoking status, times of eating occasions, CV disease, diabetes, and cancer history, the all-cause mortality hazard ratio for time windows ≥ 11 hours vs. < 11 hours was 0.236 (95% confidence interval, 0.07-0.715; P = .011).

The reduction was no longer significant on further adjustment for duration of HF, a score reflecting difficulty walking, nightly hours of sleep (which averaged 7.2 hours), daily number of eating occasions, and caloric intake, Ms. Billingsley reported.

But in the fully adjusted analysis, the HR for CV mortality for the longer vs. shorter time window was 0.368 (95% CI, 0.169-0.803; P = .013).

The issue deserves further exploration in a randomized trial, Ms. Billingsley proposed, perhaps one in which patients with HF wear accelerometers to track daily activity levels. “We’d love to do a pilot study of extending their eating window that really digs into what the mechanism of any benefit might be if we assign them to a longer time window and whether it’s related to physical activity.”

Ms. Billingsley reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

CLEVELAND – Patients with obesity and heart failure with preserved ejection fraction (HFpEF) treated with semaglutide improved in symptoms, functional capacity, and biomarkers over 1 year independently of baseline left-ventricular ejection fraction (LVEF).

The finding comes from a prespecified secondary analysis of the STEP-HFpEF trial of more than 500 nondiabetic patients with obesity and HF with an initial LVEF of 45% or greater.

They suggest that for patients with the obesity phenotype of HFpEF, semaglutide (Wegovy) could potentially join SGLT2 inhibitors on the short list of meds with consistent treatment effects whether LVEF is mildly reduced, preserved, or in the normal range.

That would distinguish the drug, a glucagon-like peptide-1 (GLP-1) receptor agonist, from mineralocorticoid receptor antagonists (MRA), sacubitril-valsartan (Entresto), and other renin-angiotensin-system inhibitors (RASi), whose benefits tend to taper off with rising LVEF.

The patients assigned to semaglutide showed significant improvement in both primary endpoints – change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and change in body weight at 52 weeks – whether their baseline LVEF was 45%-49%, 50%-59%, or 60% or greater.

Results were similar for improvements in 6-minute walk distance (6MWD) and levels of NT-terminal pro–brain natriuretic peptide (NT-proBNP) and C-reactive protein, observed Javed Butler, MD, when presenting the analysis at the annual meeting of the Heart Failure Society of America, Cleveland.

Dr. Butler, of Baylor Scott and White Research Institute, Dallas, and the University of Mississippi, Jackson, is also lead author of the study, which was published on the same day in the Journal of the American College of Cardiology.

In his presentation, Dr. Butler singled out the NT-proBNP finding as “very meaningful” with respect to understanding potential mechanisms of the drug effects observed in the trial.

For example, people with obesity tend to have lower than average natriuretic peptide levels that “actually go up a bit” when they lose weight, he observed. But in the trial, “we saw a reduction in NT-proBNP in spite of the weight loss,” regardless of LVEF category.

John McMurray, MD, University of Glasgow, the invited discussant for Dr. Butler’s presentation, agreed that it raises the question whether weight loss was the sole semaglutide effect responsible for the improvement in heart failure status and biomarkers. The accompanying NT-proBNP reductions – when the opposite might otherwise have been expected – may point to a possible mechanism of action that is “something more than just weight loss,” he said. “If that were the case, it becomes very important, because it means that this treatment might do good things in non-obese patients or might do good things in patients with other types of heart failure.”
 

‘Vital reassurance’

More definitive trials are needed “to clarify safety and efficacy of obesity-targeted therapeutics in HF across the ejection fraction spectrum,” according to an accompanying editorial).

Still, the STEP-HFpEF analysis “strengthens the role of GLP-1 [receptor agonists] to ameliorate health status” for patients with obesity and HF with mildly reduced or preserved ejection fraction, write Muthiah Vaduganathan, MD, MPH, and John W. Ostrominski, MD, Brigham and Women’s Hospital and Harvard Medical School, both in Boston.

Its findings “provide vital reassurance” on semaglutide safety and efficacy in HF with below-normal LVEF and “tentatively support the existence of a more general, LVEF-independent, obesity-related HF phenotype capable of favorable modification with incretin-based therapies.”

The lack of heterogeneity in treatment effects across LVEF subgroups “is not surprising,” but “the findings reinforce that the benefits of this therapy in those meeting trial criteria do not vary by left ventricular ejection fraction,” Gregg C. Fonarow, MD, University of California, Los Angeles, Medical Center, said in an interview.

It remains unknown, however, “whether the improvement in health status, functional status, and reduced inflammation” will translate to reduced risk of cardiovascular death or HF hospitalization, said Dr. Fonarow, who isn’t connected to STEP-HFpEF.

It’s a question for future studies, he agreed, whether semaglutide would confer similar benefits for patients with obesity and HF with LVEF less than 45% or in non-obese HF patients.

Dr. McMurray proposed that future GLP-1 receptor agonist heart-failure trials should include non-obese patients to determine whether the effects seen in STEP-HFpEF were due to something more than weight loss. Trials in patients with obesity and HF with reduced LVEF would also be important.

“If it turns out just to be about weight loss, then we need to think about the alternatives,” including diet, exercise, and bariatric surgery but also, potentially, weight-loss drugs other than semaglutide, he said.
 

No heterogeneity by LVEF

STEP-HFpEF randomly assigned 529 patients free of diabetes with an LVEF greater than or equal to 45%, a body mass index (BMI) of at least 30 kg/m², and NYHA functional status of 2-4 to either a placebo injection or 2.4-mg semaglutide subcutaneously once a week (the dose used for weight reduction) atop standard care.

As previously reported, those assigned to semaglutide showed significant improvements at 1 year in symptoms and in physical limitation, per changes in KCCQ-CSS, and weight loss, compared with the control group. Their exercise capacity, as measured by 6MWD, also improved.

The more weight patients lost while taking semaglutide, the better their KCCQ-CSS and 6MWD outcomes, a prior secondary analysis suggested. But the STEP-HFpEF researchers said weight loss did not appear to explain all of their gains, compared with usual care.

For the current analysis, the 263 patients assigned to receive semaglutide and 266 control patients were divided into three groups by baseline LVEF and compared for the same outcomes.

165413_graphic_web.jpg

A version of this article appeared on Medscape.com.

CLEVELAND – Patients with obesity and heart failure with preserved ejection fraction (HFpEF) treated with semaglutide improved in symptoms, functional capacity, and biomarkers over 1 year independently of baseline left-ventricular ejection fraction (LVEF).

The finding comes from a prespecified secondary analysis of the STEP-HFpEF trial of more than 500 nondiabetic patients with obesity and HF with an initial LVEF of 45% or greater.

They suggest that for patients with the obesity phenotype of HFpEF, semaglutide (Wegovy) could potentially join SGLT2 inhibitors on the short list of meds with consistent treatment effects whether LVEF is mildly reduced, preserved, or in the normal range.

That would distinguish the drug, a glucagon-like peptide-1 (GLP-1) receptor agonist, from mineralocorticoid receptor antagonists (MRA), sacubitril-valsartan (Entresto), and other renin-angiotensin-system inhibitors (RASi), whose benefits tend to taper off with rising LVEF.

The patients assigned to semaglutide showed significant improvement in both primary endpoints – change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and change in body weight at 52 weeks – whether their baseline LVEF was 45%-49%, 50%-59%, or 60% or greater.

Results were similar for improvements in 6-minute walk distance (6MWD) and levels of NT-terminal pro–brain natriuretic peptide (NT-proBNP) and C-reactive protein, observed Javed Butler, MD, when presenting the analysis at the annual meeting of the Heart Failure Society of America, Cleveland.

Dr. Butler, of Baylor Scott and White Research Institute, Dallas, and the University of Mississippi, Jackson, is also lead author of the study, which was published on the same day in the Journal of the American College of Cardiology.

In his presentation, Dr. Butler singled out the NT-proBNP finding as “very meaningful” with respect to understanding potential mechanisms of the drug effects observed in the trial.

For example, people with obesity tend to have lower than average natriuretic peptide levels that “actually go up a bit” when they lose weight, he observed. But in the trial, “we saw a reduction in NT-proBNP in spite of the weight loss,” regardless of LVEF category.

John McMurray, MD, University of Glasgow, the invited discussant for Dr. Butler’s presentation, agreed that it raises the question whether weight loss was the sole semaglutide effect responsible for the improvement in heart failure status and biomarkers. The accompanying NT-proBNP reductions – when the opposite might otherwise have been expected – may point to a possible mechanism of action that is “something more than just weight loss,” he said. “If that were the case, it becomes very important, because it means that this treatment might do good things in non-obese patients or might do good things in patients with other types of heart failure.”
 

‘Vital reassurance’

More definitive trials are needed “to clarify safety and efficacy of obesity-targeted therapeutics in HF across the ejection fraction spectrum,” according to an accompanying editorial).

Still, the STEP-HFpEF analysis “strengthens the role of GLP-1 [receptor agonists] to ameliorate health status” for patients with obesity and HF with mildly reduced or preserved ejection fraction, write Muthiah Vaduganathan, MD, MPH, and John W. Ostrominski, MD, Brigham and Women’s Hospital and Harvard Medical School, both in Boston.

Its findings “provide vital reassurance” on semaglutide safety and efficacy in HF with below-normal LVEF and “tentatively support the existence of a more general, LVEF-independent, obesity-related HF phenotype capable of favorable modification with incretin-based therapies.”

The lack of heterogeneity in treatment effects across LVEF subgroups “is not surprising,” but “the findings reinforce that the benefits of this therapy in those meeting trial criteria do not vary by left ventricular ejection fraction,” Gregg C. Fonarow, MD, University of California, Los Angeles, Medical Center, said in an interview.

It remains unknown, however, “whether the improvement in health status, functional status, and reduced inflammation” will translate to reduced risk of cardiovascular death or HF hospitalization, said Dr. Fonarow, who isn’t connected to STEP-HFpEF.

It’s a question for future studies, he agreed, whether semaglutide would confer similar benefits for patients with obesity and HF with LVEF less than 45% or in non-obese HF patients.

Dr. McMurray proposed that future GLP-1 receptor agonist heart-failure trials should include non-obese patients to determine whether the effects seen in STEP-HFpEF were due to something more than weight loss. Trials in patients with obesity and HF with reduced LVEF would also be important.

“If it turns out just to be about weight loss, then we need to think about the alternatives,” including diet, exercise, and bariatric surgery but also, potentially, weight-loss drugs other than semaglutide, he said.
 

No heterogeneity by LVEF

STEP-HFpEF randomly assigned 529 patients free of diabetes with an LVEF greater than or equal to 45%, a body mass index (BMI) of at least 30 kg/m², and NYHA functional status of 2-4 to either a placebo injection or 2.4-mg semaglutide subcutaneously once a week (the dose used for weight reduction) atop standard care.

As previously reported, those assigned to semaglutide showed significant improvements at 1 year in symptoms and in physical limitation, per changes in KCCQ-CSS, and weight loss, compared with the control group. Their exercise capacity, as measured by 6MWD, also improved.

The more weight patients lost while taking semaglutide, the better their KCCQ-CSS and 6MWD outcomes, a prior secondary analysis suggested. But the STEP-HFpEF researchers said weight loss did not appear to explain all of their gains, compared with usual care.

For the current analysis, the 263 patients assigned to receive semaglutide and 266 control patients were divided into three groups by baseline LVEF and compared for the same outcomes.

165413_graphic_web.jpg

A version of this article appeared on Medscape.com.

CLEVELAND – Patients with obesity and heart failure with preserved ejection fraction (HFpEF) treated with semaglutide improved in symptoms, functional capacity, and biomarkers over 1 year independently of baseline left-ventricular ejection fraction (LVEF).

The finding comes from a prespecified secondary analysis of the STEP-HFpEF trial of more than 500 nondiabetic patients with obesity and HF with an initial LVEF of 45% or greater.

They suggest that for patients with the obesity phenotype of HFpEF, semaglutide (Wegovy) could potentially join SGLT2 inhibitors on the short list of meds with consistent treatment effects whether LVEF is mildly reduced, preserved, or in the normal range.

That would distinguish the drug, a glucagon-like peptide-1 (GLP-1) receptor agonist, from mineralocorticoid receptor antagonists (MRA), sacubitril-valsartan (Entresto), and other renin-angiotensin-system inhibitors (RASi), whose benefits tend to taper off with rising LVEF.

The patients assigned to semaglutide showed significant improvement in both primary endpoints – change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and change in body weight at 52 weeks – whether their baseline LVEF was 45%-49%, 50%-59%, or 60% or greater.

Results were similar for improvements in 6-minute walk distance (6MWD) and levels of NT-terminal pro–brain natriuretic peptide (NT-proBNP) and C-reactive protein, observed Javed Butler, MD, when presenting the analysis at the annual meeting of the Heart Failure Society of America, Cleveland.

Dr. Butler, of Baylor Scott and White Research Institute, Dallas, and the University of Mississippi, Jackson, is also lead author of the study, which was published on the same day in the Journal of the American College of Cardiology.

In his presentation, Dr. Butler singled out the NT-proBNP finding as “very meaningful” with respect to understanding potential mechanisms of the drug effects observed in the trial.

For example, people with obesity tend to have lower than average natriuretic peptide levels that “actually go up a bit” when they lose weight, he observed. But in the trial, “we saw a reduction in NT-proBNP in spite of the weight loss,” regardless of LVEF category.

John McMurray, MD, University of Glasgow, the invited discussant for Dr. Butler’s presentation, agreed that it raises the question whether weight loss was the sole semaglutide effect responsible for the improvement in heart failure status and biomarkers. The accompanying NT-proBNP reductions – when the opposite might otherwise have been expected – may point to a possible mechanism of action that is “something more than just weight loss,” he said. “If that were the case, it becomes very important, because it means that this treatment might do good things in non-obese patients or might do good things in patients with other types of heart failure.”
 

‘Vital reassurance’

More definitive trials are needed “to clarify safety and efficacy of obesity-targeted therapeutics in HF across the ejection fraction spectrum,” according to an accompanying editorial).

Still, the STEP-HFpEF analysis “strengthens the role of GLP-1 [receptor agonists] to ameliorate health status” for patients with obesity and HF with mildly reduced or preserved ejection fraction, write Muthiah Vaduganathan, MD, MPH, and John W. Ostrominski, MD, Brigham and Women’s Hospital and Harvard Medical School, both in Boston.

Its findings “provide vital reassurance” on semaglutide safety and efficacy in HF with below-normal LVEF and “tentatively support the existence of a more general, LVEF-independent, obesity-related HF phenotype capable of favorable modification with incretin-based therapies.”

The lack of heterogeneity in treatment effects across LVEF subgroups “is not surprising,” but “the findings reinforce that the benefits of this therapy in those meeting trial criteria do not vary by left ventricular ejection fraction,” Gregg C. Fonarow, MD, University of California, Los Angeles, Medical Center, said in an interview.

It remains unknown, however, “whether the improvement in health status, functional status, and reduced inflammation” will translate to reduced risk of cardiovascular death or HF hospitalization, said Dr. Fonarow, who isn’t connected to STEP-HFpEF.

It’s a question for future studies, he agreed, whether semaglutide would confer similar benefits for patients with obesity and HF with LVEF less than 45% or in non-obese HF patients.

Dr. McMurray proposed that future GLP-1 receptor agonist heart-failure trials should include non-obese patients to determine whether the effects seen in STEP-HFpEF were due to something more than weight loss. Trials in patients with obesity and HF with reduced LVEF would also be important.

“If it turns out just to be about weight loss, then we need to think about the alternatives,” including diet, exercise, and bariatric surgery but also, potentially, weight-loss drugs other than semaglutide, he said.
 

No heterogeneity by LVEF

STEP-HFpEF randomly assigned 529 patients free of diabetes with an LVEF greater than or equal to 45%, a body mass index (BMI) of at least 30 kg/m², and NYHA functional status of 2-4 to either a placebo injection or 2.4-mg semaglutide subcutaneously once a week (the dose used for weight reduction) atop standard care.

As previously reported, those assigned to semaglutide showed significant improvements at 1 year in symptoms and in physical limitation, per changes in KCCQ-CSS, and weight loss, compared with the control group. Their exercise capacity, as measured by 6MWD, also improved.

The more weight patients lost while taking semaglutide, the better their KCCQ-CSS and 6MWD outcomes, a prior secondary analysis suggested. But the STEP-HFpEF researchers said weight loss did not appear to explain all of their gains, compared with usual care.

For the current analysis, the 263 patients assigned to receive semaglutide and 266 control patients were divided into three groups by baseline LVEF and compared for the same outcomes.

165413_graphic_web.jpg

A version of this article appeared on Medscape.com.

It’s as if hospitals, clinicians, and the health care system itself were unprepared for such success as a powerful multiple-drug regimen emerged for hospitalized patients with heart failure with reduced ejection fraction (HFrEF).

Uptake in practice has been sluggish for the management strategy driven by a quartet of medications, each with its own mechanisms of action, started in the hospital simultaneously or in rapid succession over a few days. Key to the regimen, dosages are at least partly uptitrated in the hospital then optimized during close postdischarge follow-up.

The so-called four pillars of medical therapy for HFrEF, defined by a left ventricular ejection fraction (LVEF) of 40% or lower, include an SGLT2 inhibitor, a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and a renin-angiotensin-system (RAS) inhibitor – preferably sacubitril-valsartan (Entresto) or, as a backup, an ACE inhibitor or angiotensin receptor blocker (ARB).

Academic consensus on the strategy is strong. The approach is consistent with heart failure (HF) guidelines on both sides of the Atlantic and is backed by solid trial evidence suggesting striking improvements in survival, readmission risk, and quality of life.

In HFrEF, the four medications “clearly reduce all-cause mortality, are nonoverlapping and truly and fully additive, and their benefits are cumulative, incremental, and begin within days,” Gregg C. Fonarow, MD, University of California, Los Angeles, said in an interview.

“Yet, when we look at their actual implementation in clinical practice, we’ve seen this slow and variable uptake.”
 

So, why is that?

The STRONG-HF trial tested a version of the multiple-drug strategy and demonstrated what it could achieve even without a contribution from SGLT2 inhibitors, which weren’t yet indicated for HF. Eligibility for the trial, with more than 1,000 patients, wasn’t dependent on their LVEF.

Patients assigned to early and rapidly sequential initiation of a beta-blocker, an MRA, and a RAS inhibitor, compared with a standard-care control group, benefited with a 34% drop (P = .002) in risk for death or HF readmission over the next 6 months.

Few doubt – and the bulk of evidence suggests – that adding an SGLT2 inhibitor to round out the four-pillar strategy would safely boost its clinical potential in HFrEF.

The strategy’s smooth adoption in practice likely has multiple confounders that include clinical inertia, perceptions of HF medical management as a long-term outpatient process, and the onerous and Kafkaesque systems of care and reimbursement in the United States.

For example, the drug initiation and uptitration process may seem too complex for integration into slow-to-change hospital practices. And there could be a misguided sense that the regimen and follow-up must abide by the same exacting detail and standards set forth in, for example, the STRONG-HF protocol.

But starting hospitalized patients with HFrEF on the quartet of drugs and optimizing their dosages in hospital and after discharge can be simpler and more straightforward than that, Dr. Fonarow and other experts explain.

The academic community’s buy-in is a first step, but broader acceptance is frustrated by an “overwhelming culture of clinical care for heart failure” that encourages a more drawn-out process for adding medications, said Stephen J. Greene, MD, Duke Clinical Research Institute, Durham, N.C. “We need to turn our thinking on its head about heart failure in clinical practice.”

The “dramatic” underuse of the four pillars in the hospital stems in part from “outmoded” treatment algorithms that clinicians are following, Dr. Fonarow said. And they have “no sense of urgency,” sometimes wrongly believing “that it takes months for these medications to ultimately kick in.”

For hospitalized patients with HFrEF, “there is an imperative to overcome these timid algorithms and timid thinking,” he said. They should be on “full quadruple therapy” before discharge.

“And for newly diagnosed outpatients, you should essentially give yourself 7 days to get these drugs on board,” he added, either simultaneously or in “very rapid sequence.”

What’s needed is a “cultural shift” in medicine that “elevates heart failure to the same level of urgency that we have in the care of some other disease states,” agreed Muthiah Vaduganathan, MD, MPH, Brigham and Women’s Hospital and Harvard Medical School, Boston.
 

Hospital as opportunity

The patient’s 4-7 days in the hospital typically represent a “wonderful opportunity” to initiate all four drug classes in rapid succession and start uptitrations. But most hospitals and other health care settings, Dr. Vaduganathan observed, lack the structure and systems to support the process. Broad application will require “buy-in from multiple parties – from the clinician, from the patient, their caregivers, and their partners as well as the health system.”

Physician awareness and support for the strategy, suggests at least one of these experts, is probably much less of a challenge to its broad adoption than the bewildering mechanics of health care delivery and reimbursement.

“The problem is not education. The problem is the way that our health care system is structured,” said Milton Packer, MD, Baylor Heart and Vascular Institute, Dallas.

For example, sacubitril-valsartan and the SGLT2 inhibitors are still under patent and are far more expensive than longtime generic beta-blockers and MRAs. That means physicians typically spend valuable time pursuing prior authorizations for the brand-name drugs under pressure to eventually discharge the patient because of limits on hospital reimbursement.

Clinicians in the hospital are “almost disincentivized by the system” to implement management plans that call for early and rapid initiation of multiple drugs, Dr. Vaduganathan pointed out.
 

One change per day

There’s no one formula for carrying out the quadruple drug strategy, Dr. Vaduganathan noted. “I make only a single change per day” to the regimen, such as uptitration or addition of a single agent. That way, tolerability can be evaluated one drug at a time, “and then the following day, I can make the next therapeutic change.”

The order in which the drugs are started mostly does not matter, in contrast to a traditional approach that might have added new drugs in the sequence of their approval for HFrEF or adoption in guidelines. Under that scenario, each successive agent might be fully uptitrated before the next could be brought on board.

Historically, Dr. Packer observed, “you would start with an ACE inhibitor, add a beta-blocker, add an MRA, switch to sacubitril-valsartan, add an SGLT2 inhibitor – and it would take 8 months.” Any prescribed sequence is pointless given the short time frame that is ideal for initiating all the drugs, he said.

Hypothetically, however, there is some rationale for starting them in an order that leverages their unique actions and side effects. For example, Dr. Vaduganathan and others observed, it may be helpful to start an SGLT2 inhibitor and sacubitril-valsartan early in the process, because they can mitigate any hyperkalemia from the subsequent addition of an MRA.

That being said, “I don’t think we have firm evidence that any particular order is more efficacious than another,” Dr. Vaduganathan said. “It’s really about getting patients on all four drugs as quickly as possible, regardless of the sequence.”

Discussions about sequencing the drugs are “a distraction for our field,” Dr. Greene said. In trials, clinical benefit from the multiple-drug regimen has emerged almost right away once the drugs were on board. “The data clearly show that initiating all four, at least at low doses, gives the best bang for your buck and would be a high-yield strategy.”

Best evidence suggests that once all four agents have been started, attention can turn to uptitration, “with the beta-blocker as the higher priority,” Dr. Greene said. “The bottom line is to keep it simple: four drugs, simultaneously or within 1 week, and prioritize initiation at low doses to maximize tolerability.”

The four-drug approach yields survival and rehospitalization benefits even when uptitrations don’t reach prespecified goals, Dr. Fonarow observed. The SGLT2 inhibitors are started and maintained at the same dosage. But for the other three agents, uptitration should aim for the highest well-tolerated level, up to the target, even if the highest tolerated is the initial dosage.
 

‘Challenging to generalize’

The goal in STRONG-HF was to start and at least partly uptitrate a beta-blocker, an MRA, and sacubitril-valsartan in the hospital and fully optimize their dosages within 2 weeks after discharge. Symptoms and laboratory biomarkers, including natriuretic peptides, were closely monitored at four in-person evaluations during the first 6 outpatient weeks.

But few believe the trial’s intensive drug regimen and postdischarge follow-up, as stipulated in the protocol, would be tolerated by current systems of care and reimbursement.

STRONG-HF “affirms the strategy in a rigorous, well conducted way,” Dr. Vaduganathan said, but would be “challenging to generalize to all health care systems.”

As a result, some in the field are “quick to almost disregard STRONG-HF in its entirety” and consider it “wishful thinking,” Dr. Greene said. Better that providers not become distracted by the precise details of its protocol.

At Duke, he said, “we see all our patients within 1 week of discharge to ensure they’re doing okay in terms of volume status and look for opportunities to escalate their guideline-directed medical therapy.”

But that can be done without in-person visits. A lot of the follow-up and uptitrations, Dr. Greene said, can be achieved by telephone or at virtual appointments in conjunction with regular laboratory testing. “That, I think, really is the path for the future, in this age when clinics are overwhelmed by in-person visits.”
 

Mildly reduced and preserved EF

STRONG-HF, in which patients were enrolled without regard to ejection fraction, suggests that its rapidly sequential drug regimen and intensive management protocol improves outcomes for patients with HF at any level of LVEF.

Those findings and others, along with DELIVER, EMPEROR-Preserved and other studies, make a tantalizing case for the quadruple drug approach in patients with HF and LVEF >40% – that is, those with mildly reduced (LVEF > 40% to < 50%, HFmrEF) or preserved LVEF > 50%, HFpEF) ejection fraction.

But the case isn’t solid enough to declare the four agents as core therapy for HF and LVEF > 40%, observed Dr. Vaduganathan. Currently, SGLT2 inhibitors “are the only drug class that we are routinely implementing” in HFmrEF and HFpEF.

There have been suggestions of clinical benefit for such patients with sacubitril-valsartan and MRAs, especially in PARAGON-HF and TOPCAT, respectively. The evidence is stronger in HFmrEF than in HFpEF, but in either case it’s weaker than the clear-cut trial support for SGLT2 inhibitors in those HF categories.

Trials also suggest that in HF with LVEF > 40%, clinical benefits from RAS inhibitors and MRAs taper off with increasing ejection fraction, especially into the > 60% range.

In both HFmrEF and HFpEF, “I routinely try to get the patient on an SGLT2 inhibitor rapidly and then treat with some of the other agents on a more individual basis,” Dr. Vaduganathan said. An LVEF in the HFmrEF range, for example, would likely call for the addition of an MRA and sacubitril-valsartan.

Dr. Packer said he would likely recommend all four agents for patients with HF and LVEF up to 60%, which he considers a more appropriate definition of HFrEF. Their clinical benefits appear consistent across that LVEF range, he said, although they thin out somewhat at the higher end.

Evidence supporting the four pillars in HF with LV > 40% and < 60% is weakest for beta-blockers, Dr. Packer noted, so arguably those drugs could be left out of the mix for patients with ejection fractions in that range.

Dr. Fonarow reported ties with Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, Johnson & Johnson, Medtronic, Merck, Novartis, and Pfizer. Dr. Greene disclosed ties with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Lilly, Bristol-Myers Squibb, Corteria, CSL Vifor, Cytokinetics, Lexicon Merck, Novartis, Pfizer, PharmaIN, Roche Diagnostics, Sanofi, scPharmaceuticals, Tricog Health, and Urovant Pharmaceuticals. Dr. Vaduganathan disclosed ties with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Galmed, Impulse Dynamics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Occlutech, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health. Dr. Packer disclosed relationships with 89bio, AbbVie, Actavis, Amarin, Amgen, AstraZeneca, Attralus, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Medtronic, Moderna, Novartis, Pharmacosmos, Reata, Regeneron, Relypsa, and Salamandra.
 

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

It’s as if hospitals, clinicians, and the health care system itself were unprepared for such success as a powerful multiple-drug regimen emerged for hospitalized patients with heart failure with reduced ejection fraction (HFrEF).

Uptake in practice has been sluggish for the management strategy driven by a quartet of medications, each with its own mechanisms of action, started in the hospital simultaneously or in rapid succession over a few days. Key to the regimen, dosages are at least partly uptitrated in the hospital then optimized during close postdischarge follow-up.

The so-called four pillars of medical therapy for HFrEF, defined by a left ventricular ejection fraction (LVEF) of 40% or lower, include an SGLT2 inhibitor, a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and a renin-angiotensin-system (RAS) inhibitor – preferably sacubitril-valsartan (Entresto) or, as a backup, an ACE inhibitor or angiotensin receptor blocker (ARB).

Academic consensus on the strategy is strong. The approach is consistent with heart failure (HF) guidelines on both sides of the Atlantic and is backed by solid trial evidence suggesting striking improvements in survival, readmission risk, and quality of life.

In HFrEF, the four medications “clearly reduce all-cause mortality, are nonoverlapping and truly and fully additive, and their benefits are cumulative, incremental, and begin within days,” Gregg C. Fonarow, MD, University of California, Los Angeles, said in an interview.

“Yet, when we look at their actual implementation in clinical practice, we’ve seen this slow and variable uptake.”
 

So, why is that?

The STRONG-HF trial tested a version of the multiple-drug strategy and demonstrated what it could achieve even without a contribution from SGLT2 inhibitors, which weren’t yet indicated for HF. Eligibility for the trial, with more than 1,000 patients, wasn’t dependent on their LVEF.

Patients assigned to early and rapidly sequential initiation of a beta-blocker, an MRA, and a RAS inhibitor, compared with a standard-care control group, benefited with a 34% drop (P = .002) in risk for death or HF readmission over the next 6 months.

Few doubt – and the bulk of evidence suggests – that adding an SGLT2 inhibitor to round out the four-pillar strategy would safely boost its clinical potential in HFrEF.

The strategy’s smooth adoption in practice likely has multiple confounders that include clinical inertia, perceptions of HF medical management as a long-term outpatient process, and the onerous and Kafkaesque systems of care and reimbursement in the United States.

For example, the drug initiation and uptitration process may seem too complex for integration into slow-to-change hospital practices. And there could be a misguided sense that the regimen and follow-up must abide by the same exacting detail and standards set forth in, for example, the STRONG-HF protocol.

But starting hospitalized patients with HFrEF on the quartet of drugs and optimizing their dosages in hospital and after discharge can be simpler and more straightforward than that, Dr. Fonarow and other experts explain.

The academic community’s buy-in is a first step, but broader acceptance is frustrated by an “overwhelming culture of clinical care for heart failure” that encourages a more drawn-out process for adding medications, said Stephen J. Greene, MD, Duke Clinical Research Institute, Durham, N.C. “We need to turn our thinking on its head about heart failure in clinical practice.”

The “dramatic” underuse of the four pillars in the hospital stems in part from “outmoded” treatment algorithms that clinicians are following, Dr. Fonarow said. And they have “no sense of urgency,” sometimes wrongly believing “that it takes months for these medications to ultimately kick in.”

For hospitalized patients with HFrEF, “there is an imperative to overcome these timid algorithms and timid thinking,” he said. They should be on “full quadruple therapy” before discharge.

“And for newly diagnosed outpatients, you should essentially give yourself 7 days to get these drugs on board,” he added, either simultaneously or in “very rapid sequence.”

What’s needed is a “cultural shift” in medicine that “elevates heart failure to the same level of urgency that we have in the care of some other disease states,” agreed Muthiah Vaduganathan, MD, MPH, Brigham and Women’s Hospital and Harvard Medical School, Boston.
 

Hospital as opportunity

The patient’s 4-7 days in the hospital typically represent a “wonderful opportunity” to initiate all four drug classes in rapid succession and start uptitrations. But most hospitals and other health care settings, Dr. Vaduganathan observed, lack the structure and systems to support the process. Broad application will require “buy-in from multiple parties – from the clinician, from the patient, their caregivers, and their partners as well as the health system.”

Physician awareness and support for the strategy, suggests at least one of these experts, is probably much less of a challenge to its broad adoption than the bewildering mechanics of health care delivery and reimbursement.

“The problem is not education. The problem is the way that our health care system is structured,” said Milton Packer, MD, Baylor Heart and Vascular Institute, Dallas.

For example, sacubitril-valsartan and the SGLT2 inhibitors are still under patent and are far more expensive than longtime generic beta-blockers and MRAs. That means physicians typically spend valuable time pursuing prior authorizations for the brand-name drugs under pressure to eventually discharge the patient because of limits on hospital reimbursement.

Clinicians in the hospital are “almost disincentivized by the system” to implement management plans that call for early and rapid initiation of multiple drugs, Dr. Vaduganathan pointed out.
 

One change per day

There’s no one formula for carrying out the quadruple drug strategy, Dr. Vaduganathan noted. “I make only a single change per day” to the regimen, such as uptitration or addition of a single agent. That way, tolerability can be evaluated one drug at a time, “and then the following day, I can make the next therapeutic change.”

The order in which the drugs are started mostly does not matter, in contrast to a traditional approach that might have added new drugs in the sequence of their approval for HFrEF or adoption in guidelines. Under that scenario, each successive agent might be fully uptitrated before the next could be brought on board.

Historically, Dr. Packer observed, “you would start with an ACE inhibitor, add a beta-blocker, add an MRA, switch to sacubitril-valsartan, add an SGLT2 inhibitor – and it would take 8 months.” Any prescribed sequence is pointless given the short time frame that is ideal for initiating all the drugs, he said.

Hypothetically, however, there is some rationale for starting them in an order that leverages their unique actions and side effects. For example, Dr. Vaduganathan and others observed, it may be helpful to start an SGLT2 inhibitor and sacubitril-valsartan early in the process, because they can mitigate any hyperkalemia from the subsequent addition of an MRA.

That being said, “I don’t think we have firm evidence that any particular order is more efficacious than another,” Dr. Vaduganathan said. “It’s really about getting patients on all four drugs as quickly as possible, regardless of the sequence.”

Discussions about sequencing the drugs are “a distraction for our field,” Dr. Greene said. In trials, clinical benefit from the multiple-drug regimen has emerged almost right away once the drugs were on board. “The data clearly show that initiating all four, at least at low doses, gives the best bang for your buck and would be a high-yield strategy.”

Best evidence suggests that once all four agents have been started, attention can turn to uptitration, “with the beta-blocker as the higher priority,” Dr. Greene said. “The bottom line is to keep it simple: four drugs, simultaneously or within 1 week, and prioritize initiation at low doses to maximize tolerability.”

The four-drug approach yields survival and rehospitalization benefits even when uptitrations don’t reach prespecified goals, Dr. Fonarow observed. The SGLT2 inhibitors are started and maintained at the same dosage. But for the other three agents, uptitration should aim for the highest well-tolerated level, up to the target, even if the highest tolerated is the initial dosage.
 

‘Challenging to generalize’

The goal in STRONG-HF was to start and at least partly uptitrate a beta-blocker, an MRA, and sacubitril-valsartan in the hospital and fully optimize their dosages within 2 weeks after discharge. Symptoms and laboratory biomarkers, including natriuretic peptides, were closely monitored at four in-person evaluations during the first 6 outpatient weeks.

But few believe the trial’s intensive drug regimen and postdischarge follow-up, as stipulated in the protocol, would be tolerated by current systems of care and reimbursement.

STRONG-HF “affirms the strategy in a rigorous, well conducted way,” Dr. Vaduganathan said, but would be “challenging to generalize to all health care systems.”

As a result, some in the field are “quick to almost disregard STRONG-HF in its entirety” and consider it “wishful thinking,” Dr. Greene said. Better that providers not become distracted by the precise details of its protocol.

At Duke, he said, “we see all our patients within 1 week of discharge to ensure they’re doing okay in terms of volume status and look for opportunities to escalate their guideline-directed medical therapy.”

But that can be done without in-person visits. A lot of the follow-up and uptitrations, Dr. Greene said, can be achieved by telephone or at virtual appointments in conjunction with regular laboratory testing. “That, I think, really is the path for the future, in this age when clinics are overwhelmed by in-person visits.”
 

Mildly reduced and preserved EF

STRONG-HF, in which patients were enrolled without regard to ejection fraction, suggests that its rapidly sequential drug regimen and intensive management protocol improves outcomes for patients with HF at any level of LVEF.

Those findings and others, along with DELIVER, EMPEROR-Preserved and other studies, make a tantalizing case for the quadruple drug approach in patients with HF and LVEF >40% – that is, those with mildly reduced (LVEF > 40% to < 50%, HFmrEF) or preserved LVEF > 50%, HFpEF) ejection fraction.

But the case isn’t solid enough to declare the four agents as core therapy for HF and LVEF > 40%, observed Dr. Vaduganathan. Currently, SGLT2 inhibitors “are the only drug class that we are routinely implementing” in HFmrEF and HFpEF.

There have been suggestions of clinical benefit for such patients with sacubitril-valsartan and MRAs, especially in PARAGON-HF and TOPCAT, respectively. The evidence is stronger in HFmrEF than in HFpEF, but in either case it’s weaker than the clear-cut trial support for SGLT2 inhibitors in those HF categories.

Trials also suggest that in HF with LVEF > 40%, clinical benefits from RAS inhibitors and MRAs taper off with increasing ejection fraction, especially into the > 60% range.

In both HFmrEF and HFpEF, “I routinely try to get the patient on an SGLT2 inhibitor rapidly and then treat with some of the other agents on a more individual basis,” Dr. Vaduganathan said. An LVEF in the HFmrEF range, for example, would likely call for the addition of an MRA and sacubitril-valsartan.

Dr. Packer said he would likely recommend all four agents for patients with HF and LVEF up to 60%, which he considers a more appropriate definition of HFrEF. Their clinical benefits appear consistent across that LVEF range, he said, although they thin out somewhat at the higher end.

Evidence supporting the four pillars in HF with LV > 40% and < 60% is weakest for beta-blockers, Dr. Packer noted, so arguably those drugs could be left out of the mix for patients with ejection fractions in that range.

Dr. Fonarow reported ties with Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, Johnson & Johnson, Medtronic, Merck, Novartis, and Pfizer. Dr. Greene disclosed ties with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Lilly, Bristol-Myers Squibb, Corteria, CSL Vifor, Cytokinetics, Lexicon Merck, Novartis, Pfizer, PharmaIN, Roche Diagnostics, Sanofi, scPharmaceuticals, Tricog Health, and Urovant Pharmaceuticals. Dr. Vaduganathan disclosed ties with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Galmed, Impulse Dynamics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Occlutech, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health. Dr. Packer disclosed relationships with 89bio, AbbVie, Actavis, Amarin, Amgen, AstraZeneca, Attralus, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Medtronic, Moderna, Novartis, Pharmacosmos, Reata, Regeneron, Relypsa, and Salamandra.
 

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

It’s as if hospitals, clinicians, and the health care system itself were unprepared for such success as a powerful multiple-drug regimen emerged for hospitalized patients with heart failure with reduced ejection fraction (HFrEF).

Uptake in practice has been sluggish for the management strategy driven by a quartet of medications, each with its own mechanisms of action, started in the hospital simultaneously or in rapid succession over a few days. Key to the regimen, dosages are at least partly uptitrated in the hospital then optimized during close postdischarge follow-up.

The so-called four pillars of medical therapy for HFrEF, defined by a left ventricular ejection fraction (LVEF) of 40% or lower, include an SGLT2 inhibitor, a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and a renin-angiotensin-system (RAS) inhibitor – preferably sacubitril-valsartan (Entresto) or, as a backup, an ACE inhibitor or angiotensin receptor blocker (ARB).

Academic consensus on the strategy is strong. The approach is consistent with heart failure (HF) guidelines on both sides of the Atlantic and is backed by solid trial evidence suggesting striking improvements in survival, readmission risk, and quality of life.

In HFrEF, the four medications “clearly reduce all-cause mortality, are nonoverlapping and truly and fully additive, and their benefits are cumulative, incremental, and begin within days,” Gregg C. Fonarow, MD, University of California, Los Angeles, said in an interview.

“Yet, when we look at their actual implementation in clinical practice, we’ve seen this slow and variable uptake.”
 

So, why is that?

The STRONG-HF trial tested a version of the multiple-drug strategy and demonstrated what it could achieve even without a contribution from SGLT2 inhibitors, which weren’t yet indicated for HF. Eligibility for the trial, with more than 1,000 patients, wasn’t dependent on their LVEF.

Patients assigned to early and rapidly sequential initiation of a beta-blocker, an MRA, and a RAS inhibitor, compared with a standard-care control group, benefited with a 34% drop (P = .002) in risk for death or HF readmission over the next 6 months.

Few doubt – and the bulk of evidence suggests – that adding an SGLT2 inhibitor to round out the four-pillar strategy would safely boost its clinical potential in HFrEF.

The strategy’s smooth adoption in practice likely has multiple confounders that include clinical inertia, perceptions of HF medical management as a long-term outpatient process, and the onerous and Kafkaesque systems of care and reimbursement in the United States.

For example, the drug initiation and uptitration process may seem too complex for integration into slow-to-change hospital practices. And there could be a misguided sense that the regimen and follow-up must abide by the same exacting detail and standards set forth in, for example, the STRONG-HF protocol.

But starting hospitalized patients with HFrEF on the quartet of drugs and optimizing their dosages in hospital and after discharge can be simpler and more straightforward than that, Dr. Fonarow and other experts explain.

The academic community’s buy-in is a first step, but broader acceptance is frustrated by an “overwhelming culture of clinical care for heart failure” that encourages a more drawn-out process for adding medications, said Stephen J. Greene, MD, Duke Clinical Research Institute, Durham, N.C. “We need to turn our thinking on its head about heart failure in clinical practice.”

The “dramatic” underuse of the four pillars in the hospital stems in part from “outmoded” treatment algorithms that clinicians are following, Dr. Fonarow said. And they have “no sense of urgency,” sometimes wrongly believing “that it takes months for these medications to ultimately kick in.”

For hospitalized patients with HFrEF, “there is an imperative to overcome these timid algorithms and timid thinking,” he said. They should be on “full quadruple therapy” before discharge.

“And for newly diagnosed outpatients, you should essentially give yourself 7 days to get these drugs on board,” he added, either simultaneously or in “very rapid sequence.”

What’s needed is a “cultural shift” in medicine that “elevates heart failure to the same level of urgency that we have in the care of some other disease states,” agreed Muthiah Vaduganathan, MD, MPH, Brigham and Women’s Hospital and Harvard Medical School, Boston.
 

Hospital as opportunity

The patient’s 4-7 days in the hospital typically represent a “wonderful opportunity” to initiate all four drug classes in rapid succession and start uptitrations. But most hospitals and other health care settings, Dr. Vaduganathan observed, lack the structure and systems to support the process. Broad application will require “buy-in from multiple parties – from the clinician, from the patient, their caregivers, and their partners as well as the health system.”

Physician awareness and support for the strategy, suggests at least one of these experts, is probably much less of a challenge to its broad adoption than the bewildering mechanics of health care delivery and reimbursement.

“The problem is not education. The problem is the way that our health care system is structured,” said Milton Packer, MD, Baylor Heart and Vascular Institute, Dallas.

For example, sacubitril-valsartan and the SGLT2 inhibitors are still under patent and are far more expensive than longtime generic beta-blockers and MRAs. That means physicians typically spend valuable time pursuing prior authorizations for the brand-name drugs under pressure to eventually discharge the patient because of limits on hospital reimbursement.

Clinicians in the hospital are “almost disincentivized by the system” to implement management plans that call for early and rapid initiation of multiple drugs, Dr. Vaduganathan pointed out.
 

One change per day

There’s no one formula for carrying out the quadruple drug strategy, Dr. Vaduganathan noted. “I make only a single change per day” to the regimen, such as uptitration or addition of a single agent. That way, tolerability can be evaluated one drug at a time, “and then the following day, I can make the next therapeutic change.”

The order in which the drugs are started mostly does not matter, in contrast to a traditional approach that might have added new drugs in the sequence of their approval for HFrEF or adoption in guidelines. Under that scenario, each successive agent might be fully uptitrated before the next could be brought on board.

Historically, Dr. Packer observed, “you would start with an ACE inhibitor, add a beta-blocker, add an MRA, switch to sacubitril-valsartan, add an SGLT2 inhibitor – and it would take 8 months.” Any prescribed sequence is pointless given the short time frame that is ideal for initiating all the drugs, he said.

Hypothetically, however, there is some rationale for starting them in an order that leverages their unique actions and side effects. For example, Dr. Vaduganathan and others observed, it may be helpful to start an SGLT2 inhibitor and sacubitril-valsartan early in the process, because they can mitigate any hyperkalemia from the subsequent addition of an MRA.

That being said, “I don’t think we have firm evidence that any particular order is more efficacious than another,” Dr. Vaduganathan said. “It’s really about getting patients on all four drugs as quickly as possible, regardless of the sequence.”

Discussions about sequencing the drugs are “a distraction for our field,” Dr. Greene said. In trials, clinical benefit from the multiple-drug regimen has emerged almost right away once the drugs were on board. “The data clearly show that initiating all four, at least at low doses, gives the best bang for your buck and would be a high-yield strategy.”

Best evidence suggests that once all four agents have been started, attention can turn to uptitration, “with the beta-blocker as the higher priority,” Dr. Greene said. “The bottom line is to keep it simple: four drugs, simultaneously or within 1 week, and prioritize initiation at low doses to maximize tolerability.”

The four-drug approach yields survival and rehospitalization benefits even when uptitrations don’t reach prespecified goals, Dr. Fonarow observed. The SGLT2 inhibitors are started and maintained at the same dosage. But for the other three agents, uptitration should aim for the highest well-tolerated level, up to the target, even if the highest tolerated is the initial dosage.
 

‘Challenging to generalize’

The goal in STRONG-HF was to start and at least partly uptitrate a beta-blocker, an MRA, and sacubitril-valsartan in the hospital and fully optimize their dosages within 2 weeks after discharge. Symptoms and laboratory biomarkers, including natriuretic peptides, were closely monitored at four in-person evaluations during the first 6 outpatient weeks.

But few believe the trial’s intensive drug regimen and postdischarge follow-up, as stipulated in the protocol, would be tolerated by current systems of care and reimbursement.

STRONG-HF “affirms the strategy in a rigorous, well conducted way,” Dr. Vaduganathan said, but would be “challenging to generalize to all health care systems.”

As a result, some in the field are “quick to almost disregard STRONG-HF in its entirety” and consider it “wishful thinking,” Dr. Greene said. Better that providers not become distracted by the precise details of its protocol.

At Duke, he said, “we see all our patients within 1 week of discharge to ensure they’re doing okay in terms of volume status and look for opportunities to escalate their guideline-directed medical therapy.”

But that can be done without in-person visits. A lot of the follow-up and uptitrations, Dr. Greene said, can be achieved by telephone or at virtual appointments in conjunction with regular laboratory testing. “That, I think, really is the path for the future, in this age when clinics are overwhelmed by in-person visits.”
 

Mildly reduced and preserved EF

STRONG-HF, in which patients were enrolled without regard to ejection fraction, suggests that its rapidly sequential drug regimen and intensive management protocol improves outcomes for patients with HF at any level of LVEF.

Those findings and others, along with DELIVER, EMPEROR-Preserved and other studies, make a tantalizing case for the quadruple drug approach in patients with HF and LVEF >40% – that is, those with mildly reduced (LVEF > 40% to < 50%, HFmrEF) or preserved LVEF > 50%, HFpEF) ejection fraction.

But the case isn’t solid enough to declare the four agents as core therapy for HF and LVEF > 40%, observed Dr. Vaduganathan. Currently, SGLT2 inhibitors “are the only drug class that we are routinely implementing” in HFmrEF and HFpEF.

There have been suggestions of clinical benefit for such patients with sacubitril-valsartan and MRAs, especially in PARAGON-HF and TOPCAT, respectively. The evidence is stronger in HFmrEF than in HFpEF, but in either case it’s weaker than the clear-cut trial support for SGLT2 inhibitors in those HF categories.

Trials also suggest that in HF with LVEF > 40%, clinical benefits from RAS inhibitors and MRAs taper off with increasing ejection fraction, especially into the > 60% range.

In both HFmrEF and HFpEF, “I routinely try to get the patient on an SGLT2 inhibitor rapidly and then treat with some of the other agents on a more individual basis,” Dr. Vaduganathan said. An LVEF in the HFmrEF range, for example, would likely call for the addition of an MRA and sacubitril-valsartan.

Dr. Packer said he would likely recommend all four agents for patients with HF and LVEF up to 60%, which he considers a more appropriate definition of HFrEF. Their clinical benefits appear consistent across that LVEF range, he said, although they thin out somewhat at the higher end.

Evidence supporting the four pillars in HF with LV > 40% and < 60% is weakest for beta-blockers, Dr. Packer noted, so arguably those drugs could be left out of the mix for patients with ejection fractions in that range.

Dr. Fonarow reported ties with Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, Johnson & Johnson, Medtronic, Merck, Novartis, and Pfizer. Dr. Greene disclosed ties with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Lilly, Bristol-Myers Squibb, Corteria, CSL Vifor, Cytokinetics, Lexicon Merck, Novartis, Pfizer, PharmaIN, Roche Diagnostics, Sanofi, scPharmaceuticals, Tricog Health, and Urovant Pharmaceuticals. Dr. Vaduganathan disclosed ties with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Galmed, Impulse Dynamics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Occlutech, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health. Dr. Packer disclosed relationships with 89bio, AbbVie, Actavis, Amarin, Amgen, AstraZeneca, Attralus, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Medtronic, Moderna, Novartis, Pharmacosmos, Reata, Regeneron, Relypsa, and Salamandra.
 

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

The second patient to be transplanted with a genetically modified pig heart at the University of Maryland Medical Center (UMMC), Baltimore, is said to be stable and doing well after the Sept. 22 operation. The organ passed an early test by avoiding hyperacute rejection.

Physicians for the patient, a 58-year-old former lab tech repeatedly turned down for standard allograft transplantation, say they are making good use of lessons from last year’s case of David Bennett, who survived in hospital with difficulty for 2 months after receiving the first such heart at the center in January 2022.

Mr. Bennett’s clinical course had been promising at first but grew turbulent with repeated bouts of infection followed by adjustments to his aggressive immunosuppressant regimen and other complications.

It was also learned weeks after the xenotransplant operation that the heart from the genetically modified donor pig had carried a porcine cytomegalovirus to Mr. Bennett’s body, although there was never evidence that the virus infected other organs or played a major role in his death.

The new xenotransplant recipient, Lawrence Faucette of Frederick, Md., is benefiting from that experience, which was documented in journal reports.

Mr. Faucette had been turned down by UMMC “and several other leading transplant hospitals due to his pre-existing peripheral vascular disease and complications with internal bleeding,” notes a UMMC press release describing his procedure.

The patient “is currently breathing on his own, and his heart is functioning well without any assistance from supportive devices,” says the statement.

Despite a few setbacks, Mr. Faucette is “on the right track,” said Muhammad M. Mohiuddin, MBBS, surgeon and xenotransplantation program director at the University of Maryland, Baltimore, in an interview.

“We’re taking one day at a time. His immune system is still intact, despite the heavy immune suppression,” he told this news organization. His heart didn’t carry a virus and “has not shown any signs of rejection so far.”

The University of Maryland team, Dr. Mohiuddin said, “is very hopeful that we will be able to at least mobilize the patient, and he can be discharged. But it’s a little too early to call.”

Mr. Faucette, as part of his immunosuppressant regimen, is receiving tegoprubart (Eledon Pharmaceuticals), an investigational antibody that blocks CD40 ligand. His predecessor Mr. Bennett, in contrast, had received a blocker of the CD40 receptor (Kiniksa Pharmaceuticals) along with other more familiar immunosuppressants.

The new anti–CD40-ligand blocker, Eledon said, is in phase 1 studies looking at efficacy in patients with conventional kidney transplants.

A version of this article appeared on Medscape.com.

The second patient to be transplanted with a genetically modified pig heart at the University of Maryland Medical Center (UMMC), Baltimore, is said to be stable and doing well after the Sept. 22 operation. The organ passed an early test by avoiding hyperacute rejection.

Physicians for the patient, a 58-year-old former lab tech repeatedly turned down for standard allograft transplantation, say they are making good use of lessons from last year’s case of David Bennett, who survived in hospital with difficulty for 2 months after receiving the first such heart at the center in January 2022.

Mr. Bennett’s clinical course had been promising at first but grew turbulent with repeated bouts of infection followed by adjustments to his aggressive immunosuppressant regimen and other complications.

It was also learned weeks after the xenotransplant operation that the heart from the genetically modified donor pig had carried a porcine cytomegalovirus to Mr. Bennett’s body, although there was never evidence that the virus infected other organs or played a major role in his death.

The new xenotransplant recipient, Lawrence Faucette of Frederick, Md., is benefiting from that experience, which was documented in journal reports.

Mr. Faucette had been turned down by UMMC “and several other leading transplant hospitals due to his pre-existing peripheral vascular disease and complications with internal bleeding,” notes a UMMC press release describing his procedure.

The patient “is currently breathing on his own, and his heart is functioning well without any assistance from supportive devices,” says the statement.

Despite a few setbacks, Mr. Faucette is “on the right track,” said Muhammad M. Mohiuddin, MBBS, surgeon and xenotransplantation program director at the University of Maryland, Baltimore, in an interview.

“We’re taking one day at a time. His immune system is still intact, despite the heavy immune suppression,” he told this news organization. His heart didn’t carry a virus and “has not shown any signs of rejection so far.”

The University of Maryland team, Dr. Mohiuddin said, “is very hopeful that we will be able to at least mobilize the patient, and he can be discharged. But it’s a little too early to call.”

Mr. Faucette, as part of his immunosuppressant regimen, is receiving tegoprubart (Eledon Pharmaceuticals), an investigational antibody that blocks CD40 ligand. His predecessor Mr. Bennett, in contrast, had received a blocker of the CD40 receptor (Kiniksa Pharmaceuticals) along with other more familiar immunosuppressants.

The new anti–CD40-ligand blocker, Eledon said, is in phase 1 studies looking at efficacy in patients with conventional kidney transplants.

A version of this article appeared on Medscape.com.

The second patient to be transplanted with a genetically modified pig heart at the University of Maryland Medical Center (UMMC), Baltimore, is said to be stable and doing well after the Sept. 22 operation. The organ passed an early test by avoiding hyperacute rejection.

Physicians for the patient, a 58-year-old former lab tech repeatedly turned down for standard allograft transplantation, say they are making good use of lessons from last year’s case of David Bennett, who survived in hospital with difficulty for 2 months after receiving the first such heart at the center in January 2022.

Mr. Bennett’s clinical course had been promising at first but grew turbulent with repeated bouts of infection followed by adjustments to his aggressive immunosuppressant regimen and other complications.

It was also learned weeks after the xenotransplant operation that the heart from the genetically modified donor pig had carried a porcine cytomegalovirus to Mr. Bennett’s body, although there was never evidence that the virus infected other organs or played a major role in his death.

The new xenotransplant recipient, Lawrence Faucette of Frederick, Md., is benefiting from that experience, which was documented in journal reports.

Mr. Faucette had been turned down by UMMC “and several other leading transplant hospitals due to his pre-existing peripheral vascular disease and complications with internal bleeding,” notes a UMMC press release describing his procedure.

The patient “is currently breathing on his own, and his heart is functioning well without any assistance from supportive devices,” says the statement.

Despite a few setbacks, Mr. Faucette is “on the right track,” said Muhammad M. Mohiuddin, MBBS, surgeon and xenotransplantation program director at the University of Maryland, Baltimore, in an interview.

“We’re taking one day at a time. His immune system is still intact, despite the heavy immune suppression,” he told this news organization. His heart didn’t carry a virus and “has not shown any signs of rejection so far.”

The University of Maryland team, Dr. Mohiuddin said, “is very hopeful that we will be able to at least mobilize the patient, and he can be discharged. But it’s a little too early to call.”

Mr. Faucette, as part of his immunosuppressant regimen, is receiving tegoprubart (Eledon Pharmaceuticals), an investigational antibody that blocks CD40 ligand. His predecessor Mr. Bennett, in contrast, had received a blocker of the CD40 receptor (Kiniksa Pharmaceuticals) along with other more familiar immunosuppressants.

The new anti–CD40-ligand blocker, Eledon said, is in phase 1 studies looking at efficacy in patients with conventional kidney transplants.

A version of this article appeared on Medscape.com.

What if cardiology were no longer an internal medicine subspecialty? Four leading cardiology societies have announced plans to create a new certification process that is independent of the American Board of Internal Medicine maintenance of certification (MOC) system.

As envisioned, the new “independent, self-governed” entity would supplant the ABIM’s long-standing and widely criticized MOC system and establish cardiology as its own specialty with its own subspecialties. Long in coming, it is only the latest response to many in the field who for years have charged that the MOC system is needlessly burdensome and expensive.

“It’s time to have a dedicated cardiovascular medicine board of our own,” said B. Hadley Wilson, MD, in the group’s announcement. “Cardiology is a distinct medical specialty, and physicians want and deserve a clinical competency and continuous certification program that is meaningful to their practice and patients.”

Hadley Wilson, Sanger Heart & Vascular Institute Vascular Kenilworth, Charlotte, N.C., is president of the American College of Cardiology, one of the four societies spearheading the initiative along with the Heart Failure Society of America, the Heart Rhythm Society, and the Society for Cardiovascular Angiography & Interventions.

Their Sept. 21 statement says that the consortium will apply to the American Board of Medical Specialties to request an independent cardiology board that follows a “new competency-based approach to continuous certification – one that harnesses the knowledge, skills, and attitudes required to sustain professional excellence and care for cardiovascular patients effectively.”

It continues, “The new board requirements will de-emphasize timed, high stakes performance exams in the continuous certification process and instead will focus on learning assessments to identify gaps in current knowledge or skills.”

“The new board’s focus on competence in the pursuit of continuous certification is a needed paradigm shift for the field,” states HFSA President John R. Teerlink, MD, University of California, San Francisco, and the San Francisco VA Medical Center, in the announcement.

“I commend these professional cardiovascular societies for taking on this important challenge,” Deepak L. Bhatt, MD, MPH, Mount Sinai Hospital and Icahn School of Medicine at Mount Sinai, New York City, told this news organization by email.

“This is an incredible opportunity to redefine what ongoing cardiovascular education means to the contemporary practicing cardiologist in a way that is relevant to improving the care of actual patients,” said Dr. Bhatt, who chairs the ACC Accreditation Oversight Committee.

“There needs to be an agile, personalized, convenient, and effective system to assist practitioners to stay current with new knowledge and demonstrate the necessary competencies,” Harlan Krumholz, MD, said in an email.

“There is a deep sense in the profession that the current approaches do not meet the needs of clinicians or society,” said Dr. Krumholz, Yale School of Medicine, New Haven, Conn., who has sat on the ABIM board of directors.

“This effort, which now will create competition, has the potential to spark innovation,” he said. “The key is that any approach needs to ask the question, ‘Is the cost and effort producing benefit for patients and society?’ If it is not, we have not found the right system.”

In a statement in response to the new development, ABIM said it plans to continue “offering and administering” its existing MOC programs across all specialties.

“Any physician choosing to maintain their ABIM certification in these disciplines will continue to have a pathway with ABIM to do so,” it says. “Questions about the cardiovascular organizations’ announcement and how it may affect individual physicians are best answered by those organizations.”

The process of approving the heart societies’ application to ABMS “is expected to take several months,” their announcement states. If approval is granted, “it will then take several additional months before initial certification and continuous certification and competency programs would begin.”

Medscape provides educational content including MOC. Medscape’s editorial content, including news and features, is developed independently of the educational content available on Medscape.

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

What if cardiology were no longer an internal medicine subspecialty? Four leading cardiology societies have announced plans to create a new certification process that is independent of the American Board of Internal Medicine maintenance of certification (MOC) system.

As envisioned, the new “independent, self-governed” entity would supplant the ABIM’s long-standing and widely criticized MOC system and establish cardiology as its own specialty with its own subspecialties. Long in coming, it is only the latest response to many in the field who for years have charged that the MOC system is needlessly burdensome and expensive.

“It’s time to have a dedicated cardiovascular medicine board of our own,” said B. Hadley Wilson, MD, in the group’s announcement. “Cardiology is a distinct medical specialty, and physicians want and deserve a clinical competency and continuous certification program that is meaningful to their practice and patients.”

Hadley Wilson, Sanger Heart & Vascular Institute Vascular Kenilworth, Charlotte, N.C., is president of the American College of Cardiology, one of the four societies spearheading the initiative along with the Heart Failure Society of America, the Heart Rhythm Society, and the Society for Cardiovascular Angiography & Interventions.

Their Sept. 21 statement says that the consortium will apply to the American Board of Medical Specialties to request an independent cardiology board that follows a “new competency-based approach to continuous certification – one that harnesses the knowledge, skills, and attitudes required to sustain professional excellence and care for cardiovascular patients effectively.”

It continues, “The new board requirements will de-emphasize timed, high stakes performance exams in the continuous certification process and instead will focus on learning assessments to identify gaps in current knowledge or skills.”

“The new board’s focus on competence in the pursuit of continuous certification is a needed paradigm shift for the field,” states HFSA President John R. Teerlink, MD, University of California, San Francisco, and the San Francisco VA Medical Center, in the announcement.

“I commend these professional cardiovascular societies for taking on this important challenge,” Deepak L. Bhatt, MD, MPH, Mount Sinai Hospital and Icahn School of Medicine at Mount Sinai, New York City, told this news organization by email.

“This is an incredible opportunity to redefine what ongoing cardiovascular education means to the contemporary practicing cardiologist in a way that is relevant to improving the care of actual patients,” said Dr. Bhatt, who chairs the ACC Accreditation Oversight Committee.

“There needs to be an agile, personalized, convenient, and effective system to assist practitioners to stay current with new knowledge and demonstrate the necessary competencies,” Harlan Krumholz, MD, said in an email.

“There is a deep sense in the profession that the current approaches do not meet the needs of clinicians or society,” said Dr. Krumholz, Yale School of Medicine, New Haven, Conn., who has sat on the ABIM board of directors.

“This effort, which now will create competition, has the potential to spark innovation,” he said. “The key is that any approach needs to ask the question, ‘Is the cost and effort producing benefit for patients and society?’ If it is not, we have not found the right system.”

In a statement in response to the new development, ABIM said it plans to continue “offering and administering” its existing MOC programs across all specialties.

“Any physician choosing to maintain their ABIM certification in these disciplines will continue to have a pathway with ABIM to do so,” it says. “Questions about the cardiovascular organizations’ announcement and how it may affect individual physicians are best answered by those organizations.”

The process of approving the heart societies’ application to ABMS “is expected to take several months,” their announcement states. If approval is granted, “it will then take several additional months before initial certification and continuous certification and competency programs would begin.”

Medscape provides educational content including MOC. Medscape’s editorial content, including news and features, is developed independently of the educational content available on Medscape.

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

What if cardiology were no longer an internal medicine subspecialty? Four leading cardiology societies have announced plans to create a new certification process that is independent of the American Board of Internal Medicine maintenance of certification (MOC) system.

As envisioned, the new “independent, self-governed” entity would supplant the ABIM’s long-standing and widely criticized MOC system and establish cardiology as its own specialty with its own subspecialties. Long in coming, it is only the latest response to many in the field who for years have charged that the MOC system is needlessly burdensome and expensive.

“It’s time to have a dedicated cardiovascular medicine board of our own,” said B. Hadley Wilson, MD, in the group’s announcement. “Cardiology is a distinct medical specialty, and physicians want and deserve a clinical competency and continuous certification program that is meaningful to their practice and patients.”

Hadley Wilson, Sanger Heart & Vascular Institute Vascular Kenilworth, Charlotte, N.C., is president of the American College of Cardiology, one of the four societies spearheading the initiative along with the Heart Failure Society of America, the Heart Rhythm Society, and the Society for Cardiovascular Angiography & Interventions.

Their Sept. 21 statement says that the consortium will apply to the American Board of Medical Specialties to request an independent cardiology board that follows a “new competency-based approach to continuous certification – one that harnesses the knowledge, skills, and attitudes required to sustain professional excellence and care for cardiovascular patients effectively.”

It continues, “The new board requirements will de-emphasize timed, high stakes performance exams in the continuous certification process and instead will focus on learning assessments to identify gaps in current knowledge or skills.”

“The new board’s focus on competence in the pursuit of continuous certification is a needed paradigm shift for the field,” states HFSA President John R. Teerlink, MD, University of California, San Francisco, and the San Francisco VA Medical Center, in the announcement.

“I commend these professional cardiovascular societies for taking on this important challenge,” Deepak L. Bhatt, MD, MPH, Mount Sinai Hospital and Icahn School of Medicine at Mount Sinai, New York City, told this news organization by email.

“This is an incredible opportunity to redefine what ongoing cardiovascular education means to the contemporary practicing cardiologist in a way that is relevant to improving the care of actual patients,” said Dr. Bhatt, who chairs the ACC Accreditation Oversight Committee.

“There needs to be an agile, personalized, convenient, and effective system to assist practitioners to stay current with new knowledge and demonstrate the necessary competencies,” Harlan Krumholz, MD, said in an email.

“There is a deep sense in the profession that the current approaches do not meet the needs of clinicians or society,” said Dr. Krumholz, Yale School of Medicine, New Haven, Conn., who has sat on the ABIM board of directors.

“This effort, which now will create competition, has the potential to spark innovation,” he said. “The key is that any approach needs to ask the question, ‘Is the cost and effort producing benefit for patients and society?’ If it is not, we have not found the right system.”

In a statement in response to the new development, ABIM said it plans to continue “offering and administering” its existing MOC programs across all specialties.

“Any physician choosing to maintain their ABIM certification in these disciplines will continue to have a pathway with ABIM to do so,” it says. “Questions about the cardiovascular organizations’ announcement and how it may affect individual physicians are best answered by those organizations.”

The process of approving the heart societies’ application to ABMS “is expected to take several months,” their announcement states. If approval is granted, “it will then take several additional months before initial certification and continuous certification and competency programs would begin.”

Medscape provides educational content including MOC. Medscape’s editorial content, including news and features, is developed independently of the educational content available on Medscape.

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

Successful catheter ablation in a recent study may have helped alleviate anxiety or depression in patients with atrial fibrillation (AFib) who had initially tested high for such psychological distress.

The finding, said the researchers, may point to an overlooked potential benefit of ablation that can be discussed with patients considering whether to have the procedure.

Importantly, the 100 adults with symptomatic paroxysmal or persistent AFib in the randomized trial weren’t blinded to treatment assignment, which was either ablation or continued medical therapy.

That leaves open the possibility that psychological distress improved in the ablation group not from any unique effect of ablation itself but because patients expected to benefit from the procedure.

The investigators acknowledged that their trial, called REMEDIAL, can’t rule out a placebo effect as part of the observed benefit. Indeed, studies suggest that there is a substantial placebo component of AFib ablation – which, notably, is usually done to make patients feel better.

But the current findings are more consistent with the conventional view that patients feel better primarily because ablation reduces the AFib causing their symptoms, the group said.

Psychological stress in the study started to fall early after the procedure and continued to decline consistently over the next 6 months (P = .006) and 12 months (P = .005), not a typical pattern for placebo, they wrote.

Moreover, the mental health benefits “correlated very strongly” with less recurrent AFib, reduced AFib burden, and withdrawal of beta-blockers and antiarrhythmic agents, outcomes that might be expected from ablation, said Jonathan M. Kalman, MBBS, PhD.

“Of course, I cannot say there is no placebo effect from having had the procedure, and maybe that something to consider,” but it’s probably not the main driver of benefit, he said in an interview. The relationship between successful AFib ablation “and improvements in physical and now mental health is overwhelming.”

Dr. Kalman, who is affiliated with Royal Melbourne Hospital, is senior author on the study, published in JAMA.

The findings add to “strong, reproducible evidence that ablation is the best way to tackle rhythm control in [AFib] populations” regardless of age, mental health status, or AFib burden, said Auroa Badin, MD, who wasn’t involved in REMEDIAL but has studied the psychological effects of arrhythmia ablation.

For example, there is “very good evidence” from CABANA and other trials that AFib ablation “considerably improves quality of life,” Dr. Badin, of OhioHealth Heart & Vascular Physicians, Columbus, said in an interview. The current study “just emphasizes that there’s also a psychological effect.”

Some of that response could be a placebo or even a nocebo effect. Most of the patients assigned to the medical arm had already been on medications that failed at rhythm control. And their management in the trial, he said, “even if you optimize it, was still drug therapy.”

Patients in the control group, therefore, could have been “disappointed” at the prospect of continued ineffective therapy in a way that influenced their outcomes. “That is another confounding factor,” Dr. Badin said.

But if the psychological results of ablation in the trial were predominantly a placebo effect, early differences in psychological test scores would not have persisted for long, certainly not for a year, he observed. Moreover, the ablation group had better test scores at 12 months than at 6 months, “indicating a likelihood of improvement over time.”

Differences between the groups would probably have been less pronounced if the control group had received a sham procedure, Dr. Badin proposed. That would potentially differentiate ablation’s clinical and placebo contributions to the outcomes.

Still, he said, any observed placebo effect in a sham-controlled trial would probably have been limited. “I think it still would have been a positive trial. It may not show the same difference, but I don’t think you would have a neutral trial just by doing a sham.”

REMEDIAL has “good data,” and its conclusions about ablation’s potential psychological benefits are “reasonable” and worth bringing up when discussing the procedure with patients, Dr. Badin said.

Indeed, psychological distress is “important and often overlooked” in patients with AFib, Dr. Kalman observed. “The dominant indication for atrial fibrillation ablation is symptomatic impact on quality of life. We should think about that broadly, about not just the physical symptoms but the impact on their mental health.”

The trial was conducted at two centers in Australia. It enrolled patients, one-third of whom were women, who were on medical management for AFib. Patients receiving treatment for severe depression were excluded. The included patients were randomly assigned to undergo catheter ablation or to continue on closely managed rhythm-control medication, with cardioversion as indicated.

Psychological distress was measured at baseline and throughout follow-up by a battery of self-administered, validated questionnaires. Baseline test scores for the two groups were similar.

Recurrence and burden of AFib were tracked primarily by daily KardiaMobile (AliveCor) ECG monitoring. A few patients were followed using already implanted cardiac rhythm devices or by 24-hour Holter monitor every 3 months, Dr. Kalman said.

Composite scores on the Hospital Anxiety and Depression Scale (HADS) at 12 months, the primary endpoint, were 7.6 and 11.8 (P = .005) for the ablation and medical groups, respectively. They were 8.2 and 11.9 (P = .006), respectively, at 6 months.

The prevalence of severe psychological distress, defined as a HADS score greater than 15, was lower in the ablation group at 6 months (14.2% vs. 34%; P = .02) and 12 months (10.2% vs. 31.9%; P = .01).

Scores on the Beck Depression Inventory–II questionnaire were also consistently and significantly better for the ablation group at 6 and at 12 months (P = .01 for both).

Monitoring picked up AFib in 47% of the ablation group and 96% of the control group (P < .001) over 12 months. Their median AFib burdens were 0% (interquartile range, 0%-3.2%) and 15.5% (IQR, 1%-46%), respectively (P < .001).

Antiarrhythmic drug use fell from a baseline of 90% to 53% 3 months after ablation and 30% at 12 months (P = .003). Use of these drugs in the control group was 89% at baseline and remained essentially the same, 85%, at 12 months.

AFib symptom severity scores were significantly lower after ablation, compared with medical management at 3, 6, and 12 months.

The observed effect of ablation on psychological stress “clearly speaks in favor of effective rhythm control, and moreover catheter ablation” and is a “novel argument” in support of catheter ablation for AFib, Julia Lurz, MD, Heart Center Leipzig (Germany) at University Leipzig, and Karl-Heinz Ladwig, MD, PhD, Technical University Munich (Germany), wrote in an editorial accompanying publication of REMEDIAL.

But the findings also “raise the question of why rhythm control was so ineffective in the medical treatment group,” they wrote.

They agreed that the randomization process itself may have had its own psychological effects. “Potential disappointment” in the medical group and “high expectations” among patients who received ablation “could have fueled the success of catheter ablation” with respect to mental health endpoints.

Dr. Kalman reported receiving grants from the National Health and Medical Research Council of Australia, Medtronic, Mooney, and Biosense Webster. Dr. Badin, Dr. Lurz, and Dr. Ladwig reported no conflicts of interest.

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

Successful catheter ablation in a recent study may have helped alleviate anxiety or depression in patients with atrial fibrillation (AFib) who had initially tested high for such psychological distress.

The finding, said the researchers, may point to an overlooked potential benefit of ablation that can be discussed with patients considering whether to have the procedure.

Importantly, the 100 adults with symptomatic paroxysmal or persistent AFib in the randomized trial weren’t blinded to treatment assignment, which was either ablation or continued medical therapy.

That leaves open the possibility that psychological distress improved in the ablation group not from any unique effect of ablation itself but because patients expected to benefit from the procedure.

The investigators acknowledged that their trial, called REMEDIAL, can’t rule out a placebo effect as part of the observed benefit. Indeed, studies suggest that there is a substantial placebo component of AFib ablation – which, notably, is usually done to make patients feel better.

But the current findings are more consistent with the conventional view that patients feel better primarily because ablation reduces the AFib causing their symptoms, the group said.

Psychological stress in the study started to fall early after the procedure and continued to decline consistently over the next 6 months (P = .006) and 12 months (P = .005), not a typical pattern for placebo, they wrote.

Moreover, the mental health benefits “correlated very strongly” with less recurrent AFib, reduced AFib burden, and withdrawal of beta-blockers and antiarrhythmic agents, outcomes that might be expected from ablation, said Jonathan M. Kalman, MBBS, PhD.

“Of course, I cannot say there is no placebo effect from having had the procedure, and maybe that something to consider,” but it’s probably not the main driver of benefit, he said in an interview. The relationship between successful AFib ablation “and improvements in physical and now mental health is overwhelming.”

Dr. Kalman, who is affiliated with Royal Melbourne Hospital, is senior author on the study, published in JAMA.

The findings add to “strong, reproducible evidence that ablation is the best way to tackle rhythm control in [AFib] populations” regardless of age, mental health status, or AFib burden, said Auroa Badin, MD, who wasn’t involved in REMEDIAL but has studied the psychological effects of arrhythmia ablation.

For example, there is “very good evidence” from CABANA and other trials that AFib ablation “considerably improves quality of life,” Dr. Badin, of OhioHealth Heart & Vascular Physicians, Columbus, said in an interview. The current study “just emphasizes that there’s also a psychological effect.”

Some of that response could be a placebo or even a nocebo effect. Most of the patients assigned to the medical arm had already been on medications that failed at rhythm control. And their management in the trial, he said, “even if you optimize it, was still drug therapy.”

Patients in the control group, therefore, could have been “disappointed” at the prospect of continued ineffective therapy in a way that influenced their outcomes. “That is another confounding factor,” Dr. Badin said.

But if the psychological results of ablation in the trial were predominantly a placebo effect, early differences in psychological test scores would not have persisted for long, certainly not for a year, he observed. Moreover, the ablation group had better test scores at 12 months than at 6 months, “indicating a likelihood of improvement over time.”

Differences between the groups would probably have been less pronounced if the control group had received a sham procedure, Dr. Badin proposed. That would potentially differentiate ablation’s clinical and placebo contributions to the outcomes.

Still, he said, any observed placebo effect in a sham-controlled trial would probably have been limited. “I think it still would have been a positive trial. It may not show the same difference, but I don’t think you would have a neutral trial just by doing a sham.”

REMEDIAL has “good data,” and its conclusions about ablation’s potential psychological benefits are “reasonable” and worth bringing up when discussing the procedure with patients, Dr. Badin said.

Indeed, psychological distress is “important and often overlooked” in patients with AFib, Dr. Kalman observed. “The dominant indication for atrial fibrillation ablation is symptomatic impact on quality of life. We should think about that broadly, about not just the physical symptoms but the impact on their mental health.”

The trial was conducted at two centers in Australia. It enrolled patients, one-third of whom were women, who were on medical management for AFib. Patients receiving treatment for severe depression were excluded. The included patients were randomly assigned to undergo catheter ablation or to continue on closely managed rhythm-control medication, with cardioversion as indicated.

Psychological distress was measured at baseline and throughout follow-up by a battery of self-administered, validated questionnaires. Baseline test scores for the two groups were similar.

Recurrence and burden of AFib were tracked primarily by daily KardiaMobile (AliveCor) ECG monitoring. A few patients were followed using already implanted cardiac rhythm devices or by 24-hour Holter monitor every 3 months, Dr. Kalman said.

Composite scores on the Hospital Anxiety and Depression Scale (HADS) at 12 months, the primary endpoint, were 7.6 and 11.8 (P = .005) for the ablation and medical groups, respectively. They were 8.2 and 11.9 (P = .006), respectively, at 6 months.

The prevalence of severe psychological distress, defined as a HADS score greater than 15, was lower in the ablation group at 6 months (14.2% vs. 34%; P = .02) and 12 months (10.2% vs. 31.9%; P = .01).

Scores on the Beck Depression Inventory–II questionnaire were also consistently and significantly better for the ablation group at 6 and at 12 months (P = .01 for both).

Monitoring picked up AFib in 47% of the ablation group and 96% of the control group (P < .001) over 12 months. Their median AFib burdens were 0% (interquartile range, 0%-3.2%) and 15.5% (IQR, 1%-46%), respectively (P < .001).

Antiarrhythmic drug use fell from a baseline of 90% to 53% 3 months after ablation and 30% at 12 months (P = .003). Use of these drugs in the control group was 89% at baseline and remained essentially the same, 85%, at 12 months.

AFib symptom severity scores were significantly lower after ablation, compared with medical management at 3, 6, and 12 months.

The observed effect of ablation on psychological stress “clearly speaks in favor of effective rhythm control, and moreover catheter ablation” and is a “novel argument” in support of catheter ablation for AFib, Julia Lurz, MD, Heart Center Leipzig (Germany) at University Leipzig, and Karl-Heinz Ladwig, MD, PhD, Technical University Munich (Germany), wrote in an editorial accompanying publication of REMEDIAL.

But the findings also “raise the question of why rhythm control was so ineffective in the medical treatment group,” they wrote.

They agreed that the randomization process itself may have had its own psychological effects. “Potential disappointment” in the medical group and “high expectations” among patients who received ablation “could have fueled the success of catheter ablation” with respect to mental health endpoints.

Dr. Kalman reported receiving grants from the National Health and Medical Research Council of Australia, Medtronic, Mooney, and Biosense Webster. Dr. Badin, Dr. Lurz, and Dr. Ladwig reported no conflicts of interest.

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

Successful catheter ablation in a recent study may have helped alleviate anxiety or depression in patients with atrial fibrillation (AFib) who had initially tested high for such psychological distress.

The finding, said the researchers, may point to an overlooked potential benefit of ablation that can be discussed with patients considering whether to have the procedure.

Importantly, the 100 adults with symptomatic paroxysmal or persistent AFib in the randomized trial weren’t blinded to treatment assignment, which was either ablation or continued medical therapy.

That leaves open the possibility that psychological distress improved in the ablation group not from any unique effect of ablation itself but because patients expected to benefit from the procedure.

The investigators acknowledged that their trial, called REMEDIAL, can’t rule out a placebo effect as part of the observed benefit. Indeed, studies suggest that there is a substantial placebo component of AFib ablation – which, notably, is usually done to make patients feel better.

But the current findings are more consistent with the conventional view that patients feel better primarily because ablation reduces the AFib causing their symptoms, the group said.

Psychological stress in the study started to fall early after the procedure and continued to decline consistently over the next 6 months (P = .006) and 12 months (P = .005), not a typical pattern for placebo, they wrote.

Moreover, the mental health benefits “correlated very strongly” with less recurrent AFib, reduced AFib burden, and withdrawal of beta-blockers and antiarrhythmic agents, outcomes that might be expected from ablation, said Jonathan M. Kalman, MBBS, PhD.

“Of course, I cannot say there is no placebo effect from having had the procedure, and maybe that something to consider,” but it’s probably not the main driver of benefit, he said in an interview. The relationship between successful AFib ablation “and improvements in physical and now mental health is overwhelming.”

Dr. Kalman, who is affiliated with Royal Melbourne Hospital, is senior author on the study, published in JAMA.

The findings add to “strong, reproducible evidence that ablation is the best way to tackle rhythm control in [AFib] populations” regardless of age, mental health status, or AFib burden, said Auroa Badin, MD, who wasn’t involved in REMEDIAL but has studied the psychological effects of arrhythmia ablation.

For example, there is “very good evidence” from CABANA and other trials that AFib ablation “considerably improves quality of life,” Dr. Badin, of OhioHealth Heart & Vascular Physicians, Columbus, said in an interview. The current study “just emphasizes that there’s also a psychological effect.”

Some of that response could be a placebo or even a nocebo effect. Most of the patients assigned to the medical arm had already been on medications that failed at rhythm control. And their management in the trial, he said, “even if you optimize it, was still drug therapy.”

Patients in the control group, therefore, could have been “disappointed” at the prospect of continued ineffective therapy in a way that influenced their outcomes. “That is another confounding factor,” Dr. Badin said.

But if the psychological results of ablation in the trial were predominantly a placebo effect, early differences in psychological test scores would not have persisted for long, certainly not for a year, he observed. Moreover, the ablation group had better test scores at 12 months than at 6 months, “indicating a likelihood of improvement over time.”

Differences between the groups would probably have been less pronounced if the control group had received a sham procedure, Dr. Badin proposed. That would potentially differentiate ablation’s clinical and placebo contributions to the outcomes.

Still, he said, any observed placebo effect in a sham-controlled trial would probably have been limited. “I think it still would have been a positive trial. It may not show the same difference, but I don’t think you would have a neutral trial just by doing a sham.”

REMEDIAL has “good data,” and its conclusions about ablation’s potential psychological benefits are “reasonable” and worth bringing up when discussing the procedure with patients, Dr. Badin said.

Indeed, psychological distress is “important and often overlooked” in patients with AFib, Dr. Kalman observed. “The dominant indication for atrial fibrillation ablation is symptomatic impact on quality of life. We should think about that broadly, about not just the physical symptoms but the impact on their mental health.”

The trial was conducted at two centers in Australia. It enrolled patients, one-third of whom were women, who were on medical management for AFib. Patients receiving treatment for severe depression were excluded. The included patients were randomly assigned to undergo catheter ablation or to continue on closely managed rhythm-control medication, with cardioversion as indicated.

Psychological distress was measured at baseline and throughout follow-up by a battery of self-administered, validated questionnaires. Baseline test scores for the two groups were similar.

Recurrence and burden of AFib were tracked primarily by daily KardiaMobile (AliveCor) ECG monitoring. A few patients were followed using already implanted cardiac rhythm devices or by 24-hour Holter monitor every 3 months, Dr. Kalman said.

Composite scores on the Hospital Anxiety and Depression Scale (HADS) at 12 months, the primary endpoint, were 7.6 and 11.8 (P = .005) for the ablation and medical groups, respectively. They were 8.2 and 11.9 (P = .006), respectively, at 6 months.

The prevalence of severe psychological distress, defined as a HADS score greater than 15, was lower in the ablation group at 6 months (14.2% vs. 34%; P = .02) and 12 months (10.2% vs. 31.9%; P = .01).

Scores on the Beck Depression Inventory–II questionnaire were also consistently and significantly better for the ablation group at 6 and at 12 months (P = .01 for both).

Monitoring picked up AFib in 47% of the ablation group and 96% of the control group (P < .001) over 12 months. Their median AFib burdens were 0% (interquartile range, 0%-3.2%) and 15.5% (IQR, 1%-46%), respectively (P < .001).

Antiarrhythmic drug use fell from a baseline of 90% to 53% 3 months after ablation and 30% at 12 months (P = .003). Use of these drugs in the control group was 89% at baseline and remained essentially the same, 85%, at 12 months.

AFib symptom severity scores were significantly lower after ablation, compared with medical management at 3, 6, and 12 months.

The observed effect of ablation on psychological stress “clearly speaks in favor of effective rhythm control, and moreover catheter ablation” and is a “novel argument” in support of catheter ablation for AFib, Julia Lurz, MD, Heart Center Leipzig (Germany) at University Leipzig, and Karl-Heinz Ladwig, MD, PhD, Technical University Munich (Germany), wrote in an editorial accompanying publication of REMEDIAL.

But the findings also “raise the question of why rhythm control was so ineffective in the medical treatment group,” they wrote.

They agreed that the randomization process itself may have had its own psychological effects. “Potential disappointment” in the medical group and “high expectations” among patients who received ablation “could have fueled the success of catheter ablation” with respect to mental health endpoints.

Dr. Kalman reported receiving grants from the National Health and Medical Research Council of Australia, Medtronic, Mooney, and Biosense Webster. Dr. Badin, Dr. Lurz, and Dr. Ladwig reported no conflicts of interest.

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

A routine role for intravascular imaging (IVI) guidance for percutaneous coronary intervention (PCI) has long been favored by many of the technology’s researchers and enthusiasts. Now evidence from large, randomized trials may be catching up with such aspirations, though not without caveats.

Recently unveiled studies collectively suggest that such IVI guidance, at least for PCI of more challenging lesions, can improve the effectiveness of coronary stent delivery in ways that directly lead to better outcomes.

One way IVI guidance may achieve that, the research suggests, albeit more speculatively, is by cutting risk for stent thrombosis, compared with the risk associated with angiography-only PCI.

The new studies, two large randomized IVI trials plus a meta-analysis of 20 such studies, were presented at the annual congress of the European Society of Cardiology.

In one, called ILUMIEN-4, PCI guided by optical coherence tomography (OCT) was associated with fewer procedural complications and better acute results – that is, larger post-PCI minimum stent area (MSA) – than in angiography-only procedures (P < .001). Poststenting MSA, an established predictor of clinical outcomes, was the primary imaging endpoint of the trial with almost 2,500 patients.

Yet the OCT group’s greater post-PCI MSA did not translate to reduced risk for the primary clinical endpoint of 2-year target-vessel failure. Among secondary endpoints, however, stent thrombosis at some point during the follow-up was 64% less likely (P = .02) with OCT guidance than angiography-only PCI.

ILUMIEN-4, despite its neutral clinical result, still “strongly advocates” for PCI guidance by OCT, at least among patients like those in the trial, said principal investigator Ziad Ali, MD, DPhil. He based that largely on the strategy’s greater postprocedure lumen areas in the trials, which are among “the strongest independent predictors for long term outcomes,” said Dr. Ali, of St. Francis Hospital & Heart Center, Roslyn, N.Y., at a press conference on IVI trials during the ESC Congress.
 

Selected complex lesion type

In contrast, the OCTOBER trial, presented at the sessions back to back with ILUMIEN-4, saw OCT guidance lead to better clinical outcomes than angiography alone after PCI of bifurcation lesions, which normally can be a special challenge for operators.

In the trial, which entered about 1,200 patients with such complex lesions, the 2-year risk for major adverse cardiac events (MACE) fell 60% after OCT-guided PCI, compared with angiography-only procedures (P = .035).

The finding is novel for showing that OCT guidance in bifurcation PCI can make a significant clinical difference, said OCTOBER investigator Niels R. Holm, MD, at the same media presentation on IVI trials.

“Multiple studies have shown that OCT allows for optimization of bifurcation PCI, and our results confirm that such optimization may improve the patient’s prognosis,” said Dr. Holm of Aarhus (Denmark) University Hospital.

ILUMIEN-4 and OCTOBER, both of which prespecified the Xience (Abbott) everolimus-eluting stent for the procedures, were published in the New England Journal of Medicine in tandem with their respective presentations at the ESC sessions.
 

Covering the spectrum

A meta-analysis presented at the same ESC session compared IVI using either OCT or intravascular ultrasound (IVUS) with angiography-only PCI across 20 randomized trials with a total of more than 12,000 patients.

Significant outcomes for IVI guidance versus angiography alone included a 31% drop in risk for target-lesion failure, the primary endpoint. And this study, as well, showed a steep 52% reduction in risk for in-stent thrombosis with the IVI-guided approach.

Stone_Gregg_W_NYC_web.jpg

And “for the first time” in IVI studies, “we demonstrated reductions in all-myocardial-infarction and all-cause death, the latter by 25%,” Gregg Stone, MD, Icahn School of Medicine at Mount Sinai, New York, said in presenting the meta-analysis. Dr. Stone is also the ILUMIEN-4 study chairperson.

“The routine use of OCT or IVUS to guide most PCI procedures will substantially improve patient event-free survival,” he predicted, “enhancing both the long-term safety and effectiveness of the procedure.”

Dr. Stone said that IVI guidance “should be standard of care, if not in all patients, then in most patients.” Part of the rationale: PCI is unlikely to be improved much further by incremental gains in drug-eluting stent design. “That technology has almost plateaued.” But there’s yet room for “substantially improved outcomes” from adjunctive treatments and techniques such as IVI guidance.

The 20 studies in the meta-analysis encompassed an array of patients and lesions both complex and noncomplex, Dr. Stone observed, including bifurcation lesions, chronic total occlusions, left-main coronary stenoses, and MI culprit lesions.

“They really covered the spectrum of PCI,” he said. “I’m not recommending that intravascular imaging be used in every single case. But I do think it should be used in the majority of patients” and be standard of care for PCI in left-main lesions and “complex coronary disease, high-risk patients, and high-risk lesions.”
 

Unique advantage

The IVI-guidance groups in both ILUMIEN-4 and the meta-analysis showed a significant drop in risk for stent thrombosis – that is, abrupt thrombotic vessel closure, which typically occurs in 1% or fewer PCI cases but can trigger an MI and pose a mortality risk up to 45%.

Those risk reductions are consistent with a unique IVI advantage: the ability to guide optimization of stent deployments. When formally presenting ILUMIEN-4 at the ESC sessions, Ali observed that IVUS and OCT imaging allows operators to identify and often correct less-than-ideal results of an initial stent delivery – such as residual gaps between stent struts and vessel wall – that may encroach on the lumen, with possible clinical consequences.

Such imaging, said Dr. Ali, “lets you identify tissue protrusions, malappositions, dissections, and untreated reference-segment disease” that may potentially trigger thrombosis. That makes a strong argument for giving IVI guidance a more common, perhaps even routine role in PCI procedures.
 

Selling routine IVI-guided PCI in practice

“I think the study results are quite clear,” said Deepak L. Bhatt, MD, MPH, as session comoderator following the OCTOBER presentation. “The challenge, though, will be convincing the average interventional cardiologist worldwide that it was specifically the imaging and not the extra care that the patient getting OCT also inherently receives.”

Bhatt_Deepak_web.jpg

Did OCT’s better trial outcomes stem from IVI itself or from greater operator attentiveness to procedural results – such as, for example, more high-pressure expansions to optimize stent placement, “the sort of thing that tends to occur when invasive imaging is added on to just plain old angiography?” Dr. Bhatt asked of Lene N. Andreasen, MD, who had just presented the OCTOBER trial. “There’s no way of uncoupling the two things.”

What can be said, “at this point, to convince interventional cardiologists that the extra time, energy, expense, is truly indicated,” that the data are “sufficient to change global practice?” asked Dr. Bhatt, Mount Sinai Hospital and Icahn School of Medicine at Mount Sinai.

That remains an open question,” acknowledged Dr. Andreasen of Aarhus University Hospital. The best argument in favor of selective IVI-guided PCI is that “we actually see a clinical benefit” in the trials. “But of course, it comes with a cost. It comes with longer procedures and more contrast.” How clinical practice responds to the new data remains to be seen, she proposed.
 

ILUMIEN-4 and OCTOBER in detail

Conducted at 80 centers in 18 countries, ILUMIEN-4 randomly assigned patients with diabetes or complex coronary lesions to undergo PCI guided by OCT or using standard angiography only, 1,233 and 1,254 patients, respectively.

Post-PCI MSA averaged 5.72 mm² with OCT guidance and 5.36 mm² in the angiography-only group (P < .001).

Their rates of target-vessel failure at 2 years were not significantly different at 7.4% and 8.2%, respectively. The 2-year composite endpoint included cardiac death, target vessel–related MI, or ischemia-driven target-vessel revascularization.

Definite or probable stent thrombosis was observed over 2 years in 0.5% of the OCT group and 1.4% of those with angiography-only PCI (hazard ratio, 0.36; 95% confidence interval, 0.14-0.91; P = .02) favoring OCT.

The OCTOBER trial, conducted at 38 centers in Europe, entered 1201 patients with stable angina or acute coronary syndromes and angiographically identified complex bifurcation lesions. They involved the left-main coronary artery in about one-fifth of cases.

Patients were randomly assigned to bifurcation PCI guided by OCT or under standard angiography, 600 and 601 patients, respectively. Rates for procedure-related complications were similar at 6.8% and 5.7%, respectively.

Over a median of 2 years, 10.1% of the OCT group and 14.1% of angiography-only patients developed a MACE event, including cardiac death, target-lesion MI, or ischemia-driven target-lesion revascularization. The adjusted HR was 0.71 (95% CI, 0.51-0.98; P = .035) in favor of OCT.
 

Meta-analysis, trials to date

The meta-analysis presented by Dr. Stone included ILUMIEN-4, OCTOBER, and 18 earlier outcomes trials comparing PCI guided by IVI, either OCT or IVUS, and angiography-only PCI. It covered 12,428 patients with chronic or acute coronary disease and followed them a mean of 26 months; the longest follow-up was 5 years. They were assigned to IVI-guided or angiography-only PCI, 7,038 and 5,390 patients, respectively.

Dr. Stone and colleagues conducted a network meta-analysis of the 20 studies, that is, a combined analysis that allowed both direct and indirect comparisons of standard angiography-only procedures to each of the other studied comparator interventions including OCT, IVUS, and either OCT or IVUS. They then derived network-estimate odds ratios for IVI-guided PCI vs angiography-only procedures.

165089_table.PNG

“Hopefully, this will impact the guidelines,” Dr. Stone said of the meta-analysis. Procedures guided by IVI might become more common in clinical practice if they were to garner a Class-I guideline recommendation, the strongest recommendation category.

“That would make a difference, but we’d also need to work to remove impediments to increasing intravascular imaging guidance” for most patients undergoing PCI, he said, referring to challenges in obtaining reimbursement for IVI-guided PCI and training enough operators to handle the projected demand.

ILUMIEN-4 was funded by Abbott. OCTOBER was supported by grants from Abbott Vascular, St. Jude Medical, and Aarhus University. The network meta-analysis received statistical support from Abbott. Dr. Ali disclosed institutional grant support from Abbott, Abiomed, Acist Medical, Boston Scientific, Cardiovascular Systems, Medtronic, the National Institutes of Health, Opsens Medical, Philips, and Teleflex; consulting fees from Astra Zeneca, Philips, Shockwave; and holding equity in Elucid, Spectrawave, Shockwave, and VitalConnect. Dr. Holm and Dr. Bhatt reported numerous conflicts of interest. Dr. Andreasen disclosed no relevant financial relationships.

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

A routine role for intravascular imaging (IVI) guidance for percutaneous coronary intervention (PCI) has long been favored by many of the technology’s researchers and enthusiasts. Now evidence from large, randomized trials may be catching up with such aspirations, though not without caveats.

Recently unveiled studies collectively suggest that such IVI guidance, at least for PCI of more challenging lesions, can improve the effectiveness of coronary stent delivery in ways that directly lead to better outcomes.

One way IVI guidance may achieve that, the research suggests, albeit more speculatively, is by cutting risk for stent thrombosis, compared with the risk associated with angiography-only PCI.

The new studies, two large randomized IVI trials plus a meta-analysis of 20 such studies, were presented at the annual congress of the European Society of Cardiology.

In one, called ILUMIEN-4, PCI guided by optical coherence tomography (OCT) was associated with fewer procedural complications and better acute results – that is, larger post-PCI minimum stent area (MSA) – than in angiography-only procedures (P < .001). Poststenting MSA, an established predictor of clinical outcomes, was the primary imaging endpoint of the trial with almost 2,500 patients.

Yet the OCT group’s greater post-PCI MSA did not translate to reduced risk for the primary clinical endpoint of 2-year target-vessel failure. Among secondary endpoints, however, stent thrombosis at some point during the follow-up was 64% less likely (P = .02) with OCT guidance than angiography-only PCI.

ILUMIEN-4, despite its neutral clinical result, still “strongly advocates” for PCI guidance by OCT, at least among patients like those in the trial, said principal investigator Ziad Ali, MD, DPhil. He based that largely on the strategy’s greater postprocedure lumen areas in the trials, which are among “the strongest independent predictors for long term outcomes,” said Dr. Ali, of St. Francis Hospital & Heart Center, Roslyn, N.Y., at a press conference on IVI trials during the ESC Congress.
 

Selected complex lesion type

In contrast, the OCTOBER trial, presented at the sessions back to back with ILUMIEN-4, saw OCT guidance lead to better clinical outcomes than angiography alone after PCI of bifurcation lesions, which normally can be a special challenge for operators.

In the trial, which entered about 1,200 patients with such complex lesions, the 2-year risk for major adverse cardiac events (MACE) fell 60% after OCT-guided PCI, compared with angiography-only procedures (P = .035).

The finding is novel for showing that OCT guidance in bifurcation PCI can make a significant clinical difference, said OCTOBER investigator Niels R. Holm, MD, at the same media presentation on IVI trials.

“Multiple studies have shown that OCT allows for optimization of bifurcation PCI, and our results confirm that such optimization may improve the patient’s prognosis,” said Dr. Holm of Aarhus (Denmark) University Hospital.

ILUMIEN-4 and OCTOBER, both of which prespecified the Xience (Abbott) everolimus-eluting stent for the procedures, were published in the New England Journal of Medicine in tandem with their respective presentations at the ESC sessions.
 

Covering the spectrum

A meta-analysis presented at the same ESC session compared IVI using either OCT or intravascular ultrasound (IVUS) with angiography-only PCI across 20 randomized trials with a total of more than 12,000 patients.

Significant outcomes for IVI guidance versus angiography alone included a 31% drop in risk for target-lesion failure, the primary endpoint. And this study, as well, showed a steep 52% reduction in risk for in-stent thrombosis with the IVI-guided approach.

Stone_Gregg_W_NYC_web.jpg

And “for the first time” in IVI studies, “we demonstrated reductions in all-myocardial-infarction and all-cause death, the latter by 25%,” Gregg Stone, MD, Icahn School of Medicine at Mount Sinai, New York, said in presenting the meta-analysis. Dr. Stone is also the ILUMIEN-4 study chairperson.

“The routine use of OCT or IVUS to guide most PCI procedures will substantially improve patient event-free survival,” he predicted, “enhancing both the long-term safety and effectiveness of the procedure.”

Dr. Stone said that IVI guidance “should be standard of care, if not in all patients, then in most patients.” Part of the rationale: PCI is unlikely to be improved much further by incremental gains in drug-eluting stent design. “That technology has almost plateaued.” But there’s yet room for “substantially improved outcomes” from adjunctive treatments and techniques such as IVI guidance.

The 20 studies in the meta-analysis encompassed an array of patients and lesions both complex and noncomplex, Dr. Stone observed, including bifurcation lesions, chronic total occlusions, left-main coronary stenoses, and MI culprit lesions.

“They really covered the spectrum of PCI,” he said. “I’m not recommending that intravascular imaging be used in every single case. But I do think it should be used in the majority of patients” and be standard of care for PCI in left-main lesions and “complex coronary disease, high-risk patients, and high-risk lesions.”
 

Unique advantage

The IVI-guidance groups in both ILUMIEN-4 and the meta-analysis showed a significant drop in risk for stent thrombosis – that is, abrupt thrombotic vessel closure, which typically occurs in 1% or fewer PCI cases but can trigger an MI and pose a mortality risk up to 45%.

Those risk reductions are consistent with a unique IVI advantage: the ability to guide optimization of stent deployments. When formally presenting ILUMIEN-4 at the ESC sessions, Ali observed that IVUS and OCT imaging allows operators to identify and often correct less-than-ideal results of an initial stent delivery – such as residual gaps between stent struts and vessel wall – that may encroach on the lumen, with possible clinical consequences.

Such imaging, said Dr. Ali, “lets you identify tissue protrusions, malappositions, dissections, and untreated reference-segment disease” that may potentially trigger thrombosis. That makes a strong argument for giving IVI guidance a more common, perhaps even routine role in PCI procedures.
 

Selling routine IVI-guided PCI in practice

“I think the study results are quite clear,” said Deepak L. Bhatt, MD, MPH, as session comoderator following the OCTOBER presentation. “The challenge, though, will be convincing the average interventional cardiologist worldwide that it was specifically the imaging and not the extra care that the patient getting OCT also inherently receives.”

Bhatt_Deepak_web.jpg

Did OCT’s better trial outcomes stem from IVI itself or from greater operator attentiveness to procedural results – such as, for example, more high-pressure expansions to optimize stent placement, “the sort of thing that tends to occur when invasive imaging is added on to just plain old angiography?” Dr. Bhatt asked of Lene N. Andreasen, MD, who had just presented the OCTOBER trial. “There’s no way of uncoupling the two things.”

What can be said, “at this point, to convince interventional cardiologists that the extra time, energy, expense, is truly indicated,” that the data are “sufficient to change global practice?” asked Dr. Bhatt, Mount Sinai Hospital and Icahn School of Medicine at Mount Sinai.

That remains an open question,” acknowledged Dr. Andreasen of Aarhus University Hospital. The best argument in favor of selective IVI-guided PCI is that “we actually see a clinical benefit” in the trials. “But of course, it comes with a cost. It comes with longer procedures and more contrast.” How clinical practice responds to the new data remains to be seen, she proposed.
 

ILUMIEN-4 and OCTOBER in detail

Conducted at 80 centers in 18 countries, ILUMIEN-4 randomly assigned patients with diabetes or complex coronary lesions to undergo PCI guided by OCT or using standard angiography only, 1,233 and 1,254 patients, respectively.

Post-PCI MSA averaged 5.72 mm² with OCT guidance and 5.36 mm² in the angiography-only group (P < .001).

Their rates of target-vessel failure at 2 years were not significantly different at 7.4% and 8.2%, respectively. The 2-year composite endpoint included cardiac death, target vessel–related MI, or ischemia-driven target-vessel revascularization.

Definite or probable stent thrombosis was observed over 2 years in 0.5% of the OCT group and 1.4% of those with angiography-only PCI (hazard ratio, 0.36; 95% confidence interval, 0.14-0.91; P = .02) favoring OCT.

The OCTOBER trial, conducted at 38 centers in Europe, entered 1201 patients with stable angina or acute coronary syndromes and angiographically identified complex bifurcation lesions. They involved the left-main coronary artery in about one-fifth of cases.

Patients were randomly assigned to bifurcation PCI guided by OCT or under standard angiography, 600 and 601 patients, respectively. Rates for procedure-related complications were similar at 6.8% and 5.7%, respectively.

Over a median of 2 years, 10.1% of the OCT group and 14.1% of angiography-only patients developed a MACE event, including cardiac death, target-lesion MI, or ischemia-driven target-lesion revascularization. The adjusted HR was 0.71 (95% CI, 0.51-0.98; P = .035) in favor of OCT.
 

Meta-analysis, trials to date

The meta-analysis presented by Dr. Stone included ILUMIEN-4, OCTOBER, and 18 earlier outcomes trials comparing PCI guided by IVI, either OCT or IVUS, and angiography-only PCI. It covered 12,428 patients with chronic or acute coronary disease and followed them a mean of 26 months; the longest follow-up was 5 years. They were assigned to IVI-guided or angiography-only PCI, 7,038 and 5,390 patients, respectively.

Dr. Stone and colleagues conducted a network meta-analysis of the 20 studies, that is, a combined analysis that allowed both direct and indirect comparisons of standard angiography-only procedures to each of the other studied comparator interventions including OCT, IVUS, and either OCT or IVUS. They then derived network-estimate odds ratios for IVI-guided PCI vs angiography-only procedures.

165089_table.PNG

“Hopefully, this will impact the guidelines,” Dr. Stone said of the meta-analysis. Procedures guided by IVI might become more common in clinical practice if they were to garner a Class-I guideline recommendation, the strongest recommendation category.

“That would make a difference, but we’d also need to work to remove impediments to increasing intravascular imaging guidance” for most patients undergoing PCI, he said, referring to challenges in obtaining reimbursement for IVI-guided PCI and training enough operators to handle the projected demand.

ILUMIEN-4 was funded by Abbott. OCTOBER was supported by grants from Abbott Vascular, St. Jude Medical, and Aarhus University. The network meta-analysis received statistical support from Abbott. Dr. Ali disclosed institutional grant support from Abbott, Abiomed, Acist Medical, Boston Scientific, Cardiovascular Systems, Medtronic, the National Institutes of Health, Opsens Medical, Philips, and Teleflex; consulting fees from Astra Zeneca, Philips, Shockwave; and holding equity in Elucid, Spectrawave, Shockwave, and VitalConnect. Dr. Holm and Dr. Bhatt reported numerous conflicts of interest. Dr. Andreasen disclosed no relevant financial relationships.

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

A routine role for intravascular imaging (IVI) guidance for percutaneous coronary intervention (PCI) has long been favored by many of the technology’s researchers and enthusiasts. Now evidence from large, randomized trials may be catching up with such aspirations, though not without caveats.

Recently unveiled studies collectively suggest that such IVI guidance, at least for PCI of more challenging lesions, can improve the effectiveness of coronary stent delivery in ways that directly lead to better outcomes.

One way IVI guidance may achieve that, the research suggests, albeit more speculatively, is by cutting risk for stent thrombosis, compared with the risk associated with angiography-only PCI.

The new studies, two large randomized IVI trials plus a meta-analysis of 20 such studies, were presented at the annual congress of the European Society of Cardiology.

In one, called ILUMIEN-4, PCI guided by optical coherence tomography (OCT) was associated with fewer procedural complications and better acute results – that is, larger post-PCI minimum stent area (MSA) – than in angiography-only procedures (P < .001). Poststenting MSA, an established predictor of clinical outcomes, was the primary imaging endpoint of the trial with almost 2,500 patients.

Yet the OCT group’s greater post-PCI MSA did not translate to reduced risk for the primary clinical endpoint of 2-year target-vessel failure. Among secondary endpoints, however, stent thrombosis at some point during the follow-up was 64% less likely (P = .02) with OCT guidance than angiography-only PCI.

ILUMIEN-4, despite its neutral clinical result, still “strongly advocates” for PCI guidance by OCT, at least among patients like those in the trial, said principal investigator Ziad Ali, MD, DPhil. He based that largely on the strategy’s greater postprocedure lumen areas in the trials, which are among “the strongest independent predictors for long term outcomes,” said Dr. Ali, of St. Francis Hospital & Heart Center, Roslyn, N.Y., at a press conference on IVI trials during the ESC Congress.
 

Selected complex lesion type

In contrast, the OCTOBER trial, presented at the sessions back to back with ILUMIEN-4, saw OCT guidance lead to better clinical outcomes than angiography alone after PCI of bifurcation lesions, which normally can be a special challenge for operators.

In the trial, which entered about 1,200 patients with such complex lesions, the 2-year risk for major adverse cardiac events (MACE) fell 60% after OCT-guided PCI, compared with angiography-only procedures (P = .035).

The finding is novel for showing that OCT guidance in bifurcation PCI can make a significant clinical difference, said OCTOBER investigator Niels R. Holm, MD, at the same media presentation on IVI trials.

“Multiple studies have shown that OCT allows for optimization of bifurcation PCI, and our results confirm that such optimization may improve the patient’s prognosis,” said Dr. Holm of Aarhus (Denmark) University Hospital.

ILUMIEN-4 and OCTOBER, both of which prespecified the Xience (Abbott) everolimus-eluting stent for the procedures, were published in the New England Journal of Medicine in tandem with their respective presentations at the ESC sessions.
 

Covering the spectrum

A meta-analysis presented at the same ESC session compared IVI using either OCT or intravascular ultrasound (IVUS) with angiography-only PCI across 20 randomized trials with a total of more than 12,000 patients.

Significant outcomes for IVI guidance versus angiography alone included a 31% drop in risk for target-lesion failure, the primary endpoint. And this study, as well, showed a steep 52% reduction in risk for in-stent thrombosis with the IVI-guided approach.

Stone_Gregg_W_NYC_web.jpg

And “for the first time” in IVI studies, “we demonstrated reductions in all-myocardial-infarction and all-cause death, the latter by 25%,” Gregg Stone, MD, Icahn School of Medicine at Mount Sinai, New York, said in presenting the meta-analysis. Dr. Stone is also the ILUMIEN-4 study chairperson.

“The routine use of OCT or IVUS to guide most PCI procedures will substantially improve patient event-free survival,” he predicted, “enhancing both the long-term safety and effectiveness of the procedure.”

Dr. Stone said that IVI guidance “should be standard of care, if not in all patients, then in most patients.” Part of the rationale: PCI is unlikely to be improved much further by incremental gains in drug-eluting stent design. “That technology has almost plateaued.” But there’s yet room for “substantially improved outcomes” from adjunctive treatments and techniques such as IVI guidance.

The 20 studies in the meta-analysis encompassed an array of patients and lesions both complex and noncomplex, Dr. Stone observed, including bifurcation lesions, chronic total occlusions, left-main coronary stenoses, and MI culprit lesions.

“They really covered the spectrum of PCI,” he said. “I’m not recommending that intravascular imaging be used in every single case. But I do think it should be used in the majority of patients” and be standard of care for PCI in left-main lesions and “complex coronary disease, high-risk patients, and high-risk lesions.”
 

Unique advantage

The IVI-guidance groups in both ILUMIEN-4 and the meta-analysis showed a significant drop in risk for stent thrombosis – that is, abrupt thrombotic vessel closure, which typically occurs in 1% or fewer PCI cases but can trigger an MI and pose a mortality risk up to 45%.

Those risk reductions are consistent with a unique IVI advantage: the ability to guide optimization of stent deployments. When formally presenting ILUMIEN-4 at the ESC sessions, Ali observed that IVUS and OCT imaging allows operators to identify and often correct less-than-ideal results of an initial stent delivery – such as residual gaps between stent struts and vessel wall – that may encroach on the lumen, with possible clinical consequences.

Such imaging, said Dr. Ali, “lets you identify tissue protrusions, malappositions, dissections, and untreated reference-segment disease” that may potentially trigger thrombosis. That makes a strong argument for giving IVI guidance a more common, perhaps even routine role in PCI procedures.
 

Selling routine IVI-guided PCI in practice

“I think the study results are quite clear,” said Deepak L. Bhatt, MD, MPH, as session comoderator following the OCTOBER presentation. “The challenge, though, will be convincing the average interventional cardiologist worldwide that it was specifically the imaging and not the extra care that the patient getting OCT also inherently receives.”

Bhatt_Deepak_web.jpg

Did OCT’s better trial outcomes stem from IVI itself or from greater operator attentiveness to procedural results – such as, for example, more high-pressure expansions to optimize stent placement, “the sort of thing that tends to occur when invasive imaging is added on to just plain old angiography?” Dr. Bhatt asked of Lene N. Andreasen, MD, who had just presented the OCTOBER trial. “There’s no way of uncoupling the two things.”

What can be said, “at this point, to convince interventional cardiologists that the extra time, energy, expense, is truly indicated,” that the data are “sufficient to change global practice?” asked Dr. Bhatt, Mount Sinai Hospital and Icahn School of Medicine at Mount Sinai.

That remains an open question,” acknowledged Dr. Andreasen of Aarhus University Hospital. The best argument in favor of selective IVI-guided PCI is that “we actually see a clinical benefit” in the trials. “But of course, it comes with a cost. It comes with longer procedures and more contrast.” How clinical practice responds to the new data remains to be seen, she proposed.
 

ILUMIEN-4 and OCTOBER in detail

Conducted at 80 centers in 18 countries, ILUMIEN-4 randomly assigned patients with diabetes or complex coronary lesions to undergo PCI guided by OCT or using standard angiography only, 1,233 and 1,254 patients, respectively.

Post-PCI MSA averaged 5.72 mm² with OCT guidance and 5.36 mm² in the angiography-only group (P < .001).

Their rates of target-vessel failure at 2 years were not significantly different at 7.4% and 8.2%, respectively. The 2-year composite endpoint included cardiac death, target vessel–related MI, or ischemia-driven target-vessel revascularization.

Definite or probable stent thrombosis was observed over 2 years in 0.5% of the OCT group and 1.4% of those with angiography-only PCI (hazard ratio, 0.36; 95% confidence interval, 0.14-0.91; P = .02) favoring OCT.

The OCTOBER trial, conducted at 38 centers in Europe, entered 1201 patients with stable angina or acute coronary syndromes and angiographically identified complex bifurcation lesions. They involved the left-main coronary artery in about one-fifth of cases.

Patients were randomly assigned to bifurcation PCI guided by OCT or under standard angiography, 600 and 601 patients, respectively. Rates for procedure-related complications were similar at 6.8% and 5.7%, respectively.

Over a median of 2 years, 10.1% of the OCT group and 14.1% of angiography-only patients developed a MACE event, including cardiac death, target-lesion MI, or ischemia-driven target-lesion revascularization. The adjusted HR was 0.71 (95% CI, 0.51-0.98; P = .035) in favor of OCT.
 

Meta-analysis, trials to date

The meta-analysis presented by Dr. Stone included ILUMIEN-4, OCTOBER, and 18 earlier outcomes trials comparing PCI guided by IVI, either OCT or IVUS, and angiography-only PCI. It covered 12,428 patients with chronic or acute coronary disease and followed them a mean of 26 months; the longest follow-up was 5 years. They were assigned to IVI-guided or angiography-only PCI, 7,038 and 5,390 patients, respectively.

Dr. Stone and colleagues conducted a network meta-analysis of the 20 studies, that is, a combined analysis that allowed both direct and indirect comparisons of standard angiography-only procedures to each of the other studied comparator interventions including OCT, IVUS, and either OCT or IVUS. They then derived network-estimate odds ratios for IVI-guided PCI vs angiography-only procedures.

165089_table.PNG

“Hopefully, this will impact the guidelines,” Dr. Stone said of the meta-analysis. Procedures guided by IVI might become more common in clinical practice if they were to garner a Class-I guideline recommendation, the strongest recommendation category.

“That would make a difference, but we’d also need to work to remove impediments to increasing intravascular imaging guidance” for most patients undergoing PCI, he said, referring to challenges in obtaining reimbursement for IVI-guided PCI and training enough operators to handle the projected demand.

ILUMIEN-4 was funded by Abbott. OCTOBER was supported by grants from Abbott Vascular, St. Jude Medical, and Aarhus University. The network meta-analysis received statistical support from Abbott. Dr. Ali disclosed institutional grant support from Abbott, Abiomed, Acist Medical, Boston Scientific, Cardiovascular Systems, Medtronic, the National Institutes of Health, Opsens Medical, Philips, and Teleflex; consulting fees from Astra Zeneca, Philips, Shockwave; and holding equity in Elucid, Spectrawave, Shockwave, and VitalConnect. Dr. Holm and Dr. Bhatt reported numerous conflicts of interest. Dr. Andreasen disclosed no relevant financial relationships.

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

Two years is a long time in the world of heart failure (HF) management, enough to see publication of more than a dozen studies with insights that would supplant and expand key sections of a far-reaching European Society of Cardiology (ESC) clinical practice guideline on HF unveiled in 2021.

“Back in 2021, we had three and a half decades of data to consider,” but recent years have seen “an amazing amount of progress” that has necessitated some adjustments and key additions, including several Class I recommendations, observed Roy S. Gardner, MBChB, MD, Golden Jubilee National Hospital, Clydebank, United Kingdom.

Much of that recent progress, driven by trials like EMPEROR-Preserved, DELIVER, STRONG-HF, and IRONMAN, has been crystalized into the “2023 Focused Update of the 2021 ESC Guidelines” on HF management, which Dr. Gardner helped unveil over several days at the annual congress of the European Society of Cardiology, held in Amsterdam.

The new document was also published in the European Heart Journal during the ESC sessions. Dr. Gardner is a co-author on both the 2021 and 2023 documents.

The task force that was charged with the focused update’s development “considered a large number of trials across the spectrum of acute chronic heart failure and the comorbidities associated with it,” Ultimately, it considered only those with “results that would lead to new or changed Class I or Class IIa recommendations,” noted Theresa A. McDonagh, MD, during the ESC sessions.

Dr. McDonagh, of King’s College Hospital, London, chaired the task force and led the document’s list of authors along with Marco Metra, MD, University of Brescia (Italy).
 

Chronic HF management

The 2021 document’s “beautiful algorithm” on managing HF with reduced ejection fraction, that is HF with an LVEF less than 40%, had helped enshrine the expeditious uptitration of the “four pillars” of drug therapy as a top management goal. That remains unchanged in the focused update, Dr. Gardner noted.

But the new document gives a boost to recommendations for HF with mildly reduced ejection fraction (HFmrEF), characterized by an LVEF greater than 40% to less than 50%. For that, the 2021 document recommended three of the four pillars of HF medical therapy: beta blockers, mineralocorticoid receptor antagonists (MRA), renin-angiotensin system (RAS) inhibitors.

The focused update, however, adds the fourth pillar – SGLT2 inhibitors – to core therapy for both HFmrEF and HF with preserved ejection fraction (HFpEF), the latter defined by an LVEF greater than 50%. Publication of trials supporting those new recommendations had narrowly missed availability for the 2021 document.

EMPEROR-Preserved, for example, was published during the same ESC 2021 sessions that introduced the 2021 guidelines. Its patients with HFpEF (which at the time included patients meeting the current definition of HFmrEF) assigned to the SGLT2 inhibitor empagliflozin (Jardiance) showed a 21% reduction in risk for a composite primary endpoint that was driven by the HF-hospitalization component.

“This wasn’t a fluke finding,” Dr. Gardner said, as the following year saw publication of the DELIVER trial, which resembled EMPEROR-Preserved in design and outcomes using the SGLT2 inhibitor dapagliflozin (Farxiga).

The two trials, backed up by meta-analyses that also included DAPA-HF and other studies, suggested as well that the two SGLT2 inhibitors “work across the spectrum of ejection fraction,” Dr. Gardner said.

The 2023 focused update indicates an SGLT2 inhibitor, either empagliflozin or dapagliflozin, for patients with either HFmrEF or HFpEF to reduce the risk of HF hospitalization or cardiovascular death. Both recommendations are of Class I, level of evidence A.

The new indications make SGLT2 inhibitors and diuretics (as needed for fluid retention) the only drugs for HFmrEF or HFpEF with a Class I recommendation. Previously established “rather weaker” Class IIb recommendation for RAS inhibitors, MRAs, and beta blockers that had been “based on subgroup analyses of neutral trials” remained unchanged in the focused update, Dr. McDonagh noted.
 

Patients hospitalized with HF

The 2021 guidelines had recommended that patients hospitalized with acute HF be started on evidence-based meds before discharge and that they return for evaluation 1 to 2 weeks after discharge. But the recommendation was unsupported by randomized trials.

That changed with the 2022 publication of STRONG-HF, in which a strategy of early and rapid uptitration of guideline-directed meds, initiated predischarge regardless of LVEF, led to a one-third reduced 6-month risk for death or HF readmission.

Based primarily on STRONG-HF, the focused update recommends “an intensive strategy of initiation and rapid up-titration of evidence-based treatment before discharge and during frequent and careful follow-up visits in the first 6 weeks after hospitalization” to reduce readmission and mortality: Class I, level of evidence B.

“There was a large consensus around this recommendation,” said STRONG-HF principal investigator Alexandre Mebazaa, MD, PhD, a co-author of both the 2021 and 2023 documents. Conducted before the advent of the four pillars of drug therapy, sometimes called quartet therapy, the trial’s requirement for evidence-based meds didn’t include SGLT2 inhibitors.

The new focused update considers the new status of those agents, especially with regard to their benefits independent of LVEF. So, it completed the quartet by adding empagliflozin or dapagliflozin to the agents that should be initiated predischarge, observed Dr. Mebazaa, University Hospitals Saint Louis‐Lariboisière, Paris, at the focused-update’s ESC 2023 sessions.

The new document also follows STRONG-HF with its emphasis on “frequent and careful follow-up” by recommending certain clinical and laboratory evaluations known to be prognostic in HF. They include congestion status, blood pressure, heart rate, natriuretic peptide (NT-proBNP) and potassium levels and estimated glomerular filtration rate.

Dr. Mebazaa stressed the importance of monitoring NT-proBNP after discharge. “What we saw in STRONG-HF is that sometimes the clinical signs do not necessarily tell you that the patient is still congested.”

After discharge, he said, NT-proBNP levels “should only go down.” So, knowing whether NT-proBNP levels “are stable or increasing” during the med optimization process can help guide diuretic dosing.
 

HF with comorbidities

The new document includes two new Class I recommendations for patients with HF and both type 2 diabetes and chronic kidney disease based on several recent randomized trials and meta-analyses.

The focused update recommends SGLT2 inhibitors as well as the selective, non-steroidal MRA finerenone (Kerendia) in HF patients with CKD and type-2 diabetes. Both Class I recommendations are supported by a level of evidence A.

The SGLT2 indication is based on DAPA-CKD and EMPA-KIDNEY plus meta-analyses that included those trials along with others. The recommendation for finerenone derives from the FIDELIO-DKD and FIGARO-DKD trials and a pooled analysis of the two studies.

The 2023 focused update also accounts for new clinical-trial insights for patients with HF and iron deficiency. The 2021 document featured recommendations for the diagnosis and iron-repletion therapy in such cases, but only as Class IIa or at lower low levels of evidence. The focused update considers more recent studies, especially IRONMAN and some meta-analyses.

The 2023 document indicates intravenous iron supplementation for symptomatic patients with iron deficiency and either HFrEF or HFmrEF to improve symptoms and quality of life (Class I, level of evidence A), and says it should be considered (Class IIa, level of evidence A) to reduce risk for HF hospitalization.

When the task force assembled to plan the 2023 focused update, Dr. Gardner observed, “the first thing we thought about was the nomenclature around the phenotyping of heart failure.”

Although the 2021 guidelines relied fundamentally on the distinctions between HFrEF, HFmrEF, and HFpEF, it had become apparent to some in the field that some meds, especially the SGLT2 inhibitors, were obscuring their LVEF-based boundaries, at least with respect to drug therapy.

The 2023 document’s developers, Dr. Gardner said, seriously considered changing the three categories to two, that is HFrEF and – to account for all other heart failure – HF with normal ejection fraction (HFnEF).

That didn’t happen, although the proposal was popular within the task force. Any changes to the 2021 document would require a 75% consensus on the matter, Dr. Gardner explained. When the task force took a vote on whether to change the nomenclature, he said, 71% favored the proposal.

Disclosures for members of the task force can be found in a supplement to the published 2023 Focused Update.

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

Two years is a long time in the world of heart failure (HF) management, enough to see publication of more than a dozen studies with insights that would supplant and expand key sections of a far-reaching European Society of Cardiology (ESC) clinical practice guideline on HF unveiled in 2021.

“Back in 2021, we had three and a half decades of data to consider,” but recent years have seen “an amazing amount of progress” that has necessitated some adjustments and key additions, including several Class I recommendations, observed Roy S. Gardner, MBChB, MD, Golden Jubilee National Hospital, Clydebank, United Kingdom.

Much of that recent progress, driven by trials like EMPEROR-Preserved, DELIVER, STRONG-HF, and IRONMAN, has been crystalized into the “2023 Focused Update of the 2021 ESC Guidelines” on HF management, which Dr. Gardner helped unveil over several days at the annual congress of the European Society of Cardiology, held in Amsterdam.

The new document was also published in the European Heart Journal during the ESC sessions. Dr. Gardner is a co-author on both the 2021 and 2023 documents.

The task force that was charged with the focused update’s development “considered a large number of trials across the spectrum of acute chronic heart failure and the comorbidities associated with it,” Ultimately, it considered only those with “results that would lead to new or changed Class I or Class IIa recommendations,” noted Theresa A. McDonagh, MD, during the ESC sessions.

Dr. McDonagh, of King’s College Hospital, London, chaired the task force and led the document’s list of authors along with Marco Metra, MD, University of Brescia (Italy).
 

Chronic HF management

The 2021 document’s “beautiful algorithm” on managing HF with reduced ejection fraction, that is HF with an LVEF less than 40%, had helped enshrine the expeditious uptitration of the “four pillars” of drug therapy as a top management goal. That remains unchanged in the focused update, Dr. Gardner noted.

But the new document gives a boost to recommendations for HF with mildly reduced ejection fraction (HFmrEF), characterized by an LVEF greater than 40% to less than 50%. For that, the 2021 document recommended three of the four pillars of HF medical therapy: beta blockers, mineralocorticoid receptor antagonists (MRA), renin-angiotensin system (RAS) inhibitors.

The focused update, however, adds the fourth pillar – SGLT2 inhibitors – to core therapy for both HFmrEF and HF with preserved ejection fraction (HFpEF), the latter defined by an LVEF greater than 50%. Publication of trials supporting those new recommendations had narrowly missed availability for the 2021 document.

EMPEROR-Preserved, for example, was published during the same ESC 2021 sessions that introduced the 2021 guidelines. Its patients with HFpEF (which at the time included patients meeting the current definition of HFmrEF) assigned to the SGLT2 inhibitor empagliflozin (Jardiance) showed a 21% reduction in risk for a composite primary endpoint that was driven by the HF-hospitalization component.

“This wasn’t a fluke finding,” Dr. Gardner said, as the following year saw publication of the DELIVER trial, which resembled EMPEROR-Preserved in design and outcomes using the SGLT2 inhibitor dapagliflozin (Farxiga).

The two trials, backed up by meta-analyses that also included DAPA-HF and other studies, suggested as well that the two SGLT2 inhibitors “work across the spectrum of ejection fraction,” Dr. Gardner said.

The 2023 focused update indicates an SGLT2 inhibitor, either empagliflozin or dapagliflozin, for patients with either HFmrEF or HFpEF to reduce the risk of HF hospitalization or cardiovascular death. Both recommendations are of Class I, level of evidence A.

The new indications make SGLT2 inhibitors and diuretics (as needed for fluid retention) the only drugs for HFmrEF or HFpEF with a Class I recommendation. Previously established “rather weaker” Class IIb recommendation for RAS inhibitors, MRAs, and beta blockers that had been “based on subgroup analyses of neutral trials” remained unchanged in the focused update, Dr. McDonagh noted.
 

Patients hospitalized with HF

The 2021 guidelines had recommended that patients hospitalized with acute HF be started on evidence-based meds before discharge and that they return for evaluation 1 to 2 weeks after discharge. But the recommendation was unsupported by randomized trials.

That changed with the 2022 publication of STRONG-HF, in which a strategy of early and rapid uptitration of guideline-directed meds, initiated predischarge regardless of LVEF, led to a one-third reduced 6-month risk for death or HF readmission.

Based primarily on STRONG-HF, the focused update recommends “an intensive strategy of initiation and rapid up-titration of evidence-based treatment before discharge and during frequent and careful follow-up visits in the first 6 weeks after hospitalization” to reduce readmission and mortality: Class I, level of evidence B.

“There was a large consensus around this recommendation,” said STRONG-HF principal investigator Alexandre Mebazaa, MD, PhD, a co-author of both the 2021 and 2023 documents. Conducted before the advent of the four pillars of drug therapy, sometimes called quartet therapy, the trial’s requirement for evidence-based meds didn’t include SGLT2 inhibitors.

The new focused update considers the new status of those agents, especially with regard to their benefits independent of LVEF. So, it completed the quartet by adding empagliflozin or dapagliflozin to the agents that should be initiated predischarge, observed Dr. Mebazaa, University Hospitals Saint Louis‐Lariboisière, Paris, at the focused-update’s ESC 2023 sessions.

The new document also follows STRONG-HF with its emphasis on “frequent and careful follow-up” by recommending certain clinical and laboratory evaluations known to be prognostic in HF. They include congestion status, blood pressure, heart rate, natriuretic peptide (NT-proBNP) and potassium levels and estimated glomerular filtration rate.

Dr. Mebazaa stressed the importance of monitoring NT-proBNP after discharge. “What we saw in STRONG-HF is that sometimes the clinical signs do not necessarily tell you that the patient is still congested.”

After discharge, he said, NT-proBNP levels “should only go down.” So, knowing whether NT-proBNP levels “are stable or increasing” during the med optimization process can help guide diuretic dosing.
 

HF with comorbidities

The new document includes two new Class I recommendations for patients with HF and both type 2 diabetes and chronic kidney disease based on several recent randomized trials and meta-analyses.

The focused update recommends SGLT2 inhibitors as well as the selective, non-steroidal MRA finerenone (Kerendia) in HF patients with CKD and type-2 diabetes. Both Class I recommendations are supported by a level of evidence A.

The SGLT2 indication is based on DAPA-CKD and EMPA-KIDNEY plus meta-analyses that included those trials along with others. The recommendation for finerenone derives from the FIDELIO-DKD and FIGARO-DKD trials and a pooled analysis of the two studies.

The 2023 focused update also accounts for new clinical-trial insights for patients with HF and iron deficiency. The 2021 document featured recommendations for the diagnosis and iron-repletion therapy in such cases, but only as Class IIa or at lower low levels of evidence. The focused update considers more recent studies, especially IRONMAN and some meta-analyses.

The 2023 document indicates intravenous iron supplementation for symptomatic patients with iron deficiency and either HFrEF or HFmrEF to improve symptoms and quality of life (Class I, level of evidence A), and says it should be considered (Class IIa, level of evidence A) to reduce risk for HF hospitalization.

When the task force assembled to plan the 2023 focused update, Dr. Gardner observed, “the first thing we thought about was the nomenclature around the phenotyping of heart failure.”

Although the 2021 guidelines relied fundamentally on the distinctions between HFrEF, HFmrEF, and HFpEF, it had become apparent to some in the field that some meds, especially the SGLT2 inhibitors, were obscuring their LVEF-based boundaries, at least with respect to drug therapy.

The 2023 document’s developers, Dr. Gardner said, seriously considered changing the three categories to two, that is HFrEF and – to account for all other heart failure – HF with normal ejection fraction (HFnEF).

That didn’t happen, although the proposal was popular within the task force. Any changes to the 2021 document would require a 75% consensus on the matter, Dr. Gardner explained. When the task force took a vote on whether to change the nomenclature, he said, 71% favored the proposal.

Disclosures for members of the task force can be found in a supplement to the published 2023 Focused Update.

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

Two years is a long time in the world of heart failure (HF) management, enough to see publication of more than a dozen studies with insights that would supplant and expand key sections of a far-reaching European Society of Cardiology (ESC) clinical practice guideline on HF unveiled in 2021.

“Back in 2021, we had three and a half decades of data to consider,” but recent years have seen “an amazing amount of progress” that has necessitated some adjustments and key additions, including several Class I recommendations, observed Roy S. Gardner, MBChB, MD, Golden Jubilee National Hospital, Clydebank, United Kingdom.

Much of that recent progress, driven by trials like EMPEROR-Preserved, DELIVER, STRONG-HF, and IRONMAN, has been crystalized into the “2023 Focused Update of the 2021 ESC Guidelines” on HF management, which Dr. Gardner helped unveil over several days at the annual congress of the European Society of Cardiology, held in Amsterdam.

The new document was also published in the European Heart Journal during the ESC sessions. Dr. Gardner is a co-author on both the 2021 and 2023 documents.

The task force that was charged with the focused update’s development “considered a large number of trials across the spectrum of acute chronic heart failure and the comorbidities associated with it,” Ultimately, it considered only those with “results that would lead to new or changed Class I or Class IIa recommendations,” noted Theresa A. McDonagh, MD, during the ESC sessions.

Dr. McDonagh, of King’s College Hospital, London, chaired the task force and led the document’s list of authors along with Marco Metra, MD, University of Brescia (Italy).
 

Chronic HF management

The 2021 document’s “beautiful algorithm” on managing HF with reduced ejection fraction, that is HF with an LVEF less than 40%, had helped enshrine the expeditious uptitration of the “four pillars” of drug therapy as a top management goal. That remains unchanged in the focused update, Dr. Gardner noted.

But the new document gives a boost to recommendations for HF with mildly reduced ejection fraction (HFmrEF), characterized by an LVEF greater than 40% to less than 50%. For that, the 2021 document recommended three of the four pillars of HF medical therapy: beta blockers, mineralocorticoid receptor antagonists (MRA), renin-angiotensin system (RAS) inhibitors.

The focused update, however, adds the fourth pillar – SGLT2 inhibitors – to core therapy for both HFmrEF and HF with preserved ejection fraction (HFpEF), the latter defined by an LVEF greater than 50%. Publication of trials supporting those new recommendations had narrowly missed availability for the 2021 document.

EMPEROR-Preserved, for example, was published during the same ESC 2021 sessions that introduced the 2021 guidelines. Its patients with HFpEF (which at the time included patients meeting the current definition of HFmrEF) assigned to the SGLT2 inhibitor empagliflozin (Jardiance) showed a 21% reduction in risk for a composite primary endpoint that was driven by the HF-hospitalization component.

“This wasn’t a fluke finding,” Dr. Gardner said, as the following year saw publication of the DELIVER trial, which resembled EMPEROR-Preserved in design and outcomes using the SGLT2 inhibitor dapagliflozin (Farxiga).

The two trials, backed up by meta-analyses that also included DAPA-HF and other studies, suggested as well that the two SGLT2 inhibitors “work across the spectrum of ejection fraction,” Dr. Gardner said.

The 2023 focused update indicates an SGLT2 inhibitor, either empagliflozin or dapagliflozin, for patients with either HFmrEF or HFpEF to reduce the risk of HF hospitalization or cardiovascular death. Both recommendations are of Class I, level of evidence A.

The new indications make SGLT2 inhibitors and diuretics (as needed for fluid retention) the only drugs for HFmrEF or HFpEF with a Class I recommendation. Previously established “rather weaker” Class IIb recommendation for RAS inhibitors, MRAs, and beta blockers that had been “based on subgroup analyses of neutral trials” remained unchanged in the focused update, Dr. McDonagh noted.
 

Patients hospitalized with HF

The 2021 guidelines had recommended that patients hospitalized with acute HF be started on evidence-based meds before discharge and that they return for evaluation 1 to 2 weeks after discharge. But the recommendation was unsupported by randomized trials.

That changed with the 2022 publication of STRONG-HF, in which a strategy of early and rapid uptitration of guideline-directed meds, initiated predischarge regardless of LVEF, led to a one-third reduced 6-month risk for death or HF readmission.

Based primarily on STRONG-HF, the focused update recommends “an intensive strategy of initiation and rapid up-titration of evidence-based treatment before discharge and during frequent and careful follow-up visits in the first 6 weeks after hospitalization” to reduce readmission and mortality: Class I, level of evidence B.

“There was a large consensus around this recommendation,” said STRONG-HF principal investigator Alexandre Mebazaa, MD, PhD, a co-author of both the 2021 and 2023 documents. Conducted before the advent of the four pillars of drug therapy, sometimes called quartet therapy, the trial’s requirement for evidence-based meds didn’t include SGLT2 inhibitors.

The new focused update considers the new status of those agents, especially with regard to their benefits independent of LVEF. So, it completed the quartet by adding empagliflozin or dapagliflozin to the agents that should be initiated predischarge, observed Dr. Mebazaa, University Hospitals Saint Louis‐Lariboisière, Paris, at the focused-update’s ESC 2023 sessions.

The new document also follows STRONG-HF with its emphasis on “frequent and careful follow-up” by recommending certain clinical and laboratory evaluations known to be prognostic in HF. They include congestion status, blood pressure, heart rate, natriuretic peptide (NT-proBNP) and potassium levels and estimated glomerular filtration rate.

Dr. Mebazaa stressed the importance of monitoring NT-proBNP after discharge. “What we saw in STRONG-HF is that sometimes the clinical signs do not necessarily tell you that the patient is still congested.”

After discharge, he said, NT-proBNP levels “should only go down.” So, knowing whether NT-proBNP levels “are stable or increasing” during the med optimization process can help guide diuretic dosing.
 

HF with comorbidities

The new document includes two new Class I recommendations for patients with HF and both type 2 diabetes and chronic kidney disease based on several recent randomized trials and meta-analyses.

The focused update recommends SGLT2 inhibitors as well as the selective, non-steroidal MRA finerenone (Kerendia) in HF patients with CKD and type-2 diabetes. Both Class I recommendations are supported by a level of evidence A.

The SGLT2 indication is based on DAPA-CKD and EMPA-KIDNEY plus meta-analyses that included those trials along with others. The recommendation for finerenone derives from the FIDELIO-DKD and FIGARO-DKD trials and a pooled analysis of the two studies.

The 2023 focused update also accounts for new clinical-trial insights for patients with HF and iron deficiency. The 2021 document featured recommendations for the diagnosis and iron-repletion therapy in such cases, but only as Class IIa or at lower low levels of evidence. The focused update considers more recent studies, especially IRONMAN and some meta-analyses.

The 2023 document indicates intravenous iron supplementation for symptomatic patients with iron deficiency and either HFrEF or HFmrEF to improve symptoms and quality of life (Class I, level of evidence A), and says it should be considered (Class IIa, level of evidence A) to reduce risk for HF hospitalization.

When the task force assembled to plan the 2023 focused update, Dr. Gardner observed, “the first thing we thought about was the nomenclature around the phenotyping of heart failure.”

Although the 2021 guidelines relied fundamentally on the distinctions between HFrEF, HFmrEF, and HFpEF, it had become apparent to some in the field that some meds, especially the SGLT2 inhibitors, were obscuring their LVEF-based boundaries, at least with respect to drug therapy.

The 2023 document’s developers, Dr. Gardner said, seriously considered changing the three categories to two, that is HFrEF and – to account for all other heart failure – HF with normal ejection fraction (HFnEF).

That didn’t happen, although the proposal was popular within the task force. Any changes to the 2021 document would require a 75% consensus on the matter, Dr. Gardner explained. When the task force took a vote on whether to change the nomenclature, he said, 71% favored the proposal.

Disclosures for members of the task force can be found in a supplement to the published 2023 Focused Update.

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