Myosin Activator May Benefit Data-Deprived Patients With Heart Failure and Low Blood Pressure

June 02, 2022

The evidence base supporting many drugs used in heart failure (HF) can be pretty thin for some types of patients, in particular those who have typically been excluded from major trials but aren’t all that rare in practice.

But a post hoc analysis based on a trial with slightly broader entry criteria could potentially make up some of the difference for one such data-deprived patient group, those with HF with reduced ejection fraction (HFrEF) and hypotension, at least down to a systolic blood pressure (SBP) of 85 mm Hg.

Patients who enrolled in GALACTIC-HF with SBP in the 85 to 100 mm Hg range were at greater risk for the trial’s primary endpoint, cardiovascular (CV) death or HF events, than those with higher SBP. But they also seemed to benefit more than higher-SBP patients from the agent under investigation, omecamtiv mecarbil (Cytokinetics), over about 2 years of follow-up.

Risk for the primary endpoint on omecamtiv mecarbil (OM), compared with placebo, fell a significant 19% among patients SBP in the lower range but by only a nonsignificant 5% among those with higher SBP. Such risk fell by a significant but less pronounced 8% across the entire trial of more than 8000 patients, as previously reported.

The lower-SBP group's apparently enhanced benefit from OM was also substantial in absolute terms, in that those on the drug experienced 9.8 fewer events per 100 patient-years, Marco Metra, MD, University of Brescia, Italy, said when presenting the analysis May 22 at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2022 sessions, held virtually and live in Madrid. He is also lead author on the study's same-day publication in the European Heart Journal.

Low SBP is known to "identify people who are at increased risk of clinical events and also poorly tolerate evidence-based medical treatment," Metra said. But such patients, he observed, were often excluded from randomized trials that established neurohormonal modulators and other agents as core HFrEF therapies, "as these drugs may excessively decrease systolic blood pressure." Moreover, hypotension has been a leading cause of patient withdrawal from such studies.

The myosin activator OM, investigational but in the late stages of US Food and Drug Administration review, works by an entirely different mechanism and wasn't associated with SBP declines in GALACTIC-HF, with its allowable entry SBP of 85 to 140 mm Hg.

A number of major HFrEF trials of beta blockers, angiotensin-receptor neprilysin inhibitors, and even SGLT2 inhibitors excluded patients with SBP below 95 to 100 mm Hg, observe Metra and colleagues in their published report. In contrast, GALACTIC-HF included 1473 patients with baseline SBP in the 85 to 100 mm Hg range.

These findings, although preliminary and with limitations, "are really welcome," said John G.F. Cleland, MD, PhD, University of Glasgow, United Kingdom, after Metra's presentation.

Low SBP as a potential guide for targeting HFrEF drug therapy is "a biologically plausible biomarker. We need more treatments for patients who have borderline renal function and hypotension, where many of our treatments are contraindicated or have to be used cautiously," said Cleland, who comoderated the HFA-ESC session featuring the analysis.

GALACTIC-HF entered 8232 patients with HFrEF and symptoms up to NYHA class 4 despite guideline-directed medical therapy who had experienced either a hospitalization or urgent outpatient visit for HF, which the study called an HF event, in the previous year.

In its primary outcome, reported in November 2020, the hazard ratio (HR) for CV death or a first HF event was 0.92 (95% CI, 0.86 - 0.99; = .03) for those assigned to OM compared with placebo.

The corresponding HR fell to 0.81 (95% CI, 0.70 - 0.94) for the 1473 patients with baseline SBP of 100 mm Hg or less, but only to 0.95 (95% CI, 0.88 - 1.03) for the 6759 who entered with higher SBP, Metra reported at the ESC-HFA sessions.

Overall in the trial, risks for the primary endpoint and its individual components climbed continuously with each 5-mm Hg drop in baseline SBP. The HRs for each such decrement were:

  • 1.05 (95% CI, 1.03 - 1.06) for CV death or a first HF event

  • 1.08 (95% CI, 1.06 - 1.09) for CV death

  • 1.04 (95% CI, 1.03 - 1.06) for a first HF event.

Omecamtiv mecarbil didn't seem to alter systolic BP, compared with placebo, over the course of the study, regardless of baseline SBP, nor was it associated with more adverse events.

The analysis wasn't prospectively planned, and the cutoff for separating lower from higher SBP was "clinically meaningful" but arbitrary, among other limitations, Metra observed. But the findings are plausible, he said, especially given that OM, in contrast to the renin-angiotensin-system inhibitors broadly indicated for HFrEF, has no apparent effect on the peripheral vasculature or blood pressure.

Metra discloses funding to his institution from Amgen and Cytokinetics; consulting fees from AstraZeneca, Bayer, and Boehringer Ingelheim; personal fees LivaNova and Vifor Pharma; fees for speaking from Abbott Vascular and Edwards Therapeutics; and participating on data safety monitoring boards for Actelion. Disclosures for the other authors are in the published report. Cleland discloses receiving honoraria for advisory boards and speaking from Medtronic and Abbott, support from Medtronic, and grants and fees for membership on advisory boards from Bayer and Bristol-Myers Squibb.

Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2022: GALACTIC-HF - omecamtiv mecarbil in HFrEF and low blood pressure. Presented May 22, 2022.

Eur Heart J. Published online May 22, 2022. Abstract

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