Myosin-Activating Heart-Failure Drug Shows LV Functional Gains in COSMIC-HF Trial

November 20, 2015

ORLANDO, FL — An investigational oral agent seeking to join the lengthening list of meds for chronic heart failure has shown significant positive effects on stroke volume as well as ventricular dimensions and volume in a randomized, placebo-controlled trial with more than 400 patients[1]. Omecamtiv mecarbil (Amgen/Cytokinetics) is described as cardiac myosin activator that boosts ventricular function by prolonging systolic ejection time, unlike the positive inotropic agents clinicians are wary about giving their patients with heart failure.

Cursory results from the Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF) trial, sans any numbers but claiming significant improvements in cardiac functional measures, were announced in press-release form about month ago and reported then by heartwire from Medscape. In a more detailed presentation last week at the American Heart Association (AHA) 2015 Scientific Sessions, from Dr John R Teerlink (University of California, San Francisco and San Francisco Veterans Affairs Medical Center), patients who received the active drug showed significant improvements in systolic ejection time (P<0.002), stroke volume (P=0.022), and natriuretic-peptide levels (P=0.007).

On average, left ventricular dimensions and volumes improved significantly as well (P=0.003 for end-systolic dimensions, P=0.013 for end-diastolic dimensions, P=0.005 for end-systolic volume, and P=0.021 for end-diastolic volume). Mean heart rate also fell moderately but significantly (P=0.007). Numerical improvements in LVEF failed to reach significance (P=0.063).

COSMIC-HF randomized 448 patients with chronic heart failure and an LVEF <40%, NT-pro-brain natriuretic peptide (NT-proBNP) levels >200 pg/mL (>1200 pg/mL in patients with atrial fibrillation) on optimal medical therapy. Nearly everyone was on ACE inhibitors or angiotensin-receptor blockers and beta-blockers, more than half were on aldosterone antagonists, and >80% were on other diuretics. Their mean LVEF was 29% and about two-thirds had ischemic heart disease.

They were assigned to receive omecamtiv at 25 mg twice daily with escalation to 50 mg twice daily (n=149) or simply 25 mg twice daily (n=150) over 20 weeks; a third group received placebo for the same period (n=149). The current analysis pooled the two active-therapy groups.

Side-effect profiles were similar for omecamtiv recipients and controls; however, actively treated patients did show a sliver of a rise in mean troponin (cardiac TnI) levels, a change of 0.004 ng/mL by week 20 that returned to baseline several weeks after halting the drug.

Dr John Teerlink

The troponin increase remains something of a mystery, Teerlink told heartwire . "It doesn't entirely make sense yet. The closest surrogates we have for good outcomes are improvements in ventricular volumes and improvements in NT-proBNP—both of which were pretty dramatic here," he said.

"This is, as far as we know, the only study of any database we've been able to look at where there's a disconnect between the NT-proBNP and troponins." Here, natriuretic peptides improved and so did ventricular dimensions, volume, and so on, he noted. "If you are doing substantial damage to the heart, one wouldn't expect that you'd have those kinds of improvements."

While the finding is still under exploration, Teerlink said, in general he played it down as a minor signal that doesn't seem related to any adverse effect. Elsewhere at the AHA sessions, he told an audience, "To put that troponin increase into context, it is less than what endurance athletes release when they do endurance exercise."

It's not an isolated finding, however. In an earlier phase-2 trial of IV omecamtiv mecarbil in patients with acute heart failure, the drug vs placebo was associated with a numerical increase in MIs, which the investigators characterized primarily as small subclinical troponin elevations.

Teerlink had no relevant financial relationships. Disclosures for the coauthors are listed in the abstract.



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