GALACTIC-HF Trial: Omecamtiv mecarbil

GALACTIC-HF Trial: Omecamtiv mecarbil

GALACTIC-HF trial evaluated omecamtiv mecarbil, a cardiac myosin activator in heart failure with reduced ejection fraction [1]. The study had 8256 patients which included inpatients and outpatients with symptomatic heart failure with an ejection fraction of 35% or less. It was a placebo controlled trial of omecamtiv mecarbil in addition to standard heart failure therapy.

Primary outcome was a composite of first heart failure event or death from cardiovascular causes. Heart failure event was defined as hospitalization or urgent hospital visit for heart failure. Over a median follow up of 21.8 months, primary outcome event occurred in 37% of the study group and 39.1% of the placebo group. Cardiovascular mortality was 19.6% in the study group and 19.4% in the placebo group. Kansas City Cardiomyopathy Questionnaire total symptom score did not capture any significant difference between the two groups on treatment. N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) level was 10% lower in the omecamtiv mecarbil group at 24 weeks. Ventricular arrhythmia and ischemic events were similar in both groups.

Previous studies on inotropic agents in heart failure have failed to improve outcome [2]. GALACTIC-HF trial also did not reduce mortality, though the primary outcome was better with omecamtiv mecarbil, driven by reduction in heart failure events. Omecamtiv mecarbil is a new class of drugs known as myotropes, which improve myocardial function by augmenting cardiac sarcomere function [3]. Conventional inotropic agents act by modulating calcium signaling in the myocardium and can be called calcitropes. 

A previous phase 2 trial of omecamtiv mecarbil (COSMIC-HF) had enrolled 150 patients in the fixed dose group and 149 patients in the pharmacokinetic dose titration and placebo groups [4]. COSMIC-HF had documented improved cardiac function and reduced left ventricular diameter. NT-pro-BNP levels were also significantly lower at 20 weeks.

Authors pointed out that previous drugs enhancing inotropy had increased myocardial ischemia, ventricular arrhythmias and death due to increased intracellular calcium transients. But omecamtiv mecarbil had no effect on calcium transients, being a selective cardiac myosin activator. This could explain the fact that myocardial ischemia, ventricular arrhythmia and mortality was not increased by omecamtiv mecarbil in the GALACTIC-HF study with almost 7500 patient years of follow up.

No adverse effects on blood pressure, heart rate, creatinine levels or potassium levels were noted with omecamtiv mecarbil. This is an advantage over most drugs used in heart failure with reduced ejection fraction.

Sacubitril–valsartan was being given in 19% of patients at baseline in GALACTIC-HF. But the use of sodium–glucose cotransporter 2 inhibitors (SGLT2 inhibitors) was only 2.6% because the compelling results of trials with these drugs were not available until GALACTIC-HF had completed enrollment.

References

1. Teerlink JR, Diaz R, Felker GM, McMurray JJV, Metra M, Solomon SD, Adams KF, Anand I, Arias-Mendoza A, Biering-Sørensen T, Böhm M, Bonderman D, Cleland JGF, Corbalan R, Crespo-Leiro MG, Dahlström U, Echeverria LE, Fang JC, Filippatos G, Fonseca C, Goncalvesova E, Goudev AR, Howlett JG, Lanfear DE, Li J, Lund M, Macdonald P, Mareev V, Momomura SI, O’Meara E, Parkhomenko A, Ponikowski P, Ramires FJA, Serpytis P, Sliwa K, Spinar J, Suter TM, Tomcsanyi J, Vandekerckhove H, Vinereanu D, Voors AA, Yilmaz MB, Zannad F, Sharpsten L, Legg JC, Varin C, Honarpour N, Abbasi SA, Malik FI, Kurtz CE; GALACTIC-HF Investigators. Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure. N Engl J Med. 2021 Jan 14;384(2):105-116.
2. Ahmad T, Miller PE, McCullough M, Desai NR, Riello R, Psotka M, Böhm M, Allen LA, Teerlink JR, Rosano GMC, Lindenfeld J. Why has positive inotropy failed in chronic heart failure? Lessons from prior inotrope trials. Eur J Heart Fail. 2019 Sep;21(9):1064-1078.
3. Psotka MA, Gottlieb SS, Francis GS, Allen LA, Teerlink JR, Adams KF Jr, Rosano GMC, Lancellotti P. Cardiac Calcitropes, Myotropes, and Mitotropes: JACC Review Topic of the Week. J Am Coll Cardiol. 2019 May 14;73(18):2345-2353.
4. Teerlink JR, Felker GM, McMurray JJ, Solomon SD, Adams KF Jr, Cleland JG, Ezekowitz JA, Goudev A, Macdonald P, Metra M, Mitrovic V, Ponikowski P, Serpytis P, Spinar J, Tomcsányi J, Vandekerckhove HJ, Voors AA, Monsalvo ML, Johnston J, Malik FI, Honarpour N; COSMIC-HF Investigators. Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial. Lancet. 2016 Dec 10;388(10062):2895-2903.