The medical treatment of HFrEF continues to evolve with new drug classes including angiotensin receptor–neprilysin inhibitors (ARNI) and sodium/glucose cotransporter-2 inhibitors (SGLT2i). Ironically, contemporary GDMT does not directly address the primary characteristic of HFrEF, decreased myocardial contractility.² Currently, the only agents in clinical use that directly increase contractility are drugs that increase intracellular calcium to promote contractility (also known as calcitropes). However, due to concerns for safety and potential for increasing mortality, the use of such drugs has been relegated to short term in-hospital use as a bridge to more definitive therapy or in the context of palliation.

New paradigms to increase cardiac inotropy are under extensive research and development.^1,3,4 Another approach focuses on increasing mitochondrial energetics, e.g. mitotropes. In contrast, myotropes offer a different mechanism of action by acting directly in the sarcomere level and can affect myosin, actin and the associated regulatory proteins without directly affecting calcium signaling.

Omecamtiv mecarbil (OM) is an inotrope in the myotrope class.^1,3,5-7 OM is a myosin specific activator which directly targets the contractile mechanism in the sarcomere by increasing the number of myosin heads that are able to pull on actin filaments in order to produce force during systole. In addition, it also appears to decrease inefficient actin-independent noncontractile energy usage.¹

In COSMIC-HF, a phase 2 randomized trial of patients with HFrEF,⁶ OM was found to be safe and associated with a longer systolic ejection time, greater stroke volume and decrease in left ventricular end-systolic and end-diastolic diameters. There was also decrease in heart rate and N-terminal pro B-type natriuretic peptide (NT-proBNP) suggesting a reduction in sympathetic activation and myocardial wall stress, respectively. In the ATOMIC-AHF, intravenous OM in the acute setting⁷ was well tolerated and increased systolic ejection time and improved dyspnea.

The GALACTIC-HF trial (Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure)⁸ was the prospective phase 3 randomized placebo-controlled trial of the OM program. The study included 8,256 patients with symptomatic HFrEF, LVEF ≤35% on GDMT, and a recent HF hospitalization or ED visit and elevated natriuretic peptide level. OM was dosed according to a pharmacokinetic protocol. The study's primary outcome was a combined endpoint of a first HF event (hospitalization or urgent visit for HF) or death from CV causes.

Major inclusion criteria were patients age 18-85 with NYHA II–IV HFrEF. Patients were enrolled either during their HF admission (25%) or as outpatient if they had HF hospitalization/urgent care visit over the last year. Major exclusion criteria include hemodynamic instability, systolic blood pressure (BP) <85 mmHg and eGFR <20.

During a median follow up period of 21.8 months, the primary outcome occurred in 37% in the OM group versus 39.1% in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P=0.03) and met the trial's primary endpoint. The primary endpoint was driven by HF hospitalization/urgent care visits. In fact, CV death was not significantly different between the groups: 808 patients (19.6%) in the OM group and 798 patients (19.4%) in the placebo group (hazard ratio, 1.01; 95% CI, 0.92 to 1.11).

Results were mostly consistent among prespecified subgroups. Of note, patients with lower ejection fractions (LVEF ≤28%) seemed to have greater benefit than patients with LVEF >28%. The prespecified secondary outcomes of death from CV cause, death from any cause, and hospitalization for HF as a first event were not different between groups. There was a modest improvement in quality of life as measured by the Kansas City Cardiomyopathy Questionnaire for inpatients but not for outpatients.

Hemodynamic effects were also reported. There was no difference in the change in systolic BP over 48 weeks between the groups, although the heart rate was slightly lower in the OM group. NT-proBNP at week 24 fell to a greater extent than in the placebo arm.  OM did not affect renal function or potassium homeostasis.

From safety and tolerability points of view, there was no significant difference regarding the rate of adverse events between the groups. There was a slight increase in troponin-I levels compared to the placebo group but there was no significant difference in rates of ischemic or ventricular arrhythmic events. Of note, there were fewer adjudicated strokes in the OM group. In a previous trial with OM,⁶ elevated troponin-I levels return to baseline values after treatment discontinuation.

The GALACTIC-HF trial is a landmark trial. It was the largest randomized placebo-controlled HFrEF study to test the hypothesis that directly improving cardiac contractility with a new class of inotrope could improve patient outcomes. Importantly, it met its primary combined outcome with a hazard ratio of 0.92 and was well tolerated and safe. However, the critical issue for clinicians is: how should they incorporate OM into their clinical practices?

A review of the trial's limitations is worthwhile in this context. First, only 19% of the patients were treated with sacubitril/valsartan and only 2.6% were treated with SGLT2i. Would the findings have been positive if more of the patients had been treated with the agents? How easy is it in clinical practice to use drug levels to guide dosing? Is a modest reduction (albeit statistically significant) in HF hospitalizations, without a reduction in CV or all-cause mortality, enough to justify polypharmacy and cost? Finally, where will OM stand relative to vericiguat (an oral guanylate cyclase stimulator), which also lowered the composite clinical endpoint of CV death or HF hospitalization in the VICTORIA⁹ trial?

One approach is to tailor therapy better to clinical phenotypes. In GALACTIC-HF, the mean systolic BP was 116 mmHg, NT-proBNP was 1977 pg/ml, eGFR was 58 cc/min/m², 25% were enrolled as inpatients, and those with the lowest LVEF may have derived a greater benefit. Thus, OM might be useful when the initiation or titration of HF GDMT is not possible due to limitations in BP, presence of chronic kidney disease or hypoperfusion. It is perhaps time to pivot to precision medicine and search for phenotypic signatures that reflect predominant pathophysiologies in HFrEF. Like in HFpEF, it may be time to embrace heterogeneity and finally move beyond treatment homogeneity.

References

1. Psotka MA, Gottlieb SS, Francis GS, et al. Cardiac calcitropes, myotropes, and mitotropes: JACC Review Topic of the Week. J Am Coll Cardiol 2019;73:2345-53.
2. Teerlink JR, Diaz R, Felker GM, et al. Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction: rationale and design of GALACTIC-HF. JACC Heart Fail 2020;8:329-40.
3. Malik FI, Hartman JJ, Elias KA, et al. Cardiac myosin activation: a potential therapeutic approach for systolic heart failure. Science 2011;331:1439-43.
4. Lim GB. Drugs targeting the sarcomere in heart failure and hypertrophic cardiomyopathy. Nat Rev Cardiol 2021;18:71.
5. Shen YT, Malik FI, Zhao X, et al. Improvement of cardiac function by a cardiac Myosin activator in conscious dogs with systolic heart failure. Circ Heart Fail 2010;3:522-7.
6. Teerlink JR, Felker GM, McMurray JJ, et al, on behalf of the 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;388:2895-2903.
7. Teerlink JR, Felker GM, McMurray JJV, et al, on behalf of the ATOMIC-AHF Investigators. Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure: The ATOMIC-AHF Study. J Am Coll Cardiol 2016;67:1444-55.
8. Teerlink JR, Diaz R, Felker GM, et al, on behalf of the GALACTIC-HF Investigators. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure. N Engl J Med 2021;384:105-16.
9. Armstrong PW, Pieske B, Anstrom KJ, et al, on behalf of the VICTORIA Study Group. Vericiguat in patients with heart failure and reduced ejection fraction. N Engl J Med 2020;382:1883-93.

Clinical Topics: Dyslipidemia, Heart Failure and Cardiomyopathies, Lipid Metabolism, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Heart Failure, AHA Annual Scientific Sessions, AHA20, Stroke Volume, Troponin I, Outpatients, Quality of Life, Actins, Neprilysin, Sodium-Glucose Transporter 2, Natriuretic Peptide, Brain, Sarcomeres, Heart Rate, Blood Pressure, Systole, Inpatients, Receptors, Angiotensin, Polypharmacy, Guanylate Cyclase, Confidence Intervals, Follow-Up Studies, Prospective Studies, Diabetes Mellitus, Type 2, Hospitalization, Actin Cytoskeleton, Myosins, Homeostasis, Ambulatory Care, Dyspnea, Renal Insufficiency, Chronic, Stroke, Research, Hospitals, Phenotype, Cardiomyopathies, Potassium

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