Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure (GALACTIC-HF)

Authors, Journal, Affiliations, Type, DOI

• Authors: John R. Teerlink, Rafael Diaz, G. Michael Felker, John J.V. McMurray, Marco Metra, Scott D. Solomon, Kirkwood F. Adams, et al., for the GALACTIC-HF Investigators
• Journal: New England Journal of Medicine, 2021;384:105–116
• Published: November 13, 2020 (online); January 14, 2021 (print)
• Type: Randomised, double-blind, placebo-controlled, phase 3 clinical trial
• Funding: Amgen, Cytokinetics, Servier — industry-sponsored; Amgen responsible for site monitoring, data collection, storage, and initial analyses; results replicated by independent academic statistician
• DOI: 10.1056/NEJMoa2025797
• Sites: 945 sites, 35 countries; enrolled January 6, 2017 – July 9, 2019

Overview

GALACTIC-HF tested omecamtiv mecarbil — the first selective cardiac myosin activator (myotrope) — against placebo on top of guideline-directed therapy in 8,232 patients with symptomatic HFrEF (LVEF ≤35%, NYHA II–IV, both inpatients and outpatients). The primary composite of HF event or CV death was reduced (HR 0.92; P=0.03), but no secondary outcome achieved significance — including CV death (HR 1.01), all-cause death (HR 1.00), first HF hospitalisation (HR 0.95), or KCCQ. A prespecified LVEF subgroup interaction showed benefit concentrated in the most impaired group (LVEF ≤28%, HR 0.84) with no detectable benefit at LVEF >28% (HR 1.04). The drug is not approved and not guideline-listed.

Keywords

Omecamtiv mecarbil, cardiac myosin activator, myotrope, heart failure with reduced ejection fraction, GALACTIC-HF, LVEF, Kansas City Cardiomyopathy Questionnaire, NT-proBNP, cardiac troponin, systolic function

Key Takeaways

Background and Mechanism

• No medication that directly enhances systolic function has previously improved HF outcomes — prior positive inotropes (digitalis, PDE3 inhibitors, beta-agonists) all caused excess ischemia, arrhythmias, or death via intracellular calcium transient augmentation
• Omecamtiv mecarbil is a selective cardiac myosin activator: binds cardiac myosin → increases the number of myosin heads in the force-generating state at the start of systole (more power strokes per cycle) → greater contractile force — without affecting calcium transients
• This calcium-independent mechanism is the pharmacological safety rationale distinguishing omecamtiv mecarbil from all prior inotropes
• Phase 2 (COSMIC-HF, Lancet 2016): 20 weeks of omecamtiv mecarbil increased LV systolic ejection time and stroke volume, decreased LV systolic and diastolic volumes (reverse remodeling signal), and reduced NT-proBNP and heart rate — provided mechanistic proof-of-concept for GALACTIC-HF

Population

• n=8,256 randomised; n=8,232 in full analysis set (24 excluded for GCP violations at one site)
• Age 18–85; LVEF ≤35%; NYHA II (46%), III (50%), IV (4%)
• Both inpatients (currently hospitalised) and outpatients (urgent ED visit or HF hospitalisation within 1 year before screening)
• NT-proBNP ≥400 pg/mL or BNP ≥125 pg/mL (higher thresholds in AF/flutter patients)
• Background: guideline-directed pharmacologic and device therapy required; >19% on sacubitril-valsartan; only 2.6% on SGLT2i (enrolled before DAPA-HF/EMPEROR-Reduced results)
• Randomised 1:1; pharmacokinetic-guided dosing: 25 mg, 37.5 mg, or 50 mg BID; investigators blinded to dose assignment
• Median follow-up 21.8 months (IQR 15.4–28.6)

Primary Outcome

• Composite of first HF event (hospitalisation or urgent visit requiring IV therapy beyond oral diuretics) or CV death
• Omecamtiv mecarbil 37.0% vs placebo 39.1%
• HR 0.92 (95% CI 0.86–0.99; P=0.03) — statistically significant; 8% RRR; 2.1 pp absolute reduction
• Effect consistent across most prespecified subgroups except LVEF (see subgroup below)

Secondary Outcomes (all non-significant)

• CV death: 19.6% vs 19.4%; HR 1.01 (95% CI 0.92–1.11; P=0.86) — no benefit
• All-cause death: 25.9% vs 25.9%; HR 1.00 (95% CI 0.92–1.09) — no benefit
• First HF hospitalisation: 27.7% vs 28.7%; HR 0.95 (95% CI 0.87–1.03) — NS
• KCCQ total symptom score at week 24: inpatients +2.5 points (95% CI 0.5–4.5); outpatients −0.5 (95% CI −1.4 to 0.5); joint omnibus F-test P=0.03 but did not meet prespecified alpha threshold of 0.002 for the hierarchical testing procedure — not significant
• Exploratory first HF event: HR 0.93 (95% CI 0.86–1.00) — borderline

LVEF Subgroup — Key Heterogeneity Signal (Prespecified)

• Median LVEF at baseline: 28%
• LVEF ≤28% (median): HR 0.84 (95% CI 0.77–0.92) — clinically meaningful reduction
• LVEF >28%: HR 1.04 (95% CI 0.94–1.16) — no benefit
• Statistically significant interaction (P-heterogeneity reported as significant in the trial)
• Biological plausibility: greater systolic impairment = more contractile reserve available for myosin activation to improve performance
• This interaction is the most clinically important subgroup finding in the trial — benefit-risk profile most favourable at the lowest LVEF

Biomarkers and Vital Signs

• NT-proBNP at week 24: 10% lower (geometric mean ratio; 95% CI 6–14%) in omecamtiv mecarbil group — consistent with improved cardiac haemodynamics
• Cardiac troponin I at week 24: +4 ng/L vs placebo (Siemens ADVIA assay; ULN 40 ng/L; LoD 6 ng/L) — small but consistent across timepoints; below ULN; no excess adjudicated MI
• Heart rate: slightly lower in omecamtiv mecarbil group at weeks 24 and 48
• Systolic blood pressure, potassium, creatinine: no difference between groups

Safety

• Discontinuation for adverse event: 9.0% vs 9.3% — similar
• Major cardiac ischemic events: 4.9% vs 4.6% — not significantly different; myocardial infarction 3.0% vs 2.9%
• Ventricular arrhythmic events: similar in both groups
• Drug withheld for suspected ACS/ischemia: 103 vs 101 patients — balanced
• No detrimental effects on blood pressure, heart rate, potassium, or creatinine
• Total ~7,500 patient-years of follow-up without calcium-mediated safety signal — mechanistic prediction confirmed

Limitations of the Document

• Excluded patients >85 years and those with haemodynamic instability — less severely ill trial population than real-world advanced HFrEF
• Only 2.6% on SGLT2i — incremental benefit of omecamtiv mecarbil on top of modern quadruple GDMT (ARNi + BB + MRA + SGLT2i) is unknown; SGLT2i independently reduces HF hospitalisations, potentially narrowing residual events available for myosin activation to prevent
• Only ~19% on ARNi — not fully representative of contemporary practice even in 2017–2019
• Only 7% Black patients, 21% women — underrepresentation limits generalisability
• Primary composite barely significant (P=0.03) with a 2.1 pp absolute difference; all secondary outcomes NS including CV death (HR 1.01) — clinical significance questioned
• LVEF subgroup interaction: benefit in LVEF ≤28% (HR 0.84) but not in LVEF 29–35% (HR 1.04) — the drug may be effective only in the most severely impaired group, narrowing the applicable population
• KCCQ gain in inpatients (+2.5 pts) below the 5-point MCID threshold; outpatients showed no QoL improvement
• Small troponin rise (+4 ng/L) without clinical correlate — mechanistic concern incompletely resolved
• 24 patients excluded for GCP violations at a single site — added to full analysis set uncertainty
• Industry-sponsored (Amgen/Cytokinetics/Servier); Amgen performed primary data analyses

Key Concepts Mentioned

• entities/HFrEF — population; GDMT background; LVEF ≤35% criterion
• entities/Omecamtiv-Mecarbil — agent studied; mechanism; outcomes

Key Entities Mentioned

• entities/Omecamtiv-Mecarbil — primary subject; cardiac myosin activator; GALACTIC-HF results
• entities/HFrEF — population and treatment context

Wiki Pages Updated

• Created wiki/sources/omecamtiv-galactichf-nejm-2021.md
• Created wiki/entities/Omecamtiv-Mecarbil.md
• Updated wiki/entities/HFrEF.md
• Updated wiki/sourceindex.md
• Updated wiki/wikiindex.md