GALACTIC-HF Trial: Omecamtiv Mecarbil in Heart Failure with Reduced Ejection Fraction
Omecamtiv mecarbil modestly reduces cardiovascular death or heart failure events in patients with HFrEF, particularly in those with severe disease (LVEF ≤30%, NYHA III/IV) or low systolic blood pressure (≤100 mmHg), but does not improve exercise capacity and remains investigational with limited guideline support. 1, 2, 3
Trial Design and Population
The GALACTIC-HF trial was a large, international, randomized, double-blind, placebo-controlled outcomes trial enrolling over 8,000 patients with chronic symptomatic HFrEF (NYHA class II-IV), LVEF ≤35%, elevated natriuretic peptides, and baseline systolic blood pressure ≥85 mmHg. 4 Patients required either current hospitalization for heart failure or a history of hospitalization/emergency department visit within the prior year. 4
Primary Results
The trial demonstrated a modest but statistically significant reduction in the primary composite endpoint of cardiovascular death or first heart failure event (HR 0.92,95% CI 0.86-0.99, P=0.03). 2 This represents approximately an 8% relative risk reduction across the overall population. 2
Key Subgroup Findings
Patients with Severe Heart Failure
The treatment effect was substantially more pronounced in patients with severe heart failure (LVEF ≤30%, NYHA class III/IV, recent HF hospitalization within 6 months), where omecamtiv mecarbil demonstrated greater benefit in reducing cardiovascular death or heart failure events. 2 This suggests the drug may be most appropriate for higher-risk phenotypes. 2
Patients with Low Blood Pressure
Omecamtiv mecarbil showed particular efficacy in patients with baseline systolic blood pressure ≤100 mmHg (HR 0.81,95% CI 0.70-0.94) compared to those with SBP >100 mmHg (HR 0.95% CI 0.88-1.03, P-interaction=0.051). 1, 3 Critically, the drug did not lower blood pressure values over time and was well-tolerated regardless of baseline blood pressure. 1, 3 This represents a unique advantage over traditional guideline-directed medical therapies that often cause hypotension. 1
Age-Related Outcomes
Treatment efficacy was consistent across age groups (<65 vs ≥65 years, P-interaction=0.76), with similar safety profiles regardless of age. 2 In patients with severe heart failure, benefit was observed in both younger patients (HR 0.77,95% CI 0.64-0.92) and older patients (HR 0.83,95% CI 0.71-0.97). 2
Mechanism of Action
Omecamtiv mecarbil is a selective cardiac myosin activator that increases the transition rate to the strongly bound myosin-actin cross-bridge state, thereby increasing systolic ejection time and stroke volume without increasing intracellular calcium or heart rate. 1, 5 This mechanism differs fundamentally from traditional inotropes that have historically increased mortality. 4, 5
Exercise Capacity Findings
Despite improvements in cardiac function and clinical outcomes, omecamtiv mecarbil did not improve peak exercise capacity (peak VO₂) in the METEORIC-HF trial (mean change -0.24 mL/kg/min vs 0.21 mL/kg/min with placebo, P=0.13). 6 This represents a significant limitation, as exercise intolerance is a cardinal manifestation of HFrEF. 6 The drug also did not improve total workload, ventilatory efficiency, or daily physical activity. 6
Safety Profile
Omecamtiv mecarbil demonstrated a favorable safety profile with adverse event rates similar to placebo, including dizziness (4.9% vs 5.5%), fatigue (4.9% vs 4.4%), and heart failure events (4.9% vs 4.4%). 6 The drug did not affect blood pressure values and was well-tolerated across all baseline blood pressure ranges. 1, 3
Current Guideline Status
The 2022 ACC/AHA/HFSA guidelines identify omecamtiv mecarbil as requiring further study in patients with stage D (advanced) HFrEF, but do not provide a formal recommendation for its use. 1 This reflects the need for additional evidence before widespread clinical adoption. 1
The 2025 European Heart Failure Association consensus statement acknowledges that omecamtiv mecarbil significantly reduced heart failure outcomes in patients with lower baseline systolic blood pressure (≤100 mmHg) without affecting blood pressure values, positioning it as a potential option for this challenging population. 1
Clinical Implications
When to Consider
- Patients with severe HFrEF (LVEF ≤30%, NYHA III/IV) who remain symptomatic despite optimal guideline-directed medical therapy 2
- Patients with low systolic blood pressure (≤100 mmHg) who cannot tolerate or adequately up-titrate standard HFrEF therapies due to hypotension 1, 3
- Patients requiring additional therapy to reduce heart failure events when standard options are maximized 2
Important Limitations
- Does not improve exercise capacity or quality of life measures 6
- Modest overall benefit (8% relative risk reduction) compared to more established therapies 2
- Requires pharmacokinetic-guided dose titration (25,37.5, or 50 mg twice daily) 1, 4
- Not yet incorporated into standard guideline-directed medical therapy algorithms 1
Developmental Context
The GALACTIC-HF trial represents a novel approach to heart failure drug development, focusing on mechanism-based endpoints (systolic ejection time) in phase II studies rather than generic surrogate markers like NT-proBNP. 1 This strategy confirmed "on-target" cardiac effects before proceeding to the outcomes trial. 1