GALACTIC-HF: Omecamtiv mecarbil in patients with heart failure with reduced ejection fraction

Bottom Line:

  • In patients with symptomatic HF with reduced ejection fraction (HFrEF), omecamtiv mecarbil did not reduce the risk of death, HF hospitalizations vs placebo over a median of 22 months.

  • Omecamtiv mecarbil did reduce the primary composite outcome (CV death, HF hospitalization or worsening HF requiring urgent outpatient visit); however, this was driven by urgent outpatient visits & is of unclear clinical importance.

Patients (n=8256):

  • Included

    • Chronic HF with NYHA 2-4 & ejection fraction ≤35%

    • Age 18-85 y

    • Either

      • Inpatient: Currently hospitalized for HF

      • Outpatient: HF hospitalization or ED visit in prior year

    • Elevated natriuretic peptides

      • NT-proBNP ≥400 pg/mL if sinus rhythm or ≥1200 pg/mL if afib

      • BNP ≥125 pg/mL if sinus rhythm or ≥375 pg/mL if afib

  • Key exclusion

    • SBP <85 mm Hg or >140 mm Hg

    • eGFR <20

    • Untreated severe ventricular arrhythmia, or use of chronic antiarrhythmic therapy (except amiodarone, beta-blockers, digoxin & CCBs)

    • Certain cardiomyopathies: Severe uncorrected valvular heart disease, hypertrophic or infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis, or clinically significant congenital heart disease

    • ACS, stroke, TIA or cardiac surgery/intervention within 3 months

    • Mechanical hemodynamic support or invasive mechanical ventilation in past 7 days

    • IV inotropes/vasopressors in past 3 days

    • IV diuretics or vasodilators, supplemental O2, non-invasive mechanical ventilation within 12 hours

  • Baseline characteristics

    • Age 64.5 y, 21% female, 78% white

    • 25% enrolled as inpatients, 75% enrolled as outpatients

    • NYHA 2 (53%), 34 (44%), 4 (3%)

    • KCCQ-Total Symptom Score: 69/100 (outpatients ~75, inpatients ~53)

    • LVEF 26.5%

    • MAGGIC risk score 23 (predicts a 1-year risk of death of ~13%)

    • T2DM 40%, AF 27%

    • SBP 116, HR 72, NT-proBNP ~2000, eGFR 59

    • Meds: ACEI/ARB/ARNI 87% (ARNI 20%), BB 94%, MRA 78%, SGLT2i 2.5%

    • Devices: CRT 14%, ICD 32%

Intervention: Omecamtiv mecarbil 25-50 mg BID based on therapeutic drug monitoring

  • Starting dose: 25 mg BID

  • Dose at 12 weeks: 10% discontinued or missing, 25 mg BID (29%), 37.5 mg BID (14%), 50 mg BID (48%)

Therapeutic drug monitoring protocol from final study protocol

Comparator: Matching placebo

Outcomes at median 22 months

Modest reduction in the risk of a primary outcome (time to first composite of cardiovascular death, HF hospitalization or worsening HF requiring urgent outpatient visit): 37.0% vs 39.1% (HR 0.92, 95% CI 0.86-0.99)

However, no differences in:

  • Death from any cause: Omecamtiv mecarbil 25.9% vs placebo 25.9%

    • Hazard ratio (HR) 1.00 (95% confidence interval [CI] 0.92-1.09)

  • First HF hospitalization: 27.7% vs 28.7% (HR 0.95, 95% CI 0.87-1.03)

Conflicting effect on quality of life with questionable clinical importance:

  • In outpatients, change vs placebo: -0.5 (95% CI -1.4 to +0.5)

  • In inpatients, change vs placebo: +2.5 (95% CI +0.5 to +4.5)

No increase in key safety outcomes:

  • Serious adverse events: 57.7% vs 59.4% (HR 0.97, 0.94-1.01)

  • Discontinuation due to adverse events: 9.0% vs 9.3% (HR 0.97, 95% CI 0.85-1.11)

  • Major cardiac ischemic events: 4.9% vs 4.6% (HR 1.06, 95% CI 0.87-1.29)

  • Ventricular tachyarrhythmia: 7.1% vs 7.4% (HR 0.95, 95% CI 0.82-1.11)

Internal validity: Low risk of allocation, performance, detection & attrition bias

  • Computer-generated randomization, stratified by setting (inpatient or outpatient)

  • Allocation concealed by interactive voice/web-response system

  • Participants, clinicians unaware of treatment assignment & drug plasma concentrations (blinded)

  • Loss-to-follow-up 2.1% (unknown vital status or died with incomplete follow-up on non-fatal events)

  • Analysis of the intention-to-treat (ITT) population

Other considerations

Are the results clinically important?

  • Although administered on top of standard of care, the ~8% relative risk reduction of the primary outcome in this trial is quite modest, especially compared with other interventions for HFrEF

    • In addition to the uncertain clinical importance of the primary outcome, it is important to note that omecamtiv mecarbil did not reduce the risk of dying, nor did it have a clear effect on HF hospitalizations.

    • Thus, the main driver of the difference in the primary outcome was worsening HF requiring an urgent outpatient visit, which is far less important than the other 2 components

Generalizability

  • Overall, the participants of this trial represent a sicker population of HFrEF patients at very high risk of death & hospitalizations, as reflected in the high event rates

  • Additionally, only a minority of GALACTIC-HF were treated with contemporary HFrEF drugs (ARNI & SGLT2i)

  • Therefore, the absolute benefits for patients who have less severe HFrEF &/or greater use of ARNIs & SGLT2i are likely to be even smaller

Practical considerations

  • Cost: Unknown as not yet marketed in Canada/US (as of Dec 29, 2020)

  • Routine:

    • Dosing: Requires twice-daily administration.

    • Monitoring: Requires therapeutic drug monitoring at least once to tailor dose for efficacy & safety - longer term requirements unknown. Does not require any electrolyte/renal monitoring.