Myosin activator less effective in patients with HFrEF and AF or atrial flutter

Influence of Atrial Fibrillation on Efficacy of Omecamtiv Mecarbil in Heart Failure: The GALACTIC-HF Trial

Presented at the ESC HF 2021 by Scott Solomon (Boston, MA, USA)

Introduction and methods

The GALACTIC-HF trial demonstrated that omecamtiv mecarbil, a cardiac myosin activator, reduces the composite outcome of a first HF event or CV death in patients with HFrEF, compared to placebo.

AF is common in patient with HF and contributes substantially to morbidity and mortality. Although AF has not influenced the treatment effect of RAASi, it may modify the treatment effect of beta-blockers. The presence of AF or atrial flutter (AFL) at baseline in the GALACTIC-HF trial modified the effectiveness of omecamtiv mecarbil with treatment being less effective in patients with AF or AFL at baseline.

This subanalysis assessed the influence of baseline AF or AFL on the treatment effectiveness of omecamtiv mecarbil in patients with HFrEF and further explored potentially other factors that may have influenced the effectiveness.

The GALACTIC-HF trial was a multicenter, international, randomized, double-blind, placebo-controlled, event-driven, phase 3 study. Inclusion criteria were: chronic HF, NYHA II-IV, LVEF ≤35%, elevated BNP/NT-proBNP that had to be 3 fold increased in patients with baseline AF/AFL, SBP ≥85 mm Hg, and eGFR ≥20 mL/min/1.73m². The trial included patients who were hospitalized for HF (inpatients) or who had been hospitalized or had an urgent visit to the hospital due to HF within 1 year prior to screening (outpatients). The total amount of patients with AF/AFL (n=2245) at baseline was capped at ~25%. Patients were randomized (1:1) to omecamtiv mecarbil (using a pharmacokinetic-guided dose selection) or placebo in addition to standard therapy.

Results

• The proportion of patients with baseline AF or AFL increased with increasing LVEF

• The treatment effect of omecamtiv mecarbil vs. placebo for the primary outcome was less in patients with baseline AF or AFL compared to patients without AF or AFL (Pinteraction=0.012). Similar modified treatment effects for patients with and without AF or AFL were observed for CV death (Pinteraction=0.002), all-cause death (Pinteraction<0.001), and HF hospitalization (Pinteraction=0.12).

• The treatment effect of omecamtiv mecarbil for the primary outcome was less in patients with baseline AF/AFL who were treated with digoxin vs. non-users (HR 1.36, 95% CI: 1.08-1.70 vs. HR 0.94, 95% CI:0.81-1.08, Pinteraction=0.007). This modified treatment effect was also observed for CV death, all-cause death, and HF hospitalization. In contrast, digoxin treated patients without baseline AF/AFL had no effect modifications.

• There was no pharmacokinetic interaction between digoxin and omecamtiv mecarbil. Also, the digoxin doses of patients were similar in both treatment arms (P=0.85). However, a pharmacodynamic interaction between omecamtiv mecarbil and digoxin in patients with AF/AFL cannot be ruled out.

• There were fewer serious adverse events of AF in the omecamtiv mecarbil treatment arm compared to the placebo arm (P=0.046).

Conclusion

AF or AFL modified the treatment effect of omecamtiv mecarbil, with a greater treatment benefit in HFrEF patients without AF/AFL at baseline. Treatment effect modifications were prominent in digoxin treated patients with AF/AFL with almost no effect modification in non-users with AF or AFL. However, digoxin did not modify the treatment effect in patients without AF/AFL.

These results, said Scott Solomon, suggest that caution should be exercised when treating patients with HFrEF and in AF/AFL with both digoxin and omecamtiv mecarbil.

– Our coverage of ESC HF 2021 is based on the information provided during the congress –