GALACTIC-HF: Omecamtiv mecarbil benefit on CV events more pronounced in patients with low BP?

The benefits of the selective cardiac myosin activator omecamtiv mecarbil on the risk of cardiovascular (CV) events in patients with heart failure with reduced ejection fraction (HFrEF) may be more evident in the difficult-to-treat population of patients with low systolic blood pressure (SBP), according to results of the phase III GALACTIC-HF trial presented at the Heart Failure 2022 annual congress.

Participants in this international, double-blind trial were 8,232 patients (~21 percent female) with New York Heart Association class II–IV HFrEF (left ventricular ejection fraction [LVEF] ≤35 percent) and SBP ≥85 to ≤140 mg Hg. Participants had eGFR levels of ≥20 mL/min/1.73 m² and an elevated BNP/NT-proBNP level, and were either currently hospitalized for HF or had an urgent emergency department visit or hospitalization for HF within 1 year pre-screening. They were randomized 1:1 to receive oral omecamtiv mecarbil (starting dose 25 mg BID followed by a pharmacokinetic-guided dose of 25, 37.5, or 50 mg BID) or placebo plus standard HF therapies.

The present substudy compared the CV outcomes between participants with low SBP (≤100 mm Hg; n=1,473 [17.9 percent]; mean age 63.4 years) with those with SBP >100 mm Hg (n=6,759 [82.1 percent]; mean age 64.8 years).

Compared with those with SBP >100 mm Hg, participants with low SBP were more likely to have atrial fibrillation or flutter and higher NT-proBNP levels, but less likely to have hypertension, type 2 diabetes, or ischaemic HF. There were also significant between-group differences with regard to types of medications and certain vital signs.

Participants with low SBP had an increased risk of the primary outcome composite of CV death or first HF event (adjusted hazard ratio [adjHR], 1.05 per 5 mm Hg decrease in SBP; p<0.001). [Heart Failure 2022, Late-Breaking Trials – Pharmacological treatment I]

The results were consistent for both first HF event and CV death (adjHRs, 1.04 and 1.08 per 5 mm Hg decrease in SBP; p<0.001 for both).

The impact of omecamtiv mecarbil vs placebo on the composite outcome was greater among patients with low SBP (absolute risk reduction [ARR], 9.8 per 100 patient-years; HR, 0.81) compared with those with SBP >100 mm Hg (ARR, 1.2 per 100 patient-years; HR, 0.95; p_interaction=0.051).

In terms of placebo-corrected change between baseline and week 24, the effect of omecamtiv mecarbil on certain vital signs and laboratory values did not significantly differ between participants with SBP ≤100 and >100 mm Hg, such as creatinine (difference, -0.02 vs 0.01 mg/dL; p=0.13), NT-proBNP ratio (difference, 0.82 vs 0.91 pg/mL; p=0.06), potassium (difference, -0.02 vs 0.01 mmol/L; p=0.36), and troponin (difference, 5 vs 4 ng/L; p=0.89).

Adverse event (AE) rates did not significantly differ between omecamtiv mecarbil and placebo recipients, regardless of SBP. These included ventricular tachyarrhythmia (9.8 percent vs 11.5 percent [SBP ≤100 mm Hg] and 7.5 percent vs 7.6 percent [SBP >100 mm Hg]), first major cardiac ischaemic events (3.6 percent vs 3.8 percent and 5.2 percent vs 4.7 percent), and myocardial infarction (2.3 percent vs 2.5 percent and 3.1 percent vs 3.0 percent).

Among participants with low SBP, treatment-emergent serious AEs were less common with omecamtiv mecarbil than placebo (63.5 percent vs 72.0 percent; p<0.001), as was the first incidence of stroke (0.8 percent vs 2.5 percent; p=0.009).

“Low SBP identifies patients with HFrEF at increased risk of clinical events and who poorly tolerate guideline-directed medical therapy,” said study author Professor Marco Metra from the University of Brescia in Brescia, Italy. “These patients are typically excluded from HFrEF trials due to the hypotensive effects of many therapies for HFrEF.”

As omecamtiv mecarbil directly improves cardiac function without reducing BP, it may present a useful alternative in this specific patient population, he said.

“[In this study,] patients with symptomatic, chronic HFrEF … with low baseline SBP experienced [an] increased risk of HF outcomes compared with patients with SBP >100 mm Hg,” said Metra.

“[They also experienced a] large absolute and relative risk reduction of the primary composite endpoint of CV death or first HF event with omecamtiv mecarbil compared with placebo,” he said.