Efficacy and Safety of Vericiguat in Heart Failure: A Systematic Review and Meta-Analysis

Patients with heart failure (HF) experience high rates of hospitalization and death, and outcomes are particularly unfavorable following recent clinical worsening or decompensation. Vericiguat is an oral soluble guanylate cyclase (sGC) stimulator that enhances nitric oxide-cyclic guanosine monophosphate signaling, with potential benefits for vascular tone and myocardial function. With the completion of recent randomized trials, an updated synthesis of the evidence is warranted. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of vericiguat across heart failure phenotypes. We searched PubMed, Embase, Web of Science, and the Cochrane Library for randomized controlled trials comparing vericiguat with placebo in chronic HF through September 2025. Five eligible trials (12,877 participants) were included. The primary efficacy outcome was a composite of cardiovascular death and first HF hospitalization. Data were pooled using a random-effects risk ratio (RR) model, and prespecified subgroup analysis was performed by HF phenotype: HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Among patients with HFrEF (three trials; n = 11,611), vericiguat was associated with a lower risk of the primary composite outcome (RR 0.92; 95% confidence interval (CI), 0.87-0.98; P = 0.009). In a secondary, hypothesis-generating analysis, all-cause mortality was also lower with vericiguat (RR 0.91; 95% CI, 0.84-0.99; P = 0.03); this finding should be interpreted with caution because all-cause mortality was not a prespecified primary or co-primary endpoint in either pivotal Phase 3 trial. No clinical benefit was observed in patients with HFpEF. Vericiguat increased the relative risk of symptomatic hypotension (RR 1.20; 95% CI, 1.07-1.35; P = 0.002) but did not increase the risk of serious adverse events (RR 0.94; 95% CI, 0.89-1.00; P = 0.04). Overall, moderate-certainty GRADE evidence suggests that vericiguat's benefit is concentrated in higher-risk HFrEF populations, particularly those with recent worsening. The evidence does not support its use for the primary composite outcome in the broader, stable ambulatory HFrEF population or in patients with HFpEF.