DOI: 10.1097/ms9.0000000000005249 ISSN: 2049-0801

Effectiveness of vericiguat in heart failure across ejection fraction phenotypes: a comprehensive meta-analytic trial sequential analysis and meta-regression analysis

Ibrahim Khalil, M. Rafiqul Islam, Manisha Das, Sunjida Amin Promi, Sajjad Ghanim Al-Badri, Sakib Abrar, Afsana Rahman Maliha, Avijit Debnath, Md Ekramul Islam, AKM Mushfiquzzaman, Md. Imran Hossain
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Background:

Heart failure (HF) remains a global health challenge, with distinct phenotypes – heart failure with reduced ejection fraction (HFrEF ≤40%) and heart failure with preserved ejection fraction (HFpEF ≥50%) – requiring tailored therapies. Vericiguat, a soluble guanylate cyclase stimulator, targets the nitric oxide -soluble guanylate cyclase-cyclic guanosine monophosphate pathway to reduce cardiac stress, showing promise in HFrEF but with unclear efficacy in HFpEF. This meta-analysis evaluates Vericiguat’s effectiveness across HF phenotypes using trial sequential analysis (TSA) and meta-regression.

Methods:

Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we included eight randomized controlled trials (17,381 patients) comparing Vericiguat to control in HFrEF and HFpEF patients. Outcomes assessed were hospitalization for HF, all-cause mortality, cardiovascular mortality, and the composite endpoint (cardiovascular death or first hospitalization). Random-effects models calculated pooled risk ratio (RR). TSA controlled for type I/II errors, and meta-regression explored covariates (age, sex, NT-proBNP, HF subgroup). Sensitivity analyses assessed robustness.

Results:

Vericiguat reduced hospitalization for HF (RR: 0.90, 95% confidence interval [CI]: 0.82–0.98, P = 0.0201) and the composite endpoint (RR: 0.88, 95% CI: 0.78–0.99, P = 0.035), but TSA indicated inconclusive evidence (required information sizes: 29,929 and 48,016 patients, respectively). No significant effect was observed for all-cause mortality (RR: 0.98, 95% CI: 0.68–1.40, P = 0.904) or cardiovascular mortality (RR: 0.91, 95% CI: 0.64–1.30, P = 0.6091). Heterogeneity was minimal ( I 2  = 0–17%). Meta-regression showed no significant covariate effects, though HFrEF trended toward benefit ( P = 0.1329). Sensitivity analysis identified VITALITY-HFpEF as an influential outlier.

Conclusions:

Vericiguat modestly reduces hospitalization and composite outcomes in HF, particularly HFrEF, but lacks mortality benefits. Larger, phenotype-specific trials are needed to confirm efficacy, especially in HFpEF, to refine Vericiguat’s role in HF management.

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