Macitentan for Heart Failure With Preserved or Mildly Reduced Ejection Fraction and Pulmonary Vascular Disease: Results of the SERENADE Randomized Clinical Trial and Open-Label Extension Study.

Summary

In the SERENADE RCT of HFpEF/HFmrEF with pulmonary vascular disease, macitentan did not reduce NT-proBNP or improve clinical outcomes versus placebo despite an enrichment design that excluded fluid retention. Only 142 of 230 enrolled patients were randomized after sequential run-ins.

Key Findings

• Macitentan did not reduce NT-proBNP at 24 weeks (geometric mean ratio 1.02, 90% CI 0.88–1.19).
• No improvement in KCCQ clinical summary score or time to worsening HF by 52 weeks.
• Enrichment run-ins excluded many patients (28 during placebo, 60 during macitentan), leaving 142 randomized of 230 enrolled.

Clinical Implications

Avoid routine use of macitentan (and likely endothelin receptor antagonists) in HFpEF/HFmrEF with pulmonary vascular disease; focus on alternative mechanisms and individualized hemodynamic targets.

Limitations

• Modest randomized sample size (n=142) after extensive run-in exclusions limits power and generalizability.
• Primary endpoint relied on surrogate biomarker (NT-proBNP) with 24-week horizon.

Future Directions

Investigate alternative pulmonary vascular and RV-targeted pathways in HFpEF, integrate precise hemodynamic phenotyping, and test combination or phenotype-guided therapies.