Oral Levosimendan for the Treatment of Pulmonary Hypertension due to Heart Failure With Preserved Ejection Fraction: Rationale and Design of the LEVEL Trial.

BACKGROUND: Pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF) represents a major unmet therapeutic need; several multicenter randomized clinical trials have demonstrated lack of benefit when using conventional pulmonary vasodilators. Recent data suggest that levosimendan, through its unique mechanism as a combined Ca2+ sensitizer and K+-ATP channel activator, may offer benefits in PH-HFpEF by targeting excessive sympathetic activation and splanchnic vasoconstriction.

METHODS: The LEVosimendan to Improve Exercise Limitation in Patients With PH-HFpEF (LEVEL) trial is a multicenter, phase-3, randomized, double-blind, placebo-controlled study evaluating oral levosimendan vs placebo in 230 patients with PH-HFpEF. Participants will receive either levosimendan (initially 2 mg/day, uptitrated to 3 mg/day) or matching placebo for 12 weeks. The primary endpoint is the change in 6-minute walk distance from baseline to week 12. Secondary endpoints include changes in the Kansas City Cardiomyopathy Questionnaire overall summary score, clinical worsening events, N-terminal pro-B-type natriuretic peptide levels, and New York Heart Association functional class.

CONCLUSIONS: LEVEL is the first phase-3 trial to investigate whether oral levosimendan can improve exercise capacity in patients with PH-HFpEF. The results may establish a new therapeutic approach and enhance understanding of the role of splanchnic vasoconstriction in PH-HFpEF pathophysiology.