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

Background: Pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF) represents a major unmet therapeutic need, with several multicenter randomized clinical trials demonstrating lack of benefit with 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 versus placebo in 230 patients with PH-HFpEF. Participants receive either levosimendan (initially 2 mg/day, up-titrated to 3 mg/day) or matching placebo for 12 weeks. The primary endpoint is change in 6-minute walk distance from baseline to Week 12. Secondary endpoints include the changes in 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.