Levosimendan Improves Hemodynamics and Exercise Tolerance in PH-HFpEF: Results of the Randomized Placebo-Controlled HELP Trial

Abstract

Objectives: The purpose of this study was to evaluate the effects of intravenous levosimendan on hemodynamics and 6-min walk distance (6MWD) in patients with pulmonary hypertension and heart failure with preserved ejection fraction (PH-HFpEF).

Background: There are no proven effective treatments for patients with PH-HFpEF.

Methods: Patients with mean pulmonary artery pressure (mPAP) ≥35 mm Hg, pulmonary capillary wedge pressure (PCWP) ≥20 mm Hg, and LVEF ≥40% underwent 6MWD and hemodynamic measurements at rest, during passive leg raise, and supine cycle exercise at baseline and after an open-label 24-h levosimendan infusion (0.1 μg/kg/min). Hemodynamic responders (those with ≥4 mm Hg reduction of exercise-PCWP) were randomized (double blind) to weekly levosimendan infusion (0.075 to 0.1 ug/kg/min for 24 h) or placebo for 5 additional weeks. The primary end point was exercise-PCWP, and key secondary end points included 6MWD and PCWP measured across all exercise stages.

Results: Thirty-seven of 44 patients (84%) met responder criteria and were randomized to levosimendan (n = 18) or placebo (n = 19). Participants were 69 ± 9 years of age, 61% female, and with resting mPAP 41.0 ± 9.3 mm Hg and exercise-PCWP 36.8 ± 11.3 mm Hg. Compared with placebo, levosimendan did not significantly reduce the primary end point of exercise-PCWP at 6 weeks (-1.4 mm Hg; 95% confidence interval [CI]: -7.8 to 4.8; p = 0.65). However, levosimendan reduced PCWP measured across all exercise stages (-3.9 ± 2.0 mm Hg; p = 0.047). Levosimendan treatment resulted in a 29.3 m (95% CI: 2.5 to 56.1; p = 0.033) improvement in 6MWD compared with placebo.

Conclusions: Six weeks of once-weekly levosimendan infusion did not affect exercise-PCWP but did reduce PCWP incorporating data from rest and exercise, in tandem with increased 6MWD. Further study of levosimendan is warranted as a therapeutic option for PH-HFpEF. (Hemodynamic Evaluation of Levosimendan in Patients With PH-HFpEF [HELP]; NCT03541603).

Keywords: exercise; heart failure with preserved ejection fraction (HFpEF); hemodynamics; levosimendan; pulmonary hypertension.

Conflict of interest statement

Funding Support and Author Disclosures This study was supported by TENAX Therapeutics. TENAX participated in the execution of the study. Data were collected and analyzed by a clinical research organization. Analysis and interpretation of the data were performed by an independent statistician and the investigators (no role of sponsor). The manuscript was prepared by the investigators. The sponsor was allowed to review the manuscript before submission but had no role in preparing or approval. Dr. Burkhoff has received an institutional research grant from TENAX Therapeutics; and advisory board/consulting from Impulse Dynamics, Corvia Medical, and Axon Therapies. Dr. Borlaug has received research grants from the National Institutes of Health (R01 HL128526, U01 HL125205), AstraZeneca, Corvia, Medtronic, Mesoblast, GlaxoSmithKline, and TENAX Therapeutics; and advisory board/consulting fees for Aria, Actelion, Boehringer-Ingelheim, Imbria, Janssen, Merck, Novartis, Lilly, Novo Nordisk, Pfizer, and VADovations. Dr. Shah has received research grants from the National Institutes of Health (R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423), American Heart Association (16SFRN28780016), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Axon Therapeutics, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Cardiora, CVRx, Cytokinetics, Eisai, GlaxoSmithKline, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi, Shifamed, TENAX, and United Therapeutics. Dr. Zolty has received research grants from the National Institutes of Health (P01 HL108797, R01 HL134905, R01 LM01), Actelion, TENAX Therapeutics, Gossamer Bio, Lung Biotech, and United Therapeutics; consulting/advisory board for Morphegen-IX, Vivus, Actelion, and Pfizer; and patent holder of FK506 for the treatment of pulmonary hypertension. Dr. Tedford has received institution research funding from TENAX Therapeutics as part of this study; has consulting relationships with Medtronic, Aria CV, Acceleron, Arena Pharmaceuticals, and United Therapeutics; is on the steering committees for Medtronic, Acceleron, and Abbott; on the research advisory board for Abiomed; and does hemodynamic core laboratory work for Actelion and Merck. Dr. Thenappan has received research grants from the Cardiovascular Medical Research and Education Fund, Lillehei Heart Institute High Risk and High Reward Award, United Therapeutics, and TENAX Therapeutics; and consulting/advisory board for United Therapeutics, Actelion, and Altavant Sciences. Dr. Zamanian has consulted for United Therapeutics, Actelion, and Alnylam. Dr. Mazurek has received advisory board honoraria from Actelion Pharmaceuticals and United Therapeutics; has received speaker honoraria from Abbott; and has received research support from Actelion, Complexa, and Corvia. Dr. Rich has consulted for Abbott, Medtronic, Boehringer-Ingelheim, and Novartis. Dr. Simon has received research grants from the National Institutes of Health (R01 AG058659, P01 HL103455), Aadi Biosciences, and Novartis; and has received consulting fees from Actelion, Acceleron, Altavant, United Therapeutics. Dr. Chung has received consulting fees from Abbott, Medtonic, Intershunt, LivaNova, CVRx, and EBR. Dr. Raza has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Majure has received a research grant from TENAX Therapeutics. Dr. Lewis has received research grants from the National Institutes of Health (1R01HL131029, R01HL151841, and AHA GPSGC24800006), Amgen, Applied Therapeutics, AstraZeneca, Corvia, Cytokinetics, and Novartis; and consulting/advisory board for American Reagent, AstraZeneca, Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb, Cytokinetics, Ironwood, Merck, Novartis, and Pfizer. Dr. Preston has received research grants from Acceleron, Actelion, Complexa, PhaseBio, United Therapeutics, and TENAX Therapeutics; steering committee for Acceleron, Actelion, and United Therapeutics; is on the consulting/advisory board for Actelion, Gilead, Liquidia, and United Therapeutics; and data and safety monitoring board for Pfizer. Dr. Rich has received consulting from TENAX Therapeutics.

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