Elsevier

JACC: Heart Failure

Volume 9, Issue 5, May 2021, Pages 360-370
JACC: Heart Failure

Mini-Focus Issue: Insights From Acute Heart Failure Trials
Clinical Research
Levosimendan Improves Hemodynamics and Exercise Tolerance in PH-HFpEF: Results of the Randomized Placebo-Controlled HELP Trial

https://doi.org/10.1016/j.jchf.2021.01.015Get rights and content
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open access

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)

Key Words

exercise
heart failure with preserved ejection fraction (HFpEF)
hemodynamics
levosimendan
pulmonary hypertension

Abbreviations and Acronyms

CO
cardiac output
CVP
central venous pressure
HF
heart failure
HFpEF
heart failure with preserved ejection fraction
MMRM
mixed-effects model with repeated measurements
PCWP
pulmonary capillary wedge pressure
PH
pulmonary hypertension
PH-HFpEF
pulmonary hypertension in the setting of heart failure with preserved ejection fraction
PVR
pulmonary vascular resistance
SVR
systemic vascular resistance

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