Levosimendan improves outcomes in heart failure patients with pulmonary hypertension, HELP trial

Pulmonary hypertension (PH) associated with heart failure (HF) with preserved ejection fraction (PH-HFpEF) is a debilitating form of PH. PH-HFpEF patients display marked impairments in exercise capacity associated with elevation in pulmonary capillary wedge pressures (PCWPs) at rest and during exercise. There are currently no approved therapies for this condition. Results from a randomised control HELP trial published in JACC's April issue have shown benefits of levosimendan in this condition.

PH-HFpEF patients display marked impairments in exercise capacity associated with elevation in pulmonary capillary wedge pressures (PCWPs) at rest and during exercise. Over time, sustained exposure to these hemodynamic abnormalities leads to development of right-side HF, with all of its signs and symptoms, including markedly reduced exercise tolerance and increased mortality.

Levosimendan is a unique drug whose properties include potassium channel activation, myofilament calcium sensitization, and phosphodiesterase-3 inhibition. In patients with acute decompensated HF with reduced ejection fraction (HFrEF), levosimendan produces dose-dependent increases of cardiac output (CO) and decreases of PCWP, central venous pressure (CVP), pulmonary vascular resistance (PVR), and systemic vascular resistance (SVR).

The purpose of this study was to evaluate the effects of intravenous levosimendan on hemodynamics and 6-min walk distance (6MWD) in patients with PH-HFpEF. 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 0.1ug/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.

Compared with placebo, levosimendan did not significantly reduce the primary end point of exercise-PCWP at 6 weeks. 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. Levosimendan was well tolerated, with no difference in the adverse event profile between treatment and placebo and no evidence of proarrhythmia.

The observed increase of 6MWD is significant because such changes have been strongly correlated with improvements of quality of life in HFpEF patients. Indeed, increased 6MWD (a measure of submaximal exercise tolerance) may be linked to reductions of CVP and PCWP at rest and during leg raise, which signifies increased capacity to deal with a low-intensity hemodynamic stress. It is also noteworthy that reductions of resting CVP and mPAP are both predictors of improved survival in patients with PH, and reduction of resting PAP is also a predictor of improved survival in the HFpEF population in general.

Notably, the HELP study is the first to show significant beneficial effects on hemodynamics and exercise tolerance in PH-HFpEF in a double-blind multicenter study. Although the study included a small number of patients and the primary end point was not met: 1) an analysis including data at rest, during leg raise, and at 25 W showed a significant decrease of PCWP; and 2) there was a significant increase in 6-min walk distance. Both findings support further study of levosimendan in PH-HFpEF.

Source: JACC J Am Coll Cardiol HF. Apr 07, 2021. Epublished DOI: 10.1016/j.jchf.2021.01.015.