Hints of Benefit With Levosimendan in Pulmonary Hypertension Due to HFpEF

For patients who have pulmonary hypertension and heart failure with preserved ejection fraction (PH-HFpEF), treatment with levosimendan (Simdax; Tenax Therapeutics) can improve both pulmonary congestion and submaximal exercise capacity when compared with placebo, according to the results of a small study.

While the phase II study missed its primary endpoint, which was a reduction in pulmonary capillary wedge pressure (PCWP) during exercise, levosimendan did reduce PCWPs across the rest, leg raise, and exercise stages. It also led to an improvement in 6-minute walk distance, investigators reported online April 7, 2021, in the Journal of the American College of Cardiology: Heart Failure.

“This is a very small study, but the results are very encouraging,” lead investigator Daniel Burkhoff, MD, PhD (Cardiovascular Research Foundation, New York, NY), told TCTMD. “It’s a pilot trial, and those don’t usually get wide coverage, but what’s exciting to me is that it’s not usual to get an exercise response in a pilot trial of such a small size. The hemodynamic responses were significant, especially at 24 hours and consistent at 6 weeks.”

Burkhoff explained that patients typically develop HFpEF first, with PH developing as a consequence of the lungs being exposed to high filling pressures. The World Health Organization classifies this type of PH as group 2, where the condition is caused by left-sided heart disease, such as LV systolic or diastolic dysfunction, among other factors. “Once you develop pulmonary hypertension, the patient’s prognosis worsens significantly,” said Burkhoff.    

Patients with PH-HFpEF have substantial impairments in exercise capacity resulting from higher PCWPs at rest and during exercise. Sustained exposure to these hemodynamic abnormalities can lead to the development of right-sided HF “with all of its signs and symptoms, including markedly reduced exercise tolerance and mortality,” according to investigators. Until recently, there were no approved treatments for HFpEF, although the US Food and Drug Administration recently approved sacubitril/valsartan on the basis of the PARAGON-HF trial.

At present, however, there are approved treatments for PH-HFpEF.

Multiple Effects on CV System

Levosimendan has multiple effects on the cardiovascular system. Mechanistically, the drug is classified as an inodilator and its vasodilatory effects are attributed to the activation of the adenosine triphosphate (ATP)-sensitive potassium channels in the arterial and venous smooth muscle cells. It is also a phosphodiesterase inhibitor with inotropic and lusitropic effects, as well as a calcium sensitizer. The drug was selected for study in patients with PH-HFpEF because of its potential impact on right-ventricle contractility, explained Burkhoff. The failing right ventricle in patients with PH is thought to contribute to their reduced exercise tolerance and mortality risk.

The study known as Hemodynamic Evaluation of Levosimendan in Patients with PH-HFpEF (HELP), was conducted in two parts. In phase 1, patients with PH-HFpEF were treated with a 24-hour open-label infusion of levosimendan. Those who responded—with more than 4-mm Hg reduction in PCWP during 3 minutes of exercise at 25 watts and no more than a 10% decrease in cardiac index after the 24-hour infusion—qualified for phase 2: weekly levosimendan infusions or placebo for 5 weeks via a peripherally inserted central catheter using a continuous ambulatory delivery device pump.

At study outset, patients underwent a standard right-heart catheterization to measure central venous pressure and systolic and diastolic arterial pressures, as well as mean pulmonary arterial pressure, PCWP, and cardiac output. Of the 37 patients who responded to treatment, 18 were randomized to levosimendan and 19 to placebo for 5 more weeks. The primary efficacy endpoint, which was the between-group difference in the change of PCWP during exercise from baseline to 6 weeks, was not statistically significant (1.4 mm Hg; P = 0.65). However, when analyzed across all the exercise stages—incorporating measurements at rest, with legs raised into the pedals of a supine ergometer for 5 minutes, and during 3 minutes of exercise at 25 watts—there was an average reduction of 3.9 mm Hg in PWCP favoring levosimendan (P = 0.047). The 6-minute walk test distance increased by 16.6 m in the levosimendan group and decreased by 12.7 m in the placebo group, a mean difference of 29.3 m that was statistically significant (P = 0.03). 

“When you look at the data in aggregate, first of all in the first 24 hours, even when including the nonresponders in the mix, we saw very, very significant effects on hemodynamics in decongestion, especially for reducing the wedge pressure and reducing the central venous pressure. So, bilateral decongestion of both the systemic and pulmonary beds,” said Burkhoff. “That was [seen] at rest, at volume challenge with legs up, and with low-level exercise. By the way, for these patients their congestion increases dramatically when they do low-level exercise. So that was gratifying to see such an acute effect.”

There were no significant changes between baseline and 6 weeks (either within or between groups) in systemic arterial pressure, cardiac index, systemic vascular resistance, pulmonary vascular resistance, other measures of pulmonary vascular properties, or right ventricular stroke work in either group.     

Despite the known mechanistic properties of levosimendan, Burkhoff said they believe the drug might exert its effects via venodilation. The group is in the midst of pulling together another paper showing that levosimendan had no effect on the right ventricle, no effect on lung vasculature, and only a small, nonsignificant effect on the systemic vasculature. Selective venodilation is a “a relatively unexplored target for heart failure,” said Burkhoff. With venodilation, there is a shift of blood from the central circulation to the peripheral circulation, which in turns lowers venous pressures of the systemic and pulmonary circulation.

Next steps will involve a larger, phase III study, which is currently being drawn up and will hopefully start in 2022, said Burkhoff.

Note: Burkhoff is an employee of the Cardiovascular Research Foundation, the publisher of TCTMD.