An inotropic and vasodilating drug with few clinical-trial victories in heart failure (HF) or other low-cardiac-output conditions showed some limited success in a specific subtype of HF with preserved ejection fraction (HFpEF).
Patients with pulmonary hypertension on top of HFpEF (PH-HFpEF) showed improvements in pulmonary capillary wedge pressure (PCWP), defined as a composite of resting and exercise readings, after six once-weekly infusions of levosimendan. Also for these patients, 6-minute walk test (6MWT) distance was significantly prolonged compared to the placebo group.
Those benefits in the phase-2 study were for secondary endpoints; no significant difference was seen between levosimendan and placebo groups in the primary endpoint of PCWP during bicycle exercise. But the benefits were enough to convince the researchers and some observers that the drug, which appeared safe during the study, should be further explored in larger trials of the PH-HFpEF phenotype.
The 6MWT improvement with levosimendan “to me is really something, because to my knowledge, this is the first medicine that has actually improved 6-minute walk distance in any patient population with HFpEF,” Barry A. Borlaug, MD, Mayo Clinic and Foundation, Rochester, Minnesota, told theheart.org | Medscape Cardiology.
Borlaug said such patients with PH-HFpEF, with at least moderate pulmonary hypertension and a high PCWP, probably make up only 10% to 20% of all patients with HFpEF. They’re “skewed to the far extreme end of the disease severity spectrum. And they’re different — their hemodynamics are different, and their right ventricles are more dilated and weaker” compared to average HFpEF patients seen in practice.
So if the drug emerges as an effective HFpEF therapy, “it wouldn’t be for everybody,” said Borlaug, who presented the Hemodynamic Evaluation of Levosimendan in Patients With PH-HFpEF (HELP) study on October 3 at the Heart Failure Society of America (HFSA) Virtual Annual Scientific Meeting 2020.
Mandeep R. Mehra, MD, told theheart.org | Medscape Cardiology that he has misgivings about applying the study’s results “to the real world of HFpEF, which is so heterogeneous.”
A calcium-sensitizing agent like levosimendan seems worth exploring for PH-HFpEF as defined in the study, “but it’s a concept where, as you advance it into the real world, you’ll encounter difficulties in phenotyping patients” and identifying those more likely to respond, said Mehra, from Brigham and Woman’s Hospital, Boston, Massachusetts.
“In a 30-patient or 40-patient study, you can tightly control the phenotype of patients entering the trial. In the real world, you can’t. If there’s anything we’ve learned, HFpEF is a poorly diagnosed entity,” he said. “My suspicion is that less than 10% of patients would actually be able to qualify for the phenotype where a drug like levosimendan would acutely show a hemodynamic response.”
The concept behind the study, said Mehra in an interview, “is an interesting one, but it’s going to be relegated to top centers who have meticulous experience with hemodynamic assessments, who can phenotype patients very accurately with imaging. And then its global impact is most likely going to be fairly low.”
Levosimendan is approved in dozens of countries worldwide to treat HF, surgical patients with low cardiac output, ventricular dysfunction in sepsis, and other conditions. It isn’t approved in the United States or Canada and has performed poorly in randomized trials of patients with acute HF or septic shock, those undergoing coronary bypass or other cardiac surgeries, and — using an oral form — patients with chronic HF.
Borlaug said the levosimendan dosage in the HELP trial is less than half what was used in the prior reduced-ejection-fraction HF trials, and the previously observed potential for proarrhythmia is probably less an issue in the HFpEF setting. “We think it will behave a bit differently, and not repeat history,” he said during the Q&A session after his formal presentation.
The study enrolled patients in New York Heart Association class 2-3 with a left-ventricular ejection fraction of at least 40%, mean pulmonary artery pressure of ≥35 mmHg, and a PCWP of at least 20 mmHg.
Researchers randomly assigned only those who hemodynamically responded to levosimendan during an initial run-in phase on the regimen that would subsequently be given double-blind weekly: a 24-hour IV infusion of 2.5 mg/mL at 0.1 µg/kg/min.
After baseline hemodynamic testing and one 24-hour course of the drug, 34 patients who showed at least a 4 mmHg drop in exercise PCWP were assigned to receive levosimendan or placebo infusions once a week for 5 more weeks. The 18 actively treated and 19 control patients were predominantly White women whose mean age was 68.
The two groups showed no significant difference in the primary endpoint of change in PCWP at bicycle exercise after the sixth infusion; the mean change over time was only 1.4 mmHg lower in the levosimendan group (P = .65).
But PCWP, according to a mixed-effect model that combined measurements at rest, during passive leg raise, and exercise, showed a 3.9 mmHg drop from baseline to week 6 among the patients on active drug compared to placebo, an improvement that just reached significance (P = .047).
Distances on 6MWT at baseline averaged 290 m and 280 m in the levosimendan and placebo groups, respectively. Actively treated patients gained approximately 17 m after 6 weeks, compared to a drop of about 12 m for the control group, for a total 6MWT difference of 29 m (P = .033).
There were few adverse events and no significant differences between the groups; two levosimendan patients and one control patient experienced worsening HF.
“All in all, significant evidence to support a phase-3 trial of this therapy,” Kavita Sharma, MD, Johns Hopkins University School of Medicine, Baltimore, Maryland, said as the invited discussant for this presentation.
Still, she said, “the study did not meet the primary endpoint of changing wedge pressure with exercise compared to placebo ― which is interesting, given that patients had to demonstrate a decrease in wedge pressure to enroll.”
That anomaly, Sharma said, might possibly have resulted from inadequate dosing or a prolonged interval between the final infusion and PCWP measurement at right-heart catheterization performed at week 6 compared to the run-in phase.
HELP was sponsored by Tenax Therapeutics. Borlaug discloses research support from Tenax, Medtronic, GlaxoSmithKline, Novartis, Mesoblast, Corvia, and AstraZeneca and serving on an advisory board or consulting for Aria, Actelion, Boehringer-Ingelheim, Imbria, Janssen, Merck, Novartis, Lilly, Novo Nordisk, Pfizer, and VADovations. Mehra discloses consulting or serving on an advisory board for Abbott, Medtronic, Janssen, Leviticus, NupulseCV, FineHeart, Portola, Bayer, and Mesoblast. Sharma discloses receiving honoraria for speaking from Novartis and Janssen and serving on an advisory board or consulting for Novartis, Janssen, and Bayer.
Heart Failure Society of America (HFSA) Virtual Annual Scientific Meeting 2020: Late Breaking Clinical Trials I. Levosimendan Improves Hemodynamics and Submaximal Exercise Capacity in PH-HFpEF: Primary Results From the Help-PH-HFpEF Multicenter Randomized Controlled Trial. Presented October 3, 2020.