SEVILLE, SPAIN — Periodic administration of the intravenous inodilator levosimendan (Orion Pharma) is not only safe and tolerable for patients with advanced, chronic heart failure (HF), it may also improve clinical outcomes, suggests new research[1].

The Levosimendan Intermittent Administration in Outpatients: Effects on Natriuretic Peptides in Advanced Chronic Heart Failure (LION-HEART) trial of 69 adults from 12 centers in Spain showed that those who were randomly assigned to receive 6-hour cycles of IV levosimendan had significantly reduced concentrations of natriuretic peptides (N-terminal pro-brain natriuretic peptide [NT-proBNP]) after 12 weeks vs those receiving placebo (the primary end point), as well as significantly fewer HF hospitalizations and a combination of all-cause deaths/hospitalizations (secondary end points).

In addition, 91% of the treatment group and 81% of the placebo group received all scheduled infusions.

"These positive effects of levosimendan on NT-proBNP levels translated into clinical improvements," Dr Josep Comín-Colet (Hospital del Mar Medical Research Institute, Barcelona, Spain) told attendees at a late-breaking trials session at the Heart Failure Congress 2015 of the European Society of Cardiology Heart Failure Association.

Dr Josep Comín-Colet

Comín-Colet later told heartwire from Medscape that the investigators were happily surprised with the secondary outcomes—and with the low number of discontinuations in the treatment arm. "Patients looked at it as something they just needed to go through, like cycles of chemotherapy if they had had cancer," he said.

Of course, he noted that bigger studies are needed to see whether the clinical outcomes can be replicated, but, at least for now, "the findings are important for a patient population that was very sick. Perhaps we have something that can keep them stable until you can do something more, such as a transplant or [left ventricular assist device] LVAD."

Limited Therapeutic Options

As reported by heartwire , past research has shown some benefit from levosimendan for patients with acute decompensated HF. However, Comín-Colet noted that "there are limited therapeutic options" for advanced, chronic-HF patients. So the investigators sought to determine whether intermittent administration of this medication would be safe and effective in this particular population.

"This was supposed to be a proof-of-concept study. We chose a primary end point based on biomarkers because we first wanted to prove that the short infusions would have certain biological effects on these patients," explained Comín-Colet.

A total of 48 older outpatients (mean age 68 years; 85% men) were randomly assigned to receive six cycles of 6-hour levosimendan infusion at a dose of 0.2 µg/kg/min without bolus every other week for 3 months total, and 21 were assigned to receive matching placebo (mean age 63 years; 76% men).

All participants had LVEF <35% and the persistence of NYHA class 3 or 4 for at least 4 weeks and had undergone intravenous therapy in the previous year for episodes of systemic or pulmonary congestion.

At the end of 12 weeks, the levosimendan group had significantly lower area under the curve (AUC) of mean NT-proBNP than the placebo group (325×103 vs 485×103, P=0.002). Plus, there was a greater change in NT-proBNP concentrations from baseline in the treatment group (P<0.001).

A total of 23% of the levosimendan group vs 67% of the placebo group experienced HF hospitalization (P=0.002), and 48% vs 81%, respectively, experienced the composite of all-cause death/HF hospitalization (P=0.02). The treatment group also had a lesser decline in health-related quality of life over time, as measured on the EQ-5D visual analog scale.

"We thought we'd see trends in lower hospitalizations, but the fact that this was significant was a kind of surprise," said Comín-Colet. "And the effect was very positive even in a reduced number of really sick patients."

During 9 months of follow-up, there were 14 deaths in the treatment group (29%) and seven (33%) in the placebo group, which was not statistically significant. In addition, 43% of the placebo group had worsening heart failure vs 25% of treatment group. On the other hand, two of the levosimendan group members had acute pulmonary edema vs none of the placebo group members; and three vs one, respectively, had respiratory infections.

However, the only significant difference in adverse events between the two groups was in additional heart treatment or LVAD implant, which occurred in 14% of those receiving placebo vs 0% of those receiving levosimendan (P=0.04).

"Using this regimen, you can keep these patients stable, out of the hospital, and prevent symptoms. If you have a patient in the advanced phase, I'd say consider this until you have a decision on what's going to be their destination therapy," said Comín-Colet.

Intriguing Findings

Assigned discussant Dr Veli-Pekka Harjola (Helsinki University Hospital, Finland) noted that although LION-HEART had a "moderate size," it used "a well-applicable, practical outpatient treatment protocol"—and showed positive results in both primary and secondary end points, as well as a good safety and tolerability profile.

However, he questioned whether comparison of the AUC of NT-proBNP by groups of treatment "was the most proper" primary end point. "It was also interesting that almost all of the patients received all infusions over a 3-month period," he added.

"The main effect, though, was from heart-failure hospitalization. And I think this is a very intriguing finding, especially in these patients," said Harjola.

He concluded by stating that the study provides a good background for future research, including a "well-sized study of outcome benefit of longer-term continuous treatment at modified intervals."

The study was funded by an unrestricted grant from Orion Pharma. Comín-Colet reports having received lecture fees from Orion. Disclosures for the coauthors are listed in the abstract.