Mirabegron effect in patients with HF may depend on HF severity

ORLANDO, Fla. — Mirabegron, a beta-3 adrenoceptor agonist approved for treatment of overactive bladder, did not improve outcomes in patients with any HF, but did improve left ventricular ejection fraction in patients with severe HF, according to data presented at the American Heart Association Scientific Sessions.

Researchers tested mirabegron (Myrbetriq, Apgdi) in patients with HF because elevated intracellular sodium levels contribute to contraction abnormalities in HF, and beta-3 adrenoceptor agonists can reduce levels of intracellular sodium by stimulating the sodium-potassium pump, potentially increasing LVEF, Henning Bundgaard, DMSc, professor at National University Hospital, Rigshospitalet, Copenhagen, Denmark, said at a press conference. Bundgaard noted that this theory had been validated in tests on sheep.

Henning Bundgaard

For the BEAT-HF study, Bundgaard and colleagues randomly assigned 70 patients with chronic HF (mean LVEF, 39%) to placebo or mirabegron starting at 25 mg twice daily and gradually uptitrating to 300 mg/day for 6 months.

The primary outcome was change in LVEF as assessed by CT. Secondary outcomes included changes in the following: N-terminal pro–B-type natriuretic peptide, cardiac output as measured by stroke volume, LV volumes, left atrial volume, diastolic function, QT interval duration, exercise tolerance and symptoms.

The researchers observed no significant difference between the groups in change in LVEF at 6 months (mean difference, 0.4%; 95% CI, –3.5 to 3.8). They also found no significant differences in any of the secondary endpoints.

However, in an exploratory analysis, they determined that mirabegron improved LVEF compared with placebo in patients with baseline LVEF of less than 40% (mean difference, 5.5%; 95% CI, 0.6-10.4; relative increase, 16%; P < .03), but not in those with baseline LVEF of at least 40% (mean difference, –2%; 95% CI, –6.8 to 2.8; P = .4), Bundgaard said.

Adverse event rates were similar between the groups and “generally mild and transient,” he said.

“The beneficial effect of the beta-3 adrenoceptor agonist only in severe [HF] is in agreement with the mechanistic foundation of our study,” Bundgaard said. “An additional study on effects of beta-3 adrenoceptor agonists in patients with severe HF is needed for the design of a phase 3 trial.”

In a discussant presentation at the press conference, Biykem Bozkurt, MD, PhD, FACC, FAHA, the Mary and Gordon Cain Chair and professor of medicine and vice chair of medicine, cardiology and medicine chief at DeBakey VA Medical Center, associate director of the Cardiovascular Research Institute, and director of the Winters Center for Heart Failure at Baylor College of Medicine, said the study has a number of limitations.

She said LVEF is not a measure of contractile performance, and drugs that improve LVEF may not improve HF, and that there was no interim analysis to detect short-term bimodal effects or acute negative inotropy.

“The report of the improvement in LVEF in patients with baseline LVEF less than 40% remains speculative,” she said. – by Erik Swain

Reference:

Bundgaard H, et al. Late-Breaking Clinical Trials 4. Presented at: American Heart Association Scientific Sessions; Nov. 7-11, 2015; Orlando, Fla.

Disclosure: The study was funded in part by the Novo Nordisk Foundation. Bundgaard reports receiving lecture fees from Amgen, AstraZeneca, Merck, Pfizer, Sanofi-Aventis and Shire, and holding partial ownership of a patent related to use of beta-3 adrenoceptor agonists in HF. Bozkurt reports no relevant financial disclosures.