Beta-3 Agonist Mirabegron May Help in Severe HF, BEAT HF Hints

Marlene Busko

November 24, 2015

ORLANDO, FL — In this 6-month, first-in-human study in 70 patients with chronic heart failure, the beta 3–adrenoceptor agonist mirabegron (Myrbetriq, Astellas Pharma), which is approved to treat overactive bladder, did not improve left ventricular ejection fraction (LVEF) compared with placebo[1]. However, in exploratory, non-prespecified analysis, it did improve this measure in patients with LVEF <40%.

Dr Henning Bundgaard (National University Hospital, Rigshospitalet, Copenhagen, Denmark) presented these findings from the Beta 3 Agonist Treatment in Heart Failure (Beat-HF) in a press briefing at the American Heart Association (AHA) 2015 Scientific Sessions.

"We really think that we have something in our hands here that might be really, really big," he told heartwire from Medscape. The researchers propose that beta 3–receptor agonists have a bimodal action—that is, they have a positive ionotropic effect in the normal heart and a negative ionotropic effect (weakening the heart's contractions and slowing the heartrate) in severe HF.

"This is a brand-new concept we are applying here, and I have to remind you that when in Sweden they started using beta-blockers in heart failure many years ago, everyone said, 'This is crazy, because we know that beta blockers are negative inotropes,' " he continued. Now clinicians treat all HF patients with beta-blockers.

These preliminary findings support a bimodal mechanism of action, since the beneficial effects were seen only in the patients with more reduced LVEF, according to Bundgaard.

Assigned discussant Dr Biykem Bozkurt (Baylor College of Medicine, Houston, TX) was less convinced. Mirabegron did not improve ejection fraction, exercise capacity, or biomarkers or reverse remodeling in this small study, she noted. "Before we go with a large-scale clinical trial, perhaps we need more complete characterization of the effects of beta-3 agonism, both in experimental and human models . . . as well as acute and chronic response."

Promising Animal Studies

Raised levels of intracellular sodium in cardiomyocytes contribute to abnormalities in heart contraction in heart failure, Bundgaard explained. Previously, in rabbit cells, the researchers showed that beta 3–receptor agonists stimulate the sodium-potassium pump via the nitric-oxide/cGMP/protein-kinase-G pathway to mediate sodium export from the cell.

Other research in sheep models suggested this action by beta 3–adrenoceptor agonists might translate into improved LV function.

BEAT-HF is a proof-of-concept, phase 2 study to see if mirabegron improves LVEF in patients with chronic HF with reduced ejection fraction (HFrEF).

The trial randomized patients with chronic HF who had LVEF <40% (based on screening echocardiography) and were receiving optimal evidence-based pharmacotherapy, including a traditional beta-blocker.

The patients received mirabegron (starting with a 25-mg twice-daily dose that was increased weekly to reach 300 mg a day or highest tolerated dose) or placebo for 6 months. The drug is approved at a dose of 25 or 50 mg/day for overactive bladder but has been used at these high doses, said Bundgaard.

At baseline, patients in the mirabegron-treated group were slightly older than those in the placebo group (mean age 62 vs 56, respectively, P=0.05); otherwise, both groups were similar. Most patients (89%) were men. Almost all (97%) were taking an ACE inhibitor/angiotensin-receptor blocker (ARB); almost all were NYHA class 2 (96%), and the rest were class 3.

The mean LVEF by a screening echocardiography was 34% and 32% in the placebo and mirabegron groups, respectively. The mean LVEF readings by computed tomography (CT) were slightly higher: 38% and 40% in the placebo and mirabegron groups, respectively.

Almost all patients (66 patients, 94%) attained the target dose, and the 61 patients who completed the study were compliant, based on pill count.

At 6 months, there was no significant difference in mean LVEF for the treated vs placebo groups (HR 0.4%, 95% CI -3.5 to 3.8; P=0.82).

However, in further analysis, on average, there was a significant 5.5% improvement in mean LVEF (95% CI 0.6–10.4, P<0.03) in patients with baseline LVEF <40%.

There was no effect on the secondary end points: physical capacity (NYHA class, 6-minute walking distance, or VO2max), laboratory measures (N-terminal pro B-type natriuretic peptide [NT-proBNP], ECG, or QT interval) or heart-volume parameters measured by CT.

Mirabegron did not have a significant effect on systolic or diastolic blood pressure or heart rate. There were eight serious adverse events in the treated group—sudden death (two), appropriate ICD shock (one), chest pain (two), and fever/infection (three)—but only five such events in the placebo group—appropriate ICD shock (three), renal impairment (one), and fever/infection (one). There were also eight other adverse events in the placebo group and 12 in the mirabegron-treated group. These differences were not significant.

Wrong Hypothesis, End Point, Study Population in Human Trial?

The proposed hypothesis of a different effect in a normal vs failing heart makes the outcome a challenging, moving target, Bozkurt said.

She raised several questions and concerns. First, is the hypothesis that the drug will decrease intracellular sodium and thus improve LV function correct? Moreover, is change in LVEF the correct end point? "There are quite a variety of studies showing . . . increased mortality with agents that have slowly increased EF," Bozkurt pointed out.

It is still not clear how safe it is to give beta-3 agents to patients who are also receiving negative inotropes such as beta-blockers or receiving positive inotropes such as digoxin, she added.

Since human beta 3–adrenoceptor agonists share half of their amino-acid sequences with beta 1- and beta 2-adrenoceptor agonists, cross-reactivity can occur, which can result in arrhythmias, tachycardia, and worsening HF.

"I would also caution against the post hoc analysis of benefit in patients with baseline EF less than 40%, as this was a very small group of patients [about eight to 10 patients]," Bozkurt added.

Last, the patients all had mild to moderate heart failure, so perhaps this was not the intended target population, and "targeted treatments for sicker populations with certain surrogate markers may be more appropriate."

Bundgaard remains convinced that this approach has huge potential but agrees that more study is needed. The researchers plan to do a larger follow-up trial in patients with more severe heart failure.

Bundgaard is on the speaker's bureaus of MSD, Sanofi, Amgen, AstraZeneca, and Pfizer. He, along with the University of Sydney, Royal North Shore Hospital, and coauthor Helge H Rasmussen patented the use of beta 3–adrenoceptor agonists in heart failure. Disclosures for the coauthors are listed in the abstract. Bozkurt has no relevant financial relationships.

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