AHA 2018: Heart failure patients with specific genetic variants could see extra benefit with beta blocker bucindolol

November 11, 2018 – A new study suggests an alternative treatment for patient groups who do not benefit from more widely used anti-arrhythmic agents.

Because many anti-arrhythmic agents for atrial fibrillation (AF) and atrial flutter (AFL) are ineffective or even unsafe for heart failure patients, researchers are investigating alternative therapies to reduce AF in this patient population.

The recently completed GENETIC-AF phase IIB clinical trial compared pharmacogenetically targeted bucindolol with metoprolol for the prevention of AF and AFL in a genotype-defined heart failure population with a high risk of AF/AFL recurrence. With 267 enrolled patients, the study showed trends for bucindolol superiority in population subgroups with the ADRB1 Arg389Arg genetic variant.

At the Scientific Sessions of the American Heart Association in Chicago Sunday, the DCRI’s Jonathan Piccini, MD, presented findings from that trial’s subgroup of 69 heart failure patients who had continuous rhythm monitoring via implanted loop recorders or other devices to evaluate AF burden (AFB). Heart failure patients with AFB of six or more hours per day, as measured by implanted cardiac devices, are more likely to be hospitalized for their heart failure, said Piccini. Therefore, AFB was defined in GENETIC-AF as 6 hours or more of AF during a 24-week follow-up period.

The substudy had two purposes: to examine AFB as an endpoint as well as its implications for clinical trial development and patient care, and to determine if pharmacogenetically guided bucindolol is superior to standard beta-blocker therapy.

“Atrial fibrillation burden is a hot topic because several studies have shown that it is linked to several cardiovascular outcomes,” Piccini said. “For example, AFB is associated with increased risks of stroke and hospitalization.”

“GENETIC-AF was an innovative study not only because it used AFB as an endpoint but also because it addressed the concept of pharmacogenetically guided therapy for AF in patients with heart failure. GENETIC-AF was designed to determine whether patients’ genetic background can be harnessed for added benefit from bucindolol — that is, reducing AF. This was the first pharmacogenetic trial for this indication- rhythm control of AF.”

Bucindolol was previously studied in the BEST phase III trial, with 2,708 congestive heart failure patients. The primary endpoint of BEST was all-cause mortality. A substudy of 1,040 patients showed genotype-dependent enhancements for several heart failure endpoints. Bucindolol has two unique pharmacologic properties that favorably interact with the Arg389Arg genotype, sympatholysis and inverse agonism, which bring clinical benefits in patients with heart failure.

“In patients with this beta-1 receptor variant, bucindolol appeared to have a stronger impact than metoprolol,” said Piccini.

Piccini’s substudy found that continuous monitoring with devices such as pacemakers tended to detect more AF/AFL events than ECG monitoring. Furthermore, the AFB events tracked with traditional measures of symptomatic AF detected by traditional electrocardiographic monitoring.

“Event rates were higher for device-based monitoring than intermittent monitoring,” said Piccini. “These results are important because with a proliferation of monitoring technologies, including the Apple Watch, we don’t have to ask patients to call in. Their symptoms and rhythm can be recorded on their phone and other handheld rhythm capture technologies.”

Piccini said that the trial asked a very fundamental question.

“In an age of personalized medicine, wouldn’t it be great to know that a particular patient with a particular genotype would do really well with, for example, bucindolol, because it can lower her AF burden?” he said. “The study also confirms that monitoring with implanted cardiac monitoring devices provides the most precise data. There is still much to learn, of course, but someday we could be looking at a new kind of concierge pharmacology for patients with AF and heart failure.”