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Short-term withdrawal of beta-blockers improved exercise outcomes in certain patients with heart failure with preserved ejection fraction (HFpEF), according to a small randomized trial.

After 2 weeks of beta-blocker withdrawal, patients with stable HFpEF and chronotropic incompetence showed a significant increase in peak oxygen consumption (VO2) during exercise (14.3 vs 12.2 mL/kg/min; P<0.001), reported Julio Núñez, MD, PhD, of the University of Valencia in Spain, and colleagues.

Likewise, peak VO2% also increased significantly after withdrawal of beta-blockers (81.1% vs 69.4%; P<0.001), they noted in the .

These results add to the mounting evidence that lowering heart rate using beta-blockers may not be beneficial for patients with HFpEF and chronotropic incompetence, the authors wrote.

"It is essential to underline that we evaluated a subset of patients with HFpEF, and thus, our results should not be extrapolated to the entire spectrum of patients with HFpEF," they noted.

Low VO2 and VO2% are indicators of chronotropic incompetence, or the inability to increase the heart rate during exercise, a prevalent condition among patients with heart failure. Beta-blockers work by blocking the effects of adrenaline, so the heart beats slower and less forcefully. They have been shown to reduce mortality and morbidity rates in patients with .

However, beta-blockers are also prescribed to , despite a . They are prescribed to those with HFpEF "empirically just because the medications allow more time for relaxation and improve the outcome of HF with reduced EF," wrote Marco Guazzi, MD, PhD, of the University of Milan, in a .

"Sometimes in medicine, 'less is more,'" Núñez told 乌鸦传媒.

The implications of chronotropic incompetence in patients with HFpEF have not been well-investigated in the past, Guazzi said. "We do not know whether exercise chronotropic insufficiency should be regarded as a therapeutic endpoint," he noted.

"This lack of consensus about the benefit of beta-blocker in HFpEF may be attributed to the phenotypic heterogeneity of this syndrome," Núñez and colleagues wrote. "These patients were treated with beta-blockers with no consideration of their HFpEF phenotype and essential factors that may determine the adequacy of such treatment, such as age, sex, presence of stable angina, type of rhythm, baseline heart rate, heart rate reserve, and chronotropic incompetence, among others."

that HFpEF is estimated to account for 50% of all heart failure diagnoses, and its prevalence has been increasing in recent years. In the U.S., 6.2 million adults suffer from heart failure,

This trial included a highly specific subset of patients with HFpEF, including those with chronotropic incompetence and a resting heart rate of <75 beats/minute, and excluded those receiving other chronic treatments such as digitalis, calcium channel blockers, or ivabradine, those with primary pulmonary disease, and those with moderate-to-severe valvular disease, among others. Of 250 patients with HFpEF initially screened for the trial, only 52 were included.

This crossover study consisted of two periods, and participants were randomized to two arms. During the first period, one arm went through complete beta-blocker withdrawal after 3 days, with outcomes measured after 2 weeks. The second arm continued on beta-blockers and went through the same tests. During the second period, the first arm returned to beta-blocker usage, while the second arm completed beta-blocker withdrawal.

A major limitation to the study was that it only included patients with stable HFpEF and established chronotropic incompetence, and excluded patients with other prevalent clinical conditions, Núñez and team noted. "Beta-blockers may have a positive effect in other phenotypes, but not in those with blunted heart response to exercise," Núñez added.

"Common HFpEF phenotypes, especially patients with atrial fibrillation and ischemic heart disease, are categories that (irrespective of exercise chronotropic insufficiency) may benefit of the pharmacological properties of beta-blockers in their functional performance," Guazzi wrote.

Both Guazzi and the study authors agreed that more study is necessary to understand the mechanisms of beta-blockers in chronotropic incompetence and HFpEF. "This step forward to untie the debated knot linking heart rate, exercise, and beta-blockers in HFpEF creates an ideal opportunity for a larger randomized trial," Guazzi concluded.

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