No Exercise Boost From Pacemaker in HFpEF With Impaired HR

Pacemaker therapy that boosts impaired heart rate (HR) response to exertion failed to improve exercise capacity or quality of life in patients with heart failure with preserved ejection fraction (HFpEF) in a small randomized trial.

The finding challenges consensus-based guidelines on treatment of HFpEF with chronotropic incompetence (CI), researchers say, especially given the complication risk associated with pacemaker therapy.

The study’s 29 patients with HFpEF and CI were implanted with pacemakers set to either atrial rate–responsive pacing or to no pacing, each for 4 weeks with crossover to the other setting for another 4 weeks.

Exercise capacity correlated with peak HR at exercise with the pacemaker set to no pacing. Heart rate rose at both low-level and at peak exercise when the device was set to demand atrial pacing, but without associated changes in exercise capacity, cardiac output, natriuretic peptides, or quality-of-life scores.

In a secondary finding, stroke volume at exercise fell significantly during atrial pacing even as the HR went up, “which may have prevented gains from cardiac output,” said Barry A. Borlaug, MD, Mayo Clinic, Rochester, Minnesota.

Given the observed prevalence of adverse events “clearly related” to the pacemakers, the findings “do not support” rate-adaptive atrial pacing as an intervention for HFpEF with CI, said Borlaug when presenting the RAPID-HF study on March 5 at the American College of Cardiology (ACC) Scientific Session/World Congress of Cardiology (WCC) 2023, held live and virtually from New Orleans, Louisiana.

Borlaug is also senior author on the same-day publication in JAMA, with lead author Yogesh N.V. Reddy, MBBS, MSc, also of the Mayo Clinic.

The findings don’t necessarily “slam the door shut” but do cast doubt on pacing therapy’s prospects for improving “subjective or objective” exercise tolerance in patients with HFpEF like those in the trial, Borlaug said in discussion following his presentation.

But given the results, he said, “I would be more optimistic about interventions that allow for greater heart rates without the need for pacing during exercise.”

On that point, Borlaug pointed to a separate, recently published trial of HFpEF patients already with pacemakers for bradycardia in which elevated resting HR led to improved quality of life and natriuretic peptide levels.

He’s therefore “open to the possibility” of pacemaker therapy for such patients, but the RAPID-HF results “really makes it unlikely that this is going to be an effective treatment for most people with HFpEF.”

RAPID-HF and the recent study to which Borlaug referred, called myPACE, “are complementary to help refine the optimal pacing strategy for HFpEF,” Markus Meyer, MD, PhD, told | Medscape Cardiology.

Together, the two studies suggest “that higher heart rates at rest make HFpEF patients feel better, but normal exercise heart rates do not improve their stamina,” said Meyer, University of Minnesota College of Medicine, Minneapolis, who was senior author on the myPACE publication but was not involved in RAPID-HF.

The RAPID-HF publication, states an accompanying editorial, shows how a “moderately sized but well-executed trial” can “disprove conventional paradigms and should prompt reconsideration of current clinical management guidelines.”

The study “furthers the case for abandoning rate-adaptive pacing for most patients with HFpEF despite their chronotropic incompetence,” write the editorialists, led by Dalane W. Kitzman, MD, Wake Forest University School of Medicine, Winston-Salem, North Carolina.

RAPID-HF randomized 29 patients (45% women) with HFpEF, defined here by an ejection fraction ≥ 40%, in New York Heart Association functional class 2-3, and in sinus rhythm with CI but no atrioventricular block. Those on beta-blockers continued to take them as prescribed.

All were implanted with dual-chamber Azure XT DR MRI SureScan (Medtronic) pacemakers, programmed for rate-responsive atrial pacing or no pacing for the alternating 4-week periods, at a single large tertiary center.

Exercise capacity by several measures was unaffected by whether the pacemakers were programmed to pace or not to pace. Neither the traditional endpoint of peak VO2 nor the primary endpoint of VO2 at the anaerobic threshold changed significantly. The latter metric, Borlaug explained, may be described as the point at which energy demand at exercise exceeds the energy supplied by aerobic metabolism.

Despite no change in cardiac output, mean stroke volume dropped by 24 mL (P = .02) in an exploratory analysis.

Six patients (21%) experienced adverse events considered to be related to the pacemaker or the implantation procedure, including a pericardial effusion requiring drainage, one case of tricuspid regurgitation thought to be caused by a pacing lead, an upper-extremity deep vein thrombosis, and three pocket incision-site reactions. “Chest discomfort or palpitations occurred in 5 patients during the pacing-on phase, compared with 1 during the pacing-off phase,” the report states.

The complication rate “is within the clinically expected range,” and the excess cases of chest pain “could have been due to higher myocardial oxygen demand from the pacing-driven increased heart rates,” the editorial observes. “Thus, the pacing strategy was not only ineffective but was harmful.”

The study, write Kitzman and associates, may help the field “embrace the broader pathophysiology of exercise intolerance in HFpEF” beyond a focus on cardiac dysfunction.

Such a view, they propose, could include “systemic and extracardiac abnormalities that are strong, modifiable contributors to symptoms and reduced exercise capacity in HFpEF, including inflammation; dysfunctional excess adipose tissue; and skeletal muscle, microvascular, and mitochondrial dysfunction.”

RAPID-HF was funded by the Mayo Clinic and Medtronic. Borlaug discloses receiving research support from the National Institutes of Health, US Dept of Defense, Axon, AstraZeneca, Corvia, Medtronic, and Tenax Therapeutics; and consulting or serving on an advisory board for Actelion, Amgen, Aria, Boehringer Ingelheim, Edwards, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, and VADovations. Disclosures for the other authors are in the report. Meyer has disclosed holding a patent for pacemakers for HFpEF licensed to Medtronic.  Kitzman reports receiving consulting fees from Bayer, Medtronic, Corvia Medical, Boehringer Ingelheim, Keyto, Rivus, Novo Nordisk, AstraZeneca, and Pfizer; holding stock in Gilead; and receiving grants to his institution from Bayer, Novo Nordisk, AstraZeneca, Rivus, and Pfizer. Disclosures for the other editorialists accompany the editorial.

American College of Cardiology Scientific Session/World Congress of Cardiology 2023. Session 407: Featured Clinical Research II. 407-08: Atrial Pacing for Heart Failure with Preserved Ejection Fraction: A Randomized Clinical Trial. Presented March 5, 2023. Abstract

JAMA. Published March 5, 2023. Abstract; Editorial

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