Rate-Adaptive Atrial Pacing for Heart Failure With Preserved Ejection Fraction: The RAPID-HF Randomized Clinical Trial

Abstract

Importance: Reduced heart rate during exercise is common and associated with impaired aerobic capacity in heart failure with preserved ejection fraction (HFpEF), but it remains unknown if restoring exertional heart rate through atrial pacing would be beneficial.

Objective: To determine if implanting and programming a pacemaker for rate-adaptive atrial pacing would improve exercise performance in patients with HFpEF and chronotropic incompetence.

Design, setting, and participants: Single-center, double-blind, randomized, crossover trial testing the effects of rate-adaptive atrial pacing in patients with symptomatic HFpEF and chronotropic incompetence at a tertiary referral center (Mayo Clinic) in Rochester, Minnesota. Patients were recruited between 2014 and 2022 with 16-week follow-up (last date of follow-up, May 9, 2022). Cardiac output during exercise was measured by the acetylene rebreathe technique.

Interventions: A total of 32 patients were recruited; of these, 29 underwent pacemaker implantation and were randomized to atrial rate responsive pacing or no pacing first for 4 weeks, followed by a 4-week washout period and then crossover for an additional 4 weeks.

Main outcomes and measures: The primary end point was oxygen consumption (V̇o2) at anaerobic threshold (V̇o2,AT); secondary end points were peak V̇o2, ventilatory efficiency (V̇e/V̇co2 slope), patient-reported health status by the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS), and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels.

Results: Of the 29 patients randomized, the mean age was 66 years (SD, 9.7) and 13 (45%) were women. In the absence of pacing, peak V̇o2 and V̇o2 at anaerobic threshold (V̇o2,AT) were both correlated with peak exercise heart rate (r = 0.46-0.51, P < .02 for both). Pacing increased heart rate during low-level and peak exercise (16/min [95% CI, 10 to 23], P < .001; 14/min [95% CI, 7 to 21], P < .001), but there was no significant change in V̇o2,AT (pacing off, 10.4 [SD, 2.9] mL/kg/min; pacing on, 10.7 [SD, 2.6] mL/kg/min; absolute difference, 0.3 [95% CI, -0.5 to 1.0] mL/kg/min; P = .46), peak V̇o2, minute ventilation (V̇e)/carbon dioxide production (V̇co2) slope, KCCQ-OSS, or NT-proBNP level. Despite the increase in heart rate, atrial pacing had no significant effect on cardiac output with exercise, owing to a decrease in stroke volume (-24 mL [95% CI, -43 to -5 mL]; P = .02). Adverse events judged to be related to the pacemaker device were observed in 6 of 29 participants (21%).

Conclusions and relevance: In patients with HFpEF and chronotropic incompetence, implantation of a pacemaker to enhance exercise heart rate did not result in an improvement in exercise capacity and was associated with increased adverse events.

Trial registration: ClinicalTrials.gov Identifier: NCT02145351.

Figure 1.. Study Design and Patient Flow in Trial of Rate-Adaptive Atrial Pacing for Heart Failure With Preserved Ejection Fraction

CPET indicates cardiopulmonary exercise test; KCCQ-OSS, Kansas City Cardiomyopathy Questionnaire Overall Summary Score; NT-proBNP, N-terminal pro-brain natriuretic peptide.

Figure 2.. Heart Rate Dynamics

A, Peak exercise heart rate during pacing-off phase was positively associated with peak oxygen consumption (V̇o₂) (r = .51, P = .006). B, Tukey box plots represent median and interquartile range, with whiskers extending to the minimum and maximum values. Pacing-on phase was associated with a higher heart rate during submaximal (stage 1 of treadmill) and peak exercise, P < .001 for both comparisons (n = 28 for all 3 pacing-off phases and n = 29 for all 3 pacing-on phases, because 1 patient did not complete the pacing-off–phase exercise test).

Figure 3.. Parallel Line Plots of Primary and Select Secondary End Points

Each vertical line represents an individual patient, with patients ordered by baseline value with pacing off, with the vertical line extending up (improvement) or down (deterioration) in the pacing-on phase. For panel A, P = .46; panel B, P = .27; and panel C, P = .86. KCCQ-OSS indicates Kansas City Cardiomyopathy Questionnaire Overall Summary Score; V̇o₂, oxygen consumption; V̇o_2,AT, oxygen consumption at anaerobic threshold.