Key Points
- Over half of the patients with HFpEF suffer from exercise intolerance, which may be often due to inability to augment heart rate (HR). As such, rate-adaptive atrial pacing may offer an innovative approach to improve their quality of life.
- In the single center RAPID-HF trial, 29 patients with HFpEF received a transvenous pacemaker and were randomized to 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.
- Despite a statistically and clinically significant increase in mean HR during exercise between the pacer-on phase or a pacer-off phase, there was no statistically significant improvement in the primary outcome of the trial, oxygen consumption (VO2) at the anaerobic threshold, nor in any of the secondary endpoints. As such, the RAPID-HF trial does not support the use of rate-adaptive atrial pacing to treat patients with HFpEF and chronotropic incompetence
Heart failure with preserved ejection fraction (HFpEF) is a very heterogeneous disease state, however one of the features that is shared by over half of all HFpEF patients is exercise intolerance, which may be often due to inability to augment heart rate (HR).
Rate-adaptive atrial pacing may offer an innovative approach to dynamically augment HR during activities of daily living, and help HFpEF patients overcome chronotropic incompetence and improve their quality of life.
The Efficacy Study of Pacemakers to Treat Slow Heart Rate in Patients With Heart Failure (RAPID-HF) was designed to address this important question, and the results were presented by the principal investigator, Dr. Barry Borlaug (Mayo Clinic) as a late-breaking clinical trial at the annual American College of Cardiology (ACC) scientific session, held this year in partnership with the World College of Cardiology (WCC) on March 3-6th in New Orleans, LA.
This was a single-center, double-blinded randomized clinical trial that enrolled a total of 29 patients with HFpEF (defined as EF>40%), New York Heart Association (NYHA) class 2-3, sinus rhythm at baseline with established chronotropic incompetence (defined as HR reserve <0.8, or <0.62 if on beta blockers), and no other indication for cardiac implantable electronic devices. The primary endpoint of the trial was oxygen consumption (VO2) at the anaerobic threshold (i.e. when the energy demand is higher than the energy supplied by the body aerobic metabolism), with secondary endpoints including Peak VO2 and patient-reported health status as assessed by the KCCQ-OSS.
Of 32 patients initially recruited, 29 patients underwent dual-chamber transvenous pacemaker implantation at the start of the study period, followed by 4 weeks of recovery post-procedure, during which they were not actively paced (i.e. all devices were initially set at VVI 30). Afterwards, they completed a baseline clinical assessment and KCCQ-OSS questionnaire. Then, half of the study cohort was randomized to start rate-adaptive atrial pacing, while the other half was managed conservatively. After 4 weeks, patients in both arms had another clinical assessment during which they completed a treadmill cardiopulmonary exercise test (CPET), as well as follow-up KCCQ-OSS questionnaire. This was followed by a 4-week washout period, after which patients crossed-over to the other group, and the same study protocol was repeated. None of the randomized patients were lost to follow-up.
Patients included in the study had a mean age of about 65 years, with 45% of female sex and mean BMI of ∼33. Notably, all patients had EF>50%. The mean HR reserve was 0.43 in the pacing first group, and 0.49 in the placebo first group. Notably, 71% of the patients in the pacing first group were on treatment with beta blockers, as were 40% of those in the placebo first group. Beta blockers were continued during the study period, both to align with the guidelines of the time and to maintain a pragmatic approach to the trial.
In terms of proxy endpoints, the study found similar heart rates during the pacer-on phase and the pacer-off phase at rest (mean HR ∼65 BPM). There was a significant increase in mean HR between the two groups during submaximal exercise (∼95 BPM during pacer-on phase vs ∼105 BPM during pacer-off phase, p<0.001) and at peak exercise (∼105 BPM during pacer-on phase vs ∼120 BPM during pacer-off phase, p<0.001). Despite this, there was no significant difference in the primary endpoint, with VO2 at anaerobic threshold of 10.7 mL/kg/min during pacer-on phase and 10.4 mL/kg/min during pacer-off phase, with an absolute difference of 0.3 mL/kg/min and 95% confidence interval -0.5 to 1.0 mL/kg/min, p-value 0.46. Similarly, there were no significant differences in any of the secondary endpoints, nor in symptoms assessed by KCCQ-OSS.
Commenting on the negative results of the study, Dr. Borlaug explained that, as already well-established for HFrEF, there may be a similar pathological blunted force-frequency response in HFpEF, causing sarcomeric dysfunction and paradoxically decrease in stroke volume and preventing gains in cardiac output as HR is artificially increased via pacing. In turn, this reduction in cardiac output may explain the lack of benefit on CPET.
In conclusion, the RAPID-HF trial does not support the use of rate-adaptive atrial pacing to treat patients with HFpEF and chronotropic incompetence.
