CardioNerds Journal Club is a monthly forum for CardioNerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the RAPID-HF Trial

Table of contents for the The CLEAR Trial summary:

RAPID-HF Rate-adaptive Atrial Pacing for Heart Failure with Preserved Ejection Fraction Reddy, Y et al March 5, 2023. JAMA

Rate-Adaptive Atrial Pacing for Heart Failure with Preserved Ejection Fraction

The RAPID-HF Randomized Clinical Trial

Yogesh N. V. Reddy, MBBS, MSc; Katlyn E. Koepp, PhD Rickey Carter, PhD

Sithu Win, MD;Christopher Charles Jain, MD; Thomas P. Olson, PhD; Bruce D. Johnson, PhD; Robert Rea, MD; Margaret M. Redfield, MD; Barry A. Borlaug, MD

Link to Manuscript

Question: Does increasing exercise heart rate in HFpEF patients with chronotropic incompetence using atrial pacing improve exercise tolerance?1

Findings: Atrial pacing increased early and peak exercise heart rates, but there was no improvement in exercise performance or quality of life. Despite a higher exercise heart rate, there was no increase in exercise cardiac output, due to a decrease in stroke volume. Pacemaker implantation was associated with adverse events.

Design: Single center (Mayo Clinic) from 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 rebreathing technique.

Main Outcomes and Measures:

  1. Exercise: Oxygen Consumption (VO2 Anaerobic Threshold), VO2 Max (Peak VO2), Ventilatory Efficiency (VE/VCO2 Slope)
  2. Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS)
  3. N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels

Relevant literature

  • Prior studies2-4 have demonstrated that patients with HFpEF may have impaired ability to increase their heart rate in response to exercise (reference). This is known as chronotropic incompetence.
  • Different competing theories3 have been circulated about whether chronotropic incompetence contributes to HFpEF symptoms, such as dyspnea and fatigue, or if these symptoms limit exercise performance and subsequent inability to elevate heart rate.
  • Recent studies have suggested that there is a spectrum of HFpEF-related chronotropic incompetence. Some patients may have impaired beta receptor sensitivity, while others may have intact sinus node but demonstrate early exercise intolerance.6

Relevant guidelines

2018 American College of Cardiology/American Heart Association Scientific Statement/ Heart Rhythm Society

  • In patients with symptomatic chronotropic incompetence, permanent pacing with rate-responsive programming is reasonable to increase exertional heart rates and improve symptoms. (IIa)7

Pacemaker Implantation:

Azure XT DR is a permanent, dual-chamber cardiac pacemaker (Medtronic, Minneapolis MN) which can respond to patient activity and increase heart rate (rate adaptive atrial pacing).

Settings: Leads in the R atrium and R ventricle. AAIR mode for pacing.

Enrollment Criteria

Enrollment Criteria:

  1. Age >18 years and able to provide informed consent to enroll in the trial, or consent through a legal guardian or power of attorney.
  2. Previous clinical diagnosis of HF with current NYHA Class II-III symptoms
  3. At least one of the following: Hospitalization for decompensated HF, Acute treatment for HF with intravenous loop diuretic or hemofiltration, Chronic treatment with a loop diuretic for control of HF symptoms + left atrial enlargement on echocardiography or E/e’ ratio (≥14 average, ≥15 septal ) on echocardiography, Resting PCWP >15 mm Hg or LV end-diastolic pressure >18 mmHg at catheterization for dyspnea and/or exercise PCWP/LV end-diastolic pressure >25 mmHg, or Elevated NT-pro-BNP level (≥300 pg/ml )
  4. Left ventricular EF ≥40% within 12 months with clinical stability
  5. Stable cardiac medical therapy for ≥30 days
  6. Sinus rhythm
  7. Chronotropic incompetence on recent (within 6 months) clinical or screening exercise test, defined as heart rate reserve (HRR) <0.80 or <0.62 if on beta blockers
  8. Meet both screening criteria on clinically-performed cardiopulmonary exercise testing within 12 months.

Exclusion Criteria

  1. Inability to exercise, or non-cardiac condition that precludes exercise testing
  2. Any contraindication to a pacemaker system
  3. Non-cardiac condition limiting life expectancy to less than one year
  4. Significant left sided structural valve disease (>mild stenosis, >moderate regurgitation)
  5. Hypertrophic cardiomyopathy
  6. Infiltrative or inflammatory myocardial disease (amyloid, sarcoid)
  7. Pericardial disease
  8. Non-group 2 pulmonary arterial hypertension
  9. Chronic stable exertional angina
  10. Acute coronary syndrome or revascularization within 60 days
  11. Other clinically important causes of dyspnea
  12. Atrial fibrillation
  13. PR interval >210 msec
  14. Resting heart rate (HR) > 100 bpm
  15. A history of reduced ejection fraction (EF<40%)
  16. Advanced chronic kidney disease (GFR < 20 ml/min/1.73m2 by modified MDRD equation)
  17. Women of child bearing potential without negative pregnancy test and effective contraception
  18. Severe anemia (Hemoglobin <10 g/dL)
  19. Severe hepatic disease
  20. Complex congenital heart disease
  21. Listed for cardiac transplantation
  22. Other class I indications for pacing

Crossover Study Design:

4 Weeks of Pacing OFF -> Randomization to Pacing ON/OFF for 4 Weeks -> Washout (Pacing OFF) for 4 weeks -> Crossover to Pacing ON or OFF for 4 weeks

Notable Baseline Characteristics

All endpoints assessed after 4 weeks of treatment with pacing


Primary Endpoint

Change in Oxygen Consumption (VO2) at Ventilatory Anaerobic Threshold (VAT)

Maximal effort cardiopulmonary exercise testing was performed on a treadmill after 4 weeks of pacing-on and after 4 weeks of pacing-off to measure volumes of oxygen consumed (VO2). Change in VO2 at anaerobic threshold (VO2,AT) determined by the V-Slope method as the point of disproportionate rise in VCO2 relative to VO2 as measured in ml/kg/min.

  • Not Significant: Mean difference, 0.3 mL/kg/min; [95% CI, −0.5 to 1.0 mL/kg/min]; P = .46)

Secondary Endpoints:

Peak Aerobic Capacity (Peak VO2)
Determined as the mean of values obtained over the final 30 seconds of exercise. Maximal effort cardiopulmonary exercise testing was performed on a treadmill after 4 weeks of pacing-on and after 4 weeks of pacing-off to measure volumes of oxygen consumed (VO2). As measured in ml/kg/min.

  • Not Significant: Mean difference, 0.4 mL/kg/min [95% CI, −0.4 to 1.2 mL/kg/min]; P = 0.27

Ventilatory Efficiency (VE/VCO2)
Determined as the nadir of VE/VCO2 ratio during exercise. Maximal effort cardiopulmonary exercise testing was performed on a treadmill after 4 weeks of pacing-on and after 4 weeks of pacing-off to measure volumes of oxygen consumed (VO2).

  • Not Significant: Mean difference, 0.5 [95% CI, −0.6 to 1.6]; P = 0.34

Change in Plasma N-terminal Pro B-type Natriuretic Peptide (NT-pro-BNP)

  • Not Significant: Mean difference, 53 pg/mL [95% CI, −117 to 221 pg/mL]; P = 0.5

Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score

  • Not Significant: Mean difference, −0.9 [95% CI, −11.0 to 9.3]; P = 0.86

Other Outcome Measures:

Mean Peak Heart Rate (HR)

  • Minimal Exercise: Mean heart rate increased by 16/min (95% CI, 10 to 23; P < .001)
  • Peak Exercise: Mean heart rate increased by 14/min (95% CI, 7 to 21; P < .001)

Adverse Events

There were 6 adverse events related to pacemaker implantation:

  • Upper extremity deep vein thrombosis x1
  • Pericardial effusion requiring drainage x1 (only event judged serious)
  • Potential case of pacemaker lead induced tricuspid regurgitation (x1)
  • Local skin reactions at pacemaker pocket site (x3)


  • There was no benefit for rate adaptive atrial pacing in patients with HFpEF and chronotropic incompetence.
  • Rate adaptive pacing can successfully elevate heart rates in HFpEF patients with chronotropic incompetence, however there was no clear improvement in exercise capacity.
  • Adverse events related to pacemaker implantation and discomfort were notable
  • No clear improvement in cardiac output was seen despite an increase in heart rate with pacing, which may underlie the lack of a benefit in exercise performance.

Limitations and Considerations:

  • Single center and relatively small cohort (n = 29)
  • Burdensome protocol including an invasive procedure, implanted device, and multiple follow-up visits
  • No direct assessment of baseline activity levels or exercise tolerance prior to enrollment
  1. Reddy YNV, Koepp KE, Carter R, et al. Rate-adaptive atrial pacing for heart failure with preserved ejection fraction: The Rapid-HF randomized clinical trial. JAMA. 2023;329(10):801-809.
  2. Brubaker PH, Joo KC, Stewart KP, Fray B, Moore B, Kitzman DW. Chronotropic incompetence and its contribution to exercise intolerance in older heart failure patients. J Cardiopulm Rehabil. 2006;26(2):86-89.
  3. Laurent G, Eicher JC, Mathe A, et al. Permanent left atrial pacing therapy may improve symptoms in heart failure patients with preserved ejection fraction and atrial dyssynchrony: a pilot study prior to a national clinical research programme. Eur J Heart Fail. 2013;15(1):85-93.
  4. Rosalia L, Ozturk C, Shoar S, et al. Device-based solutions to improve cardiac physiology and hemodynamics in heart failure with preserved ejection fraction. JACC Basic Transl Sci. 2021;6(9-10):772-795.
  5. Sarma S, Stoller D, Hendrix J, Howden E, Lawley J, Livingston S, Adams-Huet B, Holmes C, Goldstein DS, Levine BD. Mechanisms of chronotropic incompetence in heart failure with preserved ejection fraction.Circ Heart Fail. 2020; 13:e006331.
  6. 2018 ACC/AHA/HRS Guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines and the Heart Rhythm Society. Journal of the American College of Cardiology. 2019;74(7):e51-e156.
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