Cardiac resynchronization therapy (CRT) is an established treatment for patients with advanced heart failure (HF)1. CRT can be delivered through a pacemaker (CRT-P) or a defibrillator (CRT-D). Both devices provide resynchronization, but CRT-D can also deliver shocks to terminate life-threatening arrhythmias. Most defibrillator recipients never receive a shock2. Defibrillator shocks can be inappropriate and painful, drain battery, increase healthcare cost and are associated with higher risk of mortality and reduced quality of life2,3. CRT-P devices are smaller, have superior battery longevity, and are less expensive4. Current published guidelines do not separate between the indications for CRT-P versus CRT-D1. A randomized controlled trial (RCT) comparing survival in CRT-P versus CRT-D recipients is therefore important, especially in older patients5.
We conducted a pilot RCT (clinicaltrials.gov listing: NCT03031847) from 2017 to 2021 at four institutions in the United States. The protocol was approved by the institutional review board of the participating institutions and all subjects gave informed consent. The data that support the findings of this study are available from the corresponding author upon reasonable request. Study personnel approached older HF patients who were indicated for CRT device implantation about enrollment into the RCT. Patients who refused randomization were invited to participate in an observational registry and received their device of choice (Figure 1A).
Figure 1.
Overall design of the study with its observational prospective registry (n=60 patients) and its RCT (n=42 patients) components is shown in panel A. Panel B details the enrollment timeline for the observational registry and the RCT. Kaplan Meier curves are shown comparing the overall survival of patients enrolled in the observational registry versus the RCT (panel C) and for those in the randomized trial who received a CRT-P versus a CRT-D (panel D). UPMC = University of Pittsburgh Medical Center; OSUMC = Ohio State University Medical Center; VA PITT = Veterans Affairs hospital of Pittsburgh; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; CRT-P = cardiac resynchronization therapy pacemaker; CRT-D = cardiac resynchronization therapy defibrillator; OBS = observational registry; RCT = randomized controlled trial; HR = hazard ratio; CI = confidence interval.
The original inclusion criteria were: i) age≥80 years, ii) left ventricular ejection fraction ≤ 35%, iii) QRS width>120 ms, and iv) New York Heart Association class II, III, or ambulatory IV for HF on optimal medical therapy. The exclusion criteria were: i) acute myocardial infarction within 40 days, ii) coronary revascularization within 3 months or iii) prior history of cardiac arrest or sustained ventricular arrhythmia. After enrollment had been open for approximately 6 months, the age cutoff was reduced to ≥ 75 years to enhance enrollment and after consultation with all site investigators. At that point, 13 participants had been enrolled (4 into the RCT).
We followed all patients to study endpoint or all-cause mortality, with a minimum of 6 months of follow-up. We scheduled research contacts with participants at 30 days post device implantation, and at 3 months, 6 months, and every 6 months thereafter. We compared the characteristics of patients enrolled in the RCT with those who declined randomization but agreed to be in the observational registry. Survival in the RCT versus the observational registry and for CRT-P versus CRT-D recipients in the RCT were displayed using Kaplan-Meier curves. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC).
Planned enrollment in the observational registry (n=60) was completed after a total of 86 patients had been enrolled the overall trial. Of these 86 participants, 26 (30.2%) agreed to participate in the RCT and 60 (69.8%) declined randomization. Figure 1B shows enrollment accrual into the trial. The burden of comorbidities was as expected in CRT recipients, with no differences between the RCT versus the observational registry participants, except for a higher prevalence of ischemic cardiomyopathy and renal disease in the observational cohort. In the RCT, 100% of patients completed the 30-day, 97.5% the 3-month, 97.4% the 6-month, 80.5% the 12-month, and 78.5% the 24-month follow-up encounter.
A total of 28 out of 102 participants died over a median follow-up of 24 months: 6 of 42 patients in the RCT and 22 of 60 patients in the observational registry. Mortality was lower in patients enrolled in the RCT (unadjusted HR=0.38, 95% CI 0.15–0.93, Figure 1C). Of the 42 randomized participants, 41 received the device to which they were randomized (22 of 22 in the CRT-P arm and 19 of 20 in the CRT-D arm). One patient randomized to the CRT-D arm elected to cancel the procedure. There were 6 deaths in the RCT (3 in each arm) during the median 24-month follow-up (unadjusted HR=0.85, 95% CI 0.17–4.20, Figure 1D). Of the 20 CRT-D recipients in the RCT, only one patient received appropriate device shock for ventricular fibrillation, and another received inappropriate anti-tachycardia pacing for atrial fibrillation.
A total of 45 adverse events were reported among 22 RCT patients (26 in 14 CRT-P recipients and 19 in 8 CRT-D recipients). Most adverse events were non-cardiac but 16 of 45 were classified as cardiac (9 among 8 CRT-P and 7 among 3 CRT-D patients).
Our pilot study yielded important findings. First, we found that some older patients referred for CRT are willing to enroll in an RCT of CRT-P versus CRT-D, but these patients were a minority. Second, there are insufficient data to compare the survival in the observational registry and randomized groups. Third, our pilot data support clinical equipoise between CRT-P and CRT-D in this population. Finally, we obtained valuable data regarding the pace of participant accrual and retention and potential barriers to enrollment that will help inform the planning a pivotal RCT.
Sources of Funding
This trial was funded by an NHLBI grant (R34 HL132031) to Dr. Saba.
Non-Standard Abbreviations and Acronyms
- CRT
Cardiac Resynchronization Therapy
- CRT-D
Cardiac Resynchronization Therapy - Defibrillator
- CRT-P
Cardiac Resynchronization Therapy – Pacemaker
- HF
Heart Failure
- RCT
Randomized Controlled Trial
Footnotes
Disclosures
None
References
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