By Michael H. Crawford, MD, Editor
SYNOPSIS: A randomized, controlled, open-label study of upgrading patients with right ventricular pacemaker-induced left ventricular dysfunction and heart failure to cardiac resynchronization pacing plus an implantable cardioverter defibrillator (ICD) has shown reduced heart failure hospitalization and improvements in left ventricular function compared to ICD placement alone.
SOURCE: Merkely B, Hatala R, Wranicz JK, et al. Upgrade of right ventricular pacing to cardiac resynchronization therapy in heart failure: A randomized trial. Eur Heart J 2023;44:4259-4269.
In patients who have had right ventricular pacemakers (RV PMs) or implantable cardioverter defibrillators (ICDs) implanted, about one-third develop reduced left ventricular ejection fraction (LVEF) as the result of RV pacing-induced ventricular dyssynchrony, which often leads to clinical heart failure (HF). Since patients with HF and reduced EF (HFrEF) with left bundle branch block (LBBB) morphology who have de novo implantation of a cardiac resynchronization therapy (CRT) device have been shown to have better outcomes, it was hypothesized that patients with prior RV PM or ICD would benefit from an upgrade to CRT. Thus, the Biventricular Upgrade on LV Reverse Remodeling and Clinical Outcomes in Patients with LV Dysfunction and Intermittent or Permanent APical/SepTal RV Pacing Upgrade to CRT (BUDAPEST-CRT) trial was designed to compare the efficacy and safety of a CRT upgrade, compared with ICD, in HFrEF patients with a non-CRT PM or ICD and intermittent or permanent RV pacing.
BUDAPEST-CRT was a prospective, multicenter, randomized controlled trial of adults with either a PM or ICD implanted within at least six months presenting with LVEF ≤ 35%, HF symptoms, paced QRS ≥ 150 ms, and ≥ 20% RV pacing burden on guideline-directed medical therapy (GDMT). Patients were excluded if they had intrinsic LBBB, severe RV dilation, severe valve disease, or renal impairment. Enrolled patients were randomized to CRT-ICD upgrade or ICD in a 3:2 ratio. The primary outcome was the composite of HF hospitalization, all-cause mortality within one year, or < 15% reduction in LV end-systolic volume (ESV) by echocardiography at one year. Safety outcomes were the success rate and safety of implantations.
Between 2014 and 2021, 360 patients (mean age 73 years) were enrolled from 17 sites in seven countries. A total of 215 patients were randomized to CRT-ICD and 145 patients were randomized to an ICD. Mean LVEF was 25%, and most had a prior PM with a high RV pacing burden. CRT-ICD placement was unsuccessful in four patients. During the median 12-month follow-up, crossover from the ICD arm to a CRT-ICD occurred in 19%. All-cause mortality occurred in 6% of the CRT-ICD arm and 11% of the ICD arm. The primary outcome occurred in 32% of the CRT-D arm and 79% of the ICD arm (adjusted odds ratio [OR], 0.11; 95% confidence interval [CI], 0.06-0.19; P < 0.001) and a number needed to treat (NNT) of 2.2.
The secondary outcome of mortality and HF hospitalization also favored the CRT-ICD upgrade compared to ICD (10% v. 32%; OR, 0.27; 95% CI, 0.16-0.47; P < 0.001; NNT 4.7), as did the LV morphologic and functional responses compared to ICD (LVESV -39 mL and EF +10%). There was no significant difference in mortality. There were no subgroups where the results were different. The incidence of procedure- or device-related complications was not significantly different between the two arms (CRT-ICD group 12%; ICD group 8%). The authors concluded that upgrading to CRT-ICD compared to ICD alone in patients with either pacemakers or ICDs with significant RV pacing burdens and reduced LVEF resulted in a reduced risk of the combination of all-cause mortality, heart failure hospitalization, or an attenuated LV functional response.
COMMENTARY
Although patients with HFrEF and LBBB have been shown to benefit from de novo CRT, there is little data on the effect of upgrading patients with RV PM who develop LV dysfunction or PM-induced HF. Because of this paucity of data, guidelines over the last decade have varied considerably in their rating of the advisability of CRT upgrades for those with high RV pacing burdens and wide-paced QRS intervals varying from class I-B to IIa-B, to IIb-B. The B-level data rating is consistent because of the lack of randomized controlled outcome studies.
Studies of de novo CRT implantations have identified a cutoff of > 20% RV pacing as where problems with LV remodeling can be detected in observational studies, which is why this was used for an inclusion criterion in the BUDAPEST-CRT study. Also, these studies showed benefits in patients with LVEF < 50%, but BUDAPEST-CRT used < 35% as an entry criterion. In general, the patients in BUDAPEST-CRT were sicker than those in previous observational studies. The majority had ischemic heart disease, although patients with recent myocardial infarction or revascularization were excluded. The majority of patients had atrial fibrillation and about one-quarter reported prior ventricular tachycardia/ventricular fibrillation and were taking amiodarone. Also, more than one-half of patients had been hospitalized in the last 12 months for HF. In addition, they averaged > 85% RV pacing burden. Thus, these were cardiomyopathy patients with severe LV dysfunction and HF aggravation by RV pacing. The beneficial results on outcomes in the patients in BUDAPEST-CRT argue for early careful monitoring of patients with RV PM for LV dysfunction to identify patients who should be referred for CRT upgrades.
The strengths of the study are that there was an independent blinded committee that adjudicated the events, and the echocardiograms were interpreted at a central lab. Also, GDMT was robust regarding the three pillars of HFrEF therapy: angiotensin-converting enzyme/angiotensin receptor blockers, beta-blockers, and aldosterone antagonists. However, few were on angiotensin receptor/neprilysin inhibitors, and the number taking sodium-glucose transport protein 2 inhibitors is not known. Other weaknesses include that almost all the patients were men. No echocardiographic data were available for 53 patients. Recruitment was slow and the final cohort was not large. Both the latter weaknesses were greatly influenced by the COVID-19 pandemic.
Finally, this was not a blinded study. Although not statistically significant, the complication rate was higher in the CRT-ICD group, probably because of the need for redundant lead extraction in some of these patients. Despite these weaknesses, this was a much-needed prospective randomized study that supports the consideration of CRT upgrade in patients with RV pacing-induced or aggravated HF. Another alternative not studied in BUDAPEST-CRT (because it is relatively new) is conduction system pacing. Since it does not require an LV lead, the complication rate should be lower.
