Weekly journal scan: a hard <i>RAFTing</i> to improve long-term survival in heart failure with severely reduced ejection fraction

Comment on the article ‘Long-term outcomes of resynchronization–defibrillation for heart failure’ published in the New England Journal of Medicine. doi: 10.1056/NEJMoa2304542. The Resynchronization–Defibrillation for Ambulatory Heart Failure Trial (RAFT) was a multicentre, double-blind, randomized, controlled trial (RCT) aimed at assessing whether the addition of cardiac resynchronization therapy (CRT) to an implantable cardioverter–defibrillator (ICD) and optimal medical therapy results in lower mortality and fewer hospitalizations for patients with heart failure and reduced ejection fraction (HFrEF) than ICD plus optimal medical therapy alone. During a mean follow-up of 40 months, ICD with CRT (CRT-D) was associated with a significantly lower risk of death or hospitalization for HF than ICD alone.1 In the present long-term follow-up study, the authors sought to determine the long-term effects of CRT-D vs. ICD on all-cause mortality, by analysing the survival outcomes of 1050 patients enrolled at the eight highest-enrolling sites in Canada with a median follow-up of 7.7 years (nearly 14 years for those who survived).2 A total of 1798 HF patients with left ventricular ejection fraction ≤ 30%, QRS complex duration > 120 ms (including right bundle-branch block, non-specific intraventricular conduction delays) or paced QRS duration > 200 ms, and New York Heart Association (NYHA) class II or III were included in the RAFT trial and randomized in a 1:1 fashion to receive an ICD or CRT-D. Standard implantation techniques were employed, with an attempt to place the left ventricular lead in the lateral or posterolateral wall of the left ventricle whenever possible. Programming was set to minimize right ventricular pacing in the ICD arm and to maximize biventricular pacing in the CRT-D arm. After publication of a clinical trial showing a survival benefit for patients with NYHA class III HF,3 the protocol was modified to exclude this group of patients. The centres that enrolled the largest number of patients (n = 1050, of whom n = 530 in the ICD group and n = 520 in the CRT-D group) participated in the long-term follow-up study, and clinical records were used to obtain survival data. The primary outcome was death from any cause. A composite of death from any cause, heart transplantation, or implantation of a left ventricular assist device was a secondary outcome. All analyses were performed on an intention-to-treat basis. The mean age of participants was 66.5 years, with 84% men, 68% with ischaemic cardiomyopathy and 76% in NYHA class II. A total of 16% of patients had persistent atrial arrhythmia, and up to 30% had QRS morphologic features different from left bundle-branch block (right bundle-branch block, non-specific intraventricular conduction delay or paced QRS complexes). Left ventricular ejection fraction was 22% in both groups. Concomitant medications included angiotensin-converting enzyme inhibitors (ACEi)/angiotensin-receptor blockers (ARBs) (97%), beta-blockers (90%), spironolactone (42%), aspirin (70%), warfarin (37%), amiodarone (16%), and diuretics (84%). Overall, the patients had moderate chronic kidney disease. The primary outcome occurred in 76.4% of patients in the ICD group compared to 71.2% of those assigned to CRT-D. The time until death, which was adopted using the exponential accelerated failure time model for the primary analysis, was longer in the CRT-D group compared to the ICD group [acceleration factor 0.80; 95% confidence interval (CI), 0.69–0.92; P = 002]. The composite of death from any cause, heart transplantation, or implantation of a left ventricular assist device was also less frequent (75.4% vs. 77.7%) and the time until a secondary endpoint appeared to be longer in the CRT-D group than in the ICD group (acceleration factor 0.85; 95% CI, 0.74–0.98). Subgroup analyses for the primary endpoint were consistent with the main findings. In recent years, the clinical outcomes for patients with HFrEF have substantially improved, thanks to the introduction of new and effective therapies, which have substantially modified patients’ management. In this context, cardiac resynchronization represents today a solid therapeutic option for patients with HFrEF and left bundle-branch block, leading to improvements in clinical symptoms, functional capacity and survival.3,4 Following seminal studies including NYHA class III or IV HF patients,4,5 the RAFT trial has demonstrated the efficacy of CRT-D in patients with NYHA class II HF, with benefits additive to those obtained with optimal medical therapy, including ACEi or ARBs, and beta-blockers used by more than 90% of patients at baseline.1 Moreover, the beneficial effects of CRT were seen despite patient crossover from the ICD group to the CRT-D group (and vice versa, up to 6% per group in the RAFT trial1) and the inclusion of patients who did not meet the criteria for CRT implantation (e.g. right bundle-branch block or non-specific intraventricular conduction delays on electrocardiography). In the present long-term survival study conducted on a large subset of patients enrolled in the RAFT trial, the authors showed a sustained survival benefit of CRT-D, persisting over an 8-year follow-up and up to nearly 14 years in those who survived.2 These data confirm and expand those obtained at 7 years of follow-up in the population of the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT), which showed that early intervention with CRT-D was associated with a significant and sustained survival benefit among patients with mild HF symptoms, left ventricular dysfunction, and left bundle-branch block.6 Some limitations need to be acknowledged. Pharmacological therapy has considerably improved since the initial trial was completed (February 2009), with the introduction of ARB-neprilysin inhibitors and sodium-glucose cotransporter-2 inhibitors, thus the impact of CRT-D on survival in patients treated with newer drugs introduced in the first-line therapy of HFrEF remains untested. The small percentage of females (16%) and the lack of racial diversity do not allow generalizability of the results. In addition, the study does not provide information on the long-term influence of CRT-D on worsening heart failure and recurrent hospitalizations. Furthermore, it should be emphasized that, although the majority of patients in the RAFT trial had only mild HF symptoms, three-quarters being in NYHA class II at the time of enrolment in the trial, mortality within the overall population was approximately 80% at 15 years. The persistently high mortality of patients with severe reduction of EF should promote studies to evaluate the potential benefits of an earlier and broader use of CRT-D in the natural course of the disease. In this regard, a cost–benefit analysis on a preferential use of CRT-D would also be important. If, on one side, procedural complications were significantly more prevalent in the CRT-D group than in ICD alone in the RAFT trial, the recent advances in pacing technique (i.e. left bundle-branch area pacing) should improve the clinical outcomes and reduce complications, making CRT use reasonable even in patients with asymptomatic ventricular dysfunction.7 In conclusion, based on these analyses, the survival benefit of CRT-D therapy over ICD alone for patients with HFrEF, a widened QRS complex, and NYHA class II or III appears to have been sustained during nearly 14 years of follow-up. The study provides more robust evidence for the efficacy of CRT, expanding its use to patients with mild symptoms or patients for whom the benefit from resynchronization has never been demonstrated, such as those with right bundle-branch block. However, further studies will be needed to assess the effects of CRT when used in combination with recently approved and highly effective pharmacological therapies, or when compared with other pacing techniques. D.P. received speaker’s fees from Daiichi-Sankyo, outside the submitted work. M.V. reports personal fees for speaker bureau and/or consulting in Advisory Boards from Astra Zeneca, GSK, Menarini Int, Novartis Pharma, Novo Nordisk, Pfizer, and Sanofi Pasteur, outside the submitted work.

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