Cardiac Resynchronization Therapy in Heart Failure: Is the Defibrillator Needed?

Nikolaos Dagres; Gerhard Hindricks


Europace. 2018;20(11):1714-1716. 

Cardiac resynchronization therapy (CRT) has evolved to an important pillar in the management of heart failure patients with impaired left ventricular systolic function and ventricular conduction disturbances.[1] The beneficial effect of CRT on mortality and morbidity in selected populations of heart failure patients has been convincingly demonstrated in several large randomized trials.[2,3] Based on this evidence, CRT is recommended by current guidelines for treatment of symptomatic patients with heart failure, depressed left ventricular ejection fraction (LVEF) ≤35% and a broad QRS complex exceeding 130 ms with a recommendation class ranging from I to IIb depending on the QRS width and the presence of left bundle branch block or non-left bundle branch block morphology of the QRS complex.[1]

What is much less clear is the necessity of the defibrillator function when CRT is applied, i.e. whether CRT should be implemented with the use of a CRT pacemaker (CRT-P) or with the use of a CRT defibrillator (CRT-D). In symptomatic heart failure patients with severely depressed LVEF but without CRT indication, current guidelines recommend prophylactic implantation of a defibrillator for primary prevention of sudden cardiac death that is in most cases the result of ventricular tachyarrhythmic episodes.[4] These recommendations are based on the results of two pivotal trials, the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II)[5] and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)[6] that have both shown an improved survival of heart failure patients with reduced LVEF as a result of defibrillator implantation. Thus, it would seem reasonable to assume that heart failure patients with reduced LVEF undergoing implantation of a CRT device would also benefit from the defibrillator function and should therefore receive a CRT-D.

The benefit of this approach is relativized by the observation that CRT per se reduces the risk of sudden death.[7] In line with that, it is important to emphasise that the superiority of CRT-D over CRT-P has never been demonstrated in a randomized trial. The only trial that compared both a CRT-D and a CRT-P arm with optimal medical therapy was the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure trial (COMPANION).[2] However, there is no data for the direct comparison between the CRT-D and the CRT-P arms in that trial. Non-randomized data have yielded inconsistent results with some indicating no benefit of CRT-D,[8–10] whereas others reported the benefit of CRT-D compared with CRT-P only for patients with ischaemic cardiomyopathy or with specific clinical characteristics.[11–13]

The DANISH trial randomized patients with non-ischaemic systolic heart failure to defibrillator implantation or usual clinical care.[14] Importantly, the majority of the patients (58%) received a CRT device, and these patients were randomized in the trial to CRT-D or CRT-P. Thus, these 645 CRT patients of the DANISH trial provide a direct comparison between CRT-D and CRT-P. The results in this CRT subgroup were similar to the overall trial results showing no survival benefit in patients receiving CRT-D as compared with CRT-P.

Due to this absence of strong randomized evidence and the conflicting data, current guidelines of the European Society of Cardiology for treatment of heart failure patients recommend that in patients with a CRT indication, 'the clinician should choose CRT-P or CRT-D, whichever they consider appropriate'.[1] Not surprisingly, this choice that is a frequent dilemma in everyday practice, shows huge variations across different geographies with CRT-D implantations ranging from 11% to 90% of total CRT implantations in the different countries within the European Society of Cardiology.[15–17]

Consequently, it is evident that we urgently need more data in this field and in particular, tools allowing more precise risk stratification for sudden cardiac death and identification of patients that would benefit from a defibrillator as an adjunct to CRT. In this issue of EP-Europace, Leyva et al.[18] provide useful data in this regard. They report observational retrospective data from 551 patients undergoing CRT-D implantation and 999 patients receiving CRT-P in two centres in the United Kingdom over a large period of 17 years. Patients were representative of CRT recipients in clinical practice with a mean age of 70 and 73 years in CRT-D and CRT-P group, respectively, an ischaemic heart failure aetiology of 75% and 44% and predominantly New York Heart Association class III symptoms. During long-term follow-up with a median of 4.7 years, CRT-D was associated with a lower total mortality with a hazard ratio of 0.72. When corrected for multiple variables using propensity score matching, CRT-D was associated with a lower total mortality compared with CRT-P in patients with ischaemic cardiomyopathy but not in patients with non-ischaemic cardiomyopathy.

The data are important because they corroborate existing evidence, most importantly the results of the DANISH trial, questioning the additive benefit of the defibrillator as an adjunct to CRT, if applied as a general strategy. Despite the important strengths of the relatively large patient sample and long follow-up, the main shortcoming of the study by Leyva et al. remains the non-randomized character of the data. There have been numerous examples in the past where the conclusions derived from observational retrospective evidence have not been confirmed in subsequent randomized trials. Therefore, a direct randomized comparison of CRT-D with CRT-P in heart failure patients with reduced LVEF remains the only way to remove the uncertainties regarding the optimal device type in CRT and answer this major unsolved question in cardiovascular medicine.

Fortunately, such attempts are under way. A major project in the field is the RESET-CRT clinical trial ( number NCT03494933) that will randomize heart failure patients with LVEF ≤35% and a CRT indication to either CRT-D or CRT-P implantation (Figure 1). Key inclusion and exclusion criteria are depicted in Table 1. Primary endpoint is total mortality and the sample size is 2030 patients including heart failure of both ischaemic and non-ischaemic cause. The trial is funded by the German Federal Joint Committee (Gemeinsamer Bundesausschuss), the highest decision-making body of the joint self-government of physicians, dentists, hospitals, and health insurance funds in Germany.[19] Start of the recruitment is anticipated within 2018 and the trial is expected to provide conclusive evidence in the field.

Figure 1.

The time for a 'Reset' in the important question of defibrillator use in cardiac resynchronization therapy has come. The conclusive evidence that is needed to address this daily clinical dilemma can only be provided by randomized trials such as RESET-CRT ( number NCT03494933).

In summary, the question whether an individual heart failure patient with reduced LVEF should receive CRT-D or CRT-P is one of the major dilemmas in routine clinical practice in cardiovascular medicine. Observational data and the recent findings of the DANISH trial question the additive value of the defibrillator in the context of CRT. The randomized RESET-CRT trial will provide urgently needed evidence in this debated field.