of arrhythmias whilst remodelling is ongoing, but in the long term does not have survival benefit compared with CRT-P.20 Furthermore, all pacemaker devices including those delivering CRT could reduce the risk of ventricular tachycardia/ventricular fibrillation triggered by pauses and bradyarrhythmic sudden death.21 This mechanism would also contribute to explaining the similar mortality outcomes with CRT-P and CRT-D. This hypothesis is sup-

ported by the consistent reduction in rates of sudden death as a proportion of total mortality.13,22

Although there is randomised controlled trial (RCT)

evidence that ICDs reduce mortality in patients with CHF and LVSD10,23 with the two largest studies pub-

lished around 10 years ago demonstrating a hazard ratio of 0.77 and 0.69 for total mortality with ICD over OMT, these compared ICD with OMT. Patients for CRT were not included. On the other hand, the recent Defibrillator Implantation in Patients with Non-ischaemic Systolic Heart Failure trial study in 556 patients with nonischaemic cardiomyopathy failed to show a survival benefit of ICD implantation24 over OMT with CRT if indicated.

The RCTs that included both CRT-D and CRT-P devices are few and limited.6,16 Patients in the Compari-

son of Medical Therapy, Pacing and Defibrillation in Heart Failure trial study (all of whom were NYHA class III or IV) were randomized to receive OMT, OMT and CRT-P or OMT and CRT-D in a 1 : 2 : 2 ratio.6 COMPANION revealed that both CRT-P and CRT-D significantly reduced combined all-cause mortality and hospitalization rates in patients with moderate to severe CHF. However, despite stratification, the COMPANION study was underpowered to explore a survival benefit of CRT-D over CRT-P.25 Analysing mode of death, COMPANION demonstrated a reduction in sudden cardiac death but overall mortality was unchanged.26 The REVERSE study included CRT-D and CRT-P and although it showed lower mortality in patients receiving CRT-D compared with CRT-P, the device choice (D or P) was left to the investigator.16

Previous observational studies have provided conflicting results. Kutyifa et al.27 found no difference in mortality between those receiving CRT-P versus CRT-D in 1122 patients. However, in a subgroup analysis, those with ischaemic cardiomyopathy receiving CRT-D seemed to have improved survival compared with CRT-P. The multicentre prospective CERITUDE cohort in France demonstrated that at 2-year follow-up the crude mortality in patients receiving CRT-P was double that of patients receiving CRT-D.28 In that study, CRT-P patients had worse symptoms (more NYHA class IV) and cause of mortality analysis revealed a large proportion of deaths because of nonsudden cardiac death in that group implying that patients who received CRT-P had worse CHF and would not have benefited from the addition of a defibrillator.

CRT-P v CRT-D in CHF Drozd et al. 5

Although international guidelines accept a lack of clear data, they extrapolate a benefit of CRT-D over CRT-P based upon data from RCTs comparing ICDs with OMT

and therefore generally recommend CRT-D implantation.29,30 Our data serve to highlight the unresolved issue

that this may be an inappropriate extrapolation of these data to patients receiving CRT-P and that the proportional benefit of the ICD might not be clinically significant in a population of CRT recipients. The question of clinical and cost-effectiveness of CRT-D over CRT-P is pertinent as the incremental cost-effectiveness of CRT-D over CRT-P might be above the acceptable margin for payers,31 particularly given that in addition to a higher upfront cost, CRT-D devices may have a higher risk of device-related complications.11,32 For example, although the cost-effec- tive analysis of the COMPANION trial estimated incremental cost-effectiveness ratios for CRT-P at $19 600/ quality of life year (QALY) and $43 000/QALY both relative to OMT over a 7-year base-case time period, there was no comparison of CRT-P versus CRT-D.33 However, a cost-effectiveness simulation analysis based on the REVERSE study estimated an additional $46 678/QALY for the use of CRT-D versus CRT-P.34

Limitations

There are several important limitations that deserve highlighting in the interpretation of these results. First, although patient-based data collection in this study were prospective, the collection and analysis of mortality data were performed retrospectively. Second, although we collected data on consecutive, unselected patients receiving CRT devices, the nature of the device (D or P) was not allocated randomly, but rather on the discretion of the operator and according to current UK guidelines (prior to 2015). This could have introduced systematic selection bias and residual confounding for which we have not corrected. Third, although response to CRT is associated with better outcomes, no consistent measure of response that can be used to aid selection has been identified, so our study aimed to assess outcomes in all patients irrespective of symptomatic or echocardiographic response. Fourth, there were different baseline characteristics between patients who received CRT-P and CRT-D and although we adjusted for these differences and also conducted propensity score matching analyses, we cannot completely exclude the possibility of selection bias contributing to our findings.

Conclusion

In this large real-world study of unselected consecutive patients receiving a successful CRT implant, there was no evidence of a survival benefit of CRT-D compared with CRT-P. The clinical effectiveness (and therefore the cost-effectiveness) of widespread use of CRT-D versus CRT-P remains unproven. A randomized controlled trial would be required to answer this question.

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