Expanding Indications for Cardiac Resynchronisation Therapy In Heart Failure

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Expanding Indications for Cardiac Resynchronisation Therapy In Heart Failure

The indications for CRT were recently updated in the European and American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/Heart Rhythm Society (HRS) guidelines due in part to recent clinical trials on the subject.^1,10 Subsequently, the Resynchronization Reverses Remodeling in Systolic left Ventricular Dysfunction (REVERSE) and Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) trials demonstrated that subjects with New York Heart Association (NYHA) class I or II HF had better outcomes with CRT.^11–13 The Resynchronization/Defibrillation for Ambulatory Heart Failure Trial (RAFT) extended these findings with a longer follow-up showing that CRT with implantable defibrillator (ICD) backup (CRT defibrillator [CRT-D]) prolongs survival compared with ICD alone, in NYHA class II subjects.14Post hoc analysis of the patients included in the MADIT-CRT and REVERSE trials revealed that the mildly symptomatic patients with only mild left ventricular systolic dysfunction also benefitted from CRT, suggesting that a larger population of patients may benefit from CRT.¹⁵

After the revision of the guidelines, the Biventricular Versus Right Ventricular Pacing in Heart Failure Patients With Atrioventricular Block (Block-HF) trial was published showing benefit of CRT in patients with an indication for pacing and a mildly depressed ejection fraction. The BLOCK-HF trial randomised 691 patients with an indication for pacemaker placement and an ejection fraction ≤50 % to biventricular (BiV) or right ventricular (RV) pacing. The primary endpoint was a composite of death from any cause, HF care requiring intravenous therapy or evidence of adverse cardiac remodeling as measured by an increase in left ventricular end-systolic volume index of ≥15 %. There were statistically improved outcomes with CRT for both the composite primary outcome as well as a secondary outcome of HF hospitalisation.^16,17 The Block-HF trial supports the previously published Dual Chamber and VVI Implantable Defibrillator (DAVID) and Left Ventricular-Based Cardiac Stimulation Post AV Nodal Ablation Evaluation (PAVE) trials suggesting that frequency of right ventricular pacing leads to adverse clinical outcomes and adverse ventricular remodeling.^18,19

Despite the Block-HF trial, concern has been raised about the composite endpoint being driven mostly by adverse ventricular remodeling rather than ‘harder’ clinical outcomes, and that the control arm also received a LV lead that was programmed not to pace thus neutralising procedural complications.²⁰ These concerns were further heightened by the recent preliminary report of the Biventricular Pacing for Atrioventricular Block to Prevent Cardiac Desynchronization (BIOPACE) trial. The BIOPACE trial was designed to randomise subjects with an indication for permanent ventricular pacing, but no guideline indication for CRT pacing, to standard right ventricular pacing device verses BiV device. Primary endpoints include the combination of time-to-death or first HF admission and secondary endpoints include quality of life, six-minute hall walk and echocardiographic signs of adverse remodeling.²¹ Preliminary results presented at the ESC Congress 2014 were notable for a non-significant 13 % reduction in the primary endpoint with CRT.²² The inconsistent results from this and other studies may reflect some of the challenges of designing trials for implantable devices. Many of these design issues are evident comparing the REVERSE study, which had an implanted, double-blind design and MADIT-CRT, which was unblinded with one arm receiving CRT-D devices and the other arm ICD. The challenges of performing a device-based trial in HF have been discussed elsewhere.²³