Cardiac Resynchronisation Therapy in Atrial Fibrillation
Despite the abundant data on CRT among patients in sinus rhythm, this therapy in patients with atrial fibrillation (AF) has been less well studied. AF was excluded from most of the clinical trials. In RAFT, which included the largest number of AF patients randomised to CRT, the outcomes of CRT in AF were non-significant, which may be due to the relatively low BiV pacing percentage in this cohort.24 The PAVE trial showed benefit of CRT in patients with a depressed left ventricular ejection fraction undergoing atrioventricular junction (AVJ) ablation secondary to refractory, symptomatic atrial fibrillation.1,19 CRT is also recommended in permanent AF patients that have symptomatic HF with a severely depressed ejection fraction and significant interventricular conduction delay.1
Currently, AVJ ablation is recommended after the inability to achieve complete BiV pacing.1 Recent studies have indicated that a very high pacing percentage is required to achieve full CRT benefit. One large cohort of patients followed by remote telemetry monitoring suggested over 98 % of conducted beats must be paced beats in order to confer all of the mortality benefits of CRT, and that AF limited the percentage of paced beats.25 The RAFT randomised to CRT without ablation, required patients to be aggressively rate controlled before trial enrolment, with a resting heart rate <60 and a heart rate of <90 after six-minute walk, but still only achieved greater than 95 % BiV pacing in one-third of patients.24 Initial registry and meta-analysis data shows similar outcomes for patients that undergo AVJ ablation to the sinus rhythm group, but worse outcomes for patients in AF who are treated with medical rate control.26–28 Randomised controlled trials are needed to identify the optimal timing of AVJ ablation in the permanent AF population, but the emerging consensus is that more aggressive use of this technique is needed in CRT.
Cardiac Resynchronisation Therapy Non-Responders
Despite the overall benefit demonstrated by CRT, a clinical non-response is noted in approximately one-third of patients throughout the literature, although this estimate varies based on the clinical outcome used to define response.29,30 CRT is an expensive and invasive therapy thus significant interest in understanding, predicting and reducing non-responders has been evaluated. The reason for the clinical non-response is complicated and likely multifactorial in most patients with irreversibly advanced HF, myocardial scar, lead placement, lack of clinically significant dyssynchrony and lack of AV and VV optimisation all thought to play a role in certain cases.31 The remainder of this review will highlight some of the proposed methods to decrease the CRT non-response rate.
Improved Patient Selection for Cardiac Resynchronisation Therapy (Electrocardiography and Beyond)
Subgroup analyses from multiple studies have shown that the greatest response to CRT is noted with QRS prolongation and left bundle branch block (LBBB). Patients with LBBB and QRS duration >150 ms receive the most benefit from therapy and have a Class I indication in the current guidelines, whereas patients with a non-LBBB and QRS duration of 120–150 ms receive only a Class IIB in severe HF and are not indicated in mild HF.1 Given the expense of large randomised clinical trials and the number of trials that have already addressed these issues in the past, it is unlikely that a trial will be designed with enough power to further tease out the clinical and electrocardiography (ECG) factors that are the best predictors in HF patients in sinus rhythm that do not require RV pacing. Recently a large individual patient meta-analysis of the Cardiac Resynchronization in Heart Failure (CARE-HF), Multicenter InSync Randomized Clinical Evaluation (MIRACLE), REVERSE, MIRACLE ICD and RAFT studies was performed to evaluate the further predictors for CRT response. In this large cohort, QRS duration but not QRS morphology (i.e. LBBB) predicted survival or HF hospitalisations. In addition, CRT response rates did not differ based on ejection fraction including the groups of patients with a left ventricular ejection fraction over 35 %, males and females appeared to respond similarly to CRT, and there were no differences in response rates in patients with a diagnosis of ischaemic or non-ischaemic cardiomyopathy.8,9,14,24,32
There was much early enthusiasm for the use of echocardiography to identify mechanical dyssynchrony to predict CRT response. However, subsequent prospective multicentre trials failed to support this strategy. The Predictors of Response to CRT (PROSPECT) trial assessed several echocardiographic parameters (including several tissue Doppler parameters and M-mode parameters) to predict CRT response rate, and none of these parameters were found to have clinically useful value.29 More recently, the Echocardiography Guided Cardiac Resynchronization Therapy (EchoCRT) trial was a randomised trial designed to determine if mechanical dyssnchrony as identified by tissue Doppler or colour tracking radial stain predicted CRT response in patients with a QRS duration <130 ms and NYHA class III or IV HF. All patients were implanted with CRT devices with the control group having CRT turned off. The trial was stopped early by the safety monitoring board due to futility with a trend towards increased mortality at the time of trial stoppage.33 These trials further reinforced the importance of QRS duration as a predictor of CRT response.