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Cardiology Research

Review

Volume 11, Number 1, February 2020, pages 1-8

Indications of Cardiac Resynchronization in Non-Left Bundle Branch Block: Clinical Review of Available Evidence

Cardiac resynchronization therapy (CRT) benefits have been firmly established in patients with heart failure and reduced left ventricular ejection fraction (HFrEF), who remain in New York Heart Association (NYHA) functional classes II and III despite optimal medical therapy, and have a wide QRS complex [1]. An important and consistent finding in published systematic reviews and in subgroup analyses is that the benefits of CRTs are maximum for patients with a broader QRS durations, typically described as QRS duration > 150 ms, and for patients with a typical left bundle branch block (LBBB) QRS morphology [2]. It remains uncertain whether patients with non-LBBB QRS complex morphology clearly benefit from CRT or only modestly respond [3-6].

In this article, we reviewed the major trials that enriched the most recent international guidelines for CRT implantation focusing on the available data about the outcome of using CRT in non-LBBB cohort. Furthermore, we conferred the current guidelines, including the comprehensive update of the Canadian Cardiovascular Society (CCS) guidelines for the management of heart failure (HF) 2017 [2], the European Society of Cardiology (ESC) Heart Failure Association guidelines for the diagnosis and treatment of acute and chronic HF 2016 [7], the National Institute of Health and Care Excellence (NICE) guidelines for ICD (implantable cardioverter defibrillator) and CRT for arrhythmia and heart failure 2014 [8], the American College of Cardiology Foundation/American Heart Association guideline for the management of heart failure 2013 [9], the ESC European Heart Rhythm Association guidelines on cardiac pacing and cardiac resynchronisation therapy 2013 [10], and the update to National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand guidelines for the prevention, detection and management of chronic HF in Australia 2011 [11].

Non-LBBB wide QRS complex patterns include the following four groups are represented in Figure 1 as follow: 1) Atypical LBBB represent “QRS duration greater than or equal to 120 ms in adults, broad notched or slurred R wave in leads I, aVL, V5, and V6, and an occasional RS pattern in V5 and V6 attributed to displaced transition of QRS complex, absent q waves in leads I, V5, and V6, and R peak time greater than 60 ms in leads V5 and V6” with atypical feature such as Q wave in I and aVL, larger R wave in V1 and V2, or V6 QRS complex morphology which is different from those in I and aVL (Fig. 1a). 2) Complete (typical) right bundle branch block (RBBB) is described as QRS duration ≥ 120 ms in adults, rsr′, rsR′, or rSR′ in leads V1 or V2, R or r deflection is usually wider than the initial R wave patients, S wave of greater duration than R wave or greater than 40 ms in leads I and V6 in adults, and normal R peak time in leads V5 and V6 but > 50 ms in lead V (Fig. 1b). 3) Interventricular conduction delay (IVCD) which characterized by wide QRS morphology that does not resemble either typical LBBB or RBBB. The definition may also be applied to a pattern with RBBB criteria in the precordial leads and LBBB criteria in the limb leads, and vice versa (Fig. 1c). 4) Atypical RBBB may represent underlying delay in left ventricular (LV) activation as well. RBBB masks the underlying co-existent LBBB in broader QRS indicating advanced grade of dyssynchrony (Fig. 2) [12].

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Figure 1. Different ECG morphological pattern of non-LBBB wide QRS complex. (a) Atypical LBBB. (b) Typical RBBB. (c) Nonspecific interventricular conduction block. ECG: electrocardiogram; LBBB: left bundle branch block; RBBB: right bundle branch block.

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Figure 2. Atypical RBBB: broad, slurred, and notched R wave on leads I and aVL, together with a leftward axis deviation. RBBB: right bundle branch block.

The ECG morphological patterns of atypical LBBB, typical RBBB and IVCD ECGs are illustrated in Figure 1. The atypical RBBB ECG is illustrated in Figure 2.

Over last decade, 13 major studies, involving the outcomes of CRT use in patients with HFrEF, were conducted between 2002 and 2018 (Table 1, [13-25]). Remarkably, from 2002 to 2010, the ECG selection criteria were based solely on prolonged QRS duration without differentiation between types of bunch branch block morphology [13-23]. On the other hand, the ENHANCE CRT pilot study (2018) was conducted solely in such “non-LBBB” patients to investigate the advantage of using an electrophysiologic measure of left ventricular (LV) delay to guide lead placement when implanting the CRT’s biventricular lead system [25].

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Table 1. Summary of the CRT Landmark Clinical Trials

Until 2015, the major trials lacked the evidence that non-LBBB patients as a group would benefit from CRT implantation. The MIRACLE ICD trial stated that the benefit of CRT was positive regardless of QRS morphology although they admit they may have been underpowered in this regard [16].

Investigators of the COMPANION trial did a subgroup univariate analysis on factors associated with hospitalization risk for all patients in RBBB and/or IVCD and compared to LBBB, which produced clear evidence that the benefit of CRT was mainly observed in patients with LBBB (hazard ratio (HR) of 1.26). Similarly, IVCD was compared to RBBB or LBBB yielding a similar outcome (HR of 1.24) [22]. However, RAFT trial had comparable outcomes (HR = 1) [23].

The MADIT-CRT trial stated that the benefits from CRT among the trial’s patients without LBBB were not the same as LBBB patients, and in fact it suggested CRT might increase their mortality [20]. However, recently in 2018, the ENHANCE CRT study, the first head-to-head comparison of additional LV lead placement guided by electrical delay versus the standard of care, concluded that CRT is an effective therapy in patients with non-LBBB with no apparent distinction seen in responses by subgroups, including RBBB vs. IVCD, QRS interval, sex, HF cause, or left ventricular ejection fraction (LVEF). In addition, there were no significant differences between the two interventional arms in quality of life or LVEF [25]. The earlier trials finding of possible harm in non-LBBB are less relevant to this study as the included patients were in softer indications (i.e. NYHA class I to II in MADIT-CRT versus III to IV in ENHANCE CRT).

ACC/AHA/HRS, ESC, and CCS guidelines agree that if a patient has a QRS duration > 150 ms and is in NYHA functional class III or ambulatory IV, then a CRT “better to be considered” (class IIa). When QRC duration is < 150 ms, there is considerable inconsistency in the guidelines. Both ACC/AHA/HRS and ESC guidelines favor the CRT (class IIb), however the CCS guidelines do not provide a formal recommendation for this patient group; instead, they simply state that there is no clear evidence of benefit with CRT among patients with QRS duration < 150 ms because of non-LBBB conduction.

NICE guidelines recommend CRT device insertion in patients with non-LBBB QRS morphology, who have QRS duration ≥ 150 ms and in NYHA functional classes II, III, and IV. CRT pacemaker without ICD insertion is indicated in patients with non-LBBB QRS morphology who have a QRS between 120 and 149 ms and in NYHA functional class IV. NICE guidelines also provide a clear guidance on whether to implant a cardiac resynchronization therapy with pacemaker (CRT-P) or a cardiac resynchronization therapy defibrillator (CRT-D). In addition, NICE does not provide classes of recommendation or levels of evidence.

Finally, the guidelines published by the National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand in 2011, do not distinguish between LBBB and non-LBBB in their recommendations for CRT in patients in sinus rhythm. In Table 2, we summarize the different international guidelines of indications of CRT in patients with non-LBBB wide QRS complex.

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Table 2. Summary of the CRT Landmark Clinical Trials

Since the introduction of CRT in the treatment of patients with HF, an increasing number of patients with RBBB QRS morphology or long-drawn-out IVCD have been treated. The reason for that is QRS duration ≥ 120 ms had been considered initially as the only ECG selection criterion for CRT [26, 27]. Angelo et al recently reviewed the past observational studies that assessed the effect of CRT on some surrogate end points of mortality/morbidity and mortality directly. The results of two large US registries including patients with LBBB, IVCD, and RBBB were also included in the review. Neither the observational studies nor the meta-analysis demonstrated any significant benefit in CRT implant in patients with non-LBBB QRS complex pattern including typical RBBB. Moreover, the evidence of excess in mortality in RBBB CRT-treated patients than in LBBB CRT-treated patients is observed in both registries. The straightforward application of CRT in patients with typical RBBB was accordingly discouraged [28].

Although RBBB typically reflect delayed right ventricular (RV) activation, some patients with HF and RBBB pattern on ECG have concomitant superimposed delay in LV activation as well. RBBB commonly masks the underlying co-existent LBBB in broader QRS, the theory that was confirmed by electroanatomic mapping data, which demonstrated that not only RV activation is abnormally delayed but also LV activation delayed [29]. Rosenbaum et al [30] described atypical RBBB pattern as broad, slurred, sometimes bifid R wave on leads I and aVL, together with a leftward axis deviation frequently noted in LBBB QRS morphology patients (Fig. 2).

A recent review of several studies, that considered CRT in the subset of atypical RBBB, stated that acute response to CRT is clinically relevant and has positive values. Additional studies should be valued also as to whether a subset of patients with RBBB may benefit from CRT [28]. Subsequently, a study evaluated 66 patients with RBBB (31 with typical RBBB and 35 with atypical RBBB) treated with CRT and followed up for almost 2 years. The target end points of reduction in LV end-systolic volume index (ESVI) ≥ 15% or reduction in the NYHA class ≥ 1 or Packer score variation (NYHA response with no HF-related hospitalization events or death) were considered. This showed 71.4% ESVI responders in atypical RBBB group in comparison with only 19.4% in typical RBBB group (P = 0.001). Furthermore, 74.3% of patients in atypical RBBB group were NYHA responders compared with 32.3% in typical RBBB group (P = 0.002). Similarly, in the atypical and typical RBBB groups, respectively 71.4% and 29.0% of patients exhibited a 2-year Packer score of 0 (P = 0.002) [31].

We have represented the comparative number of patients studied with specified non-LBBB versus LBBB and unspecified groups in a line graph as shown in Figure 3. This graph clearly demonstrates the much greater numbers of subjects in the LBBB or unspecified IVCD arms of each study. We can see that only from 2016 onwards does the discrepancy of patients’ numbers between the two begin to narrow and increase data for non-LBBB patients.

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Figure 3. Line-graph representing the volume of patients studied over time, both LBBB/unspecified (blue) and specified non-LBBB (red). Only since 2016 can we see the gap beginning to narrow.

Non-LBBB (including atypical RBBB) in symptomatic HF patients may benefit from CRT implants. While the ESC task forces guidelines were directed towards symptomatic HF with EF < 35% patients with broad QRS > 150 ms in non-LBBB patients, yet QRS 130 - 149 may respond with modest expectations of a good response. The American guidelines have the same considerations. However, it is clear that the Canadian guidelines still weakly support non-LBBB/CRT implants if QRS > 150 ms, and in fact, it discourages CRT implants in QRS duration less than 150 ms in non-LBBB patients. Finally, NICE recommendation of non-LBBB with QRS 120 - 149 ms is only indicated in disabling HF (NYHA IV).

Non-LBBB CRT implants remain an area of debate. The previous support to CRT in those patients was on the basis of atypical features of RBBB and great IVCD. It remains a valid clinical decision to consider CRT implant in symptomatic patients (despite of optimized medical therapy) in non-LBBB with QRS duration ≥ 150 ms. Multidisciplinary approaches (e.g. cardiac electrophysiologists, HF cardiologists, physiologist and specialists liaison HF nurses) and new techniques of multipoint pacing are promising in such difficult group of patients with debated indication and expected poor responders. The data are not encouraging in regards to typical RBBB with QRS duration less than 150 ms.

Acknowledgments

None to declare.

Financial Disclosure

None to declare.

Conflict of Interest

None to declare.

Author Contributions

Maged Henin contributed to study design, manuscript writing and references check. Hany Ragy involved in manuscript review and re editing; James Mannion contributed to creating the tables of the major trials and edited the summary for each and language check. Santhosh David contributed to manuscript review and re-editing. Beshoy Refila contributed to study design, editing the manuscript and review. Usama Boles, the main supervisor, involved in study design, review, editing, and pre-submission check.

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