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. Author manuscript; available in PMC: 2024 Mar 7.
Published in final edited form as: Circulation. 2023 Jan 26;147(10):812–823. doi: 10.1161/CIRCULATIONAHA.122.062124

CRT Improves Outcomes in Patients with IVCD but not RBBB: A Patient Level Meta-Analysis of Randomized Controlled Trials

Daniel J Friedman 1,2, Sana M Al-Khatib 1,2, Frederik Dalgaard 2,3, Marat Fudim 1,2, William T Abraham 4, John G F Cleland 5, Anne B Curtis 6, Michael R Gold 7, Valentina Kutyifa 8, Cecilia Linde 9, Anthony S Tang 10, Fatima Ali-Ahmed 2, Antonio Olivas-Martinez 11, Lurdes YT Inoue 11, Gillian D Sanders 2,12,13,14
PMCID: PMC10243743  NIHMSID: NIHMS1864379  PMID: 36700426

Abstract

Background

Benefit from cardiac resynchronization therapy (CRT) varies by QRS characteristics; individual randomized trials are underpowered to assess benefit for relatively small subgroups.

Methods

We analyzed patient level data from pivotal CRT trials (MIRACLE, MIRACLE-ICD, MIRACLE-ICD II, REVERSE, RAFT, BLOCK-HF, COMPANION, and MADIT-CRT) using Bayesian Hierarchical Weibull survival regression models to assess cardiac resynchronization therapy (CRT) benefit by QRS morphology (left bundle branch block (LBBB) n=4,549; right bundle branch block (RBBB), n= 691; and interventricular conduction delay (IVCD), n= 1,024) and duration (with 150 ms partition). The continuous relationship between QRS duration and CRT benefit was also examined within subgroups defined by QRS morphology. The primary endpoint was time to heart failure hospitalization (HFH) or death; a secondary endpoint was time to all-cause death.

Results

Of the 6,264 patients included, 25% were women, the median age was 66 years (interquartile range 58, 73), and 61% received CRT (with or without an implantable cardioverter defibrillator). CRT was associated with a lower risk of HFH/death (HR 0.73, credible interval (CrI) 0.65 – 0.84) overall and among the subgroups of patients with QRS ≥150ms and either LBBB (hazard ratio (HR) 0.56, CrI 0.48 – 0.66) or IVCD (HR 0.59, CrI 0.39 – 0.89) but not RBBB (HR 0.97, CrI 0.68–1.34)(pinteraction<0.001). No significant association for CRT with HFH/death was observed when QRS was <150 ms (regardless of QRS morphology) or for RBBB. Similar relationships were observed for all-cause death.

Conclusions

CRT is associated with a reduction in HFH/death among patients with QRS ≥150 ms and LBBB or IVCD but not for those with RBBB. Aggregating RBBB and IVCD into a single “non-LBBB” category when selecting patients for CRT should be reconsidered.

Keywords: cardiac resynchronization therapy, intraventricular conduction delay, left bundle branch block, right bundle branch block, meta-analysis

INTRODUCTION

Cardiac resynchronization therapy (CRT) is an important treatment for patients with heart failure, a reduced left ventricular ejection fraction and a prolonged QRS duration. Although findings from landmark trials1–8 have led to widespread use of CRT in many patient cohorts, it is widely recognized that a substantial minority of patients (~30%) might not derive benefit from device implantation. Reasons for a lack of benefit are many and include patient factors, lead placement, and device programming.

Although randomized CRT trials initially enrolled patients based on QRS duration (120 ms or more) rather than morphology, many clinicians subsequently inferred that CRT was only consistently effective for those with a QRS duration ≥150ms9, 10and left bundle branch block (LBBB).10–12 Initially, patients were often classified as “non-LBBB,” but further analyses suggested possible differences for those with intraventricular conduction delay (IVCD) pattern or right bundle branch block (RBBB).13, 14 Subgroup analyses of individual randomized trials aimed at understanding the relationship between QRS characteristics, and the benefit of CRT have been underpowered. Observational studies, although informative, are limited by confounding and lack of a control group that helps distinguish the effects of treatment from the natural history of disease. Accordingly, we performed a patient level meta-analysis of randomized trials of CRT trials to assess the relationship between QRS duration and morphology (RBBB, LBBB, or IVCD) and outcomes.

METHODS

Data Sources

Data for this study were provided by Medtronic and Boston Scientific via data use agreements that prohibit the co-authors from data sharing. Any requests for data sharing should be directed to either Boston Scientific or Medtronic.

We performed a patient level meta-analysis of the following pivotal CRT trials: MIRACLE1, MIRACLE-ICD8, MIRACLE-ICD II2, REVERSE5, RAFT7, COMPANION3, BLOCK-HF4, and MADIT-CRT6. All trials are high quality CRT studies that have been published in high impact journals and have formed the basis for multiple CRT guideline documents. The Duke University Institutional Review Board approved analysis of trial datasets with waiver of informed consent (beyond what was already required for trial). These studies compared the effects of CRT versus either (1) no CRT implantation or (2) CRT device implantation but with CRT programmed off. For the purpose of this meta-analysis, having CRT programmed off is defined as no CRT. Use of CRT pacemaker versus CRT with defibrillator varied by study; as such, concomitant ICD was adjusted for to isolate the association between CRT and outcomes. Due to data privacy restrictions, we were not given access to European patient data which precluded inclusion of CARE-HF.15

Study Population

We included patients with available data on sex, QRS morphology (LBBB, RBBB, or IVCD), and QRS duration, with complete data for the outcomes of heart failure hospitalization (HFH) or death. We excluded patients in these studies with a left ventricular ejection fraction (LVEF) of >35%, a QRS duration of <120 ms, or a history of pacemaker or a paced QRS morphology on the baseline electrocardiogram (ECG). ECGs were centrally adjudicated for MADIT-CRT, REVERSE, and RAFT. In contrast, only individual site-based ECG interpretations were available for COMPANION, BLOCK-HF, and the MIRACLE studies.

Study outcome

The primary study outcome was time to HFH or death. The secondary outcome was time to all-cause death.

Of note, all trials included time to HFH and death as prespecified endpoints. While the primary endpoint varied by trial, most of the trials were powered to assess for a difference in time to HFH or death (MADIT-CRT, RAFT, COMPANION, and RAFT). BLOCK-HF was powered to detect a difference in HFH, death, or left ventricular reverse remodeling. The MIRACLE studies were powered for differences in functional capacity and heart failure related quality of life.

Statistical analysis

Baseline characteristics were compared between participants receiving or not receiving CRT using a t-test that allows unequal variances for numerical covariates or using a chi square test for independence for categorical variables. CRT association with outcomes (versus no CRT) was assessed overall using a Bayesian Hierarchical Weibull survival regression model with a random intercept and a random treatment effect at the trial level. Due to the heterogeneity across trials, our pre-specified analysis plan employed parametric Bayesian Weibull models rather than standard Cox models since the former is better able to incorporate several sources of heterogeneity than the later. Both Bayesian Weibull models and Cox models are proportional hazards models and therefore the interpretation is overall similar. Results are presented using hazard ratios and 95% posterior credible intervals (CrI). We fit an unadjusted model and a model adjusting for baseline characteristics [age, sex, New York Heart Association (NYHA) class, LVEF, QRS duration, QRS morphology, atrial fibrillation, diabetes, hypertension, ischemic cardiomyopathy, use of beta-blockers, and use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers] and the presence of an implantable cardioverter defibrillator (ICD). Age was modeled as a linear spline with a knot at 50 years for the endpoint of time to HFH or death, and as a linear spline with knots at 50 and 80 years for the endpoint of time to death. LVEF was modeled as a linear spline with a knot at 20% for the endpoint of time to death. The association between CRT (versus no CRT) and outcomes was assessed also within the following six QRS subgroups: LBBB ≥150 ms, LBBB <150 ms, RBBB ≥150 ms, RBBB <150 ms, IVCD ≥150 ms, IVCD <150 ms, using similar unadjusted and adjusted models but with a random treatment effect for each QRS characteristic subgroup at the trial level (interaction between CRT and QRS subgroups). To evaluate if the association of CRT with outcomes differs among the QRS subgroups, the posterior probability of no interaction between CRT effect and QRS subgroup was computed.16, 17 All priors are non-informative. For the fixed effects and the mean components of the random effect distributions, we used normal distributions as their priors. For the variance components of the random effect distributions, we used half-normal distributions as their priors, and for the shape parameter of the Weibull model we used a log-normal distribution as its prior. The proportional hazard assumption was assessed using the scaled Schoenfeld residuals from a Cox proportional hazard mixed effects model with a random intercept and a random treatment effect at the trial level.

The adjusted relationship (adjusted hazard ratios) between CRT versus no CRT overall and within the six QRS subgroups is depicted using forest plots. The heterogeneity of the treatment effect, overall and within QRS subgroups, was measured as the percentage of variability corresponding to the treatment effect in relation to the sum of the sources of variability arising from the variability of the baseline hazard and of the treatment effect across trials in the corresponding patient population. The adjusted relationship (adjusted hazard ratios) between CRT versus no CRT overall and within the six QRS subgroups is depicted using forest plots. The weights displayed in the forest plots correspond to the percentage of person time contributed by each trial. The association between QRS duration (continuous) and outcomes was assessed similar to the analysis with six QRS subgroups. This relationship between QRS duration as a continuous variable and outcomes for CRT vs. no CRT is shown in plots depicting the QRS duration on the X axis and the hazard ratio for CRT on the Y axis, subgrouping by QRS morphology (LBBB, RBBB and IVCD).

RESULTS

A total of 7,168 patients across eight pivotal CRT trials were initially considered, but after applying exclusion criteria, 6,261 patients were included in this analysis. Figure 1 is a consort diagram depicting the application of exclusion criteria. The study cohort was older [66 years, interquartile range (IQR) 58, 73], predominantly men (75%), predominantly white (87%), had a severely reduced LVEF (25%, IQR 20, 30), and had mild or moderate heart failure symptoms (NYHA II 52%, NYHA III 38%). Common comorbidities included ischemic heart disease (59%), history of hypertension (53%), and diabetes (34%). The most common QRS morphology was LBBB (n=4,549, 72.6%), followed by IVCD (n=1,024, 16.3%), and RBBB (n=691, 11.0%). Most patients had a QRS duration ≥150 ms (n=4,122, 66%). An ICD was implanted in 77% of patients (n=4,813), and 61% of patients were randomized to CRT(n=3,822). Table 1 describes the overall analysis population classified by QRS characteristics. Patients with RBBB were more likely to be men and to have ischemic heart disease. The burden of AF, diabetes, and hypertension, and the median ejection fraction, were similar across groups.

Figure 1.

Figure 1.

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Consort diagram depicting the application of exclusion criteria allowing for creation of the final study cohort.

Table 1.

Characteristics of the overall cohort and by subgroups defined by QRS characteristics

Characteristics Overall (n=6,264) LBBB ≥150ms (n=3,368) LBBB <150ms (n=1,181) RBBB ≥150ms (n=453) RBBB <150ms (n=238) IVCD ≥150ms (n=301) IVCD <150ms (n=723)
Age (years) 66 (58, 73) 66 (58, 73) 67 (58, 73) 67 (59, 75) 67 (60, 75) 66 (58, 73) 65 (57, 72)
Men 4,720 (75%) 2,374 (70%) 855 (72%) 419 (92%) 208 (87%) 240 (80%) 624 (86%)
Race/Ethnicity†
 Asian 13 (0.5%) 6 (0.4%) 0 (0%) 2 (1.1%) 1 (0.8%) 2 (1.8%) 2 (0.6%)
 Black 201 (7.8%) 102 (7.1%) 32 (7.9%) 20 (11%) 9 (7.3%) 7 (6.1%) 31 (9.1%)
 Caucasian 2,260 (87%) 1,252 (88%) 358 (88%) 148 (84%) 108 (87%) 99 (87%) 295 (87%)
 Hispanic 95 (3.7%) 58 (4.1%) 14 (3.4%) 4 (2.3%) 4 (3.2%) 6 (5.3%) 9 (2.6%)
 Native American 12 (0.5%) 3 (0.2%) 2 (0.5%) 3 (1.7%) 2 (1.6%) 0 (0%) 2 (0.6%)
 Other 9 (0.3%) 7 (0.5%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 2 (0.6%)
NYHA class
 I 324 (5%) 127 (4%) 54 (5%) 32 (7%) 21 (9%) 13 (4%) 77 (11%)
 II 3,282 (52%) 1,775 (53%) 630 (53%) 241 (53%) 141 (59%) 118 (39%) 377 (52%)
 III 2,354 (38%) 1,299 (39%) 447 (38%) 157 (35%) 69 (29%) 148 (49%) 234 (32%)
 IV 303 (5%) 166 (5%) 50 (4%) 23 (5%) 7 (3%) 22 (7%) 35 (5%)
EF (%) 25 (20, 30) 25 (20, 29) 26 (20, 30) 26.0 (20, 30) 28 (24, 30) 25 (20, 29) 26 (21, 30)
Atrial fibrillation 871 (14%) 425 (13%) 155 (13%) 74 (16%) 40 (17%) 49 (16%) 128 (18%)
Diabetes 2,158 (34%) 1,078 (32%) 425 (36%) 185 (41%) 84 (35%) 103 (34%) 283 (39%)
Hypertension 3,343 (53%) 1,734 (52%) 629 (53%) 245 (54%) 139 (58%) 171 (57%) 425 (59%)
Ischemic 3,697 (59%) 1,633 (48%) 747 (63%) 364 (80%) 202 (85%) 219 (73%) 532 (74%)
Antiarrhythmic drug¥ 635 (13%) 349 (13%) 116 (13%) 48 (14%) 14 (7%) 47 (22%) 61 (12%)
Beta blocker 5,028 (80%) 2,732 (81%) 979 (83%) 325 (72%) 183 (77%) 222 (74%) 587 (81%)
ACEi or ARB 5,848 (93%) 3,153 (94%) 1,108 (94%) 422 (93%) 219 (92%) 280 (93%) 666 (92%)
CRT 3,822 (61%) 2,038 (61%) 729 (62%) 279 (62%) 135 (57%) 187 (62%) 454 (63%)
ICD 4,813 (77%) 2,575 (76%) 917 (78%) 352 (78%) 190 (80%) 213 (71%) 566 (78%)
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Summaries presented in median (IQR) or n (%).

†

Information available only for 2,590 patients.

¥

Information available only for 4,745 patients.

ACEi: angiotensin-converting enzyme inhibitor, ARB: angiotensin receptor blocker, CRT: cardiac resynchronization therapy, EF: ejection fraction, ICD: implantable cardioverter defibrillator, ICVD: interventricular conduction delay, LBBB: left bundle branch block, NYHA: New York Heart Association, RBBB: right bundle branch block

The median follow-up for the overall cohort was 24 months (IQR 11 – 42). Study specific Kaplan Meier event rates are summarized in Tables S1 & S2. Randomization to CRT resulted in a reduction in the risk for HFH or death in an unadjusted analysis (HR 0.73, 95% CrI 0.65–0.82). Results were similar in an adjusted analysis accounting for patient characteristics and receipt of an ICD (HR 0.72, 95% CrI 0.65–0.84, Figure 2a). Similarly, randomization to CRT resulted in a reduction in all-cause death in unadjusted (HR 0.77, 95% CrI 0.66 – 0.92) and adjusted analyses (HR 0.78, 95% CrI 0.67 – 0.94; Figure 2b). There was a significant interaction between randomization to CRT and QRS characteristics subgroups (defined by morphology and duration) and HFH or death (p<0.001) and all-cause death (p<0.001). Subsequent interaction testing demonstrated a significant interaction between randomization to CRT and QRS duration of ≥150ms versus <150ms for the endpoints of HFH or death (p<0.001) and all-cause death (p<0.001) with CRT being associated with significant benefit among patients with a QRS duration of ≥150ms. Among patients with a QRS duration of ≥150ms, there was a significant interaction between QRS morphology (LBBB, RBBB, or IVCD) and HFH or death (p<0.001) and a borderline significant interaction for death (p=0.054)

Figure 2.

Figure 2.

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Forest plot depicting the adjusted model assessing association between CRT and outcomes (a, HFH or death and b, all-cause death) overall and by trial.

Unadjusted analyses were performed after stratification of patients into six groups defined by QRS morphology (LBBB, RBBB, IVCD) and duration (<150ms or ≥150ms). In unadjusted analyses, CRT was associated with a reduction in HFH or death for patients with QRS ≥150 ms and either LBBB (HR 0.55, 95% CrI 0.48 – 0.65) or IVCD (HR 0.66, 95% CrI 0.42 – 1.00). CRT was not associated with reduced HFH or death in any other subgroups (Table 2). Results were overall similar when assessing the secondary outcome of all-cause death (Table 2).

Table 2.

Association of CRT with HFH or death and all-cause death by QRS characteristics

HFH or Death All-cause death
Population Sample size† Unadjusted HR, 95% CrI Adjusted HR, 95% CrI Sample size† Unadjusted HR, 95% CrI Adjusted HR, 95% CrI
Overall, ¥ 6,264 (6,218) 0.73, 0.65 – 0.82 0.73, 0.65 – 0.84 6,266 (6,220) 0.77, 0.66 – 0.92 0.78, 0.67 – 0.94
By subgroup, £
 LBBB ≥150ms 3,368 (3,347) 0.55, 0.48 – 0.65 0.56, 0.48 – 0.66 3,368 (3,347) 0.65, 0.53 – 0.80 0.66, 0.54 – 0.81
 LBBB <150ms 1,181 (1,174) 0.84, 0.67 – 1.05 0.85, 0.68 – 1.07 1,181 (1,174) 0.84, 0.62 – 1.12 0.84, 0.61 – 1.15
 RBBB ≥150ms 453 (451) 1.06, 0.77 – 1.45 0.97, 0.68 – 1.34 454 (452) 0.96, 0.63 – 1.47 0.83, 0.55 – 1.33
 RBBB <150ms 238 (235) 1.19, 0.69 – 2.16 1.15, 0.67 – 2.09 238 (235) 0.88, 0.45 – 1.68 0.84, 0.43 – 1.76
 IVCD ≥150ms 301 (297) 0.66, 0.42 – 1.00 0.59, 0.39 – 0.89 301 (297) 0.57, 0.30 – 1.13 0.50, 0.29 – 0.89
 IVCD <150ms 723 (714) 1.06, 0.82 – 1.36 1.07, 0.83 – 1.42 724 (715) 1.19, 0.81 – 1.69 1.28, 0.88 – 1.93
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†

Values inside brackets correspond to the number of patients with complete data regarding the covariates considered for the adjusted models.

CrI: credible interval, CRT: cardiac resynchronization therapy, HR: hazard ratio, ICVD: interventricular conduction delay, LBBB: left bundle branch block, RBBB: right bundle branch block.

Adjusted models, accounting for patient characteristics and receipt of an ICD, were similar to the unadjusted models (Table 2, Figure 3a). CRT was associated with a reduction in HFH or death among patients with LBBB and QRS ≥ 150ms (HR 0.56, 95% CrI 0.48 – 0.66) and IVCD and ≥150 ms (HR 0.59, 95% CrI 0.39 – 0.89). While there were no statistically significant relationships within other subgroups, the LBBB and QRS <150 ms subgroup demonstrated a trend toward reduction in HFH or death that was not statistically significant (HR 0.85, 95% CrI 0.68 – 1.07). Subgroup findings were consistent across trials in adjusted analyses (Figure 3a). Results were similar in adjusted analyses of CRT and all-cause death among QRS subgroups and across trials (Table 2, Figure 3b).

Figure 3.

Figure 3.

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Forest plots depicting an adjusted model assessing the association between CRT and outcomes (a, HFH or death and b, all-cause death) among subgroups defined by QRS morphology (LBBB, RBBB, IVCD) and duration (≥150 ms or <150 ms).

Results were similar in sensitivity analyses using frequentist Cox mixed models (Table S3) and in Bayesian Weibull models removing data from the three trials that contribute the fewest events (Table S4).

The continuous relationship between QRS duration and CRT benefit was assessed among the three QRS morphology subgroups (LBBB, RBBB, IVCD) (Figure 4a). Among patients with LBBB, the 95% CI around the HR for the effect of CRT on the composite of HFH or death was <1.0 when QRS duration exceeded 129 ms; for IVCD this value was 165 ms and for RBBB 213 ms, although the CrI were much larger than for LBBB due to the smaller number of patients and events. Figure 4b depicts overall similar results for all-cause death, although due to fewer events the confidence intervals are wider, with thresholds of 145ms, 252ms and 210ms respectively for LBBB, IVCD and RBBB.

Figure 4.

Figure 4.

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Relationship between QRS duration, CRT, and outcomes (a, HFH or death and b, all-cause death) within each subgroup defined by QRS morphology. The black lines depict point estimates and the red lines depict the 95% posterior credible intervals. Y axes depict HR for heart failure hospitalization or death. X axes depict QRS duration. The vertical dotted lines indicate QRS durations at which the 95% CI crosses a HR of 1.0 (neutrality), indicating strong evidence of benefit.

The continuous relationship between QRS duration and CRT benefit was assessed among the three QRS morphology subgroups (LBBB, RBBB, IVCD), with additional stratification based on sex (Figure 5). Among patients with LBBB, an association between CRT and reduced HFH or death was observed when QRS duration exceeded 127ms in women and 137ms in men. Among those with IVCD, an association between CRT and reduced HFH or death was observed when QRS duration exceeded 140ms in women and 174ms in men. For RBBB, CRT may have reduced the risk of HFH or death when QRS duration exceeded 226ms for women and 223ms for men, although the CrI were much wider than for LBBB or IVCD.

Figure 5.

Figure 5.

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Relationship between QRS duration and HFH or death within each subgroup defined by sex and QRS morphology. The black lines depict point estimates and the red lines depict the 95% posterior credible intervals. Y axes depict HR for heart failure hospitalization or death. X axes depict QRS duration. The vertical dotted lines indicate QRS durations at which the 95% CI crosses a HR of 1.0 (neutrality), indicating strong evidence of benefit.

DISCUSSION

This patient level meta-analysis assessing the association of CRT with HFH or death by QRS characteristics is the largest cohort of CRT trial patients assembled for this purpose and has several clinically relevant findings. First, and consistent with prior publications, CRT was associated with a markedly lower rate of HFH or death among patients with a LBBB ≥150 ms, CRT appeared beneficial when QRS durations exceeded approximately 130 ms in the presence of LBBB. Second, although in current guidelines patients with RBBB and IVCD are combined into a singular “non-LBBB” cohort, we found that CRT was associated with a lower risk of HFH or death among patients with IVCD and QRS duration ≥150 ms but not for patients with RBBB or for IVCD when QRS duration was <150 ms. Outcomes were similar for analyses of all-cause death. In exploratory analyses, we observed sex specific differences; CRT was associated with better outcomes at a shorter QRS duration among women compared to men. These findings have important implications for patient selection for CRT.

Pivotal CRT trials enrolled patients based on QRS duration with the supposition that a prolonged QRS duration (>120 ms) was indicative of electrical dyssynchrony with significant underlying left ventricular (LV) activation delay regardless of QRS morphology. However, a substantial proportion of patients have a disappointing response to CRT, which has led to a plethora of research to improve selection of patients for CRT or improve methods of implementation.18 Early studies suggested LBBB morphology10–12 and QRS duration of >150 ms9, 10 predicted a greater response to CRT. However, LBBB is often associated with a wide QRS, which may exaggerate the benefits in LBBB, and, more importantly, overemphasize a presumed lack of benefit in non-LBBB, although RBBB was described as linked to a lack of CRT response almost from the start. Nevertheless, despite the lack of QRS morphology as an inclusion criterion or as a pre-specified subgroup analysis for most trials of CRT, guidelines make strong recommendations based on QRS morphology (dichotomized as LBBB and non-LBBB) and duration (dichotomized as ≥150 ms and <150 ms) for patient selection.19, 20 Whereas our results support the importance of considering QRS duration when assessing CRT candidacy, they do not support combining RBBB and IVCD into a single group.

While early data demonstrated that some patients with RBBB had activation delays similar to LBBB,21, 22 it was not until later that IVCD patients were studied in more detail. A body surface mapping study of patients with LBBB and IVCD confirmed the presence of LV activation delay among a subset of patients with an IVCD.23 Although both LV activation delay and QRS duration predicted response to CRT in this cohort, ventricular electrical uncoupling (the difference between mean right ventricular and LV activation times) was the strongest predictor. A secondary analysis of the SMART-AV study demonstrated that QLV (interval from QRS onset to sensed signal on the LV lead), but not QRS morphology, predicted reverse remodeling and improvement in symptoms.24 These findings helped to confirm the importance of LV activation delay and identify a physiologic rationale for an earlier finding from a MADIT-CRT secondary analysis, which suggested that patients with a “LBBB-like” IVCD derived benefit from CRT.12 Subsequent studies using the ECG-derived QRS area, a vectorcardiographic measure of electrical dyssynchrony, have demonstrated that electrical dyssynchrony is present in non-LBBB patients and that its presence is associated with more favorable long-term outcomes with CRT.25, 26

The aforementioned studies have demonstrated the plausibility of CRT benefit in patients with IVCD by documenting the presence of LV activation delay; however, the current study provides the strongest evidence to date that patients with this substrate may benefit from resynchronization. While our study demonstrates that a QRS duration of ≥150 ms may be useful for identifying patients more likely to benefit from CRT, QRS duration is likely to be an unreliable surrogate among IVCD patients (due to concomitant right ventricular activation delay), and even with this caveat, the optimal threshold of QRS duration for patient selection likely varies by sex,27, 28 ethnicity29, and body stature.27, 30 The ongoing Non-specific Intraventricular Conduction Delay CRT trial (NICD-CRT, NCT02454439)31 is a randomized trial of CRT programmed on versus off in patients with IVCD of >130 ms and LVEF <35% who were implanted with a CRT pacemaker or CRT with defibrillator. While the NICD-CRT trial may help to refine patient selection further, at present, the best approach to selection of IVCD patients for CRT may rely on careful examination of the ECG to assess for features in common with LBBB, including a longer QRS duration.

Strengths and Limitations

This meta-analysis of patient level data from eight pivotal CRT trials is the largest study of prospectively enrolled patients to assess the relationship between QRS duration and morphology and outcomes. However, a few limitations are noteworthy. Trials applied slightly different inclusion and exclusion criteria and QRS morphology classification definitions. While the study population included more than 6,000 patients, some subgroups were small, which may have reduced the power to detect statistically significant differences. While we used advanced Bayesian techniques to account for heterogeneity in study criteria and differences in variable definitions, we cannot rule out the possibility of residual confounding.

CONCLUSIONS

In this meta-analysis of patient level data from eight pivotal randomized trials, we confirmed CRT benefit among patients with LBBB and identified the novel finding that patients with RBBB and IVCD had different outcomes after CRT. CRT was associated with a lower risk of HFH or death among patients with IVCD and a QRS of ≥150 ms while RBBB patients (with any QRS duration) and IVCD patients with QRS <150 ms did not demonstrate a statistically significant association between CRT and outcomes. These findings challenge the long-standing practice of combing RBBB and IVCD into a single “non-LBBB” subgroup when assessing CRT candidacy.

Supplementary Material

SDC files

WHAT IS NEW?

  • In this-patient-level-data meta-analysis, we demonstrated that for patients with IVCD and a QRS duration ≥150ms, CRT was associated with lower rates of HF hospitalizations and all-cause mortality.

  • The magnitude of CRT benefit among patients with IVCD of ≥150ms and LBBB of ≥150ms appeared similar.

  • There was no clear CRT benefit for patients with a RBBB of any QRS duration, although we cannot rule out the potential for benefit at markedly prolonged QRS durations.

WHAT ARE THE CLINICAL IMPLICATIONS?

  • The practice of combining RBBB and IVCD patients into a single “non-LBBB” category in order to select patients for CRT is not supported by our data.

  • Patients with an IVCD ≥150ms should be offered CRT as is done for patients with a LBBB ≥150ms

Acknowledgments

Funding:

Primary funding was provided by the National Heart, Lung, and Blood Institute (1R01HL131754). NHLBI did not participate in the literature search, determination of study eligibility criteria, data analysis or interpretation, or preparation or approval of the manuscript for publication.

Disclosures:

Dr. Friedman has received: research support from American Heart Association, Boston Scientific, Biosense Webster, Merit Medical, Medtronic, the National Institutes of Health, and Abbott, and consulting fees from Abbott, AtriCure, Microport, NI Medical, and Sanofi. Dr. Al-Khatib receives research funding from Medtronic and Boston Scientific through grants to her institution. Dr. Cleland reports grants and personal fees from Pharmacosmos, personal honoraria from Abbott, Astra Zeneca, Idorsia, Myokardia, NI Medical, Novartis, Servier anmd Torrent pharmaceuticals; grants and personal honoraria from Amgen/Cytokinetics, Bayer, Bristol Myers Squibb, Johnson & Johnson, Medtronic, Vifor and Viscardia; personal honoraria and non-financial support from Boehringer-Ingelheim outside the submitted work. Dr Fudim was supported by the National Heart, Lung, and Blood Institute (NHLBI) (K23HL151744), the American Heart Association (20IPA35310955), Bayer, Bodyport, BTG Specialty Pharmaceuticals and Verily; he receives consulting fees from Abbott, Alleviant, Audicor, AxonTherapies, Bayer, Bodyguide, Bodyport, Boston Scientific, Coridea, CVRx, Daxor, Deerfield Catalyst, Edwards LifeSciences, Feldschuh Foundation, Fire1, Gradient, Intershunt, Medtronic, NXT Biomedical, Pharmacosmos, PreHealth, Shifamed, Splendo, Vironix, Viscardia, Zoll. Dr Linde has received research support to her institution from Swedish Heart-Lung Foundation, Swedish Royal Academy of Science, Roche Diagnostics, Astra Zeneca and Stockholm County Council and speaker honoraria from Medtronic, Impulse Dynamics, Bayer, Boeringer Ingelheim, Novartis, Vifor Pharma and Microport. Dr. Curtis serves on medical advisory boards for Janssen Pharmaceuticals, Medtronic, Inc., Abbott, Sanofi Aventis, Milestone Pharmaceuticals, and Eagle Pharmaceuticals; she has received honoraria for speaking from Abbott and Medtronic. Dr. Gold serves on a medical advisory board for Medtronic and EBR, receives research support to his institution from Boston Scientific, Abbott and Medtronic, and is a consultant to Boston Scientific and Medtronic. The remaining authors report no disclosures.

Footnotes

Clinical Trial Registration: NCT00271154, NCT00251251, NCT00267098, NCT00180271

Supplemental Materials

Tables S1–4

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