Results
Altogether, 3872 (76%) patients were included in this analysis (Figure 1; Table 1). The median (IQR) age of patients was 66 (58–73) years, 868 (22%) were women (Table 2), 1995 (52%) were in NYHA class III or IV, and 2232 (58%) had ischaemic heart disease, including 1926 men (64% of men) and 306 women (35% of women). Only 81 patients in REVERSE were assigned to receive CRT or back-up pacing, and, therefore, among NYHA II patients who were enrolled, the comparison was predominantly CRT-D vs. ICD. The median value for LVEF (IQR) was 24 (20–28)%; it was 116 (105–130) mmHg for systolic blood pressure and was 160 (146–176) ms for QRS duration, with 78% having LBBB.
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Figure 1.
CONSORT flow diagram showing reasons for excluding patients from analysis.
Comparing patients assigned to CRT/CRT-D or to the control group in the whole population, the HR for all-cause mortality was 0.66 (95% CI 0.57–0.77), and it was 0.65 (95% CI 0.58–0.74) for death or HF hospitalization (Figure 2A and B).
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Figure 2.
Overall effect of cardiac resynchronization therapy vs. control on all-cause mortality (A) and on death or heart failure hospitalization (B).
A significant interaction between CRT and QRS duration (Table 3) was observed, for both the composite outcome (P < 0.0001) and all-cause mortality alone (P = 0.0013), suggesting that patients with longer QRS durations derive greater benefit from CRT. Use of P-splines to examine the relationship between the effect of CRT and QRS duration as a continuous variable demonstrated a progressive increase in the benefit of CRT for both endpoints as QRS duration increased (Figure 3). The analyses yielded a significant nonlinear relationship with regard to the composite of death/HF hospitalization (P = 0.0039), with a plateau of effect beyond 180 ms for the composite outcome, but not for mortality alone (P = 0.3454). The estimated HR crossed 1.0 at 126 ms for all-cause mortality and at 132 ms for the composite, suggesting possible benefit from CRT when QRS duration exceeds these values. The 95% confidence bounds excluded 1.0 beginning at ~140 ms for each endpoint, providing robust evidence of benefit from CRT when QRS duration exceeds this limit.
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Figure 3.
Models showing hazard ratios (Y-axis and solid black line) and their 95% confidence intervals (dotted lines) for the effects of cardiac resynchronization therapy vs. control with QRS plotted on the X-axis. (A) The relationship between the effect of cardiac resynchronization therapy on all-cause mortality and QRS. (B) The corresponding relationship for heart failure hospitalization or death. The intersection of the 95% confidence interval and the line indicating a hazard ratio of 1.0 (no effect) indicates the QRS duration above which there is a high certainty of response.
Interactions between CRT and other covariates were not significant in a multivariable model that included QRS duration. Similar reductions in all-cause mortality were observed with CRT regardless of whether the comparator was or was not an ICD and regardless of age, sex, NYHA class, aetiology, systolic blood pressure, or use of beta-blockers (Figure 4). Subgroup analyses for time to first composite event of HF hospitalization or death showed similar results (Figure 5). Patients who did not have LBBB appeared to have less benefit from CRT, especially in the composite outcome, but differences were not statistically significant. QRS duration was similar in patients with LBBB [median (IQR) 160 (150–180) ms] and RBBB [160 (150–172) ms] but shorter among patients with a non-specific intra-ventricular conduction delay [139 (128–160) ms], which may account for the trend to less reduction in mortality in the latter group. Removal of the QRS duration interaction term strengthened the interaction term between QRS morphology and the composite outcome (P = 0.031), but not for mortality alone (P = 0.63).
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Figure 4.
Forest plot for univariate frailty models evaluating the effect of cardiac resynchronization therapy in pre-specified subgroups on all-cause mortality.
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Figure 5.
Forest plot for univariate frailty models evaluating the effect of cardiac resynchronization therapy in other pre-specified subgroups on death or heart failure hospitalization. Figures show hazard ratio and 95% confidence intervals.