Effect of Study Design on the Reported Effect of Cardiac Resynchronization Therapy (CRT) on Quantitative Physiological Measures: Stratified Meta‐Analysis in Narrow‐QRS Heart Failure and Implications for Planning Future Studies

Background Biventricular pacing ( CRT ) shows clear benefits in heart failure with wide QRS , but results in narrow QRS have appeared conflicting. We tested the hypothesis that study design might have influenced findings. Method and Results We identified all reports of CRT ‐P/D therapy in subjects with narrow QRS reporting effects on continuous physiological variables. Twelve studies (2074 patients) met these criteria. Studies were stratified by presence of bias‐resistance steps: the presence of a randomized control arm over a single arm, and blinded outcome measurement. Change in each endpoint was quantified using a standardized effect size (Cohen's d). We conducted separate meta‐analyses for each variable in turn, stratified by trial quality. In non‐randomized, non‐blinded studies, the majority of variables (10 of 12, 83%) showed significant improvement, ranging from a standardized mean effect size of +1.57 (95% CI +0.43 to +2.7) for ejection fraction to +2.87 (+1.78 to +3.95) for NYHA class. In the randomized, non‐blinded study, only 3 out of 6 variables (50%) showed improvement. For the randomized blinded studies, 0 out of 9 variables (0%) showed benefit, ranging from −0.04 (−0.31 to +0.22) for ejection fraction to −0.1 (−0.73 to +0.53) for 6‐minute walk test. Conclusions Differences in degrees of resistance to bias, rather than choice of endpoint, explain the variation between studies of CRT in narrow‐ QRS heart failure addressing physiological variables. When bias‐resistance features are implemented, it becomes clear that these patients do not improve in any tested physiological variable. Guidance from studies without careful planning to resist bias may be far less useful than commonly perceived.