Prevalence and Impact of Treatment Crossover in Cardiac Surgery Randomized Trials: A Meta‐Epidemiologic Study

Abstract

Background Crossover dilutes treatment effect and reduces statistical power of intention‐to‐treat analysis. We examined incidence and impact on cardiac surgery randomized controlled trial ( RCT ) outcomes of crossover from experimental to control interventions, or vice versa. Methods and Results MEDLINE , EMBASE , and Cochrane Library were searched, and RCT s (≥100 patients) comparing ≥2 adult cardiac surgical interventions were included. Crossover from the initial treatment assignment and relative risks ( RRs ) for each trial's primary end point and mortality at longest available follow‐up were extracted. All RR s were calculated as >1 favored control group and <1 favored experimental arm. Primary outcome was the effect estimate for primary end point of each RCT , and secondary outcome was all‐cause mortality; both were appraised as RR at the longest follow‐up available. Sixty articles reporting on 47 RCT s (25 440 patients) were identified. Median crossover rate from experimental to control group was 7.0% (first quartile, 2.0%; third quartile, 9.7%), whereas from control to experimental group, the rate was 1.3% (first quartile, 0%; third quartile, 3.6%). RR s for primary end point and mortality were higher in RCT s with higher crossover rate from experimental to control group ( RR , 1.01 [95% CI , 0.94–1.07] versus RR , 0.80 [95% CI , 0.66–0.97] and RR , 1.02 [95% CI , 0.95–1.11] versus RR , 0.94 [95% CI , 0.82–1.07], respectively). Crossover from control to experimental group did not alter effect estimates for primary end point or mortality ( RR , 0.82 [95% CI , 0.63–1.05] versus RR , 0.95 [95% CI , 0.86–1.04] and RR , 0.88 [95% CI , 0.73–1.07] versus RR , 1.02 [95% CI , 0.95–1.09], respectively). Conclusions Crossover from experimental to control group is associated with outcomes of cardiac surgery RCT s. Crossover should be minimized at designing stage and carefully appraised after study completion.