Prevalence and Impact of Treatment Crossover in Cardiac Surgery Randomized Trials: A Meta-Epidemiologic Study.
Gaudino M., Fremes SE., Ruel M., Di Franco A., Di Mauro M., Chikwe J., Frati G., Girardi LN., Taggart DP., Biondi-Zoccai G.
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 RCTs (≥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 RRs 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 RCTs (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%). RRs for primary end point and mortality were higher in RCTs 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 RCTs. Crossover should be minimized at designing stage and carefully appraised after study completion.