Recent analyses and commentaries on the major colchicine trials have treated COLCOT and LoDoCo2 as defining the expected benefit of colchicine for cardiovascular prevention, with CLEAR SYNERGY viewed as the discordant or outlying study because of its neutral result. We performed a descriptive analysis to examine how the trial that is least readily reconciled with an assumed true treatment effect changes depending on different assumed effects.

We used the published hazard ratios (HRs) and 95% confidence intervals from COLCOT, LoDoCo2, and CLEAR SYNERGY. For each assumed true treatment effect, we calculated the probability that a hypothetical repeat of each trial, with the same standard error as that study and centered on the assumed treatment effect, would yield a 95% confidence interval containing the estimate observed in that trial. The main analysis used the published primary composite outcome from each trial and additional exploratory analyses separately examined cardiovascular death, myocardial infarction, and stroke.

For the primary composite outcomes, the observed HRs were 0.77 for COLCOT, 0.69 for LoDoCo2, and 0.99 for CLEAR SYNERGY. Across assumed HRs from 0.65 to 1.00, the trial least readily reconciled changed from CLEAR SYNERGY under larger assumed benefits to LoDoCo2 under smaller assumed benefits. Exploratory component analyses showed different patterns by outcome: cardiovascular death estimates were relatively similar across the 3 trials (HRs 0.84, 0.80, and 1.03); myocardial infarction estimates were broadly comparable in COLCOT and CLEAR SYNERGY but more favourable in LoDoCo2 (HRs 0.91, 0.88, and 0.70); and stroke estimates were divergent across all 3 trials (HRs 0.26, 0.66, and 1.15).

When outlier status is assigned based only on observed trial results, the trial least readily reconciled with the evidence depends on the assumed true treatment effect. Although differences in design, conduct, population, or inflammatory context may explain the apparently divergent results of the 3 large colchicine trials, CLEAR SYNERGY cannot be designated the outlier on the basis of its neutral result.