Several observational studies reported that allopurinol, an effective treatment for gout, was associated with important reductions in cardiovascular events, with calls for large randomized trials, though some results were conflicting. We assessed the extent of time-related biases in these observational studies.
We searched the literature for all observational studies reporting on allopurinol and cardiovascular events, focusing on two time-related biases. Time-related confounding bias results from studies using cohorts of patients all exposed to allopurinol, with comparisons based on episodes of allopurinol discontinuation, where confounding factors are not updated over follow-up time. Immortal time bias arises from the exposure misclassification of periods of cohort follow-up during which the outcome under study cannot occur.
We identified 12 studies, of which eight were affected by time-related confounding bias or immortal time bias, while the remaining four studies avoided these biases. The studies affected by time-related confounding bias resulted in significant reductions in the incidence of cardiovascular events with allopurinol use (pooled hazard ratio 0.88; 95% CI: 0.85-0.92), as did the studies affected by immortal time bias (pooled hazard ratio 0.79; 95% CI: 0.72-0.87). The four studies that avoided these biases resulted in a pooled hazard ratio of 1.07 (95% CI: 0.91-1.25).
Observational studies reporting significantly reduced incidence of cardiovascular events with allopurinol use were affected by time-related biases. Overall, studies that avoided these biases did not find a protective effect. The ALL-HEART randomised trial will provide important and accurate evidence on the potential effectiveness of allopurinol on cardiovascular outcomes.