Effectiveness of allopurinol on reducing mortality: Time-related biases in observational studies.

Research paper by Samy S Suissa, Karine K Suissa, Marie M Hudson

Indexed on: 03 Mar '21Published on: 02 Mar '21Published in: Arthritis & Rheumatology


The treatment of gout with allopurinol is effective at reducing urate levels and the frequency of flares. Several observational studies reported important reductions in mortality with allopurinol use, with wide variations in results. The extent of bias in these studies, particularly time-related biases such as immortal time bias, is unclear. We searched the literature to identify all observational studies reporting on the effect of allopurinol versus non-use on all-cause mortality. We identified 12 observational studies, of which three were affected by immortal time bias and three by immeasurable time bias, while the remaining six studies avoided these time-related biases. Reductions in all-cause mortality with allopurinol use were observed among the studies with immortal time bias, with a pooled hazard ratio of death associated with allopurinol of 0.71 (95% CI: 0.50-1.01) and those with immeasurable time bias (pooled hazard ratio 0.62; 95% CI: 0.56-0.67). The six studies that avoided these biases found a null effect of allopurinol on mortality (pooled hazard ratio 0.99; 95% CI: 0.87-1.11), though the lack of an analysis based on treatment adherence could have attenuated somewhat the effect. Observational studies are important to provide evidence from real-world data on medication effects. The observational studies reporting significantly decreased mortality with allopurinol use cannot be used as evidence, mainly because of time-related biases that tend to greatly exaggerate the potential benefit of treatments. The ALL-HEART randomised trial, currently underway, comparing allopurinol versus usual care, will provide reliable evidence on this major outcome of mortality. This article is protected by copyright. All rights reserved.