Table 2.

Our assessment of CARES strengths, and uncertainties arising from the results

Strengths of the study

Large, double-blinded, and randomized study of relevant population (i.e., patients with gout and established CV disease), powered for cardiovascular events State-of-the-art adjudication process for relevant CV disease endpoints Direct comparison of allopurinol and febuxostat dose titration, including allopurinol dosing above 300 mg/day Use of initial gout flare prophylaxis (preferably with colchicine)

Uncertainties arising from the results

Particularly high dropout rate of ~50% on average (45–57%) in the treatment groups Inconsistent findings between fatal and non-fatal CV endpoints ~85% of deaths occurred off study drugs Without a placebo comparator, the study design does not answer the question whether allopurinol or febuxostat independently carry an increased risk of CV disease and mortality Questions about biologic plausibility, due to anti-inflammatory and anti-atherogenic effects of XOIs, and comparable primary mechanism of action of allopurinol and febuxostat on xanthine oxidoreductase Lack of data on temporal course and severity of gout flares, which can exert systemic effects potentially pertinent to CV mortality