Effects of Xanthine Oxidase Inhibition in Hyperuricemic Heart Failure Patients: The EXACT-HF Study

Multicenter, randomized, double-blind, placebo-controlled trial of 253 adults with symptomatic heart failure with reduced ejection fraction (LVEF ≤40%) and hyperuricemia (serum uric acid ≥9.5 mg/dL); median age 63 years; 82% male; 29% Black; high-risk with prior HF hospitalizations; on guideline-directed therapy; excluded if estimated glomerular filtration rate <20 mL/min; follow-up 24 weeks; analysis by intention-to-treat.

Allopurinol, orally, 300 mg daily for 1 week, then 600 mg daily (target dose); dose adjusted for renal function; 24 weeks.

Uric acid decreased significantly with allopurinol vs placebo at 12 weeks (-4.2 mg/dL) and 24 weeks (-3.5 mg/dL; P<0.0001). No improvement in the primary composite end point at 24 weeks: worsened 45% vs 46%; unchanged 42% vs 34%; improved 13% vs 19%; P=0.68. No significant differences in Kansas City Cardiomyopathy Questionnaire scores or 6-minute walk test at 12 or 24 weeks. Left ventricular ejection fraction did not change. Death or all-cause hospitalization did not differ; HF hospitalization tended to be lower with allopurinol (HR 0.67; 95% CI 0.38-1.16; P=0.15). Rash more frequent with allopurinol (10% vs 2%; P=0.01); overall adverse events similar. Conclusion: High-dose XO inhibition with allopurinol did not improve clinical status, exercise capacity, quality of life, or LV function at 24 weeks in high-risk HF with hyperuricemia; safety confirmed, but no clinical benefit observed; longer or different-population studies may be needed.

Possible underpowering for the primary endpoint due to modest sample size; short duration (24 weeks) may not capture longer-term benefits; generalizability limited to high-risk, hyperuricemic HF patients on guideline therapy; slight baseline LVEF imbalance could bias results.