News
WASHINGTON – Allopurinol has no effect on heart failure, according to results from the multicenter, double-blind EXACT-HF study.
"In heart failure patients with reduced ejection fraction and hyperuricemia, xanthine oxidase inhibition with allopurinol safely lowers uric acid levels, but has no beneficial effect on clinical status, exercise capacity, quality of life, or left ventricular structure and function. Other adjunctive therapies for high-risk heart failure patients are clearly needed," Dr. Michael M. Givertz said in presenting the EXACT-HF results at the annual meeting of the American College of Cardiology.
Hopes were high going into EXACT-HF that xanthine oxidase inhibition would provide a much needed novel therapeutic approach to heart failure. A growing body of evidence suggests that oxidative stress plays a major role in ventricular remodeling and disease progression, and xanthine oxidase – a potential source of oxidative stress in heart failure – was a logical therapeutic target.
Frontline Medical News
Dr. Michael M. Givertz
Moreover, in animal models of heart failure, as well as earlier short-term patient studies, allopurinol caused regression of left ventricular hypertrophy, improved endothelial function, and boosted myocardial efficiency while reducing myocardial oxygen demand, noted Dr. Givertz, medical director of heart transplant and circulatory assist at Brigham and Women’s Hospital, Boston.
EXACT-HF was a double-blind study in which 253 hyperuricemic heart failure patients with a median left ventricular ejection fraction (LVEF) of 24% and a median uric acid level of 11 mg/dL were placed on allopurinol or placebo and followed prospectively for 6 months. Allopurinol was started at 300 mg/day and, after 1 week, boosted to a target dose of 600 mg/day if tolerated.
The primary endpoint was a composite comprising death, hospitalization, or an emergency department or urgent care clinic visit for worsening heart failure; a medication change due to worsening heart failure; and patient global assessment. By this standard, roughly 45% of patients in both study arms were worse after 6 months, 16% were improved, and the rest were unchanged. Nor did the two groups differ significantly in terms of the various secondary and tertiary endpoints, including quality of life as assessed by the Kansas City Cardiomyopathy Score; the 6-minute walk test; levels of cystatin C, myeloperoxidase, and NT-proBNP (N-terminal of the prohormone brain natriuretic peptide); and left ventricular volume, mass, and ejection fraction.
Uric acid levels were reduced by about 45% in the allopurinol group. However, investigators never viewed hyperuricemia as a mediator of heart failure, but rather as a marker of more severe disease. And this was a population with fairly severe disease, as reflected in the 6% mortality rate at 6 months, along with a 30% rate of unscheduled outpatient visits and 38% rate of all-cause hospitalization, Dr. Givertz said.
Asked if he thought a longer treatment period might have shown therapeutic benefit, the cardiologist replied that there was one positive signal: The risk of heart failure hospitalization over the 6-month study was reduced by 33% in the allopurinol group, with the curves separating after 8-10 weeks, although the difference wasn’t statistically significant. But he was reluctant to make too much of this.
"It’s conceivable that if one treated for a year or longer with high doses of allopurinol, perhaps one might see a benefit. The argument against that is the consistency in the neutrality of the other endpoints at 6 months," according to Dr. Givertz.
Intriguingly, several recent studies suggest that colchicine – an even more venerable gout drug than allopurinol – may protect gout patients against cardiovascular events.
The EXACT-HF trial was sponsored by the National Heart, Lung, and Blood Institute and carried out by the NHLBI Heart Failure Clinical Research Network. Dr. Givertz reported serving as a consultant to Merck, Cardioxyl, and Janssen.
