Oxypurinol Compared With Placebo for Class III-IV NYHA Congestive Heart Failure - OPT-CHF


Patients with symptomatic (New York Heart Association [NYHA] class III or IV) systolic (left ventricular ejection fraction [LVEF] ≤40%) congestive heart failure (CHF) were randomized to treatment with oxypurinol (active metabolite of allopurinol) or placebo, in the background of optimal medical therapy. Safety and efficacy were monitored for 24 weeks following randomization.


Oxypurinol is associated with a significant improvement in clinical status in patients with symptomatic systolic HF at 24 weeks, with an adequate safety profile.

Study Design

Study Design:

Patients Enrolled: 405
NYHA Class: III (96%), IV (4%)
Mean Follow Up: 24 weeks
Mean Patient Age: 64.5
Female: 27
Mean Ejection Fraction: 25.6%

Patient Populations:

• Age 18-85 years
• Symptomatic (NYHA class III or IV) HF
• LVEF ≤40%
• At least one hospitalization for HF within 18 months
• An emergency room visit resulting in treatment with intravenous therapy for worsening HF
• A new drug class for HF added to regimen due to lack of medical stability
• Optimal medical therapy


• Creatinine >3.0 mg/dl

Primary Endpoints:

Change in clinical status, a composite endpoint comprised of:
• Cardiovascular death
• Hospitalization, emergency room, or emergent office/clinical visit for CHF
• Administration of a new drug class for CHF (excluding substitutions for side effects) or the administration of intravenous diuretics de novo for worsening CHF
• Permanent withdrawal of study drug due to worsening CHF
• NYHA functional class
• Patient Global Heart Failure Clinical Status

Secondary Endpoints:

• Time to first occurrence of cardiovascular death or hospitalization for worsening HF
• Change from baseline to week 24 in quality-of-life score, as assessed by the Minnesota Living with Heart Failure questionnaire
• Change from baseline to week 24 in serum uric acid levels

Drug/Procedures Used:

After a 2-week run-in period, patients were randomized to oxypurinol or placebo. For the first week, both groups received one capsule daily (100 mg of oxypurinol or matching placebo). Thereafter, both groups received six capsules daily (600 mg). Patients with impaired renal function had their study medication titrated based on serum creatinine levels; patients with creatinine >3.0 mg/dl were excluded from the study.

Concomitant Medications:

Diuretics (95%), angiotensin-converting enzyme inhibitor (73.5%), angiotensin-receptor blocker (22%), beta-blockers (91.5%), digoxin (55%), spironolactone (35%), and nitrates (33%)

Principal Findings:

A total of 405 patients were randomized, 203 to oxypurinol and 202 to placebo. About 96% of the patients had NYHA class III symptoms. The mean LVEF was 25.6%; CHF was ischemic in etiology in 61% of the patients. More than 99% of the patients were on optimal medical therapy, as determined by the study investigators. The mean baseline serum uric acid level was 7.85 mg/dl. Baseline characteristics were fairly similar between the two groups.

The proportion of patients who improved (43.3% vs. 45%), remained unchanged (32% vs. 35.6%), or worsened (24.6% vs. 19.3%) did not significantly differ between patients receiving oxypurinol or placebo (p = 0.42). Overall and cardiovascular mortality were similar between the oxypurinol and placebo arms (5% vs. 3%, p = 0.29; 4% vs. 2%, p = 0.23, respectively), as was the incidence of all-cause and HF-related hospitalizations (29% vs. 25%, p = 0.34; 13% vs. 8%, p = 0.07, respectively). There was a trend noted for increased cardiovascular death or HF hospitalizations in patients randomized to oxypurinol compared with placebo (hazard ratio 1.8, 95% confidence interval 1.0-3.1, p = 0.054). No significant difference was noted between the two groups in terms of quality-of-life assessment scores.

As expected, oxypurinol was associated with a significant reduction in uric acid levels throughout the duration of the trial (p < 0.0001). The investigators then proceeded to perform a non-prespecified subgroup analysis based on baseline serum uric acid <9.5 mg/dl (n = 294) or ≥9.5 mg/dl (n = 108). Among the patients with high serum uric acid levels, those on oxypurinol had a significant improvement in the 24-week Patient Global Heart Failure Clinical Status compared with placebo (p = 0.02), which was not noted in patients with low serum uric acid levels. Moreover, in the patients with low serum uric acid, there seemed to be an increase in all-cause mortality in the oxypurinol group (6%) compared with placebo (1%) (hazard ratio 4.5, 95% confidence interval 1.0-21.3).

Within the oxypurinol group, a significant correlation between reduction in uric acid levels and improvement in clinical status was noted (r = 0.23, p = 0.0014). Within the oxypurinol high serum uric acid subgroup, patients who improved had an average serum uric acid decrease of 3.5 mg/dl compared with 1.7 mg/dl in the patients categorized as worsened (p < 0.05). Moreover, patients who died or were hospitalized had lower degrees of serum uric acid reduction with oxypurinol compared with those who did not (p = 0.003).


The results of the OPT-CHF trial indicate that treatment with oxypurinol, a xanthine oxidase inhibitor, is not associated with a reduction in clinical outcomes in unselected patients with symptomatic systolic HF, in the background of optimal medical therapy. Exploratory analyses seem to indicate that there may be significant effect modification in its effect based on baseline serum uric acid levels, with a possible benefit noted in patients with high serum uric acid (≥9.5 mg/dl) and possible harm in patients with low serum uric acid (<9.5 mg/dl). Given the small sample size and the possibility of type I error, these results need to be verified in larger clinical trials before they can be considered clinically meaningful.


Hare JM, Mangal B, Brown J, et al., on behalf of the OPT-CHF Investigators. J Am Coll Cardiol 2008;51:2301-9.

Clinical Topics: Heart Failure and Cardiomyopathies, Statins, Acute Heart Failure

Keywords: Oxypurinol, Research Personnel, Heart Failure, Stroke Volume, Emergency Service, Hospital, Confidence Intervals, Creatinine, Capsules, Uric Acid, Xanthine Oxidase

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