乌鸦传媒

Two drugs used to treat gout, febuxostat (Uloric) and allopurinol (Zyloprim among others) were equally likely to cause adverse cardiovascular events in patients with gout and co-existing cardiovascular disease (CVD) but the risk of all-cause and cardiovascular mortality was higher with febuxostat, a head-to-head comparison of the two showed.

After a median follow-up of 32 months, 10.8% of patients treated with febuxostat had experienced an adverse cardiovascular event compared with 10.4% of patients treated with allopurinol, reported William White, MD, University of Connecticut School of Medicine, Farmingham, Connecticut and colleagues in the New England Journal of Medicine.

On the other hand, risk of all-cause mortality was 22% higher in the febuxostat arm at a hazard ratio of 1.22 (95% CI 1.01-1.47; P=0.04) while the risk of cardiovascular death was 34% higher (HR 1.34, 95% CI 1.03-1.73; P=0.03) compared with allopurinol, White and colleagues reported.

The FDA had required the study as a condition of febuxostat's approval, after "a modestly higher rate of cardiovascular events with febuxostat" was seen in the drug's clinical trials, the investigators explained.

In the current study, dubbed CARES, "Unexpectedly, all-cause mortality was higher in the febuxostat group than in the allopurinol group, because of an excess of cardiovascular deaths," White and colleagues observed.

Mary Cushman, MD, spokesperson for the American Heart Association and professor of medicine, Larner College of Medicine at the University of Vermont in Burlington, told 乌鸦传媒 that it's long been known that patients with higher uric acid levels have a higher risk of CVD outcomes.

"Thus, one might surmise that treatments that lower uric acid would prevent these outcomes," she said in an email. However, earlier studies of febuxostat indicated that this was not the case -- if anything, the opposite seemed to be true. "Therefore, it was very important to clarify this issue and determine if, in fact, this drug might cause CVD events," she emphasized.

Now that a higher risk of all-cause and cardiovascular mortality has been identified in patients receiving febuxostat, Cushman said that she would hesitate to use the drug in patients with gout, especially if they had co-existing CVD.

"In general, I think the findings here suggest trying your best with allopurinol that is dose-adjusted to kidney function before going to febuxostat," Cushman observed, adding, however, that since the mortality effect observed in the CARES study did not have its onset immediately during follow-up, "maybe it would be reasonable to treat for a limited time with febuxostat in patients who don't do well with allopurinol," she suggested.

A total of 6,190 patients were randomized to receive febuxostat at an initial dose of 40 mg once a day, increased to 80 mg once a day if serum urate levels did not decline to less than 6.0 mg/dL by week 2; or to allopurinol at a dose modified according to kidney function.

The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent revascularization for unstable angina.

Notably, over half of patients discontinued treatment prematurely. The median duration of drug exposure was, however, similar in both treatment arms at 728 days for febuxostat-treated patients and 719 days for those treated with allopurinol. Looking at events that occurred either while patients were still taking the study drug or within 30 of discontinuing treatment, the authors observed that there were no between-group differences in the incidence of the composite primary endpoint at 7.8% in the febuxostat group and 7.7% in the allopurinol group.

In contrast, the risk of cardiovascular mortality in the same data set was 49% higher in the febuxostat group compared to the allopurinol group (P=0.047).

Limitations to the CARES trial include the large percentage of patients who dropped out of the trial prematurely and who did not complete follow-up, although very similar numbers of patients dropped out of both treatment arms.

Comment