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Center for Global Research Data

Reanalysis of CARES study to investigate the incidence of cardiovascular events and death after initiation and discontinuation of allopurinol and febuxostat

Lead Investigator: Byeongzu Ghang, Jeju National University Hospital
Title of Research Proposal: Reanalysis of CARES study to investigate the incidence of cardiovascular events and death after initiation and discontinuation of allopurinol and febuxostat
Vivli Data Request: 5165
Funding Source: None
Potential Conflicts of Interest: None

Summary of the Proposed Research:

Gout is the most common inflammatory joint disease and causes pain, swelling, and joint damage. This disease is characterized by chronic hyperuricemia (an abnormally high level of uric acid in the blood) and uric acid crystal deposition in joints. There have been many reports about close association between gout and cardiovascular disease. However, whether hyperuricemia and uric acid crystal directly cause cardiovascular disease is not well known.

Febuxostat is a highly selective and potent inhibitor of xanthine oxidase, a metabolic pathway for uric acid formation, which has been developed to treat patients with insufficient response to allopurinol. The cardiovascular safety of Febuxostat and Allopurinol in patients with gout and cardiovascular disease (CARES) was evaluated as an FDA requirement to determine whether febuxostat is not inferior to allopurinol in terms of adverse major cardiovascular events. The CARES trial suggested that the incidence of all-cause mortality and cardiovascular death was higher in the febuxostat group than that in the allopurinol group. Consequently, the United States Food and Drug Administration added a boxed warning to febuxostat regarding increased risk of death.

We previously reanalyzed the CARES trial to calculate the mortality rates based on the median duration of exposure to study drugs and the median follow-up duration. A sharp increase in mortality was observed after allopurinol and febuxostat were discontinued. Even in view of the Sick-Stopper Effect, for about 40-fold increase in mortality following discontinuation of allopurinol and febuxostat, it was concluded that the sharp increase in mortality may be associated with rapid changes in uric acid level (rebound hyperuricemia), risk factor for acute gout attack.

Based on this idea, we hypothesize that some of cardiovascular events may be cardiovascular gout attacks. Considering that cardiovascular disease is frequently associated with gout, and gout is a very common disease, the outcomes of this study are very important to public health.

Requested Studies:

A Multicenter, Randomized, Active-Control, Phase 3B Study to Evaluate the Cardiovascular Safety of Febuxostat and Allopurinol in Subjects With Gout and Cardiovascular Comorbidities
Sponsor: Takeda
Study ID: NCT01101035
Sponsor ID: TMX-67_301