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.
Statistical Analysis Plan
Cox proportional-hazards models will be used to analyze the time to first occurrence of cardiovascular event and death for all patients and subgroups who did not discontinue medication due to deterioration of other diseases. Our plan is to evaluate the incidence of cardiovascular events or death based on the initiation or discontinuation of Febuxostat and Allopurinol. We will compare the incidence of cardiovascular event and death at both before and after Allopurinol and Febuxostat initiation stages. We will also investigate uric acid changes and how this correlates with cardiovascular events and deaths in all patients.
• Methods to control for bias: The risk of cardiovascular disease will be analyzed using Cox proportional-hazards models, and covariate adjustments will be made during this process.
• Model fit tests, sensitivity or heterogeneity analyses: Using Chi-Squared Test or I squared statistic
• Analysis of subgroups: allopurinol vs febuxostat.
• Different types of intervention: especially in febuxostat group (40mg vs 80mg).
• Handling of missing data: Make the most of the data other than missing data.
A Multicenter, Randomized, Active-Control, Phase 3B Study to Evaluate the Cardiovascular Safety of Febuxostat and Allopurinol in Subjects With Gout and Cardiovascular Comorbidities
Study ID: NCT01101035
Sponsor ID: TMX-67_301
Ghang B, Lee JS, Kim J, Yoo B. Increased risk of cardiovascular events and death in the initial phase after discontinuation of febuxostat or allopurinol: Another story of the CARES trial. J Rheum Dis 2021; 28(1):219.