Febuxostat was approved by the FDA in 2009 as a urate-lowering therapy for the treatment of gout. Over its 10 years of utilization, febuxostat has garnered slightly less than 10% of the urate-lowering medication market. Most patients receiving febuxostat have previously taken allopurinol, but for a number of reasons were switched febuxostat. During the phase 3 clinical trials, there was a signal for cardiovascular events for febuxostat that was not statistically significant.
However, the FDA required a warning in the prescribing information that said, “A higher rate of cardiovascular thromboembolic events was observed in patients treated with Uloric than allopurinol in clinical trials. Monitor for signs and symptoms of MI and stroke.” The FDA also required a post-marketing cardiovascular safety trial that compared febuxostat to allopurinol.
The Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) trial enrolled nearly 6,200 patients with gout who were at high risk for cardiovascular disease into a long-term, randomized, double-blind study with a 1:1 randomization to either febuxostat (40-80 mg daily) or allopurinol (200-600 mg daily).
Both groups had an initial 3-month period when therapy was up-titrated to achieve a target serum uric acid of < 6.0 mg/dL. Patients were followed for up to 85 months with a median follow-up of 32 months. The primary end-point of the trial was the occurrence of a major adverse cardiovascular event (MACE) in either treatment group.
The secondary end-points were the individual MACE components, including CV death, nonfatal MI, nonfatal stroke and unstable angina requiring urgent revascularization. All-cause mortality was also analyzed.
The primary end-point of the trial was not significantly different between febuxostat (10.8%) and allopurinol (10.4%). However, within the secondary end-points, CV death did show a significant difference between febuxostat (4.3%) and allopurinol (3.2%). This, in turn, resulted in a higher all-cause mortality for the febuxostat group.
These results were published in the New England Journal of Medicine in March 2018 and presented to the FDA Arthritis Advisory Committee in January 2019. The result of that hearing was a new FDA-approved black box warning in the Febuxostat package insert. That warning states: “Gout patients with established cardiovascular (CV) disease treated with Uloric had a higher rate of CV death compared to those treated with allopurinol in a CV outcome study.”
The warning went on to recommend: (1) to consider the risk/benefit of Uloric when prescribing or continuing patients on Uloric, (2) to only use Uloric in patients with an inadequate response or intolerance to allopurinol, or (3) to use in patients for whom allopurinol is not advisable.
Many questions remain about the meaning of the CARES study. This is the first cardiovascular safety trial for any type of medication where an increase in CV death was not paralleled by an uptick in one or more of the other MACE components. Mechanisms for the observed increased death rate were extensively investigated by the sponsoring company and the cardiologist who adjudicated this trial. To date, no physiologic mechanism has been detected.
Similarly, there was no subset within the treatment cohort of gout patients with existing CV disease that seem to be a particular risk for this outcome. The other unusual aspect of this trial is that most subjects who experienced CV death were not on medication (either febuxostat or allopurinol) when death occurred.
The CARES trial had flaws in both its design and execution. The lack of a placebo-controlled arm in this study, while probably being the correct ethical approach, leaves us wondering if CARES demonstrated true cardiotoxicity for febuxostat or whether febuxostat is simply not as cardioprotective as allopurinol. The study was also flawed in its execution by the very high rate of premature treatment discontinuation and discontinued follow-up for both arms of the trial.
The new FDA-approved warning for febuxostat is a prudent reflection of our current knowledge about CV risk when using this drug. The recommendation for the use of febuxostat only after an earnest trial of allopurinol is in keeping with how febuxostat is already being used in this country. Perhaps the results of another large, on-going, perspective trial comparing allopurinol and febuxostat will help clarify the real meaning of the CARES study findings.
N. Lawrence Edwards, MD, MACP, MACR
Vice Chairman, Department of Medicine
Program director, Medicine Residency Training Program
University of Florida
Member, Medical Policy Committee
Disclosures: Edwards reports a consultant/advisory role with Ardea Biosciences, Inc, Novartis Pharmaceuticals Corporation, Savient Pharmaceuticals, Inc and Takeda Pharmaceuticals North America, Inc.