Febuxostat, a recent anti-gout drug, increases the risk of cardiovascular and overall mortality compared to conventional treatment, according to a study presented at the US Congress of Cardiology. A surprising finding in a disease where uric acid is believed to be bad for the heart.
The results of a safety trial on the cardiovascular tolerance of febuxostat, an anti-gout drug marketed a few years ago were presented to the congress of the American College of Cardiology.
And they are going against a trend of recent years that the elevation of uric acid in the body was not only bad for the joints, by elevating the inflammation, the hyperuricemia was also bad for the heart.
The CARES study was carried out at the request of the American health agency, the FDA, to assess the importance of the cardiovascular excess risk that had been observed in the program for the development of febuxostat, a new anti-gout drug. very powerful put on the market a few years ago.
Carried out in more than 6,000 patients suffering from gout, the randomized study compared febuxostat and allopurinol and demonstrated excess cardiac mortality in the febuxostat group. The results were published in the New England Journal of Medicine.
Increased cardiovascular mortality
The primary endpoint was composite, that is, it grouped together several criteria: cardiovascular death, non-fatal infarction, non-fatal stroke and unstable angina with urgent revascularization.
The CARES trial was terminated prematurely because preliminary results show that, overall, febuxostat does not increase the risk of these events compared to allopurinol but, when the results are evaluated separately, febuxostat shows a increased risk of death from all causes and cardiovascular death.
Febuxostat is currently mainly prescribed in France in patients with renal failure who cannot take allopurinol because it is contraindicated in this case.
Patients with gout and CVD randomized to either febuxostat or allopurinol. At 32 months, there was no difference between groups in a composite CV end point, but all-cause and CV mortality were significantly higher with febuxostat. https://t.co/eP4ASWHrkV # ACC18 pic.twitter.com/cWsRiv1mWD
– NEJM (@NEJM) March 12, 2018
No obvious explanation
The rates for the composite primary endpoint are 10.8% with febuxostat and 10.4% with allopurinol (p = 0.002 for non-inferiority) by intention to treat. However, febuxostat increases the risk of all-cause mortality by 22%, due to a 34% increase in cardiovascular deaths as well as sudden deaths (2.7% vs. 1.8%).
The consistency of the results, in intention-to-treat and in per-treatment, and the analysis of the blinded data make the risk of excess mortality “robust” according to the ACC.
At this stage, there is no explanation for this excess risk of mortality with febuxostat (no change in QT or thrombotic factors), apart from the fact that the patients in the CARES study had a higher cardiovascular risk. than those of the studies of the development program, which could better reveal this excess risk.
A safety study
The febuxostat development program in more than 5,000 patients showed a higher rate of cardiovascular events with febuxostat compared to allopurinol, but without excess mortality. This is what prompted the FDA to grant a marketing authorization subject to the completion of a cardiovascular safety study.
The FDA has therefore published on its website a security alert on the risk of cardiovascular death with febuxostat, based on the preliminary analysis by CARES. The agency said at that time that it would conduct a full review of the data and issue an update after full data became available.
Allopurinol is also not risk free
These results of the CARES study with febuxostat are all the more worrying as they are obtained by comparison with allopurinol. However, another recent cardiovascular safety study compared allopurinol with probenecid, an old gout medication, from a retrospective analysis in a sample of the population drawn from the Medicare database.
This analysis, less robust than a randomized study, reveals that allopurinol would not be free from cardiovascular complications either, since there is an overall risk of cardiovascular events that is 20% lower with probenecid and a risk of all mortality. 13% lower confused causes with probenecid.
The complete analysis of the file by the health agencies is in progress.
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