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 American Congress of Cardiology. A surprising finding in an illness where uric acid is supposed to be bad for the heart.
The results of a safety trial on the cardiovascular safety of febuxostat, an anti-gout drug that was introduced a few years ago, were presented at the American College of Cardiology conference.
And they go against a trend in recent years that raising uric acid in the body was not only bad for the joints, raising inflammation, hyperuricemia was also bad for the heart.
The CARES study was conducted at the request of the US health agency, the FDA, to assess the importance of the cardiovascular over-risk that had been observed in the development program of febuxostat, a new anti-gouty very powerful put on the market a few years ago.
Conducted in more than 6,000 patients suffering from gout, the randomized study compared febuxostat and allopurinol and shows cardiac over-mortality in the febuxostat group. The results were published in the New England Journal of Medicine.
Increased cardiovascular mortality
The primary endpoint was composite, which included several criteria: cardiovascular death, nonfatal infarction, nonfatal stroke, and unstable angina with urgent revascularization.
The CARES trial was discontinued prematurely because preliminary results show that, on the whole, febuxostat does not increase the risk of these events compared with allopurinol but, when the results are evaluated separately, febuxostat shows a increased risk of all-cause death and cardiovascular death.
Febuxostat is currently mainly prescribed in France in patients with renal insufficiency who can not take allopurinol because it is contraindicated in this case.
No obvious explanation
Rates for the composite primary endpoint were 10.8% febuxostat and 10.4% allopurinol (p = 0.002 non-inferiority) in intent to treat. However, febuxostat increases the risk of all-cause mortality by 22%, due to a 34% increase in cardiovascular deaths and sudden death (2.7% vs 1.8%).
Consistent results, intention to treat and per-treatment, and blind data analysis make the risk of excess mortality "robust" according to CCA.
At this stage, there is no explanation for this excess risk of death with febuxostat (no change in QT or thrombotic factors), apart from the fact that patients in the CARES study had a higher cardiovascular risk. than those of the studies of the development program, which could better reveal this over-risk.
A security study
The febuxostat development program in more than 5,000 patients had shown a higher rate of cardiovascular events in febuxostat compared to allopurinol, but without over-mortality. This prompted the FDA to market the product subject to completion of a cardiovascular safety study.
The FDA has published a safety alert on the risk of cardiovascular death under febuxostat on its website, based on CARES preliminary analysis. The agency said at that time that it would conduct a comprehensive review of the data and post an update after full data availability.
Allopurinol is also free from risk
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 anti-gout drug, from a retrospective analysis in a population sample from the Medicare database.
This analysis, which is less robust than a randomized study, reveals that allopurinol is also free from cardiovascular complications since there is an overall risk of cardiovascular events of 20% lower with probenecid and a risk of all-cause mortality. 13% lower causes together with probenecid.
The complete analysis of the file by the health agencies is under way.