Are allopurinol and febuxostat equally beneficial in terms of protection against fatal cardiovascular events? Gout and cardiovascular disease is a dangerous combination. It’s well known that if you have a patient with heart disease who develops gout they’re more likely to drop dead of a heart attack than if they don’t have gout. And it […]
Are allopurinol and febuxostat equally beneficial in terms of protection against fatal cardiovascular events?
Gout and cardiovascular disease is a dangerous combination.
It’s well known that if you have a patient with heart disease who develops gout they’re more likely to drop dead of a heart attack than if they don’t have gout.
And it is commonly believed, largely from observational evaluations, that treating the gout with either allopurinol or febuxostat in these patients with pre-existing cardiovascular disease will reduce this risk.
But the question has been: are allopurinol and febuxostat equally beneficial in terms of protection against fatal cardiovascular events in this high-risk population?
Well, according to the findings from a large, multi-centre, double blind, noninferiority trial recently published in the New England Journal of Medicine – no.
The US study of 6190 patients with both gout and a history of major cardiovascular disease, found that while the overall rate of major cardiovascular events including nonfatal myocardial infarction and unstable angina was similar among those treated with febuxostat compared with the group treated with allopurinol, cardiovascular death and deaths from any cause were more frequent in the febuxostat group.
The CARES (Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities) trial d a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end-point and this primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke or unstable angina requiring urgent revascularisation.
Over the course of the study (median duration of follow-up being 32 months), a primary end-point event occurred in 335 patients (10.8%) in the febuxostat group and 321 patients (10.4%) in the allopurinol group.
So, the US researchers concluded that febuxostat was noninferior to allopurinol.
However, on further analysis the researchers found, the risk of death from any cause and the risk of cardiovascular death was higher among those patients treated with febuxostat (hazard ratio 1.22 and 1.34 respectively) compared with the allopurinol group.
The study authors were unable to explain this difference. “The mechanism underlying this risk of death is unclear,” they said.
“Preclinical cardiovascular studies of febuxostat have shown no toxic effects related to cardiac rhythm, function, or metabolism. In addition, the rates of adjudicated nonfatal events … were similar in the febuxostat group and the allopurinol group.”
There was an association between cardiovascular mortality and NSAID use and the absence of use of low-dose aspirin, but this was the same in both groups. Similarly, urate levels, gout flares and other factors such as serum electrolytes, blood pressure and cardiovascular medications were similar across both groups and could not explain the difference.
The study authors did point to an important limitation of the trial, namely the large number of participants who discontinued the trial or who did not complete follow-up.
“Discontinuation of treatment would be expected to bias the analysis toward the null hypothesis,” the authors suggested. However, the effect of those lost to follow-up was less easy to predict as it might not have been due to chance.
Nonetheless, given that the distribution of those lost to follow-up was approximately equal across the two groups, it was unlikely this had a significant effect on the findings.
In conclusion, all the authors could say that even though allopurinol and febuxostat were similar in terms of adverse cardiovascular events, the risk of dying from one of these events appeared to be higher on febuxostat.
Ref: NEJM 2018; 378:1200-1210
DOI: 10.1056/NEJMoa1710895
