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Medicine Matters rheumatology

The original of the FAST trial, as you may well know, is that it was a commitment by the EMA-- the European Medicine Agency-- after the pivotal trials for febuxostat compared with allopurinol. As there was some disbalance in the number of events-- cardiovascular events specifically-- and deaths. So this trial was designed to ascertain whether there was a safety signal during the treatment with febuxostat compared to allopurinol.

The first trial is somehow different from the CARES trial that took place in the US, and was published three years ago in the New England Journal of Medicine. Specifically, the FAST trial not only included cardiovascular events, but tried to answer what happened with patients at high risk of suffering cardiovascular events. And in addition, the randomization was not based on renal function, but on cardiovascular risk. So there are some differences.

Close to over 6000 patients were included. So therefore, they were randomized to over 3000 patients in each arm, and importantly-- and in contrast with the CARES trial results-- with a large number of "lost for follow up", and a large number of withdrawals. The FAST trials showed an impressive high rate of follow up. So over 90% of the patients in each arm were followed up until completion of the trial. And the number of patients that withdraw treatment were really small.

The results are that febuxostat is numerically superior to allopurinol, and statistically noninferior to allopurinol. So there is no cardiovascular safety signal in patients at high risk, in patients with previous cardiovascular events, or overall. And that's important, because it answers several questions that were not answered by the CARES trial. So to this point, febuxostat is noninferior to allopurinol. And you must consider that in the CARES trial, the highest doses of allopurinol and febuxostat were reduced compared to the CARES trial, where low doses-- for a European like me-- of febuxostat were used.

The EMA and the FDA, after the CARES trial results were released, made a black warning for febuxostat use in patients with previous cardiovascular event, or even patients at high risk of suffering a cardiovascular event. Therefore, we had our therapeutic weapons blunted. So we could not use febuxostat in a number of patients with cardiovascular risk, or cardiovascular event. To my knowledge, in the CARES trial is the only one to show a difference.

So now the FAST trial has shown that it is not real difference in treating patients either with cardiovascular event or cardiovascular risk, regarding mortality or cardiovascular events. There are some unanswered questions in the FAST trial. As the FAST trial did not include patients with severe heart failure, we have no sample for these kind of patients. The protocol was published some years ago, and you may find that these kind of patients were not included. So we have no answer to what's the risk in patients with moderate to severe chronic heart failure, for example.