For the first time, a study shows a reduction in kidney failure and cardiovascular events in the elderly alongside a decrease in uric acid in the blood (uricaemia). But only if the therapeutic objectives defined by the recommendations are achieved.
Hyperuricemia, an abnormally high level of uric acid in the blood, can cause gout, but it is also associated with an increased risk of coronary heart disease, high blood pressure, stroke, kidney failure chronic and death. On the other hand, the causal link between hyperuricaemia and these events has never been formally established because it had not been shown that the reduction in hyperuricaemia reduced the cardiovascular risk.
The study FREED2 shows a beneficial effect of lowering uric acid in the blood on cardiovascular risk: it reduces the risk of cerebral, cardiovascular and renal events by 25% in the elderly with hyperuricemia. Due to the limited size of the study, the difference is especially significant for renal failure. In addition, it does not seem to work if you just lower uricemia without reaching the recommended goals.
A controlled study versus usual treatment
The study included 1,070 people aged 65 years and over, with hyperuricemia (uric acid in the blood between 70 and 90 mg per liter) and at risk for brain, cardiovascular or renal events. This risk was defined by the association of hypertension, type 2 diabetes, kidney problems or a history of cerebral or cardiovascular disease.
These people were drawn at random to receive for 36 months, either febuxostat, at a dose of 10 to 40 mg per day, in order to fall below the therapeutic objectives defined in the consensuses, or another hypouricemic agent, allopurinol , but in low doses and only at the free choice of the doctor, as is currently practiced in the city. A healthy diet has been advised for all patients, as well as smoking cessation and the development of physical exercise.
25% reduction in vascular risk
After 36 months of the study, 537 people received febuxostat with an average dose of 29 mg and of the 533 people in the non-febuxostat group, 27% received allopurinol at a dose of 100 mg. With these 2 different treatment strategies, the average blood uric acid levels fell to 44 mg per liter in the febuxostat group (below the targets) and 67 mg per liter in the low or no dose allopurinol group. treatment (above targets).
The primary endpoint of the study includes cerebral, cardiovascular and renal events and deaths from all causes. One of these events occurred in 125 (23%) patients in the febuxostat group and in 153 (29%) patients in the non-febuxostat group. This means that, by reducing the level of uric acid in the blood below the therapeutic objectives defined by the consensus (60 mg per liter in the absence of tophus), the hypouricemic treatment reduces by 25% the risk of cardiovascular events or death (RR = 0.75; 95% confidence interval: 0.59-0.95, p = 0.017).
Pay attention to the details of the study
When we look at each cardiovascular event individually, we see that the most frequent event is renal failure and that its significant reduction greatly influences the results of the overall criterion, while the effect is much less important on death or cardiovascular disease. This may be related to the small size of the study population and the relatively short duration of the study. In addition, when the results are analyzed as a function of the uric acid levels obtained, it is not certain that it is advantageous to lower this level below 50 mg per liter.
This study is supposed to respond to a previous study (CARES) which had objectified an unexpected excess mortality with febuxostat and it is therefore reassuring. Adverse events were observed in 132 (24.6%) people in the febuxostat group and 135 (25.3%) in the non-febuxostat group, with no significant difference between the two groups (p = 0.83). Two people from the febuxostat group died.
Validation of uric acid levels
This study therefore validates above all the interest of a treatment strategy: while the hypouricemic treatment is frequently prescribed in town, the doses which are used only rarely make it possible to achieve the therapeutic objectives. Febuxostat is a more potent hypouricemic agent, with a particular profile of undesirable effects, and a possible deleterious effect if the uricemia drops too low, which is possibly the explanation of the excess mortality observed with febuxostat in a previous study (CARES) .
But, it is also possible to use allopurinol, depending on the contraindications and side effects, to achieve a reduction in uricemia. However, it is essential to use doses of allopurinol higher than those usually chosen in town, or even doses greater than the marketing authorization (in accordance with the contraindications), as is proposed. in the recommendations of international learned societies.
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