I started reading of the red flags over the cardiovascular safety of febuxostat while preparing for a talk to be given during UP Medicine’s Grand Scientific Symposium (2014?). I included data from the meta of Tayar JH (2012) to spark interest in monitoring developments. I belatedly came across the article of WB White in the American Heart Journal (2012) describing the study design for CARES. It’s quite fortunate that 4 years later I’m finally reading of the results. Interestingly, a trial using a PROBE design (allegedly it approximates real world experience better than RCTs) in determining CV safety of febuxostat (vs. allopurinol) had been described in BMJ Open (2014) by MacDonald TM, et al. – The Febuxostat versus Allopurinol Streamlined Trial (FAST).
Let me differentiate the application of CARES study in different patient scenarios.
In patients with known CV disease (prior MI, stroke/ TIA, peripheral vascular disease, unstable angina and diabetes with vascular complications), I’d choose allopurinol as my primary urate lowering drug. Since pegloticase is not available in the Philippines, I’d offer febuxostat as an alternative when the patient develops severe AEs or cannot tolerate allopurinol. And it’s use should be with full disclosure of the increased risks for CV deaths. As of now, it is not yet known whether aggressive risk modification (ASA, NSAID avoidance, statins, etc) would off-set the increase in sudden cardiac deaths. Right now, I’m already thinking of reviewing my febuxostat treated patients and will probably shift to allopurinol if without contraindications.
In patients without CV disease, the use of febuxostat in treating hyperuricemia may remain unchanged. There are still no studies to suggest a change in practice. But a little caution should be exercised probably in handling patients with higher CV risk (and yes, we’d probably need to start using CV risk calculators in the clinic for this). I wouldn’t hesitate using febuxostat in gout patients with low CV risks (some NSAID trials define this as an estimated 10 year risks of CV mortality <10%). However, for those with high CV risk (estimated 10 year risk of CV mortality >10%), I’d probably be more careful in using febuxostat but the drug still remains an option. Of course, it follows that aggressive risk modification should be implemented. I’d still use febuxostat unless the FDA issues a black box warning for the drug.
Some of you may be wondering why I still prefer placing patients on febuxostat rather than completely shifting all my patients to allopurinol. One word. COMPLIANCE. Regardless of dose, Febuxostat is given as a once a day pill. And if you have a patient being treated for multiple conditions (think HPN, HF, dyslipidemia), then having a once-a-day pill can mean a big difference in compliance.
Notice that I didn’t mention efficacy. If you back read my posts, it was only the febuxostat 80mg which was better than allopurinol 300mg in bringing down urate levels to target. In fact, as a personal rule of thumb, allopurinol 300mg may be as effective as febuxostat 40mg in bringing down SUA <6mg/dl. (Therefore, allopurinol 600 mg/d may be as effective as febuxostat 80mg/d). Maximizing allopurinol use (yes, it can be used to 800mg/d!) can bring about similar outcomes in reducing urate levels. Likewise, combining allopurinol with other drugs with uricosuric properties (losartan, fenofibrate) may help achieve those targets. If you bothered to check the secondary endpoint of the CARES study, the proportion of patients who experienced a treatment needing flare and those who achieved SUA <6mg/dl were almost comparable between groups. Allopurinol remains an effective urate lowering drug, we just have to learn to maximize it. And, please, no more Hande protocol!
The CARES study just complicated an already challenging disease to treat. It’s challenging because gout is a very treatable disease and successful management of hyperuricemia can avert complications and repeated attacks. Now aside from NSAIDs, we’d have to be wary of the impact our ULT has on heart health. Hopefully, we are clarified of this issue once the results of FAST come out (and hopefully, a meta-analysis can come out).