Authors:
Sophia Dietrich, PharmD
Michael W. Nagy, PharmD, BCACP
Reviewers:
Dawn Fuke, PharmD, BCPS
Lisa Palmisano, PharmD, BCACP
Citation: Mackenzie IS, Ford I, Nuki G, et al. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. The Lancet. 2020; S0140-6736(20): 32240-0.
The Problem:
We know gout is among the many comorbidities that increase the risk of cardiovascular disease (CVD).1,2 In 2018, the cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular morbidities (CARES) trial concluded that febuxostat was non-inferior to allopurinol.3 BUT, two of the secondary endpoints of CARES were very concerning — febuxostat was inferior to allopurinol in terms of cardiovascular death and all-cause mortality. Many clinicians were left wondering whether febuxostat was cardiotoxic …. or conversely, perhaps allopurinol was cardioprotective. The 2020 American College of Rheumatology (ACR) Guidelines for the Management of Gout recommends allopurinol as first line lowering urate lowering therapy (ULT) over febuxostat.3,4 Given the difficulty of interpreting the CARES trial results, ACR recommends switching febuxostat therapy to another ULT in patients with a history of CVD or who experience a new CVD event. Unfortunately, alternatives to allopurinol are limited. Therefore, more data regarding the cardiovascular effects of xanthine oxidase inhibitors is crucial before ruling out febuxostat for a large portion of the population. Will another cardiovascular outcome trial provide greater clarity to guide clinical practice?
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The April 2nd podcast on the use of anti-gout meds in CVD overlooked some very old data in implying that this is a new concern. As far back as Feb., 1978 a key randomized, double-blind, placebo-controlled trial published in the NEJM found remarkable benefit with a uric acid lowering drug. Why do I remember that? Because of the following experience…
Remember that 1978 was before ACCP existed and before the internet was widely available. I was finishing up the “old” post-BS Pharm.D. program in San Antonio when I was invited to interview for a position at the UMKC program on Feb. 9th which was a Thursday…the same day that the NEJM is published. The morning was challenging enough rounding with 2 different medicine teams that seemed primed with questions for me. The afternoon was to be spent meeting with their Pharm.D. faculty. I presumed that would be a series of one-on-one meeting but I was wrong….very, very wrong. I was ushered into a large room and given a seat at the end of a conference table with their faculty lining both sides of the table. The session quickly moved from polite chit chat to a grill session. Joel Covinsky was the first person to my right and he caught my attention when he sat back in his chair, got a sly grin on his face and a twinkle in his eye and then asked me “So, Dr. Bussey, do you use much sulfinpyrazone in your post-MI patients down in San Antonio?”. I had to admit that I’d never seen sulfinpyrazone used post-MI and was unaware of any clinical data. But I added that I could see a rationale because of some data that hyperuricemia had been shown to increase platelet adhesion. As the session was wrapping up, Patrick (“Rusty”) Ryan thanked me for coming up and told me not to feel bad about Joel’s sulfinpyrazone queston because none of them had had the chance to read THAT MORNING’S NEJM!! So…what was in the NEJM on Feb. 9, 1978? The Anturane Reinfarction trial which demonstrated an approximate FIFTY PERCENT reduction in cardiac death and sudden death. Check it out at https://www.nejm.org/doi/10.1056/NEJM197802092980601
More than 40 years later, Joel and I still keep in touch and I remind him of that experience whenever the opportunity arises. Remember “what goes around comes around”.