Allopurinol may finally start to get the respect that many rheumatologists feel it deserves as a first-line urate-lowering treatment for gout, following results of a randomized trial showing that it was noninferior to febuxostat both in the overall trial population and in patients with stage 3 chronic kidney disease (CKD).
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In the multicenter, randomized, double-blinded comparison trial that used a treat-to-target strategy, allopurinol met the primary outcome of noninferiority to febuxostat for preventing gout flare during the observation phase of therapy, reported James O’Dell, MD, chief of the division of rheumatology and vice chair for education in the department of internal medicine at the University of Nebraska Medical Center in Omaha.
Dr. James O'Dell
“Both agents were well tolerated, with or without CKD. Most importantly, both agents were highly effective when used in a treat-to-target protocol in getting patients to target urate levels,” he said in an oral abstract presentation during the American College of Rheumatology (ACR) 2021 Annual Meeting, which was held online.
And although febuxostat contains a boxed warning about the risks of cardiovascular adverse events with its use, there were no signals for increased cardiovascular toxicity with febuxostat compared with allopurinol, the investigators found.
The trial is the first to compare allopurinol, a decades-old drug, with febuxostat, approved in 2009, in a treat-to-target approach, Dr. O’Dell said.
American College of Physicians’ guideline ‘antiquated’
The results of the study “will hopefully teach doctors how to treat gout better by encouraging them to use higher doses of gout medications safely than they’re actually using at this time,” said Donald Thomas Jr., MD, in private practice in Greenbelt, Md., and associate professor of medicine at the Uniformed Services University of the Health Sciences in Bethesda, Md.
Dr. Donald Thomas Jr.
Dr. Thomas, who moderated a media briefing where Dr. O’Dell discussed the results of the trial, said that he had recently read the 2017 gout guideline by the American College of Physicians (ACP), which he called “antiquated.”
The ACP recommends the use of corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or low-dose colchicine to treat patients with acute gout. The ACP also recommends “against initiating long-term urate-lowering therapy in most patients after a first gout attack or in patients with infrequent attacks.”
The guideline recommends that clinicians discuss potential benefits, risks, costs, and personal preferences before starting patients on urate-lowering therapy in patients with recurrent gout attacks.
The 2017 guidelines also state, however, that “[e]vidence was insufficient to conclude whether the benefits of escalating urate-lowering therapy to reach a serum urate target (‘treat to target’) outweigh the harms associated with repeated monitoring and medication escalation.”
“I’ve been a proud member of the American College of Physicians for years, I’m a master of the ACP, and they do a lot of great things, but this is one case where their insistence that they’re not going to have a guideline that isn’t completely based in evidence from studies is getting in the way of common sense,” Dr. O’Dell said.
“Their contention is that what matters to a gout patient is a gout flare, and how do we know that gout flares are less if you treat to target or not – and that’s a fair question,” he continued, “except for the fact that in uric acid metabolism we know physiologically that there’s a magic number and that’s 6.8 mg/dL, and anything above that, every day uric acid is above 6.8, you are literally putting crystal out into all places in your body.”
In contrast, the ACR’s 2020 guideline for the management of gout strongly recommends starting urate-lowering therapy for all patients with tophaceous gout, radiographic damage because of gout, or frequent gout flares. It also advises using allopurinol as the preferred first-line urate-lowering therapy, including for those with stage 3 or greater CKD, and using a low starting dose of allopurinol of 100 mg/day or less (lower in CKD) or febuxostat at 40 mg/day or less. It endorses a treat-to-target management strategy that aims for serum urate < 6 mg/dL with dose titration of urate-lowering agents guided by serial serum urate measurements.
Dr. Thomas and Dr. O’Dell expressed hope that the results of this clinical trial will put the issue to rest, and that the ACP will update its guideline accordingly.