Gout drug feboxustat gets FDA boxed warning

The FDA issued a boxed warning for febuxostat for increased risk of cardiovascular death as well as death from all causes, as compared to allopurinol (see https://www.fda.gov/Drugs/DrugSafety/ucm631182.htm )

Details:
-- the FDA recommends that febuxostat only be used in patients who have failed or do not tolerate allopurinol
-- there was an initial warning in 2009 when febuxostat was introduced, requiring the drugmaker to conduct a postmarketing clinical trial, specifically about possible cardiovascular events
-- The CARES trial (Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities) was a randomized double-blind cardiovascular outcomes trial conducted in 6190 patients with gout treated with either of these medications, in the US/Canada/Mexico, from 2010 to 2017. (see gout CARES febox inc CVD mortality NEJM2018 in dropbox, or https://www.nejm.org/doi/pdf/10.1056/NEJMoa1710895 
    -- in brief, RCT with: 
        -- febuxotat 40-80 mg compared to allopurinal 200-600 mg, for median of 32 months
        -- urate-lowering was greater with febuxotat 
        -- similar number of gout flares with each med
        -- primary endpoint (the combo of cardiovascular death, nonfatal heart attack, non-fatal stroke, or unstable angina) found no significant difference betwen the meds
        -- seconday endpoints (individual components):
            -- 15 deaths from cardiovascular causes per 1000 patients treated with febuxotatfor a year, vs 11 deaths with allopurinol: total of 134 vs 100 deaths, 34% increase, HR 1.34 (1.03- 1.73). the curves separated after about 4 years.
                --sudden cardiac death: 83 vs 56, 2.7% vs 1.8%
            -- 26 deaths from any cause per 1000 patients treated with febuxotat for a year vs 22 with allopurinol: total of 243 vs 199 deaths, 22% increase, HR 1.22 (1.01- 1.47). the curves also separated after about 4 years.
            -- no differences in any major nonfatal cardiovascular events, hospitalizations for heart failure or arrhythmias not associated with ischemia, venous thromboembolism or TIAs
        -- no difference in serum potassium, lipids, glucose, creatinine, or blood pressure
        -- no preclinical signals for cardiac toxicity with febuxotat 
        -- but high rate of study discontinuation (57% discontinued the trial regimen and 45% discontinued follow-up), with similar numbers for each med, both had about 720 days of exposure. and the majority of deaths occurred off drug, though there was a 49% increase in cardiovascular deaths, with p=0.047, that occurred during treatment or within 30 days of discontinuation of treatment
        -- and, further safety analyses are ongoing 
  
Commentary:
-- the mechanism explaining the difference in cardiovascular mortality (which was the driver for all-cause mortality) for these 2 meds is not clear, and no real proposed mechanism was advanced
--there are lots of prior blogs on gout/hyperuricemia, several finding that either allopurinol or colchicine might lower cardiovascular risk:
    -- http://gmodestmedblogs.blogspot.com/2017/07/hyperuricemia-and-cardiometabolic.html : a Japanese study suggesting that hyperuricemia predated the development of hypertension, hyperlipidemia, chronic kidney disease, overweight/obesity, diabetes (ie, that hyperuricemia was not just the result of these conditions)
    -- http://gmodestmedblogs.blogspot.com/2016/03/hyperuricemia-allopurinol-decreases.html  : a Danish study suggesting that treating hyperuricemia with allopurinol led to fewer cardiovascular events
    -- http://gmodestmedblogs.blogspot.com/search/label/gout%2Fhyperuricemia  which includes a blog on an interesting evolutionary perspective on hyperuricemia (see  http://gmodestmedblogs.blogspot.com/2019/04/uric-acid-lowering-cardiovasc-benefit.html), as well as several others on gout (eg, gout guidelines, and the study suggesting that colchicine also lowers cardiovascular risk)
--and, a pretty recent Mendelian randomization trial did suggest that serum urate levels were likely causally associated with cardiovascular disease (see uric acid cad mendelrandom lancetdiabendo2016 in dropbox, or White J. Lancet Diabetes Endocrinol 2016; 327-336, or  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4805857/ ). This analysis of 17 prospective studies with 166,486 people found that traditional Mendelian randomization studies did find a small effect, implicating “a causal role for urate in the development of coronary heart disease”, though a more specific analysis which accounts for other risk factors playing a role (but has less statistical power), only  found a trend to statistical significance.

-- the specifics of the boxed warning (see https://general.takedapharm.com/ULORIC ): 
WARNING: CARDIOVASCULAR DEATH See full prescribing information for complete boxed warning.
• Gout patients with established cardiovascular (CV) disease treated with ULORIC had a higher rate of CV death compared to those treated with allopurinol in a CV outcomes study. 
• Consider the risks and benefits of ULORIC when deciding to prescribe or continue patients on ULORIC. ULORIC should only be used in patients who have an inadequate response to a maximally titrated dose of allopurinol, who are intolerant to allopurinol, or for whom treatment with allopurinol is not advisable. 

So, It seems pretty likely that hyperuricemia itself is related to heart disease, that allopurinol seems to help, and that it would make sense that febuxostat would follow in allopurinol’s footsteps since it is a selective inhibitor of xanthine oxidase.  Most of us, I assume, were only using febuxostat in patients who did not tolerate allopurinol (I have used it only once), and it still is likely appropriate for many of these people with clinically important gout attacks. But this CARES trial and the subsequent boxed warning should encourage us to push allopurinol even more, unless there is one of the really bad allopurinol reactions (eg, potential drug hypersensitivity reactions), though about 90% of reported reactions are not severe (and some may be from concomitant NSAIDs, for example).

Though the FDA came out with a pretty strong warning about febuxotat, some prior blogs illuminate a more generic concern with the FDA: its frequent lack of strict enforcement and overall its being quite deferential to drug companies overall.
-- http://gmodestmedblogs.blogspot.com/2013/11/more-drug-company-shenanigans.html highlights a BMJ article finding that of 585 registered clinical trials, 29% were unpublished, and the vast majority of these did not have results included on the FDA's mandated website clinicaltrials.gov. The concern is that the drug companies are not recording or publishing negative studies, and that there will then be a strong publication bias for studies with positive results (clearly in the drug company interests). and, this is the issue that led to the 2007 USA FDA Amendments Act and the Registry of Clinical Trials in the first place
-- http://gmodestmedblogs.blogspot.com/2015/08/regulation-of-medical-devices.html  , another blog which shows that FDA regulation for medical devices is much much worse than for drugs...

and, we really do need tight regulation of new drugs, expecially if they are not drugs which fundamentally change clinical care (eg, the initial direct-acting antiviral hepatitis C meds).  the CARES trial did show a signficant increase in cardiovascular disease with febuxotat, but it took 4 years to show the increased risk. so, short-term trials would have missed this pretty bad adverse outcome. And, when a drug seems to work well short-term, it is common that the study is terminated early, allowing for even less time to reveal adverse events (ie, a strong bias to benefit over risk)...

geoff

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