Feboxustat: not so bad for the heart

 The gout medication febuxostat has had a black box warning from the FDA since 2019 because of an increased risk of cardiovascular and all-cause death based on the CARES study, a post marketing randomized trial comparing febuxostat with allopurinol (see https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-increased-risk-death-gout-medicine-uloric-febuxostat ). A new study was recommended by the European Medicines Agency (the European version of the FDA) specifically to assess the long-term cardiovascular safety of febuxostat vs allopurinol in patients with gout, a multicenter prospective randomized open label noninferiority trial (see uric acid feboxustat not bad for heart lancet2020 in dropbox, or doi.org/10.1016/ S0140-6736(20)32234-0).

Details: 

-- 6128 patients with gout from the UK, Denmark, and Sweden were randomly allocated to receive allopurinol or febuxostat, from 2012-2018: the FAST trial (Febuxostat vs Allopurinol Streamlined Trial). All patients were at least 60 years old and had clinical gout, had at least one additional cardiovascular risk factor, and were already receiving allopurinol therapy

-- mean age 71, 85% men, 99% white, current smoker 8%/former smoker 57%/never smoker 35%, blood pressure 138/76, BMI 31, LDL cholesterol 112 mg/dL, baseline urate 0.297 mmol (5 mg/dL)

-- cardiovascular history: prior MI 11%, acute coronary syndrome 10%, coronary revascularization 12%, angina 12%, prior stroke 5%, established PVD 5%, hypertension 78%, heart failure 5%, overall evidence of cardiovascular disease 33%, renal disease 16%, diabetes 23%

-- mean gout symptom onset age 56, tophi 10%, episode of acute gout in past 12 months 26%, median duration of allopurinol treatment at study initiation 6 years

-- concomitant medications: statins 60%, ACE-I 40%, antiplatelet 35% (aspirin 30%), NSAIDs 28%, colchicine 3%

-- dose of allopurinol at the time of screening: 100-300mg (32% on 100 mg, 17% on 200mg, and 45% on 300 mg)

-- exclusions: those who had a myocardial infarction or stroke in the previous 6 months or had severe CHF (NYHA class III or IV) or renal impairment

-- all patients were dosed with allopurinol to achieve a serum urate concentration <6 mg/dL (up to a maximal allopurinol dose of 900 mg per day), then randomized to continue the allopurinol at the optimize dosed or switch to febuxostat 80-120 mg/day as needed to achieve the target serum urate levels. All patients were offered 6 months of prophylaxis against gout flares (first line being colchicine 0.5 mg one or 2 times a day, second line was NSAIDs with gastric protection)

-- of note, this was not a randomized controlled trial. Although patients were randomized to one of the 2 treatment wings, the participants, site staff, and treating physicians were not masked to therapy allocation, although the endpoint adjudication committee was masked. Those randomized to allopurinol just continued the med, though 36% required an increase in allopurinol dose to reach the target serum urate concentration. 

    -- At the end of this lead-in phase, the mean dose of allopurinol was 278 mg

-- after randomization 98% of those on febuxostat were on 80 mg, 2.5% on 120 mg

-- primary outcome: composite of hospitalization for nonfatal MI or biomarker-positive acute coronary syndrome, nonfatal stroke, or cardiovascular death

-- secondary outcomes: hospitalizations for nonfatal MI or biomarker positive acute coronary syndrome; nonfatal stroke; death from a cardiovascular event; all-cause death; hospitalization for heart failure; hospitalization for unstable, new or worsening angina; hospitalization for coronary revascularization; hospitalization for cerebral revascularization; nonfatal cardiac arrest; venous and peripheral arterial vascular thrombotic event; and hospitalization for arrhythmia with no evidence of ischemia

-- median follow-up time 1467 days, median on-treatment follow-up was 1324 days

 

Results: 

-- primary endpoint on-treatment:

    -- febuxostat: 172 patients, event rate 1.72 events per 100 patient-years

    -- allopurinol: 241 patients, event rate 2.05 events per 100 patient years

    -- adjusted HR 0.85 (0.70-1.03), p<0.0001 for noninferiority of febuxostat

--primary endpoint by intention-to-treat:

    -- febuxostat: 256 patients, event rate 2.05 events per 100 patient-years

    -- allopurinol: 285 patients, event rate 2.30 events per 100 patient years

    -- adjusted HR 0.89 (0.75-1.06), p<0.0001 for noninferiority of febuxostat

    -- differences between the 2 treatments became evident after about 3 years of therapy, with allopurinol exceeding febuxostat in all-cause deaths both in on-treatment and intention-to-treat analyses. The graphs of the drugs were similar for cardiovascular deaths

-- death rates (intention-to-treat, the numbers were lower but still significant for on-treatment analysis):

    -- febuxostat: 222 (7.2%) of 3063 patients died and 1720 (57%) in the safety analysis had at least one serious adverse event (23 events and 17 patients were felt to be related to treatment)

    -- allopurinol: 263 (8.6%) of 3065 patients died and 1812 (59%) of the 3050 had one or more serious adverse events (5 events in 5 patients felt related to treatment)

-- randomized treatment was discontinued in 973 (32%) of patients on febuxostat and 503 (17%) on allopurinol

-- a review of all of the secondary outcomes in the intention-to-treat analysis found noninferiority (with statistically significant p values) for:

    -- cardiovascular deaths; hospitalization for nonfatal MI or biomarker-positive ACS; nonfatal stroke; all-cause death; hospitalization for heart failure; hospitalization for unstable, new, or worsening angina; hospitalization for cerebrovascular revascularization; and hospitalization for TIA.

    -- The only item where febuxostat did worse was for hospitalization for arrhythmia with no evidence of ischemia (0.385 events/100 patient-yrs with allopurinol and 0.583 events/100 patient-yrs with febuxostat), in the intention-to-treat analysis; though there was a strong trend also in the on-treatment group

-- reduction of urate concentration was greater in the febuxostat group, with mean difference of .08 mmol/L (1.4 mg/dL), and the number of gout flares was 18/100 patient-yrs on febuxostat vs 20/100 patient-yrs on allopurinol

-- of note, 973 (32%) of those in the febuxostat group and 503 (17%) in the allopurinol group discontinued randomized therapy, mostly in the 1^st 6 months of therapy

-- 222 (7%) of patients died and 1720 (57%) had at least one serious adverse event in the febuxostat group and 263 (9%) died and 1812 (59%) had at least one serious adverse event in the allopurinol group

     --for treatment-related serious adverse event:

        -- allopurinol: 2 patients had angina, 1 thrombocytopenia, 1 dyspepsia, and 1 arthralgia  (all patients recovered)

        -- febuxostat: 4 had pancreatitis (1 patient recovered, 2 recovery was sequelae, and 1 recovered but had further pancreatitis), 1 had circulatory collapse, and 1 death

 

Commentary: 

-- this study found that febuxostat was noninferior to allopurinol with respect to the primary cardiovascular endpoint, and its long-term use was not associated with increased risk of death or serious adverse events compared with allopurinol

-- allopurinol and febuxostat are xanthine oxidase inhibitors and are most commonly used to lower uric acid levels and decrease the risk of recurrent gout flares, progressive joint damage, and potentially cardiovascular disease and mortality

    --see http://gmodestmedblogs.blogspot.com/2020/01/uric-acid-threshold-for-increased-cad.html for a recent blog on uric acid threshold and CAD mortality, with reference to many other blogs on cardiovascular risk associated with hyperuricemia, including an interesting one with an evolutionary perspective on the advantage to losing the uricase gene (the one metabolizing uric acid, lost in great apes and humans: http://gmodestmedblogs.blogspot.com/2019/04/uric-acid-lowering-cardiovasc-benefit.html )

    -- however, as noted, the relationship between hyperuricemia and cardiovascular disease is not supported by Mendelian randomization studies (though one study did state that the relationship was “highly suggestive”, as noted in http://gmodestmedblogs.blogspot.com/2019/03/gout-drug-feboxustat-gets-fda-boxed.html

-- it is important to remember that there should be prophylaxis against acute gout flares for up to 6 months, attributed to the large uric acid load that has been deposited in the body and needs to be removed

 

-- Differences between this trial and CARES (the one finding increased cardiovascular outcomes, all-cause death, and cardiovascular death, see http://gmodestmedblogs.blogspot.com/2019/03/gout-drug-feboxustat-gets-fda-boxed.html ):

    -- it was difficult to understand why in the CARES trial, those on lower doses of febuxostat had increased deaths [though this FAST trial did not even use that lower dose of 40mg]

    -- 57% of patients in the CARES trial discontinued randomized treatment prematurely, and 45% were not followed until the end of the trial and were lost to follow-up/not included in the analysis

        -- when patients lost to follow-up in CARES were contacted/included, the difference in cardiovascular deaths was no longer seen

        -- unlike CARES, this FAST trial had much more aggressive follow-up of all patients, by telephone, other personal contact, and record linkage to national hospitalization and death rates

    -- all of the patients in CARES had established cardiovascular disease, whereas 33% in this FAST trial did at baseline (though results in those with prior MIs, strokes, or ACS in the FAST trial were similar to those in the CARES trial: this group in the FAST trail had no increased risk of adverse cardiovascular events)

    -- the presence of tophi, a marker of more severe goat at baseline, was higher in the CARES trial

    -- CARES involved newly treated patients, not those who were already on established therapy (and those in the FAST trial may have therefore had a lower urate crystal burden)

 

Limitations:

-- this was not a double-blind trial; those already on allopurinol just continued it with 36% having an increased dose (and, therefore, this group was a select group who were tolerant of allopurinol, less likely to have adverse effects since they were already on it, and less likely to have a nocebo effect). However, all of these biases should favor allopurinol, yet the results of the study suggested less of a problem with febuxostat...

-- colchicine was used more frequently in the febuxostat group, perhaps related to the fact that patients were knowingly switched to febuxostat and wanted gout prophylaxis because they were no longer on allopurinol. Unclear how this might have affected the results

-- this trial had a primary outcome based on those on-treatment instead of intention-to-treat, as is true in many noninferiority trials (since a major issue is what are the adverse effects to those really taking the medications), but this type of trial does limit its generalizability to the real world

-- they did use a higher dose of febuxostat in the FAST study (80 to 120 mg, vs 40 to 80 mg in CARES), and it was notable that a lower dose was associated with more adverse effects in the CARES study (61% of the patients received the 40 mg dose)

-- this study was limited to patients with gout, and did not include patients with asymptomatic hyperuricemia or nephrolithiasis

  

So, a few points:

-- in this analysis, which seems to avoid some of the pitfalls of the CARES trial, febuxostat seems not to have any increased incidence of cardiovascular disease or all-cause mortality, and should remain as an important part of our hyperuricemia management scheme

-- to the extent that treating hyperuricemia may decrease cardiovascular events, as per the blogs above, it seems that both allopurinol and febuxostat are likely equally effective

-- allopurinol does have the problem of serious/fatal adverse reactions (Allopurinol Hypersensitivity Syndrome), with a higher likelihood in those with HLA-B*5801 mutation.  These patients with this mutation should be checked before starting on allopurinol, and febuxostat is a reasonable initial medication in those at high risk for this serious complication. note: the new guidelines recommend testing not just patients from Southeast Asian descent but also African-Americans (incidence of this mutation is 7.4% in those from Southeast Asian descent, 3.8% in African-Americans, and 0.7% in white or Latinx people: see http://gmodestmedblogs.blogspot.com/2020/06/new-gout-management-guidelines.html )

-- however, I would still support the recommendations that allopurinol in general be the 1^st drug of choice, given its long history and effectiveness, utilizing febuxostat for those intolerant of allopurinol or HLA-B*5801 positive.

geoff

 

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