N Engl J Med 2018;378: DOI: /NEJMoa Lin, Wan-Ting 2018/06/27

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1 N Engl J Med 2018;378: DOI: /NEJMoa Lin, Wan-Ting 2018/06/27 1

2 Introduction Gout is a chronic illness characterized by hyperuricemia, arthropathy, tophus development, and urolithiasis and is associated with an increased risk of cardiovascular and chronic kidney disease. The risk of cardiovascular events, including death, is substantially higher in people with gout than in those without gout. 2

3 Introduction During its development, febuxostat was compared with placebo and allopurinol in clinical trials involving more than 5000 patients with gout; these trials suggested a modestly higher rate of cardiovascular events with febuxostat. The Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) trial was therefore conducted as an FDA requirement to determine whether febuxostat was noninferior to allopurinol with regard to major cardiovascular events in patients with gout and cardiovascular disease. 3

4 Design and patients Design We conducted a multicenter, randomized, double-blind noninferiority trial. Patients (included criteria) Male or female patients > 50 years and > 55 years of age they had a diagnosis of gout fulfilling the American Rheumatism Association criteria and a history of major cardiovascular disease before randomization. serum urate level of at least 7.0 mg per deciliter (420 μmol per liter), or of at least 6.0 mg per deciliter (360 μmol per liter) with inadequately controlled gout, after a 1-to-3-week washout period from previous gout therapies. myocardial infarction, hospitalization for unstable angina, stroke, hospitalization for transient ischemic attack, peripheral vascular disease, or diabetes mellitus with evidence of microvascular or macrovascular disease 4

5 Design and patients Patients (excluded criteria) 1. Patient has secondary hyperuricemia (e.g. due to a myeloproliferative disorder). 2. History of xanthinuria. 3. Patient has received a urate-lowering therapy (i.e. allopurinol, febuxostat, probenicid) or other exclusionary medication less than 7 days prior to randomization. 4. Known hypersensitivity to febuxostat or allopurinol or any components of their formulations. 5. Active peptic ulcer disease. 6. History of cancer (other than basal cell carcinoma of the skin) within 5 years prior to the first dose of study medication. 7. Myocardial infarction or stroke within 60 days prior to screening. 8. Liver transaminases greater than 2 times the upper limit of normal during the screening period. 9. Alcohol or substance abuse/dependence within the 5 years prior to screening. 10. Investigational drug within the 30 days prior to the screening or has previously received study drug for the present study. 11. Estimated creatinine clearance is < 30 ml/minute using the Cockcroft and Gault formula based on ideal body weight. 12. History of infection with hepatitis B, hepatitis C, or human immunodeficiency virus. 13. Patient is a study site employee, or is an immediate family member (ie, spouse, parent, child, and sibling) of a study site employee involved in the conduct of this study. 5

6 Treatment and procedure Randomly assigned to receive febuxostat or allopurinol Randomization was stratified according to the estimated creatinine clearance at baseline ( 60 ml per minute vs. 30 but <60 ml per minute). Allopurinol creatinine clearance: 60 ml/min initially 300 mg increased 100 mg monthly serum urate level of less than 6.0 mg/dl receiving an allopurinol dose of 600 mg creatinine clearance: 30 but <60 ml/min initially 200 mg increased 100 mg monthly serum urate level of less than 6.0 mg/dl receiving an allopurinol dose of 400 mg 6

7 Treatment and procedure Febuxostat serum urate level of less than 6.0 mg/dl : 40 mg Initially 40 mg after 2 weeks serum urate level of higher than 6.0 mg/dl : 80 mg The patients serum urate levels were revealed to the site investigators only during a 10-week dose-adjustment period to facilitate dose increases that were based on urate response. During that period, the administration of double-blind, doubledummy trial medications was guided by an interactive voiceresponse system 7

8 Treatment and procedure All the patients received prophylaxis for the first 6 months of randomly assigned treatment. colchicine (0.6 mg daily) naproxen (250 mg twice daily) with lansoprazole (15 mg once daily) other NSAIDs or prednisone Outpatient visits were scheduled at screening and randomization and at 2, 4, 6, 8, 10, 12, and 24 weeks after randomization and every 6 months during subsequent years of the trial. Patients with reduced kidney function or who were older than 65 years of age at randomization also had visits at 9 months and 15 months to monitor serum chemical profiles. 8

9 End points Primary composite end point first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent revascularization for unstable angina Secondary safety end points a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke as well as the individual components of the primary end point death from any cause, urgent cerebrovascular revascularization, transient ischemic attack, hospitalization for heart failure, arrhythmias not associated with ischemia, and venous thromboembolic events 9

10 Statistical analysis Cox proportional-hazards models analyze the time to first occurrence of primary and secondary end-point events A determination of noninferiority of febuxostat to allopurinol required that the upper bound of the one-sided confidence interval of the hazard ratio for the primary end point be less than 1.3. (at any interim analysis when 25% 50% 75% of events had occurred) The relative risk (febuxostat vs. allopurinol) was calculated within each subgroup, with homogeneity among subgroup levels assessed with the use of the Cochran Mantel Haenszel test. 10

11 Statistical analysis Sensitivity analyses were performed by excluding events that occurred after treatment discontinuation and events that occurred more than 30 days after treatment discontinuation. 11

12 Results 2010/4~2017/5 56.6% discontinued trial (57.3%) (55.9%) (45.0%) (44.9%) mean:728 days; median:968 days mean:719 days; median:942 days Allopurinol 200mg 21.8% 300mg 44.6% 400mg 25.2% 500mg 4.3% 600mg 4.1% Febuxostat 40mg 61.0% 80mg 39.0% 12

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26 Results - Other analysis The baseline characteristics were balanced among the patients who did not complete all the trial visits and those who completed all the visits. The proportions of patients who did not complete all the trial visits were larger in the United States than in Canada or Mexico. 26

27 Conclusion In conclusion, among patients with gout and cardiovascular disease, treatment with febuxostat resulted in overall rates of major adverse cardiovascular events similar to those associated with allopurinol. Higher all-cause mortality, resulting from an imbalance in cardiovascular deaths, was observed with febuxostat than with allopurinol. 27

28 Discussion During a development program involving more than 5000 patients, the rate of cardiovascular events was higher among patients treated with febuxostat (0.74 per 100 patient-years; 95% CI, 0.36 to 1.37) than among those treated with allopurinol (0.60 per 100 patient-years; 95% CI, 0.16 to 1.53). In contrast, observational evaluations have suggested beneficial cardiovascular outcomes after treatment with febuxostat or allopurinol in patients with gout and coexisting cardiorenal conditions. 28

29 Discussion Findings were similar in the modified intention-to-treat analysis and in the prespecified analysis that included events that occurred during treatment and within 30 days after treatment discontinuation. In addition, the rates of adjudicated nonfatal events, including myocardial infarction, coronary revascularization, arrhythmias, and hospitalization for heart failure, were similar in the febuxostat group and the allopurinol group. 29

30 Discussion The only heterogeneity in the analyses of cardiovascular mortality occurred in two subgroups patients with concomitant administration of aspirin or NSAIDs. Furthermore, the occurrence and intensity of gout flares are difficult to capture accurately in clinical trials. Important limitations of this trial are the large number of participants who discontinued the trial treatment and the large number of participants who did not complete follow-up. however, approximately equal numbers of patients discontinued follow-up in the two treatment groups, and the baseline characteristics of these participants were similar to those of participants who completed follow-up. 30