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Original Article
A BS T R AC T
BACKGROUND
Cardiovascular risk is increased in patients with gout. We compared cardiovascular From the University of Connecticut
outcomes associated with febuxostat, a nonpurine xanthine oxidase inhibitor, with School of Medicine, Farmington (W.B.W.);
the University of Alabama, Birmingham
those associated with allopurinol, a purine base analogue xanthine oxidase in- (K.G.S.); University of Chicago Medicine,
hibitor, in patients with gout and cardiovascular disease. Chicago (M.A.B.), and Takeda Develop-
ment Center Americas, Deerfield (B.H.,
METHODS M.C., L.G.) — both in Illinois; the State
University of New York, Downstate Medi-
We conducted a multicenter, double-blind, noninferiority trial involving patients cal Center, Brooklyn (J.S.B.); Michigan
with gout and cardiovascular disease; patients were randomly assigned to receive State University College of Human Medi-
febuxostat or allopurinol and were stratified according to kidney function. The trial cine, Grand Rapids (P.B.G.); and Johns
Hopkins University School of Medicine,
had a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary Baltimore (A.W.). Address reprint requests
end point (a composite of cardiovascular death, nonfatal myocardial infarction, to Dr. White at the Calhoun Cardiology
nonfatal stroke, or unstable angina with urgent revascularization). Center, University of Connecticut School
of Medicine, 263 Farmington Ave., Farming-
RESULTS ton, CT 06032, or at w white@uchc.edu.
In total, 6190 patients underwent randomization, received febuxostat or allopurinol, *A complete list of the CARES investiga-
and were followed for a median of 32 months (maximum, 85 months). The trial tors is provided in the Supplementary
Appendix, available at NEJM.org.
regimen was discontinued in 56.6% of patients, and 45.0% discontinued follow-up.
In the modified intention-to-treat analysis, a primary end-point event occurred in This article was published on March 12,
2018, at NEJM.org.
335 patients (10.8%) in the febuxostat group and in 321 patients (10.4%) in the
allopurinol group (hazard ratio, 1.03; upper limit of the one-sided 98.5% confi- DOI: 10.1056/NEJMoa1710895
Copyright © 2018 Massachusetts Medical Society.
dence interval [CI], 1.23; P = 0.002 for noninferiority). All-cause and cardiovascular
mortality were higher in the febuxostat group than in the allopurinol group (haz-
ard ratio for death from any cause, 1.22 [95% CI, 1.01 to 1.47]; hazard ratio for
cardiovascular death, 1.34 [95% CI, 1.03 to 1.73]). The results with regard to the
primary end point and all-cause and cardiovascular mortality in the analysis of
events that occurred while patients were being treated were similar to the results
in the modified intention-to-treat analysis.
CONCLUSIONS
In patients with gout and major cardiovascular coexisting conditions, febuxostat was
noninferior to allopurinol with respect to rates of adverse cardiovascular events. All-
cause mortality and cardiovascular mortality were higher with febuxostat than with
allopurinol. (Funded by Takeda Development Center Americas; CARES ClinicalTrials
.gov number, NCT01101035.)
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The n e w e ng l a n d j o u r na l of m e dic i n e
G
out is a chronic illness character- drafted the manuscript, had full access to the fi-
ized by hyperuricemia, arthropathy, to- nal trial data, and vouch for the accuracy and
phus development, and urolithiasis and completeness of the data and the analyses, as well
is associated with an increased risk of cardiovas- as for the fidelity of the trial to the protocol,
cular and chronic kidney disease.1 The risk of car- which is available with the full text of this article
diovascular events, including death, is substan- at NEJM.org. The appropriate national and insti-
tially higher in people with gout than in those tutional regulatory authorities and ethics com-
without gout.2,3 When the Food and Drug Admin- mittees approved the trial design.
istration (FDA) released a guidance document
outlining specific requirements for the cardio- Patients
vascular safety assessment of antidiabetic thera- Patients were eligible for enrollment in the trial
pies,4 investigators in other therapeutic areas, in- if they had a diagnosis of gout fulfilling the
cluding those studying gout therapies, began to American Rheumatism Association criteria9 and
explore cardiovascular safety with similarly de- a history of major cardiovascular disease before
signed trials. randomization (detailed inclusion and exclusion
Febuxostat, a nonpurine inhibitor of xanthine criteria are provided in Table S1 in the Supple-
oxidase that is used for the management of hyper- mentary Appendix, available at NEJM.org). Addi-
uricemia in patients with gout, inhibits both the tional criteria for inclusion were a serum urate
oxidized and reduced forms of xanthine oxidase level of at least 7.0 mg per deciliter (420 μmol per
and decreases the formation of uric acid.5 Febuxo- liter), or of at least 6.0 mg per deciliter (360 μmol
stat provides highly selective and potent inhibi- per liter) with inadequately controlled gout, after
tion of xanthine oxidase and greater hypouricemic a 1-to-3-week washout period from previous gout
activity than do commonly used doses of allopu- therapies. Patients were regarded as having a
rinol.6 During its development, febuxostat was history of major cardiovascular disease if they
compared with placebo and allopurinol in clini- had had a myocardial infarction, hospitalization
cal trials involving more than 5000 patients with for unstable angina, stroke, hospitalization for
gout5-7; these trials suggested a modestly higher transient ischemic attack, peripheral vascular dis-
rate of cardiovascular events with febuxostat. The ease, or diabetes mellitus with evidence of mi-
Cardiovascular Safety of Febuxostat and Allopu- crovascular or macrovascular disease, as defined
rinol in Patients with Gout and Cardiovascular previously.8 All participants provided written in-
Morbidities (CARES) trial was therefore conduct- formed consent.
ed as an FDA requirement to determine whether
febuxostat was noninferior to allopurinol with Treatment and Procedures
regard to major cardiovascular events in patients Patients were randomly assigned to receive fe-
with gout and cardiovascular disease. buxostat or allopurinol administered in a double-
blind fashion once daily. Randomization was
stratified according to the estimated creatinine
Me thods
clearance at baseline (≥60 ml per minute vs. ≥30
Trial Design but <60 ml per minute).
We conducted a multicenter, randomized, double- Doses of allopurinol were modified according
blind noninferiority trial; details of the design of to kidney function. Patients with an estimated
the trial have been published previously.8 The creatinine clearance of at least 60 ml per minute
funder (Takeda Pharmaceuticals) participated in initially received allopurinol at a dose of 300 mg
the trial design, conduct, and monitoring and in once daily, which was increased in 100-mg in-
data collection, storage, and analyses. An indepen- crements monthly until the patient either had a
dent data and safety monitoring committee moni- serum urate level of less than 6.0 mg per decili-
tored the trial and had access to the unblinded ter or was receiving an allopurinol dose of 600 mg
data. Statistical analyses were performed for the once daily. Patients who had an estimated cre-
data and safety monitoring committee by an in- atinine clearance of at least 30 but less than 60 ml
dependent statistical group (WebbWrites). per minute initially received 200 mg of allopuri-
The academic authors of the present article nol; the dose was increased in 100-mg increments
2 n engl j med nejm.org
until the patient either had a serum urate level itored but would not return for study visits, tele-
of less than 6.0 mg per deciliter or was receiving phone contacts were completed, but this was not
an allopurinol dose of 400 mg once daily. preferred or recommended to the sites.
Febuxostat doses were not modified accord-
ing to kidney function. Patients who were ran- End Points
domly assigned to receive febuxostat initially The primary composite end point was the first
received 40 mg once daily and continued to re- occurrence of cardiovascular death, nonfatal myo-
ceive this dose if the serum urate level was less cardial infarction, nonfatal stroke, or urgent re-
than 6.0 mg per deciliter after 2 weeks of therapy. vascularization for unstable angina (definitions
If the serum urate level was higher than 6.0 mg are provided in Table S2 in the Supplementary Ap-
per deciliter at the week 2 visit, the dose of fe- pendix).10 The secondary safety end points included
buxostat was increased to 80 mg once daily for a composite of cardiovascular death, nonfatal
the remainder of the trial. myocardial infarction, or nonfatal stroke as well
The patients’ serum urate levels were revealed as the individual components of the primary end
to the site investigators only during a 10-week point. The consistency of effects on the primary
dose-adjustment period to facilitate dose increas- end point was explored in a variety of subgroups
es that were based on urate response. During (both prespecified and post hoc). Additional safety
that period, the administration of double-blind, end points included death from any cause, urgent
double-dummy trial medications was guided by cerebrovascular revascularization, transient isch-
an interactive voice-response system, a procedure emic attack, hospitalization for heart failure,
that prevented unblinding for patients whose dose arrhythmias not associated with ischemia, and
was not adjusted. After dose adjustments were venous thromboembolic events. An independent
completed, urate levels were concealed from in- central end-points committee, the members of
vestigators and the sponsor, and the interactive which were unaware of the treatment assign-
voice-response system was used to manage treat- ments, adjudicated all suspected end-point events.
ment throughout the trial.
At the screening visit, all urate-lowering Statistical Analysis
therapy was discontinued and, unless the patient Cox proportional-hazards models, stratified ac-
had a history of unacceptable side effects from cording to baseline kidney function, were used
colchicine, treatment with colchicine at a dose of to analyze the time to first occurrence of primary
0.6 mg daily was started for gout flare prophy- and secondary end-point events for all patients
laxis. All the patients received prophylaxis for the who underwent randomization and received treat-
first 6 months of randomly assigned treatment. If ment. A determination of noninferiority of febux-
colchicine treatment resulted in unacceptable side ostat to allopurinol required that the upper bound
effects and the estimated creatinine clearance of the one-sided confidence interval of the hazard
was at least 50 ml per minute, patients received ratio for the primary end point be less than 1.3.
naproxen (250 mg twice daily) with lansoprazole The number and percentage of patients with a
(15 mg once daily). If patients could receive nei- primary end-point event or cardiovascular death
ther colchicine nor naproxen, other nonsteroidal were tabulated for various subgroups. The rela-
antiinflammatory drugs (NSAIDs) or prednisone tive risk (febuxostat vs. allopurinol) was calculated
could be provided as prophylaxis, or the investi- within each subgroup, with homogeneity among
gators could choose to manage gout flares as subgroup levels assessed with the use of the Co-
they occurred. chran–Mantel–Haenszel test. Sensitivity analyses
Outpatient visits were scheduled at screening were performed by excluding events that occurred
and randomization and at 2, 4, 6, 8, 10, 12, and after treatment discontinuation and events that
24 weeks after randomization and every 6 months occurred more than 30 days after treatment dis-
during subsequent years of the trial. Patients with continuation.
reduced kidney function or who were older than The trial was designed to accrue 624 primary
65 years of age at randomization also had visits events for assessing the noninferiority of febuxo-
at 9 months and 15 months to monitor serum stat to allopurinol with regard to cardiovascular
chemical profiles. If patients agreed to be mon- risk, under the assumption of a true hazard ratio
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of 1.0 and 90% power. Interim analyses were of the one-sided confidence interval for the haz-
conducted when approximately 25%, 50%, and 75% ard ratio (febuxostat vs. allopurinol) would be cal-
of the events had occurred. For each group-sequen- culated with the use of the critical value from the
tial analysis, it was specified that the upper bound Lan–DeMets–O’Brien–Fleming alpha-spending
Febuxostat Allopurinol
Characteristic (N = 3098) (N = 3092)
Median age (interquartile range) — yr 64.0 (58–71) 65.0 (58–71)
Age ≥65 yr — no. (%) 1514 (48.9) 1586 (51.3)
Male sex — no. (%) 2604 (84.1) 2592 (83.8)
Duration of gout — yr 11.8±11.4 11.9±11.2
Baseline serum urate level — mg/dl 8.7±1.7 8.7±1.7
Presence of tophi — no. (%) 668 (21.6) 650 (21.0)
Median body weight (interquartile range) — kg 97.7 (84–113) 97.3 (84–113)
Body-mass index† 33.6±7.0 33.4±6.9
Race or ethnic group — no. (%)‡
White 2160 (69.7) 2140 (69.2)
Black 552 (17.8) 593 (19.2)
Asian 92 (3.0) 96 (3.1)
American Indian or Alaska Native 262 (8.5) 234 (7.6)
Native Hawaiian or other Pacific Islander 13 (0.4) 14 (0.5)
Other 19 (0.6) 15 (0.5)
Cardiovascular risk factors and history — no. (%)
Diabetes mellitus with small-vessel disease 1193 (38.5) 1213 (39.2)
Hypertension 2864 (92.4) 2851 (92.2)
Hyperlipidemia 2678 (86.4) 2702 (87.4)
Myocardial infarction 1197 (38.6) 1231 (39.8)
Hospitalization for unstable angina 855 (27.6) 869 (28.1)
Coronary revascularization 1129 (36.4) 1182 (38.2)
Cerebral revascularization 69 (2.2) 54 (1.7)
Congestive heart failure 622 (20.1) 631 (20.4)
Stroke 460 (14.8) 410 (13.3)
Peripheral vascular disease 412 (13.3) 375 (12.1)
Median estimated creatinine clearance — ml/min§
Stage 1 or 2 chronic kidney disease 75.0 73.0
Stage 3 chronic kidney disease 46.0 46.0
Stage of chronic kidney disease — no./total no. (%)
Stage 1 or 2 1456/3092 (47.1) 1459/3090 (47.2)
Stage 3 1636/3092 (52.9) 1631/3090 (52.8)
* Plus–minus values are means ±SD. There were no significant differences between the two groups with regard to any
baseline characteristic. To convert the values for urate to micromoles per liter, multiply by 59.48.
† The body-mass index is the weight in kilograms divided by the square of the height in meters.
‡ Race or ethnic group was reported by the patient.
§ Estimated creatinine clearance was calculated with the use of the Cockcroft–Gault formula and was corrected for ideal
body weight. A value of 60 ml per minute or more indicated stage 1 or 2 chronic kidney disease, and a value of at least
30 but less than 60 ml per minute indicated stage 3 chronic kidney disease.
4 n engl j med nejm.org
* The modified intention-to-treat analysis included all patients who underwent randomization with the exception of the
8 patients who never received febuxostat or allopurinol.
† The P value in parentheses is for test of the null hypothesis that the hazard ratio is at least 1.3 versus the one-sided
alternative (noninferiority). All other P values are values for the test of superiority of febuxostat to allopurinol and were
calculated with the use of a Cox regression analysis.
‡ The 97% confidence interval is provided here.
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The n e w e ng l a n d j o u r na l of m e dic i n e
B Cardiovascular Mortality
100 25
90
20
80
15
Cumulative Rate (%)
70
Febuxostat
60 10
50 5
40 Allopurinol
0
30 0 6 12 18 24 30 36 42 48 54 60 66 72
20
10
0
0 6 12 18 24 30 36 42 48 54 60 66 72
Month
No. at Risk
Febuxostat 3098 2823 2550 2174 1922 1659 1440 1243 1033 838 627 482 288
Allopurinol 3092 2807 2530 2152 1898 1637 1433 1204 1008 838 646 489 287
C All-Cause Mortality
100 25
90
20
80 Febuxostat
15
Cumulative Rate (%)
70
60 10
Allopurinol
50 5
40
0
30 0 6 12 18 24 30 36 42 48 54 60 66 72
20
10
0
0 6 12 18 24 30 36 42 48 54 60 66 72
Month
No. at Risk
Febuxostat 3098 2828 2552 2179 1928 1666 1447 1251 1038 840 631 487 289
Allopurinol 3092 2812 2540 2161 1906 1648 1444 1215 1015 842 650 489 288
6 n engl j med nejm.org
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Table 3. Events That Occurred during Treatment or within 30 Days after Discontinuation of Treatment.*
high rate of loss to follow-up is less easy to predict, resulted in overall rates of major adverse cardio-
since it may not have been random; however, vascular events similar to those associated with
approximately equal numbers of patients discon- allopurinol. Higher all-cause mortality, resulting
tinued follow-up in the two treatment groups, from an imbalance in cardiovascular deaths, was
and the baseline characteristics of these partici- observed with febuxostat than with allopurinol.
pants were similar to those of participants who
completed follow-up. Supported by Takeda Development Center Americas.
Disclosure forms provided by the authors are available with
In conclusion, among patients with gout and the full text of this article at NEJM.org.
cardiovascular disease, treatment with febuxostat We thank all the patients who participated in the trial.
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