JOURNAL READING

R.Gantira W.Danasasmita
Narasumber : Prof. Dr. dr. Harry Isbagyo, SpPD-KR, KGer
 INTRODUCTION

• Gout : inflammatory arthritis

cased by deposit
monosodium urate in
synovial fluid and other
tissues

Neogi T, Jansen TL, Dalbeth N. 2015 Gout Classification Criteria, An American

College of Rheumatology/European League Against Rheumatism
Collaborative Initiative
ARTHRITIS & RHEUMATOLOGY Vol. 67, No. 10, October 2015, pp 2557–2568
Choi HK, Maount DB, Reginato AM. Pathogenesis of Gout
Ann Intern Med. 2005;143(7):499-516.
INTRODUCTION
• Gout  chronic illness characterized by hyperuricemia, arthropathy,
tophus development, and urolithiasis
• associated with an increased risk of cardiovascular and chronic kidney disease

1. Choi HK, Curhan G. Independent impact of gout on mortality and risk for coronary heart disease. Circulation 2007; 116:
894-900.
2. Sigh JA. When gout goes to the heart does gout equal a cardiovascular disease risk factor? Ann Rheum Dis April 2015 Vol
74 No 4
INTRODUCTION
• Febuxostat : nonpurine inhibitor of xanthine oxidase  inhibits both
the oxidized and reduced forms of xanthine oxidase and decreases
the formation of uric acid
• Highly selective and potent inhibition  greater hypouricemic activity

Becker MA, Schumacher HR Jr, Wortmann RL, et al. Febuxostat

compared with allopurinol in patients with hyperuricemia and
gout. N Engl J Med 2005; 353: 2450-61.
 Multicenter, randomized, doubleblind
noninferiority trial

The funder (Takeda Pharmaceuticals)

METHODS participated  trial design, conduct,
monitoring ,data collection, storage, and
Trial Design analyses
Statistical analyses  by an independent
statistical group

White WB, Saag KG, Becker MA, Borer JS, et al. Cardiovascular Safety of
Febuxostat or Allopurinol in Patients with Gout. N Engl J Med
2018;378:1200-10.
 1. Diagnosis of gout  fulfilling the American
Rheumatism Association criteria
2. History of major cardiovascular disease before
randomization
3. Additional criteria for inclusion  serum urate >
7.0 mg per deciliter (420 μmol per liter), or > 6.0 mg
METHODS per deciliter (360 μmol per liter) with inadequately
controlled gout, after a 1-to-3-week washout period
from previous gout therapies
Patients
• History of major cardiovascular disease :
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

White WB, Saag KG, Becker MA, Borer JS, et al. Cardiovascular Safety of
Febuxostat or Allopurinol in Patients with Gout. N Engl J Med
2018;378:1200-10.
 • Patients were randomly assigned to receive febuxostat or allopurinol ,
doubleblind , once daily
• Randomization according to the estimated creatinine clearance at
baseline (≥60 ml per minute vs. ≥30 but <60 ml per minute)
• Allopurinol modified according to kidney function
• eGFR of at least 60 ml per minute : 300 mg once daily, increased
METHODS in 100-mg increments monthly until serum urate < 6.0 mg per
deciliter or was receiving an allopurinol dose of 600 mg once daily
• eGFR at least 30 but less than 60 ml per minute : 200 mg;
Treatment and increased in 100-mg increments until the patient either had a
serum urate < 6.0 mg per deciliter or was receiving an allopurinol
dose of 400 mg once daily

Procedure • Febuxostat doses were not modified according to kidney function

• Dose 40 mg once daily and continued if the serum urate < 6.0 mg
per deciliter after 2 weeks of therapy
• Serum urate level > 6.0 mg per deciliter at the week 2
visitincreased to 80 mg once daily for the remainder of the trial
• The patients’ serum urate levels were revealed to the site investigators
only during a 10-week dose-adjustment period

White WB, Saag KG, Becker MA, Borer JS, et al. Cardiovascular Safety of
Febuxostat or Allopurinol in Patients with Gout. N Engl J Med
2018;378:1200-10.
 • Schedule screening and randomization
 2, 4, 6, 8, 10, 12, and 24 weeks after
METHODS randomization and every 6 months
• Patients with reduced kidney
Treatment and function or who were older than 65
years of age  visits at 9 mo and
Procedure 15 mo to monitor serum chemical
profiles

White WB, Saag KG, Becker MA, Borer JS, et al. Cardiovascular Safety of
Febuxostat or Allopurinol in Patients with Gout. N Engl J Med
2018;378:1200-10.
METHODS
Statistical analysis
• Cox proportional-hazards models
• stratified according to baseline kidney function
• 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

White WB, Saag KG, Becker MA, Borer JS, et al. Cardiovascular Safety of
Febuxostat or Allopurinol in Patients with Gout. N Engl J Med
2018;378:1200-10.
RESULTS
Patients
• 6198 patients from 320 North American (April 2010 - May 2017)
• febuxostat group
• 61.0% of the patients received 40 mg and 39.0% received 80 mg daily as the final adjusted dose
• allopurinol group
• 21.8% of the patients received 200 mg, 44.6% received 300 mg, 25.2% received 400 mg, 4.3%
received 500 mg, and 4.1% received 600 mg
• 56.6% of patients discontinued trial treatment febuxostat 57,3% and allopurinol 55,9%
• patients who did not complete all trial visits was 45.0%
• 45.0% in the febuxostat group and 44.9% in the allopurinol group
• median duration of exposure
• febuxostat  728 days, allopurinol719 days
• median duration of follow-up
• 968 days in the febuxostat group and 942 days in the allopurinol group

White WB, Saag KG, Becker MA, Borer JS, et al. Cardiovascular Safety of
Febuxostat or Allopurinol in Patients with Gout. N Engl J Med
2018;378:1200-10.
 RESULTS
Characteristic
Patients

White WB, Saag KG, Becker MA, Borer JS, et al. Cardiovascular Safety of
Febuxostat or Allopurinol in Patients with Gout. N Engl J Med
2018;378:1200-10.
 RESULTS
Safety

• primary end-point event 

similar
• febuxostat group and allopurinol
group (10.8% and 10.4% of patients,
median period of 32 months;
hazard ratio, 1.03; 98.5%
confidence interval [CI], 1.23; P =
0.002 for noninferiority)
• the risk of death from any
cause and the risk of
cardiovascular death  higher
in the febuxostat group
• sudden cardiac death was the
most prevalent
• 83 patients (2.7%) febuxostat and
56 patients (1.8%) allopurinol
• Rates of hospitalization were
similar in the two groups White WB, Saag KG, Becker MA, Borer JS, et al. Cardiovascular Safety of
Febuxostat or Allopurinol in Patients with Gout. N Engl J Med
2018;378:1200-10.
 RESULTS

• Panel A  the time until the first occurrence of a

primary end-point event — cardiovascular death,
myocardial infarction, stroke, or urgent
revascularization due to unstable angina
• primary end-point event
• 10.8% of patients in the febuxostat and 10.4% of patients
in the allopurinol  after a median exposure of 32
months (hazard ratio, 1.03; upper bound of the one-sided
98.5% CI, 1.23)

• Panel B  the time until death from a cardiovascular

cause (hazard ratio, 1.34; 95% CI, 1.03 to 1.73)
• Panel C  the time until death from any cause (hazard
ratio, 1.22; 95% CI, 1.01 to 1.47)

White WB, Saag KG, Becker MA, Borer JS, et al. Cardiovascular Safety of
Febuxostat or Allopurinol in Patients with Gout. N Engl J Med
2018;378:1200-10.
 RESULTS

• In an analysis according to
subgroup the results with regard
to the primary end point showed
no heterogeneity associated with
any of the baseline factors
• Cardiovascular mortality
interaction for NSAID use and
the absence of use of low-dose
aspirin (unadjusted P<0.05 for
both comparisons)

White WB, Saag KG, Becker MA, Borer JS, et al. Cardiovascular Safety of
Febuxostat or Allopurinol in Patients with Gout. N Engl J Med
2018;378:1200-10.
RESULTS

• primary end-point event occurred in 7.8% of patients in the febuxostat group

and 7.7% of patients in the allopurinol group (hazard ratio, 1.00; upper
bound of the one-sided 98.5% CI, 1.22)
• rate of cardiovascular death was higher in the febuxostat group than in the
allopurinol group (hazard ratio, 1.49; 95% CI, 1.01 to 2.22)
White WB, Saag KG, Becker MA, Borer JS, et al. Cardiovascular Safety of
Febuxostat or Allopurinol in Patients with Gout. N Engl J Med
2018;378:1200-10.
DISCUSSION
• CARES trial
• major cardiovascular events that were similar  febuxostat ~ allopurinol,
among patients who had coexisting cardiovascular disease
• cardiovascular death and deaths from any cause  more frequent in the
febuxostat
• rate of cardiovascular events was higher in febuxostat (0.74 per 100 patient-
years; 95% CI, 0.36 to 1.37) than allopurinol (0.60 per 100 patient-years; 95%
CI, 0.16 to 1.53)

White WB, Saag KG, Becker MA, Borer JS, et al. Cardiovascular Safety of
Febuxostat or Allopurinol in Patients with Gout. N Engl J Med
2018;378:1200-10.
DISCUSSION
• all-cause mortalityhigher in the febuxostat
• mechanism underlying this risk of death is unclear
• Preclinical cardiovascular studies of febuxostat : shown no toxic
effects related to cardiac rhythm, function, or metabolism
• rates of adjudicated nonfatal event (myocardial infarction, coronary
revascularization, arrhythmias, and hospitalization for heart failure)
 similar
• may be associated with more frequent gout flareslead to
cardiovascular events
White WB, Saag KG, Becker MA, Borer JS, et al. Cardiovascular Safety of
Febuxostat or Allopurinol in Patients with Gout. N Engl J Med
2018;378:1200-10.
DISCUSSION
• limitations of this trial
• large number of participants who discontinued the trial treatment
• large number of participants who did not complete follow-up
• Discontinuation of treatment bias the analyses
• missing a significant difference between the groups in the primary or nonfatal
secondary outcomes

White WB, Saag KG, Becker MA, Borer JS, et al. Cardiovascular Safety of
Febuxostat or Allopurinol in Patients with Gout. N Engl J Med
2018;378:1200-10.
CONCLUSION
• patients with gout and cardiovascular disease
• Major adverse cardiovascular events febuxostat similar to those associated
with allopurinol
• Higher all-cause mortality, resulting from an imbalance in cardiovascular
deaths  was observed with febuxostat than with allopurinol

White WB, Saag KG, Becker MA, Borer JS, et al. Cardiovascular Safety of
Febuxostat or Allopurinol in Patients with Gout. N Engl J Med
2018;378:1200-10.