Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities - CARES

Contribution To Literature:

The CARES trial showed that febuxostat was noninferior to allopurinol at preventing cardiovascular events; however, all-cause mortality was increased.

Description:

The goal of the trial was to evaluate febuxostat compared with allopurinol among patients with cardiovascular disease.

Study Design

  • Randomized
  • Parallel
  • Stratified

Patients with gout and cardiovascular disease were randomized to febuxostat (n = 3,098) versus allopurinol (n = 3,092). Febuxostat was given at 40 mg daily and titrated to 80 mg daily if needed. Allopurinol was given at 300 mg daily and titrated to 600 mg daily if needed (dose reduced in chronic kidney disease).

  • Total number of enrollees: 6,190
  • Duration of follow-up: median 32 months
  • Median patient age: 64 years
  • Percentage female: 16%
  • Percentage with diabetes: 39%

Inclusion criteria:

  • Ages ≥50 years (males) or ≥55 years (females) diagnosed with gout
  • Cardiovascular disease (history of myocardial infarction, hospitalization for unstable angina, stroke/transient ischemic attack, peripheral vascular disease, or diabetes)
  • Serum uric acid level ≥7.0 mg/dl or ≥6.0 mg/dl and uncontrolled gout

Principal Findings:

The primary outcome, cardiovascular death, myocardial infarction, stroke, or urgent revascularization for unstable angina, occurred in 10.8% of the febuxostat group compared with 10.4% of the allopurinol group (p = 0.66, p for noninferiority = 0.002). The primary outcome was the same in all subgroups.

Secondary outcomes:

  • All-cause mortality: 7.8% with febuxostat vs. 6.4% with allopurinol (p = 0.04)
  • Cardiovascular mortality: 4.3% with febuxostat vs. 3.2% with allopurinol (p = 0.03)
  • Myocardial infarction: 3.6% with febuxostat vs. 3.8% with allopurinol (p = 0.61)

Interpretation:

Among patients with gout and cardiovascular disease, febuxostat was noninferior to allopurinol at preventing adverse cardiovascular events. However, febuxostat was associated with an increase in all-cause and cardiovascular mortality. The mechanism for the increase in mortality is unknown and not obviously due to myocardial infarction, arrhythmia, coronary revascularization, or heart failure.

References:

White WB, Saag KG, Becker MA, on behalf of the CARES Investigators. Cardiovascular Safety of Febuxostat or Allopurinol in Patients With Gout. N Engl J Med 2018;378:1200-10.

Presented by Dr. William B. White at the American College of Cardiology Annual Scientific Session (ACC 2018), Orlando, FL, March 12, 2018.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Acute Heart Failure, Interventions and Vascular Medicine

Keywords: ACC18, ACC Annual Scientific Session, Allopurinol, Angina, Unstable, Arrhythmias, Cardiac, Diabetes Mellitus, Gout, Heart Failure, Ischemic Attack, Transient, Metabolic Syndrome X, Myocardial Infarction, Myocardial Revascularization, Peripheral Vascular Diseases, Primary Prevention, Renal Insufficiency, Chronic


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