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evident
Original paper
2018NEJMRheumatology/Immunology

CARES

Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout

RCTGout

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Overview

In gout with cardiovascular disease, febuxostat was noninferior to allopurinol for the MACE composite, but all-cause and cardiovascular death were higher.

Clinical takeaway

CARES met noninferiority for the composite cardiovascular end point. That is not a clean safety win: all-cause and cardiovascular death were higher with febuxostat. Many patients stopped the drug or follow-up.

Key result

Modified ITT primary composite: 10.8% febuxostat vs 10.4% allopurinol (HR 1.03; one-sided 98.5% CI upper limit 1.23; P=0.002 for noninferiority). All-cause death (HR 1.22, 95% CI 1.01-1.47) and CV death (HR 1.34, 95% CI 1.03-1.73) were higher with febuxostat.

Practice impact

Febuxostat met noninferiority for the MACE composite versus allopurinol, but death rates were higher; choose it with that tradeoff in mind.

Evidence

Study design

Multicenter, double-blind, noninferiority trial of febuxostat versus allopurinol, stratified by kidney function. The prespecified noninferiority margin was a hazard ratio of 1.3.

Enrollment

6,190

Follow-up

Median 32 months (maximum 85 months).

Geography

Not listed

Clinical question

Is febuxostat noninferior to allopurinol for a composite of major cardiovascular events in patients with gout and cardiovascular disease?

Population

  • 6190 patients with gout and cardiovascular disease who underwent randomization and received febuxostat or allopurinol.

Intervention

Febuxostat.

Comparator

Allopurinol.

Primary outcome

Composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization.

Febuxostat was noninferior to allopurinol for the primary cardiovascular composite in the modified ITT analysis. Noninferiority is not a mortality advantage: all-cause and cardiovascular death were higher with febuxostat.

Hazard ratio / 1.03 / one-sided 98.5% CI upper limit 1.23 / p=0.002

Key results

  • In the modified intention-to-treat analysis, a primary end-point event occurred in 335 patients (10.8%) with febuxostat versus 321 (10.4%) with allopurinol (HR 1.03; upper limit of the one-sided 98.5% CI 1.23; P=0.002 for noninferiority).
  • All-cause mortality was higher with febuxostat (HR 1.22, 95% CI 1.01-1.47).
  • Cardiovascular death was higher with febuxostat (HR 1.34, 95% CI 1.03-1.73).
  • Results for the primary end point and for all-cause and cardiovascular mortality were similar in the on-treatment analysis. The trial regimen was discontinued in 56.6% of patients, and 45.0% discontinued follow-up.

Harms

  • All-cause mortality was higher with febuxostat than with allopurinol (HR 1.22, 95% CI 1.01-1.47).
  • Cardiovascular mortality was higher with febuxostat than with allopurinol (HR 1.34, 95% CI 1.03-1.73).

Clinical Use

Practice impact

  • If using febuxostat in gout with established cardiovascular disease, treat the primary result as noninferiority for the MACE composite and weigh the higher all-cause and cardiovascular death rates.

Applicability

  • Most applicable to patients with gout and major cardiovascular coexisting conditions. Assignment was stratified by kidney function.

Limitations

  • The trial regimen was discontinued in 56.6% of patients, and 45.0% discontinued follow-up.
  • The primary analysis was modified intention-to-treat among patients who underwent randomization and received a trial drug.
  • Per-arm randomized Ns are not reported, only the total of 6190 and the event counts.

Common misinterpretations

  • Meeting noninferiority for the composite is not evidence that febuxostat is safer than allopurinol; death was higher.
  • This is not a superiority trial of gout flare control; it is a cardiovascular safety noninferiority trial.

Citation

White WB, Saag KG, Becker MA, et al. Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout. N Engl J Med. 2018;378(13):1200-1210. doi:10.1056/NEJMoa1710895

In patients with gout and major cardiovascular coexisting conditions, febuxostat was noninferior to allopurinol with respect to rates of adverse cardiovascular events.