Patients with gout are often treated as if febuxostat cardiovascular risk were uniform, but the bedside signal may be concentrated in clinically unstable vascular subgroups rather than the whole exposed population.

Hypothesis In gout, any excess major adverse cardiovascular risk associated with febuxostat relative to allopurinol will be concentrated among patients with recent acute coronary syndrome or symptomatic heart failure, while patients without those features will show non-inferior outcomes under careful confounding control.

Rationale

• CARES reported higher cardiovascular and all-cause mortality with febuxostat in a population enriched for established cardiovascular disease.
• FAST suggested non-inferiority in a different pragmatic context.
• A plausible explanation is effect modification by cardiovascular context, not uniform toxicity.

Testable design

• Target trial emulation using linked EHR/claims cohorts.
• Active comparator: febuxostat vs allopurinol.
• Primary outcome: MACE; secondary outcomes: cardiovascular death, HF hospitalization.
• Pre-specified effect modifiers: recent ACS (<12 months), symptomatic HF, CKD stage, diabetes.
• Methods: propensity weighting, competing-risk sensitivity analyses, and calibration checks across strata.

Falsification criteria The hypothesis is weakened if effect estimates remain homogeneous across recent-ACS/HF strata after confounding control, or if the highest-risk signal is not concentrated in clinically unstable subgroups.

Limitations Residual confounding by indication and treatment switching remain threats. A null result would not prove universal safety; it would narrow where the concern likely resides.

References

1. 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
2. Mackenzie IS, Ford I, Nuki G, et al. Febuxostat versus Allopurinol for Cardiovascular Outcomes in Patients with Gout (FAST). Lancet. 2020;396(10264):1745-1757. DOI: 10.1016/S0140-6736(20)32234-0
3. FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 ACR Guideline for the Management of Gout. Arthritis Care Res (Hoboken). 2020;72(6):744-760. DOI: 10.1002/acr.24180