Achieving guideline-recommended serum urate targets with urate-lowering therapy was associated with a lower 5-year risk of major adverse cardiovascular events among patients with gout, according to a large observational study published in JAMA Internal Medicine.
Researchers analyzed data from 109,504 adults in England with newly diagnosed gout, pretreatment serum urate levels greater than 6 mg/dL, and a new prescription for urate-lowering therapy. Using Clinical Practice Research Datalink Aurum data linked to hospitalization and mortality records, the investigators emulated a target trial comparing patients who achieved serum urate levels lower than 6 mg/dL within 12 months with those who did not.
The primary outcome was first major adverse cardiovascular event, defined as nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death within 5 years of treatment initiation.
Patients who achieved the serum urate target had a weighted hazard ratio for major adverse cardiovascular events of 0.91 compared with patients who did not achieve the target, corresponding to an absolute 5-year event-free survival difference of about 1 percentage point.
The association appeared stronger among patients who achieved serum urate levels lower than 5 mg/dL. In that analysis, the weighted hazard ratio was 0.77, with an absolute survival difference of approximately 3 percentage points.
Overall, 27% of patients achieved serum urate levels lower than 6 mg/dL within 12 months. Among those patients, about 80% reached the target within 6 months. Nearly all patients in the cohort — 99% — received allopurinol, limiting generalizability to febuxostat or uricosuric therapy.
The investigators used a cloning, censoring, and weighting approach designed to minimize immortal time bias, a common issue in observational studies evaluating treatment target achievement over time. Analyses were additionally weighted for more than 40 baseline clinical and demographic variables, including adherence to urate-lowering therapy during the first year of treatment.
Secondary cardiovascular outcomes generally aligned with the primary analysis. Patients who achieved serum urate targets had lower risks of myocardial infarction, stroke, first-ever major adverse cardiovascular events, and events requiring hospitalization or resulting in death. Patients in the treat-to-target group also had fewer gout flares.
Subgroup analyses suggested the association was strongest among patients at high or very high baseline cardiovascular risk, whereas patients at moderate cardiovascular risk did not show evidence of benefit. However, those analyses were post hoc and should be interpreted cautiously.
The findings add to growing evidence linking gout flares and systemic inflammation with cardiovascular risk, but they do not establish that lowering serum urate itself directly reduces cardiovascular events.
The accompanying invited commentary noted that the findings differ from prior Mendelian randomization studies and from the ALL-HEART trial, which found no reduction in major adverse cardiovascular events with allopurinol among patients with ischemic heart disease who did not have gout. The commentators suggested the cardiovascular association observed in the current study may be more closely related to gout flare reduction and lower inflammatory burden than to urate lowering alone.
The study also has important limitations. Despite extensive adjustment, residual confounding remains possible. Patients who achieved serum urate targets may have been more adherent, more engaged with health care, or more likely to receive comprehensive cardiovascular risk management overall. The researchers attempted to address this concern using negative control outcomes and adjustment for health care utilization and medication adherence, but acknowledged that confounding could not be eliminated.
Additional limitations included possible exposure misclassification, incomplete capture of gout flares managed outside the health care system, and the possibility that some patients in the non–treat-to-target group achieved serum urate targets following the 12-month exposure window.
The findings may also highlight ongoing gaps between guideline recommendations and routine care, given that fewer than one-third of patients achieved target serum urate levels within the first year of treatment.
Disclosures: The study was funded by the Foundation for Research in Rheumatology. Access to linked Clinical Practice Research Datalink data was funded by the University of Nottingham. Cipolletta reported grants from EULAR and personal fees from Novartis, IBSA, and Horizon Therapeutics outside the submitted work. Other researchers reported relationships with Horizon Therapeutics, UpToDate, SOBI, Novartis, and Eli Lilly.
Source: JAMA Internal Medicine