Background/Purpose:

Xanthine oxidase inhibitors (XOI) reduce both urate levels and oxidative stress in the vasculature, both of which are cardiovascular disease (CVD) risk factors. However, the impact of an individual XOI agent on major cardiovascular events (MCE) may vary based on the agent’s efficacy, dosing constraints and mitigating polychronic disease.

Methods:

Gout patients (ICD-9-CM 274.xx), aged >18, with a baseline (12 months) diagnosis of stage 3/4 chronic kidney disease (CKD) and CVD (coronary artery disease (CAD), cerebrovascular disease (CBV) and peripheral vascular disease (PVD)) or heart failure were selected from the MarketScan® databases (January 2009-June 2013) upon initiating urate lowering therapy (ULT) with either allopurinol (ALO) or febuxostat (FBX). Patients were followed until disenrollment, discontinuation of the qualifying ULT or use of the alternate study agent. MCE included myocardial infarction, stroke, transient ischemic attack, non-traumatic, lower extremity (LE) amputation or coronary, cerebrovascular or LE revascularization. MCE incidence was measured per 1000 person-years (PY).  Cox proportional hazards models assessed MCE risk as a function of age, gender, region, payer, CKD stage, exposure to other anti-gout medications (NSAID, colchicine, steroids, probenecid), recent CVD hospitalization and a history of CAD, CBV, PVD, heart failure (HF), diabetes or hyperlipidemia.

Results:

A total of 2,426 patients (2056 ALO, 370 FBX) met eligibility criteria (63% male; mean age 73±11). Two thirds of patients had a history of CAD, 18% CBV and 23% PVD. There were no significant differences in CVD type by cohort. Half of patients also had HF and 73% had stage 3 CKD at the time of initiation. A total of 162 MCE occurred during follow-up in 3.8% and 7.2% of FBX and ALO cohorts respectively. A total of 80 patients (3.3%) had a CAD specific MCE, 51 (2.1%) a PVD specific event and 38 (1.6%) a CBV specific event. The MCE rate per 1000 PY (95% CI) in the FBX cohort was 51.8 (28-87) as compared to 99.3 (84-117) in the ALO cohort.

Cox model results suggest significantly increased MCE risk (any MCE) among patients with baseline PVD (HR 2.7; 95% CI 1.9 – 3.7, p<0.0001) and baseline CVD/HF hospitalization (HR 1.7; 95% CI 1.2 – 2.5, p=0.0023). Model results suggest significantly decreased MCE risk amongst patients initiating on FBX (HR 0.5; 95% CI 0.3 – 0.9, p=0.02), with baseline history of another circulatory disorder (HR 0.5; 95% CI 0.3 – 0.85, p=0.007) and those receiving other baseline anti-gout medications (HR 0.7; 95% CI 0.5 – 0.998, p=0.049). The hazard ratio (95% CI) associated with membership in the FBX cohort on PVD specific outcomes was 0.2 (0.05 – 0.8, p=0.026), on CAD specific MCE was 0.6 (0.3 – 1.3, p=0.20) and on CBV specific MCE was 0.9 (0.4 – 2.4, p=0.88).

Conclusion:

Patients with moderate to severe CKD and CVD/HF initiating on FBX had a significantly lower rate of MCE than patients initiating on ALO. This may be due to the direct effects of lower sUA or the effect of reduced oxidative stress and other pleiotropic effects on the endothelium.  It is unclear if this is due to channeling, greater clinical effectiveness on the part of FBX or to ALP under-dosing in renally impaired patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/major-cardiovascular-events-in-gout-patients-with-cardiovascular-disease-or-heart-failure-and-chronic-kidney-disease-initiating-on-allopurinol-or-febuxostat-uloric/