Date:2017/10/03 Presenter: Wen-Ching Lan Comparative effectiveness of allopurinol versus febuxostat for preventing incident renal disease in older adults: an analysis of Medicare claims data Jasvinder A Singh, John D Cleveland BMJ .2017 Date:2017/10/03 Presenter: Wen-Ching Lan

Introduction Chronic kidney disease (CKD) is a common chronic medical condition with a significant public health impact. CKD incidence in the US elderly 2000 2% → 2008 4.5% prevalence 1988-1994 18.8% → 2003-2006 24.5% That allopurinol may be protective against renal injury, and febuxostat likely even more protective, conclusive evidence supporting a protective effect is lacking. That higher allopurinol dose and a longer duration of use was independently associated with lower risk of incident renal disease in allopurinol users 65 years or older. Observational studies showed that febuxostat use was associated with a slower decline in renal function. 1

Introduction Our objective was to conduct a comparative effectiveness study of renal function preservation with allopurinol versus febuxostat. Hypothesised compared with allopurinol, febuxostat use (and dose/duration of use) will be associated with a lower risk of incident renal disease, that renal function preservation will be greater with a higher allopurinol dose or longer duration use. 2

Methods Study design and data sources This retrospective cohort study used claims data from the 5% random sample of Medicare beneficiaries for the years 2006–2012. These data were obtained from the Centers for Medicare and Medicaid Services Chronic Condition Data Warehouse. claims for inpatient, outpatient, skilled nursing facility, non-institutional provider, home health, hospice, durable medical equipment services; and claims for prescription drugs. 3

Methods Eligible population and covariates Medicare beneficiaries 65 years of age or older. enrolled continuously in the traditional Medicare fee-for-service and pharmacy coverage newly treated with allopurinol and/or febuxostat lived in the USA defined a new episode of treatment: a clean baseline of period of 183 days during which no allopurinol prescription was filled, respectively. 4

Methods Eligible population and covariates Medicare denominator file → age, gender, race/ethnicity, residence Charlson-Romano comorbidity index score (Dartmouth-Manitoba's CCI= D-M's CCI) gout medications (colchicine, probenecid, non-steroidal anti-inflammatory drugs (NSAIDs)) gout duration risk factors for renal disease (hypertension, tobacco use, hyperlipidaemia, etc) medications for cardiovascular or renal disease or medications that can impact renal function (statins, beta-blockers, diuretics, aspirin, ACE inhibitors, angiotensin receptor blockers (ARBs) and calcium channel blockers) 5

Methods 6 Study outcomes The first occurrence of incident renal disease during the follow-up, with an absence of this diagnosis in the previous 183 days (baseline period). ICD-9-CM codes, 582. xx, 583. xx, 585. xx, 586. xx or 588. xx. Start day → the earliest allopurinol initiation date during End day → ICD-9-CM code for incident renal disease losing full Medicare coverage switching of medication date of death end of the study period (31 December 2012). 6

Methods Predictor of interest: new allopurinol versus new febuxostat treatment If a patient had prescriptions for both drugs, then they were considered exposed to the one that was prescribed second. If the patient switched medications, the 30-day latency did not apply and they were immediately classified as exposed to the new medication only. 7

Methods Predictor of interest: new allopurinol versus new febuxostat treatment febuxostat use as the reference category dose Allopurinol daily dose was calculated as the mean daily use → <200, 200–299 and ≥300 mg/day febuxostat daily dose was calculated similarly → 40 and 80 mg/day duration treatment for each episode Duration of allopurinol / febuxostat → 1–180 days, 181 days to 365 days and >1 year → 1–90 days, 91–180 days, 181–365 days and >1-year (Sensitivity analyses ) 8

Methods Statistical analysis Fischer’s exact test propensity score-matched analyses (1:5 for the PSM analyses with greedy matching) Cox proportional hazard regression models sensitivity analyses Huber-White ‘Sandwich’ variance SAS V.9.4. sensitivity analyses (1) adjusting for the presence of gout; (2) adjusting for gout duration; (3) adjusting for colchicine and probenecid use; (4) limiting to patients who never crossed over from allopurinol to febuxostat or vice versa; (5) limited to renal disease codes of ICD-9 codes 582. xx and 585. xx; (6) changing baseline period from 183 days to 365 days. 9

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Results *Multivariable models were adjusted for the following variables to assess independent association of allopurinol versus febuxostat and incident renal disease. Model 1 = ULT type + age + race + gender + Charlson-Romano score + beta-blockers + diuretics + ACE inhibitors + statins. Model 2 = ULT dose + age + race + gender + Charlson-Romano score + beta-blockers + diuretics + ACE inhibitors + statins. Model 3 = ULT use duration + age + race + gender + Charlson-Romano score + beta-blockers + diuretics + ACE inhibitors + statins. Bold indicates statistically significant. ARB, angiotensin receptor blockers; Ref, referent category; ULT, urate-lowering therapy. 15

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Results Allopurinol was independently associated with significantly lower hazard (39%) of incident renal disease (opposite to our hypothesis). We observed a dose–response relationship with increasing allopurinol doses and risk reduction. 17

Results Limitations Our observational study is at potential risk of residual confounding and channelling bias related to the study design. non-availability of laboratory test results in Medicare strengths The sample size was large, >6000 outcome events occurred during exposure to either allopurinol or febuxostat. analyses were adjusted for important confounders/covariates 18

Conclusion Allopurinol was associated with a lower risk of incident renal disease in elderly patients than febuxostat. The association of allopurinol with renal protection was dose-related, and possibly duration-related, with higher reduction of hazard of incident renal disease with higher allopurinol doses. Future studies need to examine the mechanism of this potential renal benefit of allopurinol. 19

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