Reference: Ann Intern Med. 2022 Apr;175(4):461-470
Attacks of gouty arthritis can cause considerable pain, disability, and sometimes worsening of underlying chronic kidney disease (CKD). Elevated uric acid levels are independently associated with progression of CKD. Urate lowering therapies have been proposed to potentially mitigate the risk of CKD progression, with mixed results. However, two recent randomized trials that evaluated allopurinol for the treatment of hyperuricemia in the absence of gout in patients with CKD stage 3 or 4 and type 1 diabetes reported a possibly increased risk of all cause mortality in those treated with the drug. Faced with claims of potentially serious harms from a commonly prescribed medication, a group of investigators evaluated all-cause mortality related to allopurinol in patients with gout.
Investigators conducted a retrospective cohort study using 2000-2018 data from the United Kingdom’s The Health Improvement Network (THIN) database linked to National Health Service vital information. Patients aged 40-89 with gout and CKD 3 or worse were included. At baseline, patients prescribed allopurinol were generally sicker, had higher serum uric acid levels (SU), poorer renal function, and more prescriptions. After propensity matching 5,277 allopurinol initiators to non-initiators, the groups were similar with a mean age of 74 years, most used alcohol currently (76%), and had diagnoses of CKD 3, hypertension, and ischemic heart disease.
The rate of the primary outcome of all-cause mortality at 5 years was lower among allopurinol initiators compared to non-initiators (4.9 per 100 person-years vs. 5.8, respectively, hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.77-0.93). The 5-year mortality rate was lower among those patients who achieved the target SU of < 0.36 mmol/L (6.5 mg/dL) within 1 year of allopurinol initiation as compared to those patients who did not achieve this target, although the differences were within the 95% confidence intervals (HR 0.87, 95% CI 0.75-1.01).
When patients come in concerned about headlines describing potential harm from a medication, it’s tempting to react first and analyze later. This study was designed to find out if allopurinol increased mortality in patients with gout. The findings provide no plausible evidence that allopurinol increases mortality, and shows that it may in fact reduce mortality in patients being treated for gout. When applying new evidence, clinicians must consider the study population. Patients with clinical gout were excluded from both the previously published randomized trials. Additionally, the primary outcome of interest in both trials was disease-oriented: change in glomerular filtration rate. The secondary outcome of mortality was numerically higher in the allopurinol groups but was not statistically significant in either trial. This cohort study does have some limitations of its own, primarily the usual suspect of unmeasured confounders and lack of generalizability given the UK cohort. Moreover, there was a lack of detailed demographic information provided, and so the effect of allopurinol in a broader population who may be at higher or lower risk for gout or CKD remains uncertain. However, based upon the available evidence, the data indicate clinicians should focus on patient-oriented outcomes that matter. In this case, allopurinol appears to be safe among those with clinical gout. But proceed with caution when relying on the biologic basis of uric acid lowering therapy in patients with isolated hyperuricemia and no clinical gouty arthritis.
For more information, see the topic Hyperuricemia and Gout in Chronic Kidney Disease in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Carina Brown, MD, Assistant Professor at Cone Health Family Medicine Residency. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Katharine DeGeorge, MD, MS, Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Dan Randall, MD, Deputy Editor at DynaMed; Nicole Jensen, MD, Family Physician at WholeHealth Medical; Vincent Lemaitre, PhD, Senior Medical Writer at DynaMed; and Sarah Hill, MSc, Associate Editor at DynaMed.