Safety of colchicine or NSAID prophylaxis when initiating allopurinol for gout: propensity score-matched cohort studies
Problem
Gout is the most common form of inflammatory arthritis. Urate lowering therapy, most commonly prescribed in primary care, is used in the treatment of gout to lower serum urate levels and reduce the frequency of flares. initiating urate-lowering therapy for gout commonly triggers a gout flare and hence co-prescription of colchicine or non-steroidal anti-inflammatory drug (NSAID) prophylaxis is recommended. However, little is known about the incidence of adverse events associated with prophylaxis. We aimed to determine the risk of adverse events severe enough to warrant seeking healthcare associated with colchicine or NSAID prophylaxis when initiating allopurinol for gout.
Approach
We conducted two matched retrospective cohort studies, using linked data from the Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) datasets. Adults aged ≥18 years with a Read code for gout and a new allopurinol prescription between 1997 and 2016 were identified. We compared those prescribed (1) colchicine or (2) NSAID prophylaxis with those prescribed no prophylaxis, individually matched by age, sex and propensity to receive prophylaxis, to reduce the impact of confounding by indication. Adverse events were identified in CPRD and HES using Read and ICD10 codes respectively. Associations between colchicine or NSAID prophylaxis and the first occurrence of each outcome were investigated using mixed effects Cox proportional hazards models. CPRD Gold and Aurum datasets were analysed separately and then combined using inverse variance fixed-effects two-stage individual patient data meta-analysis.
Findings
13,945 individuals who initiated allopurinol with colchicine prophylaxis were matched to 13,945 who initiated without prophylaxis (mean age 63.62 years (95%CI 63.54, 63.70); 78% male). Diarrhoea was the most common adverse event in the colchicine group, followed by nausea/vomiting, myocardial infarction (MI), neuropathy, myalgia, and bone marrow suppression. Diarrhoea (Hazard Ratio 2.22 (95% CI 1.83, 2.69)), MI (1.55 (1.10, 2.17)), neuropathy (4.75 (1.20, 18.76)), myalgia (2.64 (1.45, 4.81)), and bone marrow suppression (3.29 (1.43, 7.58)) were significantly more common with colchicine prophylaxis compared with no prophylaxis.22,880 individuals who initiated allopurinol with NSAID prophylaxis were matched to 22,880 who initiated without prophylaxis (mean age 63.34 years (95%CI 63.26, 63.42); 78% male). Angina (Hazard Ratio 1.62 (95% CI 1.38, 1.90)), acute kidney injury (1.49 (1.14, 1.96)), MI (1.82 (1.37, 2.43)), and peptic ulcer disease (2.03 (1.34, 3.07)) were significantly more common with NSAID prophylaxis than without.
Consequences
Gastrointestinal, cardiorenal, myoneuropathic and haematological adverse events were associated with prophylaxis, although absolute event rates were low. This information can inform treatment decisions and choice of colchicine or NSAID for prophylaxis when initiating allopurinol.