Suboptimal Gastroprotective Coverage of NSAID Use and the Risk of Upper Gastrointestinal Complications

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) have known associated upper gastrointestinal (UGI) risks . Gastro-protective agents (GPAs) are co-prescribed to lower the risk of UGI complications, but patient adherence is suboptimal. Aim: To study the association between GPA adherence and UGI complications in non-selective (ns)NSAID users ≥ 50 yrs. Methods: A multi-database nested case-control study was conducted using primary care data from the General Practice Research Database (United Kingdom (UK), 1998-2008), the Integrated Primary Care Information database (The Netherlands (NL), 1996-2007) and the Health Search Database (Italy (IT), 2000-2007). The study was nested within a cohort of new nsNSAID users ≥ 50 yrs. Episodes of nsNSAID use were defined as a period of nsNSAID use with gaps between subsequent prescriptions that were no longer than the duration of the previous prescription. Patients could have more than one episode of nsNSAID use during follow-up, but only if at least a 180-day NSAID-free period was present prior to the start of each episode. Cases with UGI complications (UGI bleeding and (un)complicated UGI ulcers) during or within 60 days after nsNSAID use were matched to controls on age, gender, database, and calendar time. Adherence to GPAs was calculated over the most recent episode of nsNSAID use prior to the index date as the proportion of NSAID treatment days covered (PDC) by a GPA prescription. Adjusted odds ratios (OR) with 95% confidence intervals (95%CI) were calculated using multivariate conditional logistic regression analysis. Results: 1,107,266 nsNSAID episodes were counted in the nsNSAID user cohort (UK: 647,615; NL: 78,853, IT: 380,798). In 117,307 (10.6%) of the nsNSAID episodes a GPA was prescribed (UK: 11.6%; NL: 7.8%, IT: 9.5%). Of the GPA users, 4.9% had a PDC ratio <20% (low adherence), 27.0% had a PDC ratio between 20-80% (partial adherence) and 68.1% had a PDC ratio >80% (high adherence). Mean PDC was 0.81±0.28. Twenty-one percent used nsNSAIDs >30 days. In those episodes, mean adherence dropped to 0.66±0.32. Within the nsNSAID+GPA users, we identified 339 cases with an UGI complication (187 UGI bleedings and 152 (un)complicated UGI ulcers). For patients with low adherence, the risk was 1.89 (95%CI 1.09-3.28) for UGI bleeding alone and 2.39 (95%CI 1.66-3.44) for all UGI complications, compared to patients with high adherence. For every 10% decrease in adherence, the risk of UGI bleeding increased by 6% (OR: 1.06, 95%CI: 1.01-1.12) and the risk of all UGI complications increased by 9% (OR 1.09, 95%CI: 1.05-1.13). Conclusions: The risk of UGI complications in nsNSAID users significantly depends on the level of GPA adherence. This suggests that improvement of GPA adherence could be beneficial in reducing nsNSAIDrelated UGI complications.