WHAT IS ALREADY KNOWN ON THIS SUBJECT• Information from the spontaneous reporting system raised the hypothesis of an increased risk of meningioma in patients treated with high doses of cyproterone acetate (CPA).• Meningiomas are known to be hormone-sensitive tumours and express progesterone receptors and CPA has an anti-androgenic, progestagenic and antigonadotropic effect. • More formal evidence from epidemiological studies is lacking. WHAT THIS STUDY ADDS• This population-based cohort study supports the hypothesis that the exposure to high dose CPA increases the risk of meningioma • The increased risk was observed both in men and women and was only relevant for exposures longer than 1 year. AIMInformation from the spontaneous reporting system raised the hypothesis of an increased risk of meningioma in patients treated with high doses of cyproterone acetate (CPA). The objective of this study was to test the hypothesis of an increased risk of meningioma among users of high dose CPA as compared with non-users in a medical records computerized database. METHODSA retrospective cohort study was performed in a Spanish primary care database (BIFAP). Meningioma incidence rates were compared in patients exposed to high dose CPA (users) with those non-exposed and with those exposed to low dose CPA. Poisson regression analysis was used to estimate the incidence rate ratios after adjusting for age and gender. RESULTSAmong 2474 users of high dose cyproterone (6663 person-years) four meningioma cases were identified, resulting in an incidence rate (IR) of 60.0 (95% CI 16.4, 153.7) per 100 000 person-years, which was significantly higher than that observed among the non-users (IR 6.6; 95% CI 6.0, 7.3) and among women users of low dose cyproterone (IR 0.0, 95% CI upper limit 5.5). After adjusting for age and gender, patients exposed to high dose CPA showed an increased risk of meningioma of 11.4 (95% CI 4.3, 30.8) as compared with non-users. CONCLUSIONSThe results of this study support the hypothesis that the exposure to high dose CPA increases the risk of meningioma.

The risk of nonfatal AMI varied with individual tNSAIDs, duration of treatment and background cardiovascular risk. Paracetamol, metamizole and SYSADOAs did not increase the risk in any of the conditions examined.

To cite this article: Garc ıa-Poza P, de Abajo FJ, Gil MJ, Chac on A, Bryant V, Garc ıa-Rodr ıguez LA. Risk of ischemic stroke associated with non-steroidal anti-inflammatory drugs and paracetamol: a population-based case-control study. J Thromb Haemost 2015; 13: 708-18.Summary. Objective: To assess the risk of non-fatal ischemic stroke associated with non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol. The effects of dose, duration of treatment, background cardiovascular (CV) risk and use of concomitant aspirin were studied. Methods: We performed a population-based case-control study. Patients were considered exposed if they were on treatment within a 30-day window before the index date. We estimated adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) using logistic regression. Results: Two thousand eight hundred and eighty-eight cases and 20 000 controls were included. No increased risk was observed with traditional NSAIDs as a group (OR = 1.03; 95% CI, 0.90-1.19), but results varied across individual agents and conditions of use. An increased risk was found with diclofenac (OR = 1.53; 95% CI, 1.19-1.97), in particular when used at high doses (OR = 1.62; 1.06-2.46), over long-term periods (> 365 days; OR = 2.39; 1.52-3.76) and in patients with a high background CV risk (OR = 1.78; 1.23-2.58), as well as with aceclofenac when used at high doses (OR = 1.67; 1.05-2.67), in long-term treatments (OR = 2.00; 1.14-3.53) and in patients with CV risk factors (OR = 2.33; 1.40-3.87). No association was found with ibuprofen (OR = 0.94; 0.76-1.17) or naproxen (OR = 0.68; 0.36-1.29). The concomitant use of aspirin did not show a significant effect modification. Paracetamol did not increase the risk overall (OR = 0.97; 0.85-1.10) or in patients at high CV risk (OR = 0.94; 0.78-1.14). Conclusions: Diclofenac and aceclofenac increase the risk of ischemic stroke while ibuprofen and naproxen do not. Dose, duration and baseline CV risk, but not aspirin use, appear to modulate the risk. Paracetamol does not increase the risk, even in patients with a high background CV risk.

The increased risk of UGIB associated with NSAIDs was lower than previously reported, which could partly be explained by methodological differences, but a decreasing burden over time of this drug safety problem is suggested. BIFAP has shown to be a valuable tool for pharmacoepidemiological research.

The present study supports the hypothesis that allopurinol is associated with a reduced risk of non-fatal AMI, which seems to be dose-dependent and duration-dependent.