title: Risk of ischemic stroke associated with non-steroidal anti-inflammatory drugs and paracetamol: a population-based case-control study.
abstract: 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.
authors.affiliation: Clinical Pharmacology Unit, University Hospital "Príncipe de Asturias", Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: García-Poza
authors.forename: F J
authors.initials: FJ
authors.lastname: de Abajo
authors.forename: M J
authors.initials: MJ
authors.lastname: Gil
authors.forename: A
authors.initials: A
authors.lastname: Chacón
authors.forename: V
authors.initials: V
authors.lastname: Bryant
authors.forename: L A
authors.initials: LA
authors.lastname: García-Rodríguez
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D002545:Brain Ischemia / Q000139:chemically induced*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011159:Population Surveillance; D012307:Risk Factors; D020521:Stroke / Q000139:chemically induced*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000082:Acetaminophen
keywords: NSAIDs; adverse drug reaction; cerebrovascular accident; paracetamol; stroke