Non-steroidal anti-inflammatory drugs and risk of cerebrovascular events in patients with osteoarthritis: a nested case-control study

Intern Emerg Med. 2016 Feb;11(1):49-59. doi: 10.1007/s11739-015-1288-3. Epub 2015 Aug 14.


Recent studies show that the risk of cardiovascular adverse events for certain traditional non-steroidal anti-inflammatory drugs (NSAIDs) is similar to that of rofecoxib. While these results are focused on ischemic cardiomyopathy, there is little evidence concerning the risk of ischemic stroke/transient ischemic attack and hemorrhagic stroke. Additionally, there is no information on nimesulide and ketoprofen, the most frequently prescribed NSAIDs in Italy, along with diclofenac. This study aims to determine whether the use of NSAIDs is associated with an increased risk of cerebrovascular events in Italy. We performed a case-control analysis nested in a cohort of patients with osteoarthritis between 2002 and 2011 who were newly treated with NSAIDs. The patients were followed until December 31, 2012. Conditional logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (95% CI) of cerebrovascular events (index date) associated with current (until 30 days before the index date), recent (31-365 days) and past (>365 days) use of NSAIDs. Within a cohort of 29,722 patients, 1566 cases (1546 matched with controls) were identified (incidence rate = 11.0/1000 person-years). The overall rate of cerebrovascular event was not elevated with current NSAIDs overall when compared with past use. Among individual NSAIDs, diclofenac and ketoprofen were the molecules significantly associated with an increased rate of cerebrovascular events (OR = 1.53; 95% CI 1.04-2.24; OR = 1.62; 95% CI 1.02-2.58, respectively). The most frequent event was hemorrhagic stroke following the use of ketoprofen (OR = 2.09; 95% CI 1.05-4.15). Diclofenac and ketoprofen seemed to increase the risk of cerebrovascular events. These findings might influence the choice of NSAIDs according to patient characteristics.

Keywords: Cerebrovascular events; Drug safety; Non-steroidal anti-inflammatory drugs; Osteoarthritis.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Case-Control Studies
  • Cerebrovascular Disorders / epidemiology*
  • Female
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Osteoarthritis / complications
  • Osteoarthritis / drug therapy*


  • Anti-Inflammatory Agents, Non-Steroidal