Risk of Acute Cerebrovascular and Cardiovascular Events Among Users of Acetaminophen or an Acetaminophen-Codeine Combination in a Cohort of Patients with Osteoarthritis: A Nested Case-Control Study

Pharmacotherapy. 2015 Oct;35(10):899-909. doi: 10.1002/phar.1646.


Study objective: To determine whether acetaminophen or an acetaminophen-codeine combination is associated with an increased risk of acute cerebrovascular and cardiovascular events (ACCEs) in patients with osteoarthritis.

Design: Nested case-control study.

Data source: Health Search IMS Health Longitudinal Patient Database.

Patients: A total of 36,754 adults with a diagnosis of osteoarthritis and an incident (first-time) prescription of nonsteroidal antiinflammatory drugs (NSAIDs) between January 2002 and June 2012 were identified; of these patients, cases were defined as those who had a diagnosis of an ACCE during the follow-up period (index date was the date of ACCE diagnosis; 2182 cases). For each case, up to five controls were randomly selected who were matched based on age, sex, month and year of cohort entry, and duration of follow-up (10,301 controls). Matched controls were assigned the same index date as their respective cases.

Measurements and main results: For each case and matched controls, all prescriptions of acetaminophen-containing medicines filled during follow-up were identified. The risk of ACCEs was investigated with respect to the recency of use of acetaminophen and/or an acetaminophen-codeine combination. Patients were classified as current (0-90 days preceding index date), recent (91-180 days), or past (181-365 days) acetaminophen users, or nonusers (longer than 365 days), with nonusers representing the reference category. Conditional logistic regression was estimated to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Of the 36,754 patients with osteoarthritis and newly prescribed NSAIDs, the incidence rate of ACCEs was 117.6 per 10,000 person-years. No significant association between exposure to acetaminophen-containing medications and ACCEs was observed in current (OR 1.22, 95% CI 0.96-1.55), recent (OR 1.12, 95% CI 0.80-1.55), or past users (OR 1.13, 95% CI 0.86-1.48). A secondary analysis evaluating exposure to acetaminophen monotherapy or acetaminophen-codeine combination therapy showed similar results for current users.

Conclusion: Our findings indicate that no association can be made between the use of acetaminophen and/or an acetaminophen-codeine combination and the occurrence of ACCEs. This information contributes to support clinicians in the choice of acetaminophen therapy for osteoarthritis-related pain, especially in those patients presenting with cerebrovascular and cardiovascular morbidities or related risk factors.

Keywords: acetaminophen; cardiovascular events; codeine; drug safety; myocardial infarction; stroke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / administration & dosage
  • Acetaminophen / adverse effects
  • Acetaminophen / therapeutic use*
  • Aged
  • Aged, 80 and over
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Cardiovascular Diseases / epidemiology*
  • Case-Control Studies
  • Cerebrovascular Disorders / epidemiology
  • Codeine / administration & dosage
  • Codeine / adverse effects
  • Codeine / therapeutic use*
  • Cohort Studies
  • Drug Combinations
  • Female
  • Humans
  • Logistic Models
  • Male
  • Middle Aged
  • Odds Ratio
  • Osteoarthritis / drug therapy*
  • Risk Factors


  • Anti-Inflammatory Agents, Non-Steroidal
  • Drug Combinations
  • acetaminophen, codeine drug combination
  • Acetaminophen
  • Codeine