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.
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.


METHODS
Nested case-control study.


METHODS
Health Search IMS Health Longitudinal Patient Database.


METHODS
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.


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.


CONCLUSIONS
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.
Epidemiology Unit, Regional Agency for Healthcare Services of Tuscany, Florence, Italy.
Giuseppe
G
Roberto
Health Search, Italian College of General Practitioners and Primary Care, Florence, Italy.
Monica
M
Simonetti
Department of Medical and Surgical Sciences - Pharmacology Unit, University of Bologna, Bologna, Italy.
Carlo
C
Piccinni
Italian College of General Practitioners and Primary Care, Florence, Italy.
Pier
P
Lora Aprile
Health Search, Italian College of General Practitioners and Primary Care, Florence, Italy.
Iacopo
I
Cricelli
Department of Anesthesia and Postoperative Intensive Care Unit, "Istituti ortopedici Rizzoli", Bologna, Italy.
Andrea
A
Fanelli
Health Search, Italian College of General Practitioners and Primary Care, Florence, Italy.
Claudio
C
Cricelli
Health Search, Italian College of General Practitioners and Primary Care, Florence, Italy.
Francesco
F
Lapi
D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000453:epidemiology*; D016022:Case-Control Studies; D002561:Cerebrovascular Disorders / Q000453:epidemiology; D003061:Codeine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015331:Cohort Studies; D004338:Drug Combinations; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010003:Osteoarthritis / Q000188:drug therapy*; D012307:Risk Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004338:Drug Combinations; C526278:acetaminophen, codeine drug combination; D000082:Acetaminophen; D003061:Codeine
acetaminophen; cardiovascular events; codeine; drug safety; myocardial infarction; stroke