Risk of acute myocardial infarction with real‐world NSAIDs depends on dose and timing of exposure

• Published in: Pharmacoepidemiology and drug safety Vol. 27; no. 1; pp. 69 - 77
• Main Authors: Bally, Michèle, Beauchamp, Marie‐Eve, Abrahamowicz, Michal, Nadeau, Lyne, Brophy, James M.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.01.2018
• Subjects: acute myocardial infarction (MI); Aged; Aged, 80 and over; Anti-inflammatory agents; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - adverse effects; Case-Control Studies; Celecoxib; cumulative effects; Databases, Factual - statistics & numerical data; Datasets as Topic; Diclofenac; Dose-Response Relationship, Drug; Drug dosages; Exposure; Female; Follow-Up Studies; Health risk assessment; Heart attacks; Hospitalization - statistics & numerical data; Humans; Ibuprofen; Inflammation; Male; Myocardial infarction; Myocardial Infarction - chemically induced; Myocardial Infarction - epidemiology; Myocardial Infarction - therapy; Naproxen; Nonsteroidal anti-inflammatory drugs; nonsteroidal anti‐inflammatory drugs (NSAIDs); pharmacoepidemiology; Pharmacovigilance; Quebec - epidemiology; Risk Assessment; Risk Factors; Rofecoxib; Time Factors; Quebec; acute myocardial infarction (MI); nonsteroidal anti-inflammatory drugs (NSAIDs); cumulative effects; pharmacoepidemiology
• ISSN: 1053-8569; 1099-1557
• DOI: 10.1002/pds.4358

Purpose Real‐life use of nonsteroidal anti‐inflammatory drugs (NSAIDs) is dynamic. This study aimed to characterize the temporal association between time‐varying NSAID exposure and acute myocardial infarction (MI). Methods Nested case‐control analyses were conducted on a Quebec administrative health cohort. NSAID dose, confounders, and outcome status were determined for each day of follow‐up. To better account for dose and timing of past exposures, flexible weighted cumulative exposure models were also fitted. Results The cohort consisted of 233 816 older adults including 21 256 acute MI cases. Dose‐related increased risks of MI were found with current use of all NSAIDs. In models not accounting for duration of use, ORs (95%CI) for the most common current daily dose vs. no current exposure were: celecoxib 200 mg: 1.16 (1.10, 1.22), diclofenac 150 mg: 1.59 (1.38, 1.84), ibuprofen 1200 mg: 1.42 (1.17, 1.74), naproxen 750 mg: 1.38 (1.21, 1.58), and rofecoxib 25 mg: 1.54 (1.43, 1.66). Weighted cumulative exposure models confirmed that all NSAIDs—including naproxen—are associated with an increased risk of MI and suggested that doses taken up to 3 weeks ago for rofecoxib, ibuprofen, and naproxen and up to 75 days ago for diclofenac and celecoxib may contribute to the current MI risk. However, the celecoxib risk seems to require continuous use for more than 30 days, whereas for other NSAIDs, a heightened MI risk occurs within 7 days. Conclusions Weighted cumulative exposure analysis uncovered NSAID‐specific differences in the immediate MI risk and how this risk seems to accumulate. KEY POINTS Accurate assessment of drug safety requires an etiologically correct model encompassing all relevant aspects of exposure. Weighted cumulative exposure models suggest that the relative importance of past doses on the risk of MI differs among NSAIDs. All common NSAIDs are associated with an increased MI risk. Celecoxib MI risk seems to depend on continuously using the drug for more than 30 days, whereas for ibuprofen, rofecoxib, diclofenac, and naproxen, a heightened MI risk occurs within 7 days of use.