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

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Abstract
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.

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