Non-steroidal anti-inflammatory drugs and risk of myocardial infarction adjusting for use of proton pump-inhibitors in patients with no major risk factors: a nested case-control study in the UK Clinical Practice Research Datalink

Aims: Studies have found an increased risk of myocardial infarction (MI) in association with some non-steroidal anti-inflammatory drugs (NSAIDs). We evaluated this association in patients without major cardiovascular risk factors and assessed potential reverse causality bias.

Methods and results: In this nested case-control study of patients aged 40-79 in Clinical Practice Research Datalink GOLD who received at least one NSAID prescription between 2006 and 2019, we found 8639 MI cases and 34 556 matched controls. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for MI comparing NSAID users to non-exposed according to the number and timing of NSAID prescriptions and proton-pump inhibitor (PPI) use. Current diclofenac use was associated with a two-fold increased risk of MI regardless of duration of use (adjusted OR, 2.08; 95% CI, 1.82-2.38). ORs ranged from 3 to 5 among current and recent diclofenac users newly exposed to PPIs. There was no spike in risk in new current diclofenac users not exposed to PPIs, but ORs rose with increasing prescriptions. The risk of MI in ibuprofen users was concentrated in new PPI users. There was no material increased risk in naproxen users, nor in past users of most NSAIDs in the absence of PPIs.

Conclusion: The risk of MI was elevated in current diclofenac users, particularly in new concomitant PPI users. ORs increased in new users of ibuprofen and PPIs but declined with extended use and were lower in non-PPI users. This suggests that some of the findings may be explained by reverse causality bias.