Cause-Specific Cardiovascular Risk Associated with Nonsteroidal Anti-Inflammatory Drugs among Myocardial Infarction Patients - A Nationwide Study Anne-Marie Schjerning Olsen 1 *, Emil L. Fosbøl 1,3 , Jesper Lindhardsen 1 , Charlotte Andersson 1 , Fredrik Folke 1 , Mia B. Nielsen 1 , Lars Køber 2 , Peter R. Hansen 1 , Christian Torp-Pedersen 1 , Gunnar H. Gislason 1 1 Department of Cardiology, Copenhagen University Hospital, Hellerup, Denmark, 2 Department of Cardiology, the Heart Centre, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark, 3 Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, United States of America Abstract Background: Non steroidal anti-inflammatory drugs (NSAIDs) increase mortality and morbidity after myocardial infarction (MI). We examined cause-specific mortality and morbidity associated with NSAIDs in a nationwide cohort of MI patients. Methods and Results: By individual-level linkage of nationwide registries of hospitalization and drug dispensing from pharmacies in Denmark, patients aged .30 years admitted with first-time MI during 1997–2009 and their subsequent NSAID use were identified. The risk of three cardiovascular specific endpoints: cardiovascular death, the composite of coronary death and nonfatal MI, and the composite of fatal and nonfatal stroke, associated with NSAID use was analyzed by Cox proportional hazard analyses. Of 97,698 patients included 44.0% received NSAIDs during follow-up. Overall use of NSAIDs was associated with an increased risk of cardiovascular death (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.36–1.49). In particular use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with increased risk of cardiovascular death (HR 1.96 [1.79–2.15] and HR1.66 [1.44–1.91], respectively) with a dose dependent increase in risk. Use of ibuprofen was associated with increased risk of cardiovascular death (HR 1.34[1.26–1.44]), whereas naproxen was associated with the lowest risk of (e.g., HR 1.27[1.01–1.59]. Conclusion: Use of individual NSAIDs is associated with different cause-specific cardiovascular risk and in particular rofecoxib and diclofenac were associated with increased cardiovascular morbidity and mortality. These results support caution with use of all NSAIDs in patients with prior MI. Citation: Schjerning Olsen A-M, Fosbøl EL, Lindhardsen J, Andersson C, Folke F, et al. (2013) Cause-Specific Cardiovascular Risk Associated with Nonsteroidal Anti- Inflammatory Drugs among Myocardial Infarction Patients - A Nationwide Study. PLoS ONE 8(1): e54309. doi:10.1371/journal.pone.0054309 Editor: Ulrich Thiem, Marienhospital Herne - University of Bochum, Germany Received June 29, 2012; Accepted December 11, 2012; Published January 30, 2013 Copyright: ß 2013 Schjerning Olsen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The study was supported by the Department of Cardiology, Copenhagen University Hospital Gentofte, DK-2900, Denmark, FUKAP. The funding source had no influence on study design, interpretation of the results or the decision to submit the article. Dr. Gislason is supported by an independent research scholarship from the Novo Nordisk Foundation. Competing Interests: The authors have declared that no competing interests exist. * E-mail: amschjerning@gmail.com Introduction Non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with increased cardiovascular risk and previously we have reported an increased risk of all-cause death and myocardial infarction (MI) with use of some NSAIDs among patients with prior MI [1,2,3]. As NSAIDs still are widely used in the general population [4] the cardiovascular risk associated with these agents seems to be a major public health issue, not least as even commonly used NSAIDs such as diclofenac and ibuprofen are associated with increased risk. In some countries these drugs are available as over-the-counter (OTC) drugs, and despite warnings related to unfavorable cardiovascular safety NSAIDs surveys have demonstrated increased sale of painkilling OCT medications in Denmark [5]. Because of the wide availability and use of NSAIDs, awareness of their proper use, dose, and potential side effects is warranted among health care providers as well as in the general population. Data on the cause-specific mortality associated with individual NSAIDs in patients with established cardiovascular disease are sparse. Investigation on specific cardiovascular causes of mortality and morbidity associated with NSAIDs in the highly selected population of prior MI patients can establish further details to the perception of the cardiovascular risk of these agents. Therefore the objective of this study was to clarify the cause- specific cardiovascular mortality and morbidity associated with the use of individual NSAIDs in a cohort of patients with prior MI. Methods Study design The study was a nationwide registerbased cohort study in patients with prior MI in Denmark in the period 1997–2009. PLOS ONE | www.plosone.org 1 January 2013 | Volume 8 | Issue 1 | e54309