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Non-steroidal anti-inflammatory drug use and risk of atrial fibrillation or flutter: population based case-control study

BMJ 2011; 343 doi: (Published 04 July 2011) Cite this as: BMJ 2011;343:d3450
  1. Morten Schmidt, junior research fellow1,
  2. Christian F Christiansen, senior registrar1,
  3. Frank Mehnert, biostatistician1,
  4. Kenneth J Rothman, professor23,
  5. Henrik Toft Sørensen, professor1
  1. 1Department of Clinical Epidemiology, Aarhus University Hospital, 8200 Aarhus N, Denmark
  2. 2RTI Health Solutions, Research Triangle Institute, Research Triangle Park, NC, USA
  3. 3Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA
  1. Correspondence to: M Schmidt msc{at}
  • Accepted 4 March 2011


Objectives To examine the risk of atrial fibrillation or flutter associated with use of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) or selective cyclo-oxygenase (COX) 2 inhibitors.

Design Population based case-control study using data from medical databases.

Setting Northern Denmark (population 1.7 million).

Participants 32 602 patients with a first inpatient or outpatient hospital diagnosis of atrial fibrillation or flutter between 1999 and 2008; 325 918 age matched and sex matched controls based on risk-set sampling.

Main outcome measures Exposure to NSAID use at the time of admission (current use) or before (recent use). Current use was further classified as new use (first ever prescription redemption within 60 days before diagnosis date) or long term use. We used conditional logistic regression to compute odds ratios as unbiased estimates of the incidence rate ratios.

Results 2925 cases (9%) and 21 871 controls (7%) were current users of either non-selective NSAIDs or COX 2 inhibitors. Compared with no use, the incidence rate ratio associating current drug use with atrial fibrillation or flutter was 1.33 (95% confidence interval 1.26 to 1.41) for non-selective NSAIDs and 1.50 (1.42 to 1.59) for COX 2 inhibitors. Adjustments for age, sex, and risk factors for atrial fibrillation or flutter reduced the incidence rate ratio to 1.17 (1.10 to 1.24) for non-selective NSAIDs and 1.27 (1.20 to 1.34) for COX 2 inhibitors. Among new users, the adjusted incidence rate ratio was 1.46 (1.33 to 1.62) for non-selective NSAIDs and 1.71 (1.56 to 1.88) for COX 2 inhibitors. Results for individual NSAIDs were similar.

Conclusions Use of non-aspirin NSAIDs was associated with an increased risk of atrial fibrillation or flutter. Compared with non-users, the association was strongest for new users, with a 40-70% increase in relative risk (lowest for non-selective NSAIDs and highest for COX 2 inhibitors). Our study thus adds evidence that atrial fibrillation or flutter needs to be added to the cardiovascular risks to be considered when prescribing NSAIDs.


  • Contributors: MS, CFC, and HTS conceived the study idea. All authors designed the study. FM and HTS collected the data. MS, CFC, and HTS reviewed the literature. MS, CFC, FM, and HTS analysed the data. All authors participated in the interpretation of the findings. MS wrote the initial draft. All authors participated in critical revision of the manuscript for important intellectual content and approved the final version. HTS is the guarantor.

  • Funding: The study was supported by the Danish Medical Research Council (grant 271-05-0511), the Clinical Epidemiological Research Foundation, Denmark, the Danish Heart Association, and an Aarhus University scholarship. Department of Clinical Epidemiology collaborates within the EU Seventh Framework Programme: Arrhythmogenic potential of drugs (ARITMO). None of the funding sources had a role in the study design, conduct, analysis, or reporting.

  • Competing interests: All authors have completed the Unified Competing Interest form at (available on request from the corresponding author) and declare: no support from any company for the submitted work, although the Department of Clinical Epidemiology is involved in studies with funding from various companies as research grants to (and administered by) Aarhus University, none of which has any relation to the present study; no relation with organisations that might have an interest in the submitted work in the previous three years, except KJR, who received payment from Bayer for a lecture on venous thromboembolism; no non-financial interests that may be relevant to the submitted work.

  • Ethical approval: This study was approved by the Danish Data Protection Agency (record no 2004-41-4693) and the Aarhus University Hospital registry board. The study does not involve any contact with patients or any intervention, and it is not necessary to procure permission from the Danish Scientific Ethics Committee.

  • Data sharing: No additional data available.

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