Non-Steroidal Anti-Inflammatory Drug Use and Risk of Atrial Fibrillation or Flutter

Population Based Case-Control Study

Morten Schmidt; Christian F Christiansen; Frank Mehnert; Kenneth J Rothman; Henrik Toft Sørensen



In This Article


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.


Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammatory conditions and pain.[1] By inhibiting cyclo-oxygenase (COX)-1 mediated production of prostaglandins,[1] non-selective NSAIDs are known to cause gastrointestinal toxicity[1] and a variety of nephrotoxic syndromes.[2] An alternative is selective COX 2 inhibitors, available in the form of older or newer agents.[3] The newer COX 2 inhibitors, introduced into clinical practice in 1998, were developed as NSAIDs with an improved gastrointestinal side effect profile.[1] The cardiovascular safety of all marketed newer COX 2 inhibitors requires thorough evaluation in view of the increased cardiovascular[4,5,6] and renal risk[2] reported for several of these drugs.

Atrial fibrillation is the most common rhythm disorder observed in clinical practice. It more than doubles in prevalence during each advancing decade of life, from 0.5% at age 50-59 years to above 10% at age 80-89 years.[7] It is associated with increased mortality and morbidity, mainly due to haemodynamic impairments that exacerbate or even cause heart failure,[8] and a threefold to fourfold increased risk of thromboembolic stroke.[9]

Use of NSAIDs may increase the risk of atrial fibrillation through its adverse renal effects—for example, fluid retention, electrolyte disturbances, and blood pressure destabilisation [2,6]—but the evidence for such effects is limited.[10,11] Although no original research has been published on COX 2 inhibitors and atrial fibrillation, a meta-analysis summarised data from 114 clinical trials and found that rofecoxib was associated with an increased risk of cardiac arrhythmias (relative risk 2.90, 95% confidence interval 1.07 to 7.88).[10] Because the meta-analysis included only 286 incident arrhythmias, precision was low and risk of arrhythmia subtypes such as atrial fibrillation could not be examined.[10] Recently, traditional NSAIDs (that is, non-selective NSAIDs and older COX 2 inhibitors) have been associated with increased risk of chronic atrial fibrillation (incidence rate ratio 1.44, 1.08 to 1.91).[11]

Any confirmed association between use of NSAIDs and atrial fibrillation would have major clinical and public health implications. Older people are of special concern because the prevalence of use of NSAIDs and the incidence of atrial fibrillation increase with age. To address the limitations of the existing literature, we conducted a large population based case-control study examining whether and to what extent use of NSAIDs increases the risk of atrial fibrillation or flutter.


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