• Results from case-control studies suggest that nonselective NSAIDs and COX-2 inhibitors are associated with an increased risk of atrial fibrillation, with the highest risk evident for new and long-term users, particularly older persons and those with a history of chronic kidney disease.
• This association has important clinical implications because these medications are used so often to treat inflammatory conditions and pain, particularly for older patients and those with a history of hypertension or heart failure.
  

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Nonsteroidal anti-inflammatory drugs (NSAIDs), including nonselective NSAIDs and cyclooxygenase-2 (COX-2) inhibitors, frequently are prescribed for the management of pain associated with musculoskeletal conditions and injuries, as well as other sources of mild to moderate pain and inflammation. In fact, an estimated 5% of all physician appointments in the United States involve a prescription for NSAIDs.¹ A recent meta-analysis of 31 trials enrolling 116,429 patients examined the risk of cardiovascular events associated with NSAIDs.¹ When compared to placebo, significantly increased risks of myocardial infarction, stroke, cardiovascular mortality, and death were attributed to NSAID use.¹ Of the NSAIDs studies, naproxen was associated with the lowest risk of adverse cardiovascular events.¹

The relationship between the use of NSAIDs and risk of atrial fibrillation (AF) is not yet clearly understood, although the adverse renal effects associated with NSAIDs, such as fluid retention, electrolyte imbalances, and blood pressure variations, are thought to play a role in AF.² A meta-analysis that examined the relationship between COX-2 inhibitors and risk of AF evaluated data from 114 trials and reported that rofecoxib was associated with a significantly higher rate of cardiac arrhythmias (relative risk [RR], 2.90; 95% CI, 1.07-7.88). However, the analysis was limited by a low number of arrhythmia events.³

A recent analysis of approximately 3 million patients in the United Kingdom General Practice Research Database revealed that current use of NSAIDs was associated with a RR of 1.44 (95% CI, 1.08-1.91) for chronic AF. Risk declined as more time elapsed since last use of NSAIDs, while risk increased with longer duration of use. The RR for chronic AF was 1.57 (95% CI, 1.15-2.15) for patients taking NSAIDs for more than 30 days, compared with 1.80 (95% CI, 1.20-2.72) among those who used NSAIDs for more than 1 year. No relationship between NSAID therapy and risk of paroxysmal AF was observed, with the exception of patients who used NSAIDs for more than 1 year (RR, 1.74; 95% CI, 1.11-2.71).⁴

A population-based, case-control study further evaluated whether NSAIDs increased the risk of AF or flutter. The analysis included 32,602 individuals with a first inpatient or outpatient hospital diagnosis of AF or flutter and 325,918 population controls. Compared with no use of NSAIDs, the adjusted incidence rate ratio (IRR) among cases was 1.17 (95% CI, 1.10-1.24) for current nonselective NSAID use. The IRR increased to 1.27 (95% CI, 1.20-1.34) for those who used COX-2 inhibitors, with no significant differences in risk associated with newer versus older COX-2 inhibitors.²

Notably, new users of nonselective NSAIDs and COX-2 inhibitors were at highest risk of AF or flutter. The IRR for new users of nonselective NSAIDs was 1.46 (95% CI, 1.33-1.62) and 1.71 (95% CI, 1.56-1.88) for COX-2 inhibitors. Evaluation of the incidence of AF or flutter by type of NSAID for new users revealed that the risk was greatest for celecoxib (1.83; 95% CI, 1.44-2.34) and lowest for ibuprofen (1.43; 95% CI, 1.28-1.59) and naproxen (1.44; 95% CI, 0.97-2.12).² Importantly, elderly patients taking NSAIDs were at greatest risk of AF or flutter. In addition, those with chronic kidney disease were at increased risk, with an adjusted IRR of 2.87 (95% CI, 1.53-5.38) for new users of COX-2 inhibitors and 1.75 (95% CI, 1.11-2.77) for long-term users of nonselective NSAIDs. Similarly, the adjusted IRR for patients with rheumatoid arthritis who were new users of a COX-2 inhibitor was 2.49 (95% CI, 1.40-4.42) and 1.44 (95% CI, 1.01-2.03) for long-term users of nonselective NSAIDs.²

As we review these findings, it is important to acknowledge the potential for methodological limitations of these case-control studies, including the possible effects of unmeasured confounders that might affect study results. In addition, the specific biologic mechanism to explain the association between NSAIDs and risk of AF is not yet understood, although one proposed explanation suggests that an underlying inflammatory condition increases both the risk of AF and the use of NSAIDs. Alternatively, it has been suggested that NSAIDs provoke disorders such as heart failure and hypertension, which can lead to AF.⁵

With these cautions in mind, evidence from these studies suggest that AF is an additional cardiovascular risk associated with NSAIDs,^2,5 with the strongest association evident for new users and individuals who take NSAIDs for longer periods of time. These findings have clinically significant implications due to the high rate of administration of NSAIDs to treat pain and inflammation associated with a wide variety of musculoskeletal and other conditions. This is particularly important for older adults, who are at increased risk of AF by virtue of their advanced age. Of greatest concern, of course, are older patients who have been diagnosed with hypertension or heart failure and are already at increased risk for the adverse effects of NSAIDs because of these conditions.⁵

Published: 03/14/2013

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