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NSAIDs (for example, ibuprofen) Linked to Afib Risk (heart condition)
 
 
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"An association between use of NSAIDs and atrial fibrillation has important clinical and public health implications because of the high prevalence of use of these agents, particularly among older adults, and the increasing prevalence of atrial fibrillation with advancing age....Schmidt and colleagues describe an association between the use of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) or selective cyclo-oxygenase-2 (COX 2) inhibitors and atrial fibrillation or flutter.....In 2008, an expert panel convened by the National Heart, Lung, and Blood Institute highlighted that although treatments for atrial fibrillation have been studied extensively, prevention has received relatively little attention.4 Modifiable risk factors include hypertension, diabetes, obesity, and smoking.5 Predisposing clinical conditions include heart failure, myocardial infarction, valvular heart disease, thyroid disease, and sleep disordered breathing. These risk factors and predisposing conditions probably interact with various non-modifiable risk factors including age, sex, race, and genetic factors."

"Atrial fibrillation is the most commonly sustained rhythm disorder observed in clinical practice, and NSAIDs are among the most widely used drugs worldwide. No previous study has examined whether use of COX 2 inhibitors increases the risk of atrial fibrillation."

"Our study thus adds evidence that atrial fibrillation or flutter need to be added to the cardiovascular risks under consideration when prescribing NSAIDs. .....In this large population based case-control study, we found that patients starting treatment with non-aspirin NSAIDs were at increased risk of atrial fibrillation or flutter compared with those not using NSAIDs. The relative risk increase was 40-70%-equivalent to approximately four extra cases per year of atrial fibrillation per 1000 new users of non-selective NSAIDS and seven extra cases per year of atrial fibrillation per 1000 new users of COX 2 inhibitors.7 The risk appeared highest in older people. Patients with chronic kidney disease or rheumatoid arthritis were at particularly increased risk when starting treatment with COX 2 inhibitors."


"Our results may be affected by confounding from unmeasured variables, particularly by underlying inflammatory conditions leading to use of NSAIDs. Although our estimates did not change when patients with systemic inflammatory conditions were excluded in a subanalysis, we cannot rule out that new users may have more severe underlying inflammation, which may increase the risk of atrial fibrillation."

"EDITORIAL, see below full text: The risk is unproved, but NSAIDs should be used with caution in high risk patients anyway....
An association between use of NSAIDs and atrial fibrillation has important clinical and public health implications because of the high prevalence of use of these agents, particularly among older adults, and the increasing prevalence of atrial fibrillation with advancing age. The validity of the study's findings must be carefully considered, however, because case-control studies are susceptible to unmeasured confounders, potentially limiting the inferences that can be drawn from the results......The association between NSAIDs and atrial fibrillation does not imply a cause and effect relation. One proposed explanation for the association is: "the existence of an underlying inflammatory condition, increasing the risk of AF [atrial fibrillation] on the one hand and prompting the use of NSAIDs on the other."10 Perhaps a more likely scenario is that these agents trigger or exacerbate clinical conditions, such as heart failure and hypertension, that lie along the causal pathway of atrial fibrillation.....What should clinicians do in practice in the light of current evidence? With uncertainty regarding a plausible biological mechanism, the susceptibility of case-control studies to unmeasured confounders, and inconsistent results in the two studies performed to date, a cautious approach seems warranted in applying the study's results to the care of patients. However, NSAIDS (non-selective NSAIDs and COX 2 inhibitors) should continue to be used very cautiously in older patients with a history of hypertension or heart failure, who are already at high risk for adverse effects of these drugs, regardless of whether an association between NSAIDs and atrial fibrillation actually exists."

"The median age was 75 years, and 54% were male. Among cases, 80.1% had been diagnosed previously with cardiovascular disease compared with 58.7% of controls. Cancer, chronic obstructive pulmonary disease or asthma, diabetes mellitus, glucocorticoid use, hyperthyroidism, and osteoarthritis were also more common among cases than controls."

"Use of NSAIDs may increase the risk of atrial fibrillation or flutter through renal and cardiovascular related actions. Five per cent of patients treated with NSAIDs experience nephrotoxic syndromes.2 Both COX enzymes are expressed in distinct anatomic regions of adult kidney tissue.2 Thus, inhibition of synthesis of COX derived prostaglandin impairs inflammation and a variety of physiological processes.2 These changes may induce increases in blood pressure due to expansion of plasma volume, increased peripheral resistance, attenuation of diuretic and antihypertensive drug effects,2 6 and fluctuation of serum potassium as a result of decreased potassium excretion in the distal nephron.2 Thus, the increased risk among new users may be attributable to short term adverse renal effects of NSAIDs, which subsequently trigger atrial fibrillation.24 The finding that patients with chronic kidney disease have a markedly higher risk when starting treatment with COX 2 inhibitors supports this hypothesis.2 6"

"The data indicated that the risk of atrial fibrillation or flutter associated with use of NSAIDs was highest in the elderly....The increased risk was driven by new users.....Among patients with chronic kidney disease, the adjusted incidence rate ratio was 2.87 (1.53 to 5.38) for new users of COX 2 inhibitors and 1.75 (1.11 to 2.77) for long term users of non-selective NSAIDs. Among patients with rheumatoid arthritis, the adjusted incidence rate ratio was 2.49 (1.40 to 4.42) for new users of COX 2 inhibitors and 1.44 (1.01 to 2.03) for long term users of non-selective NSAIDs). Similar to the overall results, the adjusted incidence rate ratio in the secondary analysis restricted to patients without systemic inflammatory conditions was 1.45 (1.29 to 1.63). The adjusted incidence rate ratio for atrial fibrillation or flutter among new drug users was 1.43 (1.28 to 1.59) for ibuprofen, 1.44 (0.97 to 2.12) for naproxen, 1.73 (1.53 to 1.97) for diclofenac, 1.51 (1.17 to 1.95) for etodolac, 1.83 (1.44 to 2.34) for celecoxib, and 1.59 (1.24 to 2.02) for rofecoxib."

MedPage Today
Published: July 07, 2011

Action Points

* In this population-based case-control study, new NSAID users had an increased risk of developing atrial fibrillation or atrial flutter than non-users.

* Important potential confounders, such as obesity, were not measured, and this study does not prove a causal link between NSAID's and atrial fibrillatoin/flutter.

* Although the association described is tenous, it is important to remember that NSAID's can cause significant adverse events and should be prescribed cautiously.

Atrial fibrillation and flutter risk increases with non-steroidal anti-inflammatory drug (NSAID) use, though this case-control study finding drew skepticism.

Current use of a nonselective NSAID was associated with a 33% elevated incidence of atrial fibrillation or flutter (rate ratio 1.33, 95% confidence interval 1.26 to 1.41), Morten Schmidt, a combined MD/PhD student at Aarhus University Hospital in Aarhus, Denmark, and colleagues found.

The link remained significant, though attenuated, with adjustment for age, sex, and atrial fibrillation risk factors (incidence rate ratio 1.17, 95% CI 1.10 to 1.24), the group reported online in BMJ.

The same was true for COX-2 inhibitors, with incidence rate ratios of 1.50 (95% CI 1.42 to 1.59) prior to adjustment and 1.27 after adjustment (95% CI 1.42 to 1.59).

This would translate to an extra four cases of atrial fibrillation per 1,000 new users of nonselective NSAIDs and seven per 1,000 new users of COX-2 inhibitors.

These population-based results supported clinical consideration, Schmidt's group suggested.

"Our study thus adds evidence that atrial fibrillation or flutter needs to be added to the cardiovascular risks to be considered when prescribing NSAIDs," they wrote in the paper.

But "a cautious approach seems warranted in applying the study's results to the care of patients," warned Jerry H. Gurwitz, MD, of the University of Massachusetts Medical School's Meyers Primary Care Institute in Worcester, Mass.

His editorial accompanying the paper cautioned about unmeasured confounding from important clinical factors missing in the study. One example was obesity, which is an established risk factor for atrial fibrillation and also associated with osteoarthritis as one of the most common indications for NSAID use.

The researchers estimated that for an unmeasured confounder that was twice as common among NSAID users as among controls to completely explain the association they saw with atrial fibrillation or flutter, it would have to boost atrial fibrillation or flutter risk at least sixfold.

Gurwitz called this analysis only partially reassuring, noting inconsistent results between the two available studies on the association as another warning signal.

Schmidt's study of 32,602 patients with a first inpatient or outpatient hospital diagnosis of atrial fibrillation or flutter between 1999 and 2008 in population-based medical databases from Northern Denmark turned up the strongest link to NSAIDs in new users rather than with long-term use.

Compared with 325,918 age- and sex-matched controls from the Northern Denmark population, atrial fibrillation or flutter was 1.46-fold more common with a first-ever nonselective NSAID prescription within the 60 days prior to diagnosis (95% CI 1.33 to 1.62).

New users of COX-2 inhibitors were associated with an adjusted incidence rate ratio of 1.71 (95% CI 1.56 to 1.88).

In contrast, a prior study based on the British General Practice Research Database found the greatest risk among long-term rather than new users.

Neither study showed a consistent dose-response relationship, which Gurwitz wrote "makes the association even more tenuous."

Results were similar across the individual NSAIDs.

The association with atrial fibrillation or flutter was more likely to be because of NSAIDs' impact on causal factors, such as heart failure and hypertension, rather than direct causality, he suggested.

But regardless of whether the NSAID association is real or causal, these drugs require careful prescribing in the populations at high risk for atrial fibrillation anyway, he pointed out.

"Non-selective NSAIDs and COX-2 inhibitors should continue to be used very cautiously in older patients with a history of hypertension or heart failure, who are already at high risk for adverse effects of these drugs," the editorial concluded.

The study was supported by the Danish Medical Research Council, the Clinical Epidemiological Research Foundation of Denmark, the Danish Heart Association, and an Aarhus University scholarship.

Schmidt reported having no conflicts of interest to disclose.

Gurwitz reported having no conflicts of interest to disclose.

----------------------------------

BMJ 2011; 343:d3450 doi: 10.1136/bmj.d3450 (Published 4 July 2011)

Cite this as: BMJ 2011; 343:d3450

Research

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

Morten Schmidt junior research fellow 1, Christian F Christiansen senior registrar 1, Frank Mehnert

biostatistician 1, Kenneth J Rothman professor 2 3, Henrik Toft Sorensen professor 1

1Department of Clinical Epidemiology, Aarhus University Hospital, 8200 Aarhus N, Denmark; 2RTI Health Solutions, Research Triangle Institute,

Research Triangle Park, NC, USA; 3Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA

Abstract

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.

Introduction

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 toxicity1 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 cardiovascular4 5 6 and renal risk2 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.

Results

Patient characteristics


Descriptive data are presented in table 1 for the 32 602 cases and 325 918 population controls (web table 1 divides cases and controls according to their use of NSAIDs). Among the cases, 27 984 (85.8%) were diagnosed with atrial fibrillation or flutter during hospital admission, 4220 (12.9%) at an outpatient clinic, and 398 (1.2%) at an emergency department. The median age was 75 years, and 54% were male. Among cases, 80.1% had been diagnosed previously with cardiovascular disease compared with 58.7% of controls. Cancer, chronic obstructive pulmonary disease or asthma, diabetes mellitus, glucocorticoid use, hyperthyroidism, and osteoarthritis were also more common among cases than controls. High dose tablets of ibuprofen, naproxen, and diclofenac, however, were associated with higher risks than low dose tablets (data not shown).

Risk of atrial fibrillation or flutter

As table 2 shows, the age and sex matched 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 compared with non-users. The crude incidence rate ratios, dissolving the matched sets, were similar to the matched incidence rate ratios, indicating that the matched factors were on balance not associated with the exposure. Adjustment for confounders 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. Older and newer COX 2 inhibitors had similar estimates of effect. The increased risk was driven by new users with an adjusted incidence rate ratio of 1.46 (1.33 to 1.62) for non-selective NSAIDs and 1.71 (1.56 to 1.88) for COX 2 inhibitors.

The stratified analyses showed no observable sign of modified measure of effect by sex, osteoarthritis, or systemic connective tissue disease (data not shown). The data indicated that the risk of atrial fibrillation or flutter associated with use of NSAIDs was highest in the elderly (web table 2). Among patients with chronic kidney disease, the adjusted incidence rate ratio was 2.87 (1.53 to 5.38) for new users of COX 2 inhibitors and 1.75 (1.11 to 2.77) for long term users of non-selective NSAIDs (fig 1). Among patients with rheumatoid arthritis, the adjusted incidence rate ratio was 2.49 (1.40 to 4.42) for new users of COX 2 inhibitors and 1.44 (1.01 to 2.03) for long term users of non-selective NSAIDs). Similar to the overall results, the adjusted incidence rate ratio in the secondary analysis restricted to patients without systemic inflammatory conditions was 1.45 (1.29 to 1.63) for new users of non-selective NSAIDs and 1.64 (1.46 to 1.84) for new users of COX 2 inhibitors.

The results for the individual NSAIDs are shown in table 3. The adjusted incidence rate ratio for atrial fibrillation or flutter among new drug users was 1.43 (1.28 to 1.59) for ibuprofen, 1.44 (0.97 to 2.12) for naproxen, 1.73 (1.53 to 1.97) for diclofenac, 1.51 (1.17 to 1.95) for etodolac, 1.83 (1.44 to 2.34) for celecoxib, and 1.59 (1.24 to 2.02) for rofecoxib. In the direct drug comparison (web table 3), no NSAIDs were associated with a lower risk than ibuprofen, and diclofenac in particular conferred higher risk (1.19, 1.00 to 1.40 for new use). The increased effect estimates associated with use of the individual NSAIDs remained raised for both high dose and low dose tablets. High dose tablets of ibuprofen, naproxen, and diclofenac, however, were associated with higher risks than low dose tablets (data not shown).

Supporting the robustness of our findings, the results of the remaining three secondary analyses were similar to the overall results (web tables 4 and 5 show the results for patients without systemic inflammatory conditions). Finally, we estimated that an unmeasured confounder that was twice as frequent among users of NSAIDs as non-users would need to increase the risk of atrial fibrillation or flutter by a factor of six or more to fully explain the results, if no increased risk actually existed (web figure).

Discussion

In this large population based case-control study, we found that patients starting treatment with non-aspirin NSAIDs were at increased risk of atrial fibrillation or flutter compared with those not using NSAIDs. The relative risk increase was 40-70%-equivalent to approximately four extra cases per year of atrial fibrillation per 1000 new users of non-selective NSAIDS and seven extra cases per year of atrial fibrillation per 1000 new users of COX 2 inhibitors.7 The risk appeared highest in older people. Patients with chronic kidney disease or rheumatoid arthritis were at particularly increased risk when starting treatment with COX 2 inhibitors.

Several issues should be considered when interpreting our results. The study's population based design within the setting of a tax supported universal healthcare system largely removed selection biases. The positive predictive value of a diagnosis of atrial fibrillation or flutter has been reported to be as high as 97% in the Danish National Registry of Patients.19 Coding errors were thus unlikely to have had any important influence on our results. We considered cases of atrial fibrillation and flutter together, but our results were driven by atrial fibrillation. Although our findings also related to people treated with cardioversion within one year after first diagnosis, our study was limited by its inability to separate paroxysmal, persistent, and permanent atrial fibrillation.

Data in the prescription database are virtually complete.12 Although we had to use prescription data as a proxy for actual use of NSAIDs, we did not base drug exposure information on written prescriptions,11 but on actual dispensing at pharmacies.12 Requirement of co-payment increased the likelihood of compliance.13 We lacked information on over the counter use of low dose (200 mg/tablet) ibuprofen, which accounted for 30% of total ibuprofen sales and 15% of total NSAID sales during the study period.13 This misclassification of drug exposure would most likely have been non-differential and thus would have biased the effect estimates towards the null. Therefore, to the extent such misclassification occurred, our effect estimates are underestimates.

Our results may be affected by confounding from unmeasured variables, particularly by underlying inflammatory conditions leading to use of NSAIDs. Although our estimates did not change when patients with systemic inflammatory conditions were excluded in a subanalysis, we cannot rule out that new users may have more severe underlying inflammation, which may increase the risk of atrial fibrillation.30 Finally, we lacked data on lifestyle factors, including smoking and body size. Nevertheless, we note that we did adjust partly for lifestyle factors by controlling for history of cancer, chronic obstructive pulmonary disease, and ischaemic heart disease, and that our findings could not be explained by even a strong single unmeasured confounder.

Our study is the first on NSAIDs and atrial fibrillation to include both non-selective NSAIDs and COX 2 inhibitors. A case-control study of patients in the United Kingdom diagnosed in 1996 with chronic atrial fibrillation (n=1035) or paroxysmal atrial fibrillation (n=525) found that contemporary use of traditional NSAIDs was associated with an increased risk of chronic atrial fibrillation (incidence rate ratio 1.44, 95% confidence interval 1.08 to 1.91) and modestly associated with paroxysmal atrial fibrillation (1.18, 0.85 to 1.66)-that is, with magnitude of the association similar to our results.11 By contrast with our findings, however, in the UK study, long term use of NSAIDs was associated with the largest risk increase for atrial fibrillation.

The meta-analysis,10 involving 116 094 patients using newer COX 2 inhibitors, had 6394 composite renal outcome events but only 286 composite arrhythmia outcome events, of which ventricular fibrillation, cardiac arrest, and sudden cardiac death accounted for most.10 Although rofecoxib was associated with an increased relative risk for the composite renal outcome of 1.53 (95% confidence interval 1.33 to 1.76) and the composite arrhythmia outcome (2.90, 1.07 to 7.88),10 the small number and types of arrhythmias available for analysis did not allow for examination of atrial fibrillation as an outcome. In the present study, we found an increased risk of atrial fibrillation or flutter associated with older and newer COX 2 inhibitors. Notably, COX 2 inhibitors, in particular diclofenac, were associated with higher risks than non-selective NSAIDs, indicating the important pharmacological role of COX 2 inhibition.3 5

Use of NSAIDs may increase the risk of atrial fibrillation or flutter through renal and cardiovascular related actions. Five per cent of patients treated with NSAIDs experience nephrotoxic syndromes.2 Both COX enzymes are expressed in distinct anatomic regions of adult kidney tissue.2 Thus, inhibition of synthesis of COX derived prostaglandin impairs inflammation and a variety of physiological processes.2 These changes may induce increases in blood pressure due to expansion of plasma volume, increased peripheral resistance, attenuation of diuretic and antihypertensive drug effects,2 6 and fluctuation of serum potassium as a result of decreased potassium excretion in the distal nephron.2 Thus, the increased risk among new users may be attributable to short term adverse renal effects of NSAIDs, which subsequently trigger atrial fibrillation.24 The finding that patients with chronic kidney disease have a markedly higher risk when starting treatment with COX 2 inhibitors supports this hypothesis.2 6

In conclusion, we found that 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% relative risk increase (lowest for non-selective NSAIDs and highest for COX 2 inhibitors). Our study thus adds evidence that atrial fibrillation or flutter need to be added to the cardiovascular risks under consideration when prescribing NSAIDs.

---------------------------

Editorial

NSAIDs and atrial fibrillation

Jerry Gurwitz professor of medicine and executive director

Meyers Primary Care Institute, a joint endeavour of Fallon Clinic, Fallon Community Health Plan and University of Massachusetts Medical School, Worcester, MA 01609, USA

The risk is unproved, but NSAIDs should be used with caution in high risk patients anyway

More than two million Americans and more than four million people in the European Union have paroxysmal or persistent atrial fibrillation.1 Its prevalence increases dramatically with advancing age, rising from 0.1% in adults younger than 55 years to 9.0% in those aged 80 or more.2 Atrial fibrillation is associated with an increased long term risk of stroke, heart failure, and death. The healthcare costs related to this condition are substantial, largely as a result of hospital admissions, consultations, diagnostic and therapeutic procedures, and drug treatments. Many patients with atrial fibrillation need lifelong treatment with oral anticoagulants for stroke prevention, which requires careful dosing and laboratory monitoring; safety concerns about the risk of bleeding persist for these patients even under the most ideal systems of care. For these reasons, any opportunity to reduce the risk of atrial fibrillation, particularly in older adults, would be welcome. In the linked case-control study (doi:10.1136/bmj.d3450), Schmidt and colleagues describe an association between the use of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) or selective cyclo-oxygenase-2 (COX 2) inhibitors and atrial fibrillation or flutter.3

In 2008, an expert panel convened by the National Heart, Lung, and Blood Institute highlighted that although treatments for atrial fibrillation have been studied extensively, prevention has received relatively little attention.4 Modifiable risk factors include hypertension, diabetes, obesity, and smoking.5 Predisposing clinical conditions include heart failure, myocardial infarction, valvular heart disease, thyroid disease, and sleep disordered breathing. These risk factors and predisposing conditions probably interact with various non-modifiable risk factors including age, sex, race, and genetic factors.

The identification of drug related precipitants of atrial fibrillation adds an interesting new dimension to its prevention.6 Using administrative data for a Danish population from 1999 to 2008, Schmidt and colleagues examined the risk of atrial fibrillation or flutter associated with the use of non-selective NSAIDs or selective COX 2 inhibitors.3 After adjustment for age, sex, and selected risk factors for atrial fibrillation, they found a significant increase in the risk of atrial fibrillation or flutter with current drug use compared with no use (non-selective NSAIDs: adjusted odds ratio 1.17, 95% confidence interval 1.10 to 1.24; COX 2 inhibitors: 1.27, 1.20 to 1.34). Risks were greatest for new users compared with non-users (non-selective NSAIDs: 1.46, 1.33 to 1.62; COX 2 inhibitors: 1.71, 1.56 to 1.88), but much less strong for long term users compared with non-users (non-selective NSAIDs: 1.05, 0.98 to 1.13; COX 2 inhibitors: 1.10, 1.03 to 1.18).

An association between use of NSAIDs and atrial fibrillation has important clinical and public health implications because of the high prevalence of use of these agents, particularly among older adults, and the increasing prevalence of atrial fibrillation with advancing age. The validity of the study's findings must be carefully considered, however, because case-control studies are susceptible to unmeasured confounders, potentially limiting the inferences that can be drawn from the results.7 Adjusting for covariates modestly reduced the strength of the associations between the use of non-selective NSAIDs and COX 2 inhibitors and atrial fibrillation or flutter. However, Schmidt and colleagues lacked data on several important clinical measures, such as body mass index. Obesity is strongly associated with osteoarthritis,8 9 one of the most common indications for treatment with NSAIDs. This unmeasured confounding variable could have affected the study's findings, because obesity is an established risk factor for atrial fibrillation. Schmidt and colleagues' efforts to estimate the effects of a hypothetical confounder only partially allay these concerns about unmeasured confounding.

The current study is not the first case-control study to report an association between the use of NSAIDs and atrial fibrillation. A study that used data from the United Kingdom General Practice Research Database found that current use of NSAIDs was associated with an increased risk of atrial fibrillation, yet the results of that study differed from the current findings in that risk was greatest for long term users rather than for new users.10 In both studies, the dose-response relation was not consistent, which makes the association even more tenuous.7

The association between NSAIDs and atrial fibrillation does not imply a cause and effect relation. One proposed explanation for the association is: "the existence of an underlying inflammatory condition, increasing the risk of AF [atrial fibrillation] on the one hand and prompting the use of NSAIDs on the other."10 Perhaps a more likely scenario is that these agents trigger or exacerbate clinical conditions, such as heart failure and hypertension, that lie along the causal pathway of atrial fibrillation.

What should clinicians do in practice in the light of current evidence? With uncertainty regarding a plausible biological mechanism, the susceptibility of case-control studies to unmeasured confounders, and inconsistent results in the two studies performed to date, a cautious approach seems warranted in applying the study's results to the care of patients. However, NSAIDS (non-selective NSAIDs and COX 2 inhibitors) should continue to be used very cautiously in older patients with a history of hypertension or heart failure, who are already at high risk for adverse effects of these drugs, regardless of whether an association between NSAIDs and atrial fibrillation actually exists.

 
 
 
 
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