ORIGINAL INVESTIGATION Long-term Use of Anti-inflammatory Drugs and Risk of Atrial Fibrillation Raffaele De Caterina, MD, PhD; Ana Ruigo´mez, MD, PhD; Luı´s Alberto Garcı´a Rodrı´guez, MD, MSc Background: Previous reports have described an asso- ratio [RR], 2.49; 95% confidence interval [CI], 1.56- ciation between the use of corticosteroids (steroidal anti- 3.97). However, we also found that the current use of inflammatory drugs [SAIDs]) and the risk of atrial fibril- NSAIDs was associated with an increased risk of chronic lation (AF). We sought to determine the existence of a AF (RR, 1.44; 95% CI, 1.08-1.91). Such risk was further similar association for non-SAIDs (NSAIDs). increased among long-term users with a treatment du- ration of longer than 1 year (RR, 1.80; 95% CI, 1.20- Methods: We identified patients aged 40 to 89 years with 2.72). The increased risk of chronic AF was not ex- a first-ever diagnosis of AF in 1996 in a United King- plained by the occurrence of heart failure. The use of dom primary care database and classified them as hav- NSAIDs was not associated with paroxysmal AF. ing paroxysmal or chronic AF. After validation with their primary care physicians, 1035 patients were confirmed Conclusions: The use of NSAIDs, as for SAIDs, is asso- as having incident chronic AF and 525 as having parox- ciated with an increased risk of chronic AF. Because the ysmal AF. Two separate nested case-control analyses es- use of anti-inflammatory drugs in general is a marker for timated the risk of first-time chronic and paroxysmal AF underlying inflammatory disorders, inflammation may among users of SAIDs and NSAIDs. be the common cause for the use of anti-inflammatory drugs and chronic AF. Results: We confirmed the previously reported asso- ciation between current use of SAIDs and chronic AF (rate Arch Intern Med. 2010;170(16):1450-1455 TRIAL FIBRILLATION (AF) IS sumption of anti-inflammatory drugs, of a common condition. It af- which nonsteroidal anti-inflammatory drugs fects 0.4% of the general (NSAIDs) represent the most common population1 but more than therapeutic class, and AF. Herein, we re- 6% of individuals older port on such an association and speculate than 80 years.2-4 The prevalence of AF is on the possible underlying mechanisms. A5 6,7 increasing, even after adjustment for age. Atrial fibrillation reduces life expec- METHODS tancy.8,9 The most frequent pathoanatomi- cal changes in AF are atrial fibrosis and loss of atrial muscle mass. Histological exami- DATA SOURCE nation of atrial tissue of patients with AF has shown patchy fibrosis juxtaposed with The United Kingdom (UK) General Practice Re- search Database (GPRD) contains computer- normal atrial fibers, which may account 10-12 ized information entered by primary care phy- for inhomogeneities of conduction. It sicians in the UK. The vast majority of the UK is difficult to distinguish between changes population is registered with a primary care due to AF and those due to associated heart physician. At the time of the study, approxi- disease, but fibrosis may precede the on- mately 1500 physicians were participating in set of AF.13 Atrial fibrosis may be caused the GPRD, covering a population of approxi- Author Affiliations: Institute by inflammation,14 as seen in cardiac sar- mately 3 million individuals who are broadly of Cardiology and Center coidosis15 and autoimmune disorders.16 representative of the UK population. The pri- of Excellence on Aging, The coexistence of inflammatory dis- mary care physicians hold the complete medi- “G. d’Annunzio” University, eases and AF, especially in the elderly, may cal record of registered individuals, including Chieti, Italy (Dr De Caterina), demographic data, all medical diagnoses, con- and Centro Espan˜ol be causal. The use of anti-inflammatory sultant and hospital referrals, and a record of de Investigacio´n drugs may characterize a phenotype with all prescriptions issued. Prescriptions are gen- Farmacoepidemiolo´gica, an underlying inflammatory substrate. Be- erated directly from the primary care physi- Madrid, Spain (Drs Ruigo´mez cause of this, we hypothesized the exis- cian’s computer and entered into the patient’s and Rodrı´guez). tence of an association between the con- computerized file. (REPRINTED) ARCH INTERN MED/ VOL 170 (NO. 16), SEP 13, 2010 WWW.ARCHINTERNMED.COM 1450 ©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 All information is recorded by physicians during consulta- tions in a standardized fashion, and individual practices regu- Table 1. Rate Ratio (RR) of Chronic Atrial larly anonymize and send these data to the Medicines and Health- Fibrillation (AF) According to Use, Treatment Duration, and care Products Regulatory Agency (UK Department of Health), Daily Dose of Steroidal Anti-inflammatory Drugs (SAIDs)a which organizes them for use in research projects. Several vali- dation studies have shown the accuracy and completeness of Chronic AF data on diagnoses, medical information, and prescriptions re- Controls Cases corded in the GPRD.17,18 Previous studies have also confirmed SAID Exposure (n=5000) (n=1035) RR (95% CI) the validity and utility of the GPRD for research on AF.19-22 Timing Nonuse 4594 882 1 [Reference] CASE ASCERTAINMENT Current use 69 52 2.49 (1.56-3.97) Recent use 109 42 1.51 (0.89-2.57) Past use 228 59 0.84 (0.60-1.18) In previous studies, we identified patients aged 40 to 89 years Timing, d with a first-ever recorded diagnosis of AF (International Clas- Յ 20-22 30 18 18 4.73 (2.01-11.16) sification of Diseases, Eighth Revision, 4163-4164) in 1996. Ͼ30 51 34 1.90 (1.09-3.31) Patients had to be registered with the general practitioner for 31-365 25 19 1.58 (0.76-3.25) at least 2 years, and individuals with a history of cancer or heart Ͼ365 26 15 2.46 (1.06-5.69) rhythm disorders were not included. For the purposes of the Daily dose studies, patients whose arrhythmia persisted for more than 1 Low 30 21 1.95 (0.95-4.02) week were classified as having chronic AF. Those whose ar- Medium 14 6 1.93 (0.61-6.10) rhythmia reverted to sinus rhythm within 1 week, either spon- High 25 25 3.41 (1.68-6.90) taneously or after treatment, were labeled as having paroxys- mal AF. The AF diagnosis was validated through a questionnaire Abbreviation: CI, confidence interval. sent to primary care physicians, as detailed previously.21,22 In a Rate ratio adjusted for age, sex, smoking, body mass index, alcohol use, summary, primary care physicians were asked to confirm health care visits, ischemic heart disease, heart failure, valvular disease, whether this AF episode was the first-ever diagnosis of AF for hypertension, diabetes, and use of digoxin, anticoagulants, aspirin, and non-SAIDs. their patients and to provide information on diagnostic tests, procedures, and the etiology of the disorder, including details of drug therapies. Patient confidentiality was always pre- profen, 150; ketorolac, 30; mefenamic acid, 1000; meloxican, served. We obtained valid responses in 93% of the 2040 pa- 7.5; nabumetone, 1000; naproxen, 750; piroxicam, 10; sulin- tients who were originally identified with AF and for whom vali- dac, 200; tenoxicam, 10; and tiaprofenic acid, 600. Doses less dation of diagnosis was requested, and in the end, 1035 patients than or equal to the cutoff value were grouped under low- were confirmed as having incident chronic AF and 525 as hav- medium doses, and doses greater than the cutoff value were ing paroxysmal AF. considered high doses. Duration of use was computed among current users summing the days included in the time interval NESTED CASE-CONTROL ANALYSES of “consecutive” prescriptions and categorized into 3 groups: use for less than 1 month, use between 1 month and 1 year, Two separate case-control analyses were performed to esti- and use for more than 1 year. mate the risk of first-time chronic AF and paroxysmal AF among users of NSAIDs. We included all patients with confirmed STATISTICS chronic AF and paroxysmal AF, and the date of their initial di- agnosis was the index date. We assigned a random date to all We used unconditional logistic regression to compute multi- members of the study cohort where AF cases were ascer- variate estimates of odds ratios and 95% confidence intervals tained, and randomly sampled 2 groups of 5000 controls from (CIs) of AF associated with SAID or NSAID use as well as the the pool of eligible members: one for the set of chronic AF cases dose and duration response. All estimates were adjusted by age, and the other for the set of paroxysmal AF cases. The random sex, and other risk factors, including smoking status; body mass date was used as the index date. index; alcohol consumption; prior health care visits; presence of diabetes, hypertension, heart failure, ischemic heart dis- EXPOSURE DEFINITION ease, or valvular heart disease; and use of digoxin, anticoagu- lants, and aspirin. Under our design of incidence density sam- Exposure to NSAIDs and SAIDs was categorized as current when pling, the odds ratio is an unbiased estimator of the incidence the supply of the most recent prescription lasted until the in- rate ratio (RR). dex date or ended in the month before it; as recent when it ended between 1 and 6 months before the index date; as past when it ended more than 6 months before the index date; and as non- RESULTS use when there was no recorded use ever before the index date.