Long-Term Use of Anti-Inflammatory Drugs and Risk of Atrial Fibrillation

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 duration 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 association 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.

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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 validation 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 paroxysmal 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 diagnosis 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, anticoagulants, 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. The effect of daily dose and treatment duration was examined RISK OF CHRONIC AF ACCORDING among current users. TO USE, TREATMENT DURATION, AND DAILY Regarding oral SAIDs, prednisolone doses up to 5 mg/d were DOSE OF SAIDs classified as low, doses up to 10 mg/d as medium, and doses higher than 10 mg/d as high. The corresponding cutoff values were We found that use of SAIDs is associated with an in- 20 and 40 mg/d for hydrocortisone, 0.8 and 1.5 mg/d for dexa- methasone, and 25 and 50 mg/d for cortisone. Regarding creased risk of chronic AF (RR, 2.49; 95% CI, 1.56-3.97 NSAIDs, specific cutoff values for doses, in milligrams, were for current use, and RR, 1.51; 95% CI, 0.89-2.57 for re- as follows: acemetacin, 120; azapropazone, 600; diclofenac, 100; cent use), confirming previous findings (Table 1). When diflunisal, 1500; etodolac, 400; fenbufen, 900; fenoprofen, 1200; we grouped low and medium doses in 1 category, the es- flurbiprofen, 150; ibuprofen, 1200; indomethacin, 75; keto- timate of RR was 1.95 (95% CI, 1.05-3.60), and the cor-

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 Table 2. Rate Ratio (RR) of Chronic Atrial Fibrillation (AF) Table 3. Rate Ratio (RR) of Paroxysmal Atrial Fibrillation According to Use, Treatment Duration, and Daily Dose of (AF) According to Use, Treatment Duration, and Daily Dose Nonsteroidal Anti-inflammatory Drugs (NSAIDs)a of Nonsteroidal Anti-inflammatory Drugs (NSAIDs)a

Chronic Paroxysmal Controls AF Cases Controls AF Cases NSAID Exposure (n=5000) (n=1035) RR (95% CI) NSAID Exposure (n=5000) (n=525) RR (95% CI) Timing Timing Nonuse 2239 423 1 [Reference] Nonuse 2269 225 1 [Reference] Current use 359 119 1.44 (1.08-1.91) Current use 370 62 1.18 (0.85-1.66) Recent use 350 79 1.24 (0.89-1.473) Recent use 350 43 0.99 (0.67-1.45) Past use 2072 414 1.11 (0.92-1.33) Past use 1911 195 0.94 (0.76-1.18) Duration, d Duration, d Յ30 125 22 1.04 (0.59-1.83) Յ30 116 11 0.85 (0.43-1.68) Ͼ30 234 97 1.57 (1.15-2.15) Ͼ30 254 51 1.30 (0.90-1.88) 31-365 127 42 1.35 (0.88-2.09) 31-365 136 16 0.85 (0.48-1.51) Ͼ365 107 55 1.80 (1.20-2.72) Ͼ365 118 35 1.74 (1.11-2.71) Daily doseb Daily doseb Low-medium 210 76 1.45 (1.03-2.05) Low-medium 194 43 1.39 (0.93-2.06) High 149 43 1.41 (0.92-2.15) High 176 19 0.90 (0.53-1.54) Individual NSAID Individual NSAID Diclofenac 107 33 1.33 (0.82-2.15) Diclofenac 116 19 1.05 (0.60-1.83) Ibuprofen 128 44 1.31 (0.84-2.04) Ibuprofen 112 17 1.17 (0.67-2.07) Indomethacin 20 5 1.18 (0.34-4.15) Indomethacin 31 2 0.41 (0.09-1.81) Naproxen 40 13 1.22 (0.56-2.65) Naproxen 46 8 1.57 (0.69-3.58) Piroxicam 14 4 1.79 (0.53-6.04) Other NSAIDs 65 16 1.63 (0.87-3.06) Other NSAIDs 50 20 2.25 (1.21-4.18) Abbreviation: CI, confidence interval. Abbreviation: CI, confidence interval. aRate ratio adjusted for age, sex, smoking, body mass index, alcohol use, a Rate ratio adjusted for age, sex, smoking, body mass index, alcohol use, health care visits, ischemic heart disease, heart failure, valvular disease, health care visits, ischemic heart disease, heart failure, valvular disease, hypertension, and use of digoxin, anticoagulants, aspirin, and NSAIDs. hypertension, diabetes, and use of digoxin, anticoagulants, aspirin, and bSpecific cutoff values for dose, in milligrams, were as follows: aceclofenac, NSAIDs. 200; acemetacin, 120; azapropazone, 600; diclofenac, 100; etodolac, 400; b Specific cutoff values for dose, in milligrams, were as follows: fenbufen, 900; fenoprofen, 1200; flurbiprofen, 150; ibuprofen, 1200; aceclofenac, 200; acemetacin, 120; azapropazone, 600; diclofenac, 100; indomethacin, 75; ketoprofen, 150; mefenamic acid, 1000; meloxican, 7.5; etodolac, 400, fenbufen, 900; fenoprofen, 1200; flurbiprofen, 150; ibuprofen, nabumetone, 1000; naproxen, 750; piroxicam, 10; sulindac, 200; tenoxicam, 10; 1200; indomethacin, 75; ketoprofen, 150; mefenamic acid, 1000; meloxican, and tiaprofenic, 600. Doses less than or equal to the cutoff value were grouped 7.5; nabumetone, 1000; naproxen, 750; piroxicam, 10; sulindac, 200; under low-medium doses and doses greater than the cutoff value were grouped tenoxicam, 10; and tiaprofenic, 600. Doses less than or equal to the cutoff under high doses. value were grouped under low-medium doses and doses greater than the cutoff value were grouped under high doses. although the 95% CI for individual NSAIDs always en- responding estimate of RR among users of a high daily compassed unity, as a result—most likely—of reduced dose was 3.41 (95% CI, 1.68-6.90). The main indication statistical power (Table 2). We found no association be- for SAID treatment was respiratory disease (asthma and tween the use of paracetamol and the risk of paroxys- chronic obstructive pulmonary disease), and the corre- mal AF (RR, 0.98; 95% CI, 0.69-1.39) or chronic AF (RR, sponding estimate of RR was 3.67 (95% CI, 1.96-6.88). 1.00; 95% CI, 0.78-1.30). The estimate of RR for SAIDS among patients with paroxysmal AF was 1.37 (95% CI, 0.80-2.33). RISK OF PAROXISMAL AF ACCORDING TO USE, TREATMENT RISK OF CHRONIC AF ACCORDING DURATION, AND DAILY DOSE OF NSAIDs TO USE, TREATMENT DURATION, AND DAILY DOSE OF NSAIDs Similar increased risk between use of NSAIDs and the risk of chronic AF was not found for paroxysmal AF, with We found that the current use of NSAIDs was associ- the sole exception of users with more than 1 year of treat- ated with an RR of 1.44 (95% CI, 1.08-1.91) for chronic ment, among whom the estimate of RR was 1.74 (95% AF. The increased risk tended to disappear with time CI, 1.11-2.71) (Table 3). elapsing since last NSAID use (Table 2). The RR associated with the use of NSAIDs for more than 30 days was INTERACTION BETWEEN USE OF NSAIDs AND 1.57 (95% CI, 1.15-2.15), and the RR was highest for the ANTECEDENTS OF HEART FAILURE IN THE use of NSAIDs for more than 1 year (RR, 1.80; 95% CI, RELATIONSHIP WITH CHRONIC AF 1.20-2.72) (Table 2). We found no dose-response effect in the association when we divided daily use into low- Because it is conceivable that the long-term use of NSAIDs medium and high (Table 2). becomes associated with AF owing to the known asso- We also sought to ascertain whether individual NSAIDs ciation of NSAIDs with increased risk of myocardial in- were different from each other in their relationship with farction, thereby causing more heart failure (HF), which chronic AF. The increased RR occurred for all NSAIDs, in turn causes a higher rate of AF among NSAIDs users,

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 we hypothesized that the association is present only in individuals with HF and absent in individuals without Table 4. Rate Ratio (RR) of Chronic Atrial Fibrillation (AF) HF. Among patients with HF, however, there was no ma- Associated With Use of Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Stratified According to Antecedents jor increased risk of chronic AF in current NSAID users of Heart Failure (HF)a (RR, 0.93; 95% CI, 0.38-2.27). Conversely, among patients without HF, there was an increased risk of AF in Chronic NSAID users (RR, 1.49; 95% CI, 1.10-2.02) (Table 4). NSAID Exposure Controls AF Cases RR (95% CI) This finding indirectly speaks against a major role for HF Individuals with 113 224 in mediating the association between the use of NSAIDs antecedents of HF and increased risk of chronic AF. Timing Nonuse 47 93 1 [Reference] Current use 10 25 0.93 (0.38-2.27) COMMENT Recent use 10 13 0.68 (0.24-1.92) Past use 246 93 0.93 (0.53-1.65) Individuals without 4887 811 We found that the current use of NSAIDs is associated antecedents of HF with a statistically significant 44% increase in the risk of Timing chronic AF, while no similar association was found re- Nonuse 2192 330 1 [Reference] garding paroxysmal AF. We also confirmed previous find- Current use 349 94 1.49 (1.10-2.02) ings regarding the association of the use of SAIDs with Recent use 320 66 1.31 (0.92-1.87) Past use 2026 321 1.14 (0.94-1.39) an increased risk of chronic AF. Several drugs have been associated with an increased Abbreviation: CI, confidence interval. 23 risk of AF, but knowledge about the role of drugs in aRate ratio adjusted for age, sex, smoking, body mass index, alcohol use, the development of AF is scarce. In a comprehensive re- health care visits, ischemic heart disease, heart failure, valvular disease, view article that was published in 2004,23 corticoste- hypertension, diabetes, and use of digoxin, anticoagulants, aspirin, and NSAIDs. roids were included among the several drug categories for which such an association had been reported. In- ment duration, although our data are compatible with a deed, several case reports and small-series observa- greater risk associated with long-term use. We found no tional studies,24-32 as well as 1 case-control study,33 had apparent dose-relationship when we divided daily use into reported on such an association. Such findings were con- low-medium and high. In essence, the use of NSAIDs, firmed in an extensive series based on the Rotterdam irrespective of the dosing, appeared to coincide with a Study,34 a population-based cohort study involving 7983 higher risk of AF. At the same time, we found no overall older adults.35 Several hypotheses were raised at that time association between use of NSAIDs and the risk of par- to explain the association: (1) high-dose corticosteroids oxysmal AF, although long-term NSAIDs users also pre- mediate (local) potassium efflux via a direct effect on the sented an increased risk of paroxysmal AF. cell membrane, which may induce arrhythmias25; (2) the The use of cyclooxygenase-2 inhibitors, both selec- mineral corticosteroid effect of high doses of glucocor- tive (coxibs) and traditional NSAIDs, has been found to ticosteroids can cause retention of sodium and fluid, which be associated with an increased risk of acute myocardial in turn may cause hypertension, left atrial enlargement, infarction,39-43 largely currently interpreted as attribut- and congestive heart failure—all known risk factors for able to an increased risk of thrombosis after the impair- AF36; and (3) corticosteroids may favor the development of prostacyclin production, which is mainly cy- ment of late potentials and occasionally cause profound clooxygenase-2 dependent.44 This increased risk of peripheral vasodilatation and anaphylactic reac- thrombosis might translate into an increased risk of late tions.37,38 However, there is as yet no conclusive evi- HF, in turn explaining the higher risk of AF compared dence for any of these mechanisms, and it was con- with patients with no previous myocardial infarction. cluded then that high-dose corticosteroid therapy may However, such a hypothesis does not seem to be com- act as a trigger rather than as a single cause for AF, in patible with our data. When we stratified the analysis ac- line with the earlier-described trigger-substrate relation- cording to antecedents of HF, we found that the in- ship in drug-induced AF.23 The present report confirms creased risk of chronic AF associated with the use of those earlier observations. Current and recent use of SAIDs NSAIDs was actually present in patients without HF but (mostly because of chronic obstructive pulmonary dis- absent in those with prior HF. ease and rheumatic diseases) was associated with a higher However, the association of increased risk of AF with risk of AF with a clear dose-response relationship. the use of NSAIDs does not imply a cause-and-effect re- Importantly, however, our report now extends those lationship. Indeed, a likely explanation for our findings earlier observations to the therapeutic group of NSAIDs, is the existence of an underlying inflammatory condi- which are mostly devoid of the above-reported postu- tion, increasing the risk of AF on the one hand and lated proarrhythmogenic properties of SAIDs but share prompting the use of NSAIDs on the other. Underlying with SAIDs the indication as treatment for chronic in- inflammatory conditions could favor the onset or main- flammatory conditions. We found, in particular, that the tenance of AF. Atrial fibrosis is the most frequent patho- current use of NSAIDs was associated with a significant anatomical change found in AF. Patchy fibrosis in close 44% increased risk of chronic AF, with the risk tending proximity with normal atrial fibers may account for con- to disappear after the NSAID treatment was discontin- duction inhomogeneities,10-12 and it has been argued that ued. The increased risk was present irrespective of treat- fibrosis precedes the onset of AF.13 Atrial fibrosis is cur-

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 rently the main structural target for the proposed use of Administrative, technical, and material support: Garcıá drugs inhibiting the renin-angiotensin system in AF45,46 Rodrı´guez. Study supervision: De Caterina and Garcıá and may be caused by inflammation,14 as seen in cardiac Rodrı´guez. sarcoidosis15 and autoimmune disorders.16 Inflamma- Financial Disclosure: None reported. tion, possibly also through the production of throm- Funding/Support: The original data collection for the as- boxane A2 and prostaglandin F2␣, has recently been shown certainment of cases of AF was performed with an un- to cause inflammatory tachycardia.47 It is possible, and restricted research grant to Centro Espan˜ ol de Investiga- we would like to propose, that conditions presenting sys- cioń Farmacoepidemiolo´gica from AstraZeneca. temic inflammation, such as autoimmune and rheu- Additonal Contributions: We thank the participating pri- matic disorders, represent an independent risk factor for mary care physicians for their collaboration in the vali- atrial fibrosis and subsequently for an increased risk of dation of patients with AF. onset or persistence of AF. 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Less Is More

The Archives of Internal Medicine is excited to launch Less Is More—a new feature identifying articles that provide evidence about situations in which less health care results in better health. For more details, please see the edi- torial in the April 12, 2010, issue, page 584.

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