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Original Investigation |

Long-term Use of Anti-inflammatory Drugs and Risk of Atrial Fibrillation FREE

Raffaele De Caterina, MD, PhD; Ana Ruigómez, MD, PhD; Luís Alberto García Rodríguez, MD, MSc
[+] Author Affiliations

Author Affiliations: Institute of Cardiology and Center of Excellence on Aging, “G. d’Annunzio” University, Chieti, Italy (Dr De Caterina), and Centro Español de Investigación Farmacoepidemiológica, Madrid, Spain (Drs Ruigómez and Rodríguez).


Arch Intern Med. 2010;170(16):1450-1455. doi:10.1001/archinternmed.2010.305.
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Published online

Background  Previous reports have described an association between the use of corticosteroids (steroidal anti-inflammatory drugs [SAIDs]) and the risk of atrial fibrillation (AF). We sought to determine the existence of a similar association for non-SAIDs (NSAIDs).

Methods  We identified patients aged 40 to 89 years with a first-ever diagnosis of AF in 1996 in a United Kingdom primary care database and classified them as having paroxysmal or chronic AF. After validation with their primary care physicians, 1035 patients were confirmed as having incident chronic AF and 525 as having paroxysmal AF. Two separate nested case-control analyses estimated the risk of first-time chronic and paroxysmal AF among users of SAIDs and NSAIDs.

Results  We confirmed the previously reported association between current use of SAIDs and chronic AF (rate ratio [RR], 2.49; 95% confidence interval [CI], 1.56-3.97). However, we also found that the current use of NSAIDs was associated with an increased risk of chronic AF (RR, 1.44; 95% CI, 1.08-1.91). Such risk was further increased among long-term users with a treatment duration of longer than 1 year (RR, 1.80; 95% CI, 1.20-2.72). The increased risk of chronic AF was not explained by the occurrence of heart failure. The use of NSAIDs was not associated with paroxysmal AF.

Conclusions  The use of NSAIDs, as for SAIDs, is associated with an increased risk of chronic AF. Because the use of anti-inflammatory drugs in general is a marker for underlying inflammatory disorders, inflammation may be the common cause for the use of anti-inflammatory drugs and chronic AF.

A trial fibrillation (AF) is a common condition. It affects 0.4% of the general population1 but more than 6% of individuals older than 80 years.24 The prevalence of AF is increasing,5 even after adjustment for age.6,7 Atrial fibrillation reduces life expectancy.8,9 The most frequent pathoanatomical changes in AF are atrial fibrosis and loss of atrial muscle mass. Histological examination of atrial tissue of patients with AF has shown patchy fibrosis juxtaposed with normal atrial fibers, which may account for inhomogeneities of conduction.1012 It is difficult to distinguish between changes due to AF and those due to associated heart disease, but fibrosis may precede the onset of AF.13 Atrial fibrosis may be caused by inflammation,14 as seen in cardiac sarcoidosis15 and autoimmune disorders.16

The coexistence of inflammatory diseases and AF, especially in the elderly, may be causal. The use of anti-inflammatory drugs may characterize a phenotype with an underlying inflammatory substrate. Because of this, we hypothesized the existence of an association between the consumption of anti-inflammatory drugs, of which nonsteroidal anti-inflammatory drugs (NSAIDs) represent the most common therapeutic class, and AF. Herein, we report on such an association and speculate on the possible underlying mechanisms.

DATA SOURCE

The United Kingdom (UK) General Practice Research Database (GPRD) contains computerized information entered by primary care physicians in the UK. The vast majority of the UK population is registered with a primary care physician. At the time of the study, approximately 1500 physicians were participating in the GPRD, covering a population of approximately 3 million individuals who are broadly representative of the UK population. The primary care physicians hold the complete medical record of registered individuals, including demographic data, all medical diagnoses, consultant and hospital referrals, and a record of all prescriptions issued. Prescriptions are generated directly from the primary care physician's computer and entered into the patient's computerized file.

All information is recorded by physicians during consultations in a standardized fashion, and individual practices regularly anonymize and send these data to the Medicines and Healthcare Products Regulatory Agency (UK Department of Health), which organizes them for use in research projects. Several validation studies have shown the accuracy and completeness of data on diagnoses, medical information, and prescriptions recorded in the GPRD.17,18 Previous studies have also confirmed the validity and utility of the GPRD for research on AF.1922

CASE ASCERTAINMENT

In previous studies, we identified patients aged 40 to 89 years with a first-ever recorded diagnosis of AF (International Classification of Diseases, Eighth Revision, 4163-4164) in 1996.2022 Patients had to be registered with the general practitioner for at least 2 years, and individuals with a history of cancer or heart rhythm disorders were not included. For the purposes of the studies, patients whose arrhythmia persisted for more than 1 week were classified as having chronic AF. Those whose arrhythmia reverted to sinus rhythm within 1 week, either spontaneously or after treatment, were labeled as having paroxysmal AF. The AF diagnosis was validated through a questionnaire sent to primary care physicians, as detailed previously.21,22 In summary, primary care physicians were asked to confirm whether this AF episode was the first-ever diagnosis of AF for 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 preserved. We obtained valid responses in 93% of the 2040 patients who were originally identified with AF and for whom validation of diagnosis was requested, and in the end, 1035 patients were confirmed as having incident chronic AF and 525 as having paroxysmal AF.

NESTED CASE-CONTROL ANALYSES

Two separate case-control analyses were performed to estimate the risk of first-time chronic AF and paroxysmal AF among users of NSAIDs. We included all patients with confirmed chronic AF and paroxysmal AF, and the date of their initial diagnosis was the index date. We assigned a random date to all members of the study cohort where AF cases were ascertained, and randomly sampled 2 groups of 5000 controls from the pool of eligible members: one for the set of chronic AF cases and the other for the set of paroxysmal AF cases. The random date was used as the index date.

EXPOSURE DEFINITION

Exposure to NSAIDs and SAIDs was categorized as current when the supply of the most recent prescription lasted until the index 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 nonuse when there was no recorded use ever before the index date. The effect of daily dose and treatment duration was examined among current users.

Regarding oral SAIDs, prednisolone doses up to 5 mg/d were 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 20 and 40 mg/d for hydrocortisone, 0.8 and 1.5 mg/d for dexamethasone, and 25 and 50 mg/d for cortisone. Regarding NSAIDs, specific cutoff values for doses, in milligrams, were as follows: acemetacin, 120; azapropazone, 600; diclofenac, 100; diflunisal, 1500; etodolac, 400; fenbufen, 900; fenoprofen, 1200; flurbiprofen, 150; ibuprofen, 1200; indomethacin, 75; ketoprofen, 150; ketorolac, 30; mefenamic acid, 1000; meloxican, 7.5; nabumetone, 1000; naproxen, 750; piroxicam, 10; sulindac, 200; tenoxicam, 10; and tiaprofenic acid, 600. Doses less than or equal to the cutoff value were grouped under low-medium doses, and doses greater than the cutoff value were considered high doses. Duration of use was computed among current users summing the days included in the time interval of “consecutive” prescriptions and categorized into 3 groups: use for less than 1 month, use between 1 month and 1 year, and use for more than 1 year.

STATISTICS

We used unconditional logistic regression to compute multivariate estimates of odds ratios and 95% confidence intervals (CIs) of AF associated with SAID or NSAID use as well as the dose and duration response. All estimates were adjusted by age, sex, and other risk factors, including smoking status; body mass index; alcohol consumption; prior health care visits; presence of diabetes, hypertension, heart failure, ischemic heart disease, or valvular heart disease; and use of digoxin, anticoagulants, and aspirin. Under our design of incidence density sampling, the odds ratio is an unbiased estimator of the incidence rate ratio (RR).

RISK OF CHRONIC AF ACCORDING TO USE, TREATMENT DURATION, AND DAILY DOSE OF SAIDs

We found that use of SAIDs is associated with an increased risk of chronic AF (RR, 2.49; 95% CI, 1.56-3.97 for current use, and RR, 1.51; 95% CI, 0.89-2.57 for recent use), confirming previous findings (Table 1). When we grouped low and medium doses in 1 category, the estimate of RR was 1.95 (95% CI, 1.05-3.60), and the corresponding estimate of RR among users of a high daily dose was 3.41 (95% CI, 1.68-6.90). The main indication for SAID treatment was respiratory disease (asthma and chronic obstructive pulmonary disease), and the corresponding estimate of RR was 3.67 (95% CI, 1.96-6.88). The estimate of RR for SAIDS among patients with paroxysmal AF was 1.37 (95% CI, 0.80-2.33).

Table Graphic Jump LocationTable 1. Rate Ratio (RR) of Chronic Atrial Fibrillation (AF) According to Use, Treatment Duration, and Daily Dose of Steroidal Anti-inflammatory Drugs (SAIDs)a
RISK OF CHRONIC AF ACCORDING TO USE, TREATMENT DURATION, AND DAILY DOSE OF NSAIDs

We found that the current use of NSAIDs was associated with an RR of 1.44 (95% CI, 1.08-1.91) for chronic AF. The increased risk tended to disappear with time elapsing since last NSAID use (Table 2). The RR associated with the use of NSAIDs for more than 30 days was 1.57 (95% CI, 1.15-2.15), and the RR was highest for the use of NSAIDs for more than 1 year (RR, 1.80; 95% CI, 1.20-2.72) (Table 2). We found no dose-response effect in the association when we divided daily use into low-medium and high (Table 2).

Table Graphic Jump LocationTable 2. Rate Ratio (RR) of Chronic Atrial Fibrillation (AF) According to Use, Treatment Duration, and Daily Dose of Nonsteroidal Anti-inflammatory Drugs (NSAIDs)a

We also sought to ascertain whether individual NSAIDs were different from each other in their relationship with chronic AF. The increased RR occurred for all NSAIDs, although the 95% CI for individual NSAIDs always encompassed unity, as a result—most likely—of reduced statistical power (Table 2). We found no association between the use of paracetamol and the risk of paroxysmal AF (RR, 0.98; 95% CI, 0.69-1.39) or chronic AF (RR, 1.00; 95% CI, 0.78-1.30).

RISK OF PAROXISMAL AF ACCORDING 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 the sole exception of users with more than 1 year of treatment, among whom the estimate of RR was 1.74 (95% CI, 1.11-2.71) (Table 3).

Table Graphic Jump LocationTable 3. Rate Ratio (RR) of Paroxysmal Atrial Fibrillation (AF) According to Use, Treatment Duration, and Daily Dose of Nonsteroidal Anti-inflammatory Drugs (NSAIDs)a
INTERACTION BETWEEN USE OF NSAIDs AND ANTECEDENTS OF HEART FAILURE IN THE RELATIONSHIP WITH CHRONIC AF

Because it is conceivable that the long-term use of NSAIDs becomes associated with AF owing to the known association of NSAIDs with increased risk of myocardial infarction, thereby causing more heart failure (HF), which in turn causes a higher rate of AF among NSAIDs users, we hypothesized that the association is present only in individuals with HF and absent in individuals without HF. Among patients with HF, however, there was no major increased risk of chronic AF in current NSAID users (RR, 0.93; 95% CI, 0.38-2.27). Conversely, among patients without HF, there was an increased risk of AF in NSAID users (RR, 1.49; 95% CI, 1.10-2.02) (Table 4). This finding indirectly speaks against a major role for HF in mediating the association between the use of NSAIDs and increased risk of chronic AF.

Table Graphic Jump LocationTable 4. Rate Ratio (RR) of Chronic Atrial Fibrillation (AF) Associated With Use of Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Stratified According to Antecedents of Heart Failure (HF)a

We found that the current use of NSAIDs is associated with a statistically significant 44% increase in the risk of chronic AF, while no similar association was found regarding paroxysmal AF. We also confirmed previous findings regarding the association of the use of SAIDs with an increased risk of chronic AF.

Several drugs have been associated with an increased risk of AF,23 but knowledge about the role of drugs in the development of AF is scarce. In a comprehensive review article that was published in 2004,23 corticosteroids were included among the several drug categories for which such an association had been reported. Indeed, several case reports and small-series observational studies,2432 as well as 1 case-control study,33 had reported on such an association. Such findings were confirmed in an extensive series based on the Rotterdam Study,34 a population-based cohort study involving 7983 older adults.35 Several hypotheses were raised at that time to explain the association: (1) high-dose corticosteroids mediate (local) potassium efflux via a direct effect on the cell membrane, which may induce arrhythmias25; (2) the mineral corticosteroid effect of high doses of glucocorticosteroids can cause retention of sodium and fluid, which in turn may cause hypertension, left atrial enlargement, and congestive heart failure—all known risk factors for AF36; and (3) corticosteroids may favor the development of late potentials and occasionally cause profound peripheral vasodilatation and anaphylactic reactions.37,38 However, there is as yet no conclusive evidence for any of these mechanisms, and it was concluded then that high-dose corticosteroid therapy may act as a trigger rather than as a single cause for AF, in line with the earlier-described trigger-substrate relationship in drug-induced AF.23 The present report confirms those earlier observations. Current and recent use of SAIDs (mostly because of chronic obstructive pulmonary disease and rheumatic diseases) was associated with a higher risk of AF with a clear dose-response relationship.

Importantly, however, our report now extends those earlier observations to the therapeutic group of NSAIDs, which are mostly devoid of the above-reported postulated proarrhythmogenic properties of SAIDs but share with SAIDs the indication as treatment for chronic inflammatory conditions. We found, in particular, that the current use of NSAIDs was associated with a significant 44% increased risk of chronic AF, with the risk tending to disappear after the NSAID treatment was discontinued. The increased risk was present irrespective of treatment duration, although our data are compatible with a greater risk associated with long-term use. We found no apparent dose-relationship when we divided daily use into low-medium and high. In essence, the use of NSAIDs, irrespective of the dosing, appeared to coincide with a higher risk of AF. At the same time, we found no overall association between use of NSAIDs and the risk of paroxysmal AF, although long-term NSAIDs users also presented an increased risk of paroxysmal AF.

The use of cyclooxygenase-2 inhibitors, both selective (coxibs) and traditional NSAIDs, has been found to be associated with an increased risk of acute myocardial infarction,3943 largely currently interpreted as attributable to an increased risk of thrombosis after the impairment of prostacyclin production, which is mainly cyclooxygenase-2 dependent.44 This increased risk of thrombosis might translate into an increased risk of late HF, in turn explaining the higher risk of AF compared with patients with no previous myocardial infarction. However, such a hypothesis does not seem to be compatible with our data. When we stratified the analysis according to antecedents of HF, we found that the increased risk of chronic AF associated with the use of NSAIDs was actually present in patients without HF but absent in those with prior HF.

However, the association of increased risk of AF with the use of NSAIDs does not imply a cause-and-effect relationship. Indeed, a likely explanation for our findings is the existence of an underlying inflammatory condition, increasing the risk of AF on the one hand and prompting the use of NSAIDs on the other. Underlying inflammatory conditions could favor the onset or maintenance of AF. Atrial fibrosis is the most frequent pathoanatomical change found in AF. Patchy fibrosis in close proximity with normal atrial fibers may account for conduction inhomogeneities,1012 and it has been argued that fibrosis precedes the onset of AF.13 Atrial fibrosis is currently the main structural target for the proposed use of drugs inhibiting the renin-angiotensin system in AF45,46 and may be caused by inflammation,14 as seen in cardiac sarcoidosis15 and autoimmune disorders.16 Inflammation, possibly also through the production of thromboxane A2 and prostaglandin F, has recently been shown to cause inflammatory tachycardia.47 It is possible, and we would like to propose, that conditions presenting systemic inflammation, such as autoimmune and rheumatic disorders, represent an independent risk factor for atrial fibrosis and subsequently for an increased risk of onset or persistence of AF. Consequently, the use of anti-inflammatory drugs may be a proxy for an underlying inflammatory substrate favoring AF. We believe that this hypothesis deserves further investigation.

We acknowledge a few limitations of our study. The diagnosis of chronic AF is not in keeping with the currently used distinction between AF that is amenable to cardioversion (“persistent” AF) and AF for which cardioversion is deemed unsuitable (“permanent” AF)48 but was the only one available at the time of the entry of data in our primary care database, in which the duration of AF was the only distinctive criterion between paroxysmal and chronic AF. Most likely, our definition of chronic AF includes all cases of currently defined permanent AF cases and a certain proportion of persistent AF cases. Confirmatory analyses of more recent databases should clarify this better. The possibility of unknown confounders underlying the relationship cannot be totally discarded. Also, we have no clear explanation for the stronger association of NSAID use with chronic AF than with paroxysmal AF. One possibility is that the underlying atrial fibrosis, caused by inflammation—for the presence of which the use of anti-inflammatory agents is a marker—is a condition that predisposes more to perpetuating than to actually causing AF. Another possibility, however, is the smaller sample size of paroxysmal AF cases (n = 525) compared with chronic AF cases (n = 1035). Indeed, the estimates of risk associated with paroxysmal AF and chronic AF were overlapping; actually—when analyzing the long-term use of NSAIDs defined as continuous use for more than 1 year—the estimates were quite similar (RR, 1.74; 95% CI, 1.11-2.71 vs RR, 1.80; 95% CI, 1.20-2.72). All such issues need to be addressed in future analyses. Furthermore, future studies on the association of SAIDs or NSAIDs with AF should ideally include a description of left ventricular function, atrial size and/or function, and inflammatory markers, which would help to make the association more biologically plausible.

Correspondence: Raffaele De Caterina, MD, PhD, Institute of Cardiology, c/o Ospedale SS Annunziata, Via dei Vestini, 66013 Chieti, Italy (rdecater@unich.it).

Accepted for Publication: February 17, 2010.

Author Contributions:Study concept and design: De Caterina and García Rodríguez. Acquisition of data: Ruigómez and García Rodríguez. Analysis and interpretation of data: De Caterina, Ruigómez, and García Rodríguez. Drafting of the manuscript: De Caterina and García Rodríguez. Critical revision of the manuscript for important intellectual content: Ruigómez. Statistical analysis: Ruigómez and García Rodríguez. Obtained funding: García Rodríguez. Administrative, technical, and material support: García Rodríguez. Study supervision: De Caterina and García Rodríguez.

Financial Disclosure: None reported.

Funding/Support: The original data collection for the ascertainment of cases of AF was performed with an unrestricted research grant to Centro Español de Investigación Farmacoepidemiológica from AstraZeneca.

Additonal Contributions: We thank the participating primary care physicians for their collaboration in the validation of patients with AF.

Ostrander  LD  JrBrandt  RLKjelsberg  MOEpstein  FH Electrocardiographic findings among the adult population of a total natural community, Tecumseh, Michigan. Circulation 1965;31888- 898
PubMed Link to Article
Flegel  KMShipley  MJRose  G Risk of stroke in non-rheumatic atrial fibrillation. Lancet 1987;1 (8532) 526- 529
PubMed Link to Article
Wolf  PAAbbott  RDKannel  WB Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22 (8) 983- 988
PubMed Link to Article
Furberg  CDPsaty  BMManolio  TAGardin  JMSmith  VERautaharju  PM Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study). Am J Cardiol 1994;74 (3) 236- 241
PubMed Link to Article
Friberg  JBuch  PScharling  HGadsbphioll  NJensen  GB Rising rates of hospital admissions for atrial fibrillation. Epidemiology 2003;14 (6) 666- 672
PubMed Link to Article
Wolf  PABenjamin  EJBelanger  AJKannel  WBLevy  DD’Agostino  RB Secular trends in the prevalence of atrial fibrillation: The Framingham Study. Am Heart J 1996;131 (4) 790- 795
PubMed Link to Article
Tsang  TSPetty  GWBarnes  ME  et al.  The prevalence of atrial fibrillation in incident stroke cases and matched population controls in Rochester, Minnesota: changes over three decades. J Am Coll Cardiol 2003;42 (1) 93- 100
PubMed Link to Article
 Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994;154 (13) 1449- 1457
PubMed Link to Article
Stewart  SHart  CLHole  DJ McMurray  JJ A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am J Med 2002;113 (5) 359- 364
PubMed Link to Article
Guiraudon  CErnst  NYee  RLein  G The pathology of drug resistant lone atrial fibrillation in eleven surgically treated patients. Kingma  JVan Hernel  NLie  KAtrial Fibrillation A Treatable Disease? Dordrecht, the Netherlands Kluwer Academic Publishers1992;41- 57
Allessie  MAusma  JSchotten  U Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res 2002;54 (2) 230- 246
PubMed Link to Article
Frustaci  AChimenti  CBellocci  FMorgante  ERusso  MAMaseri  A Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 1997;96 (4) 1180- 1184
PubMed Link to Article
Bharti  SLev  M Histology of the normal diseased atrium. Fall  RPodrid  PAtrial Fibrillation Mechanism and Management. New York, NY Raven Press1992;15- 39
Pokharel  Svan Geel  PPSharma  UC  et al.  Increased myocardial collagen content in transgenic rats overexpressing cardiac angiotensin-converting enzyme is related to enhanced breakdown of N-acetyl-Ser-Asp-Lys-Pro and increased phosphorylation of Smad2/3. Circulation 2004;110 (19) 3129- 3135
PubMed Link to Article
Sharma  OPMaheshwari  AThaker  K Myocardial sarcoidosis. Chest 1993;103 (1) 253- 258
PubMed Link to Article
Maixent  JMPaganelli  FScaglione  JLévy  S Antibodies against myosin in sera of patients with idiopathic paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 1998;9 (6) 612- 617
PubMed Link to Article
Jick  HJick  SSDerby  LE Validation of information recorded on general practitioner based computerised data resource in the United Kingdom. BMJ 1991;302 (6779) 766- 768
PubMed Link to Article
Jick  SSKaye  JAVasilakis-Scaramozza  C  et al.  Validity of the general practice research database. Pharmacotherapy 2003;23 (5) 686- 689
PubMed Link to Article
Rietbrock  SHeeley  EPlumb  Jvan Staa  T Chronic atrial fibrillation: incidence, prevalence, and prediction of stroke using the Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack (CHADS2) risk stratification scheme. Am Heart J 2008;156 (1) 57- 64
PubMed Link to Article
Ruigómez  AJohansson  SWallander  MAGarcía Rodríguez  LA Risk of mortality in a cohort of patients newly diagnosed with chronic atrial fibrillation. BMC Cardiovasc Disord 2002;25
PubMed Link to Article
Ruigómez  AJohansson  SWallander  MAGarcía Rodríguez  LA Predictors and prognosis of paroxysmal atrial fibrillation in general practice in the UK. BMC Cardiovasc Disord 2005;520
PubMed Link to Article
Ruigómez  AJohansson  SWallander  MARodríguez  LA Incidence of chronic atrial fibrillation in general practice and its treatment pattern. J Clin Epidemiol 2002;55 (4) 358- 363
PubMed Link to Article
van der Hooft  CSHeeringa  Jvan Herpen  GKors  JAKingma  JHStricker  BH Drug-induced atrial fibrillation. J Am Coll Cardiol 2004;44 (11) 2117- 2124
PubMed Link to Article
Ueda  NYoshikawa  TChihara  MKawaguchi  SNiinomi  YYasaki  T Atrial fibrillation following methylprednisolone pulse therapy. Pediatr Nephrol 1988;2 (1) 29- 31
PubMed Link to Article
Fujimoto  SKondoh  HYamamoto  YHisanaga  STanaka  K Holter electrocardiogram monitoring in nephrotic patients during methylprednisolone pulse therapy. Am J Nephrol 1990;10 (3) 231- 236
PubMed Link to Article
Chikanza  CFernandes  L Arrhythmia after pulse methylprednisolone therapy. Br J Rheumatol 1991;30 (5) 392- 393
PubMed Link to Article
McLuckie  AESavage  RW Atrial fibrillation following pulse methylprednisolone therapy in an adult. Chest 1993;104 (2) 622- 623
PubMed Link to Article
Moretti  RTorre  PAntonello  RMZorzon  MCazzato  G Recurrent atrial fibrillation associated with pulse administration of high doses of methylprednysolone: a possible prophylactic treatment. Eur J Neurol 2000;7 (1) 130
PubMed Link to Article
Aslam  AKVasavada  BCSacchi  TJKhan  IA Atrial fibrillation associated with systemic lupus erythematosus and use of methylprednisolone. Am J Ther 2001;8 (4) 303- 305
PubMed Link to Article
Bocanegra  TSCastañeda  MOEspinoza  LRVasey  FBGermain  BF Sudden death after methylprednisolone pulse therapy. Ann Intern Med 1981;95 (1) 122
PubMed Link to Article
Moses  RE McCormick  ANickey  W Fatal arrhythmia after pulse methylprednisolone therapy. Ann Intern Med 1981;95 (6) 781- 782
PubMed Link to Article
Thompson  JFChalmers  DHWood  RFKirkham  SRMorris  PJ Sudden death following high-dose intravenous methylprednisolone. Transplantation 1983;36 (5) 594- 596
PubMed Link to Article
Huerta  CLanes  SFGarcía Rodríguez  LA Respiratory medications and the risk of cardiac arrhythmias. Epidemiology 2005;16 (3) 360- 366
PubMed Link to Article
van der Hooft  CSHeeringa  JBrusselle  GG  et al.  Corticosteroids and the risk of atrial fibrillation. Arch Intern Med 2006;166 (9) 1016- 1020
PubMed Link to Article
Hofman  AGrobbee  DEde Jong  PTvan den Ouweland  FA Determinants of disease and disability in the elderly: the Rotterdam Elderly Study. Eur J Epidemiol 1991;7 (4) 403- 422
PubMed Link to Article
Go  ASHylek  EMPhillips  KA  et al.  Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285 (18) 2370- 2375
PubMed Link to Article
Freedman  MDSchocket  ALChapel  NGerber  JG Anaphylaxis after intravenous methylprednisolone administration. JAMA 1981;245 (6) 607- 608
PubMed Link to Article
Ozen  STokgozoglu  LSaatci  U Are late potentials operative in arrhythmias following methylprednisolone pulse therapy. Int J Cardiol 1992;36 (2) 234- 235
PubMed Link to Article
Andersohn  FSuissa  SGarbe  E Use of first- and second-generation cyclooxygenase-2-selective nonsteroidal antiinflammatory drugs and risk of acute myocardial infarction. Circulation 2006;113 (16) 1950- 1957
PubMed Link to Article
Chan  ATManson  JEAlbert  CM  et al.  Nonsteroidal antiinflammatory drugs, acetaminophen, and the risk of cardiovascular events. Circulation 2006;113 (12) 1578- 1587
PubMed Link to Article
Gislason  GHJacobsen  SRasmussen  JN  et al.  Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial infarction. Circulation 2006;113 (25) 2906- 2913
PubMed Link to Article
Solomon  DHSchneeweiss  SGlynn  RJ  et al.  Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 2004;109 (17) 2068- 2073
PubMed Link to Article
García Rodríguez  LATacconelli  SPatrignani  P Role of dose potency in the prediction of risk of myocardial infarction associated with nonsteroidal anti-inflammatory drugs in the general population. J Am Coll Cardiol 2008;52 (20) 1628- 1636
PubMed Link to Article
FitzGerald  GA COX-2 and beyond: approaches to prostaglandin inhibition in human disease. Nat Rev Drug Discov 2003;2 (11) 879- 890
PubMed Link to Article
Burstein  BNattel  S Atrial structural remodeling as an antiarrhythmic target. J Cardiovasc Pharmacol 2008;52 (1) 4- 10
PubMed Link to Article
Gillis  AM Angiotensin-receptor blockers for prevention of atrial fibrillation—a matter of timing or target? N Engl J Med 2009;360 (16) 1669- 1671
PubMed Link to Article
Takayama  KYuhki  KOno  K  et al.  Thromboxane A2 and prostaglandin F2alpha mediate inflammatory tachycardia. Nat Med 2005;11 (5) 562- 566
PubMed Link to Article
Fuster  VRydén  LECannom  DS  et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society, ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114 (7) e257- e354
PubMed Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Rate Ratio (RR) of Chronic Atrial Fibrillation (AF) According to Use, Treatment Duration, and Daily Dose of Steroidal Anti-inflammatory Drugs (SAIDs)a
Table Graphic Jump LocationTable 2. Rate Ratio (RR) of Chronic Atrial Fibrillation (AF) According to Use, Treatment Duration, and Daily Dose of Nonsteroidal Anti-inflammatory Drugs (NSAIDs)a
Table Graphic Jump LocationTable 3. Rate Ratio (RR) of Paroxysmal Atrial Fibrillation (AF) According to Use, Treatment Duration, and Daily Dose of Nonsteroidal Anti-inflammatory Drugs (NSAIDs)a
Table Graphic Jump LocationTable 4. Rate Ratio (RR) of Chronic Atrial Fibrillation (AF) Associated With Use of Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Stratified According to Antecedents of Heart Failure (HF)a

References

Ostrander  LD  JrBrandt  RLKjelsberg  MOEpstein  FH Electrocardiographic findings among the adult population of a total natural community, Tecumseh, Michigan. Circulation 1965;31888- 898
PubMed Link to Article
Flegel  KMShipley  MJRose  G Risk of stroke in non-rheumatic atrial fibrillation. Lancet 1987;1 (8532) 526- 529
PubMed Link to Article
Wolf  PAAbbott  RDKannel  WB Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22 (8) 983- 988
PubMed Link to Article
Furberg  CDPsaty  BMManolio  TAGardin  JMSmith  VERautaharju  PM Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study). Am J Cardiol 1994;74 (3) 236- 241
PubMed Link to Article
Friberg  JBuch  PScharling  HGadsbphioll  NJensen  GB Rising rates of hospital admissions for atrial fibrillation. Epidemiology 2003;14 (6) 666- 672
PubMed Link to Article
Wolf  PABenjamin  EJBelanger  AJKannel  WBLevy  DD’Agostino  RB Secular trends in the prevalence of atrial fibrillation: The Framingham Study. Am Heart J 1996;131 (4) 790- 795
PubMed Link to Article
Tsang  TSPetty  GWBarnes  ME  et al.  The prevalence of atrial fibrillation in incident stroke cases and matched population controls in Rochester, Minnesota: changes over three decades. J Am Coll Cardiol 2003;42 (1) 93- 100
PubMed Link to Article
 Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994;154 (13) 1449- 1457
PubMed Link to Article
Stewart  SHart  CLHole  DJ McMurray  JJ A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am J Med 2002;113 (5) 359- 364
PubMed Link to Article
Guiraudon  CErnst  NYee  RLein  G The pathology of drug resistant lone atrial fibrillation in eleven surgically treated patients. Kingma  JVan Hernel  NLie  KAtrial Fibrillation A Treatable Disease? Dordrecht, the Netherlands Kluwer Academic Publishers1992;41- 57
Allessie  MAusma  JSchotten  U Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res 2002;54 (2) 230- 246
PubMed Link to Article
Frustaci  AChimenti  CBellocci  FMorgante  ERusso  MAMaseri  A Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 1997;96 (4) 1180- 1184
PubMed Link to Article
Bharti  SLev  M Histology of the normal diseased atrium. Fall  RPodrid  PAtrial Fibrillation Mechanism and Management. New York, NY Raven Press1992;15- 39
Pokharel  Svan Geel  PPSharma  UC  et al.  Increased myocardial collagen content in transgenic rats overexpressing cardiac angiotensin-converting enzyme is related to enhanced breakdown of N-acetyl-Ser-Asp-Lys-Pro and increased phosphorylation of Smad2/3. Circulation 2004;110 (19) 3129- 3135
PubMed Link to Article
Sharma  OPMaheshwari  AThaker  K Myocardial sarcoidosis. Chest 1993;103 (1) 253- 258
PubMed Link to Article
Maixent  JMPaganelli  FScaglione  JLévy  S Antibodies against myosin in sera of patients with idiopathic paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 1998;9 (6) 612- 617
PubMed Link to Article
Jick  HJick  SSDerby  LE Validation of information recorded on general practitioner based computerised data resource in the United Kingdom. BMJ 1991;302 (6779) 766- 768
PubMed Link to Article
Jick  SSKaye  JAVasilakis-Scaramozza  C  et al.  Validity of the general practice research database. Pharmacotherapy 2003;23 (5) 686- 689
PubMed Link to Article
Rietbrock  SHeeley  EPlumb  Jvan Staa  T Chronic atrial fibrillation: incidence, prevalence, and prediction of stroke using the Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack (CHADS2) risk stratification scheme. Am Heart J 2008;156 (1) 57- 64
PubMed Link to Article
Ruigómez  AJohansson  SWallander  MAGarcía Rodríguez  LA Risk of mortality in a cohort of patients newly diagnosed with chronic atrial fibrillation. BMC Cardiovasc Disord 2002;25
PubMed Link to Article
Ruigómez  AJohansson  SWallander  MAGarcía Rodríguez  LA Predictors and prognosis of paroxysmal atrial fibrillation in general practice in the UK. BMC Cardiovasc Disord 2005;520
PubMed Link to Article
Ruigómez  AJohansson  SWallander  MARodríguez  LA Incidence of chronic atrial fibrillation in general practice and its treatment pattern. J Clin Epidemiol 2002;55 (4) 358- 363
PubMed Link to Article
van der Hooft  CSHeeringa  Jvan Herpen  GKors  JAKingma  JHStricker  BH Drug-induced atrial fibrillation. J Am Coll Cardiol 2004;44 (11) 2117- 2124
PubMed Link to Article
Ueda  NYoshikawa  TChihara  MKawaguchi  SNiinomi  YYasaki  T Atrial fibrillation following methylprednisolone pulse therapy. Pediatr Nephrol 1988;2 (1) 29- 31
PubMed Link to Article
Fujimoto  SKondoh  HYamamoto  YHisanaga  STanaka  K Holter electrocardiogram monitoring in nephrotic patients during methylprednisolone pulse therapy. Am J Nephrol 1990;10 (3) 231- 236
PubMed Link to Article
Chikanza  CFernandes  L Arrhythmia after pulse methylprednisolone therapy. Br J Rheumatol 1991;30 (5) 392- 393
PubMed Link to Article
McLuckie  AESavage  RW Atrial fibrillation following pulse methylprednisolone therapy in an adult. Chest 1993;104 (2) 622- 623
PubMed Link to Article
Moretti  RTorre  PAntonello  RMZorzon  MCazzato  G Recurrent atrial fibrillation associated with pulse administration of high doses of methylprednysolone: a possible prophylactic treatment. Eur J Neurol 2000;7 (1) 130
PubMed Link to Article
Aslam  AKVasavada  BCSacchi  TJKhan  IA Atrial fibrillation associated with systemic lupus erythematosus and use of methylprednisolone. Am J Ther 2001;8 (4) 303- 305
PubMed Link to Article
Bocanegra  TSCastañeda  MOEspinoza  LRVasey  FBGermain  BF Sudden death after methylprednisolone pulse therapy. Ann Intern Med 1981;95 (1) 122
PubMed Link to Article
Moses  RE McCormick  ANickey  W Fatal arrhythmia after pulse methylprednisolone therapy. Ann Intern Med 1981;95 (6) 781- 782
PubMed Link to Article
Thompson  JFChalmers  DHWood  RFKirkham  SRMorris  PJ Sudden death following high-dose intravenous methylprednisolone. Transplantation 1983;36 (5) 594- 596
PubMed Link to Article
Huerta  CLanes  SFGarcía Rodríguez  LA Respiratory medications and the risk of cardiac arrhythmias. Epidemiology 2005;16 (3) 360- 366
PubMed Link to Article
van der Hooft  CSHeeringa  JBrusselle  GG  et al.  Corticosteroids and the risk of atrial fibrillation. Arch Intern Med 2006;166 (9) 1016- 1020
PubMed Link to Article
Hofman  AGrobbee  DEde Jong  PTvan den Ouweland  FA Determinants of disease and disability in the elderly: the Rotterdam Elderly Study. Eur J Epidemiol 1991;7 (4) 403- 422
PubMed Link to Article
Go  ASHylek  EMPhillips  KA  et al.  Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285 (18) 2370- 2375
PubMed Link to Article
Freedman  MDSchocket  ALChapel  NGerber  JG Anaphylaxis after intravenous methylprednisolone administration. JAMA 1981;245 (6) 607- 608
PubMed Link to Article
Ozen  STokgozoglu  LSaatci  U Are late potentials operative in arrhythmias following methylprednisolone pulse therapy. Int J Cardiol 1992;36 (2) 234- 235
PubMed Link to Article
Andersohn  FSuissa  SGarbe  E Use of first- and second-generation cyclooxygenase-2-selective nonsteroidal antiinflammatory drugs and risk of acute myocardial infarction. Circulation 2006;113 (16) 1950- 1957
PubMed Link to Article
Chan  ATManson  JEAlbert  CM  et al.  Nonsteroidal antiinflammatory drugs, acetaminophen, and the risk of cardiovascular events. Circulation 2006;113 (12) 1578- 1587
PubMed Link to Article
Gislason  GHJacobsen  SRasmussen  JN  et al.  Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial infarction. Circulation 2006;113 (25) 2906- 2913
PubMed Link to Article
Solomon  DHSchneeweiss  SGlynn  RJ  et al.  Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 2004;109 (17) 2068- 2073
PubMed Link to Article
García Rodríguez  LATacconelli  SPatrignani  P Role of dose potency in the prediction of risk of myocardial infarction associated with nonsteroidal anti-inflammatory drugs in the general population. J Am Coll Cardiol 2008;52 (20) 1628- 1636
PubMed Link to Article
FitzGerald  GA COX-2 and beyond: approaches to prostaglandin inhibition in human disease. Nat Rev Drug Discov 2003;2 (11) 879- 890
PubMed Link to Article
Burstein  BNattel  S Atrial structural remodeling as an antiarrhythmic target. J Cardiovasc Pharmacol 2008;52 (1) 4- 10
PubMed Link to Article
Gillis  AM Angiotensin-receptor blockers for prevention of atrial fibrillation—a matter of timing or target? N Engl J Med 2009;360 (16) 1669- 1671
PubMed Link to Article
Takayama  KYuhki  KOno  K  et al.  Thromboxane A2 and prostaglandin F2alpha mediate inflammatory tachycardia. Nat Med 2005;11 (5) 562- 566
PubMed Link to Article
Fuster  VRydén  LECannom  DS  et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society, ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114 (7) e257- e354
PubMed Link to Article

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