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ISSN: 1524-4539 Copyright © 2005 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online 72514 Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX DOI: 10.1161/CIRCULATIONAHA.105.552984 2005;112;3225-3231 Circulation Ulf Stenestrand, Johan Lindbäck, Lars Wallentin and for the RIKS-HIA Registry Intensive Care Admissions (RIKS-HIA) Study From the Register of Information and Knowledge About Swedish Heart Myocardial Infarction Influences Long-Term Outcome: A Prospective Cohort Anticoagulation Therapy in Atrial Fibrillation in Combination With Acute http://circ.ahajournals.org/cgi/content/full/112/21/3225 located on the World Wide Web at: The online version of this article, along with updated information and services, is http://www.lww.com/static/html/reprints.html Reprints: Information about reprints can be found online at journalpermissions@lww.com Street, Baltimore, MD 21202-2436. Phone 410-5280-4050. Fax: 410-528-8550. Email: Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, 351 West Camden http://circ.ahajournals.org/subsriptions/ Subscriptions: Information about subscribing to Circulation is online at by on December 25, 2006 circ.ahajournals.orgDownloaded from Anticoagulation Therapy in Atrial Fibrillation in Combination With Acute Myocardial Infarction Influences Long-Term Outcome A Prospective Cohort Study From the Register of Information and Knowledge About Swedish Heart Intensive Care Admissions (RIKS-HIA) Ulf Stenestrand, MD, PhD; Johan Lindbäck, MSc; Lars Wallentin, MD, PhD; for the RIKS-HIA Registry Background—The American and European guidelines do not agree with regard to antithrombotic treatment in patients with atrial fibrillation (AF) and acute myocardial infarction (AMI), thus causing uncertainty among physicians. We investigated the prescription of oral anticoagulation (OAC) in patients discharged alive with AF after an AMI and the influence of OAC treatment on 1-year mortality. Methods and Results—This was a prospective cohort study using data from the Register of Information and Knowledge about Swedish Heart Intensive care Admissions (RIKS-HIA) on patients admitted to the coronary care units of 72 Swedish hospitals from 1995 to 2002. A total of 6182 patients discharged alive with first registry-recorded AMI and AF on discharge ECG were included. One-year mortality data were obtained from the Swedish National Cause of Death Register. Only 30% (n�1848) of the 6182 patients with AF were prescribed OAC. At 1 year, the unadjusted mortality was 31% (1183 deaths) in the platelet-inhibitors only group and 22% (414 deaths) in the OAC-treated group. In Cox regression analysis with adjustment for confounding factors, OAC treatment was associated with a reduction in 1-year mortality (relative risk 0.73; 95% CI 0.62 to 0.86; P�0.001) in hospital survivors of AMI with AF. The reduction in mortality appeared to be caused primarily by a lower rate of ischemic heart death (55.6% versus 62.0%) and fatal stroke (5.7% versus 7.5%) in the OAC group. This reduction of mortality was similar among most subgroups based on age, sex, baseline characteristics, previous disease manifestations, and medications. Conclusions—In daily clinical practice, OAC was only given to a minority (30%) of AMI patients with AF, despite the fact that OAC was associated with a 29% relative and 7% absolute reduction in 1-year mortality after adjustment for confounding variables. The results emphasize the importance of OAC treatment for AF after AMI. (Circulation. 2005; 112:3225-3231.) Key Words: anticoagulants � complications � myocardial infarction � patients � prognosis � atrial fibrillation Atrial fibrillation (AF) is a common arrhythmia afteracute myocardial infarction (AMI), with a reported incidence in previous studies between 5% and 23%.1–4 Mortality in AMI patients with AF has also been shown to be up to twice as high as for those without AF.1,5–7 There are several trials and reviews concerning the efficacy of oral anticoagulants (OACs) in patients with AF without AMI8 and regarding OAC in AMI without AF.9–12 However, there are no results available from large randomized trials or observa- tional cohorts with regard to the efficacy of OAC in patients with both AMI and AF. The treatment guidelines for AF13 recommend OAC treatment in AF patients with an additional risk factor, eg, coronary artery disease. In patients with ST-elevation myocardial infarction and AF, the American Editorial p 3225 College of Cardiology and American Heart Association guidelines14 recommend OAC therapy, whereas the European Society of Cardiology guidelines15 give no evidence-based recommendation for OAC with or without acetylsalicylic acid (ASA) or thienopyridine in this category of patients. We sought to investigate physician habits with regard to the prescription of OAC in patients discharged alive with AF after an AMI and the influence of OAC treatment on 1-year mortality in these patients. Methods The Register of Information and Knowledge about Swedish Heart Intensive care Admissions (RIKS-HIA) registers all patients admit- Received March 30, 2005; revision received July 8, 2005; accepted July 25, 2005. From the Department of Cardiology (U.S.), University Hospital of Linköping, Sweden, and Uppsala Clinical Research Center (J.L., L.W.), University Hospital Uppsala, Sweden. Correspondence to Ulf Stenestrand, MD, PhD, Department of Cardiology, University Hospital, SE 581 85 Linköping, Sweden. E-mail stenestrand@riks-hia.se © 2005 American Heart Association, Inc. Circulation is available at http://www.circulationaha.org DOI: 10.1161/CIRCULATIONAHA.105.552984 3225 Arrhythmia/Electrophysiology by on December 25, 2006 circ.ahajournals.orgDownloaded from ted to the coronary care units of all participating hospitals. Informa- tion is reported on case record forms that include 100 variables, as described elsewhere.16 Briefly, the register includes information on baseline characteristics, previous medication, symptoms, in-hospital examinations and tests, interventions, major complications, risk assessments, and medications at discharge. The full protocol is available at the register’s World Wide Web site (www.riks-hia.se). Data on previous history of stroke, dementia, renal failure, conges- tive heart failure, chronic pulmonary disease, or cancer were ob- tained by merging the registry data with the National Patient Register, which includes diagnoses for all patients hospitalized in Sweden from 1987 forward. One-year mortality data were obtained by merging the RIKS-HIA database with the National Cause of Death Register, which includes the vital status of all Swedish citizens from 1995 through 2003. All patients for whom data were entered into the RIKS-HIA were informed of their participation in the register (patients could request to be excluded from the register). The register and the merging with registries were approved by an ethics committee and the National Board of Health and Welfare. After data were merged with other registers, all patient identifications were removed from the RIKS-HIA data file. Only patients discharged alive with AF on the discharge ECG and AMI as the final diagnosis were included in the present study. The criteria for the diagnosis of AMI were standardized and were identical for all participating hospitals using the World Health Organization criteria.17 The bio- chemical criterion was at least 1 measurement indicating twice the upper limit of normal of an appropriate biochemical marker, such as creatine kinase-MB protein concentration or troponin. During the years 1995 to 2000, the former limits still applied in Sweden, with creatine kinase-MB mass �10 �g/L and troponin T �0.1 �g/L as the discrimination limits for AMI. The new limits in the consensus document18 were applied from January 2001. Data verification was performed by comparison of entered data in RIKS-HIA with the hospital records of 1972 randomly chosen patients at 21 different hospitals. Statistical Analysis Different patient strata were compared by �2 tests for categorical variables and by the t test for continuous variables. A propensity score was calculated for each patient that estimated the probability of receiving an OAC at discharge given the background characteristics and other treatments given. Adjustment for the propensity score in the analysis aimed to balance the groups with regard to differences in background characteristics, based on prescription of OAC, which also led to a simpler model with a higher precision of parameter estimates. A multiple logistic regression model was fitted to estimate the propensity score. The model included 25 covariates: age (as a second-degree polynomial), sex, history of CABG surgery, history of percutaneous coronary intervention, previous myocardial infarction, history of diabetes mellitus, history of stroke, congestive heart failure, renal failure, chronic pulmonary disease, dementia, cancer within 3 years, history of hypertension, medications used before study entry (including ACE inhibitors or angiotensin II receptor blockers, anticoagulants, �-blockers, aspirin or platelet inhibitors, calcium channel blockers, digitalis, diuretics, lipid-lowering drugs, and long-acting nitrates), circulatory arrest at arrival, presence of AF, signs of congestive heart failure, and reperfusion therapy. Cox proportional hazards regression analyses were used to identify whether OAC at discharge by itself had a significant influence on 1-year mortality. The models included the propensity scores and discharge treatments (�-blockers, diabetes medication, ACE inhibi- tors or angiotensin II receptor blockers, calcium channel blockers, digitalis, diuretics, lipid-lowering drugs, long-acting nitrates, and revascularization within 14 days). Several 2-way interaction terms were included in the propensity score model. The interactions included were selected with the Akaike19 information criteria. Stratification was performed for use of OACs versus nonuse at admission in order to meet model assumptions. Statistical analyses were performed with the statistical program R version 2.0 (R foundation for Statistical Computing; URL: http//www.r-project.org) and SPSS version 12 software (SPSS Inc). Results Validation of Data When 1972 computer forms from 38 hospitals comprising 161 280 variables were closely reviewed by an external monitor, there was 97% agreement between the registered information and the source data in the patient records among the variables included in our analyses. Total AF Material Among the 82 565 first-time admission AMI patients dis- charged alive between the years 1995 and 2002, 7.6% (n�6275) had AF. The occurrence of AF increased with age and was present in 13.1% of those older than 75 years. Among those discharged with AF, 78% had AF on admission, whereas 22% did not when they were admitted for the index event. Of the AMI patients with AF at discharge, 29% (n�1848) were prescribed an OAC, whereas 60% (n�3768) were given ASA and/or thienopyridine, and 11% (n�659) did not receive any antiplatelet or anticoagulation therapy. These 659 patients without any antithrombotic treatment had signif- icantly higher 1-year mortality (45%, n�297) than patients receiving platelet inhibitors only (31%, n�1183) or OACs (alone or in combination with platelet inhibitors; 22%, n�414). Patients who did not receive any antiplatelet or anticoagulation therapy were not included in the remaining analyses because these patients might have had severe co- morbidities that explained both the lack of any antithrombotic treatment and the high mortality. OAC and Non-OAC Treatment The AF patients who received OAC treatment were signifi- cantly younger (Table 1) and had less history of chronic pulmonary disease, less cancer, and less dementia but more frequently had a history of stroke or coronary revasculariza- tion. Of those discharged with OAC treatment, 46% were already taking this medication before admission. For 4% of the patients who had AF on discharge ECG, OACs were discontinued and replaced with a platelet inhibitor while the patients were hospitalized for AMI. AF was present on admission in 80% among those discharged with OAC, whereas 73% had AF on admission in the no-OAC group. There was no difference between the groups with regard to bundle-branch block, ST-segment elevation, or T-wave in- version on the presenting ECG. During hospitalization, intra- venous �-blockers were more commonly used among those discharged with OAC, whereas there was no difference between the groups with regard to reperfusion therapy or in-hospital congestive heart failure. At discharge, ASA or other antiplatelet medication was given in 100% of the current no-OAC group and 26% of the OAC group. ACE inhibitors, �-blockers, digitalis, and lipid-lowering medica- tion were all given significantly more often in patients discharged with OAC, whereas they less frequently received long-acting nitroglycerin. Early coronary revascularization within 14 days was performed less frequently in the OAC group (Table 1). The crude results indicated that mortality was significantly higher in the group discharged with ASA or thienopyridine than in the OAC group, both at 30 days and at 1 year (Table 3226 Circulation November 22, 2005 TABLE 1. Overview of Data From Patients Discharged Alive With AF and a Diagnosis of AMI Divided Into 2 Groups of Antithrombotic Therapy at Discharge ASA and/or Thienopyridine (n�3768) OAC � Platelet Inhibitor (n�1848) P Mean age �SD, y 79.1�8.1 74.9�8.0 �0.001 Male gender 60.6 66.2 �0.001 History of stroke 18.5 22.5 �0.001 History of renal failure 1.9 2.1 0.66 History of chronic obstructive pulmonary disease 8.4 6.8 0.040 Dementia 0.5 0.2 0.042 Cancer within 3 years 5.3 3.7 0.012 History of congestive heart failure 31.9 32.4 0.71 History of hypertension 39.4 41.6 0.12 Diabetes mellitus 25.6 25.9 0.78 History of myocardial infarction 37.1 35.7 0.29 History of coronary revascularization 7.0 12.1 �0.001 OAC therapy before admission 3.8 45.7 �0.001 Current smoker 11.1 11.4 0.77 ECG at admission AF 73.4 80.5 �0.001 Normal STT region 9.1 9.2 0.84 Left bundle-branch blockage 11.2 12.2 0.28 ST-segment elevation 29.2 29.1 0.92 ST-segment depression 30.2 27.0 0.014 T-wave inversion 10.4 10.1 0.77 Other pathological changes in STT region 9.9 12.3 0.006 In-hospital events Circulatory arrest 0.8 1.4 0.47 Congestive heart failure 59.4 59.3 0.94 Reperfusion therapy 20.3 19.3 0.35 Intravenous or subcutaneous anticoagulants 43.5 38.5 �0.001 Intravenous �-blocker 29.1 34.6 �0.001 Percutaneous coronary intervention 5.4 5.1 0.64 Discharge medication Aspirin or platelet inhibitor 100.0 25.9 �0.001 ACE inhibitor 50.1 63.1 �0.001 �-Blocker 69.1 75.2 �0.001 Calcium channel blocker 16.4 16.4 0.94 Diabetes medication (oral or insulin) 19.8 21.6 0.11 Digitalis 42.1 47.9 �0.001 Diuretics 73.2 73.1 0.89 Lipid-lowering medication 20.1 30.1 �0.001 Long-acting nitroglycerin 47.0 41.3 �0.001 Revascularization within 14 days 8.5 6.4 0.007 Outcome 30-Day mortality 6.1 4.1 0.002 1-Year mortality 31.4 22.4 �0.001 All values are percentages, except for age. History of stroke, dementia, renal failure, chronic obstructive pulmonary disease, cancer within 3 years, and congestive heart failure were all based on International Classification of Diseases–9th Revision or 10th Revision (ICD-9 or ICD-10) diagnosis received during prior hospitalizations attained from the National Patient Register. History of diabetes, hypertension requiring medication, prior coronary revascularization, and myocardial infarction were patient-reported variables. Stenestrand et al Anticoagulants in AMI With AF 3227 1). The unadjusted absolute risk reduction of death within 1 year was 9% in the OAC group. After adjustment for the propensity score for receiving OACs, 1-year survival was still significantly better among those discharged with OACs, with a relative risk of 0.73 (95% CI 0.62 to 0.86; P�0.001) compared with those discharged with only ASA or thienopy- ridine (Figure 1). The adjusted absolute risk reduction by OAC at 1 year was 7%. This survival benefit showed no heterogeneity for a large number of subgroups analyzed (Table 2), except for patients discharged without �-blockers, among whom there was a tendency toward increased risk with OAC. New myocardial infarction or stroke (including both ischemic and hemorrhagic) were both more common causes of death among no-OAC versus OAC patients (Table 3). Bleeding complications were similar in both groups, whereas both fatal and nonfatal ischemic strokes were signif- icantly more common in patients without OAC (Table 4). OAC With and Without Platelet Inhibitor Versus Platelet Inhibitors Only When the data were analyzed with patients divided into 3 groups, the unadjusted 1-year mortality was lower in both OAC groups (OAC�ASA 19.2% [92/479], OAC alone 23.5% [322/1369], and ASA and/or thienopyridine 31.4% [1183/3768]; Kaplan-Meier cumulative hazard curves are shown in Figure 2). After adjustment for the propensity score of receiving OAC and for covariates that could influence survival, OAC was still associated with a lower risk of death (relative risk 0.74, 95% CI 0.62 to 0.88) than for ASA and/or thienopyridine, and OAC plus ASA had a relative risk of 0.70 (95% CI 0.55 to 0.90) compared with the group given only ASA and/or thienopyridine (Figure 3). Discussion When we performed a PubMed search in January 2005, we found no trial on the subject of anticoagulation in patients with AMI and AF. Nevertheless, the treatment guidelines for AF recommend OAC treatment in patients with AF and an additional risk factor, and in case of simultaneous coronary disease, a combination of OAC and ASA is even suggest- ed.13,20 On the other hand, the Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology stated in their document15 that subsets of patients, eg, those with large anterior akinesia, AF, or echographically proven left ventricular thrombus, might benefit from OAC, but large randomized trials for these indications are lacking. The American Collage of Cardiology/American Heart Asso- ciation guidelines for ST-elevation myocardial infarction recommend OAC alone as secondary prevention in all such patients with either paroxysmal or persistent AF (class I, level of evidence A).14 The same guidelines recommend combina- tion therapy of OAC and ASA in patients younger than 75 Figure 1. Propensity score–adjusted Cox cumulative hazard curves in patients discharged with AF and a diagnosis of AMI and the influence of OAC on 1-year survival. TABLE 2. Adjusted Relative Risk of 1-Year Mortality in Patients Discharged Alive With AF and a Diagnosis of AMI on OAC � Platelet Inhibitor Versus ASA and/or Thienopyridine Treatment Proportion, % Relative Risk 95% CI All 100.0 0.71 0.56–0.91 Age �75 years 33.6 0.61 0.40–0.93 Age �75 years 66.4 0.71 0.53–0.96 Men 62.8 0.60 0.43–0.82 Women 37.2 0.93 0.64–1.36 No history of stroke 80.3 0.67 0.50–0.90 History of stroke 19.7 0.88 0.57–1.36 No history of congestive heart failure 68.0 0.63 0.46–0.88 History of congestive heart failure 32.0 0.86 0.59–1.24 No history of hypertension 59.8 0.54 0.38–0.77 History of hypertension 40.2 0.96 0.69–1.34 No diabetes mellitus 74.8 0.64 0.47–0.86 Diabetes mellitus 25.2 0.85 0.56–1.30 No history of myocardial infarction 64.0 0.64 0.46–0.91 History of myocardial infarction 36.0 0.83 0.59–1.17 No reperfusion therapy 79.9 0.72 0.55–0.94 Reperfusion therapy 20.1 0.67 0.37–1.22 No percutaneous coronary intervention 94.9 0.77 0.60–0.99 Percutaneous coronary intervention 5.1 0.20 0.05–0.80 No OCA therapy before admission 82.3 0.78 0.58–1.05 OCA therapy before admission 17.7 0.66 0.41–1