Anticoagulation Therapy in Atrial Fibrillation in Combination With Acute Myocardial Infarction Influences Long-Term Outcome
http://www.100md.com
《循环学杂志》
the Department of Cardiology (U.S.), University Hospital of Linkping, Sweden, and Uppsala Clinical Research Center (J.L., L.W.), University Hospital Uppsala, Sweden.
Abstract
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.
Key Words: anticoagulants complications myocardial infarction patients prognosis atrial fibrillation
Introduction
Atrial fibrillation (AF) is a common arrhythmia after acute 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 observational 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 admitted to the coronary care units of all participating hospitals. Information 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, congestive heart failure, chronic pulmonary disease, or cancer were obtained 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 biochemical 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 μg/L and troponin T 0.1 μg/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 inhibitors 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 discharged 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 significantly 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 comorbidities 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 significantly 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 revascularization. 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 inversion on the presenting ECG. During hospitalization, intravenous -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 medication 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 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 thienopyridine (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 significantly 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 suggested.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 Association 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 combination therapy of OAC and ASA in patients younger than 75 years of age without specific indication for anticoagulation (class IIa, level of evidence B). Obviously, both solid evidence and consistent guidelines are lacking for antithrombotic treatment in patients with the combination of AMI and AF. This lack of knowledge emphasizes the importance of the present study for shedding light on the unresolved issue of antithrombotic treatment of AF, which involves 8% of the total AMI population discharged alive and 13% of those older than 75 years. The importance of this issue is further emphasized by the fact that this complication is associated with markedly increased mortality.
The ambiguous treatment recommendations for these patients are reflected in the different therapy strategies used in real life. The vast majority of AMI survivors with AF were prescribed ASA and/or thienopyridine, whereas only one third of the patients received OAC. Although combination treatment with OAC and ASA appeared to be superior to OAC therapy alone in the unadjusted survival analysis, this favorable effect disappeared after propensity score and covariate adjustments. Still, both OAC strategies were significantly superior to the ASA and/or thienopyridine regimen even after adjustments for a large number of covariates in the present study. According to previous trials, ASA plus fixed low-dose or low-intensity OACs is not better than ASA alone in preventing new ischemic events.21–23 Moderate- to high-intensity OAC (international normalized ratio >2.0) plus ASA, however, resulted in fewer reocclusions after successful lysis than ASA alone.24 This combination therapy was also found to reduce the composite of death, reinfarction, and stroke in 2 recent postinfarction studies (Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2 [ASPECT-2, n=993] and the Warfarin, Aspirin Reinfarction Study-2 [WARIS-2, n=3640]),9,10 although it was associated with a doubling in the low rate of nonfatal bleeding complications. This caused the European Task Force on the Management of Acute ST-Elevation Myocardial Infarction15 to state that currently, no recommendations can be made for the combined routine use of OACs and aspirin after AMI, whereas the American counterpart to this task force has an intermediate recommendation for combination therapy.14
The validity of the results of the present study were strengthened by the fact that OAC treatment primarily was associated with a reduction in fatalities caused by stroke and ischemic heart disease, which is in keeping with the expected effects of OAC treatment. Furthermore, the homogenous results in the vast majority subgroups support the idea that OAC treatment is superior to ASA and its combination with thienopyridine in patients with AF after myocardial infarction.
The most important limitations of the present study are the nonrandomized assignment of treatment strategy and the possibility that unknown differences in background characteristics between the groups contributed to the result. To address this concern, we used advanced statistical methods to minimize the problems of bias inherent to observational studies.25,26 On the other hand, the present study has the strength that no patients were excluded because of certain inclusion or exclusion criteria, which is always the case in controlled randomized trials. Thus, the present results reflect all of the patients discharged from routine intensive coronary care with AMI and AF.
Today, the only way to administer OAC is as vitamin K antagonists. This treatment involves regular and well-managed controls of the international normalized ratio with frequent dose adjustments. The treatment is complicated by many food and drug interactions. Treatment with vitamin K antagonists is thus costly and time consuming both for the patients and their healthcare providers. These drawbacks contribute to the hesitation to recommend routine prescription of OAC even to patients discharged with AF after myocardial infarction. The upcoming new OAC treatments, eg, oral thrombin inhibitors or Xa inhibitors, are highly warranted to facilitate the use of routine OAC treatment in AF.
Conclusions
Today, the evidence base for the most appropriate antithrombotic treatment of AF after myocardial infarction is limited, and there are differences between the European and the American guidelines. In daily clinical practice, OAC was only given to a minority (30%) of these patients. Still, after adjustment for confounding variables, OAC treatment was associated with a 29% relative and a 7% absolute reduction in 1-year mortality, mainly caused by a reduction in fatal stroke. These results support the American recommendation of routine OAC treatment for AF after myocardial infarction. These results emphasize the need for randomized trials to provide a better evidence base for the antithrombotic treatment of AF after myocardial infarction.
Acknowledgments
The RIKS-HIA registry has been supported by unrestricted grants from the National Board of Health and Welfare, the Federation of County Councils in Sweden, and the Swedish Heart-Lung Foundation. The registry’s sponsors had no influence on or input with regard to the study’s results. We thank all the participating hospitals in Sweden for their help and cooperation in contributing data to RIKS-HIA. All participating centers, physicians, and nurses and the details of the RIKS-HIA technology are presented on the registry’s World Wide Web site (www.riks-hia.se).
References
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Abstract
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.
Key Words: anticoagulants complications myocardial infarction patients prognosis atrial fibrillation
Introduction
Atrial fibrillation (AF) is a common arrhythmia after acute 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 observational 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 admitted to the coronary care units of all participating hospitals. Information 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, congestive heart failure, chronic pulmonary disease, or cancer were obtained 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 biochemical 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 μg/L and troponin T 0.1 μg/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 inhibitors 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 discharged 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 significantly 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 comorbidities 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 significantly 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 revascularization. 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 inversion on the presenting ECG. During hospitalization, intravenous -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 medication 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 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 thienopyridine (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 significantly 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 suggested.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 Association 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 combination therapy of OAC and ASA in patients younger than 75 years of age without specific indication for anticoagulation (class IIa, level of evidence B). Obviously, both solid evidence and consistent guidelines are lacking for antithrombotic treatment in patients with the combination of AMI and AF. This lack of knowledge emphasizes the importance of the present study for shedding light on the unresolved issue of antithrombotic treatment of AF, which involves 8% of the total AMI population discharged alive and 13% of those older than 75 years. The importance of this issue is further emphasized by the fact that this complication is associated with markedly increased mortality.
The ambiguous treatment recommendations for these patients are reflected in the different therapy strategies used in real life. The vast majority of AMI survivors with AF were prescribed ASA and/or thienopyridine, whereas only one third of the patients received OAC. Although combination treatment with OAC and ASA appeared to be superior to OAC therapy alone in the unadjusted survival analysis, this favorable effect disappeared after propensity score and covariate adjustments. Still, both OAC strategies were significantly superior to the ASA and/or thienopyridine regimen even after adjustments for a large number of covariates in the present study. According to previous trials, ASA plus fixed low-dose or low-intensity OACs is not better than ASA alone in preventing new ischemic events.21–23 Moderate- to high-intensity OAC (international normalized ratio >2.0) plus ASA, however, resulted in fewer reocclusions after successful lysis than ASA alone.24 This combination therapy was also found to reduce the composite of death, reinfarction, and stroke in 2 recent postinfarction studies (Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2 [ASPECT-2, n=993] and the Warfarin, Aspirin Reinfarction Study-2 [WARIS-2, n=3640]),9,10 although it was associated with a doubling in the low rate of nonfatal bleeding complications. This caused the European Task Force on the Management of Acute ST-Elevation Myocardial Infarction15 to state that currently, no recommendations can be made for the combined routine use of OACs and aspirin after AMI, whereas the American counterpart to this task force has an intermediate recommendation for combination therapy.14
The validity of the results of the present study were strengthened by the fact that OAC treatment primarily was associated with a reduction in fatalities caused by stroke and ischemic heart disease, which is in keeping with the expected effects of OAC treatment. Furthermore, the homogenous results in the vast majority subgroups support the idea that OAC treatment is superior to ASA and its combination with thienopyridine in patients with AF after myocardial infarction.
The most important limitations of the present study are the nonrandomized assignment of treatment strategy and the possibility that unknown differences in background characteristics between the groups contributed to the result. To address this concern, we used advanced statistical methods to minimize the problems of bias inherent to observational studies.25,26 On the other hand, the present study has the strength that no patients were excluded because of certain inclusion or exclusion criteria, which is always the case in controlled randomized trials. Thus, the present results reflect all of the patients discharged from routine intensive coronary care with AMI and AF.
Today, the only way to administer OAC is as vitamin K antagonists. This treatment involves regular and well-managed controls of the international normalized ratio with frequent dose adjustments. The treatment is complicated by many food and drug interactions. Treatment with vitamin K antagonists is thus costly and time consuming both for the patients and their healthcare providers. These drawbacks contribute to the hesitation to recommend routine prescription of OAC even to patients discharged with AF after myocardial infarction. The upcoming new OAC treatments, eg, oral thrombin inhibitors or Xa inhibitors, are highly warranted to facilitate the use of routine OAC treatment in AF.
Conclusions
Today, the evidence base for the most appropriate antithrombotic treatment of AF after myocardial infarction is limited, and there are differences between the European and the American guidelines. In daily clinical practice, OAC was only given to a minority (30%) of these patients. Still, after adjustment for confounding variables, OAC treatment was associated with a 29% relative and a 7% absolute reduction in 1-year mortality, mainly caused by a reduction in fatal stroke. These results support the American recommendation of routine OAC treatment for AF after myocardial infarction. These results emphasize the need for randomized trials to provide a better evidence base for the antithrombotic treatment of AF after myocardial infarction.
Acknowledgments
The RIKS-HIA registry has been supported by unrestricted grants from the National Board of Health and Welfare, the Federation of County Councils in Sweden, and the Swedish Heart-Lung Foundation. The registry’s sponsors had no influence on or input with regard to the study’s results. We thank all the participating hospitals in Sweden for their help and cooperation in contributing data to RIKS-HIA. All participating centers, physicians, and nurses and the details of the RIKS-HIA technology are presented on the registry’s World Wide Web site (www.riks-hia.se).
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