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(Circulation. 2002;105:557.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
From the Department of Veterans Affairs Cooperative Studies Program Coordinating Center (P.P.), West Haven, Conn; the Medicine Service, Department of Veterans Affairs Boston Health Care System (L.D.F., M.T.B.), Boston, Mass; the Medical Service, Department of Veterans Affairs New England Health Care System (M.D.E.), New Haven, Conn; the Medical Service, Department of Veterans Affairs Medical Center (D.L.), Washington DC; and the Department of Veterans Affairs Medical Center (J.S.), Albany, NY.
Correspondence to Louis Fiore, MD, MPH, MAVERIC (151 MAV), VA Boston Healthcare System, 150 S Huntington Ave, Boston, MA 02130 (e-mail louis.fiore{at}med.va.gov), and reprint requests to Dr Michael D. Ezekowitz, Department of Veterans Affairs Cooperative Studies Program Coordinating Center (151A), VA Connecticut Health Care System, 950 Campbell Ave, West Haven, CT 06516. E-mail michael.ezekowitz@drexel.edu
| Abstract |
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Methods and Results We conducted a randomized open-label study to compare the efficacy of warfarin (target international normalized ratio 1.5 to 2.5 IU) plus aspirin (81 mg daily) with the efficacy of aspirin monotherapy (162 mg daily) in reducing the total mortality in 5059 patients enrolled within 14 days of infarction and followed for a median of 2.7 years. Secondary end points included recurrent myocardial infarction, stroke, and major hemorrhage. Four hundred thirty-eight (17.3%) of 2537 patients assigned to the aspirin group and 444 (17.6%) of 2522 patients assigned to the combination group died (log-rank P=0.76). Recurrent myocardial infarction occurred in 333 patients (13.1%) taking aspirin and in 336 patients (13.3%) taking combination therapy (log-rank P=0.78). Stroke occurred in 89 patients (3.5%) taking aspirin and in 79 patients (3.1%) taking combination therapy (log-rank P=0.52). Major bleeding occurred more frequently in the combination therapy group than in the aspirin group (1.28 versus 0.72 events per 100 person years of follow-up, respectively; P<0.001). There were 14 individuals with intracranial bleeds in both the aspirin and combination therapy groups.
Conclusions In postmyocardial infarction patients, warfarin therapy (at a mean international normalized ratio of 1.8) combined with low-dose aspirin did not provide a clinical benefit beyond that achievable with aspirin monotherapy.
Key Words: myocardial infarction aspirin anticoagulants trials
| Introduction |
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Given that aspirin and oral anticoagulants inhibit thrombosis by different mechanisms, we proposed that the coadministration of these agents (combination hemotherapy) might have a synergistic antithrombotic effect. In the past, there has been reluctance to combine these agents in clinical trials and clinical practice. This view stems from the high bleeding rates observed in a series of older studies designed to reduce embolic stroke in patients with prosthetic heart valves.3
We hypothesized that by lowering the dose of aspirin to 81 mg daily and monitoring the effect of oral anticoagulants by use of the international normalized ratio (INR) at a range between 1.5 and 2.5 IU, the therapeutic benefit of combination hemotherapy would be preserved, and the major bleeding rate would be reduced.
| Methods |
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Patients
We have described the design of the present study in detail elsewhere.4 Briefly, veterans of either sex and of any age were eligible to participate in the study if they sustained a qualifying AMI within the preceding 14 days and fulfilled none of the exclusion criteria (Table 1). Each participating site was instructed to screen all patients with AMI for study eligibility.
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Treatment Regimen and Follow-Up
After confirming the patients eligibility with local site personnel by telephone, the Cooperative Studies Program Coordinating Center randomly assigned each patient to receive open-label combination hemotherapy or aspirin according to a permuted-block design with stratification by center. Patients in the aspirin monotherapy group received chewable aspirin (162 mg daily) as recommended by the Fifth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy.5 Patients in the combination hemotherapy group received warfarin sodium (Coumadin, DuPont Pharmaceuticals) titrated to an INR of 1.5 to 2.5 IU along with chewable aspirin (81 mg daily, Bayer Pharmaceuticals). In the combination group, the 81-mg daily dose was chosen on the basis of other recent studies of combination therapy.610 The dose of 81 mg was associated with lower rates of major gastrointestinal bleeding without compromising efficacy. Monitoring of the INR was performed locally by using a dose-adjustment protocol. Delay in the initiation of protocol-assigned therapy after randomization was permitted to allow subjects to undergo invasive procedures before receiving protocol-determined anticoagulant therapy.
A study coordinator saw patients 3 months after randomization and then every 6 months for the duration of the study. Subjects in the combination therapy group were seen between these scheduled visits either by the study coordinator or by the anticoagulation clinic staff to titrate their warfarin dosage. At each follow-up visit, the study staff provided counseling regarding adherence to the study regimen and asked about the occurrence of events and side effects since the previous visit.
Outcomes
The primary outcome of the present study was all-cause mortality. Secondary outcomes were recurrent myocardial infarction and stroke, as reported by local investigators using standardized definitions in the protocol.4 A composite secondary outcome of cardiovascular events was defined as vascular mortality, recurrent myocardial infarction, or stroke. Major hemorrhage was defined as any fatal, intracranial, or retroperitoneal bleed or any bleed that led to a hospitalization or transfusion and was accompanied by a fall in the hemoglobin of at least 2 g/dL. Cause of death and major hemorrhage were adjudicated by the end-points committee, which was blinded to treatment assignment. Secondary end points were not adjudicated.
Statistical Analysis
All analyses were conducted according to the intention-to-treat principle. Sample size was determined to detect a 15% reduction in annual mortality with combination therapy relative to aspirin alone. The target sample size to detect this effect size with 80% power and 5% type I error was 8000 patients and 1000 deaths. The trial was planned as a study of duration and not information. Differences in cumulative mortality rates between treatment groups were tested by the log-rank statistic. Interim monitoring of treatment mortality differences was performed by using the
spending method of Lan and DeMets11 with sloped boundaries, with the "looks" at the data corresponding to the annual meetings of the Data Monitoring Board. Adverse event rates were expressed as the number of events per 100 person years of follow-up. The permutation test was used to test whether the rate ratio (combination/aspirin) was different from 1; 95% bootstrap confidence limits for rate ratio were determined.12
Analysis of secondary end points was tested at the 1% level of significance to provide some control for multiplicity. Two planned subgroup analyses were performed with patients stratified by age (younger or older than 60 years) and by myocardial function (severe, moderate, or mild/normal left ventricular dysfunction). Severe ventricular dysfunction was defined as a measured ejection fraction by angiography or radionuclide study of
25% or a qualitative finding of "markedly depressed" myocardial function on echocardiographic assessment. Moderate ventricular dysfunction was defined as a measured ejection fraction >25% but <40% or a qualitative echographic finding of "moderately depressed" myocardial function. In addition, we evaluated the effects of treatment according to location, type of infarction, and the presence or absence of diabetes to determine whether adverse events, particularly stroke, were reduced in these high-risk subgroups.
The Cox proportional hazards model13 was used to identify independent baseline predictors of mortality and to determine the relationship between the date of initiation of protocol therapy and mortality within each treatment arm. The fit of the model to the data was evaluated by examining residuals.14
| Results |
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Patients randomly assigned to the 2 treatment groups were similar at baseline with respect to demographic and clinical variables (Table 2). The population was characterized by high rates of hypertension, diabetes, and previous myocardial infarction. The median age was 62 years.
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Cumulative initiation rates of protocol-assigned therapy in the aspirin and combination groups were 74% versus 61% at 1 month and 92% versus 84% at 1 year, respectively. Among patients initiated on therapy, 290 (12.6%) in the aspirin group and 517 (25.3%) in the combination group had therapy permanently discontinued during the study. Thus, the proportion of total follow-up time on protocol-assigned therapy was 86% for the aspirin group and 71% for the combination group. Patients who never had protocol therapy initiated or those who had it discontinued were treated at the discretion of their local physician.
Anticoagulation
INR values of patients in the combination therapy arm were measured and reported at each of the follow-up visit appointments and are displayed in Figure 1. The median INR for all values obtained at all scheduled follow-up visits was 1.8 IU. Values of 1.4 IU and 2.2 IU correspond to the lowest and highest quartiles, respectively, of measured INRs. These INR results reflect the intensity of anticoagulation only during the 71% of follow-up time during which patients randomized to combination therapy were receiving protocol-assigned treatment.
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Outcomes
Overall, 438 patients (17.3%) assigned to the aspirin group and 444 patients (17.6%) assigned to the combination group died (log-rank P=0.76). Adjudicated cause of death is given in Table 3. Clinical characteristics of patients who died are presented in Table 4. Recurrent myocardial infarction occurred in 333 patients (13.1%) taking aspirin and 336 patients (13.3%) taking combination therapy (log-rank P=0.78). Of the total 789 reinfarctions (in 669 subjects) reported, 667 (85%) were classified as definite, and 122 (15%) were classified as probable. Stroke occurred in 89 patients (3.5%) taking aspirin and 79 patients (3.1%) taking combination therapy (log-rank P=0.52). The cumulative 5-year Kaplan-Meier curves were virtually identical for these outcomes as well as for the composite outcome of cardiovascular events (Figure 2). Hazard ratios for combination therapy relative to aspirin therapy with 95% CIs for the primary and secondary outcomes by subgroups are given in Figure 3.
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An exploratory analysis was performed to examine the relationship between the initiation of therapy and survival. Patients were stratified by the duration of the delay between randomization and the initiation of protocol-assigned therapy according to the following: initiation of protocol therapy within 14 days, initiation of therapy from 15 to 28 days, initiation of therapy after 28 days, or no initiation of protocol therapy. Patients for whom therapy was initiated within 14 days were used as the reference group. There was no association between delay in initiation of therapy and overall survival (Table 5). Patients for whom protocol-assigned therapy was never begun had an increased hazard ratio for mortality in both the aspirin and combination therapy groups.
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Adverse Events
The annual incidence of major bleeding episodes (Table 6) was greater in the combination therapy group, with a rate ratio of 1.78 (95% bootstrap confidence limits 1.27 to 2.72). Major bleeds were primarily gastrointestinal in origin in both the combination therapy group (71%) and aspirin group (63%). Confirmed intracranial hemorrhage occurred with equal frequency in both groups, but 18 strokes in the aspirin group and 21 strokes in the combination therapy arm were not evaluated for hemorrhagic or ischemic etiology. Fatal hemorrhage occurred in 7 patients in the aspirin group and 10 patients in the combination group.
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| Discussion |
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Although the annual major bleeding complication rates were low, levels were higher in the combination group (1.28%) than in the aspirin group (0.72%, P<0.001). Intracranial hemorrhage was virtually identical in the 2 groups.
The protocol required randomization to occur within 2 weeks of the infarction. By 1 month after study entry, a proportion of patients had not begun protocol-assigned therapy (27.6% for aspirin and 40.6% for combination therapy). The primary reason for the delay in protocol-assigned therapy initiation was the reluctance of investigators to anticoagulate patients in whom invasive procedures were either anticipated or in whom procedures had been recently performed. The delay in study drug initiation in the combination therapy group, relative to the aspirin therapy group, was not responsible for the lack of difference in survival in the 2 groups. In addition, survival was not associated with the length of delay between randomization and drug initiation.
Of the 444 deaths in the combination therapy group, 117 (26%) occurred in patients who had never begun warfarin therapy. Of the 438 deaths in the aspirin group, 86 (19.6%) occurred in patients who had never begun aspirin therapy. An exploratory analysis excluding randomized patients who had never begun study medication failed to show any difference in any of the outcome measures (data not shown).
Adherence to the treatment assigned is a major concern in trials using oral anticoagulant therapy. Despite the delay in initiation of the study drug in many individuals, the proportion of follow-up time spent on protocol-assigned therapy was high: 86% for the aspirin group and 71% for the combination group. Withdrawals from both the aspirin group (12.6%) and the combination therapy group (25.3%) were within the rates seen in other major secondary prevention studies using these agents.15 The proportion of INR values (74%) at or above the lower end of the specified therapeutic rang (1.5 IU) was also typical.16
A potential limitation of the present study is open-label drug administration with resultant differential follow-up between treatment arms. Patients in the combination group were seen by study personnel more frequently, resulting in inherent informational biases, including detection, recall, and interviewer bias. Differential misclassification may result from these biases and affect the identification and classification of bleeding episodes and other secondary outcomes. These limitations were addressed by defining total mortality as the primary study end point and adjudicating all bleeding episodes by a blinded end-points committee.
The other published post-AMI trial evaluating warfarin and aspirin in combination, the Coumadin Aspirin Reinfarction Study (CARS), also failed to demonstrate the superiority of combination therapy compared with aspirin monotherapy.6 In that trial, 8803 patients were randomized within 21 days of qualifying infarct to 1 of 3 arms: aspirin monotherapy (160 mg daily) or a combination of aspirin (80 mg) and warfarin at a fixed dose of either 1 or 3 mg daily. The intensity of anticoagulation was considerably lower than that in the Combination Hemotherapy and Mortality Prevention (CHAMP) trial; the median INR was 1.04 IU in the 1 mg warfarin group and 1.19 IU in the 3 mg warfarin group. No differences in the primary event rates of reinfarction, nonfatal ischemic stroke, or cardiovascular death were observed after a median follow-up of 14 months. Major bleeding rates were similar in the 2 studies and higher in the combination therapy groups for both studies. Thus, it appears that the combination of aspirin and warfarin at a mean INR of
1.8 is no better than aspirin alone.
In addition to these 2 studies, 3 trials have failed to demonstrate the superiority of combination therapy using low-intensity warfarin (mean INR <2.0 IU) compared with control treatment in the settings of unstable angina and nonQ-wave AMI,9 stroke prevention in nonvalvular atrial fibrillation,7 and prevention of atherosclerosis in aortocoronary saphenous vein bypass grafts.8 Two small studies that evaluated combination therapy with the use of moderate-intensity warfarin (INR 2.0 to 2.5 IU)9 and high-intensity warfarin (INR 3.0 to 4.5 IU)10 have shown improved short-term outcomes (3 months) in patients with acute coronary ischemia compared with outcomes in patients after control treatment. The question of the efficacy of higher intensity warfarin in combination with aspirin for long-term secondary prevention after AMI is being addressed by ongoing studies, including the Warfarin Reinfarction Study II (WARIS II) and the Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis II (ASPECT II).
| Appendix |
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Offices of the Chairmen are as follows: Department of Veterans Affairs Medical Center, Boston, Mass: L. Fiore (Cochairman) and S. Craine (Administrative Officer); Department of Veterans Affairs Medical Center, West Haven, Conn: M. Ezekowitz (Cochairman) and M. Farqui (Study Recruitment Coordinator).
The following persons are in the Department of Veterans Affairs Cooperative Studies Program Coordinating Center, West Haven, Conn: D. Collins, (Chief), P. Peduzzi (Assistant Chief and Study Biostatistician), L. Durant (Statistical Assistant), M. Lee, A. DeRosa, P. Collins, L. Franklin, S. Marcinauskis, and M. Antonelli.
The following persons are in the Department of Veterans Affairs Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque, NM: M. Sather (Chief), C. CoIling, and J. Peterson.
The following persons are located at VA Headquarters, Washington, DC: J.R. Feussner (Chief Research and Development Officer) and D. Deykin (Former Chief, Cooperative Studies Program).
Committees are as follows: Data Monitoring Board: B. Weksler (Chair), M. Dunn, S. Kelsey, G. Raskob, and G. Beck; Executive Committee: L. Fiore, M. Brophy, P. Peduzzi, M. Ezekowitz, J. Sacco, D. Lu, C. Colling, and D. Collins; and End Points Committee: J. Plehn (Chair), P.S. Rahko, M. Cohen, R. Homer, E. Benjamin, and L. Mendes.
| Acknowledgments |
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| Footnotes |
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Received June 19, 2001; revision received November 20, 2001; accepted November 20, 2001.
| References |
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4. Fiore L, Brophy M, Peduzzi P, et al. Combination Hemotherapy and Mortality Prevention (CHAMP) Study Rationale and Design. J Thromb Thrombolysis. 1998; 6: 133140.[CrossRef][Medline] [Order article via Infotrieve]
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Cairns JA, Theroux P, Lewis DL, et al. Antithrombotic agents in coronary artery disease. Chest. 1998; 114: 611S633S.
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Lan KKG, De Mets DL. Discrete sequential boundaries for clinical trials. Biometrika. 1983; 70: 659663.
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J. Ansell, J. Hirsh, L. Poller, H. Bussey, A. Jacobson, and E. Hylek The Pharmacology and Management of the Vitamin K Antagonists: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 204S - 233S. [Abstract] [Full Text] [PDF] |
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M. N. Levine, G. Raskob, R. J. Beyth, C. Kearon, and S. Schulman Hemorrhagic Complications of Anticoagulant Treatment: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 287S - 310S. [Abstract] [Full Text] [PDF] |
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R. A. Harrington, R. C. Becker, M. Ezekowitz, T. W. Meade, C. M. O'Connor, D. A. Vorchheimer, and G. H. Guyatt Antithrombotic Therapy for Coronary Artery Disease: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 513S - 548S. [Abstract] [Full Text] [PDF] |
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M. A. Earl and V. F. Mauro The Clinical Impact of Administering Warfarin to Post-Myocardial Infarction Patients Journal of Pharmacy Practice, August 1, 2004; 17(4): 266 - 269. [Abstract] [PDF] |
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E. M Antman The re-emergence of anticoagulation in coronary disease Eur. Heart J. Suppl., April 1, 2004; 6(suppl_B): B2 - B8. [Abstract] [Full Text] [PDF] |
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M. O'Donnell and J. Hirsh Establishing an Optimal Therapeutic Range for Coumarins: Filling in the Gaps Arch Intern Med, March 22, 2004; 164(6): 588 - 590. [Full Text] [PDF] |
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M. J. Quinn, H. D. Aronow, R. M. Califf, D. L. Bhatt, S. Sapp, N. S. Kleiman, R. A. Harrington, D. F. Kong, D. E. Kandzari, and E. J. Topol Aspirin dose and six-month outcome after an acute coronary syndrome J. Am. Coll. Cardiol., March 17, 2004; 43(6): 972 - 978. [Abstract] [Full Text] [PDF] |
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J. Herlitz, J. Holm, M. Peterson, B. W Karlson, M. Haglid Evander, L. Erhardt, and for the LoWASA study group Effect of fixed low-dose warfarin added to aspirin in the long term after acute myocardial infarction: the LoWASA Study Eur. Heart J., February 1, 2004; 25(3): 232 - 239. [Abstract] [Full Text] [PDF] |
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M.J. Zibaeenezhad, A. Mowla, and M.H. Sorbi Warfarin and Aspirin Versus Aspirin Alone in Patients with Acute Myocardial Infarction: A Pilot Study Angiology, January 1, 2004; 55(1): 17 - 20. [Abstract] [PDF] |
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A. P. Coletta, J. G.F. Cleland, N. Freemantle, H. Loh, A. Memon, and A. L. Clark Clinical trials update from the European Society of Cardiology: CHARM, BASEL, EUROPA and ESTEEM Eur J Heart Fail, October 1, 2003; 5(5): 697 - 704. [Abstract] [Full Text] [PDF] |
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M. E van der Elst, H. Buurma, M. L Bouvy, and A. de Boer Drug Therapy for Prevention of Recurrent Myocardial Infarction Ann. Pharmacother., October 1, 2003; 37(10): 1465 - 1477. [Abstract] [Full Text] [PDF] |
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A. S Jeddy and B. L Gleason Aspirin and Warfarin Versus Aspirin Monotherapy After Myocardial Infarction Ann. Pharmacother., October 1, 2003; 37(10): 1502 - 1505. [Abstract] [Full Text] [PDF] |
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J. Hirsh, V. Fuster, J. Ansell, and J. L. Halperin American Heart Association/American College of Cardiology Foundation guide to warfarin therapy J. Am. Coll. Cardiol., May 7, 2003; 41(9): 1633 - 1652. [Full Text] [PDF] |
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J. Hirsh, V. Fuster, J. Ansell, and J. L. Halperin American Heart Association/American College of Cardiology Foundation Guide to Warfarin Therapy Circulation, April 1, 2003; 107(12): 1692 - 1711. [Full Text] [PDF] |
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S. S. Anand and S. Yusuf Oral anticoagulants in patients with coronary artery disease J. Am. Coll. Cardiol., February 19, 2003; 41(4_Suppl_S): 62S - 69S. [Abstract] [Full Text] [PDF] |
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The Task Force on the Management of Acute Myocardi, F. Van de Werf, D. Ardissino, A. Betriu, D. V. Cokkinos, E. Falk, K. A.A. Fox, D. Julian, M. Lengyel, F.-J. Neumann, et al. Management of acute myocardial infarction in patients presenting with ST-segment elevation Eur. Heart J., January 1, 2003; 24(1): 28 - 66. [Full Text] [PDF] |
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OTHER ARTICLES NOTED (Nov 01 to 18 Oct 02) Evid. Based Nurs., January 1, 2003; 6(1): e1 - 1. [Full Text] [PDF] |
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P. Sobieszczyk, M. C. Fishbein, and S. Z. Goldhaber Acute Pulmonary Embolism: Don't Ignore the Platelet Circulation, October 1, 2002; 106(14): 1748 - 1749. [Full Text] [PDF] |
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M. Hurlen, M. Abdelnoor, P. Smith, J. Erikssen, and H. Arnesen Warfarin, Aspirin, or Both after Myocardial Infarction N. Engl. J. Med., September 26, 2002; 347(13): 969 - 974. [Abstract] [Full Text] [PDF] |
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R. C. Becker Antithrombotic Therapy after Myocardial Infarction N. Engl. J. Med., September 26, 2002; 347(13): 1019 - 1022. [Full Text] [PDF] |
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V. M Oh Warfarin combined with low dose aspirin in myocardial infarction did not provide clinical benefit beyond that of aspirin alone Evid. Based Med., September 1, 2002; 7(5): 140 - 140. [Full Text] [PDF] |
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M. A. Brouwer, P. J.P.C. van den Bergh, W. R.M. Aengevaeren, G. Veen, H. E. Luijten, D. P. Hertzberger, A. J. van Boven, R. P.J.W. Vromans, G. J.H. Uijen, and F. W.A. Verheugt Aspirin Plus Coumarin Versus Aspirin Alone in the Prevention of Reocclusion After Fibrinolysis for Acute Myocardial Infarction: Results of the Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis (APRICOT)-2 Trial Circulation, August 6, 2002; 106(6): 659 - 665. [Abstract] [Full Text] [PDF] |
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M. A. Brouwer and F. W.A. Verheugt Oral Anticoagulation for Acute Coronary Syndromes Circulation, March 19, 2002; 105(11): 1270 - 1274. [Full Text] [PDF] |
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