Papers

Clinical effects of anticoagulant therapy in suspected acute myocardial infarction: systematic overview of randomised trials

^a BHF/MRC/ICRF Clinical Trial Service Unit, University of Oxford, Oxford OX2 6HE, ^b Clinical Trials Research Unit, University of Auckland, Auckland, New Zealand, ^c Clinical Trials and Evaluation Unit, Royal Brompton Hospital, London SW3 6NP, ^d Medical Department B, Rigshospitalet, Copenhagen, Denmark, ^e HGH-McMaster Clinic, Hamilton General Hospital, Hamilton, Ontario, Canada

Correspondence to: Professor Rory Collins, Clinical Trial Service Unit, Radcliffe Infirmary, Oxford OX2 6HE.

Abstract

Objectives: Most randomised trials of anticoagulant therapy for suspected acute myocardial infarction have been small and, in some, aspirin and fibrinolytic therapy were not used routinely. A systematic overview (meta-analysis) of their results is needed, in particular to assess the clinical effects of adding heparin to aspirin.
Design: Computer aided searches, scrutiny of reference lists, and inquiry of investigators and companies were used to identify potentially eligible studies. On central review, 26 studies were found to involve unconfounded randomised comparisons of anticoagulant therapy versus control in suspected acute myocardial infarction. Additional information on study design and outcome was sought by correspondence with study investigators.
Subjects: Patients with suspected acute myocardial infarction.
Interventions: No routine aspirin was used among about 5000 patients in 21 trials (including half of one small trial) that assessed heparin alone or heparin plus oral anticoagulants, and aspirin was used routinely among 68 000 patients in six trials (including the other half of one small trial) that assessed the addition of intravenous or high dose subcutaneous heparin.
Main outcome measurements: Death, reinfarction, stroke, pulmonary embolism, and major bleeds (average follow up of about 10 days).
Results: In the absence of aspirin, anticoagulant therapy reduced mortality by 25% (SD 8%; 95% confidence interval 10% to 38%; 2P = 0.002), representing 35 (11) fewer deaths per 1000. There were also 10 (4) fewer strokes per 1000 (2P = 0.01), 19 (5) fewer pulmonary emboli per 1000 (2P<0.001), and non-significantly fewer reinfarctions, with about 13 (5) extra major bleeds per 1000 (2P = 0.01). Similar sized effects were seen with the different anticoagulant regimens studied. In the presence of aspirin, however, heparin reduced mortality by only 6% (SD 3%; 0% to 10%; 2P = 0.03), representing just 5 (2) fewer deaths per 1000. There were 3 (1.3) fewer reinfarctions per 1000 (2P = 0.04) and 1 (0.5) fewer pulmonary emboli per 1000 (2P = 0.01), but there was a small non-significant excess of stroke and a definite excess of 3 (1) major bleeds per 1000 (2P<0.0001).
Conclusions: The clinical evidence from randomised trials does not justify the routine addition of either intravenous or subcutaneous heparin to aspirin in the treatment of acute myocardial infarction (irrespective of whether any type of fibrinolytic therapy is used).

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Bhatt, D. L., Scheiman, J., Abraham, N. S., Antman, E. M., Chan, F. K.L., Furberg, C. D., Johnson, D. A., Mahaffey, K. W., Quigley, E. M., Harrington, R. A., Bates, E. R., Bridges, C. R., Eisenberg, M. J., Ferrari, V. A., Hlatky, M. A., Kaul, S., Lindner, J. R., Moliterno, D. J., Mukherjee, D., Schofield, R. S., Rosenson, R. S., Stein, J. H., Weitz, H. H., Wesley, D. J. (2008). ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use: A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 52: 1502-1517 [Full text]  
• Bhatt, D. L., Scheiman, J., Abraham, N. S., Antman, E. M., Chan, F. K.L., Furberg, C. D., Johnson, D. A., Mahaffey, K. W., Quigley, E. M. (2008). ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use: A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation 118: 1894-1909 [Full text]  
• Schulman, S., Beyth, R. J., Kearon, C., Levine, M. N. (2008). Hemorrhagic Complications of Anticoagulant and Thrombolytic Treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133: 257S-298S [Abstract] [Full text]  
• Goodman, S. G., Menon, V., Cannon, C. P., Steg, G., Ohman, E. M., Harrington, R. A. (2008). Acute ST-Segment Elevation Myocardial Infarction: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133: 708S-775S [Abstract] [Full text]  
• Authors/Task Force Members, , Bassand, J.-P., Hamm, C. W., Ardissino, D., Boersma, E., Budaj, A., Fernandez-Aviles, F., Fox, K. A.A., Hasdai, D., Ohman, E. M., Wallentin, L., Wijns, W., ESC Committee for Practice Guidelines (CPG), , Vahanian, A., Camm, J., De Caterina, R., Dean, V., Dickstein, K., Filippatos, G., Kristensen, S. D., Widimsky, P., McGregor, K., Sechtem, U., Tendera, M., Hellemans, I., Gomez, J. L. Z., Silber, S., Funck-Brentano, C., Document Reviewers, , Kristensen, S. D., Andreotti, F., Benzer, W., Bertrand, M., Betriu, A., De Caterina, R., DeSutter, J., Falk, V., Ortiz, A. F., Gitt, A., Hasin, Y., Huber, K., Kornowski, R., Lopez-Sendon, J., Morais, J., Nordrehaug, J. E., Silber, S., Steg, P. G., Thygesen, K., Tubaro, M., Turpie, A. G.G., Verheugt, F., Windecker, S. (2007). Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: The Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology. Eur Heart J 28: 1598-1660 [Full text]  
• Fidan, D., Unal, B., Critchley, J., Capewell, S. (2007). Economic analysis of treatments reducing coronary heart disease mortality in England and Wales, 2000-2010. QJM 100: 277-289 [Abstract] [Full text]  
• De Caterina, R., Husted, S., Wallentin, L., Agnelli, G., Bachmann, F., Baigent, C., Jespersen, J., Kristensen, S. D., Montalescot, G., Siegbahn, A., Verheugt, F. W.A., Weitz, J. (2007). Anticoagulants in heart disease: current status and perspectives. Eur Heart J 0: ehl492v1-34 [Full text]  
• Francis, C. W. (2007). Prophylaxis for Thromboembolism in Hospitalized Medical Patients. NEJM 356: 1438-1444 [Full text]  
• Stark, J. E., Vesta, K. S. (2006). A Pharmacist-Initiated Method to Improve Venous Thromboembolic Prophylaxis Rates in Medically Ill Patients. Journal of Pharmacy Practice 19: 275-279 [Abstract]  
• Hilbrich, L., Sleight, P. (2006). Progress and problems for randomized clinical trials: from streptomycin to the era of megatrials. Eur Heart J 27: 2158-2164 [Abstract] [Full text]  
• Guyatt, G., Gutterman, D., Baumann, M. H., Addrizzo-Harris, D., Hylek, E. M., Phillips, B., Raskob, G., Lewis, S. Z., Schunemann, H. (2006). Grading Strength of Recommendations and Quality of Evidence in Clinical Guidelines: Report From an American College of Chest Physicians Task Force. Chest 129: 174-181 [Abstract] [Full text]  
• Eikelboom, J. W., Quinlan, D. J., Mehta, S. R., Turpie, A. G., Menown, I. B., Yusuf, S. (2005). Unfractionated and Low-Molecular-Weight Heparin as Adjuncts to Thrombolysis in Aspirin-Treated Patients With ST-Elevation Acute Myocardial Infarction: A Meta-Analysis of the Randomized Trials. Circulation 112: 3855-3867 [Abstract] [Full text]  
• Califf, R. M. (2005). Simple Principles of Clinical Trials Remain Powerful. JAMA 293: 489-491 [Full text]  
• Leizorovicz, A., Mismetti, P. (2004). Preventing Venous Thromboembolism in Medical Patients. Circulation 110: IV-13-IV-19 [Abstract] [Full text]  
• Guyatt, G., Schunemann, H. J., Cook, D., Jaeschke, R., Pauker, S. (2004). Applying the Grades of Recommendation for Antithrombotic and Thrombolytic Therapy: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126: 179S-187S [Abstract] [Full text]  
• Harrington, R. A., Becker, R. C., Ezekowitz, M., Meade, T. W., O'Connor, C. M., Vorchheimer, D. A., Guyatt, G. H. (2004). Antithrombotic Therapy for Coronary Artery Disease: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126: 513S-548S [Abstract] [Full text]  
• Dukkipati, S., O'Neill, W. W., Harjai, K. J., Sanders, W. P., Deo, D., Boura, J. A., Bartholomew, B. A., Yerkey, M. W., Sadeghi, H. M., Kahn, J. K. (2004). Characteristics of cerebrovascular accidents after percutaneous coronary interventions. J Am Coll Cardiol 43: 1161-1167 [Abstract] [Full text]  
• Stark, J. E, Kilzer, W. J (2004). Venous Thromboembolic Prophylaxis in Hospitalized Medical Patients. The Annals of Pharmacotherapy 38: 36-40 [Abstract] [Full text]  
• Lip, G. Y H, Chin, B. S P, Prasad, N. (2002). ABC of antithrombotic therapy: Antithrombotic therapy in myocardial infarction and stable angina. BMJ 325: 1287-1289 [Full text]  
• Priori, S.G., Aliot, E., Blomstrom-Lundqvist, C., Bossaert, L., Breithardt, G., Brugada, P., Camm, A.J., Cappato, R., Cobbe, S.M., Di Mario, C., Maron, B.J., McKenna, W.J., Pedersen, A.K., Ravens, U., Schwartz, P.J., Trusz-Gluza, M., Vardas, P., Wellens, H.J.J., Zipes, D.P. (2001). Task Force on Sudden Cardiac Death of the European Society of Cardiology. Eur Heart J 22: 1374-1450  
• Hirsh, J., Anand, S. S., Halperin, J. L., Fuster, V. (2001). Guide to Anticoagulant Therapy: Heparin : A Statement for Healthcare Professionals From the American Heart Association. Arterioscler. Thromb. Vasc. Bio. 21 : e9-e9 [Full text]  
• Hirsh, J., Anand, S. S., Halperin, J. L., Fuster, V. (2001). Guide to Anticoagulant Therapy: Heparin : A Statement for Healthcare Professionals From the American Heart Association. Circulation 103: 2994-3018 [Full text]  
• Guyatt, G., Schunemann, H., Cook, D., Jaeschke, R., Pauker, S., Bucher, H. (2001). Grades of Recommendation for Antithrombotic Agents. Chest 119: 3S-7S [Full text]  
• Hirsh, J., Warkentin, T. E., Shaughnessy, S. G., Anand, S. S., Halperin, J. L., Raschke, R., Granger, C., Ohman, E. M., Dalen, J. E. (2001). Heparin and Low-Molecular-Weight Heparin Mechanisms of Action, Pharmacokinetics, Dosing, Monitoring, Efficacy, and Safety. Chest 119: 64S-94S [Full text]  
• Geerts, W. H., Heit, J. A., Clagett, G. P., Pineo, G. F., Colwell, C. W., Anderson, F. A. Jr., Wheeler, H. B. (2001). Prevention of Venous Thromboembolism. Chest 119: 132S-175S [Full text]  
• Cairns, J. A., Theroux, P., Lewis, H. D. Jr., Ezekowitz, M., Meade, T. W. (2001). Antithrombotic Agents in Coronary Artery Disease. Chest 119: 228S-252S [Full text]  
• (2000). Tackling myocardial infarction. DTB 38: 17-22 [Abstract] [Full text]  
• Gottlieb, S, Goldbourt, U, Boyko, V, Harpaz, D, Mandelzweig, L, Khoury, Z, Stern, S, Behar, S, for the SPRINT and Israeli Thrombolytic Survey Gro, (2000). Mortality trends in men and women with acute myocardial infarction in coronary care units in Israel. A comparison between 1981-1983 and 1992-1994. Eur Heart J 21: 284-295 [Abstract]  
• Yarnell, J. W. G., Sweetnam, P. M., Rumley, A., Lowe, G. D. O. (2000). Lifestyle and Hemostatic Risk Factors for Ischemic Heart Disease : The Caerphilly Study. Arterioscler. Thromb. Vasc. Bio. 20: 271-279 [Abstract] [Full text]  
• Klement, P., Liao, P., Bajzar, L. (1999). A Novel Approach to Arterial Thrombolysis. Blood 94: 2735-2743 [Abstract] [Full text]  
• Frostfeldt, G., Ahlberg, G., Gustafsson, G., Helmius, G., Lindahl, B., Nygren, A., Siegbahn, A., Swahn, E., Venge, P., Wallentin, L. (1999). Low molecular weight heparin (dalteparin) as adjuvant treatment to thrombolysis in acute myocardial infarction--a pilot study: Biochemical Markers in Acute Coronary Syndromes (BIOMACS II). J Am Coll Cardiol 33: 627-633 [Abstract] [Full text]  
• Bates, S. M., Weitz, J. I. (1999). Prevention of activation of blood coagulation during acute coronary ischemic syndromes: beyond aspirin and heparin. Cardiovasc Res 41: 418-432 [Abstract] [Full text]  
• Collins, R., Peto, R., Baigent, C., Sleight, P. (1997). Aspirin, Heparin, and Fibrinolytic Therapy in Suspected Acute Myocardial Infarction. NEJM 336: 847-860 [Full text]  
• James, M. A, Hood, S., Birnie, D., Collins, R., Baigent, C., Peto, R., Ketley, D, Woods, K L (1997). Clinical effects of anticoagulants in suspected acute myocardial infarction. BMJ 314: 222-222 [Full text]  
• (1996). ADDING HEPARIN TO ASPIRIN OF LITTLE BENEFIT IN ACUTE MI. JWatch General 1996: 1-1 [Full text]  
• Liaw, P. C. Y., Becker, D. L., Stafford, A. R., Fredenburgh, J. C., Weitz, J. I. (2001). Molecular Basis for the Susceptibility of Fibrin-bound Thrombin to Inactivation by Heparin Cofactor II in the Presence of Dermatan Sulfate but Not Heparin. J. Biol. Chem. 276: 20959-20965 [Abstract] [Full text]