Dose-ranging trial of enoxaparin for unstable angina: results of TIMI 11A. The Thrombolysis in Myocardial Infarction (TIMI) 11A Trial Investigators

OBJECTIVES: The Thrombolysis in Myocardial Infarction (TIMI) 11A trial compared the safety and tolerability of two weight-adjusted regimens of subcutaneous injections of enoxaparin, a low molecular weight heparin, in patients with unstable angina/non-Q wave myocardial infarction (NQMI). BACKGROUND: The optimal dose of enoxaparin in patients with arterial disorders has not been established. METHODS: Patients with unstable angina/NQMI were treated over a 14-day period in an open label dose-ranging trial. During the in-hospital phase, patients received either 1.25 mg/kg body weight (dose tier 1) or 1.0 mg/kg (dose tier 2) of enoxaparin subcutaneously every 12 h. A fixed dose of either 60 mg (body weight > or = 65 kg) or 40 mg (body weight < 65 kg) was administered subcutaneously every 12 h after hospital discharge. RESULTS: In an initial cohort of 321 patients (dose tier 1), the rate of major bleeding through 14 days was 6.5% and occurred predominantly at instrumented sites. In a second cohort of 309 patients (dose tier 2), the rate of major hemorrhage was reduced to 1.9%. In both dose tiers, only 3% to 5% of patients withdrew consent for subcutaneous injections during the home treatment phase. Through 14 days, the incidence of death, recurrent myocardial infarction or recurrent ischemia requiring revascularization was 5.6% in dose tier 1 and 5.2% in dose tier 2. CONCLUSIONS: An acute phase regimen of enoxaparin (1.0 mg/kg every 12 h) is associated with an acceptable rate of major hemorrhage during the in-hospital phase. There is a high rate of patient compliance during the home treatment phase. A Phase III trial is now underway to test the benefits of uninterrupted treatment with enoxaparin during both the in-hospital and outpatient treatment phases.

This article has been cited by other articles:

				R. A. Harrington, R. C. Becker, C. P. Cannon, D. Gutterman, A. M. Lincoff, J. J. Popma, G. Steg, G. H. Guyatt, and S. G. Goodman Antithrombotic Therapy for Non-ST-Segment Elevation Acute Coronary Syndromes: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 670S - 707S. [Abstract] [Full Text] [PDF]

				G. Montalescot, M. Cohen, G. Salette, W. J. Desmet, C. Macaya, P. E.G. Aylward, Ph. G. Steg, H. D. White, R. Gallo, S. R. Steinhubl, et al. Impact of anticoagulation levels on outcomes in patients undergoing elective percutaneous coronary intervention: insights from the STEEPLE trial Eur. Heart J., February 2, 2008; 29(4): 462 - 471. [Abstract] [Full Text] [PDF]

				Authors/Task Force Members, J.-P. Bassand, C. W. Hamm, D. Ardissino, E. Boersma, A. Budaj, F. Fernandez-Aviles, K. A.A. Fox, D. Hasdai, E. M. Ohman, et al. 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., July 1, 2007; 28(13): 1598 - 1660. [Full Text] [PDF]

				H. D. White, E. Braunwald, S. A. Murphy, A. J. Jacob, N. Gotcheva, L. Polonetsky, and E. M. Antman Enoxaparin vs. unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction in elderly and younger patients: results from ExTRACT-TIMI 25 Eur. Heart J., May 1, 2007; 28(9): 1066 - 1071. [Abstract] [Full Text] [PDF]

				N. Bhala, M. Hamon, J. W. Riddell, G. Karthikeyan, V. Pasceri, J. Schuler, J. Altenberger, M. Heigert, G. Montalescot, H. D. White, et al. Enoxaparin in elective percutaneous coronary intervention. N. Engl. J. Med., December 28, 2006; 355(26): 2788 - 2789. [Full Text] [PDF]

				G. Montalescot, H. D. White, R. Gallo, M. Cohen, P. G. Steg, P. E.G. Aylward, C. Bode, M. Chiariello, S. B. King III, R. A. Harrington, et al. Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention. N. Engl. J. Med., September 7, 2006; 355(10): 1006 - 1017. [Abstract] [Full Text] [PDF]

				P. Meurin, J. Y. Tabet, H. Weber, N. Renaud, and A. B. Driss Low-Molecular-Weight Heparin as a Bridging Anticoagulant Early After Mechanical Heart Valve Replacement Circulation, January 31, 2006; 113(4): 564 - 569. [Abstract] [Full Text] [PDF]

				J.-P. Collet, G. Montalescot, G. Agnelli, F. Van de Werf, E. P. Gurfinkel, J. Lopez-Sendon, C. V. Laufenberg, M. Klutman, N. Gowda, D. Gulba, et al. Non-ST-segment elevation acute coronary syndrome in patients with renal dysfunction: benefit of low-molecular-weight heparin alone or with glycoprotein IIb/IIIa inhibitors on outcomes. The Global Registry of Acute Coronary Events Eur. Heart J., November 1, 2005; 26(21): 2285 - 2293. [Abstract] [Full Text] [PDF]

				H. U. Jones, J. B. Muhlestein, K. W. Jones, D. G. Renlund, T. L. Bair, T. J. Bunch, B. D. Horne, D. L. Lappe, J. L. Anderson, and D. B. Doty Early Postoperative Use of Unfractionated Heparin or Enoxaparin is Associated with Increased Surgical Re-Exploration for Bleeding Ann. Thorac. Surg., August 1, 2005; 80(2): 518 - 522. [Abstract] [Full Text] [PDF]

				S. A. Spinler, P. Dobesh, C. Macie, and J. Douketis Dose Capping Enoxaparin Is Unjustified and Denies Patients With Acute Coronary Syndromes a Potentially Effective Treatment Chest, June 1, 2005; 127(6): 2288 - 2290. [Full Text] [PDF]

				M. S. Sabatine, D. A. Morrow, R. P. Giugliano, P. B.J. Burton, S. A. Murphy, C. H. McCabe, C. M. Gibson, and E. Braunwald Association of Hemoglobin Levels With Clinical Outcomes in Acute Coronary Syndromes Circulation, April 26, 2005; 111(16): 2042 - 2049. [Abstract] [Full Text] [PDF]

				L. R Moser and J. S Kalus Role of Low-Molecular-Weight Heparin in Invasive Management of Non-ST-Elevation Acute Coronary Syndromes Ann. Pharmacother., December 1, 2004; 38(12): 2094 - 2104. [Abstract] [Full Text] [PDF]

				J. M Ma, C. A Jackevicius, and E. Yeo Anti-Xa Monitoring of Enoxaparin for Acute Coronary Syndromes in Patients with Renal Disease Ann. Pharmacother., October 1, 2004; 38(10): 1576 - 1581. [Abstract] [Full Text] [PDF]

				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]

				G. Montalescot, J.P. Collet, M.L. Tanguy, A. Ankri, L. Payot, R. Dumaine, R. Choussat, F. Beygui, V. Gallois, and D. Thomas Anti-Xa Activity Relates to Survival and Efficacy in Unselected Acute Coronary Syndrome Patients Treated With Enoxaparin Circulation, July 27, 2004; 110(4): 392 - 398. [Abstract] [Full Text] [PDF]

				P. Das and D. J. Moliterno Fractionating Heparins and Their Clinical Trial Data--Something for Everyone JAMA, July 7, 2004; 292(1): 101 - 103. [Full Text] [PDF]

				M. L. Simoons, I. W. G. Bobbink, J. Boland, M. Gardien, P. Klootwijk, A. W. A. Lensing, W. Ruzyllo, V. A. W. M. Umans, A. Vahanian, F. Van De Werf, et al. A dose-finding study of fondaparinux in patients with non-ST-segment elevation acute coronary syndromes: The Pentasaccharide in Unstable Angina (PENTUA) study J. Am. Coll. Cardiol., June 16, 2004; 43(12): 2183 - 2190. [Abstract] [Full Text] [PDF]

				U. Elkayam, H. Singh, A. Irani, and M. W. Akhter Anticoagulation in Pregnant Women With Prosthetic Heart Valves Journal of Cardiovascular Pharmacology and Therapeutics, April 1, 2004; 9(2): 107 - 115. [Abstract] [PDF]

				S. D. Wiviott, C. P. Cannon, D. A. Morrow, S. A. Murphy, C. M. Gibson, C. H. McCabe, M. S. Sabatine, N. Rifai, R. P. Giugliano, P. M. DiBattiste, et al. Differential Expression of Cardiac Biomarkers by Gender in Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A TACTICS-TIMI 18 (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18) Substudy Circulation, February 10, 2004; 109(5): 580 - 586. [Abstract] [Full Text] [PDF]

				D. J. Moliterno, J. B. Hermiller, D. J. Kereiakes, E. Yow, R. J. Applegate, G. A. Braden, E. J. Dippel, M. I. Furman, C. L. Grines, N. S. Kleiman, et al. A novel point-of-care enoxaparin monitor for use during percutaneous coronary intervention: Results of the Evaluating Enoxaparin Clotting Times (ELECT) Study J. Am. Coll. Cardiol., September 17, 2003; 42(6): 1132 - 1139. [Abstract] [Full Text] [PDF]

				N. R. Bijsterveld, A. H. Moons, J. C. M. Meijers, M. Levi, H. R. Buller, and R. J. G. Peters The impact on coagulation of an intravenous loading dose in addition to a subcutaneousregimen of low-molecular-weight heparinin the initial treatment of acute coronary syndromes J. Am. Coll. Cardiol., August 6, 2003; 42(3): 424 - 427. [Abstract] [Full Text] [PDF]

				J. D. Marmur, S. X. Anand, R. S. Bagga, J. Fareed, C.-M. Pan, S. K. Sharma, and M. F. Richard The activated clotting time can be used to monitor the low molecular weight heparin dalteparin after intravenous administration J. Am. Coll. Cardiol., February 5, 2003; 41(3): 394 - 402. [Abstract] [Full Text] [PDF]

				G. C. Wong, R. P. Giugliano, and E. M. Antman Use of Low-Molecular-Weight Heparins in the Management of Acute Coronary Artery Syndromes and Percutaneous Coronary Intervention JAMA, January 15, 2003; 289(3): 331 - 342. [Abstract] [Full Text] [PDF]

				J.-P. Collet, G. Montalescot, E. Fine, J.-L. Golmard, M. Dalby, R.e. Choussat, A. Ankri, R. Dumaine, C. Lesty, N. Vignolles, et al. Enoxaparin in unstable angina patients who would have been excluded from randomized pivotal trials J. Am. Coll. Cardiol., January 1, 2003; 41(1): 8 - 14. [Abstract] [Full Text] [PDF]

				D. L. Bhatt, B. I. Lee, P. J. Casterella, M. Pulsipher, M. Rogers, M. Cohen, V. E. Corrigan, T. J. Ryan Jr, J. A. Breall, J. W. Moses, et al. Safety of concomitant therapy with eptifibatide and enoxaparin in patients undergoing percutaneous coronary intervention: Results of the coronary revascularization using integrilin and single bolus enoxaparin study J. Am. Coll. Cardiol., January 1, 2003; 41(1): 20 - 25. [Abstract] [Full Text] [PDF]

				R.e. Choussat, G. Montalescot, J. P. Collet, E. Vicaut, A. Ankri, V. Gallois, G.e. Drobinski, I. Sotirov, and D. Thomas A unique, low dose of intravenous enoxaparin in elective percutaneous coronary intervention J. Am. Coll. Cardiol., December 4, 2002; 40(11): 1943 - 1950. [Abstract] [Full Text] [PDF]

				J. Schweizer, A. Muller, L. Forkmann, G. Hellner, and W. Kirch Potential Use of a Low-Molecular-Weight Heparin to Prevent Restenosis in Patients with Extensive Wall Damage Following Peripheral Angioplasty Angiology, October 1, 2001; 52(10): 659 - 669. [Abstract] [PDF]

				A. M. Ross, P. Molhoek, C. Lundergan, M. Knudtson, Y. Draoui, L. Regalado, V. Le Louer, F. Bigonzi, W. Schwartz, E. de Jong, et al. Randomized Comparison of Enoxaparin, a Low-Molecular-Weight Heparin, With Unfractionated Heparin Adjunctive to Recombinant Tissue Plasminogen Activator Thrombolysis and Aspirin: Second Trial of Heparin and Aspirin Reperfusion Therapy (HART II) Circulation, August 7, 2001; 104(6): 648 - 652. [Abstract] [Full Text] [PDF]

				A. G. G. Turpie and E. M. Antman Low-Molecular-Weight Heparins in the Treatment of Acute Coronary Syndromes Arch Intern Med, June 25, 2001; 161(12): 1484 - 1490. [Abstract] [Full Text] [PDF]

				J. Ph. Collet, G. Montalescot, L. Lison, R. Choussat, A. Ankri, G. Drobinski, I. Sotirov, and D. Thomas Percutaneous Coronary Intervention After Subcutaneous Enoxaparin Pretreatment in Patients With Unstable Angina Pectoris Circulation, February 6, 2001; 103(5): 658 - 663. [Abstract] [Full Text] [PDF]

				W. Ageno and A. G. Turpie Therapy of unstable angina with the low molecular weight heparins Vascular Medicine, November 1, 2000; 5(4): 217 - 223. [Abstract] [PDF]

				S. Kaul and P. K. Shah Low molecular weight heparin in acute coronary syndrome: evidence for superior or equivalent efficacy compared with unfractionated heparin? J. Am. Coll. Cardiol., June 1, 2000; 35(7): 1699 - 1712. [Abstract] [Full Text] [PDF]

				G. Montalescot, V. Polle, J. P. Collet, P. Leprince, A. Bellanger, I. Gandjbakhch, and D. Thomas Low Molecular Weight Heparin After Mechanical Heart Valve Replacement Circulation, March 14, 2000; 101(10): 1083 - 1086. [Abstract] [Full Text] [PDF]

				D. A. Morrow, N. Rifai, E. M. Antman, D. L. Weiner, C. H. McCabe, C. P. Cannon, and E. Braunwald Serum amyloid A predicts early mortality in acute coronary syndromes: a TIMI 11A substudy J. Am. Coll. Cardiol., February 1, 2000; 35(2): 358 - 362. [Abstract] [Full Text] [PDF]

				Y. Yeghiazarians, J. B. Braunstein, A. Askari, and P. H. Stone Unstable Angina Pectoris N. Engl. J. Med., January 13, 2000; 342(2): 101 - 114. [Full Text] [PDF]

				E. M. Antman, C. H. McCabe, E. P. Gurfinkel, A. G. G. Turpie, P. J. L. M. Bernink, D. Salein, A. Bayes de Luna, K. Fox, J.-M. Lablanche, D. Radley, et al. Enoxaparin Prevents Death and Cardiac Ischemic Events in Unstable Angina/Non-Q-Wave Myocardial Infarction : Results of the Thrombolysis In Myocardial Infarction (TIMI) 11B Trial Circulation, October 12, 1999; 100(15): 1593 - 1601. [Abstract] [Full Text] [PDF]

				P. J. Zed, J. E. Tisdale, and S. Borzak Low-Molecular-Weight Heparins in the Management of Acute Coronary Syndromes Arch Intern Med, September 13, 1999; 159(16): 1849 - 1857. [Abstract] [Full Text] [PDF]

				T. J. Ryan, E. M. Antman, N. H. Brooks, R. M. Califf, L. D. Hillis, L. F. Hiratzka, E. Rapaport, B. Riegel, R. O. Russell, E. E. Smith III, et al. 1999 update: ACC/AHA guidelines for the management of patients with acute myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction) J. Am. Coll. Cardiol., September 1, 1999; 34(3): 890 - 911. [Full Text] [PDF]

				S A J Chamuleau, R J de Winter, M Levi, R Adams, H R Büller, M H Prins, K I Lie, and R J G Peters Low molecular weight heparin as an adjunct to thrombolysis for acute myocardial infarction: the FATIMA study Heart, July 1, 1998; 80(1): 35 - 39. [Abstract] [Full Text]

				R. J. Leadley Jr, C. J. Kasiewski, J. S. Bostwick, R. Bentley, C. T. Dunwiddie, and M. H. Perrone Inhibition of Repetitive Thrombus Formation in the Stenosed Canine Coronary Artery by Enoxaparin, But Not by Unfractionated Heparin Arterioscler. Thromb. Vasc. Biol., June 1, 1998; 18(6): 908 - 914. [Abstract] [Full Text] [PDF]

				J. I. Weitz Low-Molecular-Weight Heparins N. Engl. J. Med., September 4, 1997; 337(10): 688 - 699. [Full Text] [PDF]

				M. Cohen, C. Demers, E. P. Gurfinkel, A. G.G. Turpie, G. J. Fromell, S. Goodman, A. Langer, R. M. Califf, K. A.A. Fox, J. Premmereur, et al. A Comparison of Low-Molecular-Weight Heparin with Unfractionated Heparin for Unstable Coronary Artery Disease N. Engl. J. Med., August 14, 1997; 337(7): 447 - 452. [Abstract] [Full Text] [PDF]

				P. W. Armstrong Heparin in Acute Coronary Disease -- Requiem for a Heavyweight? N. Engl. J. Med., August 14, 1997; 337(7): 492 - 494. [Full Text]