New heparin dosing recommendations for patients with acute coronary syndromes


      Despite major innovations in antithrombotic and antiplatelet therapy, unfractionated intravenous heparin is widely used to treat acute coronary syndromes. Recommendations for unfractionated heparin dosing in acute myocardial infarction and unstable angina have been issued in two recent American College of Cardiology/American Heart Association guidelines. An initial heparin bolus of 60 U/kg (maximum, 4000 U) followed by a 12-U/kg/h infusion (maximum 1000 U/h) is recommended with alteplase for ST-elevation myocardial infarction. When intravenous heparin is administered for myocardial infarction with non-ST elevation and unstable angina, an initial bolus of 60 to 70 U/kg (maximum, 5000 U) followed by a 12- to 15-U/kg/h infusion is recommended. The goal is to achieve an activated partial thromboplastin time of 50 to 70 seconds. Here, we review these new dosing regimens and explain the rationale for their use. We also review the risk of bleeding with heparin, especially when administered concurrently with aspirin, thrombolytic agents, and glycoprotein IIb/IIIa antagonists, and the relationship between activated partial thromboplastin time and cardiac events.
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      1. Fuster V, Fallon JT, Nemerson Y. Coronary thrombosis. Lancet. 1996;348(suppl 1):s7–s10.

        • Zabel K.M
        • Granger C.B
        • Becker R.C
        • et al.
        Use of bedside activated partial thromboplastin time monitoring to adjust heparin dosing after thrombolysis for acute myocardial infarction; results of GUSTO-I.
        Am Heart J. 1998; 136: 868-876
        • Antman E.M
        Hirudin in acute myocardial infarction. Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B trial.
        Circulation. 1996; 94: 911-921
        • Granger C.B
        • Hirsh J
        • Califf R.M
        • et al.
        Activated partial thromboplastin time and outcome after thrombolytic therapy for acute myocardial infarction.
        Circulation. 1996; 93: 870-878
        • GUSTO IIa Investigators
        Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes.
        Circulation. 1994; 90: 1631-1637
        • Antman E.M
        Hirudin in acute myocardial infarction. Safety report from the thrombolysis and thrombin inhibition in myocardial infarction (TIMI) 9A Trial.
        Circulation. 1994; 90: 1624-1630
        • InTIME-II Investigators
        Intravenous NPA for the treatment of infarcting myocardium early.
        Eur Heart J. 2000; 21: 2005-2013
        • Ryan T.J
        • Antman E.M
        • Brooks N.H
        • et al.
        ACC/AHA guidelines for the management of patients with acute myocardial infarction. A report of the ACC/AHA taskforce on practice guidelines.
        J Am Coll Cardiol. 1999; 34: 890-911
        • Braunwald E
        • Antman E.M
        • Beasley J.W
        • et al.
        ACC/AHA guidelines for the management of patients with unstable angina, and non-ST-segment elevation myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee of the Management of Patients with Unstable Angina).
        J Am Coll Cardiol. 2000; 36: 970-1062
        • DeSwart C.A.M
        • Nijmeyer B
        • Roelofs J.M.M
        • Sixma J.J
        Kinetics of intravenously administered heparin in normal humans.
        Blood. 1982; 60: 1251-1258
        • Bjornsson T.O
        • Wolfram B.S
        • Kitchell B.B
        Heparin kinetics determined by three assay methods.
        Clin Pharmacol Ther. 1982; 31: 104-113
        • Hirsh J
        • van Aken W.G
        • Gallus A.S
        • et al.
        Heparin kinetics in venous thrombosis and pulmonary embolism.
        Circulation. 1976; 53: 691-695
        • Young E
        • Prins M.H
        • Levine M.N
        • Hirsh J
        Heparin binding to plasma proteins, an important mechanism for heparin resistance.
        Thromb Haemost. 1992; 67: 639-643
        • Cohen M
        • Demers C
        • Gurfinkel E.P
        • et al.
        A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group.
        N Engl J Med. 1997; 337: 447-452
        • Antman E.M
        • McCabe C.H
        • Gurfinkel E.P
        • et al.
        Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q wave myocardial infarction.
        Circulation. 1999; 100: 1593-1601
        • Klein W
        • Buchwald A
        • Hillis S.E
        • et al.
        • FRIC Investigators
        Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for six weeks in the management of unstable coronary artery disease.
        Circulation. 1997; 96: 61-68
      2. Low-molecular-weight heparin during instability in coronary artery disease. Fragmin during Instability in Coronary Artery Disease (FRISC) Study Group. Lancet 1996;347:561–568.

      3. Low molecular weight heparin seems safe when used with gp IIb/IIIa blockers in acute coronary syndromes. Heartwire.

        • Madan M
        • Berkowitz S.D
        • Tcheng J.E
        Glycoprotein IIb/IIIa integrin blockade.
        Circulation. 1998; 98: 2629-2635
        • PURSUIT Trial Investigators
        Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes.
        N Engl J Med. 1998; 339: 436-443
        • PRISM Study Investigators
        A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina.
        N Engl J Med. 1998; 338: 1498-1505
        • PRISM-PLUS Study Investigators
        Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction.
        N Engl J Med. 1998; 338: 1488-1497
        • EPIC Investigators
        Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty.
        N Engl J Med. 1994; 330: 956-961
        • EPILOG Investigators
        Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization.
        N Engl J Med. 1997; 336: 1689-1696
        • CAPTURE Investigators
        Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina.
        Lancet. 1997; 349: 1429-1435
        • EPISTENT Investigators
        Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of glycoprotein IIb/IIIa blockade. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting.
        Lancet. 1998; 352: 87-92
        • Brener S.J
        • Barr L.A
        • Burchenal J.E
        • et al.
        Randomized placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction.
        Circulation. 1998; 98: 734-741
        • RESTORE Investigators
        Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty.
        Circulation. 1997; 96: 1445-1453
        • IMPACT-II Investigators
        Randomized placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention.
        Lancet. 1997; 349: 1422-1428
        • Stevenson K.J
        • Easton A.C
        • Curry A
        • et al.
        The reliability of activated partial thromboplastin time methods and the relationship to lipid composition and ultrastructure.
        Throm Haemost. 1986; 55: 250-258
        • Shapiro G
        • Hutzinger S.W
        • Wilson J.E
        Variation among commercial activated partial thromboplastin reagents in response to heparin.
        Am J Clin Pathol. 1980; 74: 569-574
        • Barrowcliffe T.W
        • Gray E
        Studies of phospholipid reagents used in coagulation II.
        Thromb Haemost. 1981; 46: 634-637
        • Owen J
        • Payne E
        • Carstairs K
        Erroneous activated partial thromboplastin time.
        Ann Intern Med. 1978; 89: 146-147
        • Baenez E.I
        • Triplett D.A
        • Koepke J
        Laboratory monitoring of heparin therapy.
        Am J Clin Pathol. 1980; 74: 569-574
        • Brandt J.T
        • Triplett D.A
        Laboratory monitoring of heparin.
        Am J Clin Pathol. 1981; 76: 530-537
        • Heyns A.D
        • van den Berg D.J
        • Kleynhans P.H
        • du Toit P.W
        Unsuitability of evacuated tubes for monitoring heparin therapy by activated partial thromboplastin time.
        J Clin Pathol. 1981; 34: 63-68
        • D’Angelo A
        • Sereso M.P
        • D’Angelo S.V
        • et al.
        Effects of clot-detection methods and reagents on activated partial thromboplastin time (aPTT); implication in heparin monitoring by aPTT.
        Am J Clin Pathol. 1990; 94: 297-306
        • Chiu H.M
        • Hirsh J
        • Yung W.L
        • et al.
        Relationship between anticoagulant and antithrombotic effects of heparin in experimental venous thrombosis.
        Blood. 1977; 49: 171-184
        • Hull R.D
        • Raskob G.E
        • Hirsh J
        • et al.
        Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal vein thrombosis.
        N Engl J Med. 1986; 315: 1109-1114
        • Brandjes D.P
        • Heijboer H
        • Buller H.R
        • et al.
        Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis.
        N Engl J Med. 1992; 327: 1485-1489
        • White R.H
        • Zhou H
        • Woo L
        • Mungall D
        Effect of weight, sex, age, clinical diagnosis and thromboplastin reagent on steady state intravenous heparin requirements.
        Arch Intern Med. 1997; 157: 2468-2472
        • Hirsh J
        • Van Aken W.G
        • Gallus A.S
        • et al.
        Heparin kinetics in venous thrombosis and pulmonary embolism.
        Circulation. 1976; 53: 691-695
        • Gore J.M
        • Granger C.B
        • Simoons M.L
        • et al.
        Stroke after thrombolysis. Mortality and functional outcomes in the GUSTO-I trial.
        Circulation. 1995; 92: 2811-2818
        • Maggioni A.P
        • Franzosi M.G
        • Santoro E
        • et al.
        The risk of stroke in patients with acute myocardial infarction after thrombolytic and antithrombotic treatment.
        N Engl J Med. 1992; 327: 1-6
        • White H.D
        • Barabash G.I
        • Modan M
        • et al.
        After correcting for worse baseline characteristics, women treated with thrombolytic therapy for acute myocardial infarction have the same mortality and morbidity as men except for a higher incidence of hemorrhagic stroke.
        Circulation. 1993; 88: 2097-2103
        • International Study Group
        In-hospital mortality and clinical course of 20,891 patients with suspected acute myocardial infarction randomized between alteplase and streptokinase with or without heparin.
        Lancet. 1990; 336: 71-75
        • GUSTO Investigators
        An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction.
        N Engl J Med. 1993; 329: 673-682
        • De Bono D.P
        • Simmons M.L
        • Tijssen J
        • et al.
        Effect of early intravenous heparin on coronary patency, infarct size and bleeding complications after alteplase thrombolysis.
        Br Heart J. 1992; 67: 122-128
        • Hsia J
        • Hamilton W.P
        • Kleiman N
        A comparison between heparin and low dose aspirin as adjunctive therapy with tissue plasminogen activator for acute myocardial infarction.
        N Engl J Med. 1990; 323: 1433-1437
        • Bleich S.D
        • Nichols T.C
        • Schumacher R.R
        • et al.
        Effect of heparin on coronary arterial patency after thrombolysis with tissue plasminogen activator in acute myocardial infarction.
        Am J Cardiol. 1990; 66: 1412-1417
        • GUSTO IIb Investigators
        A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes.
        N Engl J Med. 1996; 335: 775-782
        • Thiemann D.R
        • Coresh J
        • Schulman S.P
        • et al.
        Lack of benefit for intravenous thrombolysis in patients with myocardial infarction who are older than 75 years.
        Circulation. 2000; : 2239-2246
        • Raschke R.A
        • Reilly B.M
        • Guidry J.R
        • et al.
        The weight-based heparin dosing nomogram compared with a “standard care” nomogram.
        Ann Intern Med. 1993; 119: 874-881
        • Antman E.M
        • Giugliano R.P
        • Gibson M.C
        • et al.
        Abciximab facilitates the rate and extent of thrombolysis. Results of the thrombolysis in myocardial infarction (TIMI) 14 trial.
        Circulation. 1999; 99: 2720-2732
        • Chesebro J.H
        • Knatterud G
        • Roberts R
        • et al.
        Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase 1.
        Circulation. 1987; 76: 142-154
        • Berkowitz S.D
        • Granger C.B
        • Pieper K.S
        • et al.
        Incidence and predictors of bleeding after contemporary thrombolytic therapy for myocardial infarction.
        The GUSTO Investigators Circulation. 1997; 11: 2508-2516
        • OASIS-2 Investigators
        Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularization procedures in patients with acute myocardial ischemia without ST elevation.
        Lancet. 1999; 353: 429-438
        • Popma J.J
        • Prpic R
        • Lansky A
        • Piana R
        Heparin dosing in patients undergoing coronary intervention.
        Am J Cardiol. 1998; 82: 19P-24P
        • Young J.A
        • Kisker C.T
        • Doty D.B
        Adequate anticoagulation during cardiopulmonary bypass determined by activated clotting time and the appearance of fibrin monomer.
        Ann Thorac Surg. 1978; 26: 231-240
        • Popma J.J
        • Satler L.F
        • Pichard A.D
        • et al.
        Vascular complications after balloon and new device angioplasty.
        Circulation. 1993; 88: 1569-1578
        • Madan M
        • Blankenship J.C
        • Berkowitz S.D
        Bleeding complications with platelet glycoprotein IIb/IIIa receptor antagonists.
        Curr Opin Hematol. 1999; 6: 334-441
        • Ferguson J.J
        • Dougherty K.G
        • Gaos C.M
        • et al.
        Relationship between procedural activated clotting time and outcome after PTCA.
        J Am Coll Cardiol. 1994; 5: 1061-1065
        • Ogilby J.D
        • Kopelman H.A
        • Klein L.W
        • Agarwal J.B
        Adequate heparinization during PTCA.
        Cathet Cardiovasc Diagn. 1989; 18: 206-209
        • Lincoff A.M
        • Tcheng J.E
        • Califf R.M
        • et al.
        Standard versus low dose weight adjusted heparin in patients treated with glycoprotein IIb/IIIa receptor antibody fragment abciximab (c7E3Fab) during percutaneous coronary revascularization.
        Am J Cardiol. 1997; 79: 286-291
        • Becker R.C
        • Cannon C.P
        • Tracy R.P
        • et al.
        Relationship between systemic anticoagulation as determined by activated partial thromboplastin time and heparin measurements and in-hospital clinical events in unstable angina and non-Q wave myocardial infarction.
        Am Heart J. 1996; 131: 421-433
        • Xiao Z
        • Theroux P
        Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin inhibitor.
        Circulation. 1998; 97: 251-256
        • Cipolle R.J
        • Seifert R.D
        • Neilan B.A
        • et al.
        Heparin kinetics.
        Clin Pharmacol Ther. 1981; 29: 387-393
        • Hirsh J
        • Hoak J
        Management of deep vein thrombosis and pulmonary embolism. A statement for health care professionals.
        Circulation. 1996; 93: 2212-2245
        • Braunwald E
        • Mark D.B
        • Jones R.H
        • et al.
        Unstable Angina. Diagnosis and Management. U.S. Dept. of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, and National Heart, Lung, and Blood Institute, Rockville, MD1994
        • Hirsh J
        • Warkentin T.E
        • Raschke R
        • et al.
        Heparin and low-molecular weight heparin.
        Chest. 1998; 114: 489S-510S
        • Ryan T.J
        • Anderson J.L
        • Antman E.M
        • et al.
        ACC/AHA guidelines for the management of patients with acute myocardial infarction. A report of the ACC/AHA Task Force on Practice Guidelines.
        J Am Coll Cardiol. 1996; 28: 1328-1428
        • Becker R.C
        • Ball S.P
        • Eisenberg P
        • et al.
        A randomized, multicenter trial of weight adjusted intravenous heparin dose titration and point of care coagulation monitoring in hospitalized patients with active thromboembolic disease.
        Am Heart J. 1999; 137: 59-71
        • Hochman J.S
        • Wali A.U
        • Gavrila D
        • et al.
        A new regimen for heparin use in acute coronary syndromes.
        Am Heart J. 1999; 138: 313-318
        • Ranucci M
        • Isgro G
        • Cazzaniga A
        • et al.
        Predictors for heparin resistance in patients undergoing coronary artery bypass grafting.
        Perfusion. 1999; 14: 437-442
        • Ansell J
        • Tiarks C
        • Hirsh J
        • et al.
        Measurement of the activated partial thromboplastin time from a capillary fingerstick sample of whole blood. A new method for monitoring heparin therapy.
        Am J Clin Pathol. 1991; 95: 222-227
        • Kershaw B
        • White R.H
        • Mungall D
        • et al.
        Computer-assisted dosing of heparin. Management with a pharmacy-based anticoagulation service.
        Arch Intern Med. 1994; 154: 1005-1011
        • Cannon C.P
        • Dingemanse J
        • Kleinblosem C.H
        • et al.
        . Automated heparin-delivery system to control activated partial thromboplastin time. Evaluation in normal volunteers.
        Circulation. 1999; 99: 751-756
        • Hyers T.H
        • Agnelli G
        • Hull R.D
        • et al.
        Antithrombotic treatment for venous thromboembolic disease.
        Chest. 1998; 114: 561S-578S
      4. Pieper K. Duke Clinical Research Institute, Personal Communication.

        • GUSTO III Investigators
        A comparison of reteplase with alteplase for acute myocardial infarction.
        N Engl J Med. 1997; 337: 1118-1123
        • ASSENT Investigators
        Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction.
        Lancet. 1999; 354: 716-722
        • PARAGON Investigators
        International, randomized, controlled trial of lamifiban (a platelet glycoprotein IIb/IIIa inhibitor), heparin, or both in unstable angina.
        Circulation. 1998; 97: 2386-2395
        • Hassan W.M
        • Flaker G.C
        • Feutz C
        • et al.
        Improved anticoagulation with weight-adjusted heparin nomogram in patients with acute coronary syndromes.
        J Thromb Thrombolysis. 1995; 2: 245-249