Prevention of Cardiovascular Events after Acute Coronary Syndrome

ABSTRACT

Given the pivotal role of thrombin in the pathogenesis of acute coronary syndromes (ACS) and its persistent activation at the site of arterial lesions, antithrombin agents are essential for the prevention of coronary events. Antiplatelet agents are used routinely in the prevention of ACS, but their inability to prevent thrombin generation might contribute to the remaining high rates of recurrent ischemic events after intense antithrombotic treatment in the acute phase. Combination treatment with antiplatelet agents and anticoagulants, such as low-molecular-weight heparins (LMWH) and vitamin K antagonists, provides improved efficacy in the secondary prevention of ACS but these agents have limitations that prevent widespread adoption of their use for long-term treatment. Ximelagatran is the first oral agent in the new class of direct thrombin inhibitors (DTIs) and has considerable therapeutic potential in ACS. The DTIs are able to inhibit free and fibrin-bound thrombin by directly binding to the thrombin catalytic site. Furthermore, the oral administration and predictable pharmacokinetics of ximelagatran mean that it can be used at a fixed dose without coagulation monitoring and is convenient for long-term therapy. The efficacy of ximelagatran in the prevention of coronary events has been investigated in patients with recent myocardial infarction (MI) in the phase II Efficacy and Safety of the Oral Direct Thrombin inhibitor Ximelagatran in Patients with Recent Myocardial Damage (ESTEEM) trial. Ximelagatran (24 to 60 mg twice daily) added to aspirin (160 mg once daily) reduced the risk of the composite end point of death, MI, and severe recurrent ischemia by 24% versus aspirin alone, with no significant increase in major bleeding. Elevated serum transaminase enzymes developed during the first 1 to 6 months of treatment in a proportion of patients given ximelagatran. These elevations usually abated without clinical sequelae whether or not treatment was continued. The ESTEEM results highlight the potential for ximelagatran as an efficacious and well-tolerated long-term treatment for the prevention of arterial thrombotic events.

KEYWORDS

Acute coronary syndromes - antiplatelet agents - antithrombotic agents - heparins - vitamin K antagonists - ximelagatran - ESTEEM

REFERENCES

• 1 Furman M I, Dauerman H L, Goldberg R J, Yarzebski J, Lessard D, Gore J M. Twenty-two year (1975 to 1997) trends in the incidence, in-hospital and long-term case fatality rates from initial Q-wave and non-Q-wave myocardial infarction: a multi-hospital, community-wide perspective.  J Am Coll Cardiol. 2001;  37 1571-1580
• 2 American Heart Association Statistics . 2004;  Available at: http://www.americanheart.org
• 3 Fuster V, Badimon L, Badimon J J, Chesebro J H. The pathogenesis of coronary artery disease and the acute coronary syndromes (2).  N Engl J Med. 1992;  326 310-318
• 4 Libby P. Current concepts of the pathogenesis of the acute coronary syndromes.  Circulation. 2001;  104 365-372
• 5 Weitz J I. Activation of blood coagulation by plaque rupture: mechanisms and prevention.  Am J Cardiol. 1995;  75 18B-22B
• 6 Patel V B, Topol E J. The pathogenesis and spectrum of acute coronary syndromes: from plaque formation to thrombosis.  Cleve Clin J Med. 1999;  66 561-571
• 7 Ault K A, Cannon C P, Mitchell J et al.. Platelet activation in patients after an acute coronary syndrome: results from the TIMI-12 trial. Thrombolysis in Myocardial Infarction.  J Am Coll Cardiol. 1999;  33 634-639
• 8 Merlini P A, Bauer K A, Oltrona L et al.. Persistent activation of coagulation mechanism in unstable angina and myocardial infarction.  Circulation. 1994;  90 61-68
• 9 Antithrombotic Trialists’ Collaboration . Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.  BMJ. 2002;  324 71-86
• 10 Roux S, Christeller S, Ludin E. Effects of aspirin on coronary reocclusion and recurrent ischemia after thrombolysis: a meta-analysis.  J Am Coll Cardiol. 1992;  19 671-677
• 11 Meijer A, Verheugt F W, Werter C J, Lie K I, van der Pol J M, van Eenige M J. Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT Study.  Circulation. 1993;  87 1524-1530
• 12 White H D, French J K, Hamer A W et al.. Frequent reocclusion of patent infarct-related arteries between 4 weeks and 1 year: effects of antiplatelet therapy.  J Am Coll Cardiol. 1995;  25 218-223
• 13 Boersma E, Akkerhuis K M, Theroux P, Califf R M, Topol E J, Simoons M L. Platelet glycoprotein IIb/IIIa receptor inhibition in non-ST-elevation acute coronary syndromes: early benefit during medical treatment only, with additional protection during percutaneous coronary intervention.  Circulation. 1999;  100 2045-2048
• 14 Simoons M L. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial.  Lancet. 2001;  357 1915-1924
• 15 Chew D P, Bhatt D L, Sapp S, Topol E J. Increased mortality with oral platelet glycoprotein IIb/IIIa antagonists: a meta-analysis of phase III multicenter randomized trials.  Circulation. 2001;  103 201-206
• 16 Yusuf S, Zhao F, Mehta S R, Chrolavicius S, Tognoni G, Fox K K. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.  N Engl J Med. 2001;  345 494-502
• 17 Eikelboom J W, Weitz J I, Budaj A et al.. Clopidogrel does not suppress blood markers of coagulation activation in aspirin-treated patients with non-ST-elevation acute coronary syndromes.  Eur Heart J. 2002;  23 1771-1779
• 18 Kleiman N S, Tracy R P, Talley J D et al.. Inhibition of platelet aggregation with a glycoprotein IIb-IIIa antagonist does not prevent thrombin generation in patients undergoing thrombolysis for acute myocardial infarction.  J Thromb Thrombolysis. 2000;  9 5-12
• 19 Hamm C W, Bertrand M, Braunwald E. Acute coronary syndrome without ST elevation: implementation of new guidelines.  Lancet. 2001;  358 1533-1538
• 20 Hirsh J, Warkentin T E, Shaughnessy S G et al.. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety.  Chest. 2001;  119 64S-94S
• 21 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. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial.  Circulation. 1999;  100 1593-1601
• 22 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
• 23 Goodman S G, Fitchett D, Armstrong P W, Tan M, Langer A. Randomized evaluation of the safety and efficacy of enoxaparin versus unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes receiving the glycoprotein IIb/IIIa inhibitor eptifibatide.  Circulation. 2003;  107 238-244
• 24 Blazing M A, De Lemos J A, Dyke C K, Califf R M, Bilheimer D, Braunwald E. The A-to-Z Trial: methods and rationale for a single trial investigating combined use of low-molecular-weight heparin with the glycoprotein IIb/IIIa inhibitor tirofiban and defining the efficacy of early aggressive simvastatin therapy.  Am Heart J. 2001;  142 211-217
• 25 Ferguson J J, Califf R M, Antman E M et al.. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial.  JAMA. 2004;  292 45-54
• 26 Cohen M, Theroux P, Borzak S et al.. Randomized double-blind safety study of enoxaparin versus unfractionated heparin in patients with non-ST-segment elevation acute coronary syndromes treated with tirofiban and aspirin: the ACUTE II study. The Antithrombotic Combination Using Tirofiban and Enoxaparin.  Am Heart J. 2002;  144 470-477
• 27 Petersen J L, Mahaffey K W, Hasselblad V et al.. Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-ST-Segment elevation acute coronary syndromes: a systematic overview.  JAMA. 2004;  292 89-96
• 28 Long-term low-molecular-mass heparin in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. FRagmin and Fast Revascularisation during InStability in Coronary artery disease. Investigators.  Lancet. 1999;  354 701-707
• 29 Simoons M L, Bobbink I W, Boland J 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. 2004;  43 2183-2190
• 30 Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) Research Group. Effect of long-term oral anticoagulant treatment on mortality and cardiovascular morbidity after myocardial infarction.  Lancet. 1994;  343 499-503
• 31 Smith P, Arnesen H, Holme I. The effect of warfarin on mortality and reinfarction after myocardial infarction.  N Engl J Med. 1990;  323 147-152
• 32 Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction.  N Engl J Med. 2002;  347 969-974
• 33 Coumadin Aspirin Reinfarction Study (CARS) Investigators . Randomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction.  Lancet. 1997;  350 389-396
• 34 Fiore L D, Ezekowitz M D, Brophy M T, Lu D, Sacco J, Peduzzi P. Department of Veterans Affairs Cooperative Studies Program Clinical Trial comparing combined warfarin and aspirin with aspirin alone in survivors of acute myocardial infarction: primary results of the CHAMP study.  Circulation. 2002;  105 557-563
• 35 Granger C B, Miller J M, Bovill E G et al.. Rebound increase in thrombin generation and activity after cessation of intravenous heparin in patients with acute coronary syndromes.  Circulation. 1995;  91 1929-1935
• 36 Van Aken H, Bode C, Darius H et al.. Anticoagulation: the present and future.  Clin Appl Thromb Hemost. 2001;  7 195-204
• 37 Theroux P, Waters D, Lam J, Juneau M, McCans J. Reactivation of unstable angina after the discontinuation of heparin.  N Engl J Med. 1992;  327 141-145
• 38 Weitz J I. Biological rationale for the therapeutic role of specific antithrombins.  Coron Artery Dis. 1996;  7 409-419
• 39 Weitz J I, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors.  J Clin Invest. 1990;  86 385-391
• 40 Weitz J I. A novel approach to thrombin inhibition.  Thromb Res. 2003;  109(Suppl 1) S17-S22
• 41 White H. Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: the HERO-2 randomised trial.  Lancet. 2001;  358 1855-1863
• 42 Lincoff A M, Bittl J A, Kleiman N S et al.. Comparison of bivalirudin versus heparin during percutaneous coronary intervention (the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events [REPLACE]-1 trial).  Am J Cardiol. 2004;  93 1092-1096
• 43 Bittl J A, Chaitman B R, Feit F, Kimball W, Topol E J. Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: final report reanalysis of the Bivalirudin Angioplasty Study.  Am Heart J. 2001;  142 952-959
• 44 The Direct Thrombin Inhibitor Trialists' Collaborative group . Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients' data.  Lancet. 2002;  359 294-302
• 45 Elg M, Gustafsson D, Carlsson S. Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat.  Thromb Res. 1999;  94 187-197
• 46 Johansson L C, Frison L, Logren U, Fager G, Gustafsson D, Eriksson U G. Influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor.  Clin Pharmacokinet. 2003;  42 381-392
• 47 Johansson L C, Andersson M, Fager G, Gustafsson D, Eriksson U G. No influence of ethnic origin on the pharmacokinetics and pharmacodynamics of melagatran following oral administration of ximelagatran, a novel oral direct thrombin inhibitor, to healthy male volunteers.  Clin Pharmacokinet. 2003;  42 475-484
• 48 Wallentin L, Wilcox R G, Weaver W D et al.. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial.  Lancet. 2003;  362 789-797
• 49 Wallentin L. Oral Direct Thrombin Inhibition for anticoagulation in coronary artery disease-focus on the ESTEEM trial.  European Heart Journal. 2004;  6 B9-B14
• 50 van Es R F, Jonker J J, Verheugt F W, Deckers J W, Grobbee D E. Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial.  Lancet. 2002;  360 109-113
• 51 Lee W M, Larrey D, Olsson R et al.. Hepatic findings in long-term clinical trials of ximelagatran.  Drug Saf. 2005;  28 351-370
• 52 Schulman S, Wåhlander K, Lundström T, Clason S B, Eriksson H. THRIVE III Investigators . Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran.  N Engl J Med. 2003;  349 1713-1721