Skip to main content
Top
Published in: Cardiovascular Drugs and Therapy 3/2012

01-06-2012 | REVIEW ARTICLE

Novel Oral Anticoagulants After Acute Coronary Syndromes

Authors: Newton B. Wiggins, Christopher B. Granger, John H. Alexander

Published in: Cardiovascular Drugs and Therapy | Issue 3/2012

Login to get access

Abstract

Purpose

A number of novel oral anticoagulants, including direct thrombin inhibitors and direct factor Xa inhibitors, have been developed. This review discusses these agents and their respective clinical trials in patients with acute coronary syndromes.

Methods

This review discusses the results of phase 2 and 3 clinical trials with novel oral anticoagulants.

Results

Phase 2 clinical trials demonstrated that novel oral anticoagulants increase the risk of bleeding in a dose-related fashion, particularly when used in addition to dual antiplatelet therapy. What was less clear is their impact on recurrent ischemic events. In phase 3 trials, rivaroxaban was found to have a benefit on ischemic events and perhaps a greater benefit at the lower dose. The phase 3 trial with apixaban was stopped early due to increased bleeding without a meaningful reduction in ischemic events.

Conclusions

Novel oral anticoagulants represent a promising, potentially beneficial treatment for patients with a recent acute coronary syndrome but come with a risk of bleeding. The benefits and risks of these agents will need to be carefully weighed and may depend on both patient risk and concomitant therapy. Additional research is needed to determine how to best integrate these medications into the care of patients with acute coronary syndromes.
Literature
1.
go back to reference Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001–15.PubMedCrossRef Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001–15.PubMedCrossRef
2.
go back to reference Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. 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.PubMedCrossRef Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. 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.PubMedCrossRef
3.
go back to reference Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–57.PubMedCrossRef Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–57.PubMedCrossRef
4.
go back to reference Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey Jr DE, et al. 2011 ACCF/AHA Focused Update Incorporated Into the ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;123:e426–579.PubMedCrossRef Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey Jr DE, et al. 2011 ACCF/AHA Focused Update Incorporated Into the ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;123:e426–579.PubMedCrossRef
5.
go back to reference Kushner FG, Hand M, Smith Jr SC, King 3rd SB, Anderson JL, Antman EM, et al. 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2009;120:2271–306.PubMedCrossRef Kushner FG, Hand M, Smith Jr SC, King 3rd SB, Anderson JL, Antman EM, et al. 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2009;120:2271–306.PubMedCrossRef
6.
go back to reference Rothberg MB, Celestin C, Fiore LD, Lawler E, Cook JR. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit. Ann Intern Med. 2005;143:241–50.PubMed Rothberg MB, Celestin C, Fiore LD, Lawler E, Cook JR. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit. Ann Intern Med. 2005;143:241–50.PubMed
7.
go back to reference Weitz JI, Buller HR. Direct thrombin inhibitors in acute coronary syndromes: present and future. Circulation. 2002;105:1004–11.PubMedCrossRef Weitz JI, Buller HR. Direct thrombin inhibitors in acute coronary syndromes: present and future. Circulation. 2002;105:1004–11.PubMedCrossRef
9.
go back to reference Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:234S–56S.PubMedCrossRef Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:234S–56S.PubMedCrossRef
10.
go back to reference Herault JP, Bernat A, Pflieger AM, Lormeau JC, Herbert JM. Comparative effects of two direct and indirect factor Xa inhibitors on free and clot-bound prothrombinase. J Pharmacol Exp Ther. 1997;283:16–22.PubMed Herault JP, Bernat A, Pflieger AM, Lormeau JC, Herbert JM. Comparative effects of two direct and indirect factor Xa inhibitors on free and clot-bound prothrombinase. J Pharmacol Exp Ther. 1997;283:16–22.PubMed
11.
go back to reference Krishnaswamy S, Vlasuk GP, Bergum PW. Assembly of the prothrombinase complex enhances the inhibition of bovine factor Xa by tick anticoagulant peptide. Biochemistry. 1994;33:7897–907.PubMedCrossRef Krishnaswamy S, Vlasuk GP, Bergum PW. Assembly of the prothrombinase complex enhances the inhibition of bovine factor Xa by tick anticoagulant peptide. Biochemistry. 1994;33:7897–907.PubMedCrossRef
12.
go back to reference Wallentin L, Wilcox RG, Weaver WD, Emanuelsson H, Goodvin A, Nystrom P, et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet. 2003;362:789–97.PubMedCrossRef Wallentin L, Wilcox RG, Weaver WD, Emanuelsson H, Goodvin A, Nystrom P, et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet. 2003;362:789–97.PubMedCrossRef
13.
go back to reference Oldgren J, Budaj A, Granger CB, Khder Y, Roberts J, Siegbahn A, et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J. 2011;32:2781–9.PubMedCrossRef Oldgren J, Budaj A, Granger CB, Khder Y, Roberts J, Siegbahn A, et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J. 2011;32:2781–9.PubMedCrossRef
14.
go back to reference Alexander JH, Becker RC, Bhatt DL, Cools F, Crea F, Dellborg M, et al. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation. 2009;119:2877–85.PubMedCrossRef Alexander JH, Becker RC, Bhatt DL, Cools F, Crea F, Dellborg M, et al. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation. 2009;119:2877–85.PubMedCrossRef
15.
go back to reference Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3:692–4.PubMedCrossRef Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3:692–4.PubMedCrossRef
16.
go back to reference Mega JL, Braunwald E, Mohanavelu S, Burton P, Poulter R, Misselwitz F, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet. 2009;374:29–38.PubMedCrossRef Mega JL, Braunwald E, Mohanavelu S, Burton P, Poulter R, Misselwitz F, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet. 2009;374:29–38.PubMedCrossRef
17.
go back to reference Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, et al. Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation. 1987;76:142–54.PubMedCrossRef Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, et al. Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation. 1987;76:142–54.PubMedCrossRef
18.
go back to reference Steg PG, Mehta SR, Jukema JW, Lip GY, Gibson CM, Kovar F, et al. RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome. Eur Heart J. 2011;32:2541–54.PubMedCrossRef Steg PG, Mehta SR, Jukema JW, Lip GY, Gibson CM, Kovar F, et al. RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome. Eur Heart J. 2011;32:2541–54.PubMedCrossRef
19.
go back to reference Alexander JH, Lopes RD, James S, Kilaru R, He Y, Mohan P, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011;365:699–708.PubMedCrossRef Alexander JH, Lopes RD, James S, Kilaru R, He Y, Mohan P, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011;365:699–708.PubMedCrossRef
20.
go back to reference Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366:9–19.PubMedCrossRef Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366:9–19.PubMedCrossRef
21.
go back to reference Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation. 2006;114:774–82.PubMedCrossRef Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation. 2006;114:774–82.PubMedCrossRef
22.
go back to reference Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–92.PubMedCrossRef Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–92.PubMedCrossRef
23.
go back to reference Frost C, Song Y, Barrett YC, Wang J, Li T, LaCreta F, editors. Direct Comparison of the Pharmacokinetics and Pharmacodynamics of Apixaban and Rivaroxaban. XXIII Congress of the International Society on Thrombosis and Haemostasis; Kyoto, Japan: Bristol-Myers Squibb; 2011. Frost C, Song Y, Barrett YC, Wang J, Li T, LaCreta F, editors. Direct Comparison of the Pharmacokinetics and Pharmacodynamics of Apixaban and Rivaroxaban. XXIII Congress of the International Society on Thrombosis and Haemostasis; Kyoto, Japan: Bristol-Myers Squibb; 2011.
24.
go back to reference Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–91.PubMedCrossRef Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–91.PubMedCrossRef
25.
go back to reference Yusuf S, Mehta SR, Chrolavicius S, Afzal R, Pogue J, Granger CB, et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006;354:1464–76.PubMedCrossRef Yusuf S, Mehta SR, Chrolavicius S, Afzal R, Pogue J, Granger CB, et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006;354:1464–76.PubMedCrossRef
26.
go back to reference Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–51.PubMedCrossRef Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–51.PubMedCrossRef
Metadata
Title
Novel Oral Anticoagulants After Acute Coronary Syndromes
Authors
Newton B. Wiggins
Christopher B. Granger
John H. Alexander
Publication date
01-06-2012
Publisher
Springer US
Published in
Cardiovascular Drugs and Therapy / Issue 3/2012
Print ISSN: 0920-3206
Electronic ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-012-6386-0

Other articles of this Issue 3/2012

Cardiovascular Drugs and Therapy 3/2012 Go to the issue