Abstract
Background: The benefit of unfractionated heparin (UFH) added to aspirin in patients with acute coronary syndromes (ACS) was described more than 20 years ago. Ever since, a wide variety of anticoagulant drugs have become available for clinical use, including low-molecular-weight heparins (LMWH), direct thrombin inhibitors and selective factor Xa inhibitors.
Objective: The aim of this study was to critically review the available evidence on the cost and incremental cost effectiveness of anticoagulants in patients with ACS.
Methods: Studies were identified using specialist databases (UK NHS Economic Evaluation Database [NHS EED] and Cost-Effectiveness Analysis [CEA] Registry), PubMed and the reference lists of recovered articles. Only studies based on randomized controlled trials were considered for inclusion. Finally, 22 studies were included in the review.
Results: Enoxaparin is the only LMWHthat has been shown to reduce the risk of death or myocardial infarction in patients with non-ST-elevation ACS (NSTE-ACS). In economic studies based on the ESSENCE trial conducted in the late 1990s, enoxaparin was consistently associated with a lower risk of coronary events, a reduction in the number of revascularization procedures and a lower cost per patient thanUFH.However, these results refer to patients managed conservatively, with little use of thienopyridines and glycoprotein IIb/IIIa inhibitors, and the results are difficult to extrapolate to moderate-tohigh- risk patients managed with the present day early invasive strategy.
Available studies of LMWH in ACS with persistent elevation of ST-segment (STE-ACS) are limited to patients treated with thrombolysis. In this scenario, enoxaparin was shown to be a dominant alternative compared with UFH in a study based on the ASSENT-3 study and was considered an economically attractive alternative in three studies based on the ExTRACT-TIMI 25 study. However, these results should be interpreted cautiously due to the heterogeneity of the supportive randomized trials and the possible underestimation of bleeding costs.
The effectiveness and safety of bivalirudin, a direct thrombin inhibitor, were evaluated in the ACUITY study (NSTE-ACS patients managed invasively) and the HORIZONS-AMI study (STE acute myocardial infarction patients planned for primary percutaneous coronary intervention). Bivalirudin monotherapy was not inferior to heparin plus a glycoprotein IIb/IIIa inhibitor and reduced the risk of major bleeding. The economic evaluations based on these studies suggest that bivalirudin is an attractive alternative to heparin plus a glycoprotein-IIb/IIIa inhibitor.
In the OASIS-5 trial, compared with enoxaparin, fondaparinux reduced the mortality in patients with NSTE-ACS, probably because of a reduced risk of bleeding. In three economic evaluations of fondaparinux versus enoxaparin based on this trial, fondaparinux was the dominant strategy in two of them, and still economically attractive in a third.
Taken as a whole, the usefulness of economic studies of anticoagulants in patients with ACS is undermined by the quality of the evidence about their effectiveness and safety; the narrow spectrum of the analysed scenarios; the lack of economic evaluations based on systematic reviews; the limitations of sensitivity analyses reported by the available economic evaluations; and their substantial risk of commercial bias.
Conclusions: The available studies suggest that enoxaparin is an economically attractive alternative compared with UFH in patients with NSTE-ACS treated conservatively and STE-ACS patients treated with thrombolysis. Bivalirudin in patients with ACS treated invasively is cost effective compared with heparin plus a glycoprotein IIb/IIIa inhibitor. In patients with NSTEACS, fondaparinux is cost effective compared with enoxaparin. The usefulness of these results for decision making in contemporary clinical practice is limited due to problems of internal and external validity.
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References
Lloyd-Jones D, Adams RJ, Brown TM, et al. Heart disease and stroke statistics–2010 update: a report from the American Heart Association. Circulation 2010 Feb 23; 121 (7): e46–215
Kolansky DM. Acute coronary syndromes: morbidity, mortality, and pharmacoeconomic burden. Am J Manag Care 2009 Mar; 15 (2 Suppl.): S36–41
Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation 2001 Jul 17; 104 (3): 365–72
Antman EM, Hand M, Armstrong PW, et al. 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2008 Jan 15; 117 (2): 296–329
Anderson JL, Adams CD, Antman EM, et al. 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/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2007 Aug 14; 50 (7): e1–157
Bonaca MP, Steg PG, Feldman LJ, et al. Antithrombotics in acute coronary syndromes. J Am Coll Cardiol 2009 Sep 8; 54 (11): 969–84
Gharacholou SM, Lopes RD, Washam JB, et al. Antithrombotic therapy in acute coronary syndromes: guidelines translated for the clinician. J Thromb Thrombolysis 2010 May; 29 (4): 516–28
Tricoci P, Allen JM, Kramer JM, et al. Scientific evidence underlying the ACC/AHA clinical practice guidelines. JAMA. 2009 Feb 25; 301 (8): 831–41
Borg S, Persson U, Allikmets K, et al. Comparative costeffectiveness of anticoagulation with bivalirudin or heparin with and without a glycoprotein IIb/IIIa-receptor inhibitor in patients undergoing percutaneous coronary intervention in Sweden: a decision-analytic model. Clin Ther 2006 Nov; 28 (11): 1947–59
Bosanquet N, Jonsson B, Fox KA. Costs and cost effectiveness of low molecular weight heparins and platelet glycoprotein IIb/IIIa inhibitors: in the management of acute coronary syndromes. Pharmacoeconomics 2003; 21 (16): 1135–52
Huston SA, Hawkins D. Pharmacoeconomics of anticoagulants in acute coronary syndrome and percutaneous coronary intervention. Curr Pharm Des 2008; 14 (12): 1197–204
Nutescu EA, Steinmetz Pater K. Economic evaluation of the use of enoxaparin in non-ST-elevation acute coronary syndrome. Expert Opin Pharmacother 2008 Jan; 9 (1): 95–105
White HD. Pharmacological and clinical profile of bivalirudin in the treatment of patients with acute coronary syndrome. Expert Opin Drug Metab Toxicol 2009 May; 5 (5): 529–38
Janzon M, Levin LA, Swahn E. Cost effectiveness of extended treatment with low molecular weight heparin (dalteparin) in unstable coronary artery disease: results from the FRISC II trial. Heart 2003 Mar; 89 (3): 287–92
Evers S, Goossens M, de Vet H, et al. Criteria list for assessment of methodological quality of economic evaluations: consensus on health economic criteria. Int J Technol Assess Health Care 2005; 21 (2): 240–5
Magee KD, Campbell SG, Moher D, et al. Heparin versus placebo for acute coronary syndromes. Cochrane Database Syst Rev 2008; 2: CD003462
Cohen M, Demers C, Gurfinkel EP, 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 Aug 14; 337 (7): 447–52
Antman EM, McCabe CH, Gurfinkel EP, 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 Oct 12; 100 (15): 1593–601
Ferguson JJ, Califf RM, Antman EM, et al. Enoxaparin vs unfractionated heparin in high-risk patients with non-STsegment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA 2004 Jul 7; 292 (1): 45–54
Malhotra S, Bhargava VK, Grover A, et al. A randomized trial to compare the efficacy, safety, cost and platelet aggregation effects of enoxaparin and unfractionated heparin (the ESCAPEU trial). Int J Clin Pharmacol Ther 2001 Mar; 39 (3): 110–5
Shafiq N, Malhotra S, Pandhi P, et al. A randomized controlled clinical trial to evaluate the efficacy, safety, costeffectiveness and effect on PAI-1 levels of the three lowmolecular-weight heparins: enoxaparin, nadroparin and dalteparin–the ESCAPe-END study. Pharmacology 2006; 78 (3): 136–43
ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001 Aug 25; 358 (9282): 605–13
Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versus unfractionated heparin with fibrinolysis for STelevation myocardial infarction. N Engl J Med 2006 Apr 6; 354 (14): 1477–88
Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006 Nov 23; 355 (21): 2203–16
Yusuf S, Mehta SR, Chrolavicius S, et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006 Apr 6; 354 (14): 1464–76
Blazing MA, de Lemos JA, White HD, et al. Safety and efficacy of enoxaparin vs unfractionated heparin in patients with non-ST-segment elevation acute coronary syndromes who receive tirofiban and aspirin: a randomized controlled trial. JAMA 2004 Jul 7; 292 (1): 55–64
Cohen M, Theroux P, Borzak S, et al. Randomized doubleblind 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 Sep; 144 (3): 470–7
Goodman SG, Fitchett D, Armstrong PW, et al. 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 Jan 21; 107 (2): 238–44
Murphy SA, Gibson CM, Morrow DA, et al. Efficacy and safety of the low-molecular weight heparin enoxaparin compared with unfractionated heparin across the acute coronary syndrome spectrum: a meta-analysis. Eur Heart J 2007 Sep; 28 (17): 2077–86
Mark DB, Cowper PA, Berkowitz SD, et al. Economic assessment of low-molecular-weight heparin (enoxaparin) versus unfractionated heparin in acute coronary syndrome patients: results from the ESSENCE randomized trial – Efficacy and Safety of Subcutaneous Enoxaparin inNon-Qwave Coronary Events [unstable angina or non-Q-wave myocardial infarction]. Circulation 1998 May 5; 97 (17): 1702–7
Bosanquet N, Fox K. Longer-term economic benefits reflect improved clinical outcomes with enoxaparin versus unfractionated heparin in acute coronary syndromes: oneyear data. Br J Cardiol 2001; 8: 36–7
Fox K, Bosanquet N. Assessing the UK cost implications of the use of low molecular weight heparin in unstable coronary artery disease. Br J Cardiol 1998; 5: 95–105
Bozovich G, Gurfinkel E, Kuster F, et al. Reduccion de la tasa de revascularizacion y costos hospitalarios en pacientes con sindromes agudos coronarios tipo no-Q tratados con enoxaparina en comparacion con heparina no fraccionada en la Argentina y el Uruguay. Rev Argent Cardiol 1999; 67 (2): 131–6
Detournay B, Huet X, Fagnani F, et al. Economic evaluation of enoxaparin sodium versus heparin in unstable angina: a French sub-study of the ESSENCE trial. Pharmacoeconomics 2000 Jul; 18 (1): 83–9
O’Brien BJ, Willan A, Blackhouse G, et al. Will the use of low-molecular-weight heparin (enoxaparin) in patients with acute coronary syndrome save costs in Canada? Am Heart J 2000 Mar; 139 (3): 423–9
Balen RM, Marra CA, Zed PJ, et al. Cost-effectiveness analysis of enoxaparin versus unfractionated heparin for acute coronary syndromes: a Canadian hospital perspective. Pharmacoeconomics 1999 Nov; 16 (5 Pt 2): 533–42
Orlewska E, Budaj A, Tereszkowski-Kaminski D. Cost-effectiveness analysis of enoxaparin versus unfractionated heparin in patients with acute coronary syndrome in Poland: modelling study from the hospital perspective. Pharmacoeconomics 2003; 216 (10): 737–48
Brosa M, Rubio-Terres C, Farr I, et al. Cost-effectiveness analysis of enoxaparin versus unfractionated heparin in the secondary prevention of acute coronary syndrome. Pharmacoeconomics 2002; 20 (14): 979–87
Nicholson T, McGuire A, Milne R. Cost-utility of enoxaparin compared with unfractionated heparin in unstable coronary artery disease. BMC Cardiovasc Disord 2001; 1: 2
Kaul P, Armstrong PW, Cowper PA, et al. Economic analysis of the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT-3) study: costs of reperfusion strategies in acute myocardial infarction. Am Heart J 2005 Apr; 149 (4): 637–44
Welsh RC, Sauriol L, Zhang Z, et al. Cost-effectiveness of enoxaparin compared with unfractionated heparin in ST elevation myocardial infarction patients undergoing pharmacological reperfusion: a Canadian analysis of the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment–Thrombolysis in Myocardial Infarction (ExTRACT-TIMI) 25 trial. Can J Cardiol 2009 Dec; 25 (12): e399–405
Marcoff L, Zhang Z, Zhang W, et al. Cost effectiveness of enoxaparin in acute ST-segment elevation myocardial infarction: the ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis In Myocardial Infarction 25) study. J Am Coll Cardiol 2009 Sep 29; 54 (14): 1271–9
Menown I, Montalescot G, Pal N, et al. Enoxaparin is a cost-effective adjunct to fibrinolytic therapy for STelevation myocardial infarction in contemporary practice. Adv Ther 2010 Mar; 27 (3): 181–91
Pinto DS, Stone GW, Shi C, et al. Economic evaluation of bivalirudin with or without glycoprotein IIb/IIIa inhibition versus heparin with routine glycoprotein IIb/IIIa inhibition for early invasive management of acute coronary syndromes. J Am Coll Cardiol 2008 Nov 25; 52 (22): 1758–68
Schwenkglenk M, Brazier J, Szucs T, et al. Cost-effectiveness of bivalirudin versus heparin plus glycoprotein IIb/IIIa inhibitor in the treatment of non-ST-segment elevation acute coronary syndromes. Value Health 2011; 14 (1): 24–33
Sculpher M, Lozano-Ortega G, Sambrook J, et al. Cost-effectiveness in France of fondaparinux versus enoxaparin in non-ST-elevation acute coronary syndrome: an analysis using data from OASIS-5 [abstract]. Eur Heart J 2007; 28: 4804
Sculpher MJ, Lozano-Ortega G, Sambrook J, et al. Fondaparinux versus enoxaparin in non-ST-elevation acute coronary syndromes: short-term cost and long-term costeffectiveness using data from the fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators (OASIS-5) trial. Am Heart J 2009 May; 157 (5): 845–52
Latour-Perez J, de-Miguel-Balsa E. Cost effectiveness of fondaparinux in non-ST-elevation acute coronary syndrome. Pharmacoeconomics 2009; 27 (7): 585–95
Maxwell CB, Holdford DA, Crouch MA, et al. Cost effectiveness analysis of anticoagulation strategies in non-ST-elevation acute coronary syndromes. Ann Pharmacother 2009 Apr; 43 (4): 586–95
U.S. Census Bureau. The 2012 statistical abstract: prices–consumer price indexes, cost of living index [online]. Available from URL: http://www.census.gov/compendia/statab/cats/prices/consumer_price_indexes_cost_of_living_index.html [Accessed 2012 Jan 21]
Ross AM, Molhoek P, Lundergan C, 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 2001 Aug 7; 104 (6): 648–52
Baird SH, Menown IB, McBride SJ, et al. Randomized comparison of enoxaparin with unfractionated heparin following fibrinolytic therapy for acute myocardial infarction. Eur Heart J 2002 Apr; 23 (8): 627–32
Antman EM, Louwerenburg HW, Baars HF, et al. Enoxaparin as adjunctive antithrombin therapy for ST-elevation myocardial infarction: results of the ENTIRE-Thrombolysis in Myocardial Infarction (TIMI) 23 Trial. Circulation 2002 Apr 9; 105 (14): 1642–9
Wallentin L, Goldstein P, Armstrong PW, et al. Efficacy and safety of tenecteplase in combination with the lowmolecular-weight heparin enoxaparin or unfractionated heparin in the prehospital setting: the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen(ASSENT)-3 PLUS randomized trial in acute myocardial infarction. Circulation 2003 Jul 15; 108 (2): 135–42
Cequier A, Moris C, Badia X, et al. Cost-minimization analysis of bivalirudin versus heparin plus planned abciximab in patients undergoing percutaneous coronary intervention [in Spanish]. Rev Esp Econ Salud 2006; 5 (3): 168–76
Cohen DJ, Lincoff AM, Lavelle TA, et al. Economic evaluation of bivalirudin with provisional glycoprotein IIB/IIIA inhibition versus heparin with routine glycoprotein IIB/IIIA inhibition for percutaneous coronary intervention: results from the REPLACE-2 trial. J Am Coll Cardiol 2004 Nov 2; 44 (9): 1792–800
Rao SV, Kaul PR, Liao L, et al. Association between bleeding, blood transfusion, and costs among patients with non-ST-segment elevation acute coronary syndromes. Am Heart J 2008 Feb; 155 (2): 369–74
Di Nisio M, Middeldorp S, Buller HR. Direct thrombin inhibitors. N Engl J Med 2005 Sep 8; 353 (10): 1028–40
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 Jan 26; 359 (9303): 294–302
Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003 Feb 19; 289 (7): 853–63
Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008 May 22; 358 (21): 2218–30
GRACE Investigators. Rationale and design of the GRACE (Global Registry of Acute Coronary Events) Project: a multinational registry of patients hospitalized with acute coronary syndromes. Am Heart J 2001 Feb; 141 (2): 190–9
Mehta SR, Boden WE, Eikelboom JW, et al. Antithrombotic therapy with fondaparinux in relation to interventional management strategy in patients with ST- and non-ST-segment elevation acute coronary syndromes: an individual patient-level combined analysis of the fifth and sixth Organization to Assess Strategies in Ischemic Syndromes (OASIS 5 and 6) randomized trials. Circulation 2008 Nov 11; 118 (20): 2038–46
Yusuf S, Mehta SR, Chrolavicius S, et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA 2006 Apr 5; 295 (13): 1519–30
Majure DT, Aberegg SK. Fondaparinux versus enoxaparin in acute coronary syndromes. N Engl J Med 2006 Jun 29; 354 (26): 2829
Yusuf S, Granger C, Mehta SR. Fondaparinux versus enoxaparin in acute coronary syndromes [reply]. N Engl J Med 2006; 354 (26): 2830
Dobesh PP, Phillips KW, Haines ST. Optimizing antithrombotic therapy in patients with non-ST-segment elevation acute coronary syndrome. Am J Health Syst Pharm 2008 Aug 1; 65 (15 Pt 7): S22–8
Anderson JA, Hirsh J, Yusuf S, et al. Comparison of the anticoagulant intensities of fondaparinux and enoxaparin in the Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS)-5 trial. J Thromb Haemost 2010 Feb; 8 (2): 243–9
Lexchin J, Light DW. Commercial influence and the content of medical journals. BMJ 2006 Jun 17; 332 (7555): 1444–7
Hanratty B, Craig D, Nixon J, et al. Are the best available clinical effectiveness data used in economic evaluations of drug therapies? J Health Serv Res Policy 2007 Jul; 12 (3): 138–41
Drummond MF, Iglesias CP, Cooper NJ. Systematic reviews and economic evaluations conducted for the National Institute for Health and Clinical Excellence in the United Kingdom: a game of two halves? Int J Technol Assess Health Care 2008; 24 (2): 146–50
Jolly SS, Amlani S, Hamon M, et al. Radial versus femoral access for coronary angiography or intervention and the impact on major bleeding and ischemic events: a systematic review and meta-analysis of randomized trials. Am Heart J 2009 Jan; 157 (1): 132–40
Lyseng-Williamson KA. Bivalirudin: a pharmacoeconomic profile of its use in patients with acute coronary syndromes. Pharmacoeconomics 2011; 29 (4): 343–59
Acknowledgements
This review was commissioned by the journal. The preparation of the manuscript was not supported by any external funding. The authors have no conflicts of interest that are directly relevant to the content of this review and the opinions expressed are those of the authors.
Dr Latour-Pérez contributed to the conception and design of the study; literature research; data extraction; data analysis and interpretation; and manuscript preparation and revision, and approved the final version of the manuscript.
Dra de-Miguel-Balsa contributed to the literature research; data extraction; data analysis and interpretation; and manuscript editing and revision, and approved the final version of the manuscript.
Dr Latour-Pérez is the guarantor of the overall content of this review.
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Latour-Pérez, J., de -Miguel-Balsa, E. Cost Effectiveness of Anticoagulation in Acute Coronary Syndromes. PharmacoEconomics 30, 303–321 (2012). https://doi.org/10.2165/11589290-000000000-00000
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DOI: https://doi.org/10.2165/11589290-000000000-00000