The arterial thrombosis responsible for. Easing the Economic Burden of Acute Coronary Syndromes: Cost-effectiveness of Emerging Therapies REPORTS

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1 Easing the Economic Burden of Acute Coronary Syndromes: Cost-effectiveness of Emerging Therapies Edith A. Nutescu, PharmD Abstract Although only part of the entire treatment regimen, antithrombotic therapy represents a large portion of the total costs associated with acute coronary syndromes (ACS) treatment. Unfractionated heparin (UFH), the mainstay of antithrombotic therapy, carries the risk of bleeding and associated interventions, and must be closely monitored. UFH therapy also has an increased risk of heparin-induced thrombocytopenia (HIT) and osteoporosis. These drawbacks prompted the development of newer antithrombotic agents, particularly low molecular weight heparins (LMWH) and factor Xa inhibitors. LMWH have several clinical advantages over UFH and has been demonstrated to be more effective than UFH in ACS. Because UFH is inexpensive, newer therapies need to demonstrate economic attractiveness over UFH. In addition to acquisition costs, it is important to consider the cost of all key components throughout the continuum of care. Health economic analyses show that the clinical advantages of the LMWH enoxaparin are also likely to result in net cost-saving benefits, due to reductions in diagnostic catheterization, percutaneous transluminal coronary angioplasty, and intensive care unit length of stay. Fondaparinux, an indirect inhibitor of factor Xa, does not require routine monitoring or multiple daily dosing, and is unlikely to interact with HIT antibodies. Large randomized clinical trials have shown that fondaparinux is at least as safe and efficacious as enoxaparin or UFH in the prevention of venous thromboembolism (VTE) and treatment of deep vein thrombosis or pulmonary embolism. Data from 2 recently published trials are similarly indicating noninferiority of fondaparinux in ACS patients. Health economic analysis of fondaparinux treatment is currently limited to VTE scenarios but point to a cost benefit associated with fondaparinux compared with enoxaparin. (Am J Manag Care. 2006;12:S444-S450) The arterial thrombosis responsible for acute coronary syndromes (ACS) begins with the rupture of the atherosclerotic plaque, exposing components of the arterial subendothelium that attract and bind platelets to the damaged arterial surface. The bound platelets secrete substances that promote vasoconstriction, attract other platelets that increase the size of the thrombus at the site of injury, and trigger the formation of clotting factor Xa. The latter catalyzes the transformation of prothrombin to thrombin, which then converts fibrinogen to fibrin, stabilizing the developing thrombus. 1 Because of the key role of thrombosis in ACS, antithrombotic therapy is central to its treatment. 1-3 Although it is but one part of the entire treatment regimen, antithrombotic therapy represents a sizeable portion of the total costs associated with ACS treatment. 4 Newer, more cost-effective antithrombotic agents could, therefore, significantly ease the economic burden associated with the treatment of ACS. Newer Antithrombotics Although unfractionated heparin (UFH) has been the mainstay of anticoagulant therapy for nearly 60 years, 5-7 it has a narrow therapeutic window and carries the risk of hemorrhage and its attendant costs for transfusion and other associated interventions. 8 Moreover, the dose-response characteristics of UFH vary significantly from patient to patient. 8 As a result, its anticoagulant effect must be closely monitored, introducing its own costs for personnel and laboratory work. 4,8 Additionally, UFH requires continuous intravenous infusion in Kenneth Lane and Thomas May contributed to the writing of this article. Address correspondence to: Edith A. Nutescu, PharmD, Department of Pharmacy Practice, University of Illinois at Chicago, College of Pharmacy, 833 S. Wood St., RM 164, MC886, Chicago, IL enutescu@uic.edu. S444 THE AMERICAN JOURNAL OF MANAGED CARE DECEMBER 2006

2 Easing the Economic Burden of Acute Coronary Syndromes acute treatment of ACS, necessitating the prolonged hospitalization of patients who might otherwise be well enough for discharge. 9 UFH also carries the risk of heparininduced thrombocytopenia (HIT) and osteoporosis. 4,8 These drawbacks have prompted the development of newer antithrombotic agents, including low molecular weight heparins (LMWH) and factor Xa inhibitors, such as fondaparinux. LMWH. LMWH have been a major boon to antithrombotic therapy, because they have several advantages over UFH. LMWH are produced by the chemical degradation of UFH into component peptides of varying length and molecular weight. 10 The introduction of these heparin derivatives has had a significant impact on antithrombotic/anticoagulant therapy, 7,8 and they have become increasingly popular for the prevention and treatment of venous thromboembolism (VTE) and for the management of ACS. 8,9 Their longer plasma half-lives permit onceor twice-daily dosing, 11 providing the option of continuing antithrombotic therapy on an outpatient basis after hospital discharge. In addition, their greater bioavailability and more predictable dose-response characteristics, compared with UFH, lessen the need for coagulation monitoring and dose adjustment LMWH Safety and Efficacy. The advantages of LMWH have prompted their investigation in the treatment of ACS, and they have proved safer and more effective than UFH in several different patient populations. 4,8,15-20 As a result, the 2002 guidelines of the American College of Cardiology/ American Heart Association (ACC/AHA) and the European Society of Cardiology recommend LMWH, in combination with aspirin or clopidogrel, for the treatment of unstable angina (UA) and non ST-segment elevation myocardial infarction (NSTEMI). 21,22 The 2005 updated ACC/ AHA/SCAI [Society for Cardiovascular Angiography and Interventions] guidelines for percutaneous coronary intervention (PCI) state that LMWH are reasonable alternatives to UFH in patients with UA/STEMI undergoing PCI. 23 Most studies of LMWH in ACS have focused on enoxaparin, and there is considerable evidence that, especially in the acute setting, enoxaparin is more effective than UFH. 15,16,24 The Efficacy and Safety of Subcutaneous Enoxaparin in Non Q-wave Coronary Events (ESSENCE) trial, for example, found enoxaparin to be superior to UFH at both 30-day and 1-year follow-up of patients with UA and NSTEMI. 24,25 Several other clinical trials have also yielded favorable results regarding the safety and efficacy of enoxaparin in ACS. For example, both the National Investigators Collaborating on Enoxaparin (NICE) 1 and NICE 4 trials found that enoxaparin alone or in conjunction with a glycoprotein IIb/IIIa (GpIIb/IIIa) inhibitor provided safe and effective anticoagulation in patients undergoing PCI, with infrequent episodes of bleeding. 26 Additionally, a meta-analysis of the clinical data from the ESSENCE and Thrombolysis in Myocardial Infarction 11B (TIMI 11B) trials showed that, compared with UFH, enoxaparin was associated with a 20% lower risk of death and serious cardiac ischemic events, without significant increase in the frequency of major bleeding. 24 A systematic overview of combined data from the ESSENCE, A to Z, and SYNERGY [Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors] trials found a statistically significant reduction in favor of enoxaparin over UFH in the combined end point of death or myocardial infarction (MI) at 30 days. 27 Moreover, the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 trial, in which a combined regimen of tenecteplase with enoxaparin, UFH, or the GpIIb/IIIa inhibitor abciximab was used for the medical management of patients with acute MI, found a lower rate for each of the end point components of 30-day mortality, reinfarction during initial hospitalization, or recurrent ischemia for tenecteplase in combination with enoxaparin than in combination with UFH. 28 Results from the SYNERGY trial showed noninferiority of enoxaparin compared with UFH at 30 and 90 days, 29 and later extended out to 6 months and 1 year. 30 The investigators noted a modest increase in bleeding with enoxaparin with a statistically signifi- VOL. 12, NO. 16, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S445

3 Figure 1. Cumulative 30-Day Direct Medical Costs for UFH Versus Enoxaparin in UA or Non Q-wave MI Drug costs Physician fees Hospital costs Total costs Enoxaparin UFH Mean cost ($US) UFH indicates unfractionated heparin; UA, unstable angina; MI, myocardial infarction. Source: Adapted with permission from Reference 8. cant increase in TIMI major bleeding (9.1% vs 7.6% for UFH; P <.008). 29 A subgroup analysis of the impact of prerandomization antithrombotic therapy showed that patients who continued to take enoxaparin after randomization had a lower rate of death or MI than those who continued on UFH. 31 LMWH Economic Considerations. Because UFH is quite inexpensive, newer therapies need to demonstrate economic attractiveness to ensure adoption of the new therapy in practice. Here, economic attractiveness means that the newer therapy is as good or better clinically with net cost saving (economically dominant), or the newer therapy is better and more costly, but the extra health benefit is deemed worth the additional cost (cost-effective). Health economic analyses show that the clinical advantages of enoxaparin are also likely to result in net cost-saving benefits (Figure 1). 8 Although the acquisition cost of treatmentdose LMWH for ACS is approximately 25-fold greater than for UFH, 32 this does not necessarily mean that using an LMWH instead of UFH leads to an increase in the overall cost of treatment. In order to obtain a realistic assessment of all costs involved in treating a patient, it is not appropriate to look at acquisition costs alone. Instead, one must consider the cost of all key components throughout the continuum of care. Regarding the use of anticoagulants in ACS, comprehensive evaluations have been completed. Several health economics analyses based on the ESSENCE trial have considered various other components of care besides drug acquisition costs One of these analyses found that diagnostic catheterization, percutaneous transluminal coronary angioplasty, and intensive care unit length of stay were significantly lower with enoxaparin than with UFH at 30-day follow-up, which resulted in significant cost savings (cumulative total cost savings, $1172; P =.04). 33 In the Analysis of Coronary Ultrasound Thrombolysis Endpoints in Acute Myocardial Infarction (ACUTE) trial, the percentage of rehospitalizations a large contributor to additional treatment costs was much lower with enoxaparin (1.6%) than with UFH (7.1%) (P =.002), 17 although it was similar in the ESSENCE trial. 33 Based on ESSENCE, lower costs of medical resources associated with enoxaparin, compared with UFH, reflect downstream savings of lower revascularization costs, secondary to fewer ischemic events For example, in the US cohort, Mark et al found a mean 30-day cumulative saving of $929 in hospital costs (P <.02) and $317 in physician fees (P <.03) in favor of enoxaparin. 33 There was an accompanying drop in resource use such as percutaneous transluminal angioplasty and coronary artery bypass graft ( 6% and 3% respectively). The higher acquisition cost of enoxaparin, compared with UFH, is evidently compensated for by savings in medical resource costs. Such cost savings, in addition to improved clinical effectiveness, make LMWH therapy a dominant strategy over UFH therapy in the treatment of ACS Fondaparinux. Fondaparinux is an indirect inhibitor of factor Xa, binding strongly and selectively to antithrombin III (ATIII) to modify the latter s conformation and potentiate its inactivation of factor Xa by approximately 300-fold. 39 Fondaparinux is a synthetic pentasaccharide, synthesized based on the ATIII-binding sequence of both UFH S446 THE AMERICAN JOURNAL OF MANAGED CARE DECEMBER 2006

4 Easing the Economic Burden of Acute Coronary Syndromes and LMWH. Because it does not inactivate thrombin itself, fondaparinux is unlikely to interfere with thrombin s postulated woundhealing properties. 40 In contrast to UFH, fondaparinux does not require routine monitoring of its anticoagulant effect. Additionally, a long half-life of 17 to 21 hours permits once-daily dosing. 41 Its synthetic nature and high selectivity for factor Xa make fondaparinux unlikely to interact with the antibodies responsible for HIT in patients who carry such antibodies. 40,42 Because of its renal elimination, however, fondaparinux is contraindicated in patients with severe renal dysfunction (creatinine clearance <30 ml/min), and it should be used with care in patients with moderate renal dysfunction (creatinine clearance ml/min). 41 Fondaparinux Safety and Efficacy. Fondaparinux has shown efficacy in each of the major areas for which enoxaparin is indicated. Efficacy has been demonstrated in the prevention of VTE after major orthopedic 43 and abdominal 44 surgery, as well as in older patients with acute medical conditions. 45 In addition, fondaparinux has shown efficacy in the treatment of acute deep vein thrombosis (DVT) 46 and pulmonary embolism (PE), 9 and in the management of patients with ACS. 13,47 A meta-analysis of the data from 4 major randomized trials comparing fondaparinux with enoxaparin in major orthopedic surgery found that the use of fondaparinux resulted in an overall risk reduction of VTE greater than 50% during the first 11 days after surgery, without increasing the risk of clinically relevant bleeding. 43 Furthermore, the results of 2 large, randomized, controlled trials indicated that fondaparinux is at least as safe and efficacious as enoxaparin or UFH in the treatment of DVT 46 and PE, 9 respectively. Fondaparinux has also shown promise in a number of studies investigating its use in ACS. In phase II of the Pentasaccharide as an Adjunct to Fibrinolysis in ST-Elevation Acute Myocardial Infarction (PENTALYSE) study, in which 3 dose levels of fondaparinux were compared with UFH in patients given aspirin or alteplase for evolving MI, 60% to 69% of the fondaparinux-treated patients showed full arterial patency at 90 minutes (as reflected by TIMI [Thrombolysis in Myocardial Infarction] grade 3 flow) compared with 68% of those treated with UFH. 48 There was also a trend toward less reocclusion and fewer revascularizations with fondaparinux. The 2004 ACC/AHA guidelines for the management of ST-segment elevation MI (STEMI) noted this comparability in the PENTALYSE study, and suggested that factor Xa inhibitors could constitute future therapeutic options for patients with STEMI. 2 More recently, 2 large-scale, randomized trials have demonstrated the noninferiority of fondaparinux versus enoxaparin and UFH in the treatment of ACS. In the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS-5) trial, which involved more than patients with UA or NSTEMI, fondaparinux produced results comparable to that of enoxaparin for the composite outcome measures of death, MI, or refractory ischemia, as well as producing a significantly lower rate of major bleeding than enoxaparin, with these effects persisting throughout the 180-day follow-up period of the study. 13 In the Sixth Organization for the Assessment of Strategies for Ischemic Syndromes (OASIS-6) trial, which included more than patients with STEMI, fondaparinux produced a relative reduction in the risk of death of 17% at 9 days, 14% at 30 days, and 12% at the study end point of 3 Figure 2. Fondaparinux Versus Enoxaparin: VTE Costs* at 90 Days Cost ($US) Enoxaparin Fondaparinux *2003 US dollars. VTE indicates venous thromboembolism. Adapted with permission from Reference 50. Others Major bleeding Clinical VTE events Prophylaxis VOL. 12, NO. 16, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S447

5 to 6 months, compared with placebo or UFH, and was associated with no greater major bleeding than either of the latter 2 drugs. 47 No benefit was found for patients undergoing PCI; however, the authors suggest that fondaparinux may be a useful treatment after PCI, with UFH used during the procedure. Fondaparinux Economic Considerations. Economic data with fondaparinux at this time are limited to VTE. One of the few health economic studies that have been conducted in this area investigated its use in orthopedic surgery and found cost savings with fondaparinux over enoxaparin, which grew from $61 per patient at 30 days after hospital discharge to $155 at 5 years in a clinical trial-based analysis. 49 In a more recent study involving patients undergoing hip fracture surgery, the use of fondaparinux was associated with 30 fewer episodes of VTE per 1000 patients, at a savings of $361 per patient at 3 months (Figure 2) and an estimated savings of $466 per patient at 5 years. 50 Although no health economic data on fondaparinux in ACS are currently available, the use of fondaparinux instead of enoxaparin is likely to result in overall cost savings because of several factors, such as its lower dose in ACS as well as the lower rates of bleeding reported in recent trials. 13,47 Conclusion Because antithrombotic therapy comprises the largest portion of the costs associated with the treatment of ACS, it is therefore important to find the most costeffective treatment that is both safe and effective. Although UFH represents standard therapy, newer treatments such as LMWH or factor Xa inhibitors are efficacious alternatives that are less costly in terms of overall treatment costs, including not only acquisitions costs but also monitoring expenses and costs of bleeding and other side effects. According to recent trials, fondaparinux appears to be equivalent to enoxaparin in terms of efficacy in ACS patients; recent analyses suggest that it may even turn out to be cost saving due to lower rates of bleeding and lower drug dosages required. REFERENCES 1. Moliterno DJ, Granger CB. Differences between unstable angina and acute myocardial infarction. In: Topol E, ed. Acute Coronary Syndromes. New York, NY: Marcel Dekker; 1998: Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA 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 (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). Circulation. 2004;110:e82-e Popma JJ, Berger P, Ohman EM, Harrington RA, Gvines C, Weitz JI. Antithrombotic therapy during percutaneous coronary intervention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 suppl):576s-599s. 4. Bosanquet N, Jonsson B, Fox KA. Costs and costeffectiveness of low-molecular-weight heparins and platelet glycoprotein IIb/IIIa inhibitors in the management of acute coronary syndromes. Pharmacoeconomics. 2003;21: Hirsh J. Antithrombotic therapy. In: Goldman L, Ausiello D, eds. Cecil Textbook of Medicine. 22nd ed. Philadelphia, Pa: Saunders; 2004: Morris TA. Heparin and low-molecular-weight heparin: background and pharmacology. Clin Chest Med. 2003;24: Nutescu E, Racine E. Traditional versus modern anticoagulant strategies: summary of the literature. Am J Health Syst Pharm. 2002;59(20 suppl 6):S7-S Bergqvist D. Enoxaparin: a pharmacoeconomic review of its use in the prevention and treatment of venous thromboembolism and in acute coronary syndromes. Pharmacoeconomics. 2002;20: Büller HR, Davidson BL, Decousus H, et al. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med. 2003;349: Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest. 2001;119(1 suppl):64s-94s. 11. Nutescu EA, Helgason CM. Evolving concepts in the treatment of venous thromboembolism: the role of factor Xa inhibitors. Pharmacotherapy. 2004;24(7 pt 2):82S-87S. 12. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 suppl):338s-400s. 13. The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006;354: Hawkins D, Huston SA. Pharmacoeconomic considerations on anticoagulant drug use. Exp Opin Pharmacother. 2006;7: Cohen M, Demers C, Gurfinkel EP, et al; for the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Group. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med. 1997;337: S448 THE AMERICAN JOURNAL OF MANAGED CARE DECEMBER 2006

6 Easing the Economic Burden of Acute Coronary Syndromes 16. 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 11B trial. Circulation. 1999;100: Cohen M, Theroux P, Borzak S, et al; ACUTE II Investigators. 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: Goodman SG, Fitchett D, Armstrong PW, Tan M, Langer A; Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT) Trial Investigators. 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: Blazing MA, de Lemos JA, White HD, et al; A to Z Investigators. 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;292: Ferguson JJ, Califf RM, Antman EM, et al; SYNERGY Trial Investigators. 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: Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guideline update for the management of patients with unstable angina and non-st-segment elevation myocardial infarction 2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). Circulation. 2002;106: Bertrand ME, Simoons ML, Fox KA, et al. Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. The Task Force on the Management of Acute Coronary Syndromes of the European Society of Cardiology. Eur Heart J. 2002;23: Smith SC Jr, Antman EM, Feldman TE, et al. ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention: a Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention) Available at: clinical/guidelines/percutaneous/update/index. pdf. Accessed November 15, Antman EM, Cohen M, Radley D, et al; for the TIMI 11B and ESSENCE Investigators. Assessment of the treatment effect of enoxaparin for unstable angina/ non-q-wave myocardial infarction. TIMI 11B/ESSENCE meta-analysis. Circulation. 1999;100: Antman EM, Cohen M, McCabe CH, et al; for the TIMI 11B and ESSENCE Investigators. Enoxaparin is superior to unfractionated heparin for preventing clinical events at 1-year follow-up of TIMI 11B and ESSENCE. Eur Heart J. 2002;23: Kereiakes DJ, Grines C, Fry E, et al; for the NICE 1 and NICE 4 Investigators. Enoxaparin and abciximab adjunctive pharmacotherapy during percutaneous coronary intervention. J Invasive Cardiol. 2001;13: Petersen JL, Mahaffey KW, 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: Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (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;358: Ferguson JJ, Califf RM, Antman EM, et al; SYNERGY Trial Investigators. 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: Mahaffey KW, Cohen M, Garg J, et al; SYNERGY Trial Investigators. High-risk patients with acute coronary syndromes treated with low-molecular-weight or unfractionated heparin: outcomes at 6 months and 1 year in the SYNERGY trial. JAMA. 2005;294: Cohen M, Mahaffey KW, Pieper K, et al; SYNERGY Trial Investigators. A subgroup analysis of the impact of prerandomization antithrombin therapy on outcomes in the SYNERGY trial: enoxaparin versus unfractionated heparin in non-st-segment elevation acute coronary syndromes. J Am Coll Cardiol. 2006;48: UFH and Lovenox AWP comparison based on an average of 3 UFH suppliers and Lovenox AWPs. In: Red Book 2003 Drug Topics. Montvale, NJ: Medical Economics, Thomson Healthcare; 2003: 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 in Non-Q wave Coronary Events (unstable angina or non Q-wave myocardial infarction). Circulation. 1998;97: Balen RM, Marra CA, Zed PJ, Cohen M, Frighetto L. Cost-effectiveness analysis of enoxaparin versus unfractionated heparin for acute coronary syndromes. A Canadian hospital perspective. Pharmacoeconomics. 1999;16(5 pt 2): O Brien BJ, Willan A, Blackhouse G, Goeree R, Cohen M, Goodman S. Will the use of low-molecularweight heparin (enoxaparin) in patients with acute coronary syndrome save costs in Canada? Am Heart J. 2000; 139: Fox KA, 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: Brosa M, Rubio-Terres C, Farr I, Nadipelli V, Froufe J. Cost-effectiveness analysis of enoxaparin versus unfractionated heparin in the secondary prevention of acute coronary syndrome. Pharmacoeconomics. 2002; 20: Bosanquet N, Fox KA. Longer term economic benefits reflect improved clinical outcomes with enoxaparin versus unfractionated heparin in acute coronary syndromes: one-year data. Br J Cardiol. 2001;8: VOL. 12, NO. 16, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S449

7 39. Turpie AG, Gallus AS, Hoek JA; Pentasaccharide Investigators. A synthetic pentasaccharide for the prevention of deep vein thrombosis after total hip replacement. N Engl J Med. 2001;344: Dager WE, Andersen J, Nutescu E. Special considerations with fondaparinux therapy: heparin-induced thrombocytopenia and wound healing. Pharmacotherapy. 2004; 24(7 pt 2):88S-94S. 41. Arixtra [prescribing information]. Triangle Research Park, NC: GlaxoSmithKline; Efird LE, Kockler DR. Fondaparinux for thromboembolic treatment and prophylaxis of heparin-induced thrombocytopenia. Ann Pharmacother. 2006;40: Turpie AG, Bauer KA, Eriksson BI, Lassen MR. Fondaparinux vs. enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med. 2002;162: Agnelli G, Bergqvist D, Cohen AT, Gallus AS, Gent M; the PEGASUS Investigators. Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery. Br J Surg. 2005;92: Cohen AT, Davidson BI, Gallus AS, et al; the ARTEMIS Investigators. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomized placebocontrolled trial. BMJ. 2006;332: Büller HR, Davidson BL, Decousus H, et al; for the MATISSE Investigators. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med. 2004;140: The OASIS-6 Trial Group. Effects of fondaparinux on mortality and reinfarction in patients with acute STsegment-elevation myocardial infarction. JAMA. 2006; 295: Coussement PK, Bassand JP, Convens C, et al; for the PENTALYSE Investigators. A synthetic factor-xa inhibitor (ORG31540/SR9017A) as an adjunct to fibrinolysis in acute myocardial infarction. The PENTALYSE study. Eur Heart J. 2001;22: Sullivan SD, Davidson BL, Kahn SR, Muntz JE, Oster G, Raskob G. A cost-effectiveness analysis of fondaparinux sodium compared with enoxaparin sodium as prophylaxis against venous thromboembolism: use in patients undergoing major orthopaedic surgery. Pharmacoeconomics. 2004;22: Sullivan SD, Kwong L, Nutescu E. Cost-effectiveness of fondaparinux compared with enoxaparin as prophylaxis against venous thromboembolism in patients undergoing hip fracture surgery. Value Health. 2006; 9: S450 THE AMERICAN JOURNAL OF MANAGED CARE DECEMBER 2006