Economic Implications Of Direct Thrombin Inhibitors In The Cath Lab
L. Brian Cross, PharmD, CDE*
Coronary artery disease (CAD)—which includes myocardial infarction (MI), angina pectoris, atherosclerosis, and other diseases of the heart—affects nearly 14 million Americans.1 Each year, there are approximately 700 000 episodes of recurrent acute CAD; 500 000 new episodes; and 175 000 "silent" first heart attacks.1 According to the Healthcare Cost and Utilization Project of the US Agency for Healthcare Research and Quality, coronary atherosclerosis accounts for more in-hospital treatment costs than any other disease or condition, with total annual expenses of $38.4 billion. MI is the second most costly condition, with total annual hospital costs of $27.8 billion.1
The acute coronary syndromes of unstable angina and MI are usually caused when thrombus forms within a coronary artery and obstructs blood flow.2 Percutaneous coronary intervention (PCI) using balloon angioplasty, stents, and related procedures restores circulation through the blocked artery, and reduces mortality and the incidence of other ischemic complications. In contemporary practice, PCI is performed using several adjunctive medications, including oral and parenteral antiplatelet agents and an anticoagulant (typically heparin).3 Although these agents have reduced the incidence of ischemic complications of PCI, the beneficial effects of these antithrombotic regimens are often countered to some extent by increased bleeding complications.4,5 These pharmacotherapy regimens also add complexity and significant cost to PCI treatment.6,7
Heparin has long been the mainstay of adjunctive anticoagulation therapy in PCI. Heparin reduces the activity and the generation of thrombin, an enzyme that is central to the coagulation process and the formation of blood clots.8 Thrombin produces several effects that promote thrombus formation in PCI. It activates platelets; increases the expression of platelet glycoprotein (GP) IIb/IIIa receptors, which are required for platelet aggregation; and catalyzes the conversion of fibrinogen to fibrin.9-11 Although heparin reduces thrombus formation and improves clinical outcomes in PCI, it also possesses several pharmacologic properties that limit its effectiveness. Heparin produces a highly variable anticoagulation response, and it must be administered by continuous intravenous infusion over several hours.8 Some patients develop heparin-induced thrombocytopenia (HIT) with prolonged heparin treatment, in which complexes of heparin and antiheparin antibodies stimulate widespread platelet aggregation throughout the vasculature.12 HIT develops in as many as 5% of patients who receive heparin infusions. It can cause numerous ischemic complications, including MI, stroke, renal injury, and death. Finally, heparin is associated with an increased risk of bleeding complications, especially when used at high doses or combined with platelet GP IIb/IIIa inhibitors.
Direct thrombin inhibitors (DTIs) provide a potential alternative to heparin for procedural anticoagulation in PCI. Although the initial clinical studies of the DTI hirudin in patients with acute CAD found that hirudin increased the number of patients with bleeding complications,3 clinical trials have suggested that a second agent, bivalirudin, may provide efficacy similar or superior to that of heparin in PCI, but with a significantly lower risk of bleeding complications.13,14 Bivalirudin was recently examined in the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) study, a large randomized, multinational, double-blind clinical trial in which patients undergoing PCI were treated with clopidogrel or ticlopidine and were randomly assigned to one of 2 treatment strategies.15 One group of patients received conventional treatment with heparin and a platelet GP IIb/IIIa receptor inhibitor. In the other group, all of the patients received bivalirudin, and GP IIb/IIIa inhibitors were administered only when needed for procedural or angiographic complications (eg, dissection of the artery or the development of thrombus). This study found that the strategy of bivalirudin and provisional GP IIb/IIIa inhibition produced improvement in ischemic outcomes that were similar to those of the conventional treatment strategy, but with a significantly lower incidence of bleeding complications.
As a consequence of the relatively low rate of GP IIb/IIIa inhibitor use and the reduced incidence of bleeding complications, the investigators hypothesized that bivalirudin treatment may be associated with lower treatment cost than the conventional strategy. Although some previous anecdotal reports had suggested that the use of bivalirudin in place of heparin reduced the number of patients who required GP IIb/IIIa inhibitors and reduced total treatment costs,13 no large prospective studies had previously examined the economic impact of replacing heparin and GP IIb/IIIa antagonists with a DTI and provisional GP IIb/IIIa inhibition. Therefore, the REPLACE-2 investigators conducted a preplanned analysis of the economic impact of replacing heparin and GP IIb/IIIa inhibitors with bivalirudin by examining hospital resource use and costs for patients who were enrolled in the trial at study centers in the United States.7 In this analysis, Cohen et al demonstrated that the strategy of bivalirudin and provisional GP IIb/IIIa inhibition was associated with significantly lower overall cost of PCI, which was primarily because of a reduction in the costs of anticoagulation therapy.7
This issue of Advanced Studies in Pharmacy examines the efficacy, safety, and cost effectiveness of DTIs as adjunctive pharmacotherapy in PCI. A review article by David J. Cohen, MD, MSc, who was the principal author of the REPLACE-2 economic analysis, summarizes the clinical and economic impact of DTI therapy in PCI, and especially the importance of ischemic and bleeding complications. This issue also features a clinician interview with Ann K. Wittkowsky, PharmD, CACP, FASHP. Dr Wittkowsky discusses the role of DTI therapy in pharmacy practice, and how procedural anticoagulation in PCI may change in response to clinical trials of DTIs. This issue also includes a reprint of the REPLACE-2 economic analysis article.
1. American Heart Association. Heart Disease and Stroke Statistics — 2005 Annual Update. Dallas, Tex: American Heart Association; 2005.
2. Weitz JI, Bates ER. Direct thrombin inhibitors in cardiac disease. Cardiovasc Toxicol. 2003;3:13-25.
3. French MH, Faxon DP. Current anticoagulation options in percutaneous intervention: designing patient-specific strategies. Rev Cardiovasc Med. 2002;3:176-182.
4. EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. The EPIC investigation. N Engl J Med. 1994;330:956-961.
5. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med. 1997;336:1689-1696.
6. Cohen DJ, O'Shea JC, Pacchiana CM, et al; ESPRIT Investigators. In-hospital costs of coronary stent implantation with and without eptifibatide (the ESPRIT trial). Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin. Am J Cardiol. 2002;89:61-64.
7. 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. J Am Coll Cardiol. 2004;44:1792-1800.
8. Nutescu EA, Shapiro NL, Chevalier A, Amin AN. A pharmacologic overview of current and emerging anticoagulants. Cleve Clin J Med. 2005;72(suppl 1):S2-S6.
9. Brass LF. Thrombin and platelet activation. Chest. 2003;124(suppl 3):18S-22S.
10. Giesberts AN, van Willigen G, Lapetina EG, Akkerman JW. Regulation of platelet glycoprotein IIb/IIIa (integrin alpha IIB beta 3) function via the thrombin receptor. Biochem J. 1995;309:613-620.
11. Jarvis GE, Atkinson BT, Frampton J, Watson SP. Thrombin-induced conversion of fibrinogen to fibrin results in rapid platelet trapping which is not dependent on platelet activation or GPIb. Br J Pharmacol. 2003;138:574-583.
12. Bartholomew JR, Begelman SM, Almahameed A. Heparin-induced thrombocytopenia: principles for early recognition and management. Cleve Clin J Med. 2005;72(suppl 1):S31-S36.
13. Compton A. A practical cost analysis of bivalirudin. Pharmacotherapy. 2002;22:119S-127S.
14. Moscucci M. Frequency and costs of ischemic and bleeding complications after percutaneous coronary interventions: rationale for new antithrombotic agents. J Invasive Cardiol. 2002;14(suppl B):55B-64B.
15. 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. JAMA. 2003;289:853-863. Erratum in: JAMA. 2003;289:1638.
*Assistant Professor, University of Tennessee Health Science Center, Colleges of Pharmacy & Medicine, Director of Pharmacotherapy Services, UT St. Francis Family Practice Center, Memphis, Tennessee.
Address correspondence to: L. Brian Cross, PharmD, CDE, University of Tennessee College of Pharmacy, 920 Madison Ave, Ste 326, Memphis, TN 38163.