Abciximab: Cost-effective survival advantage in clinical trials and clinical practice

Abciximab: Cost-effective survival advantage in clinical trials and clinical practice John J. Young, MD, and Dean J. Kereiakes, MD Cincinnati, Ohio

Adjunctive blockade of the platelet glycoprotein (GP) IIb/IIIa receptor during either percutaneous coronary intervention (PCI) or for patients who present with non-ST segment elevation acute coronary syndromes has demonstrated efficacy in reducing platelet-mediated adverse cardiovascular ischemic events. The three currently available agents (abciximab, eptifibatide, tirofiban) differ markedly in pharmacodynamic and pharmacokinetic profiles, receptor affinity, and cost. Although pharmacoeconomic substudies are available from placebo-controlled randomized trials of platelet GPIIb/IIIa blockade during PCI, “real-world” cost-effectiveness data from high-volume practice are lacking. Therefore, in-hospital and late (6-month) clinical outcomes and cumulative cost/charge data were analyzed on 1472 consecutive PCI procedures (70% received abciximab) performed by high-volume operators at a single institution.1 Data were adjusted for lack of randomized treatment allocation with the use of a propensity scoring technique. Adjunctive abciximab therapy for PCI was associated with a significant (3.4%) reduction in mortality to 6 months. Based on the economic cost-effectiveness concept of cost per life year gained relative to standard therapy,2,3 abciximab provided a cost-effective survival advantage in high-volume interventional practice that compares very favorably with currently accepted standards. Clinical and procedural demographics associated with increased cost-effectiveness include multivessel coronary intervention, stent deployment, recent (<1 week) myocardial infarction (MI), and impaired left-ventricular (LV) function. (Am Heart J 2000;140:S148-53.)

Platelet GPIIb/IIIa receptor blockade improves clinical outcomes after PCI and for patients who present with non-ST segment elevation acute coronary syndromes. Although 3 platelet GPIIb/IIIa inhibitors have received U.S. Food and Drug Administration approval and are commercially available for use, these agents differ markedly in pharmacodynamic profile and cost. Differences in the duration of action at the platelet target receptor, receptor affinity, and differential binding sites on the GPIIb/IIIa receptor have been demonstrated for the monoclonal antibody abciximab compared with the cyclic heptapeptide eptifibatide and the nonpeptide tyrosine derivative tirofiban.4 Uncertainty exists as to whether these pharmacodynamic differences will translate into measurable differences in clinical outcomes for patients treated with different agents. Recent data have also suggested that purported differences in clinical outcomes observed in nonrandomized comparisons of separate clinical trials using different GPIIb/IIIa agents may not be solely explained by the intensity of platelet GPIIb/IIIa inhibition alone.4 With wide variation in the cost of these agents, cost-effectiveness of this adjunctive pharmacotherapy has been scrutinized. Furthermore extrapolation of cost-efficacy observations from clinical trials to clinical interventional practice is problematic. From The Carl and Edyth Lindner Center for Research and Education, and The Ohio Heart Health Center. Reprint requests: Dean J. Kereiakes, MD, The Carl and Edyth Lindner Center for Research and Education, 2123 Auburn Ave, Suite 424, Cincinnati, OH 45219. Copyright © by Mosby, Inc. 0002-8703/00/$12. + 0 4/0/111604 doi:10.1067/mhj.2000.111604

Economic concepts Medical cost analysis incorporates concepts from both economics and accounting. Economics provides the theoretical and conceptual framework for cost analysis, whereas accounting provides practical measurement tools. One consequence of this admixture is that several distinct but overlapping sets of terminology are used in cost analysis. A major precept of economics is that any societal decision to use resources in the production of goods and services is accompanied by a loss of opportunity to do something else with these resources. Health care systems incur a “cost” through their consumption of resources that are then lost for other uses. The technical term for this concept is “opportunity cost.”2 Economists are far more concerned with the concept of opportunity cost than they are with measuring dollars spent. Another important related concept is that society’s collective resources are finite. Taken together, these concepts suggest that there will not be sufficient resources to fulfill all of society’s needs, thereby forcing choices to be made among competing priorities and costs. Unfortunately, although opportunity cost represents the purest definition of “true cost,” it is a theoretical construct that does not have practical measurement. Societal perspective is most often used by cost analysts in medicine because it offers the broadest possible perspective that incorporates all cost and health benefits related to the proposed change in medical care. Several terms and definitions are used (fixed costs, direct costs, marginal costs, etc) to define the various sources of cost incurred in the delivery of health care services.3 The

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key concept is that it is not sufficient to consider only immediate cost but instead, cost incurred “downstream” and subsequent “cost savings” provide a more accurate description of the global economic impact of a particular technology or treatment strategy. During the last decade, empirical cost data collection from large-scale randomized trials and from single-site observational studies have been the principal method for estimating medical costs.3 By generating an empirical database for costs, a more extensive investigation can be performed to assess cost-effectiveness. “Costeffectiveness” analyzes the value of medical care by assessing the added costs of treatment relative to the medical benefit obtained. Typically, cost-effectiveness analyses are expressed in terms of the extra dollars (cost) required to add an additional year of life with the new treatment strategy relative to the previous standard of care.2 Thus a cost per life-year gained can be determined for new treatment strategies tested in clinical trials. Incremental cost-effectiveness ratios (ICERs) expressed as a cost-per-life-year-gained can be calculated from costs associated with treatment (T) minus those associated with placebo (P) divided by the corresponding differences in effectiveness expressed as life expectancy. 2 This can be more simply expressed as follows: ICER =

CT - CP LET - LEP

where C = lifetime cost for each treatment arm, LE = life expectancy, T = new treatment arm, and P = placebo arm. Conventional thinking in this field is that costeffectiveness ratios less than $20,000 per-life-year gained are highly cost-effective, $20,000 to 50,000 are cost-effective, and a ratio exceeding $100,000 is “economically unattractive.”2

Economic analyses of GPIIb/IIIa receptor antagonists The 3 currently available intravenous platelet GPIIb/IIIa receptor blockers have been studied in 5 large-scale trials of percutaneous coronary revascularization with prospective economic analyses. The EPIC (Evaluation of Monoclonal Antibody to Prevent Ischemic Complications) trial randomized 2099 high risk patients who had undergone percutaneous transluminal coronary angioplasty to 1 of 3 arms: placebo, bolus abciximab, and bolus plus infusion abciximab.5 All patients received aspirin and non–weight-adjusted unfractionated heparin. At 30 days bolus plus 12-hour infusion of abciximab reduced the primary composite clinical end point of death, recurrent myocardial infarction, or requirement for urgent revascularization by 35% relative to placebo but doubled major in-hospital bleeding episodes (from 7% to 14%). Six-month primary end-

point events were further reduced by 23%. An economic substudy of EPIC was conducted prospectively. During the index hospitalization, baseline costs in EPIC (excluding the cost of abciximab) were not different by pharmacologic treatment strategy. With the use of an “explanatory” regression model, these investigators demonstrated that the lower incidence of ischemic events attributed to abciximab was associated with a cost savings estimated at $622 per patient.2 However, an excess in major bleeding events in the bolus plus 12hour infusion abciximab arm was associated with a $521 per patient cost increment for this same treatment group. Clinical follow-up to 6 months demonstrated a 23% decrease in rehospitalization and a 22% decrease in repeat revascularization procedures for the abciximab treatment arm and was associated with an additional cost savings (reduced resource consumption) of $1270 per patient. Combining baseline and follow-up costs for each treatment arm yielded a net 6-month cost increment for abciximab bolus and infusion of $293 per patient.2 Based on these data, the investigators hypothesized that if abciximab efficacy in EPIC could be replicated in the context of a reduction in major bleeding, abciximab therapy had the potential to “pay for itself” over a 6-month period after PCI. EPIC was the first large-scale trial of adjunctive GPIIb/ IIIa platelet inhibition during PCI and demonstrated that this class of drug provides clinical benefit. However, the increased risk of major bleeding attributed to abciximab provided an objective for enhancing safety of this therapy. The EPILOG trial was conducted to validate the efficacy of abciximab as demonstrated in EPIC and to test strategies designed to enhance abciximab safety.6 To this effect, a weight-adjusted reduced dose of heparin was administered in conjunction with abciximab and was coupled with early postprocedural vascular sheath removal at an activated clotting time of ≤180 seconds. This trial demonstrated a 57% reduction in the same composite clinical primary end point (death, MI, emergency revascularization) in patients treated with abciximab + low-dose (70 U/kg) weight-adjusted heparin (vs heparin 100 U/kg and aspirin alone). Furthermore the strategy of reduced-dose weight-adjusted heparin and early sheath removal successfully reduced the rate of major bleeding. A prospective cost analysis performed in EPILOG demonstrated that total baseline costs for the abciximab + low-dose heparin treatment arm (including $1457 cost for the abciximab) was $10,215 compared with $9632 in patients treated with placebo for a net cost increment attributable to abciximab of only $583 per patient.10 Thus EPILOG confirmed the premise derived from the EPIC economic analysis that a reduction in bleeding risk (in the context of clinical efficacy) could result in a net cost offset of approximately $600 during the initial hospitalization.7 However, clinical follow-up in EPILOG did not reveal a

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reduction in subsequent hospitalizations or the requirement for cardiac procedures in patients treated with abciximab. Thus the net “total cost” of abciximab therapy in the EPILOG study (approximately $600) is approximately twice the cost increment predicted by the EPIC trial, in which a reduction in revascularization procedures performed in follow-up was observed (approximately $300). The EPISTENT trial tested the safety of coronary stenting in conjunction with abciximab GPIIb/IIIa platelet inhibition.8 This trial confirmed the safety (low incidence of major bleeding or transfusion) of administering abciximab in conjunction with low-dose weightadjusted heparin in patients undergoing coronary stent deployment and demonstrated a survival advantage in favor of abciximab therapy (absolute % vs placebo) of 0.7% at 6 months and 1.4% at 1 year in patients who had received stents.9 The calculated cost-per-life-yeargained based on the observed 1-year survival advantage (1.4%) attributed to abciximab therapy in patients who had received stents was $6213.9 This figure is certainly “highly cost-effective” based on the current economic concepts discussed previously. The IMPACT (Integrilin to Minimize Platelet Aggregation and Prevent Coronary Thrombosis) II trial tested 2dose regimens of eptifibatide versus placebo in a cohort of 4010 patients undergoing PCI.10 At 30 days no significant reduction in the primary composite clinical end point of the trial was observed for eptifibatide therapy analyzed by intention to treat. In follow-up there was no differential effect of eptifibatide on rehospitalization or repeat procedures, and the associated cost offset was small. The RESTORE (Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis) trial randomized 2212 patients with acute coronary syndromes who were referred for PCI to either tirofiban or placebo.10 A significant 38% reduction in the composite clinical end point of the trial (death, MI, or any revascularization) was observed in favor of tirofiban at 48 hours but was not sustained (16% reduction) at 30 days. When the primary end point was redefined as death, MI, or urgent revascularization, tirofiban treatment demonstrated a 24% end-point reduction to 30 days.11 The published 6month follow-up from RESTORE demonstrates no evidence for a longer-term benefit of tirofiban on clinical outcomes. The economic analysis of this trial was performed with hospital billing data for a subset of patients enrolled in the United States.12 Although a trend for reduced resource consumption used to treat recurrent ischemic events was associated with a $300 to $400 cost offset in favor of tirofiban, no significant effect of tirofiban on total cost was observed. The cost of tirofiban was estimated at $700 ($350/vial × 2 vials) per patient treated in this trial. 12 Of the 4 major studies using intravenous GPIIb/IIIa

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receptor blockers in patients with acute coronary syndrome, CAPTURE (abciximab),13 PURSUIT (eptifibatide),14 PRISM, and PRISM-Plus (tirofiban), only PURSUIT has included a prospective economic analysis. The PURSUIT trial randomized 10,948 patients presenting with acute coronary syndrome to 1 of 3 pharmacologic treatment arms; a bolus and 72-hour infusion of eptifibatide was administered in 2 treatment arms, and a placebo infusion was administered in the third.15 Follow-up at 30 days after enrollment showed a 1.5% absolute reduction in the composite clinical end point (death or MI) in the bolus plus 72-hour infusion regimen of eptifibatide. Prospective cost data were collected in 2464 of the 3519 patients enrolled in the United States. During the index hospitalization, no effect of eptifibatide on major resource consumption was found. Baseline medical costs were equivalent (eptifibatide versus placebo), and resource consumption to 6 months of follow-up did not demonstrate treatment-related differences. In the second phase of the economic analysis of PURSUIT, a cost-effectiveness model using incremental cost-effectiveness ratios demonstrated a calculated costper-life-year-gained of $16,292 attributable to eptifibatide therapy.15 Modeled survival data that used Duke University cardiovascular database information were used to calculate survival to 1 year (not actual or observed mortality) in this analysis.15

Economic analysis of abciximab in a high-volume interventional practice Multiple randomized trials, some detailed in the previous text, have demonstrated unequivocal efficacy of GPIIb/IIIa agents for reducing risk of important periprocedural ischemic events after PCI. In this era of rising medical costs and increasing concern for cost containment, adjunctive platelet GPIIb/IIIa blockade has been scrutinized with respect to cost-effectiveness. The clinical benefit attributable to GPIIb/IIIa blockade must justify the net cost increment of therapy. In addition, the cost increment of administering GPIIb/IIIa therapy may be counter-balanced by cost decrements related to a reduced hospital length of stay or incidence occurrence of costly adverse clinical outcomes. Adverse events (bleeding, transfusion) related to adjunctive pharmacotherapy are also associated with incremental costs that must be included in the equation for net cost of treatment, as previously described. A recent study at our own institution was performed to analyze the impact of adjunctive pharmacotherapy with abciximab platelet GPIIb/IIIa blockade during PCI on costs and clinical outcomes.1,16 From January 1, 1997, through December 31, 1997, a total of 1472 consecutive PCI procedures were performed by Ohio Heart Health Center interventional operators on 1305 patients at The Christ Hospital in

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Cincinnati, Ohio. Interventional physicians used a modified Summit database and prospectively collected patient and procedural demographics, hospital outcomes, and length of stay. Hospital charges were obtained with a dedicated software system, and end points (death, new MI, urgent revascularization) and complications (bleeding, transfusion) were specifically assessed. Six-month follow-up by personal telephone contact was available on 1011 patients after the index PCI procedure.1,16 Standard t tests and contingency table likelihood ratios were used to detect treatment differences in measures of patient acuity and demographic characteristics and in cost-effectiveness outcomes. Because this was an observational study and by nature nonrandomized, a propensity scoring method was used to estimate treatment differences “adjusted” for observed imbalances in patient acuity and demographics between groups. This method has been previously described and validated.17,18 Propensity scoring states that outcome differences are computed only for patients who are well matched and grouped into “bins” based on acuity and demographic characteristics.19,20 Therefore, to adjust for nonrandomization, patients were sorted by their estimated propensity score into 5 different bins based on the likelihood (or propensity) for receiving abciximab therapy. The difference in cost-effectiveness was then calculated within each bin. An ICER, expressed as a cost-per-life-year-gained, was calculated in a similar fashion to that described previously (see ICER in the previous text). Assumptions made in this calculation were (1) cost = charges × 0.75 and (2) survival from 6 months implies an additional life expectancy of 14 years, which were then discounted at 3% per year to yield 11.6 discounted years.20-22 ICER statistics were calculated for specific patient subsets (all, diabetic, nondiabetic, stent patients) with the use of both unadjusted and adjusted cost and survival differences.1 Patient and procedural demographics for 1472 consecutive PCI procedures involving 1338 patients in 1997 are shown in Table I. Abciximab was administered during 986 (70%) procedures. Patients receiving abciximab were less often diabetic or hypertensive and were more likely to have incurred MI within 30 days, particularly 1 to 7 days before PCI. Patients treated with abciximab had lower LV ejection fractions, more coronary stenoses, and coronary vessels undergoing angioplasty and were more likely to have a coronary stent deployed. Multivariate logistic regression analysis identified the number of vessels intervened during the index PCI, stent deployment, lower LV ejection fraction, and MI within 7 days before PCI as positive predictors and diabetes mellitus as a negative predictor for administration of abciximab. Despite the demographic profile of patients treated with abciximab, a significant

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Table I. Patient and procedural demographics for 1472 consecutive percutaneous coronary interventions Abciximab (986) Age (y) (± SE) Weight (kg) (± SE) % Female % Diabetics % Hypertension % Smoke % MI ≤30 days 1-7 Days ≤1 Day LVEF % (± SD) No. stenoses Rx 1 (%) ≥2 (%) No. vessels Rx 2 (%) 3 (%) 4 (%) % Stent % First procedure

No Abciximab P (486) value

61.4 ± 0.38 84.9 ± 0.60 34.1 21.0 70.2 58.0 31.8 17.3 13.1 50.7 ± 0.35

61.3 ± 0.54 84.7 ± 0.86 36.4 25.9 76.3 58.2 20.8 5.8 12.7 52.1 ± 0.50

.96 .84 .38 .03 .01 .88 <.0001 .0001

62.3 37.2

80.4 19.6

<.0001

27.9 6.0 1.7 69.5 93.7

15.8 1.4 0.2 60.0 79.2

<.0001 <.0001 <.0001

.03

MI, Myocardial infarction; LVEF, left ventricular ejection fraction.

survival advantage was observed at 6-month follow-up in favor of abciximab therapy for all patients who had undergone PCI and especially for patients who had coronary stent deployment (Figure 1).16 No difference in major bleeding or transfusion between patients treated with abciximab and those not treated with abciximab was observed. The cost-per-life-year-gained for patients who received stents in our study was $5193 (unadjusted) or $1933 (adjusted) based on a 3.4% (unadjusted average) survival advantage to 6 months (adjusted 4.9%) for patients treated with abciximab.1 The greater efficacy (enhanced survival) attributable to abciximab in our series compared with that observed in the EPISTENT trial23 (absolute % survival advantage 1.4% at 1 year) may be explained by the greater acuity of patients in clinical practice. Patients in our series were older, more often women, hypertensive, active smokers, and had a higher incidence of recent MI and more frequent requirement for multivessel PCI (Table II). The EPISTENT trial excluded patients who presented with cardiogenic shock or those with evolving acute myocardial infarction. In our series patients with profound depression (30%) in LV ejection fraction and those with evolving infarction were included in the analysis. It would appear that incremental drug costs are similar and greater cost-effectiveness for abciximab in clinical practice is driven by a more pronounced survival advantage observed in patients with higher acuity. This observational study, done in a high-volume interventional practice, demonstrates cost-effectiveness of

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Figure 1

Mortality (percent) in hospital and to 6 months after percutaneous coronary intervention by Ohio Heart operators at The Christ Hospital in 1997. Data are shown for all interventions and for patients having coronary stent deployment.

<.001 .196 <.0001 <.0001 <.0001 <.0001

imab in patients who receive stents.9,24,25 Our study also provides information that helps to define a patient subpopulation that may derive greatest benefit (enhanced survival) from abciximab therapy at a cost savings (reduction in total cardiac charges to 6 months). The distinguishing demographics of these patients included multivessel PCI and stent deployment performed within 1 week of MI in patients with depressed LV function. These demographic factors were predictive for greatest relative clinical benefit of abciximab.

<.0001

Conclusion

Table II. Comparative demographics for patients undergoing PCI EPISTENT (N = 2374) Mean age Diabetic (%) Male sex (%) Smokers (%) Hypertension (%) Myocardial infarction (%) ≤12 hours ≤7 days No. native vessels attempted (%) 1 2 ≥3

Lindner/ OHHC P (n = 1011) value

59.5 20.5 75 36.6 52.5

62.5 22.5 65 57.4 72

1 16.4

14.5 26.9

2103 (88.6) 197 (8.3) 7 (0.3)

688 (68.1) 257 (25.4) 62 (6.1)

OHHC, Ohio Heart Health Center.

adjunctive abciximab therapy for PCI. The significance of this finding lies in its direct applicability to clinical practice outside the usual protocol-driven confines of randomized controlled trials. Results of this observational study parallel those of recently published metaanalyses and pooled analyses of multiple trials of abciximab therapy during PCI, demonstrating a survival advantage in favor of administration of abcix-

Platelet GPIIb/IIIa platelet receptor inhibitors represent a major advance in the pharmacotherapy of acute coronary disease or after PCI. For patients undergoing PCI, the greatest volume of economic data is available with abciximab. This agent costs on average $1350 to $1450 to treat a patient. Economic analyses from randomized clinical trials and our results from high-volume interventional practice demonstrate that abciximab provides a cost-effective survival advantage after PCI and compares very favorably with currently accepted standards of care. Clinical and procedural demographics associated with increased cost-effectiveness in highvolume clinical practice include multivessel coronary intervention, stent deployment, recent (<1 week) MI, and impaired LV function.

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References 1. Kereiakes DJ, Obenchain RL, Barber BL, et al. Abciximab provides cost effective survival advantage in high volume interventional practice. Am Heart J 2000;140:603-10. 2. Mark DB. Economics of glycoprotein IIb/IIIa inhibition. In: Lincoff AM, Topol EJ, editors. Contemporary cardiology: platelet glycoprotein IIb/IIIa inhibitors in cardiovascular disease. Totowa (NJ): Humana Press Inc; 1999. p. 253-66. 3. Mark DB. Medical economics in cardiovascular medicine. In: Topol EJ, editor. Textbook of cardiovascular medicine. New York: Lippincott-Raven; 1997. p. 1033-62. 4. Kereiakes DJ, Broderick TM, Roth EM, et al. Time course, magnitude and consistency of platelet inhibition of abciximab, tirofiban or eptifibatide in patients with unstable angina pectoris undergoing percutaneous coronary intervention. Am J Cardiol 1999;84:391-5. 5. The EPIC investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high risk coronary angioplasty. N Engl J Med 1994;330:956-61. 6. The EPILOG investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1994;336:1689-96. 7. Lincoff AM, Mark DB, Califf RM, et al. Economic assessment of platelet glycoprotein IIb/IIIa receptor blockade during coronary intervention in the EPILOG trial. [abstract] J Am Coll Cardiol 1997;29:240A. 8. The EPISTENT investigators. Randomized placebo-controlled and balloon- angioplasty-controlled trial to assess safety of coronary stenting with the use of platelet glycoprotein IIb/IIIa blockade. Lancet 1998;352:87-92. 9. Topol EJ, Mark DB, Lincoff AM, et al. Outcomes at 1 year and economic implications of platelet glycoprotein IIb/IIIa blockade in patients undergoing coronary stenting: results from a multicenter randomized trial. Lancet 1999;354:2019-24. 10. The IMPACT-II investigators. Effects of competitive platelet glycoprotein IIb/IIIa inhibition with integrilin in reducing complications of percutaneous coronary intervention. Lancet 1997;349:1422-8. 11. The RESTORE investigators. Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis. Circulation 1997;96:1445-53. 12. Weintraub WS, Culler S, Boccuzzi SJ, et al. Economic impact of GP IIb/IIIa blockade after high-risk angioplasty. Results from the RESTORE Trial. J Am Coll Cardiol 1999;34:1061-6.

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13. The CAPTURE investigators. Randomized placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study. Lancet 1997;349: 1429-35. 14. The PURSUIT investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes without persistent ST-segment elevation. N Engl J Med 1998;339: 436-43. 15. Mark DB, Harrington RA, Lincoff AM, et al. Cost-effectiveness of platelet glycoprotein IIb/IIIa inhibition with eptifibatide in patients with non-ST-elevation acute coronary syndromes. Circulation 2000;101:366-71. 16. Kereiakes DJ, Obenchain RL, Barber BL, et al. Abciximab provides cost-effective survival advantage in high volume interventional practice. [abstract] Circulation 1999;100:I-733. 17. D’Agostino RB Jr. Tutorial in biostatistics: propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med 1998;17:2265-81. 18. Rosenbaum PR, Rubin DB. Reducing bias in observational studies using subclassification on the propensity score. J Am Stat Assoc 1984;79:516-24. 19. Obenchain RL. http://www.math.iupui.edu/~indyasa/download.htm 1999 20. Lipscomb J, Weinstein MC, Torrence GW. Time preference. In: Gold MR, Siegel JE, Russell LB, et al, editors. Cost-effectiveness in health and medicine. New York (NY): Oxford University Press; 1996. p. 214-46. 21. Mark DB, Hlatky MA, Califf RM, et al. Cost effectiveness of thrombolytic therapy with tissue plasminogen activator as compared with streptokinase for acute myocardial infarction. N Engl J Med 1995;332:1418-24. 22. Mark DB, Talley JD, Topol EJ, et al. Economic assessment of platelet glycoprotein IIb/IIIa inhibition for prevention of ischemic complications of high risk coronary angioplasty. Circulation 1996;94:62935. 23. Lincoff AM, Califf RM, Moliterno DJ, et al. Complementary clinical benefits of coronary-artery stenting and blockade of platelet glycoprotein IIb/IIIa receptors. N Engl J Med 1999;34:319-27. 24. Anderson KM, Ferguson JJ, Stoner GL, et al. Long-term mortality benefit with abciximab in patients undergoing percutaneous coronary intervention (PCI). [abstract] Circulation 1997;96:I-63. 25. Bhatt DL, Marso SP, Lincoff AM, et al. Abciximab reduces death in diabetics following percutaneous coronary intervention. [abstract] Circulation 1999;100:I-67.