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Potential Economic Impact of Glycoprotein IIb-IIIa Inhibitors in Improving Outcomes of Patients with Acute Ischemic Coronary Syndromes
Potential Economic Impact of Glycoprotein IIb-IIIa Inhibitors in Improving Outcomes of Patients With Acute Ischemic Coronary Syndromes Newell E. McElwee,
PharmD, MSPH,
and Eric R. Johnson,
PhD
Despite the institution of various cost control measures in the 1980s, healthcare costs have continued to rise. Following the adoption of the Medicare prospective payment system, the Health Care Financing Administration (HFCA) recognized the need to assess medical effectiveness as well as the cost of care. Coronary artery bypass graft (CABG) and percutaneous transluminal coronary angioplasty (PTCA) procedures have been reported as
the primary cost drivers in hospitalized patients with unstable angina, a form of acute ischemic coronary syndromes. Evaluation of glycoprotein IIb-IIIa inhibitors as primary therapy for these patients suggests that good value for money is possible, especially if the use of these agents results in a reduction in revascularization procedures. Q1997 by Excerpta Medica, Inc. Am J Cardiol 1997;80(4A):39B– 43B
aying for health care has become difficult in the P United States because healthcare costs, both absolute and as a percentage of gross national product
measures had been put into place in the United States. Some of these measures were aimed at limiting the supply of available healthcare resources, and others at decreasing the demand for healthcare resources (Table I). Neither these measures nor the implementation of prospective payments has had much apparent impact on curbing rising healthcare costs, and many have the disadvantage of slowing the development and adoption of new technologies. It also became apparent to healthcare purchasers such as HCFA and managed care organizations that resource allocation should not be based solely on costs. Thus the debate was shifted, at least in part, from costs to “medical effectiveness” and “outcomes management.”4,5 For example, one issue that received considerable attention was whether higher rates of coronary revascularization procedures in certain geographic areas were associated with better patient outcomes. If so, then the question was whether the additional costs represented a good value. However, sound data on patient outcomes were not generally available; clinical trial data were of limited generalizability, and the duration of patient follow-up was often short. One approach to measuring value with limited data has been to perform a decision analysis on the relevant treatment options to determine the option that delivers the best value. This type of analysis requires that treatment consequences be made explicit and that there be a common measure of effectiveness so that treatment value can be benchmarked. The most commonly used effectiveness measure has been life expectancy. In situations in which better patient outcomes are achieved at higher costs, value can be estimated using an incremental cost-effectiveness ratio; that is, net cost (in dollars or other currency) divided by net effectiveness (in years or qualityadjusted life years [QALY]). The following section illustrates the use of a decision-analysis model to estimate an incremental costeffectiveness ratio for various scenarios using the platelet glycoprotein (GP) IIb-IIIa receptor inhibitor in
(GNP), have risen over the past 25 years (Figure 1).1 In 1995, medical expenditures exceeded $1 trillion, representing approximately 14% of the GNP. Perhaps of more concern is that the increase in healthcare costs over time is nonlinear and continues to rise despite efforts to control costs. Similar trends have been observed in Germany, France, and Great Britain.2 Over the years, many financial stakeholders have attempted to identify the causes of rising healthcare costs and to implement programs to control costs. One of the first major conferences on this topic was the Sun Valley conference held in 1977.3 During the 1970s, hospitals were reimbursed for patient care on a costbased system, physicians were reimbursed on a feefor-service system, and healthcare insurance plans were generous. The consensus at the 1977 conference was that new technologies contributed relatively little to rising healthcare costs; instead, other factors were believed to be responsible. Two factors emerged as the most important causes of rising healthcare costs: (1) physicians and patients were insulated from information about costs, and (2) existing reimbursement programs created incentives for physicians and hospitals to use more healthcare resources. The recommendation from the Sun Valley conference was to create a set of incentives that would lead to more efficient use of healthcare resources. This recommendation led to the development of the Medicare prospective payment system (DRG [diagnostic-related group] reimbursement), implemented in 1984 by the Health Care Financing Administration (HCFA). By the mid to late 1980s, various cost-control From Integrated Therapeutics Group, Inc., a subsidiary of ScheringPlough, Kenilworth, New Jersey. Address for reprints: Newell E. McElwee, PharmD, MSPH, Integrated Therapeutics Group, Inc., Schering-Plough Corporation, 2000 Galloping Hill Road, Kenilworth, New Jersey 07830. ©1997 by Excerpta Medica, Inc. All rights reserved.
0002-9149/97/$17.00 PII S0002-9149(97)00576-6
39B
TABLE II Trial Design Strategies for GP IIb-IIIa Inhibitors Agent All Comers Eptifibatide Lamifiban Tirofiban PTCA Only Eptifibatide Abciximab Abciximab Abciximab Tirofiban
FIGURE 1. US medical expenditures.
TABLE I Cost-Containment Measures in the United States Supply Side Generic substitution Formularies Therapeutic substitution Registration fees PBMs Limited access to physicians Group buying
Demand Side Prescriber monitoring Positive lists Lifetime payment caps Increasing copayments Incentives for substitution Pharmacy prescribing
Adapted from Spectrum.15
patients with unstable angina and non–Q-wave myocardial infarction.
ISSUES IN ASSESSING THE VALUE OF GP IIb-IIIa INHIBITOR THERAPY IN ACUTE ISCHEMIC CORONARY SYNDROMES The potential clinical role of GP IIb-IIIa inhibitor therapy in acute ischemic coronary syndromes has been well documented in terms of decreased thrombosis-related morbidity and mortality. In this section, we comment on the economics of GP IIb-IIIa therapy from the perspective of a treating hospital. We first assess the role of GP IIb-IIIa adjunctive therapy in reducing the complications associated with abrupt closure after percutaneous transluminal coronary angioplasty (PTCA); then we turn to the use of these drugs as primary therapy for acute ischemic coronary syndromes. Several trials of these drugs in PTCA have already been completed (Table II). There are numerous differences among the trials described in Table II regarding patient selection (primary vs adjunctive therapy, high-risk patients vs all comers) and trial endpoints; these differences are of both clinical and economic interest. We explore some of these issues using a decision analytic model for unstable angina. Cost determinants in unstable angina and non–Qwave myocardial infarction: Many patients hospital-
ized with a diagnosis of unstable angina or non–Qwave myocardial infarction do not have major clinical complications or undergo revascularization procedures, and it is this group of patients who have the lowest level of medical resource consumption and hospitalization costs. Revascularization procedures 40B
THE AMERICAN JOURNAL OF CARDIOLOGYT
Population
Trial
Status
Unstable angina Unstable angina Unstable angina
PURSUIT PARAGON PRISM
Completed Completed Completed
All comers (UA/AMI) High risk (UA/AMI) Low risk (stable angina) Unstable angina High risk (UA/AMI)
IMPACT II
Completed
EPIC
Completed
EPILOG
Completed
CAPTURE RESTORE
Completed Completed
PTCA 5 percutaneous transluminal coronary angioplasty; UA 5 unstable angina; AMI 5 acute myocardial infarction; PURSUIT 5 Platelet IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy; PARAGON 5 Platelet IIb-IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network; PRISM 5 Platelet Receptor Inhibition for Ischemic Syndrome Management; PARADIGM 5 Platelet Aggregation Receptor Antagonist Dose Investigation for Gain in Myocardial Infarction; IMPACT 5 Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis; EPIC 5 Evaluation of 7E3 for the Prevention of Ischemic Complications; EPILOG 5 Evaluation of PTCA to Improve Long-term Outcome by 7E3 GP IIb-IIIa Receptor Blockade; CAPTURE 5 Chimeric 7E3 Antiplatelet Therapy in Unstable Angina Refractory to Standard Treatment; RESTORE 5 Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis.
and clinical complications requiring treatment add incrementally to the baseline costs for an uncomplicated clinical course. The decision tree in Figure 2 reflects these events, the costs and probabilities of which depend on treatment. We begin by discussing costs of standard therapy. Conti6 estimated the costs for a baseline hospitalization and the incremental costs for revascularization procedures, using medical resource consumption data from the third Thrombolysis in Myocardial Infarction (TIMI IIIB) trial and average reimbursement data (charges) from his own institution. Costs were $6,525 for baseline hospitalization, $3,330 –$5,089 for diagnostic catheterization, $13,462 for PTCA, and $36,540 for coronary artery bypass graft (CABG). The amount HCFA allows for DRG reimbursement, as reflected in Table III, is lower than the amount hospitals charge. Although DRG reimbursement does not reflect the true cost to the hospital, it is correlated with true costs. Indeed, the DRG payment system is based on the average resource consumption by patients within a DRG, taking into account the length of stay and number and intensity of services. A better approach to estimating true costs was used by Mark et al,7 based on a regression analysis of cost data from the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) trial of abciximab for PTCA. These data should be interpreted with caution because the study population consisted only of patients who received a PTCA, and of these, not all had unstable angina. The incremental costs were $4,973 for nonurgent PTCA, $8,852 for urgent PTCA, $14,760 for nonurgent CABG, $27,349 for urgent CABG, $5,896 for major bleeding, and $1,327 for
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AUGUST 18, 1997
FIGURE 2. Decision analytic model for unstable angina and non–Q-wave myocardial infarction (MI). In 2A, the plus signs indicate those patients who continue on to the decision trees in 2B or 2C. NQMI 5 non–Q-wave myocardial infarction; PTCA 5 percutaneous transluminal coronary angioplasty; CABG 5 coronary artery bypass graft.
minor bleeding. Baseline hospitalization costs incurred by all patients, e.g., the intercept term from the regression model, were not reported. Differences in resource consumption patterns, including length of stay, between urgent and nonurgent revascularization procedures are reflected in the differences in estimated costs between the urgent and nonurgent procedures. Neither death nor acute myocardial infarction was identified as a major cost determinant in the regression model. Despite the limitations of these cost data derived from disparate sources, there is strong evidence that CABG and, to a lesser extent, PTCA are major determinants of cost for hospitalized patients with acute ischemic coronary syndromes. Estimating the value of GP IIb-IIIa therapy in various hypothetical scenarios: A decision analytic
model was developed to estimate the value of GP IIb-IIIa therapy under various conditions. The initial decision tree is shown in Figure 2A, with subsequent branches for patients with nonfatal myocardial infarction or diagnostic catheterization shown in Figures 2B and 2C, respectively. The costs assigned to revascularization procedures and acute myocardial infarction (nonfatal) were estimated from regression analyses of the Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis II (IMPACT II) trial data and other sources for the initial hospitalization (Table IV). Costs after the initial hospitalization were
not considered in this model, because we were interested in the perspective of the treating hospital. Although the IMPACT II cost data suffer from some of the same limitations described for the EPIC cost regression estimates, the incremental costs for revascularization procedures are more conservative than those from EPIC. The initial revascularization procedures in the model were assumed to be 50% urgent, and the second revascularization procedures after PTCA failures were assumed to be 75% urgent. Initial revascularization rates were varied in the model from 25% to 65%, reflecting regional variations in the United States. The ratio of CABG to PTCA to stents was assumed to be 1 : 2 : 2 for the initial revascularization and 1 : 1 : 1 for the second revascularization. Death and nonfatal myocardial infarction rates after revascularization were estimated from published literature or GP IIb-IIIa trial data. The 30-day death and nonfatal myocardial infarction risks after PTCA were assumed to be 1.5% and 8.5%, respectively, based on data from the IMPACT II, EPIC, and Chimeric 7E3 Antiplatelet Therapy in Unstable Angina Refractory to Standard Treatment (CAPTURE) trials. These rates were also used for stents, although trial data were not available. Because experts believed that the death and nonfatal myocardial infarction rates after stenting might be substantially lower, we conducted a sensitivity analysis using poststent rates that
A SYMPOSIUM: ACUTE ISCHEMIC CORONARY SYNDROMES
41B
TABLE III 1996 Health Care Financing Administration (HCFA) Reimbursement DRG No. 112 106 121 122 123
GMLOS†
DRG Name
1996*
Percutaneous cardiac procedure Coronary bypass with cardiac catheterization AMI with complications AMI without complications AMI expired
$7,969
3.6
$22,475
11.2
$6,584 $4,646 $5,748
7.0 4.9 2.8
*National average payment. † Geometric mean length of stay. AMI 5 acute myocardial infarction; DRG 5 diagnostic-related group. Adapted from St. Anthony’s DRG Guidebook.16
TABLE IV Cost Assumptions Procedure Urgent CABG Elective CABG Urgent PTCA Elective PTCA Stent Catheterization only Nonfatal MI Baseline
Cost $19,000 $14,000 $6,500 $3,300 $5,550 $1,500 $5,000 $7,500
CABG 5 coronary artery bypass graft; PTCA 5 percutaneous transluminal coronary angioplasty; MI 5 myocardial infarction. Source: IMPACT II regression estimates and St. Anthony’s DRG Guidebook.16 All costs in 1996 US dollars.
had been lowered by 50% and determined that altering these rates did not change the model results. The death and nonfatal myocardial infarction rates after CABG were assumed to be 3% and 15%, respectively, based on recently published data.8 –12 We were unable to identify sources of data for death and nonfatal myocardial infarction rates in patients who did not undergo revascularization; therefore, we calculated these values by subtracting the postprocedure rates from an overall death and nonfatal myocardial infarction rate of 8.0% (37.5% of the difference in total rates were allocated to the death branch). Estimates of the cost of standard therapy in patients with unstable angina over a range of revascularization rates are shown in Figure 3. The average cost per patient ranges from approximately $11,000 in scenarios in which the revascularization rate is 25% to approximately $15,000 in those in which the revascularization rate is 65%. Assessing the value of primary GP IIb-IIIa inhibitor therapy requires an assumption about its effect on reducing the frequency of clinical complications and revascularization procedures. All cost assumptions for GP IIb-IIIa therapy were based on the current price of abciximab in the United States, i.e., $450 per 10-mg vial. Cost calculations were made on the assumption of an average patient weight of 82 kg, an abciximab bolus dose of 0.25 mg/kg, and an infusion rate of 0.6 mg/hour. The infusion duration was assumed to be 60 hours for primary GP IIb-IIIa therapy and 24 hours for 42B
THE AMERICAN JOURNAL OF CARDIOLOGYT
the PTCA/stent-only scenario. A 24-hour infusion was chosen for the latter treatment option on the basis of the CAPTURE dosing regimen; CAPTURE is the only trial that has specifically evaluated abciximab in unstable angina patients. A 60-hour infusion was chosen for GP IIb-IIIa primary therapy because clinical complications in an all-comers unstable angina population typically occur over a 48 –72-hour period after admission, in contrast to clinical events after revascularization that typically occur near the time of the procedure. Using these cost calculations, the average price of primary GP IIb-IIIa therapy was $2,700 per patient and the average price of treating patients who had percutaneous revascularization only was $1,800 per patient. The treatment effects assumed for the GP IIb-IIIa/ percutaneous revascularization-only scenario were the relative reductions in death, nonfatal myocardial infarction, and urgent revascularization at 30 days observed in the CAPTURE trial, i.e., 35.6%, 52.6%, and 32.4%, respectively.13 Because there are no trial data for the treatment effects of GP IIb-IIIa inhibitors used for primary therapy, we conducted analyses using a range of treatment effects: 20%, 30%, or 40%. The average costs per patient receiving GP IIb-IIIa inhibitors as primary therapy and restricted to PTCA or stent-only patients are shown in Figure 4. The cost offsets, mostly from reduced revascularization procedures, increase as the background revascularization rate increases. With high revascularization rates ($45%) and with primary therapy treatment effects of .30%, treating all comers with GP IIb-IIIa inhibitors may be cost saving and lifesaving compared with treating only those who receive percutaneous revascularization. Lifetime survival was estimated using the average survival for patients with acute myocardial infarction that was observed in the Global Utilization of Streptokinase and t-PA for Occluded Arteries (GUSTO) trial, i.e., 15.4 years.14 Survival was discounted at 5% per year. In all scenarios, survival was better in patients who received GP IIb-IIIa as primary therapy than in those who were revascularized only and received GP IIb-IIIa therapy. Incremental cost-effectiveness ratios were calculated for the range of treatment effects and revascularization rates in which primary therapy was both more costly and more effective. The results suggest that GP IIb-IIIa primary therapy will be an exceptionally good value (#$20,000 per year of life saved) at treatment effects of 30% and 40% and in the range of value considered generally acceptable (#$50,000 per year of life saved) at a treatment effect of 20% (Figure 5). However, the assumption that the initial revascularization rate can be reduced is critical. Cost-effectiveness ratios when no effect on revascularization rate is assumed are less favorable, particularly as the revascularization rate increases above 35% for the 20% treatment effect scenario and above 45–50% for the 30% and 40% treatment effect scenarios.
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AUGUST 18, 1997
hospitalization costs have been shown to be a large component of total treatment costs, and revascularization procedures have been observed to be the single largest contributor to overall hospitalization costs. In treating these patients, GP IIb-IIIa therapy, either adjunctive or primary, would appear to yield “good value for money” relative to the present standard of care. Primary therapy with GP IIb-IIIa inhibitors for patients with unstable angina may represent wise allocation of healthcare resources compared with treating only those patients who undergo percutaneous revascularization, particularly if this drug class is proven to reduce the initial revascularization rate. And finally, it will be necessary to confirm these preliminary estimates of economic value using empiric data from GP IIb-IIIa trials.
FIGURE 3. Estimated cost of standard therapy.
1. Levit KR, Cowan CA, Lazenby HC, McDonnell PA, Sensenig AL, Stiller JM,
FIGURE 4. Average cost of revascularization-only versus all comers (AC) by revascularization rate.
FIGURE 5. Average cost-effectiveness of revascularization-only versus all comers (AC) by revascularization rate.
CONCLUSION In conclusion, it is clearly advantageous to consider value— defined above as “incremental cost effectiveness ratio”—rather than cost alone in assessing the economic impact of new healthcare interventions. As discussed in this article, this conclusion holds true for the new class of GP IIb-IIIa inhibitors. In managing patients with acute ischemic coronary syndromes,
Won DK. II. National health spending trends, 1960 –1993. Health Affairs 1994; (winter):14 –31. 2. Whitney CR. Rising health costs threaten generous benefits in Europe. New York Times August 6, 1996:A1, A4. 3. Altman SH, Blendon RJ, eds. Medical technology: the culprit behind health care costs? Proceedings of the 1977 Sun Valley Forum on National Health. DHEW publication no. 79-3216, Washington, DC: U.S. Government Printing Office, 1979. 4. Roper WL, Winkenwerder W, Hackbarth GM, Krakauer H. Effectiveness in health care: an initiative to evaluate and improve medical practice. N Engl J Med 1988;319:1197–1202. 5. Ellwood PM, Shattuck lecture-outcomes management: a technology of patient experience. N Engl J Med 1988;318:1549 –1556. 6. Conti CR. Unstable angina: cost of conservative and invasive strategies using TIMI 3 B as a model. (Editorial) Clin Cardiol 1995;18:187–188. 7. Mark DB, Talley JD, Topol EJ, Bowman L, Lam LC, Anderson KM, Jollis JA, Cleman MW, Lee KL, Aversano T, Untereker WJ, Davidson-Ray L, Califf RM, for the EPIC Investigators. Economic assessment of platelet glycoprotein IIb/IIIa inhibition for prevention of ischemic complications of high-risk coronary angioplasty. Circulation 1996;94:629 – 635. 8. Louagie Y, Buche M, Jamart J, Eucher P, Haxhe JP, Schoevaerdts JC. Operative risk assessment in coronary artery bypass surgery, 1990 –1993: evaluation of perioperative variables. Thorac Cardiovasc Surg 1995;43:134 –141. 9. Brandrup-Wognsen G, Haglid M, Karlsson T, Berggren H, Herlitz J. Preoperative risk indicators of death at an early and late stage after coronary artery bypass grafting. Thorac Cardiovasc Surg 1995;43:77– 82. 10. Orr RK, Maini BS, Sottile FD, Dumas EM, O’Mara P. A comparison of four severity-adjusted models to predict mortality after coronary artery bypass graft surgery. Arch Surg 1995;130:301–306. 11. Pragliola C, Kootstra GJ, Lanzillo G, Rose PA, Quafford M, Uitdenhaag G. Current results of coronary bypass surgery after failed angioplasty. J Cardiovasc Surg 1994;35:365–369. 12. Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med 1996;335:217–225. 13. Simoons ML. Presentation of the CAPTURE 30 day study results. American College of Cardiology meeting. Orlando, March 1996. 14. Mark DB, Hlatky MA, Califf RM, Naylor CD, Lee KL, Armstrong PW, Barbash G, White H, Simoons ML, Nelson CL, Clapp-Channing N, Knight JD, Harrell FE Jr, Simes J, Topol EJ. Cost effectiveness of thrombolytic therapy with tissue plasminogen activator as compared with streptokinase for acute myocardial infarction. N Engl J Med 1995;332:1418 –1424. 15. James BG. Pricing innovative drugs. Spectrum 1996;121:1–15. 16. St. Anthony’s DRG Guidebook 1996. Reston, VA: St. Anthony Publishing, 1996.
A SYMPOSIUM: ACUTE ISCHEMIC CORONARY SYNDROMES
43B
PharmD, MSPH,
and Eric R. Johnson,
PhD
Despite the institution of various cost control measures in the 1980s, healthcare costs have continued to rise. Following the adoption of the Medicare prospective payment system, the Health Care Financing Administration (HFCA) recognized the need to assess medical effectiveness as well as the cost of care. Coronary artery bypass graft (CABG) and percutaneous transluminal coronary angioplasty (PTCA) procedures have been reported as
the primary cost drivers in hospitalized patients with unstable angina, a form of acute ischemic coronary syndromes. Evaluation of glycoprotein IIb-IIIa inhibitors as primary therapy for these patients suggests that good value for money is possible, especially if the use of these agents results in a reduction in revascularization procedures. Q1997 by Excerpta Medica, Inc. Am J Cardiol 1997;80(4A):39B– 43B
aying for health care has become difficult in the P United States because healthcare costs, both absolute and as a percentage of gross national product
measures had been put into place in the United States. Some of these measures were aimed at limiting the supply of available healthcare resources, and others at decreasing the demand for healthcare resources (Table I). Neither these measures nor the implementation of prospective payments has had much apparent impact on curbing rising healthcare costs, and many have the disadvantage of slowing the development and adoption of new technologies. It also became apparent to healthcare purchasers such as HCFA and managed care organizations that resource allocation should not be based solely on costs. Thus the debate was shifted, at least in part, from costs to “medical effectiveness” and “outcomes management.”4,5 For example, one issue that received considerable attention was whether higher rates of coronary revascularization procedures in certain geographic areas were associated with better patient outcomes. If so, then the question was whether the additional costs represented a good value. However, sound data on patient outcomes were not generally available; clinical trial data were of limited generalizability, and the duration of patient follow-up was often short. One approach to measuring value with limited data has been to perform a decision analysis on the relevant treatment options to determine the option that delivers the best value. This type of analysis requires that treatment consequences be made explicit and that there be a common measure of effectiveness so that treatment value can be benchmarked. The most commonly used effectiveness measure has been life expectancy. In situations in which better patient outcomes are achieved at higher costs, value can be estimated using an incremental cost-effectiveness ratio; that is, net cost (in dollars or other currency) divided by net effectiveness (in years or qualityadjusted life years [QALY]). The following section illustrates the use of a decision-analysis model to estimate an incremental costeffectiveness ratio for various scenarios using the platelet glycoprotein (GP) IIb-IIIa receptor inhibitor in
(GNP), have risen over the past 25 years (Figure 1).1 In 1995, medical expenditures exceeded $1 trillion, representing approximately 14% of the GNP. Perhaps of more concern is that the increase in healthcare costs over time is nonlinear and continues to rise despite efforts to control costs. Similar trends have been observed in Germany, France, and Great Britain.2 Over the years, many financial stakeholders have attempted to identify the causes of rising healthcare costs and to implement programs to control costs. One of the first major conferences on this topic was the Sun Valley conference held in 1977.3 During the 1970s, hospitals were reimbursed for patient care on a costbased system, physicians were reimbursed on a feefor-service system, and healthcare insurance plans were generous. The consensus at the 1977 conference was that new technologies contributed relatively little to rising healthcare costs; instead, other factors were believed to be responsible. Two factors emerged as the most important causes of rising healthcare costs: (1) physicians and patients were insulated from information about costs, and (2) existing reimbursement programs created incentives for physicians and hospitals to use more healthcare resources. The recommendation from the Sun Valley conference was to create a set of incentives that would lead to more efficient use of healthcare resources. This recommendation led to the development of the Medicare prospective payment system (DRG [diagnostic-related group] reimbursement), implemented in 1984 by the Health Care Financing Administration (HCFA). By the mid to late 1980s, various cost-control From Integrated Therapeutics Group, Inc., a subsidiary of ScheringPlough, Kenilworth, New Jersey. Address for reprints: Newell E. McElwee, PharmD, MSPH, Integrated Therapeutics Group, Inc., Schering-Plough Corporation, 2000 Galloping Hill Road, Kenilworth, New Jersey 07830. ©1997 by Excerpta Medica, Inc. All rights reserved.
0002-9149/97/$17.00 PII S0002-9149(97)00576-6
39B
TABLE II Trial Design Strategies for GP IIb-IIIa Inhibitors Agent All Comers Eptifibatide Lamifiban Tirofiban PTCA Only Eptifibatide Abciximab Abciximab Abciximab Tirofiban
FIGURE 1. US medical expenditures.
TABLE I Cost-Containment Measures in the United States Supply Side Generic substitution Formularies Therapeutic substitution Registration fees PBMs Limited access to physicians Group buying
Demand Side Prescriber monitoring Positive lists Lifetime payment caps Increasing copayments Incentives for substitution Pharmacy prescribing
Adapted from Spectrum.15
patients with unstable angina and non–Q-wave myocardial infarction.
ISSUES IN ASSESSING THE VALUE OF GP IIb-IIIa INHIBITOR THERAPY IN ACUTE ISCHEMIC CORONARY SYNDROMES The potential clinical role of GP IIb-IIIa inhibitor therapy in acute ischemic coronary syndromes has been well documented in terms of decreased thrombosis-related morbidity and mortality. In this section, we comment on the economics of GP IIb-IIIa therapy from the perspective of a treating hospital. We first assess the role of GP IIb-IIIa adjunctive therapy in reducing the complications associated with abrupt closure after percutaneous transluminal coronary angioplasty (PTCA); then we turn to the use of these drugs as primary therapy for acute ischemic coronary syndromes. Several trials of these drugs in PTCA have already been completed (Table II). There are numerous differences among the trials described in Table II regarding patient selection (primary vs adjunctive therapy, high-risk patients vs all comers) and trial endpoints; these differences are of both clinical and economic interest. We explore some of these issues using a decision analytic model for unstable angina. Cost determinants in unstable angina and non–Qwave myocardial infarction: Many patients hospital-
ized with a diagnosis of unstable angina or non–Qwave myocardial infarction do not have major clinical complications or undergo revascularization procedures, and it is this group of patients who have the lowest level of medical resource consumption and hospitalization costs. Revascularization procedures 40B
THE AMERICAN JOURNAL OF CARDIOLOGYT
Population
Trial
Status
Unstable angina Unstable angina Unstable angina
PURSUIT PARAGON PRISM
Completed Completed Completed
All comers (UA/AMI) High risk (UA/AMI) Low risk (stable angina) Unstable angina High risk (UA/AMI)
IMPACT II
Completed
EPIC
Completed
EPILOG
Completed
CAPTURE RESTORE
Completed Completed
PTCA 5 percutaneous transluminal coronary angioplasty; UA 5 unstable angina; AMI 5 acute myocardial infarction; PURSUIT 5 Platelet IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy; PARAGON 5 Platelet IIb-IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network; PRISM 5 Platelet Receptor Inhibition for Ischemic Syndrome Management; PARADIGM 5 Platelet Aggregation Receptor Antagonist Dose Investigation for Gain in Myocardial Infarction; IMPACT 5 Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis; EPIC 5 Evaluation of 7E3 for the Prevention of Ischemic Complications; EPILOG 5 Evaluation of PTCA to Improve Long-term Outcome by 7E3 GP IIb-IIIa Receptor Blockade; CAPTURE 5 Chimeric 7E3 Antiplatelet Therapy in Unstable Angina Refractory to Standard Treatment; RESTORE 5 Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis.
and clinical complications requiring treatment add incrementally to the baseline costs for an uncomplicated clinical course. The decision tree in Figure 2 reflects these events, the costs and probabilities of which depend on treatment. We begin by discussing costs of standard therapy. Conti6 estimated the costs for a baseline hospitalization and the incremental costs for revascularization procedures, using medical resource consumption data from the third Thrombolysis in Myocardial Infarction (TIMI IIIB) trial and average reimbursement data (charges) from his own institution. Costs were $6,525 for baseline hospitalization, $3,330 –$5,089 for diagnostic catheterization, $13,462 for PTCA, and $36,540 for coronary artery bypass graft (CABG). The amount HCFA allows for DRG reimbursement, as reflected in Table III, is lower than the amount hospitals charge. Although DRG reimbursement does not reflect the true cost to the hospital, it is correlated with true costs. Indeed, the DRG payment system is based on the average resource consumption by patients within a DRG, taking into account the length of stay and number and intensity of services. A better approach to estimating true costs was used by Mark et al,7 based on a regression analysis of cost data from the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) trial of abciximab for PTCA. These data should be interpreted with caution because the study population consisted only of patients who received a PTCA, and of these, not all had unstable angina. The incremental costs were $4,973 for nonurgent PTCA, $8,852 for urgent PTCA, $14,760 for nonurgent CABG, $27,349 for urgent CABG, $5,896 for major bleeding, and $1,327 for
VOL. 80 (4A)
AUGUST 18, 1997
FIGURE 2. Decision analytic model for unstable angina and non–Q-wave myocardial infarction (MI). In 2A, the plus signs indicate those patients who continue on to the decision trees in 2B or 2C. NQMI 5 non–Q-wave myocardial infarction; PTCA 5 percutaneous transluminal coronary angioplasty; CABG 5 coronary artery bypass graft.
minor bleeding. Baseline hospitalization costs incurred by all patients, e.g., the intercept term from the regression model, were not reported. Differences in resource consumption patterns, including length of stay, between urgent and nonurgent revascularization procedures are reflected in the differences in estimated costs between the urgent and nonurgent procedures. Neither death nor acute myocardial infarction was identified as a major cost determinant in the regression model. Despite the limitations of these cost data derived from disparate sources, there is strong evidence that CABG and, to a lesser extent, PTCA are major determinants of cost for hospitalized patients with acute ischemic coronary syndromes. Estimating the value of GP IIb-IIIa therapy in various hypothetical scenarios: A decision analytic
model was developed to estimate the value of GP IIb-IIIa therapy under various conditions. The initial decision tree is shown in Figure 2A, with subsequent branches for patients with nonfatal myocardial infarction or diagnostic catheterization shown in Figures 2B and 2C, respectively. The costs assigned to revascularization procedures and acute myocardial infarction (nonfatal) were estimated from regression analyses of the Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis II (IMPACT II) trial data and other sources for the initial hospitalization (Table IV). Costs after the initial hospitalization were
not considered in this model, because we were interested in the perspective of the treating hospital. Although the IMPACT II cost data suffer from some of the same limitations described for the EPIC cost regression estimates, the incremental costs for revascularization procedures are more conservative than those from EPIC. The initial revascularization procedures in the model were assumed to be 50% urgent, and the second revascularization procedures after PTCA failures were assumed to be 75% urgent. Initial revascularization rates were varied in the model from 25% to 65%, reflecting regional variations in the United States. The ratio of CABG to PTCA to stents was assumed to be 1 : 2 : 2 for the initial revascularization and 1 : 1 : 1 for the second revascularization. Death and nonfatal myocardial infarction rates after revascularization were estimated from published literature or GP IIb-IIIa trial data. The 30-day death and nonfatal myocardial infarction risks after PTCA were assumed to be 1.5% and 8.5%, respectively, based on data from the IMPACT II, EPIC, and Chimeric 7E3 Antiplatelet Therapy in Unstable Angina Refractory to Standard Treatment (CAPTURE) trials. These rates were also used for stents, although trial data were not available. Because experts believed that the death and nonfatal myocardial infarction rates after stenting might be substantially lower, we conducted a sensitivity analysis using poststent rates that
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TABLE III 1996 Health Care Financing Administration (HCFA) Reimbursement DRG No. 112 106 121 122 123
GMLOS†
DRG Name
1996*
Percutaneous cardiac procedure Coronary bypass with cardiac catheterization AMI with complications AMI without complications AMI expired
$7,969
3.6
$22,475
11.2
$6,584 $4,646 $5,748
7.0 4.9 2.8
*National average payment. † Geometric mean length of stay. AMI 5 acute myocardial infarction; DRG 5 diagnostic-related group. Adapted from St. Anthony’s DRG Guidebook.16
TABLE IV Cost Assumptions Procedure Urgent CABG Elective CABG Urgent PTCA Elective PTCA Stent Catheterization only Nonfatal MI Baseline
Cost $19,000 $14,000 $6,500 $3,300 $5,550 $1,500 $5,000 $7,500
CABG 5 coronary artery bypass graft; PTCA 5 percutaneous transluminal coronary angioplasty; MI 5 myocardial infarction. Source: IMPACT II regression estimates and St. Anthony’s DRG Guidebook.16 All costs in 1996 US dollars.
had been lowered by 50% and determined that altering these rates did not change the model results. The death and nonfatal myocardial infarction rates after CABG were assumed to be 3% and 15%, respectively, based on recently published data.8 –12 We were unable to identify sources of data for death and nonfatal myocardial infarction rates in patients who did not undergo revascularization; therefore, we calculated these values by subtracting the postprocedure rates from an overall death and nonfatal myocardial infarction rate of 8.0% (37.5% of the difference in total rates were allocated to the death branch). Estimates of the cost of standard therapy in patients with unstable angina over a range of revascularization rates are shown in Figure 3. The average cost per patient ranges from approximately $11,000 in scenarios in which the revascularization rate is 25% to approximately $15,000 in those in which the revascularization rate is 65%. Assessing the value of primary GP IIb-IIIa inhibitor therapy requires an assumption about its effect on reducing the frequency of clinical complications and revascularization procedures. All cost assumptions for GP IIb-IIIa therapy were based on the current price of abciximab in the United States, i.e., $450 per 10-mg vial. Cost calculations were made on the assumption of an average patient weight of 82 kg, an abciximab bolus dose of 0.25 mg/kg, and an infusion rate of 0.6 mg/hour. The infusion duration was assumed to be 60 hours for primary GP IIb-IIIa therapy and 24 hours for 42B
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the PTCA/stent-only scenario. A 24-hour infusion was chosen for the latter treatment option on the basis of the CAPTURE dosing regimen; CAPTURE is the only trial that has specifically evaluated abciximab in unstable angina patients. A 60-hour infusion was chosen for GP IIb-IIIa primary therapy because clinical complications in an all-comers unstable angina population typically occur over a 48 –72-hour period after admission, in contrast to clinical events after revascularization that typically occur near the time of the procedure. Using these cost calculations, the average price of primary GP IIb-IIIa therapy was $2,700 per patient and the average price of treating patients who had percutaneous revascularization only was $1,800 per patient. The treatment effects assumed for the GP IIb-IIIa/ percutaneous revascularization-only scenario were the relative reductions in death, nonfatal myocardial infarction, and urgent revascularization at 30 days observed in the CAPTURE trial, i.e., 35.6%, 52.6%, and 32.4%, respectively.13 Because there are no trial data for the treatment effects of GP IIb-IIIa inhibitors used for primary therapy, we conducted analyses using a range of treatment effects: 20%, 30%, or 40%. The average costs per patient receiving GP IIb-IIIa inhibitors as primary therapy and restricted to PTCA or stent-only patients are shown in Figure 4. The cost offsets, mostly from reduced revascularization procedures, increase as the background revascularization rate increases. With high revascularization rates ($45%) and with primary therapy treatment effects of .30%, treating all comers with GP IIb-IIIa inhibitors may be cost saving and lifesaving compared with treating only those who receive percutaneous revascularization. Lifetime survival was estimated using the average survival for patients with acute myocardial infarction that was observed in the Global Utilization of Streptokinase and t-PA for Occluded Arteries (GUSTO) trial, i.e., 15.4 years.14 Survival was discounted at 5% per year. In all scenarios, survival was better in patients who received GP IIb-IIIa as primary therapy than in those who were revascularized only and received GP IIb-IIIa therapy. Incremental cost-effectiveness ratios were calculated for the range of treatment effects and revascularization rates in which primary therapy was both more costly and more effective. The results suggest that GP IIb-IIIa primary therapy will be an exceptionally good value (#$20,000 per year of life saved) at treatment effects of 30% and 40% and in the range of value considered generally acceptable (#$50,000 per year of life saved) at a treatment effect of 20% (Figure 5). However, the assumption that the initial revascularization rate can be reduced is critical. Cost-effectiveness ratios when no effect on revascularization rate is assumed are less favorable, particularly as the revascularization rate increases above 35% for the 20% treatment effect scenario and above 45–50% for the 30% and 40% treatment effect scenarios.
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hospitalization costs have been shown to be a large component of total treatment costs, and revascularization procedures have been observed to be the single largest contributor to overall hospitalization costs. In treating these patients, GP IIb-IIIa therapy, either adjunctive or primary, would appear to yield “good value for money” relative to the present standard of care. Primary therapy with GP IIb-IIIa inhibitors for patients with unstable angina may represent wise allocation of healthcare resources compared with treating only those patients who undergo percutaneous revascularization, particularly if this drug class is proven to reduce the initial revascularization rate. And finally, it will be necessary to confirm these preliminary estimates of economic value using empiric data from GP IIb-IIIa trials.
FIGURE 3. Estimated cost of standard therapy.
1. Levit KR, Cowan CA, Lazenby HC, McDonnell PA, Sensenig AL, Stiller JM,
FIGURE 4. Average cost of revascularization-only versus all comers (AC) by revascularization rate.
FIGURE 5. Average cost-effectiveness of revascularization-only versus all comers (AC) by revascularization rate.
CONCLUSION In conclusion, it is clearly advantageous to consider value— defined above as “incremental cost effectiveness ratio”—rather than cost alone in assessing the economic impact of new healthcare interventions. As discussed in this article, this conclusion holds true for the new class of GP IIb-IIIa inhibitors. In managing patients with acute ischemic coronary syndromes,
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