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An industry perspective on health economics studies
An industry perspective on health economics studies Keaven M. Anderson, PhD, Mohan V. Bala, PhD, and Harlan F. Weisman, MD Malvern, Pa
It has become increasingly important for the developers of new drugs and biologics to establish not only that their new products produce clinical benefits but also that such benefits can be achieved in a cost-effective manner.This article will review two specific study designs for clinical trials with ReoPro (abciximab), an antiplatelet agent designed to prevent coronary thrombosis.The purpose of this discussion is to establish costbenefit information for clinical trials with ReoPro.The first study design that is reviewed here was used in the Evaluation of c7E3 Fab [ReoPro] in Prevention of Ischemic Complications (EPIC) trial, a randomized, double-blind, placebo-controlled trial.An analysis of health economics from EPIC provided the basis for promotional materials that have been approved for use by the Food and Drug Administration (FDA). This article proposes a second design for the study of ReoPro as a medical therapy for unstable angina. Although this second study would include randomization, it is proposed that the study not be a double-blind study but rather one with an open-label design. Such a design is suggested because the use of ReoPro may allow a more rapid treatment of patients than standard therapy would allow; which, in turn, would decrease patient treatment costs while providing clinical benefit.
Health economics in the EPIC trial Trial design and methods
The EPIC trial was a multicenter, double-blind, placebo-controlled, randomized study in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) or atherectomy who were at high risk for subsequent acute ischemic complications.1 The trial enrolled a total of 2099 patients in 3 treatment arms: placebo bolus followed by a 12-hour placebo infusion (placebo), ReoPro bolus followed by a 12-hour placebo infusion (bolus), and ReoPro bolus followed by a 12-hour ReoPro infusion (bolus plus infusion).The primary end point for the trial was a composite end point of death, myocardial infarction (MI), or the need for urgent intervention through a period of 30 days after randomization. Urgent intervention primarily comprised urgent repeat PTCA From Centocor, Inc. Reprint requests: Keaven Anderson, PhD, Department of Biostatistics, Centocor, Inc, 200 Great Valley Pkwy, Malvern, PA 19355. Am Heart J 1999;137:S129-S132. Copyright © 1999 by Mosby, Inc. 0002-8703/99/$8.00 + 0 4/0/96449
and urgent coronary artery bypass graft (CABG) surgery. Follow-up through 6 months2 and 3 years3 was also performed. Hospital bills were collected both for the baseline hospitalization in which the study treatment was given and also for any subsequent hospitalization during the 6 months after randomization.4 In addition to hospital bills, Medicare Cost Reports were collected from participating hospitals so that cost-to-charge ratios could be calculated for various cost centers (eg, pharmacy, laboratory) within each hospital.These cost-to-charge ratios were used to convert hospital charges to hospital costs.5 Physicians’ fees were also estimated by using clinical data along with a Medicare fee schedule.All of these data were audited in a fashion similar to the audit of clinical data.Analyses of baseline hospitalization costs and hospitalization costs through 6 months were performed.
Results The EPIC trial showed a statistically significant reduction in the primary end point of death, MI, and urgent intervention through 30 days of 35%, a reduction from 12.8% in the placebo group, to 8.3% in the bolus-plusinfusion group (P = .008).A 10% reduction from the placebo group to an 11.5% primary end-point event rate in the bolus treatment group was not statistically significant.1 The ReoPro benefit observed at 30 days was maintained through 6 months, with a 23% reduction in the rate of the composite end point of death, MI, or any repeat revascularization (urgent or nonurgent), from 35.1% in the placebo treatment group to 27.0% in the bolus-plus-infusion group (P = .001).2 In contrast, there was an increase in major bleeding not associated with CABG during the baseline hospitalization, according to the Thrombolysis in Myocardial Infarction criteria,6 from 3.3% in the placebo group to 8.6% in the bolus group (P < .001) and to 10.6% in the bolus-plus-infusion group (P < .001).7 The increased incidence of bleeding observed with ReoPro in the EPIC trial probably was caused by the use of high-dose, non–weight-adjusted heparin. In the Evaluation of PTCA to Improve Long-term Outcome by c7E3 GPIIb/IIIa Receptor Blockade (EPILOG) trial, excess bleeding with ReoPro in patients undergoing PTCA was essentially eliminated through the use of lowdose, weight-adjusted heparin.8 In EPIC, the baseline hospitalization costs (exclusive of the study drug) plus physicians’ fees were nearly identical in the placebo group ($13,434) and the bolus-plus-
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infusion group (13,577; P = not significant).4 Linear regression modeling suggested that a $444 reduction in average costs by improved efficacy in the bolus-plusinfusion arm was offset by $531 in excess costs associated with bleeding. In the bolus-plus-infusion group, the decreased need for repeat revascularization after the baseline hospitalization resulted in a total cost of hospitalizations plus physicians’ fees that was lower through 6 months (again, exclusive of the study drug cost) by $1114, representing a cost reduction from $17,976 to $16,862 in this group.After including the average cost of the study drug per patient ($1407), the net cost of treatment was $293.The cost of hospitalizations after baseline was reduced significantly from the placebo group to the bolus-plus-infusion group (P = .018).The intention-to-treat analyses presented above suggest that for every 1000 patients, 81 would receive clinical benefit by avoiding death, MI, or repeat revascularization during the 6 months after treatment, at an average net cost of $293 per patient. In the subset of patients with unstable angina in the EPIC trial, the use of ReoPro showed a trend toward greater benefit and greater savings than it showed in the case of the remaining patient population treated with ReoPro.9 Initial hospitalization costs for patients with unstable angina were $13,929 ± $6474 with ReoPro bolus-plus-infusion compared with $15,072 ± $18,374 with placebo (P = .130), a difference that would largely reduce the average ReoPro cost of $1407 to a net cost of $264. In addition, average hospital costs for these patients over the subsequent 6-month period were $3508 ± $8889 with ReoPro bolus-plus-infusion compared with $4625 ± $9893 with placebo (P = .430), an additional reduction of $1017.This reduction, minus the net cost of $264 during the baseline hospitalization, would suggest savings of $753, including the cost of drug, in this patient population over the course of 6 months.Although cost differences were not statistically significant in the unstable angina subgroup, the analyses suggest the possibility of a subgroup of patients in which the cost-benefit ratio might be particularly great, with even the possibility of cost savings. It is an unfortunate fact that power for detecting treatment group differences in economic outcomes is often lower than it is for clinical outcomes; thus trials designed to detect clinical differences are insufficiently sized to detect statistically significant differences in costs associated with treatments. In the particular indication studied in the EPIC trial, there is a small number of patients with hospitalization costs in excess of $100,000. In trials of this size (700 patients per arm), each of these observations increases the average hospital cost for all patients in a treatment group by more than $100. Costs in such patients often appear to be related more to underlying patient disease or to events probably not related to study treatment than they are to
American Heart Journal May 1999
the indication of interest. Such extreme cases are an example of the large variability that must be overcome to demonstrate treatment benefits in an economic study.This large variability is the primary reason for reduced power in economic studies.
Health economics for medical therapy of unstable angina As noted above, ReoPro therapy appeared to be particularly cost-effective in unstable angina patients undergoing PTCA. In the Chimeric Anti-Platelet Therapy in Unstable Angina Refractory to Standard Medical Therapy (CAPTURE) trial, unstable angina patients undergoing PTCA who received medical therapy with ReoPro for 18 to 24 hours before PTCA benefited from this treatment before, during, and after PTCA.10 The primary end point of death, MI, or urgent intervention through 30 days was reduced by 29%, from 15.9% in the placebo group to 11.3% in the ReoPro group. In addition, a 69% reduction in the MI rate, from 2.1% in the placebo group to 0.6% in the ReoPro group (P = .029), was observed during the period of medical therapy before PTCA. These results suggest that patients with unstable angina may benefit from treatment with medical therapy even when subsequent PTCA is not performed.Treatment of patients with unstable angina with medical therapy has been performed for a minimum of 48 hours in recent large trials of newer antithrombotic agents, including the glycoprotein IIb/IIIa inhibitors tirofiban (PRISM,11 PRISM-PLUS12) and eptifibatide (PURSUIT13) and the low-molecular-weight heparin enoxaparin (ESSENCE14). Because these trials were double blind, there was no opportunity to test whether these new medical therapies might be effective with a shorter planned hospitalization time than that required with standard therapy with heparin and nitrates. Such a treatment strategy of shorter infusion periods might allow incremental cost increases associated with an effective study agent to be offset by decrements in other hospitalization costs resulting from a shorter hospital stay. Unstable angina is the sudden worsening of preexisting coronary artery disease characterized by 1 or more of the following: new onset of angina, worsening-ofeffort angina, or angina at rest.The pathogenesis of unstable angina is characterized by the rupture or ulceration of an atherosclerotic plaque that produces a highly thrombogenic arterial surface. If the plaque is associated with high-grade stenosis, the patient may be particularly at risk for nonocclusive or intermittently occlusive platelet-mediated coronary artery thrombosis. Classic medical therapy for unstable angina attempts to “cool down” symptoms while permitting plaque healing (passivation of the arterial wall) to occur.This medical therapy usually consists of bed rest, nitrates, aspirin, heparin, β-blockers, and calcium antagonists. In this con-
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servative strategy, a high-grade stenosis would be opened by percutaneous intervention or CABG surgery only if evidence of myocardial ischemia were still present after a reasonable trial of medical therapy. To test the validity of conservative medical therapy as a cost-effective approach as compared with another treatment strategy, an open-label randomized trial offers advantages over a standard double-blind design. For example, ReoPro might reduce costs associated with PTCA in patients with unstable angina by allowing earlier interventions, lowering the risk of thrombotic complications, improving clinical outcomes, and allowing a shorter time from intervention to discharge.To examine the possibility that the use of ReoPro might affect such health economic benefits, costs associated with the care of hospitalized patients with unstable angina were obtained on an informal basis from several hospitals in different regions of the United States.An analysis of these costs showed, for example, that by reducing the average length of stay in a coronary care unit from 2 to 3 days to 0 to 1 day, savings of $1348 to $4044 might be achieved. By reducing heparin and its monitoring from 2 to 3 days to 0 days, $448 to $575 might be saved. These two reductions total from $1796 to $4619 in cost savings before PTCA.After PTCA, average coronary care unit length of stay might be reduced from approximately 1 day to none, saving $1348. Hospital room length of stay might be reduced from 2 days to 1 day, saving $762, thereby achieving a total post-PTCA savings of $2110.Totaling both pre-PTCA and post-PTCA savings results in a $3906 to $6829 savings in hospitalization costs.This savings would more than pay for a ReoPro cost of $1350 to $1800. The obvious difficulty in this alternative trial design is that the lack of blinding and the differences in hospital length of stay could alter the assessment of clinical end points in the two treatment arms. However, given the efficacy of ReoPro previously demonstrated in PTCA trials,1-3,8-10,15,16 this might be an acceptable limitation.17 Certainly, secondary analyses showing benefit over the early time period in which patients from each treatment group would be in the hospital would be important to establish treatment differences.
Discussion EPIC was a double-blind trial used to establish the efficacy of ReoPro.The double-blind method was required to minimize any potential differences in patient treatment or assessment that might confound the interpretation of treatment group differences.This approach forced the use of standard-dose heparin in all treatment arms.8-10 Unfortunately, the use of standard heparin therapy with ReoPro produced a higher rate of bleeding complications, which apparently eliminated any early cost benefit that might have been expected
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from a reduced need for repeat interventions. In this case, the benefit of a reduced need for repeat revascularization during the 6 months after baseline hospitalization paid for much of the up-front ReoPro cost.The results of the EPILOG trial substantiate the fact that reducing bleeding incidence by using lower-dose, weight-adjusted heparin is a way to regain this early cost advantage of ReoPro treatment. How the results of the EPIC health-economics study might be applied depends greatly on the perspective of the user.A total health management organization providing not only health benefits but also workers’ compensation benefits and disability management might view the EPIC trial as one that provides evidence of a cost-effective treatment. From such an organization’s perspective, ReoPro has an estimated average net cost of $293 per patient and saves, on average, 81 “poor outcomes” (death, MI, or repeat revascularization over 6 months) per 1000 patients. Because the “poor outcomes” avoided would also likely have been associated with lost productivity, an additional cost savings not taken into account in the $293 average net cost figure could also be realized. Conversely, a hospital pharmacist might see ReoPro largely as a treatment that costs, on average, $1407 per patient and places a severe strain on the pharmacy budget.An administrator for a catheterization laboratory might also view the cost as $1407 per patient and find that cost difficult to justify in a fixed budget that includes personnel, device, and pharmacy costs. By assuming that bleeding risk can be controlled, a physician might conclude that the net cost of ReoPro during a given hospitalization is, on average, somewhat less than $1407, and that the therapy prevents, on average, 45 events (death, MI, urgent intervention) per 1000 patients over a relatively short term (30 days).Thus the potential purchaser of ReoPro must decide which cost and which benefit is the most relevant in decision making. It is often a significant challenge to present cost-effectiveness data to hospital pharmacy and therapeutics committees in a manner that is relevant to them.As discussed above, one likely reason for this fact is that costeffectiveness analysis typically uses a societal perspective that is applied to clinical trial results to address whether a particular drug is cost-effective as compared with placebo. Pharmacy and therapeutics committees, on the other hand, are interested in determining which subgroups of patients benefit sufficiently from treatment with a new drug to justify its higher cost, given the availability of alternative therapies.They wish to address how the new therapy can become part of a treatment protocol for cost-effective management of the disease under consideration. Hence it is important to generalize and reinterpret the cost-effectiveness results from the clinical trial in a disease management context; this approach assists pharmacy and therapeutics committees in developing guidelines for the cost-
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effective use of a new therapy. In doing this, it is useful to start with a description of the disease population of interest, the criteria for risk stratification, and treatment algorithms for both the high-risk and low-risk groups. This process then allows the pharmacy and therapeutics committee to clearly see the role of the new drug in the cost-effective management of the disease population. It is also useful to allow the pharmacy and therapeutics committee to change the unit-cost and lengthof-stay results from the trial to make the cost-effectiveness results more relevant to the institution(s) that they represent and to eliminate any costs induced by the protocol.As an example, although ReoPro benefits broad populations of patients undergoing coronary interventions,1,8,10,15,16 many institutions confine its use to 50% of PTCA patients. The open-label trial model proposed here, a model designed to establish the clinical and economic benefit of medical therapy with ReoPro for unstable angina, is one that might be unacceptable for a new therapy. However, it might be acceptable for an agent with established efficacy in an indication with events caused by a mechanism of action similar to that of unstable angina, as is the case with ReoPro in PTCA. Compared with a standard trial, an open-label type of trial has the potential to demonstrate both improved clinical outcomes for individual patients treated with ReoPro and, from a societal perspective, a reduced total cost of medical treatment.
References 1. 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. 2. Topol EJ, Califf RM, Weisman HF, et al, on behalf of the EPIC Investigators. Randomised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at 6 months. Lancet 1994;343:881-6. 3. Topol EJ, Ferguson JJ, Weisman HF, et al, for the EPIC Investigator Group. Long-term protection from myocardial ischemic events in a randomized trial of brief integrin β3 blockade with percutaneous coronary intervention. JAMA 1997;278:479-84. 4. Mark DB, Talley JD, Topol EJ, et al, for the EPIC Investigators. Economic assessment of platelet glycoprotein IIb/IIIa inhibition for prevention of ischemic complication of high-risk coronary angioplasty. Circulation 1996;94:629-35.
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5. Mark DB. Medical economics and health policy issues for interventional cardiology. In: Topol EJ, editor. Textbook of interventional cardiology. 2nd ed. Philadelphia: WB Saunders; 1993. p 1323-53. 6. Rao AK, Pratt C, Berke A, et al, for the TIMI Investigators. Thrombolysis in myocardial infarction (TIMI) trial: phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988;11:1-11. 7. Aguirre FV, Topol EJ, Ferguson JJ, et al. Bleeding complications with the chimeric antibody to platelet glycoprotein IIb/IIIa integrin in patients undergoing percutaneous coronary intervention. Circulation 1994;91:2282-90. 8. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997;336:1689-96. 9. Lincoff AM, Califf RM, Anderson KM, et al, for the EPIC Investigators. Evidence for prevention of death and myocardial infarction with platelet membrane glycoprotein IIb/IIIa receptor blockade by abciximab (c7E3 Fab) among patients with unstable angina undergoing percutaneous coronary revascularization. J Am Coll Cardiol 1997;30:149-56. 10. 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. 11. PRISM Study Investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med 1998;338:1498-1505. 12. PRISM-PLUS Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Qwave myocardial infarction. N Engl J Med 1998;338:1488-97. 13. Simoons ML, for the PURSUIT Investigators. Platelet IIb/IIIa in unstable angina: receptor suppression using integrilin trial (PURSUIT). Presented at the European meeting of cardiology, Stockholm, August 25, 1997. 14. Cohen M, Demers C, Gurfinkel EP, et al, for the ESSENCE Study Group. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 1997;337:447-52. 15. The EPISTENT Investigators. Randomized placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein IIb/IIIa blockade. Lancet 1998;352:87-92. 16. Brener SJ, Barr LA, Burchenal JEB, et al, on behalf of the RAPPORT Investigators. Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. Circulation. 1998;98:734-41. 17. Freemantle N, Drummond M. Should clinical trials with concurrent economic analyses be blinded? JAMA, 1997;277;63-4.
It has become increasingly important for the developers of new drugs and biologics to establish not only that their new products produce clinical benefits but also that such benefits can be achieved in a cost-effective manner.This article will review two specific study designs for clinical trials with ReoPro (abciximab), an antiplatelet agent designed to prevent coronary thrombosis.The purpose of this discussion is to establish costbenefit information for clinical trials with ReoPro.The first study design that is reviewed here was used in the Evaluation of c7E3 Fab [ReoPro] in Prevention of Ischemic Complications (EPIC) trial, a randomized, double-blind, placebo-controlled trial.An analysis of health economics from EPIC provided the basis for promotional materials that have been approved for use by the Food and Drug Administration (FDA). This article proposes a second design for the study of ReoPro as a medical therapy for unstable angina. Although this second study would include randomization, it is proposed that the study not be a double-blind study but rather one with an open-label design. Such a design is suggested because the use of ReoPro may allow a more rapid treatment of patients than standard therapy would allow; which, in turn, would decrease patient treatment costs while providing clinical benefit.
Health economics in the EPIC trial Trial design and methods
The EPIC trial was a multicenter, double-blind, placebo-controlled, randomized study in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) or atherectomy who were at high risk for subsequent acute ischemic complications.1 The trial enrolled a total of 2099 patients in 3 treatment arms: placebo bolus followed by a 12-hour placebo infusion (placebo), ReoPro bolus followed by a 12-hour placebo infusion (bolus), and ReoPro bolus followed by a 12-hour ReoPro infusion (bolus plus infusion).The primary end point for the trial was a composite end point of death, myocardial infarction (MI), or the need for urgent intervention through a period of 30 days after randomization. Urgent intervention primarily comprised urgent repeat PTCA From Centocor, Inc. Reprint requests: Keaven Anderson, PhD, Department of Biostatistics, Centocor, Inc, 200 Great Valley Pkwy, Malvern, PA 19355. Am Heart J 1999;137:S129-S132. Copyright © 1999 by Mosby, Inc. 0002-8703/99/$8.00 + 0 4/0/96449
and urgent coronary artery bypass graft (CABG) surgery. Follow-up through 6 months2 and 3 years3 was also performed. Hospital bills were collected both for the baseline hospitalization in which the study treatment was given and also for any subsequent hospitalization during the 6 months after randomization.4 In addition to hospital bills, Medicare Cost Reports were collected from participating hospitals so that cost-to-charge ratios could be calculated for various cost centers (eg, pharmacy, laboratory) within each hospital.These cost-to-charge ratios were used to convert hospital charges to hospital costs.5 Physicians’ fees were also estimated by using clinical data along with a Medicare fee schedule.All of these data were audited in a fashion similar to the audit of clinical data.Analyses of baseline hospitalization costs and hospitalization costs through 6 months were performed.
Results The EPIC trial showed a statistically significant reduction in the primary end point of death, MI, and urgent intervention through 30 days of 35%, a reduction from 12.8% in the placebo group, to 8.3% in the bolus-plusinfusion group (P = .008).A 10% reduction from the placebo group to an 11.5% primary end-point event rate in the bolus treatment group was not statistically significant.1 The ReoPro benefit observed at 30 days was maintained through 6 months, with a 23% reduction in the rate of the composite end point of death, MI, or any repeat revascularization (urgent or nonurgent), from 35.1% in the placebo treatment group to 27.0% in the bolus-plus-infusion group (P = .001).2 In contrast, there was an increase in major bleeding not associated with CABG during the baseline hospitalization, according to the Thrombolysis in Myocardial Infarction criteria,6 from 3.3% in the placebo group to 8.6% in the bolus group (P < .001) and to 10.6% in the bolus-plus-infusion group (P < .001).7 The increased incidence of bleeding observed with ReoPro in the EPIC trial probably was caused by the use of high-dose, non–weight-adjusted heparin. In the Evaluation of PTCA to Improve Long-term Outcome by c7E3 GPIIb/IIIa Receptor Blockade (EPILOG) trial, excess bleeding with ReoPro in patients undergoing PTCA was essentially eliminated through the use of lowdose, weight-adjusted heparin.8 In EPIC, the baseline hospitalization costs (exclusive of the study drug) plus physicians’ fees were nearly identical in the placebo group ($13,434) and the bolus-plus-
S130 Anderson, Bala, and Weisman
infusion group (13,577; P = not significant).4 Linear regression modeling suggested that a $444 reduction in average costs by improved efficacy in the bolus-plusinfusion arm was offset by $531 in excess costs associated with bleeding. In the bolus-plus-infusion group, the decreased need for repeat revascularization after the baseline hospitalization resulted in a total cost of hospitalizations plus physicians’ fees that was lower through 6 months (again, exclusive of the study drug cost) by $1114, representing a cost reduction from $17,976 to $16,862 in this group.After including the average cost of the study drug per patient ($1407), the net cost of treatment was $293.The cost of hospitalizations after baseline was reduced significantly from the placebo group to the bolus-plus-infusion group (P = .018).The intention-to-treat analyses presented above suggest that for every 1000 patients, 81 would receive clinical benefit by avoiding death, MI, or repeat revascularization during the 6 months after treatment, at an average net cost of $293 per patient. In the subset of patients with unstable angina in the EPIC trial, the use of ReoPro showed a trend toward greater benefit and greater savings than it showed in the case of the remaining patient population treated with ReoPro.9 Initial hospitalization costs for patients with unstable angina were $13,929 ± $6474 with ReoPro bolus-plus-infusion compared with $15,072 ± $18,374 with placebo (P = .130), a difference that would largely reduce the average ReoPro cost of $1407 to a net cost of $264. In addition, average hospital costs for these patients over the subsequent 6-month period were $3508 ± $8889 with ReoPro bolus-plus-infusion compared with $4625 ± $9893 with placebo (P = .430), an additional reduction of $1017.This reduction, minus the net cost of $264 during the baseline hospitalization, would suggest savings of $753, including the cost of drug, in this patient population over the course of 6 months.Although cost differences were not statistically significant in the unstable angina subgroup, the analyses suggest the possibility of a subgroup of patients in which the cost-benefit ratio might be particularly great, with even the possibility of cost savings. It is an unfortunate fact that power for detecting treatment group differences in economic outcomes is often lower than it is for clinical outcomes; thus trials designed to detect clinical differences are insufficiently sized to detect statistically significant differences in costs associated with treatments. In the particular indication studied in the EPIC trial, there is a small number of patients with hospitalization costs in excess of $100,000. In trials of this size (700 patients per arm), each of these observations increases the average hospital cost for all patients in a treatment group by more than $100. Costs in such patients often appear to be related more to underlying patient disease or to events probably not related to study treatment than they are to
American Heart Journal May 1999
the indication of interest. Such extreme cases are an example of the large variability that must be overcome to demonstrate treatment benefits in an economic study.This large variability is the primary reason for reduced power in economic studies.
Health economics for medical therapy of unstable angina As noted above, ReoPro therapy appeared to be particularly cost-effective in unstable angina patients undergoing PTCA. In the Chimeric Anti-Platelet Therapy in Unstable Angina Refractory to Standard Medical Therapy (CAPTURE) trial, unstable angina patients undergoing PTCA who received medical therapy with ReoPro for 18 to 24 hours before PTCA benefited from this treatment before, during, and after PTCA.10 The primary end point of death, MI, or urgent intervention through 30 days was reduced by 29%, from 15.9% in the placebo group to 11.3% in the ReoPro group. In addition, a 69% reduction in the MI rate, from 2.1% in the placebo group to 0.6% in the ReoPro group (P = .029), was observed during the period of medical therapy before PTCA. These results suggest that patients with unstable angina may benefit from treatment with medical therapy even when subsequent PTCA is not performed.Treatment of patients with unstable angina with medical therapy has been performed for a minimum of 48 hours in recent large trials of newer antithrombotic agents, including the glycoprotein IIb/IIIa inhibitors tirofiban (PRISM,11 PRISM-PLUS12) and eptifibatide (PURSUIT13) and the low-molecular-weight heparin enoxaparin (ESSENCE14). Because these trials were double blind, there was no opportunity to test whether these new medical therapies might be effective with a shorter planned hospitalization time than that required with standard therapy with heparin and nitrates. Such a treatment strategy of shorter infusion periods might allow incremental cost increases associated with an effective study agent to be offset by decrements in other hospitalization costs resulting from a shorter hospital stay. Unstable angina is the sudden worsening of preexisting coronary artery disease characterized by 1 or more of the following: new onset of angina, worsening-ofeffort angina, or angina at rest.The pathogenesis of unstable angina is characterized by the rupture or ulceration of an atherosclerotic plaque that produces a highly thrombogenic arterial surface. If the plaque is associated with high-grade stenosis, the patient may be particularly at risk for nonocclusive or intermittently occlusive platelet-mediated coronary artery thrombosis. Classic medical therapy for unstable angina attempts to “cool down” symptoms while permitting plaque healing (passivation of the arterial wall) to occur.This medical therapy usually consists of bed rest, nitrates, aspirin, heparin, β-blockers, and calcium antagonists. In this con-
American Heart Journal Volume 137, Number 5
servative strategy, a high-grade stenosis would be opened by percutaneous intervention or CABG surgery only if evidence of myocardial ischemia were still present after a reasonable trial of medical therapy. To test the validity of conservative medical therapy as a cost-effective approach as compared with another treatment strategy, an open-label randomized trial offers advantages over a standard double-blind design. For example, ReoPro might reduce costs associated with PTCA in patients with unstable angina by allowing earlier interventions, lowering the risk of thrombotic complications, improving clinical outcomes, and allowing a shorter time from intervention to discharge.To examine the possibility that the use of ReoPro might affect such health economic benefits, costs associated with the care of hospitalized patients with unstable angina were obtained on an informal basis from several hospitals in different regions of the United States.An analysis of these costs showed, for example, that by reducing the average length of stay in a coronary care unit from 2 to 3 days to 0 to 1 day, savings of $1348 to $4044 might be achieved. By reducing heparin and its monitoring from 2 to 3 days to 0 days, $448 to $575 might be saved. These two reductions total from $1796 to $4619 in cost savings before PTCA.After PTCA, average coronary care unit length of stay might be reduced from approximately 1 day to none, saving $1348. Hospital room length of stay might be reduced from 2 days to 1 day, saving $762, thereby achieving a total post-PTCA savings of $2110.Totaling both pre-PTCA and post-PTCA savings results in a $3906 to $6829 savings in hospitalization costs.This savings would more than pay for a ReoPro cost of $1350 to $1800. The obvious difficulty in this alternative trial design is that the lack of blinding and the differences in hospital length of stay could alter the assessment of clinical end points in the two treatment arms. However, given the efficacy of ReoPro previously demonstrated in PTCA trials,1-3,8-10,15,16 this might be an acceptable limitation.17 Certainly, secondary analyses showing benefit over the early time period in which patients from each treatment group would be in the hospital would be important to establish treatment differences.
Discussion EPIC was a double-blind trial used to establish the efficacy of ReoPro.The double-blind method was required to minimize any potential differences in patient treatment or assessment that might confound the interpretation of treatment group differences.This approach forced the use of standard-dose heparin in all treatment arms.8-10 Unfortunately, the use of standard heparin therapy with ReoPro produced a higher rate of bleeding complications, which apparently eliminated any early cost benefit that might have been expected
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from a reduced need for repeat interventions. In this case, the benefit of a reduced need for repeat revascularization during the 6 months after baseline hospitalization paid for much of the up-front ReoPro cost.The results of the EPILOG trial substantiate the fact that reducing bleeding incidence by using lower-dose, weight-adjusted heparin is a way to regain this early cost advantage of ReoPro treatment. How the results of the EPIC health-economics study might be applied depends greatly on the perspective of the user.A total health management organization providing not only health benefits but also workers’ compensation benefits and disability management might view the EPIC trial as one that provides evidence of a cost-effective treatment. From such an organization’s perspective, ReoPro has an estimated average net cost of $293 per patient and saves, on average, 81 “poor outcomes” (death, MI, or repeat revascularization over 6 months) per 1000 patients. Because the “poor outcomes” avoided would also likely have been associated with lost productivity, an additional cost savings not taken into account in the $293 average net cost figure could also be realized. Conversely, a hospital pharmacist might see ReoPro largely as a treatment that costs, on average, $1407 per patient and places a severe strain on the pharmacy budget.An administrator for a catheterization laboratory might also view the cost as $1407 per patient and find that cost difficult to justify in a fixed budget that includes personnel, device, and pharmacy costs. By assuming that bleeding risk can be controlled, a physician might conclude that the net cost of ReoPro during a given hospitalization is, on average, somewhat less than $1407, and that the therapy prevents, on average, 45 events (death, MI, urgent intervention) per 1000 patients over a relatively short term (30 days).Thus the potential purchaser of ReoPro must decide which cost and which benefit is the most relevant in decision making. It is often a significant challenge to present cost-effectiveness data to hospital pharmacy and therapeutics committees in a manner that is relevant to them.As discussed above, one likely reason for this fact is that costeffectiveness analysis typically uses a societal perspective that is applied to clinical trial results to address whether a particular drug is cost-effective as compared with placebo. Pharmacy and therapeutics committees, on the other hand, are interested in determining which subgroups of patients benefit sufficiently from treatment with a new drug to justify its higher cost, given the availability of alternative therapies.They wish to address how the new therapy can become part of a treatment protocol for cost-effective management of the disease under consideration. Hence it is important to generalize and reinterpret the cost-effectiveness results from the clinical trial in a disease management context; this approach assists pharmacy and therapeutics committees in developing guidelines for the cost-
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effective use of a new therapy. In doing this, it is useful to start with a description of the disease population of interest, the criteria for risk stratification, and treatment algorithms for both the high-risk and low-risk groups. This process then allows the pharmacy and therapeutics committee to clearly see the role of the new drug in the cost-effective management of the disease population. It is also useful to allow the pharmacy and therapeutics committee to change the unit-cost and lengthof-stay results from the trial to make the cost-effectiveness results more relevant to the institution(s) that they represent and to eliminate any costs induced by the protocol.As an example, although ReoPro benefits broad populations of patients undergoing coronary interventions,1,8,10,15,16 many institutions confine its use to 50% of PTCA patients. The open-label trial model proposed here, a model designed to establish the clinical and economic benefit of medical therapy with ReoPro for unstable angina, is one that might be unacceptable for a new therapy. However, it might be acceptable for an agent with established efficacy in an indication with events caused by a mechanism of action similar to that of unstable angina, as is the case with ReoPro in PTCA. Compared with a standard trial, an open-label type of trial has the potential to demonstrate both improved clinical outcomes for individual patients treated with ReoPro and, from a societal perspective, a reduced total cost of medical treatment.
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