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The impact of the cost-effectiveness study of GUSTO-1 on decision making with regard to fibrinolytic therapy
The impact of the cost-effectiveness study of GUSTO-1 on decision making with regard to fibrinolytic therapy Robert M. Califf, MD, FACC,a David Stump, MD,b Eric J. Topol, MD,c and Daniel B. Mark, MD, MPHa Durham, NC, San Francisco, Calif, and Cleveland, Ohio
The standard method for assessing the effect of fibrinolytic therapy on clinical outcome is the mortality trial. Although streptokinase is a relatively inexpensive fibrinolytic treatment that has been widely used, it has some undesirable properties.Thus, the opportunity to improve the profile of fibrinolytic agents stimulated the medical community to develop new approaches to fibrinolytic therapies, which led to the designing of new molecules such as alteplase,duteplase,and anistreplase.Initially,these new treatments—considerably more expensive (and theoretically more attractive) than conventional therapy—did not appear to provide significant clinical benefit when studied in 2 large international trials:the Third International Study of Infarction Survival (ISIS-3) trial1 and the GISSI-2 trial.2 However,when dosing and adjuvant-therapy strategies were improved,the Global Utilization of Streptokinase and Tissue Plasminogen Activator (t-PA) for Occluded Coronary Arteries (GUSTO-1) trial3 ultimately demonstrated a clinical benefit—mortality reduction—with t-PA.At the time this result was published, the simultaneous presentation and subsequent publication of prospective, academically based cost-effectiveness analyses provided critical data for Pharmacy and Therapeutics (P&T) committees to assess the new treatments that were the focal points of these trials.4 When the initial published studies from ISIS-3 and GISSI-2 provided negative conclusions about the new tPA treatments, U.S. sales of alteplase (t-PA) declined. However, with the completion of GUSTO-1 and its demonstration of clinical benefit, sales of alteplase increased steadily as a proportion of market share.The period of this increase included the time of the publication of the main clinical results from GUSTO-1 and the publication of the cost-effectiveness analysis related to the trial.These findings alone do not prove the benefit of cost-effectiveness studies. But the overall findings in this article support the concept that when credible costFrom aDuke Clinical Research Institute; bGenentech, Inc; and cthe Department of Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, The Cleveland Clinic Foundation. Reprint requests: Robert M. Califf, MD, FACC, Director, Duke Clinical Research Institute, P.O. Box 17969, Durham, NC 27715. Am Heart J 1999;137:S90-S93. Copyright © 1999 by Mosby, Inc. 0002-8703/99/$8.00 + 0 4/0/97028
effectiveness information demonstrates that the cost of a clinical benefit is within the range of the costs of other accepted therapies, this information can lead to a preference for a more expensive therapy, particularly in the United States, where the willingness to pay for more expensive therapies is greatest. The use of prospective cost-effectiveness studies has been a major thrust of modern cardiovascular clinical trials.This effort has been particularly aided by employing a large, simple trial methodology in which the goal is twofold: to enroll patients who reflect the composition of patients seen in practice and to exert minimal interference with the normal therapies of these patients. When such a trial methodology is applied, it minimizes the confounding of the results of economic studies by the protocol requirements. Fibrinolytic therapy was used only in a restricted manner until the early 1980s, when definitive mortality trials demonstrated that it achieved a reduction in mortality rates. Even then, however, the clinical community did not embrace myocardial reperfusion until the development of t-PA, a novel fibrinolytic agent manufactured through recombinant technology. Shortly after t-PA’s development, several large mortality trials, which included ISIS3 and GISSI-2, demonstrated no difference in mortality rates between patients treated with t-PA and those treated with streptokinase.1,2 The impact of these trials on the use of t-PA was tempered by concerns of some in the medical community that the studies had not tested tPA under appropriate circumstances because the dose was given as a fixed dose without front-loading and without concomitant intravenous heparin.These theoretical concerns were clearly not sufficient, however, to obviate the need for a mortality trial to provide a definitive comparison between the 2 therapies.
Background A host of animal and human experiments have demonstrated that the early restoration of blood flow to an acutely occluded coronary artery will reduce the size of a myocardial infarction (MI).5 An improved understanding of the coagulation system has yielded a variety of biologic agents that can lyse thrombus and therefore could restore coronary blood flow in the setting of coronary thrombosis.As of 1985, 3 different fibrinolytic
American Heart Journal Volume 137, Number 5
Califf et al S91
Figure 1
Change in market share of t-PA and streptokinase as a function of fiscal year. Note that changes track with availability of critical clinical trial and cost-effectiveness data.
agents had been demonstrated to reduce the risk of death in patients with ST-segment elevation myocardial infarction who were treated within 12 hours of symptom onset. The GISSI-1 and ISIS-2 studies6-7 demonstrated a 25% reduction in mortality rate with streptokinase.A 50% mortality reduction with anisoylated streptokinase plasminogen activator complex (APSAC) was demonstrated in the APSAC International Mortality Study (AIMS).8 ASSET (Anglo-Scandinavian Study of Early Thrombosis) demonstrated a 29% mortality reduction with alteplase.9 As part of a National Institutes of Health program, the Thrombolysis in Myocardial Infarction (TIMI-1) trial compared t-PA with streptokinase and used an angiographic end point.10 When t-PA was found to produce a markedly higher rate of early coronary perfusion, the study was stopped early and the investigators assumed that t-PA would be superior to streptokinase in producing better clinical outcomes. Despite this assumption by the TIMI investigators, both the ISIS and GISSI groups decided to evaluate streptokinase compared with the newer fibrinolytic agents by conducting large-scale randomized comparisons. Both trial groups decided that a 1% absolute reduction in mortality rate was clinically important and performed studies with a sample size adequate to detect a difference of that magnitude.The ISIS-3 trial compared streptokinase with APSAC and with duteplase, a different form of t-PA. The GISSI-2 study had a simpler
design, comparing alteplase with streptokinase. Neither trial found a difference between the mortality rates with streptokinase compared with t-PA, and both trials found a higher rate of hemorrhagic stroke with t-PA. As discussed previously, neither study administered intravenous heparin with t-PA, although several angiographic studies had demonstrated a more sustained perfusion rate when heparin was used with tPA. Furthermore, while ISIS-3 and GISSI-2 were being conducted, a series of angiographic studies had demonstrated an improved perfusion rate when t-PA was administered with a front-loaded regimen.11-14
Design of study The GUSTO-1 trial was designed to answer conclusively the fundamental question of whether early and sustained reperfusion in acute myocardial infarction would result in an improved clinical outcome.The comparative arms in the initial design received streptokinase (intended to achieve reperfusion slowly), accelerated alteplase (designed to achieve rapid reperfusion), and the combination of alteplase and streptokinase (designed to achieve reperfusion rapidly and to maximize sustained perfusion). The sponsor of the trial initially declined to provide the funding for a cost-effectiveness study. However, an agreement was reached to fund a study of the quality of life in patients who had suffered myocardial infarction. In a ran-
American Heart Journall May 1999
S92 Califf et al
Table I. Cost-effectiveness ratios for t-PA as compared with streptokinase in the primary analysis and for selected subgroups of patients
Table not available
dom sample of 3000 patients from North America, complete hospital bills were collected and all admissions over the next year were reviewed with the ascertainment of the hospital bills and supporting documentation.
Initial presentation and publication The patients in the mortality study were randomized from December 27, 1990, until February 22, 1993; the final 30-day mortality data were accrued in March 1993. That month the initial results were presented at the Scientific Sessions of the American Federation for Clinical Research.The article presenting the primary result of the study was published on September 2, 1993. Despite the optimistic picture suggested by the initial 30-day mortality data, concern about the accuracy of the predictions of 1-year mortality made investigators cautious about submitting a final publication on cost-effectiveness issues. Furthermore, by this time the New England Journal of Medicine had revised its policy on publishing cost-effectiveness studies, making its criteria for considering such studies much more restrictive than before.The article was submitted on November 4, 1994 and finally accepted for publication on March 14, 1995, with publication occurring on May 25, 1995.15 The primary result of the GUSTO-1 trial was a 1% absolute reduction (15% relative reduction) in the mortality rate in patients treated with alteplase compared with those receiving other treatments.The 30-day mortality rate in the alteplase-treated group was 6.3% compared with 7.2% in patients treated with streptoki-
nase and subcutaneous heparin, 7.4% in patients treated with streptokinase and intravenous heparin, and 7.0% in those treated with the combination of both fibrinolytic agents.3 This difference among treatment arms was maintained at 1 year.16 The mortality advantage for patients receiving alteplase was partially offset by a 0.2% increase in their risk of nonfatal strokes, half of which were disabling.Thus the net clinical outcomes of death and nonfatal stroke at 1 year were 6.9% with alteplase and 7.8% with intravenous and subcutaneous heparin in conjunction with streptokinase (P = .001). The other secondary end points all showed a trend in favor of alteplase. The cost-effectiveness study of GUSTO-1 demonstrated no difference among the treatment groups in downstream clinical outcomes, use of medical resources, or directly measured costs as a function of thrombolytic compliance.After 1 year of follow-up, the average patient treated with alteplase had a higher cost ($2845) to balance the 1.1% better survival rate.The average incremental cost-effectiveness ratio was $32,678 per year of life saved.The most favorable cost-effectiveness ratios occurred in patients with anterior myocardial infarction and in older patients, as shown in Table I. Fig 1 demonstrates the market share of alteplase relative to streptokinase, with key time points indicated. After the results of ISIS-3 and GISSI-2 were announced, the sales of alteplase relative to streptokinase significantly declined.When the GUSTO-1 trial was initiated, the market share of alteplase increased.When the results of GUSTO-1 were first announced, including the preliminary cost-effectiveness data, sales of alteplase almost immediately increased further. A further increase was seen shortly after the primary clinical outcome results were published. Finally, a steady increase continued through the publication of the cost-effectiveness results. No subsequent studies have demonstrated a benefit of any fibrinolytic agent beyond that observed in GUSTO, and the market share for alteplase has remained stable.
Discussion In retrospect the academic study group and the sponsor agreed that the cost-effectiveness study for GUSTO-1 provided substantial support for the case to use alteplase.The degree to which the study played a significant direct role with decision makers remains uncertain. But all parties judged that the immediate presentation of the fundamental result of the costeffectiveness study at the time of the primary clinical presentation played a major role in placing the study in perspective.The trends in decision making by P&T committees and individual prescribing physicians were already entrenched by the time of the final publication of the cost-effectiveness study. However, the fact that the study met the stringent criteria for publication in a
American Heart Journal Volume 137, Number 5
prestigious journal was probably an important factor in the sustained preference for alteplase that has been described. We believe that many aspects of the GUSTO costeffectiveness study provide a model for future investigations.The study was prospectively designed at the inception of the main clinical trial, which sought to enroll all eligible patients and did not alter routine clinical care beyond administering the fibrinolytic agent and acute antithrombotic therapy.The results of the costeffectiveness study were analyzed and authored by an independent academic group.The data-intensive phase of the study was relatively free of assumptions because it depended on source-documented billing records. Complex modeling was necessary, however, to estimate the effects of the acute benefit on long-term outcome. Because the long-term survival of the patients was not known, models had to be built from an independent population, which yielded financial modeling that required a number of assumptions. Fortunately, acute myocardial infarction is a disease state with substantial previous data, and access to long-term follow-up from the Duke Cardiovascular Databank provided a credible independent source of data.The independence of the study group was critical to the acceptance of the study results. The study of GUSTO-1 demonstrated that the incremental cost-effectiveness of alteplase was within the range of accepted therapies. Unfortunately, for most other therapies considered by P&T committees, such information is rarely available. Given the large initial expense of alteplase, placing the benefit within the cost-effectiveness framework provided a rationale for its use even in financially constrained situations. Active control, comparative clinical outcome trials are rare, and comparative cost-effectiveness studies in which 2 marketed therapies are compared by an independent study group are even less common.Excellent studies have documented the economic attractiveness of treatment with β-blockers,lipid-lowering agents,and angiotensin-converting enzyme inhibitors.However,no direct studies have been done comparing different lipid-lowering agents, β-blockers, or angiotensin-converting enzyme inhibitors. It is hoped that the positive experience of the GUSTO-1 cost-effectiveness study will provide a model for others to use.
References 1. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. ISIS-3: a randomized comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs
Califf et al S93
2.
3.
4.
5.
6.
7.
8.
9.
10. 11.
12.
13.
14.
15.
16.
aspirin alone among 41,299 cases of suspected acute myocardial infarction. Lancet 1993;339:753-70. The International Study Group. In-hospital mortality and clinical course of 20,891 patients with suspected acute myocardial infarction randomized between alteplase and streptokinase with or without heparin. Lancet 1990;336;71-5. The GUSTO Investigators. An international randomized trial comparing four thrombolytic regimens consisting of tissue plasminogen activator, streptokinase, or both for acute myocardial infarction. N Engl J Med 1993;329:673-82. Lincoff AM, Topol EJ. Illusion of reperfusion: does anyone achieve optimal reperfusion during acute myocardial infarction? Circulation 1993;87:1792-805. Califf RM, Topol EJ, Gersh BJ. From myocardial salvage to patient salvage in acute myocardial infarction: the role of reperfusion therapy. J Am Coll Cardiol 1989;14:1382-8. Gruppo Italiano per lo Studio della Streptochinaisi nell’Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397-402. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349-60. AIMS Trial Study Group. Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebocontrolled clinical trial. Lancet 1988;2:545-9. Wilcox RG, von der Lippe G, Olsson CG, Jensen G, Skene AM, Hampton JR, for the ASSET Study Group. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction. Lancet 1988;2:525-30. The TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase 1 findings. N Engl J Med 1985;312:932. Neuhaus KL, Feuerer W, Jeep-Tebbe S, Niederer W, Vogt A, Tebbe U. Improved thrombolysis with a modified dose regimen of recombinant tissue-type plasminogen activator. J Am Coll Cardiol 1989;14: 1566-9. Neuhaus KL, Von Essen R, Tebbe U, et al. Improved thrombolysis in acute myocardial infarction with front-loaded administration of alteplase: result of the rt-PA-APSAC patency study (TAPS). J Am Coll Cardiol 1992;19:885-91. Carney RJ, Murphy GA, Brandt TR, et al. Randomized angiographic trial of recombinant tissue type plasminogen activator (alteplase) in myocardial infarction. J Am Coll Cardiol 1992;2017–23. Wall TC, Califf RM, George BS, et al, for the TAMI-7 Study Group. Accelerated plasminogen activator dose regimens for coronary thrombolysis. J Am Coll Cardiol 1992;19:482-9. 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. Califf RM, White HD, Van der Werf F, et al, for the GUSTO-I Investigators. One-year results from the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO-I) trial. Circulation 1996;94:1233-8.
The standard method for assessing the effect of fibrinolytic therapy on clinical outcome is the mortality trial. Although streptokinase is a relatively inexpensive fibrinolytic treatment that has been widely used, it has some undesirable properties.Thus, the opportunity to improve the profile of fibrinolytic agents stimulated the medical community to develop new approaches to fibrinolytic therapies, which led to the designing of new molecules such as alteplase,duteplase,and anistreplase.Initially,these new treatments—considerably more expensive (and theoretically more attractive) than conventional therapy—did not appear to provide significant clinical benefit when studied in 2 large international trials:the Third International Study of Infarction Survival (ISIS-3) trial1 and the GISSI-2 trial.2 However,when dosing and adjuvant-therapy strategies were improved,the Global Utilization of Streptokinase and Tissue Plasminogen Activator (t-PA) for Occluded Coronary Arteries (GUSTO-1) trial3 ultimately demonstrated a clinical benefit—mortality reduction—with t-PA.At the time this result was published, the simultaneous presentation and subsequent publication of prospective, academically based cost-effectiveness analyses provided critical data for Pharmacy and Therapeutics (P&T) committees to assess the new treatments that were the focal points of these trials.4 When the initial published studies from ISIS-3 and GISSI-2 provided negative conclusions about the new tPA treatments, U.S. sales of alteplase (t-PA) declined. However, with the completion of GUSTO-1 and its demonstration of clinical benefit, sales of alteplase increased steadily as a proportion of market share.The period of this increase included the time of the publication of the main clinical results from GUSTO-1 and the publication of the cost-effectiveness analysis related to the trial.These findings alone do not prove the benefit of cost-effectiveness studies. But the overall findings in this article support the concept that when credible costFrom aDuke Clinical Research Institute; bGenentech, Inc; and cthe Department of Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, The Cleveland Clinic Foundation. Reprint requests: Robert M. Califf, MD, FACC, Director, Duke Clinical Research Institute, P.O. Box 17969, Durham, NC 27715. Am Heart J 1999;137:S90-S93. Copyright © 1999 by Mosby, Inc. 0002-8703/99/$8.00 + 0 4/0/97028
effectiveness information demonstrates that the cost of a clinical benefit is within the range of the costs of other accepted therapies, this information can lead to a preference for a more expensive therapy, particularly in the United States, where the willingness to pay for more expensive therapies is greatest. The use of prospective cost-effectiveness studies has been a major thrust of modern cardiovascular clinical trials.This effort has been particularly aided by employing a large, simple trial methodology in which the goal is twofold: to enroll patients who reflect the composition of patients seen in practice and to exert minimal interference with the normal therapies of these patients. When such a trial methodology is applied, it minimizes the confounding of the results of economic studies by the protocol requirements. Fibrinolytic therapy was used only in a restricted manner until the early 1980s, when definitive mortality trials demonstrated that it achieved a reduction in mortality rates. Even then, however, the clinical community did not embrace myocardial reperfusion until the development of t-PA, a novel fibrinolytic agent manufactured through recombinant technology. Shortly after t-PA’s development, several large mortality trials, which included ISIS3 and GISSI-2, demonstrated no difference in mortality rates between patients treated with t-PA and those treated with streptokinase.1,2 The impact of these trials on the use of t-PA was tempered by concerns of some in the medical community that the studies had not tested tPA under appropriate circumstances because the dose was given as a fixed dose without front-loading and without concomitant intravenous heparin.These theoretical concerns were clearly not sufficient, however, to obviate the need for a mortality trial to provide a definitive comparison between the 2 therapies.
Background A host of animal and human experiments have demonstrated that the early restoration of blood flow to an acutely occluded coronary artery will reduce the size of a myocardial infarction (MI).5 An improved understanding of the coagulation system has yielded a variety of biologic agents that can lyse thrombus and therefore could restore coronary blood flow in the setting of coronary thrombosis.As of 1985, 3 different fibrinolytic
American Heart Journal Volume 137, Number 5
Califf et al S91
Figure 1
Change in market share of t-PA and streptokinase as a function of fiscal year. Note that changes track with availability of critical clinical trial and cost-effectiveness data.
agents had been demonstrated to reduce the risk of death in patients with ST-segment elevation myocardial infarction who were treated within 12 hours of symptom onset. The GISSI-1 and ISIS-2 studies6-7 demonstrated a 25% reduction in mortality rate with streptokinase.A 50% mortality reduction with anisoylated streptokinase plasminogen activator complex (APSAC) was demonstrated in the APSAC International Mortality Study (AIMS).8 ASSET (Anglo-Scandinavian Study of Early Thrombosis) demonstrated a 29% mortality reduction with alteplase.9 As part of a National Institutes of Health program, the Thrombolysis in Myocardial Infarction (TIMI-1) trial compared t-PA with streptokinase and used an angiographic end point.10 When t-PA was found to produce a markedly higher rate of early coronary perfusion, the study was stopped early and the investigators assumed that t-PA would be superior to streptokinase in producing better clinical outcomes. Despite this assumption by the TIMI investigators, both the ISIS and GISSI groups decided to evaluate streptokinase compared with the newer fibrinolytic agents by conducting large-scale randomized comparisons. Both trial groups decided that a 1% absolute reduction in mortality rate was clinically important and performed studies with a sample size adequate to detect a difference of that magnitude.The ISIS-3 trial compared streptokinase with APSAC and with duteplase, a different form of t-PA. The GISSI-2 study had a simpler
design, comparing alteplase with streptokinase. Neither trial found a difference between the mortality rates with streptokinase compared with t-PA, and both trials found a higher rate of hemorrhagic stroke with t-PA. As discussed previously, neither study administered intravenous heparin with t-PA, although several angiographic studies had demonstrated a more sustained perfusion rate when heparin was used with tPA. Furthermore, while ISIS-3 and GISSI-2 were being conducted, a series of angiographic studies had demonstrated an improved perfusion rate when t-PA was administered with a front-loaded regimen.11-14
Design of study The GUSTO-1 trial was designed to answer conclusively the fundamental question of whether early and sustained reperfusion in acute myocardial infarction would result in an improved clinical outcome.The comparative arms in the initial design received streptokinase (intended to achieve reperfusion slowly), accelerated alteplase (designed to achieve rapid reperfusion), and the combination of alteplase and streptokinase (designed to achieve reperfusion rapidly and to maximize sustained perfusion). The sponsor of the trial initially declined to provide the funding for a cost-effectiveness study. However, an agreement was reached to fund a study of the quality of life in patients who had suffered myocardial infarction. In a ran-
American Heart Journall May 1999
S92 Califf et al
Table I. Cost-effectiveness ratios for t-PA as compared with streptokinase in the primary analysis and for selected subgroups of patients
Table not available
dom sample of 3000 patients from North America, complete hospital bills were collected and all admissions over the next year were reviewed with the ascertainment of the hospital bills and supporting documentation.
Initial presentation and publication The patients in the mortality study were randomized from December 27, 1990, until February 22, 1993; the final 30-day mortality data were accrued in March 1993. That month the initial results were presented at the Scientific Sessions of the American Federation for Clinical Research.The article presenting the primary result of the study was published on September 2, 1993. Despite the optimistic picture suggested by the initial 30-day mortality data, concern about the accuracy of the predictions of 1-year mortality made investigators cautious about submitting a final publication on cost-effectiveness issues. Furthermore, by this time the New England Journal of Medicine had revised its policy on publishing cost-effectiveness studies, making its criteria for considering such studies much more restrictive than before.The article was submitted on November 4, 1994 and finally accepted for publication on March 14, 1995, with publication occurring on May 25, 1995.15 The primary result of the GUSTO-1 trial was a 1% absolute reduction (15% relative reduction) in the mortality rate in patients treated with alteplase compared with those receiving other treatments.The 30-day mortality rate in the alteplase-treated group was 6.3% compared with 7.2% in patients treated with streptoki-
nase and subcutaneous heparin, 7.4% in patients treated with streptokinase and intravenous heparin, and 7.0% in those treated with the combination of both fibrinolytic agents.3 This difference among treatment arms was maintained at 1 year.16 The mortality advantage for patients receiving alteplase was partially offset by a 0.2% increase in their risk of nonfatal strokes, half of which were disabling.Thus the net clinical outcomes of death and nonfatal stroke at 1 year were 6.9% with alteplase and 7.8% with intravenous and subcutaneous heparin in conjunction with streptokinase (P = .001). The other secondary end points all showed a trend in favor of alteplase. The cost-effectiveness study of GUSTO-1 demonstrated no difference among the treatment groups in downstream clinical outcomes, use of medical resources, or directly measured costs as a function of thrombolytic compliance.After 1 year of follow-up, the average patient treated with alteplase had a higher cost ($2845) to balance the 1.1% better survival rate.The average incremental cost-effectiveness ratio was $32,678 per year of life saved.The most favorable cost-effectiveness ratios occurred in patients with anterior myocardial infarction and in older patients, as shown in Table I. Fig 1 demonstrates the market share of alteplase relative to streptokinase, with key time points indicated. After the results of ISIS-3 and GISSI-2 were announced, the sales of alteplase relative to streptokinase significantly declined.When the GUSTO-1 trial was initiated, the market share of alteplase increased.When the results of GUSTO-1 were first announced, including the preliminary cost-effectiveness data, sales of alteplase almost immediately increased further. A further increase was seen shortly after the primary clinical outcome results were published. Finally, a steady increase continued through the publication of the cost-effectiveness results. No subsequent studies have demonstrated a benefit of any fibrinolytic agent beyond that observed in GUSTO, and the market share for alteplase has remained stable.
Discussion In retrospect the academic study group and the sponsor agreed that the cost-effectiveness study for GUSTO-1 provided substantial support for the case to use alteplase.The degree to which the study played a significant direct role with decision makers remains uncertain. But all parties judged that the immediate presentation of the fundamental result of the costeffectiveness study at the time of the primary clinical presentation played a major role in placing the study in perspective.The trends in decision making by P&T committees and individual prescribing physicians were already entrenched by the time of the final publication of the cost-effectiveness study. However, the fact that the study met the stringent criteria for publication in a
American Heart Journal Volume 137, Number 5
prestigious journal was probably an important factor in the sustained preference for alteplase that has been described. We believe that many aspects of the GUSTO costeffectiveness study provide a model for future investigations.The study was prospectively designed at the inception of the main clinical trial, which sought to enroll all eligible patients and did not alter routine clinical care beyond administering the fibrinolytic agent and acute antithrombotic therapy.The results of the costeffectiveness study were analyzed and authored by an independent academic group.The data-intensive phase of the study was relatively free of assumptions because it depended on source-documented billing records. Complex modeling was necessary, however, to estimate the effects of the acute benefit on long-term outcome. Because the long-term survival of the patients was not known, models had to be built from an independent population, which yielded financial modeling that required a number of assumptions. Fortunately, acute myocardial infarction is a disease state with substantial previous data, and access to long-term follow-up from the Duke Cardiovascular Databank provided a credible independent source of data.The independence of the study group was critical to the acceptance of the study results. The study of GUSTO-1 demonstrated that the incremental cost-effectiveness of alteplase was within the range of accepted therapies. Unfortunately, for most other therapies considered by P&T committees, such information is rarely available. Given the large initial expense of alteplase, placing the benefit within the cost-effectiveness framework provided a rationale for its use even in financially constrained situations. Active control, comparative clinical outcome trials are rare, and comparative cost-effectiveness studies in which 2 marketed therapies are compared by an independent study group are even less common.Excellent studies have documented the economic attractiveness of treatment with β-blockers,lipid-lowering agents,and angiotensin-converting enzyme inhibitors.However,no direct studies have been done comparing different lipid-lowering agents, β-blockers, or angiotensin-converting enzyme inhibitors. It is hoped that the positive experience of the GUSTO-1 cost-effectiveness study will provide a model for others to use.
References 1. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. ISIS-3: a randomized comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs
Califf et al S93
2.
3.
4.
5.
6.
7.
8.
9.
10. 11.
12.
13.
14.
15.
16.
aspirin alone among 41,299 cases of suspected acute myocardial infarction. Lancet 1993;339:753-70. The International Study Group. In-hospital mortality and clinical course of 20,891 patients with suspected acute myocardial infarction randomized between alteplase and streptokinase with or without heparin. Lancet 1990;336;71-5. The GUSTO Investigators. An international randomized trial comparing four thrombolytic regimens consisting of tissue plasminogen activator, streptokinase, or both for acute myocardial infarction. N Engl J Med 1993;329:673-82. Lincoff AM, Topol EJ. Illusion of reperfusion: does anyone achieve optimal reperfusion during acute myocardial infarction? Circulation 1993;87:1792-805. Califf RM, Topol EJ, Gersh BJ. From myocardial salvage to patient salvage in acute myocardial infarction: the role of reperfusion therapy. J Am Coll Cardiol 1989;14:1382-8. Gruppo Italiano per lo Studio della Streptochinaisi nell’Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397-402. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349-60. AIMS Trial Study Group. Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebocontrolled clinical trial. Lancet 1988;2:545-9. Wilcox RG, von der Lippe G, Olsson CG, Jensen G, Skene AM, Hampton JR, for the ASSET Study Group. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction. Lancet 1988;2:525-30. The TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase 1 findings. N Engl J Med 1985;312:932. Neuhaus KL, Feuerer W, Jeep-Tebbe S, Niederer W, Vogt A, Tebbe U. Improved thrombolysis with a modified dose regimen of recombinant tissue-type plasminogen activator. J Am Coll Cardiol 1989;14: 1566-9. Neuhaus KL, Von Essen R, Tebbe U, et al. Improved thrombolysis in acute myocardial infarction with front-loaded administration of alteplase: result of the rt-PA-APSAC patency study (TAPS). J Am Coll Cardiol 1992;19:885-91. Carney RJ, Murphy GA, Brandt TR, et al. Randomized angiographic trial of recombinant tissue type plasminogen activator (alteplase) in myocardial infarction. J Am Coll Cardiol 1992;2017–23. Wall TC, Califf RM, George BS, et al, for the TAMI-7 Study Group. Accelerated plasminogen activator dose regimens for coronary thrombolysis. J Am Coll Cardiol 1992;19:482-9. 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. Califf RM, White HD, Van der Werf F, et al, for the GUSTO-I Investigators. One-year results from the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO-I) trial. Circulation 1996;94:1233-8.