Journal of the American College of Cardiology © 2006 by the American College of Cardiology Foundation Published by Elsevier Inc.

Vol. 47, No. 3, 2005 ISSN 0735-1097/05/$32.00 doi:10.1016/j.jacc.2005.08.070

The Role of Risk Stratification in the Decision to Provide Upstream Versus Selective Glycoprotein IIb/IIIa Inhibitors for Acute Coronary Syndromes
A Cost-Effectiveness Analysis
Ruchira Glaser, MD,* Henry A. Glick, PHD,† Howard C. Herrmann, MD, FACC,* Stephen E. Kimmel, MD, MSCE, FACC*‡ Philadelphia, Pennsylvania
We endeavored to determine under what conditions a strategy of upstream use of small molecule platelet glycoprotein (GP) IIb/IIIa inhibitors for all acute coronary syndromes (ACS) patients is cost effective compared to that of selective use of abciximab in only those patients requiring percutaneous coronary intervention (PCI). BACKGROUND Small molecule GP IIb/IIIa inhibitors have shown benefit in ACS, but abciximab, the more expensive GP IIb/IIIa inhibitor, may be more effective during PCI. However, abciximab does not have proven efficacy in medical management. No prior study has attempted to balance these competing benefits. METHODS A decision analysis was performed to examine two strategies: 1) treat all ACS patients upstream with a small molecule GP IIb/IIIa inhibitor and continue through medical management and PCI, if performed; or 2) wait, and selectively use abciximab only in patients who ultimately undergo PCI. Applicable randomized controlled trial data were used for the principal analysis. RESULTS The strategy of upstream use of a small molecule GP IIb/IIIa inhibitor was superior to selective use, and economically acceptable, with a cost-effectiveness ratio of $18,000 per year of life gained. The superiority of the upstream use strategy persisted over the majority of sensitivity analyses. When stratified by risk according to Thrombolysis in Myocardial Infarction risk score, a strategy of upstream use was only cost effective in those patients with moderate or high risk. CONCLUSIONS Upstream use of small molecule GP IIb/IIIa inhibition in ACS patients with moderate or high risk for cardiovascular events is a cost-effective approach that should be considered in this subset of patients. (J Am Coll Cardiol 2005;47:529 –37) © 2006 by the American College of Cardiology Foundation OBJECTIVES

Randomized trials of patients with acute coronary syndromes (ACS) have demonstrated a significant reduction in myocardial infarction (MI) and death with the use of the small molecule platelet glycoprotein (GP) IIb/IIIa receptor inhibitors, tirofiban and eptifibatide (1– 4). In contrast, the See page 538 alternative GP IIb/IIIa inhibitor, abciximab, was not beneficial when administered to a predominantly medically managed ACS population (5). However, during percutaneous coronary intervention (PCI) abciximab was superior to the small molecule GP IIb/IIIa inhibitor, tirofiban (6). These findings suggest that small molecule GP IIb/IIIa inhibitors may provide some benefit during medical management of ACS, but may not be as effective during PCI as abciximab, a drug that is more costly and provides no benefit during medical management.
From the *Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; †University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and the ‡Center for Clinical Epidemiology and Biostatistics and Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. Manuscript received December 3, 2004; revised manuscript received July 22, 2005, accepted August 23, 2005.

No randomized controlled trial has addressed the key question that clinicians must answer when a patient with ACS presents for care; namely, whether a strategy of upstream use of a small molecule platelet GP IIb/IIIa inhibitor, with continuation of the drug in those patients undergoing PCI, or a strategy of selective use of abciximab in only those patients undergoing PCI, is the optimal therapeutic option. In addition, validated measures of risk, such as the Thrombolysis In Myocardial Infarction (TIMI) risk score (7), have not been applied to upstream versus selective GP IIb/IIIa inhibition (8 –10). Decision analysis allows clinicians to compare the possible outcomes of different therapeutic strategies, particularly in the face of uncertainty, when no appropriate randomized clinical trial is available (11). The purpose of this study was to use decision analysis and primary data from randomized controlled trials to determine whether one strategy is superior to the other, to calculate the cost-effectiveness of that strategy, and to assess the value of the TIMI risk score in choosing the most cost-effective strategy.

METHODS
Decision tree. We performed a decision analysis (DATA version 4.0, TreeAge Software Inc., Williamstown, Massa-

and the RR for the event with small molecule versus abciximab during PCI. and those who died within 30 days (life expectancy ϭ 0).” represents the strategy in which no GP IIb/IIIa inhibitor is given upon presentation. EFFECTIVENESS. measured as the difference in cost of the two strategies divided by the difference in life expectancy (both discounted at a rate of 3% per year. Major bleeding rates were based on pooled estimates of bleeding rates in randomized controlled ACS trials (13).15. coronary artery bypass graft (CABG). 6-month. Data assumptions. The cost assigned to each 10-mg vial of abciximab was $450. The primary outcome measure was the incremental cost-effectiveness ratio (ICER). the absolute probability was calculated as a function of the absolute probability of the event with PCI using abciximab (calculated as above). or they can die. “selective abciximab. 2005:529–37 Abbreviations and Acronyms ACS ϭ acute coronary syndromes CABG ϭ coronary artery bypass graft GP ϭ glycoprotein ICER ϭ incremental cost-effectiveness ratio MI ϭ myocardial infarction OR ϭ odds ratio PCI ϭ percutaneous coronary intervention QALY ϭ quality-adjusted life years RR ϭ relative risk TACTICS ϭ Treat angina with Aggrastat and determine Cost of Therapy with Invasive or Conservative Strategy chusetts) of patients presenting with unstable angina and non–ST-segment elevation MI ACS (Fig. Life expectancies were modeled for four main outcomes in the decision tree: survivors who did not require PCI or CABG. as opposed to separate risks across potentially different patient populations. For all three of these possible therapies. life expectancy for those who underwent PCI without nonfatal MI was simi- . A total of 24% of these patients underwent PCI (13). survivors who had a subsequent nonfatal MI. or neither PCI nor CABG (Fig. “upstream small molecule. For small molecule PCI-related risks.. Relative risks (RR) and odds ratios (OR) from randomized controlled trials of GP IIb/IIIa inhibitors in ACS patients were used to derive all further probabilities as follows. Outcomes. Costs after six months (for the lifetime cost estimate) were derived from projections for a typical 60-year-old MI patient from the Cholesterol And Recurrent Events (CARE) trial population (17. and abciximab is selectively given only to patients who ultimately undergo PCI. patients can get one of three therapies: PCI. Life expectancy for those with ACS who had a nonfatal MI was derived from modeling from Kaplan-Meier estimates in patients with creatine kinase elevation after PCI. All costs were further adjusted to 2002 dollars. life expectancy values and life years that are described throughout the Results section reflect such discounting).060) assigned to upstream small molecule GP IIb/IIIa inhibitor was based on the mean cost of drug in the Treat angina with Aggrastat and determine Cost of Therapy with Invasive or Conservative Strategy (TACTICS) trial (median duration of therapy ϭ 48 h in the invasive arm) (21). However.” represents the strategy in which a small molecule GP IIb/IIIa inhibitor is given upstream to all patients upon presentation with ACS and continued during PCI in those patients receiving PCI. For PCI with abciximabrelated risks. RRs or ORs were obtained from direct randomized comparison data representative of each particular branch in the tree. COSTS. This assumption enabled the use of one set of baseline risks for the entire tree. Life expectancy for patients with ACS who did not require PCI or CABG was derived from vital statistics data (23). The second option. they can survive without MI (either with or without a major bleed). In each strategy. Where possible.350) (17–20). $1. and of increased length of stay. The secondary end point was difference in major bleeding rate. and lifetime costs. No. 2005 February 7. Point estimates and ranges for the probabilities used in the model are summarized in Table 1. The ORs for death and MI with small molecule GP IIb/IIIa inhibitors in patients who do not undergo PCI were derived from the pooled ORs of death and MI versus placebo for the five major randomized trials comparing small molecule GP IIb/IIIa inhibitors versus placebo in a predominantly medically managed population. These costs include the costs of MI. 47.21).16). The 30-day and 6-month costs of procedures and hospital stay were derived by adjustment of costs reported for the invasive arm of the TACTICS trial and for the Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade (EPILOG) trial (18. they can have a nonfatal MI (either with or without a major bleed). 1). 1). we did not exclude those receiving PCI from the pooled estimate.22). Cost-Effectiveness of Upstream GP IIb/IIIa JACC Vol. It was assumed that the rates of revascularization therapy would not be influenced by whether or not a GP IIb/IIIa inhibitor was used up front (13). 3. It was assumed that probability of MI in placebo patients with medical management would approximate the probability of MI in placebo patients with PCI. Effectiveness was measured in terms of additional life expectancy. The first option. with an assumption of a mean of three vials used per patient (i. The probabilities of PCI and CABG were obtained from the invasive arm of a contemporary trial of invasive versus conservative management of ACS (12). survivors who required PCI or CABG and did not have a subsequent nonfatal MI. Bleeding after CABG was estimated using the published subanalyses of these trials (12. because the exclusion of a subgroup of patients based on their subsequent care could bias our estimates (14). with lifetime cost used to calculate the ICER. the absolute probability was calculated as a function of the probability of the event in medical management patients and the RR with PCI using abciximab.e. bleeding. Estimates were obtained for 30-day.530 Glaser et al. The cost ($1.

CABG ϭ coronary artery bypass grafting.JACC Vol. circles ϭ chance events. intermediate-. 2005 February 7. No. The mean age in the cohorts used to derive life expectancy values was 61 years. Sensitivity analyses were performed for important clinical questions. and high-risk score patients. Cost-Effectiveness of Upstream GP IIb/IIIa 531 Figure 1. 47. triangles ϭ outcomes. Assessment of the role of risk stratification. Sensitivity analyses. for all survivors who had a subsequent nonfatal MI was 13. ACS ϭ acute coronary syndrome. MI ϭ myocardial infarction. and high risk (7). including those derived from the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PUR- SUIT) trial and Duke database (25. Effects of the treatments on the patients’ quality of life were examined separately in a sensitivity analysis (27).592 years. intermediate.535 years. for survivors who required PCI or CABG and did not have a nonfatal MI was 15. These analyses provided the cost-effectiveness of upstream use of GP IIb/IIIa inhibition in low-. Life expectancy estimates matched closely the estimates used in other cost-effectiveness analyses of GP IIb/IIIa inhibitors. larly derived from patients without creatine kinase elevation (24). Stability of the model’s predictions was assessed by varying all parameters in the tree across a .26). Baseline patient risk was assessed by published risk for death and MI according to TIMI risk score at six weeks (9) and categorized as low. Life expectancy for survivors who did not require PCI or CABG was 17.524 years. 2005:529–37 Glaser et al. Squares ϭ decision. and 76% of patients were men. Decision tree comparing upstream early use of tirofiban or eptifibatide in all patients versus selective use of abciximab in patients undergoing percutaneous coronary intervention (PCI). 3.

2005 February 7. small molecule. PRISM (placebo group) (1. MI PCI with abciximab. bleed PCI with abciximab. PCI MI abciximab) RR 1. PURSUIT (time until PCI or surgery) (1–3.2–0.5. EPIC ϭ Evaluation of c7E3 for Prevention of Ischemic Complications trial. TARGET ϭ Do Tirofiban and Reo-Pro Give Similar Efficacy Outcome Trial. RR ϭ relative risk. MI CABG. death PCI with abciximab.65–3. PRISM PLUS first 48 h (medical therapy). (meta-analysis of pre-PCI events).48 RR 0. TACTICS ϭ Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy. MI 0.0 (vs.051 GUSTO IV ACS (placebo arm) (5) Boersma et al.49–2. PRISM PLUS.95 Boersma et al.15 0. RITA 3 ϭ Randomized Intervention Trial of unstable Angina.3–2. (placebo arm) (13) CAPTURE (4) CAPTURE (4) CAPTURE (4) Selective use abciximab during PCI only No PCI.0 (vs.4 References Base Case TACTICS. FRISC II ϭ Fragmin and Fast Revascularization during Instability in Coronary Artery disease trial.039–0. PRISM no PCI cohort. RITA 3.01 PURSUIT (1) Empiric Boersma et al. death RR 0.58 RR 1.2) CAPTURE (4) CAPTURE (4) CAPTURE (4) RR 1. PRISM (1. MI CABG.135 0.27–2. GUSTO IV (1–3. .8–2.42) TACTICS. (placebo arm) (13) Boersma et al.35 PRISM. (placebo arm) (13) 0. small molecule.045 RR 2. no drug. (placebo arm) (13) PURSUIT (placebo group) (1) Boersma et al. (meta-analysis of pre-PCI events). 47. 3.0 (vs. small molecule. PRISM PLUS first 48 h (medical therapy). bleed PCI. PURSUIT (1.95 Boersma et molecule Boersma et molecule al. (small analysis) (13) No PCI. GP ϭ glycoprotein.8 CABG 0. FRISC II.5 RR 0–2.7 RR 0–2.78 0.42) PURSUIT.09 PURSUIT.01 0.93 0.8 RR 0.037 RR 0. CAPTURE ϭ C7E3 Anti Platelet Therapy in Unstable REfractory angina trial. PRISM (placebo group) (1. MI ϭ myocardial infarction. PCI bleed abciximab) RR 1. small molecule. PRISM (1. CI ϭ confidence interval. no drug.28 0. small molecule.5 Empiric PURSUIT.42) Boersma et al. MI PCI. (small analysis) (13) al. CABG ϭ coronary artery bypass grafting.40.5.081 0.21 0.09 0.03 0. PRISM PLUS ϭ Platelet Receptor Inhibition in ischemic Syndrome Management in Patients Limited by Unstable Signs and symptoms trial.41) FRISC II (40) Factor PCI Range 0. CABG no GP IIb/IIIa inhibitor death) RR 1.11–0. death CABG. PURSUIT. PCI ϭ percutaneous coronary intervention. bleed No PCI. death Upstream use small molecule GP IIb/IIIa inhibitor in all ACS patients No PCI. bleed CABG. PRISM no PCI cohort. (small molecule analysis) (13) CABG. bleed CABG. GUSTO IV ϭ Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries IV trial.75 0.12.88 RR 0.03–4.41–0. death PCI.058 1. TACTICS. PCI death abciximab) 0.4 RR 0.30–0. CABG no GPIIb/IIIa inhibitor MI) RR 1. invasive arm (12) Additional References for Range or 95% CI Source GUSTO IV.029–0. PURSUIT (time until PCI or surgery) (1–3. (placebo arm) (13) Boersma et al.47–0. (placebo arm) (13) Boersma et al.07 RR 0. Probability of Outcomes Used in the Decision Model Base Case Probability or Relative Risk 0.532 Glaser et al.2–0.2) RR 0.5 (vs. death 0. bleed No PCI. Cost-Effectiveness of Upstream GP IIb/IIIa JACC Vol. MI No PCI.06–0.41) Boersma et al. PURSUIT ϭ Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Supression Using Integrellin Therapy trial. RITA 3.01–0. No. 2005:529–37 Table 1. PRISM PLUS.2) PURSUIT. (placebo arm) (13) Boersma et al.045–0.3.88 RR 1. small molecule.2) RR 0.5 TARGET (6) TARGET ACS cohort (44) TARGET ACS cohort (44) TARGET (6) TARGET ACS cohort (44) TARGET ACS cohort (44) ACS ϭ acute coronary syndromes.0 (vs.05 RR 0. EPIC (12. no drug. (small molecule analysis) (13) Boersma et al.

and Incremental Cost-Effectiveness Ratio for Upstream Use Strategy Compared With Selective Use Strategy Selective Use Abciximab During PCI Only 30-day cost per patient 6-month cost per patient Lifetime cost per patient* Incremental lifetime cost per patient Incremental lifetime cost per 100. 2005 February 7.000.76 with selective use of abciximab. ACS ϭ acute coronary syndromes.564. The average life expectancy was 15.463 $81.6% and 3.124 — — 1. the upstream use strategy became less cost effective if the probability of CABG was also extremely high. In contrast. The probability of major bleeding was 10.210 $24.568.631 $23. Patients with low TIMI risk scores (0 to 2) had a gain of only 1. $1. Effectiveness.68 years with the upstream strategy.000 4.64 years for selective abciximab. PCI ϭ percutaneous coronary intervention.000 years of life per 100.000 per year of life gained (Table 2).000 patients* Years of life per 100.000 patients Incremental cost per year of life gained $17.2% with upstream use and 9.0%. quality-adjusted life years (QALY).730 and $14. and cost-effectiveness.000 years of life per 100. 47.000 1. Cost effectiveness of upstream glycoprotein IIb/IIIa use according to Thrombolysis In Myocardial Infarction (TIMI) risk score of patient. with upstream and selective abciximab use. in moderate and high TIMI risk score patients. Quality adjustment to years of life gained yielded an average life expectancy of 14.7% in the selective abciximab strategy. Fig. However. Thus.092 $81. . compared with 15.300 per year of life gained (Fig.9% in the upstream strategy and 12.444 per year of life gained. if the probability of CABG was 30% and the probability of Figure 2.80 QALYs with upstream use versus 14. respectively.276 per year of life gained) for the upstream GP IIb/IIIa strategy if the probability of PCI was increased to 80%. Increasing patient baseline risk for adverse events amplified the benefits of the upstream use strategy. with an ICER of $58. Despite the higher drug cost of abciximab ($1. respectively.844 $720 $72. 2). the use of upstream small molecule GP IIb/IIIa inhibitors resulted in an ICER of $18.1% in the selective abciximab strategy.000 per QALY gained. For instance.000 *Used for calculation of incremental cost-effectiveness ratio. in large part. No.000 patients treated with the strategy of upstream small molecule GP IIb/IIIa inhibition. an upstream strategy of small molecule GP IIb/IIIa inhibition for all ACS patients was more costly than selective abciximab use. The role of risk stratification.000 patients treated with upstream use.060 for small molecule). of the higher proportion of patients receiving a GP IIb/IIIa inhibitor in the upstream strategy. This yielded a cost-effectiveness ratio of $18. with an incremental lifetime cost of $720 per patient (Table 2) because.000 patients Incremental years of life gained per 100. Cost-Effectiveness of Upstream GP IIb/IIIa 533 — $18. patients with moderate or higher TIMI risk scores (3 to 4 and 5 to 7) had more years of life saved with an upstream GP IIb/IIIa inhibitor strategy. life expectancy. Costs. 3. GP ϭ glycoprotein. This yielded a gain of 4. range defined either by clinical plausibility or by the variables’ 95% confidence intervals observed in the randomized trials. resulting in economically favorable cost-effectiveness ratios ($24. 2005:529–37 Table 2. The probability of death or MI at 30 days was 11.000 Glaser et al. Further sensitivity analyses of high-risk patients revealed an extremely favorable cost-effectiveness ratio ($1.000 — Upstream Use Small Molecule GPIIb/IIIa Inhibitor in All ACS Patients $18.350 per patient for abciximab vs. 2).JACC Vol. The rates of non-CABG-related major bleeding were 3. Costs. RESULTS Probabilities.

2 LE ϭ 1.000 — *Represents years of life per 100.000 1. 47.000 1.000 7.000 5.000 4.000 1.000 1.000 patients treated with upstream versus selective use.000 1.000 18.000 16.574.000 Years of Life Gained With Upstream Use* 4.000 1.000 1.564. Cost-Effectiveness of Upstream GP IIb/IIIa JACC Vol.000 1.000 4.000 4.000 1. MI RR 0.552.06 0. If the probability of ACS patients undergoing PCI was 65% or greater.135 No PCI. upstream use of small molecule GP IIb/IIIa inhibitors was .000 1.09 No PCI.000 7.000 2. ACS ϭ acute coronary syndromes.0 PCI.000 Cost Effectiveness of Upstream Use (Dollars per Year Life Gained) 18.000 1.577.000 1.000 1.565.000 4.000 1.8 0.575.000 2.565.000 18.000 Years of Life With Selective Abciximab Use* 1.000 36.564.48 0.000 1.572. upstream GP IIb/IIIa use had a borderline favorable cost-effectiveness ratio of $55.000 1.88 0.000 1.000 years of life saved per 100.000 24.564.577.000 patients treated). 3.565.000 1.000 1. MI ϭ myocardial infarction. selective use of abciximab was more effective than upstream use of small molecule GP IIb/IIIa inhibitors (Fig.200 36. The use of the same.000 14. CABG ϭ coronary artery bypass grafting.564. †Represents relative risk versus PCI with abciximab.000) 1. the ICER was $16.000 patients.556.5 PCI.400 36.568.11 0.957.41 1. 2005:529–37 Table 3.565.000 1.045 0.000 5.700 24.570.000 1. Thus.000 1. MI with upstream small molecule in all ACS patients RR 0.800 1.961.000 5.000 10.5 1.565. death RR 0.000 1.039 0.0 No PCI.000 Subject of Sensitivity Analysis Principal simulation PCI rate CABG rate 0. Incremental Cost-Effectiveness Ratios in Sensitivity Analyses Principal Analysis Estimate 0.582. If the probability of PCI was greater than 60%.564.000 1.000 1.577.15 4.081 0.000 1.569.400 72.000 1. 3).000 18.029 0. death with upstream small molecule in all ACS patients† RR 1.000 Ϫ3.562.058 PCI with abciximab.539.563.564.88 0.000 1.575.045 0.0 1. The assumption that small molecule GP IIb/IIIa inhibitors and abciximab have equal efficacy during PCI resulted in further effectiveness of an upstream use strategy (5. small molecule GP IIb/IIIa inhibitor selectively or upstream resulted in 5.000 18.536.000 1.000 1.000 1.571.000 1.000 1. PCI ϭ percutaneous coronary intervention.544.000 4.596.000 1.498.568.534 Glaser et al. death 0. death 0.75 0.564.0 2.35 No PCI.551.000 24.000 1.5 Life expectancy discount rate 3% 1% 5% 1.000 1.000 4.000 3.000 2.566.579.47 1.286.000 1.568.000 3.40 Estimates Used for Sensitivity Analyses (threshold 0.960 per year of life gained.564. death with upstream small molecule in all ACS patients RR 0.000 1.289.400 1.501.000 1.300 3.000 Ϫ20.037 0.000 1.000 1. MI with upstream small molecule in all ACS patients† RR 1.000 72.522.000 36. LE ϭ life expectancy.000 1. there was also a higher incremental lifetime cost of $848 for upstream use.000 Years of Life With Upstream Small Molecule Use* 1.000 14.000 24.566.000 1.000 4.000 (threshold RR 1.500 1.565.000 14. MI 0.000 18.000 4. 2005 February 7.573.564.000 5.0 2.21 0.561. RR ϭ relative risk. MI 0.30 0.800 — 18.2 0.000 1.000 1.000 1.000 18.000 3. No.520.000 years of life gained per 100.27 2.603. PCI was 50%.546.000 2.051 CABG.574. Additional sensitivity analyses.000 1.000 1.28 CABG.000 1.000 18.564.78 PCI with abciximab.569. The superior effectiveness of upstream use of GP IIb/IIIa inhibition persisted in most cases when applying a wide range of plausible probabilities in reduction of death and MI for both strategies during sensitivity analyses (Table 3).63) 0.

but no such trial has been completed yet (28). we found that upstream use of small molecule GP IIb/IIIa inhibitors in ACS patients is superior to selective use of abciximab.200. and a cost-effectiveness ratio of $21. and thus no longer cost effective. DISCUSSION The use of upstream GP IIb/IIIa inhibition versus selective use in only those patients undergoing PCI is a key question that clinicians face when caring for the ACS patient. In the absence of a specific randomized trial. a decision analysis may provide formal insight into what conditions may make one strategy potentially more beneficial than another.0% in selective use of abciximab at the lower limit of the 95% confidence interval of CABG-related bleeding. 2005 February 7.29 –31). an upstream strategy was still superior (Table 2). Cost-Effectiveness of Upstream GP IIb/IIIa 535 Figure 3. When the effect of GP IIb/IIIa inhibitors in medically managed patients was varied from an OR of 0.JACC Vol. In sensitivity analyses of bleeding.97 for the two strategies to break even. It has been argued that a randomized clinical trial examining this question is needed. There has been considerable controversy about the extent of reduction in death or MI with GP IIb/IIIa inhibitors during medical management. the benefits of upstream GP IIb/IIIa inhibition were marginal.0 (to examine ORs from other published subanalyses). Bleeding rates were 14. These findings support the American College of Cardiology and American Heart Association recommendation to manage ACS patients with upstream GP IIb/IIIa inhibition based on level of risk (32). The ICER of $18.000 or greater). Both the post-randomization categorization of patients into “medically managed” versus “PCI” subgroups.000 per year of life gained per patient with upstream use is economically attractive compared with other widely accepted cardiovascular treatments (21. patients with moderate or high risk showed benefit and favorable cost effectiveness with upstream GP IIb/IIIa inhibition. Through an analysis that utilized randomized trial data. 2005:529–37 Glaser et al. This also held true when ORs were simultaneously varied for death and MI in two-way sensitivity analyses. Importantly. Benefits of upstream versus selective glycoprotein (GP) IIb/IIIa use by rates of percutaneous coronary intervention (PCI). Sensitivity analyses in which the costs of abciximab and small molecule GP IIb/IIIa inhibitors were equal yielded a higher incremental cost of upstream use of $848. though. In contrast. rates were 5.0% in upstream use versus 4. CE ϭ cost effectiveness. No. 3. 47.47 to 1.0% with selective use of abciximab when CABG-related bleeding was at the upper limit of the 95% confidence interval. The OR death or MI with small molecule versus placebo would need to be 0.0% with a strategy of upstream use versus 13. not cost effective (ICER of $100. when using TIMI risk score as a measure of a patient’s baseline risk for adverse outcome. and the use of meta-analysis have been . in those patients with the lowest risk.

338:1488 –97. Lancet 2001. First.upenn. unlike in the present model. Second. but that small molecules have greater efficacy than abciximab during medical management. 9 Founders Cardiology-HUP. despite using randomized trial data. However. Sabatine MS. Giugliano RP. However. our study was not designed to examine the potential benefits of novel antiplatelet therapies including clopidigrel. RRs from the Chimeric 7E3 Antiplatelet Therapy in Unstable Angina REfractory to Standard Treatment (CAPTURE) trial were used to estimate the effect of abciximab during PCI. cost-effective strategy that should be considered for those moderate and high-risk patients presenting with ACS. the effect of clopidigrel in reducing potential efficacy of GP IIb/IIIa inhibitors is not known and therefore could not be studied in our analysis. it has been suggested that at proper doses of tirofiban. Third. Bernink PJ. The TIMI risk score for unstable angina/non ST elevation MI: a method for prognostication and therapeutic decision making.39). if clopidigrel reduces further the overall risk for death and MI in the ACS patient by 30%. Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study.40 – 44). Reprint requests and correspondence: Dr. 5. if one assumes an equivalent effect of small molecules and abciximab during PCI. We found that a strategy of upstream use of eptifibatide was superior to selective eptifibatide.edu. Implications of upstream glycoprotein IIb/IIIa inhibition and coronary artery stenting in the invasive management of unstable angina/non ST elevation myocardial infarction: a comparison of the Thrombolysis in Myo- . Indirect and long-term costs may not be fully incorporated. However. For instance.33–35). For one. there are also limitations to our analysis. For instance. this strategy was superior. those patients at high risk for adverse outcomes may have been excluded. Cost-Effectiveness of Upstream GP IIb/IIIa JACC Vol.12. but should not change the incremental cost of upstream use. The PURSUIT Investigators. This analysis quantifies under what conditions a strategy of upstream small molecule use is superior to selective use of abciximab. which would increase overall costs of both strategies.284:835– 42. Sensitivity analyses may provide a rough estimate of the effects of clopidigrel. even if PCI rates are very high. we could estimate that as long as upstream therapy reduced risk of death or MI by more than 3%. N Engl J Med 2001. abciximab was administered for a period before PCI. et al. PRISM Study Investigators. 4. 2005 February 7. Simoons ML and GUSTO IV Investigators. for the prevention of ischemic events with percutaneous coronary revascularization. A systematic approach to the appropriate selection of therapy becomes increasingly important when multiple therapeutic options. Further. Finally. The major strength of the decision model in this study is that each comparison was based directly on randomized controlled trial data (1– 6. Our analysis suggests superiority of an upstream use strategy if one assumes all GP IIb/IIIa inhibitors have equal efficacy during PCI. we did not directly take into account the timing of PCI. Philadelphia. N Engl J Med 1998. but no randomized trial has simultaneously compared GP IIb/IIIa inhibition versus placebo and early PCI versus late PCI. Ruchira Glaser. N Engl J Med 1998. or with the use of eptifibatide. and still had a favorable ICER. It further suggests that the upstream use of small molecule GP IIb/IIIa inhibitors is a superior. patients who are highly (65% or greater) likely to undergo PCI may benefit from a selective abciximab strategy. Lancet 1997. CAPTURE Investigators. Pennsylvania 19104.357:1915–24. 2005:529–37 criticized (14. Second. we may not be able to fully account for variable patient presentation.13. each with individually proven benefits and incremental costs.344:1888 –94.349:1429 –35. JAMA 2000. the small molecule class of GP IIb/IIIa inhibitors may be equally effective as abciximab during PCI (36 –38). Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non–Qwave myocardial infarction. Cohen M. Fourth. in that trial. 2. 3400 Spruce Street. and this is a potentially significant limitation to all cost-effectiveness analyses performed using randomized trials. University of Pennsylvania School of Medicine.glaser@uphs. Medicine-Cardiology. Our analysis enabled us to examine additional important questions that have not been formally tested as of yet in clinical trials. 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