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The Role of Risk Stratification in the Decisionto Provide Upstream Versus Selective GlycoproteinIIb/IIIa Inhibitors for Acute Coronary Syndromes

A Cost-Effectiveness AnalysisRuchira Glaser, MD,* Henry A. Glick, PHD, Howard C. Herrmann, MD, FACC,*Stephen E. Kimmel, MD, MSCE, FACC*

Philadelphia, Pennsylvania

OBJECTIVES We endeavored to determine under what conditions a strategy of upstream use of smallmolecule 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 thosepatients requiring percutaneous coronary intervention (PCI).

BACKGROUND Small molecule GP IIb/IIIa inhibitors have shown benefit in ACS, but abciximab, the moreexpensive GP IIb/IIIa inhibitor, may be more effective during PCI. However, abciximab doesnot have proven efficacy in medical management. No prior study has attempted to balancethese competing benefits.

METHODS A decision analysis was performed to examine two strategies: 1) treat all ACS patients upstreamwith 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 undergoPCI. 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 toselective use, and economically acceptable, with a cost-effectiveness ratio of $18,000 per yearof life gained. The superiority of the upstream use strategy persisted over the majority ofsensitivity analyses. When stratified by risk according to Thrombolysis in MyocardialInfarction risk score, a strategy of upstream use was only cost effective in those patients withmoderate or high risk.

CONCLUSIONS Upstream use of small molecule GP IIb/IIIa inhibition in ACS patients with moderate orhigh risk for cardiovascular events is a cost-effective approach that should be considered inthis subset of patients. (J Am Coll Cardiol 2005;47:529 37) 2006 by the AmericanCollege of Cardiology Foundation

Randomized trials of patients with acute coronary syn-dromes (ACS) have demonstrated a significant reduction inmyocardial infarction (MI) and death with the use of thesmall molecule platelet glycoprotein (GP) IIb/IIIa receptorinhibitors, tirofiban and eptifibatide (1 4). In contrast, the

See page 538

alternative GP IIb/IIIa inhibitor, abciximab, was not ben-eficial when administered to a predominantly medicallymanaged ACS population (5). However, during percutane-ous coronary intervention (PCI) abciximab was superior tothe small molecule GP IIb/IIIa inhibitor, tirofiban (6).These findings suggest that small molecule GP IIb/IIIainhibitors may provide some benefit during medical man-agement of ACS, but may not be as effective during PCI asabciximab, a drug that is more costly and provides no benefitduring medical management.

No randomized controlled trial has addressed the keyquestion that clinicians must answer when a patient withACS presents for care; namely, whether a strategy ofupstream use of a small molecule platelet GP IIb/IIIainhibitor, with continuation of the drug in those patientsundergoing PCI, or a strategy of selective use of abciximabin only those patients undergoing PCI, is the optimaltherapeutic option. In addition, validated measures of risk,such as the Thrombolysis In Myocardial Infarction (TIMI)risk score (7), have not been applied to upstream versusselective GP IIb/IIIa inhibition (810).

Decision analysis allows clinicians to compare the possi-ble outcomes of different therapeutic strategies, particularlyin the face of uncertainty, when no appropriate randomizedclinical trial is available (11). The purpose of this study wasto use decision analysis and primary data from randomizedcontrolled trials to determine whether one strategy is supe-rior to the other, to calculate the cost-effectiveness of thatstrategy, and to assess the value of the TIMI risk score inchoosing the most cost-effective strategy.

METHODS

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

From the *Division of Cardiovascular Medicine, Department of Medicine, Uni-versity of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; Universityof Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and the Center forClinical Epidemiology and Biostatistics and Department of Biostatistics and Epide-

miology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.Manuscript received December 3, 2004; revised manuscript received July 22, 2005,accepted August 23, 2005.

Journal of the American College of Cardiology Vol. 47, No. 3, 2005 2006 by the American College of Cardiology Foundation ISSN 0735-1097/05/$32.00Published by Elsevier Inc. doi:10.1016/j.jacc.2005.08.070

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chusetts) of patients presenting with unstable angina andnonST-segment elevation MI ACS (Fig. 1). The firstoption, upstream small molecule, represents the strategyin which a small molecule GP IIb/IIIa inhibitor is given

upstream to all patients upon presentation with ACS andcontinued during PCI in those patients receiving PCI. Thesecond option, selective abciximab, represents the strategyin which no GP IIb/IIIa inhibitor is given upon presenta-tion, and abciximab is selectively given only to patients whoultimately undergo PCI.

In each strategy, patients can get one of three therapies:PCI, coronary artery bypass graft (CABG), or neither PCInor CABG (Fig. 1). For all three of these possible therapies,they can survive without MI (either with or without a majorbleed), they can have a nonfatal MI (either with or withouta major bleed), or they can die.

Data assumptions. Point estimates and ranges for the prob-abilities used in the model are summarized in Table 1.Theprobabilities of PCI and CABG were obtained from theinvasive arm of a contemporary trial of invasive versus conser-vative management of ACS (12). It was assumed that the ratesof revascularization therapy would not be influenced bywhether or not a GP IIb/IIIa inhibitor was used up front (13).

Relative risks (RR) and odds ratios (OR) from random-ized controlled trials of GP IIb/IIIa inhibitors in ACSpatients were used to derive all further probabilities asfollows. Where possible, RRs or ORs were obtained fromdirect randomized comparison data representative of each

particular branch in the tree. For PCI with abciximab-related risks, the absolute probability was calculated as afunction of the probability of the event in medical manage-ment patients and the RR with PCI using abciximab. It wasassumed that probability of MI in placebo patients withmedical management would approximate the probability ofMI in placebo patients with PCI. This assumption enabledthe use of one set of baseline risks for the entire tree, asopposed to separate risks across potentially different patientpopulations. For small molecule PCI-related risks, theabsolute probability was calculated as a function of theabsolute probability of the event with PCI using abciximab

(calculated as above), and the RR for the event with smallmolecule versus abciximab during PCI. The ORs for death

and MI with small molecule GP IIb/IIIa inhibitors inpatients who do not undergo PCI were derived from thepooled ORs of death and MI versus placebo for the fivemajor randomized trials comparing small molecule GPIIb/IIIa inhibitors versus placebo in a predominantly med-ically managed population. A total of 24% of these patients

underwent PCI (13). However, because the exclusion of asubgroup of patients based on their subsequent care couldbias our estimates (14), we did not exclude those receivingPCI from the pooled estimate.

Major bleeding rates were based on pooled estimates ofbleeding rates in randomized controlled ACS trials (13).Bleeding after CABG was estimated using the publishedsubanalyses of these trials (12,15,16).Outcomes. The primary outcome measure was the incre-mental cost-effectiveness ratio (ICER), measured as the differ-ence in cost of the two strategies divided by the difference inlife expectancy (both discounted at a rate of 3% per year; life

expectancy values and life years that are described throughoutthe Results section reflect such discounting). The secondaryend point was difference in major bleeding rate.

COSTS. Estimates were obtained for 30-day, 6-month, andlifetime costs, with lifetime cost used to calculate the ICER.The cost assigned to each 10-mg vial of abciximab was$450, with an assumption of a mean of three vials used perpatient (i.e., $1,350) (1720). The cost ($1,060) assigned toupstream small molecule GP IIb/IIIa inhibitor was based onthe mean cost of drug in the Treat angina with Aggrastatand determine Cost of Therapy with Invasive or Conservative

Strategy (TACTICS) trial (median duration of therapy

48 hin the invasive arm) (21).The 30-day and 6-month costs of procedures and hospi-

tal stay were derived by adjustment of costs reported for theinvasive arm of the TACTICS trial and for the Evaluationin PTCA to Improve Long-term Outcome with abciximabGP IIb/IIIa blockade (EPILOG) trial (18,21). These costsinclude the costs of MI, bleeding, and of increased length ofstay. All costs were further adjusted to 2002 dollars. Costsafter six months (for the lifetime cost estimate) were derivedfrom projections for a typical 60-year-old MI patient fromthe Cholesterol And Recurrent Events (CARE) trial pop-

ulation (17,22).EFFECTIVENESS. Effectiveness was measured in terms ofadditional life expectancy. Life expectancies were modeledfor four main outcomes in the decision tree: survivors whodid not require PCI or CABG; survivors who required PCIor CABG and did not have a subsequent nonfatal MI;survivors who had a subsequent nonfatal MI; and those whodied within 30 days (life expectancy 0). Life expectancyfor patients with ACS who did not require PCI or CABGwas derived from vital statistics data (23). Life expectancyfor those with ACS who had a nonfatal MI was derivedfrom modeling from Kaplan-Meier estimates in patients

with creatine kinase elevation after PCI; life expectancy forthose who underwent PCI without nonfatal MI was simi-

Abbreviations and Acronyms

ACS acute coronary syndromesCABG coronary artery bypass graftGP glycoproteinICER incremental cost-effectiveness ratioMI myocardial infarctionOR odds ratioPCI percutaneous coronary interventionQALY quality-adjusted life yearsRR relative risk

TACTICS Treat angina with Aggrastat and determineCost of Therapy with Invasive orConservative Strategy

530 Glaser et al. JACC Vol. 47, No. 3, 2005

Cost-Effectiveness of Upstream GP IIb/IIIa February 7, 2005:52937

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larly derived from patients without creatine kinase elevation(24). The mean age in the cohorts used to derive lifeexpectancy values was 61 years, and 76% of patients weremen. Life expectancy for survivors who did not require PCIor CABG was 17.592 years; for survivors who required PCIor CABG and did not have a nonfatal MI was 15.535 years;for all survivors who had a subsequent nonfatal MI was13.524 years. Life expectancy estimates matched closelythe estimates used in other cost-effectiveness analyses ofGP IIb/IIIa inhibitors, including those derived from the

Platelet Glycoprotein IIb/IIIa in Unstable Angina: Re-ceptor Suppression Using Integrilin Therapy (PUR-

SUIT) trial and Duke database (25,26). Effects of thetreatments on the patients quality of life were examinedseparately in a sensitivity analysis (27).Assessment of the role of risk stratification. Baselinepatient risk was assessed by published risk for death and MIaccording to TIMI risk score at six weeks (9)and categorizedas low, intermediate, and high risk (7). These analyses providedthe cost-effectiveness of upstream use of GP IIb/IIIa inhibitionin low-, intermediate-, and high-risk score patients.Sensitivity analyses. Sensitivity analyses were performed for

important clinical questions. Stability of the models predic-tions was assessed by varying all parameters in the tree across a

Figure 1. Decision tree comparing upstream early use of tirofiban or eptifibatide in all patients versus selective use of abciximab in patients undergoingpercutaneous coronary intervention (PCI). Squares decision;circles chance events;triangles outcomes. ACS acute coronary syndrome; CABG

coronary artery bypass grafting; MI myocardial infarction.

531JACC Vol. 47, No. 3, 2005 Glaser et al.

February 7, 2005:52937 Cost-Effectiveness of Upstream GP IIb/IIIa

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Table 1. Probability of Outcomes Used in the Decision Model

Factor

Base CaseProbability orRelative Risk Range

ReferencesBase Case

Additional Referencesfor Range or

95% CI Source

PCI 0.4 0.20.8 TACTICS, invasive arm (12) GUSTO IV, FRISC II, RITA3, PRISM PLUS,

PURSUIT (1,3,5,40,41)CABG 0.15 0.110.35 PRISM, PRISM PLUS,

PURSUIT, TACTICS,RITA 3, GUSTOIV (13,5,12,41)

FRISC II(40)

Selective use abciximab during PCI onlyNo PCI, no drug, bleed 0.01 0.010.03 Boersma et al.

(placebo arm) (13)GUSTO IV ACS (placebo arm)

(5)No PCI, no drug, MI 0.081 0.0390.135 Boersma et al.

(placebo arm) (13)Boersma et al. (placebo arm)

(13)No PCI, no drug, death 0.037 0.0290.051 Boersma et al.

(placebo arm) (13)Boersma et al. (placebo arm)

(13)CABG, bleed RR 0.93 PURSUIT

(placebo group)(1)

CABG, MI 0.21 0.060.28 Boersma et al.(placebo arm) (13) PURSUIT, PRISM (placebogroup) (1,2)CABG, death 0.045 0.0450.058 Boersma et al.

(placebo arm) (13)PURSUIT, PRISM (placebo

group) (1,2)PCI with abciximab, bleed RR 2.05 1.034.09 CAPTURE (4) CAPTURE (4)PCI with abciximab, MI RR 0.48 0.300.78 CAPTURE (4) CAPTURE (4)PCI with abciximab, death RR 0.75 0.272.09 CAPTURE (4) CAPTURE (4)

Upstream use small molecule GP IIb/IIIainhibitor in all ACS patients

No PCI, small molecule, bleed RR 1.4 RR 1.32.07 Boersma et al. (smallmolecule analysis)(13)

Boersma et al. (small moleculeanalysis) (13)

No PCI, small molecule, MI RR 0.88 RR 0.470.95 Boersma et al. (smallmolecule analysis)(13)

Boersma et al. (meta-analysis ofpre-PCI events), PRISM noPCI cohort, PRISM PLUSfirst 48 h (medical therapy),

PURSUIT (time until PCI orsurgery) (13,42)

No PCI, small molecule, death RR 0.88 RR 0.410.95 Boersma et al. (smallmolecule analysis)(13)

Boersma et al. (meta-analysis ofpre-PCI events), PRISM noPCI cohort, PRISM PLUSfirst 48 h (medical therapy),PURSUIT (time until PCI orsurgery) (13,42)

CABG, bleed 0.58 0.20.8 PURSUIT(1) TACTICS, EPIC (12,42)CABG, MI RR 1.0 (vs. CABG

no GPIIb/IIIainhibitor MI)

RR 0.653.01 Empiric PURSUIT, PRISM (1,2)

CABG, death RR 1.0 (vs. CABGno GP IIb/IIIa

inhibitor death)

RR 0.492.5 Empiric PURSUIT, PRISM (1,2)

PCI, small molecule, bleed RR 1.0 (vs. PCIbleed abciximab)

RR 0.82.7 TARGET (6) TARGET (6)

PCI, small molecule, MI RR 1.5 (vs. PCIMI abciximab)

RR 02.5 TARGET ACS cohort(44) TARGET ACS cohort(44)

PCI, small molecule, death RR 1.0 (vs. PCIdeath abciximab)

RR 02.5 TARGET ACS cohort(44) TARGET ACS cohort(44)

ACS acute coronary syndromes; CABG coronary artery bypass grafting; CAPTURE C7E3 Anti Platelet Therapy in Unstable REfractory angina trial; CI confidenceinterval; EPIC Evaluation of c7E3 for Prevention of Ischemic Complications trial; FRISC II Fragmin and Fast Revascularization during Instability in Coronary Arterydisease trial; GP glycoprotein; GUSTO IV Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries IV trial; MI myocardialinfarction; PCI percutaneous coronary intervention; PRISM PLUS Platelet Receptor Inhibition in ischemic Syndrome Management in Patients Limited by Unstable Signsand symptoms trial; PURSUIT Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Supression Using Integrellin Therapy trial; RITA 3 Randomized InterventionTrial of unstable Angina; RR relative risk; TACTICS Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy; TARGET Do Tirofiban and Reo-Pro Give Similar Efficacy Outcome Trial.



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range defined either by clinical plausibility or by the variables95% confidence intervals observed in the randomized trials.

RESULTS

Probabilities. The probability of death or MI at 30 dayswas 11.9% in the upstream strategy and 12.1% in theselective abciximab strategy. The probability of major bleed-ing was 10.2% with upstream use and 9.7% in the selectiveabciximab strategy. The rates of non-CABG-related majorbleeding were 3.6% and 3.0%, with upstream and selectiveabciximab use, respectively.Costs, life expectancy, quality-adjusted life years (QALY),and cost-effectiveness. Despite the higher drug cost ofabciximab ($1,350 per patient for abciximab vs. $1,060 for

small molecule), an upstream strategy of small molecule GPIIb/IIIa inhibition for all ACS patients was more costlythan selective abciximab use, with an incremental lifetimecost of $720 per patient (Table 2)because, in large part, ofthe higher proportion of patients receiving a GP IIb/IIIainhibitor in the upstream strategy.

The average life expectancy was 15.68 years with theupstream strategy, compared with 15.64 years for selectiveabciximab. This yielded a gain of 4,000 years of life per100,000 patients treated with the strategy of upstream smallmolecule GP IIb/IIIa inhibition.

Thus, the use of upstream small molecule GP IIb/IIIainhibitors resulted in an ICER of $18,000 per year of lifegained (Table 2). Quality adjustment to years of life gainedyielded an average life expectancy of 14.80 QALYs withupstream use versus 14.76 with selective use of abciximab.This yielded a cost-effectiveness ratio of $18,000 per QALYgained.

The role of risk stratification. Increasing patient baselinerisk for adverse events amplified the benefits of the upstreamuse strategy. Patients with low TIMI risk scores (0 to 2) hada gain of only 1,000 years of life per 100,000 patients treatedwith upstream use, with an ICER of $58,300 per year of lifegained (Fig. 2). In contrast, patients with moderate or higherTIMI risk scores (3 to 4 and 5 to 7) had more years of lifesaved with an upstream GP IIb/IIIa inhibitor strategy,resulting in economically favorable cost-effectiveness ratios($24,730 and $14,444 per year of life gained, in moderateand high TIMI risk score patients, respectively,Fig. 2).

Further sensitivity analyses of high-risk patients revealedan extremely favorable cost-effectiveness ratio ($1,276 peryear of life gained) for the upstream GP IIb/IIIa strategy ifthe probability of PCI was increased to 80%. However, theupstream use strategy became less cost effective if theprobability of CABG was also extremely high. For instance,if the probability of CABG was 30% and the probability of

Figure 2. Cost effectiveness of upstream glycoprotein IIb/IIIa use according to Thrombolysis In Myocardial Infarction (TIMI) risk score of patient.

Table 2. Costs, Effectiveness, and IncrementalCost-Effectiveness Ratio for Upstream Use StrategyCompared With Selective Use Strategy

Selective UseAbciximabDuring PCI

Only

Upstream Use SmallMolecule GPIIb/IIIa

Inhibitor in AllACS Patients

30-day cost per patient $17,631 $18,2106-month cost per patient $23,463 $24,092Lifetime cost per patient* $81,124 $81,844Incremental lifetime cost

per patient $720

Incremental lifetime costper 100,000 patients*

$72,000,000

Years of life per 100,000patients

1,564,000 1,568,000

Incremental years of lifegained per 100,000patients

4,000

Incremental cost per year

of life gained

$18,000

*Used for calculation of incremental cost-effectiveness ratio.ACS acute coronary syndromes; GP glycoprotein; PCI percutaneous

coronary intervention.



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PCI was 50%, upstream GP IIb/IIIa use had a borderlinefavorable cost-effectiveness ratio of $55,571.Additional sensitivity analyses. The superior effectivenessof upstream use of GP IIb/IIIa inhibition persisted in mostcases when applying a wide range of plausible probabilitiesin reduction of death and MI for both strategies duringsensitivity analyses (Table 3). The assumption that smallmolecule GP IIb/IIIa inhibitors and abciximab have equalefficacy during PCI resulted in further effectiveness of an

upstream use strategy (5,000 years of life gained per 100,000patients treated).

The use of the same, small molecule GP IIb/IIIa inhib-itor selectively or upstream resulted in 5,000 years of lifesaved per 100,000 patients treated with upstream versusselective use; there was also a higher incremental lifetimecost of $848 for upstream use. Thus, the ICER was $16,960per year of life gained.

If the probability of ACS patients undergoing PCI was65% or greater, selective use of abciximab was more effectivethan upstream use of small molecule GP IIb/IIIa inhibitors

(Fig. 3). If the probability of PCI was greater than 60%,upstream use of small molecule GP IIb/IIIa inhibitors was

Table 3. Incremental Cost-Effectiveness Ratios in Sensitivity Analyses

Subject of Sensitivity Analysis

PrincipalAnalysisEstimate

Estimates Usedfor Sensitivity

Analyses

Years of LifeWith UpstreamSmall Molecule

Use*

Years ofLife WithSelective

Abciximab Use*

Years ofLife Gained

WithUpstream Use*

Cost Effectivenessof Upstream Use(Dollars per Year

Life Gained)

Principal simulation 1,568,000 1,564,000 4,000 18,000

PCI rate 0.40 (threshold 0.63)0.2 1,603,000 1,596,000 7,000 5,8000.8 1,498,000 1,501,000 3,000

CABG rate 0.150.11 1,577,000 1,573,000 4,000 18,0000.35 1,522,000 1,520,000 2,000 36,000

No PCI, MI 0.0810.039 1,577,000 1,574,000 3,000 24,0000.135 1,556,000 1,552,000 4,000 18,000

No PCI, death 0.0370.029 1,577,000 1,575,000 2,000 36,0000.051 1,551,000 1,546,000 5,000 14,400

CABG, MI 0.210.06 1,572,000 1,569,000 3,000 24,000

0.28 1,566,000 1,562,000 4,000 18,000CABG, death 0.0450.045 1,568,000 1,564,000 4,000 18,0000.058 1,565,000 1,561,000 4,000 18,000

PCI with abciximab, MI RR 0.480.30 1,570,000 1,565,000 5,000 14,4000.78 1,565,000 1,563,000 2,000 36,000

PCI with abciximab, death RR 0.750.27 1,579,000 1,575,000 4,000 18,0002.09 1,539,000 1,536,000 3,000 24,000

No PCI, MI with upstream smallmolecule in all ACS patients

RR 0.88

0.47 1,574,000 1,564,000 10,000 7,2001.0 1,566,000 1,564,000 2,000 36,000

No PCI, death with upstream small

molecule in all ACS patients

RR 0.88

0.41 1,582,000 1,564,000 18,000 4,0001.0 1,565,000 1,564,000 1,000 72,000

PCI, MI with upstream smallmolecule in all ACS patients

RR 1.5

1.0 1,569,000 1,564,000 5,000 14,4002.5 1,565,000 1,564,000 1,000 72,000

PCI, death with upstream smallmolecule in all ACS patients

RR 1.0 (threshold RR 1.2 LE 1,565,000)

1.0 1,568,000 1,564,000 4,000 18,0002.5 1,544,000 1,564,000 20,000

Life expectancy discount rate 3%1% 1,961,800 1,957,500 4,300 16,7005% 1,289,000 1,286,000 3,000 24,000

*Represents years of life per 100,000 patients; Represents relative risk versus PCI with abciximab.ACS acute coronary syndromes; CABG coronary artery bypass grafting; LE life expectancy; MI myocardial infarction; PCI percutaneous coronary intervention;

RR relative risk.



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not cost effective (ICER of $100,000 or greater). When theeffect of GP IIb/IIIa inhibitors in medically managed patientswas varied from an OR of 0.47 to 1.0 (to examine ORs fromother published subanalyses), an upstream strategy was stillsuperior (Table 2). This also held true when ORs weresimultaneously varied for death and MI in two-way sensi-tivity analyses. The OR death or MI with small moleculeversus placebo would need to be 0.97 for the two strategiesto break even.

Sensitivity analyses in which the costs of abciximab andsmall molecule GP IIb/IIIa inhibitors were equal yielded ahigher incremental cost of upstream use of $848, and a

cost-effectiveness ratio of $21,200.In sensitivity analyses of bleeding, rates were 5.0% inupstream use versus 4.0% in selective use of abciximab at thelower limit of the 95% confidence interval of CABG-relatedbleeding. Bleeding rates were 14.0% with a strategy ofupstream use versus 13.0% with selective use of abciximabwhen CABG-related bleeding was at the upper limit of the95% confidence interval.

DISCUSSION

The use of upstream GP IIb/IIIa inhibition versus selectiveuse in only those patients undergoing PCI is a key question

that clinicians face when caring for the ACS patient. It hasbeen argued that a randomized clinical trial examining this

question is needed, but no such trial has been completed yet(28). In the absence of a specific randomized trial, a decisionanalysis may provide formal insight into what conditionsmay make one strategy potentially more beneficial thananother. Through an analysis that utilized randomized trialdata, we found that upstream use of small molecule GPIIb/IIIa inhibitors in ACS patients is superior to selectiveuse of abciximab. The ICER of $18,000 per year of lifegained per patient with upstream use is economically attrac-tive compared with other widely accepted cardiovasculartreatments (21,2931).

Importantly, though, when using TIMI risk score as a

measure of a patients baseline risk for adverse outcome, thebenefits of upstream GP IIb/IIIa inhibition were marginal,and thus no longer cost effective, in those patients with thelowest risk. In contrast, patients with moderate or high riskshowed benefit and favorable cost effectiveness with up-stream GP IIb/IIIa inhibition. These findings support theAmerican College of Cardiology and American HeartAssociation recommendation to manage ACS patients withupstream GP IIb/IIIa inhibition based on level of risk (32).

There has been considerable controversy about the extentof reduction in death or MI with GP IIb/IIIa inhibitorsduring medical management. Both the post-randomization

categorization of patients into medically managed versusPCI subgroups, and the use of meta-analysis have been

Figure 3. Benefits of upstream versus selective glycoprotein (GP) IIb/IIIa use by rates of percutaneous coronary intervention (PCI). CE cost effec-tiveness.



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criticized (14,3335). By developing a decision tree wherethe effects of GP IIb/IIIa inhibition in medical managementmay be more precisely examined, we could estimate that aslong as upstream therapy reduced risk of death or MI bymore than 3%, this strategy was superior.

Our analysis enabled us to examine additional important

questions that have not been formally tested as of yet inclinical trials. For one, it has been suggested that at properdoses of tirofiban, or with the use of eptifibatide, the smallmolecule class of GP IIb/IIIa inhibitors may be equallyeffective as abciximab during PCI (3638). Our analysissuggests superiority of an upstream use strategy if oneassumes all GP IIb/IIIa inhibitors have equal efficacy duringPCI, but that small molecules have greater efficacy thanabciximab during medical management. Second, it is notknown whether the use of upstream eptifibatide for all ACSpatients is superior to using eptifibatide selectively in onlyPCI patients. We found that a strategy of upstream use of

eptifibatide was superior to selective eptifibatide, and stillhad a favorable ICER.

The results of this analysis may also help to guide underwhich clinical conditions one particular therapy is moreappropriate. For instance, patients who are highly (65% orgreater) likely to undergo PCI may benefit from a selectiveabciximab strategy. However, there are few cases in which aclinician is that certain the patient will undergo percutane-ous revascularization. Contemporary trials of ACS haveshown that a relatively small proportion (64%) of patientswith ACS will subsequently undergo PCI, even with ag-gressive revascularization strategies (12,39). In addition, if

one assumes an equivalent effect of small molecules andabciximab during PCI, then the upstream use strategyremains superior, even if PCI rates are very high.

The major strength of the decision model in this study isthat each comparison was based directly on randomizedcontrolled trial data (16,12,13,4044). However, there arealso limitations to our analysis. First, despite using random-ized trial data, we may not be able to fully account forvariable patient presentation. Randomized trials may notrepresent the full spectrum of ACS patients; those patientsat high risk for adverse outcomes may have been excluded.However, increasing patient risk of death or MI in sensi-

tivity analyses further improved the cost-effectiveness of astrategy of upstream use. Second, our study was not de-signed to examine the potential benefits of novel antiplatelettherapies including clopidigrel, which may reduce the base-line risk of the ACS patient and/or the risk of MI and deathduring PCI (45). Sensitivity analyses may provide a roughestimate of the effects of clopidigrel. For instance, ifclopidigrel reduces further the overall risk for death and MIin the ACS patient by 30%, upstream GP IIb/IIIa inhibi-tion still has a favorable ICER of $26,500 per year of lifegained. However, the effect of clopidigrel in reducingpotential efficacy of GP IIb/IIIa inhibitors is not known and

therefore could not be studied in our analysis. Third, we didnot directly take into account the timing of PCI. Markedly

earlier PCI in both strategies may diminish the benefit ofupstream use (39), but no randomized trial has simulta-neously compared GP IIb/IIIa inhibition versus placebo andearly PCI versus late PCI. Fourth, RRs from the Chimeric7E3 Antiplatelet Therapy in Unstable Angina REfractory toStandard Treatment (CAPTURE) trial were used to estimate

the effect of abciximab during PCI, but, in that trial,abciximab was administered for a period before PCI, unlikein the present model. Finally, our cost analysis did notaccount for the incremental costs of drug-eluting stent use,which would increase overall costs of both strategies, butshould not change the incremental cost of upstream use.Indirect and long-term costs may not be fully incorporated.Further, cost and utilization data are limited to that fromrandomized trials, and this is a potentially significantlimitation to all cost-effectiveness analyses performed usingrandomized trials.

A systematic approach to the appropriate selection of

therapy becomes increasingly important when multipletherapeutic options, each with individually proven benefitsand incremental costs, are available. This analysis quantifiesunder what conditions a strategy of upstream small moleculeuse is superior to selective use of abciximab, and confirmsthe importance of risk stratification in guiding therapy. Itfurther suggests that the upstream use of small molecule GPIIb/IIIa inhibitors is a superior, cost-effective strategy thatshould be considered for those moderate and high-riskpatients presenting with ACS.

Reprint requests and correspondence: Dr. Ruchira Glaser, Uni-

versity of Pennsylvania School of Medicine, Medicine-Cardiology,9 Founders Cardiology-HUP, 3400 Spruce Street, Philadelphia,Pennsylvania 19104. E-mail: [email protected].

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