Journal of the American College of Cardiology

2004 by the American College of Cardiology Foundation

Published by Elsevier Inc.

Vol. 44, No. 9, 2004

ISSN 0735-1097/04/$30.00
doi:10.1016/j.jacc.2004.05.085

Cost-Effectiveness and Cardiac Interventions

Economic Evaluation of Bivalirudin With

Provisional Glycoprotein IIb/IIIa Inhibition
Versus Heparin With Routine Glycoprotein IIb/IIIa
Inhibition for Percutaneous Coronary Intervention
Results From the REPLACE-2 Trial
David J. Cohen, MD, MSC,* A. Michael Lincoff, MD, Tara A. Lavelle, BS, Huei-Ling Chen, PHD,
Ameet Bakhai, MD,* Ronna H. Berezin, MPH, Daniel Jackman, MD, Ian J. Sarembock, MB, CHB,
Eric J. Topol, MD, on behalf of the REPLACE-2 Investigators
Boston and Brookline, Massachusetts; Tyler, Texas; Charlottesville, Virginia; and Cleveland, Ohio
The purpose of this study was to compare the cost of percutaneous coronary intervention
(PCI) using bivalirudin with provisional platelet glycoprotein (GP) IIb/IIIa inhibition with
that of heparin routine GP IIb/IIIa inhibition.
BACKGROUND Although GP IIb/IIIa inhibition has been shown to reduce ischemic complications in a broad
range of patients undergoing PCI, many patients currently do not receive such therapy
because of concerns about bleeding complications or cost. Recently, bivalirudin with
provisional GP IIb/IIIa inhibition has been validated as an alternative to heparin routine
GP IIb/IIIa inhibition for patients undergoing PCI. However, the cost-effectiveness of this
novel strategy is unknown.
METHODS
In the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events
(REPLACE)-2 trial, 4,651 U.S. patients undergoing non-emergent PCI were randomized to
receive bivalirudin with provisional GP IIb/IIIa (n 2,319) versus heparin routine GP
IIb/IIIa (n 2,332). Resource utilization data were collected prospectively through 30-day
follow-up on all U.S. patients. Medical care costs were estimated using standard methods
including bottom-up accounting (for procedural costs), the Medicare fee schedule (for
physician services), hospital billing data (for 2,821 of 4,862 admissions), and regression-based
approaches for the remaining hospitalizations.
RESULTS
Among the bivalirudin group, 7.7% required provisional GP IIb/IIIa. Thirty-day ischemic
outcomes including death or myocardial infarction were similar for the bivalirudin and GP
IIb/IIIa groups, but bivalirudin resulted in lower rates of major bleeding (2.8% vs. 4.5%, p
0.002) and minor bleeding (15.1% vs. 28.1%, p 0.001). Compared with routine GP
IIb/IIIa, in-hospital and 30-day costs were reduced by $405 (95% confidence interval [CI]
$37 to $773) and $374 (95% CI $61 to $688) per patient with bivalirudin (p 0.001 for
both). Regression modeling demonstrated that, in addition to the costs of the anticoagulants
themselves, hospital savings were due primarily to reductions in major bleeding (cost savings
$107/patient), minor bleeding ($52/patient), and thrombocytopenia ($47/patient).
CONCLUSIONS Compared with heparin routine GP IIb/IIIa inhibition, bivalirudin provisional GP
IIb/IIIa inhibition resulted in similar acute ischemic events and cost savings of $375 to
$400/patient depending on the analytic perspective. (J Am Coll Cardiol 2004;44:
1792 800) 2004 by the American College of Cardiology Foundation

OBJECTIVES

Over the past decade, numerous clinical trials have demonstrated that the combination of an intravenous platelet
glycoprotein (GP) IIb/IIIa inhibitor and low-dose unfractionated heparin leads to substantial reductions in periprocedural ischemic complications compared with unfractionated heparin alone in patients undergoing percutaneous
From the *Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston,
Massachusetts; Harvard Clinical Research Institute, Brookline, Massachusetts;
Mother Frances Hospital, Tyler, Texas; Cardiovascular Division and Cardiovascular Research Center, University of Virginia Health System, Charlottesville, Virginia;
and the Cleveland Clinic Foundation, Cleveland, Ohio. Supported by a grant from
The Medicines Company.
Manuscript received February 3, 2004; revised manuscript received March 31,
2004, accepted May 11, 2004.

coronary intervention (PCI) (13). Although the data are

somewhat less definitive, several recent meta-analyses suggest that such therapy improves long-term survival as well
See page 1809
(4,5). Nonetheless, many PCI patients both in the U.S. and
worldwide do not receive a GP IIb/IIIa inhibitor, in part,
owing to concerns about bleeding complications and cost.
Recently, the direct thrombin inhibitor, bivalirudin, has
been shown to result in rates of ischemic complications
similar to those with heparin GP IIb/IIIa inhibition in a
multicenter clinical trial of more than 6,000 PCI patients

JACC Vol. 44, No. 9, 2004

November 2, 2004:1792800

Abbreviations and Acronyms

CABG
coronary artery bypass graft surgery
CI
confidence interval
CK-MB
creatine kinase-MB fraction
GP
glycoprotein
MI
myocardial infarction
PCI
percutaneous coronary intervention
REPLACE Randomized Evaluation in PCI Linking
Angiomax to Reduced Clinical Events

(6). In this trial, bivalirudin was associated with a nonsignificant increase in ischemic events (primarily nonQwave myocardial infarctions [MIs]) and a significant reduction in protocol-defined major and minor bleeding. The net
impact of these two effects on overall medical care costs is
unknown. Given the large number of angioplasty procedures performed in the U.S. (currently estimated at 1
million/year) (7), even modest cost savings on a per patient
basis have the potential to result in substantial savings to the
health care system. Therefore, we performed a prospective
economic evaluation in conjunction with the Randomized
Evaluation in PCI Linking Angiomax to Reduced Clinical
Events (REPLACE)-2 trial. The objectives of the study
were: 1) to compare the in-hospital and 30-day costs of PCI
using bivalirudin provisional GP IIb/IIIa inhibition with
those of PCI using the standard anticoagulation regimen of
heparin routine GP IIb/IIIa inhibition, and 2) to explore
the impact of both ischemic and bleeding complications on
the cost of PCI in contemporary practice.

METHODS
Patient population and treatment protocol. Between
October 2001 and August 2002, 6,010 patients undergoing
non-emergent PCI were enrolled in the REPLACE-2 trial.
As specified in the study protocol, the economic analysis
was confined to those patients enrolled at U.S. treatment
sites (n 4,651). Details of the study design have been
described previously (6). Patients were eligible if they were
undergoing PCI with an approved device. Key exclusion
criteria included: ongoing acute MI; recent receipt of one of
the study drugs or low-molecular-weight heparin; or need
for concomitant warfarin therapy. Patients were also excluded if they had a platelet count 100,000, serum
creatinine 4.0 mg/dl, or were at increased risk of bleeding
complications. The study protocol was approved by the
institutional review board at each site, and each patient
provided informed consent before enrollment.
Patients were randomized in a double-blind, tripledummy fashion to treatment with bivalirudin provisional
GP IIb/IIIa inhibition or heparin routine GP IIb/IIIa
inhibition. Randomization was stratified by study site and
by the operators intent to use either abciximab or eptifibatide as the GP IIb/IIIa inhibitor. Bivalirudin was administered as a 0.75 mg/kg bolus followed by a 1.75 mg/kg/h

Cohen et al.
Cost-Effectiveness of Bivalirudin for PCI

1793

infusion for the duration of the PCI procedure. Patients

could receive up to 4 h of prolonged bivalirudin infusion at
the completion of the PCI procedure at the operators
discretion. Heparin was administered as a 65 U/kg bolus.
Additional boluses of bivalirudin or heparin were given as
needed to maintain an activated clotting time 225 s.
Abciximab and eptifibatide were administered using the
Food and Drug Administration-approved doses for each
with infusion durations of 12 and 18 h, respectively (2,3).
Provisional GP IIb/IIIa inhibition (or matching placebo for
patients already receiving such therapy) was given at the
operators discretion to treat potential thrombotic complications. All patients received aspirin before PCI, and
pretreatment with clopidogrel (300 mg) was strongly encouraged. After PCI, all patients received aspirin clopidogrel (75 mg/day) for at least 30 days.
Assessment of in-hospital outcomes and clinical follow-up.
Baseline characteristics, procedural details, and clinical outcomes during the initial hospitalization and 30-day
follow-up period were recorded on standardized case report
forms. Myocardial infarction was defined as either development of new, pathologic Q waves; elevation of creatine
kinase, MB fraction (CK-MB) to 3 the upper limit of
normal within 48 h of PCI; or elevation of CK-MB to 2
the upper limit of normal at any other time during followup. Major bleeding was defined as any intracranial or
retroperitoneal hemorrhage, clinically overt blood loss resulting in a 3 g/dl decrease in hemoglobin, any decrease in
hemoglobin 4 g/dl, or transfusion of 2 U of packed red
cells (6). Minor bleeding was defined as any other clinically
overt blood loss that did not meet criteria for major
bleeding.
Determination of medical care costs. Medical care costs
for the initial hospitalization and for the 30-day follow-up
period were assessed from a societal perspective using a
combination of bottom-up and top-down methods as
previously described (8).
Detailed resource utilization was recorded for each procedure,
and the cost of each item was estimated on the basis of the
mean hospital acquisition cost for the item in 2002. Costs
for study drugs (bivalirudin, abciximab, eptifibatide) were
based on the measured bolus and infusion volumes for each
and current average wholesale prices, assuming that partially
unused vials would be discarded. Costs of additional disposable equipment, overhead, and depreciation for the
cardiac catheterization laboratory were estimated on the
basis of the average cost per procedure at Beth Israel
Deaconess Medical Center in 2002 and adjusted for actual
procedure duration.

CARDIAC CATHETERIZATION LABORATORY COSTS.

OTHER HOSPITAL COSTS. All other hospital costs were

determined using top-down accounting methods based on
each hospitals Medicare cost report (8). For 2,500 randomly selected patients, itemized bills were obtained for the
initial hospitalization and any subsequent cardiovascular

1794

Cohen et al.
Cost-Effectiveness of Bivalirudin for PCI

hospitalizations during the follow-up period. In addition,

we obtained billing data on all patients who experienced a
major in-hospital complication. Overall, billing data were
collected for 2,821 of 4,862 hospital admissions during the
30-day study period. Hospital costs were determined by
multiplying itemized hospital charges by the cost-center
specific cost-to-charge ratio obtained from the hospitals
Medicare cost report as previously described (9,10).
For those admissions for which billing data were not
collected (n 2,041), non-procedural hospital costs were
imputed on the basis of a linear regression model developed
using the hospital admissions for which complete billing
information was available. Independent variables for this
model included length of stay, intensive care unit length of
stay, ischemic complications, bleeding complications, and
revascularization procedures (model R2 0.74).
Physicians fees for inpatient services, major
cardiac procedures, and surgical procedures were based on
the 2002 Medicare Fee Schedule. Costs for outpatient
medical services and medications were not assessed.
Statistical analysis. The prespecified primary end point of
the economic study was total 30-day costs. In addition, a
secondary end point of index hospital costs was examined to
consider the perspective of a typical hospital that is reimbursed for each episode of care. To reduce the impact of
high cost outliers on group means, the protocol specified
that 30-day costs greater than the 99th percentile for each
treatment group were assigned costs equal to the 99th
percentile for the group. Discrete data are reported as
frequencies; continuous data are reported as mean SD.
Cost data are reported as both mean and median values.
Discrete variables were compared by Fisher exact test.
Normally distributed continuous variables were compared
by Student t test. Cost and length of stay data were
compared by the Wilcoxon rank-sum test. All statistical
analyses were performed according to the intention-to-treat
principle.
Multiple linear regression was performed to identify
independent predictors of initial hospital costs. Candidate
variables for this analysis included patient characteristics,
ischemic complications, repeat procedures, and bleeding
complications. Because the goal of this analysis was explanatory rather than predictive, length of stay variables were not
considered. Untransformed cost was used as the dependent
variable for these analyses for ease of interpretation and
because model fit did not improve appreciably using logtransformed costs. Attributable costs were calculated by
multiplying the independent cost of each event (derived
from the regression model) by its frequency in the treatment
group. The absolute cost savings associated with prevention
of specific clinical events were estimated by multiplying the
independent cost of each event by the difference in event
frequency between the bivalirudin and heparin GP
IIb/IIIa groups.
OTHER COSTS.

JACC Vol. 44, No. 9, 2004

November 2, 2004:1792800
Table 1. Baseline Clinical and Treatment Characteristics

Age (yrs)
Gender (% male)
Diabetes mellitus (%)
Smoking in last 12 months (%)
Previous myocardial infarction (%)
Previous CABG (%)
Previous PCI (%)
Multivessel PCI (%)
SVG PCI (%)
Prespecified GP IIb/IIIa inhibitor
Eptifibatide (%)
Abciximab (%)
Device selection
Stent (%)
Atherectomy (%)

Bivalirudin
Group
(n 2,319)

Heparin
GP IIb/IIIa Group
(n 2,332)

63 11
72.7
29.5
26.2
36.3
20.0
37.3
17.3*
6.5

63 11
72.8
28.1
24.7
35.6
21.3
37.6
14.6
7.1

60.2
39.8

60.1
39.9

86.9
4.2

86.5
4.3

*p 0.05 versus heparin GP IIb/IIIa; all other comparisons p NS.

CABG coronary artery bypass graft surgery; GP glycoprotein; PCI
percutaneous coronary intervention; SVG saphenous vein graft.

RESULTS
Patient population. Baseline characteristics of the two
treatment groups were generally well-matched (Table 1).
The mean age was 63 11 years. Approximately 30% were
diabetic, 20% had undergone previous coronary artery bypass graft surgery (CABG), and more than one-third had
undergone previous PCI. There was a modest excess of
patients who underwent multivessel PCI in the bivalirudin
group (17.3% vs. 14.6%, p 0.01). Approximately 60% of
patients in both groups were preselected for eptifibatide as
the GP IIb/IIIa inhibitor, and 87% of patients underwent
stent placement.
Procedural resource utilization and cost. Table 2 summarizes resource utilization and cost for the initial PCI
procedures. The major difference in resource utilization
between the two groups was related to procedural anticoagulants. In the bivalirudin group, 26.9% of patients required 1 vial of bivalirudin, and mean use was 1.35 vials.
In addition, 7.7% of patients assigned to bivalirudin received
a GP IIb/IIIa inhibitor on a provisional basis. Among the
heparin GP IIb/IIIa group, patients selected for abciximab required an average of 3.37 vials/patient, whereas
those patients selected for eptifibatide required an average of
4.73 vials/patient. Overall, anticoagulant costs were reduced
by approximately $400/patient for the bivalirudin group
compared with the heparin GP IIb/IIIa group (95%
confidence interval [CI] $373 to $431; p 0.001). This
difference was substantially greater for those patients selected for abciximab (mean difference $848, 95% CI $803 to
$894) versus those selected for eptifibatide (mean difference
$106, 95% CI $85 to $128).
There was a trend toward increased stent use in the
bivalirudin group compared with the heparin GP IIb/IIIa
group (1.36 vs. 1.31, p 0.13). This trend was explained by
the imbalance in multivessel PCI procedures between the

Cohen et al.
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1795

Table 2. Procedural Resource Utilization and Cost

Procedure duration (min)

Contrast volume (ml)
Balloons (n)
Stents (n)
Guide wires (n)
Guiding catheters (n)
Bivalirudin use
Number of vials
1 vial used (%)
GP IIb/IIIa inhibitor use
Provisional GP IIb/IIIa (%)
Abciximab vials*
Eptifibatide vials
Costs
All anticoagulants
Bivalirudin
Abciximab*
Eptifibatide
Devices
Supplies
Room/overhead
Non-physician personnel
Total index procedure cost

Bivalirudin
Group

Heparin GP IIb/IIIa
Group

p Value

69 55
209 119
1.27 1.07
1.36 1.00
1.60 1.05
1.56 1.10

68 54
208 119
1.24 1.05
1.31 0.96
1.57 1.03
1.55 1.11

0.52
0.84
0.39
0.13
0.33
0.86

1.35 0.89
26.9%

00
0%

0.001
0.001

7.7%
0.30 0.99
0.34 1.26

0%
3.37 1.08
4.73 1.35

0.001
0.001
0.001

$530 445
$453 299
$130 $432
$42 $156
$2,075 1,399
$715 238
$1,162 496
$123 56
$4,606 1,916 [$4,141]

$932 545
$0 0
$1,467 466
$580 183
$2,024 1,257
$709 236
$1,153 482
$122 54
$4,941 1,793 [$4,603]

0.001
0.001
0.001
0.001
0.38
0.30
0.61
0.61
0.001

*Among patients preselected for abciximab (n 1,949). Among patients preselected for eptifibatide (n 2,792). Values in
brackets are medians.
GP glycoprotein.

two groups, however, as there were no significant differences

in mean stent use among patients undergoing single-vessel
PCI (1.19 vs. 1.18, p 0.98) or multivessel PCI (2.23 vs.
2.21, p 0.55). There were no significant differences in any
other resource measures between the two groups. Total
costs for the index revascularization procedure were reduced

by $335/patient in the bivalirudin group versus the GP

IIb/IIIa group (95% CI $229 to $441, p 0.001).
Initial hospital outcomes, resource utilization, and costs.
Table 3 summarizes initial hospital outcomes for the two
treatment groups. Consistent with the results of the overall
trial, there was no significant difference in the combined

Table 3. Initial Hospital Outcomes, Resource Utilization, and Cost

Death (%)
Non-fatal MI (%)
Any
CK-MB 35
CK-MB 510
CK-MB 10
Repeat revascularization (%)
Any
PCI
CABG
Bleeding complication (%)
Major bleed
Minor bleed
Length of stay (days)
ICU length of stay (days)
Medical costs
Initial procedure
Repeat procedures
Hospital room/ancillary
Doctor fees
Total

Bivalirudin
Group

Heparin GP IIb/IIIa
Group

p Value

0.04

0.34

0.04

7.2
2.7
2.7
1.6

6.3
2.8
1.8
1.5

0.27
0.69
0.03
0.82

1.6
0.8
0.9

1.3
0.8
0.6

0.40
0.87
0.23

2.8
15.1
2.0 2.3 [1]
0.5 1.1 [0]
$4,606 1,916 [$4,141]
$81 547 [$0]
$3,655 5,295 [$2,263]
$2,220 $810 [$2,042]
$10,561 6,267 [$9,136]*

4.5
28.1
2.1 2.6 [1]
0.5 1.4 [0]
$4,941 1,793 [$4,603]
$80 593 [$0]
$3,725 5,586 [$2,374]
$2,221 825 [$2,042]
$10,966 6,524 [$9,616]*

0.002
0.001
0.54
0.45
0.001
0.83
0.39
0.41
0.001

Values in brackets are medians.

CABG coronary artery bypass graft surgery; CK-MB creatine kinase-MB fraction; GP glycoprotein; ICU intensive
care unit; MI myocardial infarction; PCI percutaneous coronary intervention.

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Cost-Effectiveness of Bivalirudin for PCI

JACC Vol. 44, No. 9, 2004

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Table 4. Follow-up Events, Resource Utilization, and Cost

Events between discharge and 30 days

Death (%)
Myocardial infarction (%)
Repeat hospitalization (%)
CABG (%)
PCI (%)
Diagnostic catheterization (%)
Follow-up costs
Total costs (study entry to 30 days)

Bivalirudin
Group

Heparin GP IIb/IIIa
Group

p Value

0.1
0.6
7.8
0.3
0.5
2.6
$488 2,829 [$0]
$10,868 5,479 [$9,321]*

0.1
0.5
8.5
0.2
0.8
2.2
$441 2,586 [$0]
$11,242 5,420 [$9,774]*

1.00
0.85
0.42
0.58
0.28
0.39
0.62
0.001

Values in brackets are medians. *Total costs do not equal the sum of initial hospital costs and follow-up costs because 30-day
costs were trimmed at the 99th percentile for each group.
CABG coronary artery bypass surgery; GP glycoprotein; PCI percutaneous coronary intervention.

incidence of death or MI between the bivalirudin and

heparin GP IIb/IIIa groups (7.3% vs. 6.6%). However,
bivalirudin provisional GP IIb/IIIa inhibition was associated with a significant and consistent reduction in bleeding complications compared with heparin routine GP
IIb/IIIa inhibition. Protocol-defined major bleeding was
reduced by 38% (2.8% vs. 4.5%, p 0.002), minor bleeding
was reduced by 46% (15.1% vs. 28.1%, p 0.001), and
thrombocytopenia (defined as any platelet count 100,000/
l) was reduced by 54% (0.7% vs. 1.5%, p 0.01).
There was a modest trend toward lower hospital room
and ancillary costs in the bivalirudin group compared with
the heparin GP IIb/IIIa group ($3,655 vs. $3,725, p
0.38). There were no important differences in repeat procedure costs or physician fees between the two treatment
groups, however. When combined with the lower costs for
the initial revascularization procedures, initial hospital costs

were reduced by an average of $405 per patient with

bivalirudin compared with standard anticoagulation (95%
CI $37 to $773, p 0.001).
Follow-up resource utilization and costs. Between hospital discharge and 30-day follow-up, there were no significant differences in clinical outcomes or resource utilization
between the two treatment groups (Table 4). As a result,
follow-up medical care costs were generally similar for the
two groups, and aggregate 30-day costs remained $374/
patient lower for the bivalirudin group compared with the
heparin GP IIb/IIIa group (95% CI $61 to $688, p
0.001).
Subgroup analyses. Prespecified subgroup analyses according to gender, age, and the presence of an acute coronary
syndrome (defined as unstable angina within 48 h or MI
within 7 days of PCI) failed to reveal any significant
interactions between baseline patient characteristics and the

Figure 1. Stratified analyses of aggregate 30-day costs by treatment group according to prespecified patient characteristics. The graph indicates the mean
difference in costs between the bivalirudin provisional glycoprotein (GP) IIb/IIIa and heparin routine GP IIb/IIIa groups (black squares) along with
the associated 95% confidence interval (bars). There was no evidence of heterogeneity of treatment effect across any of the subgroups (p value for interaction
0.05).

Cohen et al.
Cost-Effectiveness of Bivalirudin for PCI

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1797

Table 5. Multivariable Linear Regression Model of Initial Hospital Costs

Factor
Events
In-hospital CABG
Repeat PCI
Major bleed
Thrombocytopenia
MI (CK-MB 10)
Diagnostic catheterization
MI (CK-MB 510)
MI (CK-MB 35)
Minor bleed
Patient characteristics
Multivessel PCI
ACS
History of CHF
Total for events

Estimated
Cost*

Incidence in Heparin
GP IIb/IIIa Group

Incidence in
Bivalirudin
Group

Attributable cost in
Heparin
GP IIb/IIIa Group

Net Cost Difference

Associated With
Bivalirudin

$29,506
$8,187
$6,300
$5,842
$4,084
$2,446
$2,233
$1,165
$396

0.56%
0.77%
4.46%
1.50%
1.54%
2.66%
1.76%
2.83%
28.13%

0.86%
0.82%
2.76%
0.69%
1.64%
2.98%
2.72%
2.67%
15.05%

$165
$63
$281
$88
$63
$64
$39
$33
$111

$87
$4
($107)
($47)
$4
$8
$21
($2)
($52)

$1,710
$1,534
$1,165

14.60%
23.10%
6.60%

17.30%
22.70%
7.30%

$206
$354
$77
$907

$46
($6)
$8
($84)

*Estimated cost of each complication derived from linear regression model of initial hospital costs (model R2 0.46). All coefficients were significant at the p 0.05 level.
Difference in incidence between groups statistically significant (p 0.05).
ACS acute coronary syndrome; CABG coronary artery bypass graft surgery; CHF congestive heart failure; CK-MB creatine kinase-MB fraction; GP
glycoprotein; MI myocardial infarction.

magnitude of cost savings seen with bivalirudin (Fig. 1).

The extent of cost savings among patients selected for
eptifibatide as the comparison GP IIb/IIIa inhibitor was
somewhat less than among those patients selected for
abciximab ($185 vs. $559/patient); however, there was no
evidence of statistical heterogeneity of the treatment effect
on cost between subgroups (p value for interaction 0.37).
Among patients who underwent single-vessel PCI (n
3,906), bivalirudin reduced 30-day costs by $401/patient
compared with $506/patient for those who underwent
multivessel PCI (n 739).
Determinants of hospital cost. Independent predictors of
initial hospital cost (exclusive of study drug costs) are
displayed in Table 5. Repeat revascularization procedures
(in-hospital CABG, repeat PCI) were the strongest correlates of in-hospital cost. Among procedural complications,
major bleeding, thrombocytopenia, and large periprocedural
MI (CK-MB 10 upper limit of normal) had the greatest
independent impact on cost, whereas small-to-moderate
post-procedure MI and minor bleeding had lesser impacts.
Several baseline patient characteristics, including the need
for multivessel PCI, acute coronary syndrome presentation,
and a history of congestive heart failure, were also associated
with higher initial hospital costs.
Attributable cost calculations indicated that adverse outcomes accounted for $907 of the initial hospital cost for the
heparin GP IIb/IIIa group (9% of total hospital cost)
(Table 5). The complications with the largest individual
contributions to hospital cost included major bleeding,
in-hospital CABG, minor bleeding, and thrombocytopenia.
Comparison of event-related costs between the bivalirudin
and heparin GP IIb/IIIa groups indicated that reductions
in major bleeding accounted for $107/patient in hospital
cost savings with bivalirudin, whereas reductions in thrombocytopenia and minor bleeding accounted for savings of

$47 and $52 per patient, respectively. These savings were

partially counterbalanced by increased costs of $87/patient
due to bypass surgery and $21/patient due to the higher
incidence of moderate-sized MIs in the bivalirudin group.
Finally, $46/patient of excess cost for the bivalirudin group
was attributable to the baseline imbalance in multivessel
PCI procedures between the two groups. Overall, differences in hospital outcomes accounted for $84/patient in cost
savings between the two groups (21% of the observed
difference). When the analysis was restricted to those
outcomes that differed significantly between the two groups
(major bleeding, thrombocytopenia, moderate-sized MI,
and minor bleeding), event-related cost savings with bivalirudin increased to $185/patient (in addition to differences
in study drug costs).
The impact of reduced complications on in-hospital costs
was particularly important among the subgroup of patients
for whom eptifibatide was selected as the GP IIb/IIIa
inhibitor. Among this large subset (n 2,792), differences
in in-hospital complications actually accounted for cost
savings of $132/patient71% of the observed cost savings
in the subgroup. On the other hand, among those patients
preselected for abciximab, differences in in-hospital complications only accounted for $26/patient in cost savings
5% of the observed reduction in 30-day costs for this
subgroup.

DISCUSSION
In the REPLACE-2 trial, a strategy of bivalirudin with
provisional GP IIb/IIIa inhibition led to similar in-hospital
and 30-day outcomes among patients undergoing contemporary PCI procedures compared with the standard anticoagulation regimen of heparin with routine GP IIb/IIIa
inhibition (6). Because these outcomes met prespecified

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Cost-Effectiveness of Bivalirudin for PCI

statistical criteria for non-inferiority, a prospective economic

substudy was performed to determine which treatment
strategy might be preferred on economic grounds. In our
economic substudy of more than 4,600 U.S. patients,
clinical outcomes were similar to those observed in the
overall trial, whereas economic outcomes favored the bivalirudin provisional GP IIb/IIIa group. The absolute
magnitude of cost savings ranged from $405/patient during
the initial hospitalization period to $374/patient over the
entire 30-day follow-up period and was consistent across a
variety of prespecified patient subsets.
The reduction in initial hospital costs with bivalirudin
was driven by two main factors: the anticoagulants themselves and periprocedural complications. Approximately
80% of the reduction in in-hospital costs occurred during
the index revascularization procedure owing to the lower
acquisition cost of bivalirudin compared with parenteral GP
IIb/IIIa inhibitors. Importantly, these savings were observed
despite the fact that 7% of patients assigned to bivalirudin
received a provisional GP IIb/IIIa inhibitor at the time of
PCI. The remaining 20% of hospital cost savings associated
with bivalirudin were related to differences in rates of
ischemic and hemorrhagic complications. Although bivalirudin was associated with marginally higher rates of
in-hospital bypass surgery and non-fatal MI, the excess
costs of these events were more than offset by savings
associated with lower rates of major bleeding, minor bleeding, and thrombocytopenia. The impact of reduced complications on in-hospital costs was particularly important
among the subgroup of patients for whom eptifibatide was
selected as the comparison GP IIb/IIIa inhibitor. For this
subgroup, differences in in-hospital complications actually
accounted for more than 70% of the observed cost savings
with bivalirudin.
In addition to quantifying the extent of cost savings
associated with the use of bivalirudin, this study adds
importantly to our understanding of those factors that
determine the cost of contemporary PCI. On a per
event basis, the most costly complications were the need
for unplanned bypass surgery or repeat PCI before
hospital discharge. On the other hand, when the frequency of complications was also considered, the most
costly complications on a per patient basis were major
bleeding (attributable cost $342/patient in the heparin
GP IIb/IIIa group), minor bleeding ($151/patient), and
in-hospital bypass surgery ($150/patient). Although the
definition of major bleeding used in the REPLACE-2
trial was somewhat more liberal than that used in
previous trials, the substantial cost of major bleeding on
both a per event and per patient basis confirms that this
definition has both clinical and economic relevance in
contemporary practice.
Previous studies have demonstrated the important impact
of both ischemic and bleeding complications on hospital
cost for PCI patients. In a single-center study of more than
1,200 patients, Ellis et al. (11) found that the strongest

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independent predictors of hospital cost were urgent bypass

surgery, blood product transfusion, and acute renal failure.
In the economic analysis of the Evaluation of c7E3 for the
Prevention of Ischemic Complications (EPIC) trial, the
incremental costs of repeat revascularization ranged from
$4,973/event for non-urgent repeat PCI to $27,349/event
for urgent CABG (12), whereas bleeding costs ranged from
$1,327/event for minor bleeding to $5,896/event for major
bleeding (using somewhat different definitions than in the
current trial). Similar findings were reported in the Evaluation of PTCA to Improve Long-term Outcome by c7E3
GP IIb/IIIa receptor (abciximab) blockade (EPILOG) and
Randomized Efficacy Study of Tirofiban for Outcome and
Restenosis (RESTORE) trials as well (13,14).
Although our findings are qualitatively similar to many
previous studies, the current study is the first to directly
examine hospital costs and their determinants in a large
population of patients undergoing contemporary PCI with
stent implantation. Compared with previous studies from
the balloon angioplasty era, the contribution of ischemic
complications to in-hospital costs of PCI has fallen dramatically. For example, in the EPIC trial, complications increased initial hospital costs by $2,000/patient in the
control group, of which ischemic complications accounted
for 80% (12). In contrast, in the REPLACE-2 trial, the
aggregate cost of complications was $1,000/patient, of
which ischemic events accounted for less than 40%. These
findings reflect a shift in the predominant mode of ischemic
complications from abrupt closure requiring repeat revascularization to non-fatal MImany of which are clinically
silent. As a result, more than 60% of complication-related
costs are now associated with hemorrhagic events and
related outcomes (e.g., thrombocytopenia). Also noteworthy
is the substantial cost associated with even minor bleeding
complications. Although these events are associated with
only a modest increase in costs on a per event basis, the fact
that more than 25% of all patients treated with the heparin
GP IIb/IIIa inhibition experienced a minor bleed led to
substantial excess costs in the overall population.
Practice implications. Our study has important implications for the selection of a periprocedural anticoagulation
regimen in patients undergoing non-emergent PCI. Previous economic evaluations have demonstrated that heparin
routine GP IIb/IIIa inhibition is reasonably cost-effective
compared with heparin alone for patients undergoing PCI
with stent placement, whether the GP IIb/IIIa inhibitor is
abciximab or eptifibatide (15,16). Given the lower cost and
similar clinical outcomes obtained with bivalirudin in the
current study, there seems little question that bivalirudin
would be reasonably cost-effective compared with heparin as
well.
Given its lower cost and similar outcomes compared with
heparin routine GP IIb/IIIa inhibition, it is reasonable to
question whether bivalirudin provisional GP IIb/IIIa
inhibition should be considered an economically dominant
anticoagulation regimen for contemporary PCI. However,

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Cost-Effectiveness of Bivalirudin for PCI

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in light of the design of the current study, some caution is

warranted in interpreting these results. Although formal
statistical analysis demonstrated non-inferiority based on
the primary results of the REPLACE-2 trial, these calculations were based on a combination of regulatory considerations and clinical insight. Indeed, modest increases in
overall costs (such as those observed with routine GP
IIb/IIIa inhibition in this trial) might still be acceptable if
long-term survival were, in fact, improved. At present,
however, there is little evidence to support this assumption.
In fact, both 30-day (0.2% vs. 0.4%, p 0.26) and one-year
(1.9% vs. 2.6%, p 0.15) mortality rates from the
REPLACE-2 trial tended to favor the bivalirudin group
(17).
Moreover, recent studies have suggested that for patients
at very low risk of ischemic complications, a combination of
high-dose heparin 600 mg of clopidogrel may yield
similar rates of ischemic complications as low-dose heparin
GP IIb/IIIa inhibition (18). In light of these findings, it
is unclear whether bivalirudin provisional GP IIb/IIIa
inhibition would offer economic or clinical advantages for
these low-risk populations. Further studies with adequate
statistical power to demonstrate modest differences in ischemic complication rates are an essential first step to resolve
this issue.
Study limitations. Several limitations of our study are
worth noting. We did not collect primary cost data on all
study participants. Given the size and scope of the trial, we
felt that such an effort would have been relatively inefficient.
Instead, we elected to collect primary cost data on a large
subset of patients (2,500) selected at random, including all
patients who experienced a major complication. As a result,
our imputation model was highly predictive (R2 0.74) and
stable over a broad range of alternative sampling scenarios.
Second, the time frame encompassed by our analysis was
relatively brief. Because six-month rates of target vessel
revascularization did not differ between the two treatment
groups in the current study (17), however, it is unlikely that
longer-term follow-up would have improved our estimation
of the relevant cost differences.
Third, the heparin dose selected for our study (65 U/kg)
was slightly higher than the dose previously studied in the
Enhanced Suppression of the Platelet IIb/IIIa Receptor
with Integrilin Therapy (ESPRIT) trial (60 U/kg) (3).
Whether use of a lower heparin dose would have mitigated
the excess bleeding events seen in the heparin GP
IIb/IIIa arm of the REPLACE-2 trial with no loss of
efficacy is purely speculative, however. Fourth, the results of
our economic analysis apply only to those patients who were
actually studied in the REPLACE-2 trial. Because patients
with ongoing acute MI or high-risk acute coronary syndromes receiving GP IIb/IIIa inhibition before PCI were
excluded by protocol, our findings should not be extrapolated to these specific populations.
Finally, it is likely that we have underestimated the extent
of cost savings that might ultimately be achieved by biva-

1799

lirudin in contemporary PCI. In particular, it is possible that

the design of the REPLACE-2 trial artificially increased
hospital costs for the bivalirudin group. The mean infusion
duration for bivalirudin was 44 min, compared with 12 h for
abciximab and 18 h for eptifibatide. Nonetheless, as a
double-blind trial, all patients in the bivalirudin group
received 12 to 18 h of a placebo infusion, thus eliminating
an important opportunity to streamline care and reduce
cost. Outpatient PCI is rarely performed in U.S. today, in
part because of the need for extended infusions of antiplatelet agents as well as lower reimbursement levels compared
with inpatient procedures. Given its brief infusion duration
and enhanced safety profile, bivalirudin with provisional GP
IIb/IIIa inhibition might lead to substantial additional
savings in the future by facilitating PCI in the outpatient
setting.
Reprint requests and correspondence: Dr. David J. Cohen,
Cardiovascular Division, Beth Israel Deaconess Medical Center,
330 Brookline Avenue, Boston, Massachusetts 02215. E-mail:
dcohen@caregroup.harvard.edu.

REFERENCES
1. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor
blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997;336:1689 96.
2. The EPISTENT Investigators. Randomised placebo-controlled and
balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Lancet 1998;
352:8792.
3. The ESPRIT Investigators. Novel dosing regimen of eptifibatide in
planned coronary stent implantation (ESPRIT): a randomised,
placebo-controlled trial. Lancet 2000;356:2037 44.
4. Anderson KM, Califf RM, Stone GW, et al. Long-term mortality
benefit with abciximab in patients undergoing percutaneous coronary
intervention. J Am Coll Cardiol 2001;37:2059 65.
5. Karvouni E, Katritsis DG, Ioannidis JP. Intravenous glycoprotein
IIb/IIIa receptor antagonists reduce mortality after percutaneous
coronary interventions. J Am Coll Cardiol 2003;41:26 32.
6. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional
glycoprotein IIb/IIIa blockade compared with heparin and planned
glycoprotein IIb/IIIa blockade during percutaneous coronary intervention:
REPLACE-2 randomized trial. JAMA 2003;289:853 63.
7. American Heart Association. Heart Disease and Stroke Statistics
2004 Update. Dallas, TX: American Heart Association, 2003.
8. Cohen DJ, Krumholz HM, Sukin CA, et al. In-hospital and one-year
economic outcomes after coronary stenting or balloon angioplasty:
results from a randomized clinical trial. Circulation 1995;92:2480 7.
9. Shwartz M, Young DW, Siegrist R. The ratio of costs to charges: how
good a basis for estimating hospital costs. Inquiry 1995;32:476 81.
10. Taira DA, Seto TB, Siegrist R, Cosgrove R, Berezin R, Cohen DJ.
Comparison of analytic approaches for the economic evaluation of new
technologies alongside multicenter clinical trials. Am Heart J 2003;
145:452 8.
11. Ellis SG, Miller DP, Brown KJ, et al. In-hospital cost of percutaneous
coronary revascularization: critical determinants and implications.
Circulation 1995;92:7417.
12. Mark D, Talley J, Topol E, et al. Economic assessment of platelet
glycoprotein IIb/IIIa inhibition for prevention of ischemic complications of high-risk coronary angioplasty. Circulation 1996;94:629 35.
13. Lincoff AM, Mark DB, Tcheng JE, et al. Economic assessment of
platelet glycoprotein IIb/IIIa receptor blockade with abciximab and

1800

Cohen et al.
Cost-Effectiveness of Bivalirudin for PCI

low-dose heparin during percutaneous coronary revascularization:

results from the EPILOG randomized trial. Circulation 2000;102:
29239.
14. Weintraub WS, Culler S, Boccuzzi SJ, et al. Economic impact of GP
IIb/IIIa blockade after high-risk angioplasty: results from the RESTORE
trial. J Am Coll Cardiol 1999;34:1061 6.
15. Topol E, Mark D, Lincoff A, et al. Outcomes at 1 year and economic
implications of platelet glycoprotein IIb/IIIa blockade in patients
undergoing coronary stenting: results from a multicentre randomised
trial (EPISTENT). Lancet 1999;354:2019 24.
16. Cohen DJ, Cosgrove RS, Berezin RH, et al. Cost-effectiveness of

JACC Vol. 44, No. 9, 2004

November 2, 2004:1792800
eptifibatide in patients undergoing planned coronary stenting:
results from the ESPRIT trial (abstr). Circulation 2001;104:
I386 7.
17. Lincoff AM, Topol EJ. Long-term efficacy of bivalirudin and provisional GP IIb/IIIa blockade compared with heparin and planned GP
IIb/IIIa blockade during percutaneous coronary intervention: 6-month
and 1-year results of the REPLACE-2 trial (abstr). Circulation
2003;108:IV569.
18. Kastrati A, Mehilli J, Schuhlen H, et al. A clinical trial of abciximab
in elective percutaneous coronary intervention after pretreatment with
clopidogrel. N Engl J Med 2004;350:232 8.