Journal of the American College of Cardiology
© 2005 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 45, No. 6, 2005
ISSN 0735-1097/05/$30.00
doi:10.1016/j.jacc.2004.11.051
Long-Term Cost-Effectiveness of Clopidogrel
Given for Up to One Year in Patients With Acute
Coronary Syndromes Without ST-Segment Elevation
William S. Weintraub, MD, FACC,* Elizabeth M. Mahoney, SCD,† Andre Lamy, MD,‡
Steven Culler, PHD,* Yong Yuan, PHD,§ Jaime Caro, MD,储 Sylvie Gabriel, MD,¶
Salim Yusuf, MD, FACC,‡ on behalf of the CURE Study Investigators
Atlanta, Georgia; Watertown and Concord, Massachusetts; Hamilton, Ontario, Canada; Princeton, New Jersey;
and Paris, France
We sought to evaluate the long-term cost-effectiveness of clopidogrel for up to one year after
an acute coronary syndrome (ACS) without ST-segment elevation.
BACKGROUND The efficacy of platelet inhibition with clopidogrel for up to one year after ACS was
demonstrated in the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE)
trial, a randomized trial of 12,562 patients in 28 countries that was conducted between 1998
and 2000. Patients were given clopidogrel (300-mg load followed by 75 mg/day) versus
placebo, both in addition to aspirin, for a mean of nine months.
METHODS
We used patient-level clinical outcomes and resource use from the CURE trial and estimates
of life expectancy gains as a result of the prevention of the clinical events of death, stroke, and
myocardial infarction on the basis of data from external sources.
RESULTS
Excluding clopidogrel costs, average costs of hospitalizations alone were $325 less for the
clopidogrel arm (95% confidence interval ⫺$722 to $45) using diagnosis-related group-based
Medicare reimbursement rates. When including clopidogrel costs ($766 greater for the
clopidogrel arm), average total costs were $442 higher for the clopidogrel arm (95%
confidence interval $62 to $820). The incremental cost-effectiveness ratio (ICER) on the
basis of the Framingham Heart Study was $6,318 per life-year gained (LYG) with
clopidogrel, with 94% of bootstrap-derived ICER estimates ⬍$50,000/LYG; based on
Saskatchewan, the ICER was $6,475/LYG with 98% of estimates ⬍$50,000.
CONCLUSIONS Platelet inhibition with clopidogrel in patients for up to one year after presentation with an
acute coronary syndrome is both effective and cost-effective. (J Am Coll Cardiol 2005;45:
838 – 45) © 2005 by the American College of Cardiology Foundation
OBJECTIVES
The Clopidogrel in Unstable angina to prevent Recurrent
Events (CURE) trial evaluated the efficacy and safety of
clopidogrel plus aspirin compared with aspirin alone when
initiated early and continued long term (up to 12 months,
average of 9 months), in patients presenting with unstable
angina or a non–ST-segment elevation myocardial infarction (MI) (1). In CURE, clopidogrel reduced the risk of the
primary outcome of cardiovascular death, MI, or stroke.
Additionally, there was a reduction in refractory ischemia
needing urgent intervention, other ischemic events, and
pulmonary edema. A recent study evaluated the cost per
event prevented with clopidogrel versus placebo on the basis
of in-trial results from the CURE trial (2). To estimate the
long-term cost-effectiveness of nine months of therapy with
clopidogrel in terms of cost per life-year gained (LYG), it is
necessary to evaluate the impact of clopidogrel on life
expectancy. The purpose of the present study is to evaluate
From *Emory University, Atlanta, Georgia; †New England Research Institutes,
Watertown, Massachusetts; ‡McMaster University, Hamilton, Ontario, Canada;
§Bristol-Myers Squibb, Princeton, New Jersey; 储Caro Research Institute, Concord,
Massachusetts; and ¶Sanofi-Synthelabo, Paris, France. Supported by grants from
Sanofi-Aventis and Bristol-Myers Squibb to Drs. Weintraub, Caro, and Yusuf. Dr.
Yuan is an employee of Bristol-Myers Squibb. Dr. Gabriel is an employee of
Sanofi-Aventis.
Manuscript received July 26, 2004; revised manuscript received November 13,
2004, accepted November 16, 2004.
the long-term cost-effectiveness of clopidogrel by translating the reduction in primary fatal and nonfatal events
observed with clopidogrel in the CURE trial into estimates
of gains in life expectancy to arrive at an estimate of the
incremental cost/LYG.
METHODS
Design of the CURE trial. The CURE study, a large,
multicenter randomized controlled trial, has been described
previously in detail (1). Briefly, 12,562 patients were recruited from December 1998 to September 2000 at 482
centers from 28 countries. Patients were eligible if they were
hospitalized within 24 h of onset of symptoms indicative
of acute coronary syndrome (ACS) and did not have
significant ST-segment elevation. Patients were assigned
randomly to clopidogrel (loading dose of 300 mg followed
by 75 mg per day) or a placebo for an average period of
nine months. All patients received acetylsalicylic acid (75 to
325 mg daily). The primary clinical outcome was a composite of cardiovascular death, nonfatal MI, or stroke. All
patients in both arms received conventional treatments,
including thrombolytic agents, heparin, diuretics, antianginal therapy, antihypertensive medication, cholesterolreducing agents, and glycoprotein IIb/IIIa antagonists during percutaneous coronary intervention (PCI). The CURE
JACC Vol. 45, No. 6, 2005
March 15, 2005:838–45
Abbreviations and Acronyms
ACS
⫽ acute coronary syndrome
CURE ⫽ Clopidogrel in Unstable angina to prevent
Recurrent Events trial
DRG ⫽ diagnosis-related group
ICER ⫽ incremental cost-effectiveness ratio
MI
⫽ myocardial infarction
LOS
⫽ length of stay
LYG ⫽ life-year gained
PCI
⫽ percutaneous coronary intervention
QALYs ⫽ quality-adjusted life-years
trial was approved by the institutional review board at all
sites and analytic centers and complies with the Helsinki
protocol for protection of human subjects.
Economic analysis plan and assessment of cost. The
economic analysis plan was to compare the costs of the two
treatment arms and, if the clopidogrel arm was more costly as
well as more effective, to perform an incremental costeffectiveness analysis (3,4). Costs included in the analysis are
direct medical care costs for hospitalizations and the cost of
clopidogrel. No data are available from the CURE trial to
calculate indirect costs due to lost productivity. Cost after the
first year and life expectancy were discounted 3% annually. The
analysis uses U.S. dollars as the unit of analysis but uses
resource use and clinical outcomes from all 12,562 patients.
Cardiovascular health care resource use associated with
the index, and all follow-up hospitalizations were recorded
prospectively, including diagnostic tests, therapeutic procedures, and medications. Ambulatory care, including outpatient diagnostic procedures and testing (other than coronary
angiography), was not recorded. Because most resourceintensive procedures and tests are performed while patients
are hospitalized, it is likely that most of the major components of health care resource use were collected. Possible
exceptions would include same-day testing not requiring
hospitalization, such as nuclear imaging studies or echocardiograms, and nursing home and rehabilitation stays after
stroke. The use of medication other than study drug was not
found to differ between the study arms. The use of openlabel clopidogrel and adherence to double-blind treatment
were recorded during hospitalizations and at periodic
follow-up visits.
The initial and subsequent hospitalizations were assigned
a diagnosis-related group (DRG), as used in the Medicare
program in the U.S., by coders who were blinded to
treatment group. Noncardiovascular follow-up hospitalizations were recorded but not included in this analysis because
their frequency was rare and because they were distributed
equally between treatment arms. Costs for each DRG were
estimated using average Medicare reimbursement rates
(5,6), which were obtained from the Medicare Part A data
file (7), and average private payer reimbursement rates,
which were obtained from the MEDSTAT database (5,8).
A blended MEDSTAT-Medicare cost estimate was gener-
Weintraub et al.
Cost-Effectiveness of Clopidogrel in ACS
839
ated by applying MEDSTAT costs to the CURE trial
patients younger than 65 years of age and Medicare costs
to patients older than 65 years of age. The MEDSTAT
estimates include professional costs; for Medicare, professional costs were calculated as a percentage of hospital costs
by DRG, according to the method of Mitchell et al. (9).
Costs beyond the trial period were estimated as the average
per capita participant Medicare reimbursement of $4,370 in
2001 (10).
Life expectancy estimation. Life expectancy for patients
with and without nonfatal events was estimated from two
independent sources: the Framingham Heart Study (11,12)
and the Saskatchewan Health database (13). For the latter,
survival data on all 15,956 patients with acute MIs as
defined by the International Classification of Diseases-9th
Revision-code 410, from the years 1990 to 1995 with
follow-up through the end of 2000, were analyzed using
published methods (13). Briefly, mean survival beyond the
end of the trial was estimated by integrating the survival
curves, adjusted for various patient characteristics, including
experience of specific subsequent ischemic events (13,14).
Cox proportional hazards survival models for each time
period were derived for patients with age, diabetes, previous
MI, previous ischemic stroke, previous coronary artery
bypass graft, and hypolipidemic use as covariates (13–18).
The cumulative survival functions over the course of time
were derived by applying the hazard functions in sufficiently
brief intervals that the hazard can be assumed to be constant
during the period.
For both the Framingham Heart Study and Saskatchewan
Health database, gender and age-specific estimates of life-years
lost due to events were obtained by subtracting life expectancy
estimates for individuals with a given event pattern from life
expectancy estimates for individuals with no events (14). These
estimates were then applied to the CURE trial patient population. For patients who experienced multiple events of different types during the trial, lost life expectancy was estimated
assuming a hierarchy of death, stroke, and MI. It was assumed
that clopidogrel would be stopped at the end of the trial and
that there would be no further reduction (or increase) in
nonfatal events between the two arms. As a sensitivity analysis,
cardiovascular death (as used in the clinical endpoint) rather
than all-cause death (the primary analysis for the economic
study) was used to estimate years of life lost. The difference
between treatment groups in average life-years lost because of
events (placebo ⫺ clopidogrel) yields an estimate of LYG with
clopidogrel. Variability associated with these lost life expectancy estimates was not accounted for in the cost-effectiveness
analyses.
Estimation of cost-effectiveness. The cost-effectiveness of
clopidogrel was expressed as the incremental costeffectiveness ratio (ICER), which is the added cost in the
clopidogrel arm divided by LYG. Bootstrap methods (5,000
replicates) were used to estimate the 95% CIs for both cost
and LYG with clopidogrel (19). Sensitivity analyses included reducing life expectancy gains by 50% and then by
840
Weintraub et al.
Cost-Effectiveness of Clopidogrel in ACS
JACC Vol. 45, No. 6, 2005
March 15, 2005:838–45
Table 1. Clinical Summary
Baseline Characteristics
Age
Women
MI at presentation
Previous MI
Diabetes
Hypertension
Clinical outcomes for
economic study
Death (any cause)
MI
Stroke
Bleeding, major, or
life-threatening
Major
Life threatening
Major ⫹ life-threatening
Minor bleeding
Clopidogrel
(n ⴝ 6,259)
Placebo
(n ⴝ 6,303)
p Value
64 ⫾ 11
39%
26%
32%
22%
60%
9.3%
64 ⫾ 11
38%
26%
32%
23%
58%
11.4%
0.7448
0.6450
0.6098
0.6314
0.5920
0.0168
⬍0.0001
5.8%
5.2%
1.2%
3.70%
6.2%
6.7%
1.4%
2.70%
0.2779
0.0004
0.3532
0.0015
1.5%
2.1%
0.1%
5.1%
0.9%
1.7%
0.1%
2.4%
0.002
0.10
1.00
⬍0.0001
MI ⫽ myocardial infarction.
80%, adding estimated costs associated with bleeding,
adding costs due to added years of life, and quality adjusting
survival. The impact of bleeding on cost could not be
calculated directly because the costing was based on DRGs,
which would not necessarily be affected by bleeding. Therefore, the impact of bleeding on hospital length of stay
(LOS) was estimated using CURE trial data, and the
concomitant cost increase was estimated assuming an average cost of $2,000 per day.
RESULTS
Summary of the clinical data. No differences existed
between treatment groups in age, gender, or MI either at
presentation or in previous history, diabetes, or hypertension (Table 1). The clinical outcome, the composite of
all-cause death, MRI, or stroke by 12 months follow-up was
significantly lower in the clopidogrel group, 9.3% versus
11.4%, p ⬍ 0.001, relative risk 0.80 (95% CI 0.72 to 0.90).
There were trends toward a reduction in death from any
cause as well as stroke. There was a significant reduction in
MI. Bleeding was increased with clopidogrel. Hospitalizations by treatment group for each DRG assignment, and
their associated unit costs are shown in Table 2.
Estimation of LYG. Using both the Framingham Heart
Study and Saskatchewan Health database, there were trends
toward life expectancy gains with clopidogrel as a result of
the reduction in each of the individual events of death, MI,
and stroke (Table 3). Overall, patients in the clopidogrel
arm were estimated to have gained an average of 0.0699
life-years relative to patients in the control arm using
Framingham data and 0.0682 life-years using Saskatchewan. Overall nine-month mortality for Saskatchewan patients with characteristics similar to the CURE placebo
group was 7.7%, compared with 5.9% within CURE.
Mortality at nine months in the CURE trial was 4.0% in
patients who did not suffer and MI and 26% in patients who
did suffer an MI between randomization and nine months
(hazard ratio 5.74, p ⬍ 0.0001 adjusted for age, gender,
previous MI, diabetes, smoking). This result compares with
a nine-month mortality of 3.7% without an MI and 25%
with an MI using Saskatchewan data. Similarly mortality at
nine months in the CURE trial was 5.1% in patients who
did not suffer a stroke and 23% in patients who did (hazard
ratio 4.3, p ⬍ 0.0001 corrected for age, gender, previous
MI, diabetes, smoking).
In-trial costs. Exclusive of clopidogrel costs, initial hospitalization, rehospitalization, and total costs tended to be
lower in the clopidogrel arm (Table 4). On the basis of
Medicare costs, total costs were significantly higher in the
clopidogrel group, whereas for MEDSTAT and the Medicare/MEDSTAT blend, the differences were not significant. Total costs based on Medicare for subgroups defined
Table 2. DRGs, Associated Costs, and Distribution of DRGs for Initial and Subsequent Hospitalizations
Initial Hospitalization
(Frequency)
Subsequent
Hospitalization
(Frequency)
DRG
DRG
Code
MEDSTAT Cost
($)
Medicare Cost
($)
Clopidogrel
Placebo
Clopidogrel
Placebo
Unstable angina
Unstable angina with angiography
MI—expired
MI—simple
MI—complex
Other cardiovascular
PCI
CABG surgery
PCI ⫹ CABG
Stroke
Chest pain
Nonfatal cardiac arrest
Heart failure
Other CT surgery
140
124
123
122
121
120
112
107
106
14
143
129
127
108
4,295
11,947
15,441
12,132
15,198
23,109
14,209
36,080
46,660
11,776
3,914
12,380
8,142
52,148
3,542
8,010
7,651
6,337
8,643
10,897
10,342
29,127
38,850
6,493
3,447
5,627
5,449
29,034
2,759
742
44
1,247
140
44
793
479
6
5
0
0
0
0
2,710
684
48
1,231
163
56
876
519
11
5
0
0
0
0
738
489
54
1
123
20
486
436
3
46
144
7
195
19
688
479
47
3
156
9
475
455
3
62
210
4
186
25
CABG ⫽ coronary artery bypass grafting; CT ⫽ cardio-thoracic; DRG ⫽ diagnosis-related group; MI ⫽ myocardial infarction; PCI ⫽ percutaneous coronary intervention.
Weintraub et al.
Cost-Effectiveness of Clopidogrel in ACS
JACC Vol. 45, No. 6, 2005
March 15, 2005:838–45
841
Table 3. Life-Years Lost Attributable to Cardiovascular Events
Clopidogrel
Placebo
Life-Years Gained
With Clopidogrel
0.4563
0.0208
0.0557
0.5327
0.4920
0.0305
0.0802
0.6026
0.0357
0.0097
0.0245
0.0699
⫺0.0303
⫺0.0009
0.0108
⫺0.0077
to
to
to
to
0.1106
0.0199
0.0397
0.1440
0.3044
0.0255
0.0611
0.3910
0.3343
0.0336
0.0913
0.4592
0.0299
0.0081
0.0302
0.0682
⫺0.0185
⫺0.0027
0.0176
0.0122
to
to
to
to
0.0822
0.0190
0.0440
0.1190
Framingham
Death
MI
Stroke
Total
Saskatchewan
Death
MI
Stroke
Total
95% CI for Life-Years
Gained With Clopidogrel
CI ⫽ confidence interval; MI ⫽ myocardial infarction.
according to age, gender, diabetes, and previous MI are
shown in Figure 1. Results for all subgroups resemble those
for the total population, with trends toward slightly higher
costs in the clopidogrel arm.
Cost-effectiveness. Using Framingham study-based estimates, not including costs beyond the trial period, the ICERs
ranged from $4,833 with MEDSTAT to $6,318 with Medicare, with more than 90% of bootstrap estimates ⬍$50,000/
LYG (Table 5). Similarly, using Saskatchewan data-based
estimates, ICERs ranged from $4,953 with MEDSTAT to
$6,475 with Medicare, with more than 95% of bootstrap
estimates ⬍$50,000/LYG. The ICERs are systematically
higher using the average Medicare cost per year to estimate
costs beyond the trial period. A plot of the bootstrap-derived
joint distribution of cost and effectiveness differences on the
basis of Medicare costing and Framingham-based effectiveness
estimates is shown in Figure 2, and cost-effectiveness acceptability curves on the basis of Medicare, MEDSTAT, and the
blended costing approaches and Framingham life expectancy
estimates are shown in Figure 3. The three costing approaches
yielded similar results, with most of bootstrap-derived costeffectiveness estimates ⬍$15,000/LYG. Incremental costeffectiveness ratios for subgroups, on the basis of Medicare
costing and both Framingham and Saskatchewan life expectancy estimates, are shown in Figure 4. Results for most of the
subgroups are similar to the overall estimate, with the exception of women, for whom the ICER was higher. Because of
four more noncardiovascular deaths in the clopidogrel arm,
ICERs for women are considerably lower when cardiovascular
death was considered in the estimation of life-years lost (along
with nonfatal stroke and MI), rather than all-cause death
($29,130 on the basis of Framingham and Medicare, $49,369
on the basis of Saskatchewan and Medicare). For all other
subgroups there was little difference in ICERs on the basis of
all-cause versus cardiovascular death.
Sensitivity analyses. These analyses required the use of
external databases to project life expectancy beyond the end
of the trial. The life expectancy gain with clopidogrel may
be either smaller or larger than projected. If the estimated
gain in life expectancy is only half of that projected, using
the blended costing approach and Framingham life expectancy estimates, the ICER would be $9,820, with 91.9% of
bootstraps samples ⬍$50,000/LYG; on the basis of
Saskatchewan data, it would be $10,065, with 96.7%
⬍$50,000/LYG. If the life expectancy gain is just 20% of
that projected, the ICER would be $24,549, with 77.7%
Table 4. Costs
Initial hospitalization
Medicare
MEDSTAT
Medicare/MEDSTAT blend
Rehospitalization
Medicare
MEDSTAT
Medicare/MEDSTAT blend
Total, exclusive of clopidogrel
Medicare
MEDSTAT
Medicare/MEDSTAT blend
Clopidogrel costs
Total, including clopidogrel
Medicare
MEDSTAT
Medicare/MEDSTAT blend
CI ⫽ confidence interval.
Clopidogrel
Placebo
⌬ (Clopidogrel ⴚ Placebo)
95% CI for ⌬
$7,680
$10,953
$9,291
$7,918
$11,265
$9,586
⫺$238
⫺$312
⫺$295
⫺483 to 10
⫺628 to ⫺14
⫺576 to ⫺37
$4,557
$6,189
$5,284
$4,644
$6,306
$5,413
⫺$86
⫺$117
⫺$128
⫺426 to 252
⫺580 to 340
⫺512 to 272
$12,237
$17,142
$14,575
$782
$12,562
$17,570
$14,998
$16
⫺$325
⫺$428
⫺$423
$766
⫺722
⫺947
⫺880
757
$13,019
$17,924
$15,357
$12,578
$17,586
$15,014
$442
$338
$343
to
to
to
to
45
53
25
776
62 to 820
⫺165 to 827
⫺90 to 784
842
Weintraub et al.
Cost-Effectiveness of Clopidogrel in ACS
JACC Vol. 45, No. 6, 2005
March 15, 2005:838–45
Figure 1. Total costs by treatment group overall and for subgroups based on Medicare costs. Solid bars ⫽ placebo; hatched bars ⫽ clopidogrel. CI ⫽
confidence interval; MI ⫽ myocardial infarction.
⬍$50,000/LYG on the basis of Framingham, and $25,161,
with 81.8% ⬍$50,000/LYG based on Saskatchewan.
For hospitalizations in which a major bleed occurred,
LOS increased 5.94 days. In hospitalizations in which a
life-threatening bleed occurred, LOS increased 4.57 days,
and a major and life-threatening bleed 9.91 days. Combining the LOS data with the bleeding incidence from Table 1
adds an incremental average of 0.05392 days to LOS. If an
additional day in the hospital, independent of the DRG
assignment, costs $2,000 per day, then incremental bleeding
due to clopidogrel adds $108 to the average cost per patient.
This would increase the ICER for Framingham, using
Medicare costing, from $6,318 to $7,868.
Utility was not measured in CURE and, thus, we could
not calculate quality-adjusted life-years (QALYs) directly
using patient-level data. Because there were more nonfatal
events in the placebo arm, it might be reasonable to expect
utility to be higher in the clopidogrel arm, rendering results
described above conservative. However, if utility is ⬍1.0 but
equal for both arms, the ICER in terms of cost per QALY
gained would be higher than the cost per LYG estimate. If
utility was 0.80 in both arms (20), then the ICER using
Framingham life expectancy and Medicare costs would be
$7,898/QALY gained. If costs in added years of life were
also included, the ICER would be $11,430/QALY gained.
DISCUSSION
For patients with ACS, antiplatelet therapy with clopidogrel is cost-effective, with ICERs ranging from $4,910
to $6,473/LYG, and with ⬎90% of bootstrap samples
⬍$50,000/LYG for all models (21,22). These results were
Table 5. Cost Effectiveness
No direct costs beyond trial period
Framingham
Medicare
MEDSTAT
Blend
Saskatchewan
Medicare
MEDSTAT
Blend
Including direct costs beyond trial period*
Framingham
Medicare
MEDSTAT
Blend
Saskatchewan
Medicare
MEDSTAT
Blend
⌬ Cost
⌬ Life-Years
ICER
% Dominant
% Dominated
% <50,000/LYG
$442
$338
$343
0.0699
0.0699
0.0699
$6,318
$4,833
$4,910
1.20%
9.30%
6.90%
4.00%
4.00%
4.00%
93.9%
93.9%
94.5%
$442
$338
$343
0.0682
0.0682
0.0682
$6,475
$4,953
$5,032
1.20%
9.30%
6.90%
0.70%
0.70%
0.77%
97.7%
98.1%
98.3%
$639
$535
$541
0.0699
0.0699
0.0699
$9,144
$7,654
$7,742
0.60%
2.70%
2.00%
4.00%
4.00%
4.00%
92.8%
93.4%
93.4%
$637
$534
$540
0.0682
0.0682
0.0682
$9,343
$7,833
$7,921
0.1%
2.3%
1.5%
0.70%
0.70%
0.70%
97.0%
97.6%
97.5%
*Assuming $4,370 annual follow-up medical cost.
ICER ⫽ incremental cost-effectiveness ratio; LYG ⫽ life year gained.
JACC Vol. 45, No. 6, 2005
March 15, 2005:838–45
Weintraub et al.
Cost-Effectiveness of Clopidogrel in ACS
843
Figure 2. Scatterplot of the joint distribution of cost and effectiveness differences in the cost-effectiveness plane using Medicare costs and Framingham life
expectancy estimates.
consistent for the three DRG-based approaches to costing
hospitalizations and the two approaches to estimating the
gain in life expectancy by the prevention of events. The
results remained favorable when estimated direct medical
care costs associated with increased life expectancy in the
clopidogrel arm are included and when estimated qualityof-life adjustments were incorporated. The ICERs were
favorable for nearly all subgroups considered. Only in
women were estimated ICERs ⬎$50,000 per LYG, due in
large part to a trend toward more noncardiovascular deaths
in women in the clopidogrel arm. Such results highlight the
difficulty in drawing inferences with respect to both clinical
efficacy and cost-effectiveness in underpowered clinical trial
subgroups (23). Incremental cost-effectiveness ratios for
women became more attractive when life-year estimates
were made on the basis of cardiovascular death, which was
a prespecified end point in the CURE trial.
Antiplatelet therapy with aspirin and adenosine diphosphate blockers has been shown to be beneficial in the
treatment of vascular disease and to prevent thrombosis
Figure 3. Cost-effectiveness acceptability curves based on Medicare, MEDSTAT, and Medicare/MEDSTAT costs, and Framingham life expectancy
estimates.
844
Weintraub et al.
Cost-Effectiveness of Clopidogrel in ACS
JACC Vol. 45, No. 6, 2005
March 15, 2005:838–45
Figure 4. Incremental cost-effectiveness ratio (ICER) both overall and for subgroups based on Medicare costs and both Framingham and Saskatchewan life
expectancy estimates. *ICER in women considering life expectancy gains due to the prevention of cardiovascular death rather than all-cause death (in addition to
nonfatal stroke and myocardial infarction [MI]): $29,130 on the basis of Framingham; $49,369 on the basis of Saskatchewan. LYG ⫽ life-year gained.
after PCI. In the CURE trial, clopidogrel therapy for up to
one year was shown to prevent cardiovascular events in
patients presenting with ACS (1). There was a slightly
increased risk of non–life-threatening bleeding with clopidogrel, which largely was associated with procedures within
the first 30 days after randomization, and managed successfully (24). The beneficial effects of clopidogrel also were
found in the subset of patients who underwent PCI in the
PCI-CURE study (25) and in Clopidogrel for the Reduction of Events During Observation (CREDO) trial (26).
The present analysis builds on an assessment of shortterm cost-effectiveness conducted from the perspective of
the United Kingdom, U.S., Sweden, France, and Canada on
the basis of results from the CURE trial (2). In that study,
cost per primary outcome event avoided with clopidogrel
was £10,366 in United Kingdom, $22,484 in the U.S., SKr
127,951 in Sweden, €16,186 in France, and C$7,973 in
Canada (2). In addition, a Swedish study suggested that
clopidogrel is cost-effective in cost/LYG (27). One additional analysis, using decision analytic methodology, suggested that multiyear therapy with clopidogrel would only
be cost-effective in patients who cannot tolerate aspirin (28).
A strength of the present analysis is that it was performed
with patient-level data directly from the CURE trial. Moreover, as a randomized comparison, the assessment of both
effectiveness and cost reflect the actual exposure to treatments
independently of selection bias. In the CURE trial, concomitant medicine use reflected care consistent with American
College of Cardiology/American Heart Association ACS
guidelines; in particular, statins, angiotensin-converting enzyme inhibitors and beta-blockers. Thus, the CURE trial
serves as a contemporary evaluation of the effectiveness of
clopidogrel and aspirin versus aspirin and placebo.
Study limitations. One limitation of our study is that the
CURE trial was a multinational trial and our approach of
applying U.S. costs to trial-wide hospitalizations on the
basis of DRGs does not fully account for possible differences
in treatment practices and resource use between countries or
health care systems. If a large proportion of patients come
from countries for which the threshold for hospitalization
differs considerably from that in the U.S., the difference in
costs between treatments may be underestimated or overestimated. However, unless within a DRG the costs are
higher in one treatment arm, this approach to costing
hospitalizations should yield unbiased overall cost estimates
and, in fact, should reduce unwanted variability in the
evaluation of cost differences attributable to treatment.
No outpatient treatment, rehabilitation, or nursing home
resource use was collected in the CURE trial, and associated
costs are therefore excluded from this analysis, as well as
indirect costs associated with lost productivity. However,
those costs might be expected to be higher in the placebo
arm because of the higher in-trial nonfatal event rate, which
would result in our estimates being conservative.
The costs of bleeding were not directly measured in the
CURE trial. However, when analyzed using LOS as a proxy
for cost, the effect on the ICER was modest. This sensitivity
analysis may double count some of the cost of bleeding
because some of this cost may be accounted for by DRG
assignment, thus increasing the ICER.
External databases were used to estimate life expectancy.
Multiple improvements in medical care have extended life of
patients with vascular disease such that a database like
Framingham may not adequately reflect these improvements.
However, the Saskatchewan patient sample was based on index
hospitalizations occurring between 1990 and 1995, yielding
similar life expectancy results to Framingham. That the two
external databases yielded similar results offers reassurance that
the estimates used in this analysis are reasonable. More
importantly, although nine-month mortality was actually
slightly higher in the Saskatchewan patient sample than in the
CURE trial, mortality rates with and without an MI were
JACC Vol. 45, No. 6, 2005
March 15, 2005:838–45
similar between the two sources. Although the Saskatchewan
data still may not perfectly reflect current prognosis during a
longer term, a greater hazard of death without contemporary
therapy would mean the projected life expectancy would be
shorter, rendering these results conservative. Similarly, the data
from Saskatchewan was all from MIs, which may have a higher
hazard long term than the ACS patients in the CURE trial,
again rendering the present analysis conservative. In addition,
there is little doubt that events do predict future increased
mortality (29,30). If the prognostic importance of events in the
CURE trial was just 20% of that in Framingham and
Saskatchewan, the ICERs would still be reasonable. The
impact of an MI occurring in the CURE trial between
randomization and nine months follow-up was large, with a
mortality of 26.3% versus 4.0% in patients suffering versus not
suffering an MI; this suggests that these events are worth
preventing.
Conclusions. From a U.S. societal perspective, clopidogrel
for up to one year in the setting of ACS is cost-effective
according to commonly used benchmarks.
Acknowledgment
The authors thank Patrick Moneuse for statistical assistance.
Reprint requests and correspondence: Dr. William S. Weintraub,
Emory Center for Outcomes Research, 1256 Briarcliff Road, Suite
1N, Atlanta, Georgia 30306. E-mail: [email protected].
REFERENCES
1. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK.
Effects of clopidogrel in addition to aspirin in patients with acute
coronary syndromes without ST-segment elevation. N Engl J Med
2001;345:494 –502.
2. Lamy A, Chrolavicius S, Gafni A, et al. The cost-effectiveness of the
use of clopidogrel in acute coronary syndromes based upon the CURE
study (abstr). Circulation 2002;106:II758.
3. Gold MR, Siegel JE, Russel LB, Weinstein MC. Cost-Effectiveness
in Health and Medicine. New York, NY: Oxford University Press,
1996.
4. Drummond MF, O’Brien B, Stoddart GL, Torrance GW. Methods
for the economic evaluation of health care programmes. Oxford:
Oxford Medical Publications, 1987.
5. Pedersen TR, Kjekshus J, Berg K, et al. Cholesterol lowering and the
use of healthcare resources. Results of the Scandinavian Simvastatin
Survival Study. Circulation 1996;93:1796 – 802.
6. Johannesson M, Jonsson B, Kjekshus J, Olsson AG, Pedersen TR,
Wedel H. Cost effectiveness of simvastatin treatment to lower cholesterol levels in patients with coronary heart disease. Scandinavian
Simvastatin Survival Study Group. N Engl J Med 1997;336:332– 6.
7. Centers for Medicare and Medicaid Services. Medicare Part A. Available
at: www.cms.gov/statistics/medpar/shtstay01drg.pdf. Accessed January
10, 2005.
8. The Medstat Group. DRG Guide: Descriptions and Normative
Values. Ann Arbor, MI: Medstat Group, 1994.
9. Mitchell J, Burge R, Lee A, et al. Per case prospective payment for
episodes of hospital care. Springfield, VA: U.S. Department of
Commerce National Technical Information Service, 1995.
Weintraub et al.
Cost-Effectiveness of Clopidogrel in ACS
845
10. Fried VM, Prager K, MacKay AP, Zia H. Chartbook on Trends in the
Health of Americans. Hyattsville, MD: National Center for Health
Statistics, 2003.
11. Peeters A, Mamun AA, Willekens F, Bonneux L. A cardiovascular life
history. A life course analysis of the original Framingham Heart Study
cohort. Eur Heart J 2002;23:458 – 66.
12. Mahoney EM, Jurkovitz CT, Chu H, et al. Cost and cost-effectiveness
of an early invasive vs conservative strategy for the treatment of
unstable angina and non–ST-segment elevation myocardial infarction.
JAMA 2002;288:1851– 8.
13. Caro J, Ishak KJ, Migliaccio-Walle K. Estimating survival for costeffectiveness analysis: a case study in atherothrombosis. Value Health
2004;7:627–35.
14. Caro J, Migliaccio-Walle K, Ishak KJ, Weintraub WS. Estimating
life-years lost due to atherothrombotic events: flexible survival functions to use in disease modeling (abstr). J Am Coll Cardiol 2004;43
Suppl A:425A.
15. Nieto FJ, Coresh J. Adjusting survival curves for confounders: a review
and a new method. Am J Epidemiol 1996;143:1059 – 68.
16. Lee J, Yoshizawa C, Wilkens L, Lee HP. Covariance adjustment of
survival curves based on Cox’s proportional hazards regression model.
Comput Appl Biosci 1992;8:23–7.
17. Makuch RW. Adjusted survival curve estimation using covariates.
J Chronic Dis 1982;35:437– 43.
18. Ghali WA, Quan H, Brant R, et al. Comparison of 2 methods for
calculating adjusted survival curves from proportional hazards models.
JAMA 2001;286:1494 –7.
19. Efron B, Tibshirani R. An Introduction to the Bootstrap. New York,
NY: Chapman and Hall, 1993.
20. Bauer C, Chapman D, Lin P, et al. The CEA registry: standardizing
the methods and practices of cost-effectiveness analysis. Harvard
Center for Risk Analysis. Available at: http://www.hsph.harvard.edu/
cearegistry/. Accessed January 10, 2005.
21. Goldman L, Gordon DJ, Rifkind BM, et al. Cost and health
implications of cholesterol lowering. Circulation 1992;85:1960 – 8.
22. Laupacis A, Feeny D, Detsky AS, Tugwell PX. Tentative guidelines
for using clinical and economic evaluations revisited. CMAJ 1993;148:
927–9.
23. Yusuf S, Wittes J, Probstfield J, Tyroler HA. Analysis and interpretation of treatment effects in subgroups of patients in randomized
clinical trials. JAMA 1991;266:93– 8.
24. Yusuf S, Mehta SR, Zhao F, et al. Early and late effects of clopidogrel in
patients with acute coronary syndromes. Circulation 2003;107:966 –72.
25. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with
clopidogrel and aspirin followed by long-term therapy in patients
undergoing percutaneous coronary intervention: the PCI-CURE
study. Lancet 2001;358:527–33.
26. Steinhubl SR, Berger PB, Mann JT 3rd, et al. Early and sustained dual
oral antiplatelet therapy following percutaneous coronary intervention:
a randomized controlled trial. JAMA 2002;288:2411–20.
27. Lindgren P, Jonsson B. Modeling the cost-effectiveness of clopidogrel
in acute coronary syndromes without ST-segment elevation in Sweden
(abstr). J Am Coll Cardiol 2003;41 Suppl A:540A.
28. Gaspoz JM, Coxson PG, Goldman PA, et al. Cost effectiveness of
aspirin, clopidogrel, or both for secondary prevention of coronary heart
disease. N Engl J Med 2002;346:1800 – 6.
29. Kleiman NS, Lakkis N, Cannon CP, et al. Prospective analysis of
creatine kinase muscle-brain fraction and comparison with troponin T
to predict cardiac risk and benefit of an invasive strategy in patients
with non–ST-elevation acute coronary syndromes. J Am Coll Cardiol
2002;40:1044 –50.
30. Ghazzal Z, Ashfaq S, Morris DC, et al. Prognostic implication of
creatine kinase release after elective percutaneous coronary intervention in the pre-IIb/IIIa antagonist era. Am Heart J 2003;145:1006 –12.