(Circulation. 2000;102:2923.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
From the Department of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio (A.M.L., E.J.T.); Duke Clinical Research Institute, Durham, NC (D.B.M., J.E.T., R.M.C., L.D.R., J.D.R.); and Centocor, Malvern, Pa (M.V.B., K.M.A., C.F.C.).
Correspondence to A. Michael Lincoff, MD, Associate Professor of Medicine, Department of Cardiology, Desk F25, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195.
| Abstract |
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Methods and ResultsA prospective economic assessment was performed in the 2792 patients enrolled in EPILOG. Patients were randomized to receive placebo with standard-dose weight-adjusted heparin, abciximab with low-dose weight-adjusted heparin, or abciximab with standard-dose weight-adjusted heparin during percutaneous coronary intervention. Hospital billing data for the baseline hospitalization were collected for 2581 patients (92.4% of total) and imputed for the remainder, with physician fees estimated from the Medicare Fee Schedule. For the baseline hospitalization, medical costs (hospitalization and physician fees) averaged $9632 for the placebo arm compared with $8758 (P=0.005) and $9092 (P=0.176) for the abciximab with low-dose and standard-dose heparin arms, respectively. Inclusive of average drug cost ($1454 to $1457), the net incremental baseline cost of these 2 abciximab strategies was $583 with low-dose weight-adjusted heparin and $914 with standard-dose weight-adjusted heparin. During 6-month follow-up, average hospital costs were not significantly different in the 3 treatment groups; cumulative net incremental costs were $1236 and $1268 in the abciximab with low-dose and standard-dose heparin groups, respectively.
ConclusionsTreatment with abciximab and low-dose, weight-adjusted heparin during percutaneous coronary revascularization reduces ischemic events and associated costs, thereby offsetting some of the cost of the drug. The suppression of bleeding complications associated with this agent by heparin dose reduction optimizes the economic attractiveness of this treatment strategy.
| Introduction |
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$1400 cost of
this drug. The purchase price of a therapeutic agent, however, may not
accurately reflect its true economic impact, because adverse events
prevented by the treatment may result in savings that offset the
acquisition cost. In the first study of abciximab during
coronary intervention, the Evaluation of c7E3 for the
Prevention of Ischemic Complications (EPIC) trial, treatment
with abciximab reduced the incidence of ischemic events by 35%
over 30 days and doubled bleeding
complications.1 In that
trial, cost savings associated with diminished ischemic
complications during the initial hospitalization were neutralized by
increased costs associated with bleeding
events,6 raising concerns
regarding the economic attractiveness of this therapeutic
strategy. The subsequent multicenter Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade (EPILOG) trial demonstrated that hemorrhagic risk associated with abciximab therapy could be nearly eliminated by weight-adjustment and reduction of conjunctive heparin dosing, with a resultant 56% reduction in ischemic complications over the first 30 days.2 Given the enhanced efficacy and reduced bleeding complications in EPILOG compared with EPIC, we hypothesized that the net costs associated with this therapy might be substantially reduced. We herein report the results of a prospective economic analysis performed within the EPILOG trial.
| Methods |
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All patients were treated with aspirin and randomized in a double-blind fashion to 1 of 3 treatment groups: placebo with standard-dose, weight-adjusted heparin; abciximab with standard-dose, weight-adjusted heparin; or abciximab with low-dose, weight-adjusted heparin. Postprocedural use of heparin was discouraged, and vascular sheaths were to be removed within 2 to 6 hours (during abciximab infusion). Guidelines were provided for use of coronary stents and management of vascular access sites, uncontrolled bleeding, urgent coronary artery bypass surgery, thrombocytopenia, and blood transfusions. The primary efficacy end point was a composite of death, myocardial infarction, or urgent repeat revascularization within 30 days. Major bleeding was defined by a hemoglobin drop of >5 g/dL or intracranial hemorrhage, and minor bleeding was classified by a hemoglobin drop of >3 to 5 g/dL or gross hematuria or hematemesis.7
Summary of Principal EPILOG Clinical
Outcomes
As reported
previously,2 the incidence of
the composite end point at 30 days was 11.7% in the placebo group,
5.2% in the abciximab with low-dose heparin group (58% relative risk
reduction, P<0.0001), and
5.4% in the abciximab with standard-dose heparin group (54% relative
risk reduction, P<0.0001).
Major end-point components that were reduced by abciximab include
myocardial infarction (8.7% versus 3.7% and 3.8% in the placebo,
abciximab with low-dose heparin, and abciximab with standard-dose
heparin groups, respectively), urgent repeat
percutaneous coronary
revascularization (3.8% versus 1.2% and 1.5%,
respectively), and urgent CABG surgery (1.7% versus 0.4% and 0.9%,
respectively). Stents were reserved for manifest or abrupt closure and
were utilized in 11.8% of patients. Rates of major bleeding
unassociated with CABG surgery were 1.1% in the placebo group, 1.1%
in the abciximab with low-dose heparin group, and 1.9% in the
abciximab with standard-dose heparin group; rates of minor bleeding
were 3.3%, 4.0%, and 7.6%, respectively.
By 6-month follow-up, differences among treatment groups observed at 30 days with regard to death, myocardial infarction, and urgent repeat revascularization were maintained. However, overall repeat revascularization rates were not different (19.4% versus 19.0% and 18.4%, respectively) owing to a trend toward excess nonurgent revascularization procedures in the abciximab treatment groups (13.8% versus 16.7% and 15.4%, respectively, P=NS).2
Design of the Economic Substudy
A prospective economic substudy of patients within
the EPILOG trial was performed in which medical costs and medical
resource consumption were assessed. Methods were identical to those
used in the EPIC trial.6
Hospital bills were collected for all hospitalizations during the study
period, except for those at Canadian, Veterans Administration (VA),
or military hospitals or other hospitals that based charges on a per
diem rate. Of the 2792 patients randomized, 111 (4.0%) and 86 (3.1%)
were enrolled at Canadian and VA or other per diem sites, respectively.
Of the 2595 remaining patients, hospital bills were successfully
collected for the index hospitalization on 2581 (92.4% of total
enrollment, 99.5% of patients hospitalized at centers that generated
bills). Complete hospitalization cost data through 6-month follow-up
were collected on 2474 (88.6%) of the 2782 patients surviving to
initial hospital discharge. Summary UB 92 bill forms were obtained for
each hospitalization, and charges were converted to costs by use of
department-specific cost-to-charge ratios obtained from each
hospitals annual Medicare Cost Report. Physician fees were estimated
based on the resource-based, relative value Medicare Fee Schedule (1994
North Carolina version). Physician activities used to estimate fees
included admission evaluation (intensive care unit [ICU] and
non-ICU), daily follow-up care (ICU, non-ICU), cardiac
catheterization, coronary angioplasty, CABG
surgery, and management of major bleeding. The cost of abciximab was
calculated from the weight-adjusted dose, assigning a cost of $450 per
10-mg vial and assuming that partially unused vials remaining at the
end of the patients treatment would be wasted. Costs for outpatient
care (aside from cardiac catheterization) were not
assessed.
For the 211 patients for whom baseline hospitalization cost could not be obtained due to unavailable bills, all-inclusive or per diem charges, or unavailable cost-to-charge ratios, hospital costs were imputed. Multivariable linear regression modeling was applied to estimate the cost of major resources and selected complications (hospital length of stay, catheterization, percutaneous revascularization, stent placement, CABG surgery, and major and minor bleeding unassociated with coronary bypass surgery), with data from patients with complete hospital cost collection. This model was then used to impute costs for patients with missing data. Because the results of analyses with and without the imputed cost data were unchanged, only the total cohort data (including imputed values) are presented in this article.
Data Analysis
Descriptive statistics are presented as
counts and percentages for discrete variables and medians and
interquartile ranges (25th to 75th percentile) for continuous
variables. Cost data are presented as means and SDs, as the
most relevant estimate of total costs associated with a particular
treatment strategy in a large number of patients. Because of the skewed
distribution of cost data, some variables are presented as
medians reflecting the cost to treat a "typical" patient. All
analyses were performed according to the intention-to-treat
principle. Pairwise comparisons of costs and hospital stay durations
between each abciximab arm and the placebo arm were performed by the
van der Waerden normal scores test, with Fishers exact test used to
assess differences in repeat hospitalization rates. Confidence
intervals for differences in costs were computed with the
bias-corrected bootstrap with 16 000 samples.
The association of costs with procedures or ischemic and bleeding end points was explored with the multivariable linear regression model that had been used to impute costs for patients with unavailable bills. Estimates of the costs of major resources derived from this model were multiplied by incidence rates to calculate the estimated average costs for such events among all randomized patients within each treatment group.
| Results |
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Medical Resource Consumption
The composite efficacy end point of death, myocardial
infarction, or urgent revascularization during the
baseline hospitalization occurred in 10.8% of patients in the placebo
group, 4.9% of patients in the abciximab with low-dose heparin group
(54% relative risk reduction,
P<0.001), and 5.6% of
patients in the abciximab with standard-dose heparin group (48%
relative risk reduction,
P<0.001). Medical hospital
resource consumption during the initial hospitalization is summarized
in
Table 1
according to treatment group. The median
length of hospitalization tended to be shorter in the abciximab
treatment groups. Patients randomized to abciximab required fewer CABG
surgery, repeat percutaneous
revascularization, or cardiac
catheterization procedures, with a trend toward fewer
unplanned ("bailout") stents in the abciximab with low-dose heparin
group. Rates of myocardial infarction were reduced by abciximab.
Bleeding events were not increased relative to placebo in the abciximab
with low-dose heparin arm but were somewhat increased in the abciximab
with standard-dose heparin arm.
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Medical resource consumption during the follow-up period
between baseline hospital discharge and 6 months is also summarized in
Table 1
. Although there were no significant differences in
rates of rehospitalization, catheterization, or
revascularization, these events tended to occur
more frequently among patients randomized to
abciximab.
Medical Costs
Hospital costs and associated physician fees for the
baseline hospitalization (exclusive of abciximab drug cost) are listed
in
Table 2
. Costs tended to be lower among patients randomized
to receive abciximab compared with placebo; these differences were
statistically significant for the abciximab with low-dose heparin
group. Total costs for the baseline hospitalization were reduced by
$874 by abciximab with low-dose heparin (95% CI $341 to $1396;
P=0.005) and by $540 by
abciximab with standard-dose heparin (95% CI $19 more to $1121 less;
P=0.176). Including the cost of
the weight-adjusted abciximab ($1457 and $1454 in the low-dose and
standard-dose heparin groups, respectively), the total net costs of
this therapy during the baseline hospitalization were $583 (95% CI $19
to $1079; P<0.001) in the
abciximab with low-dose heparin group and $914 (95% CI $380 to $1458;
P<0.001) in the abciximab with
standard-dose heparin group.
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To analyze the sources of cost differentials between
the placebo and abciximab treatment groups during the baseline
hospitalization, multivariable linear regression was performed.
Table 3
summarizes the estimated savings in baseline
hospital costs (not including physician fees) associated with abciximab
therapy due to reduction in ischemic events and associated
procedures ("efficacy"), as well as the estimated increased costs
due to bleeding complications. Rates of ischemic and bleeding
events from which these estimates were derived have been detailed in
Table 1
. Of the $806 of baseline hospital cost savings in
the abciximab with low-dose heparin group, $603 was allocated by the
regression model to efficacy, principally owing to the reduction in
CABG surgery rates, use of unplanned stenting, and hospital length of
stay. Similarly, of the $489 of baseline hospital cost savings in the
abciximab with standard-dose heparin group, $484 was allocated to
efficacy because of reduced hospital length-of-stay and rates of bypass
surgery, repeat percutaneous coronary
intervention, and myocardial infarction. There were essentially no
excess costs (-$2) associated with bleeding among patients randomized
to abciximab with low-dose heparin, whereas $40 in cost savings was
lost among patients treated with abciximab with standard-dose heparin
owing to the modest increase in major and minor bleeding events. A
small proportion of the observed cost savings ($205 and $45 in the
abciximab with low-dose heparin and standard-dose heparin groups,
respectively) was not accounted for by the efficacy or bleeding
variables included in the multivariable regression
model.
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Table 4
shows the hospital costs over the 6-month follow-up
period after baseline hospital discharge. There were no significant
differences in follow-up costs among the 3 treatment groups.
Nevertheless, there was a trend toward increased hospital costs among
patients receiving abciximab, due to increased rates of nonurgent
revascularization in these treatment groups (see
Table 1
). Costs accumulated gradually over time after the
baseline hospitalization discharge. By 6 months, total follow-up
hospitalization costs were $653 higher compared with placebo in the
abciximab with low-dose heparin group (95% CI $1609 higher to $118
lower; P=0.144) and $355 higher
in the abciximab with standard-dose heparin group (95% CI $1275 higher
to $430 lower; P=0.429).
Cumulative net costs (including abciximab cost) over the entire 6-month
study period (hospitalization plus follow-up) were therefore $1236
higher than with placebo in the abciximab with low-dose heparin group
(95% CI $209 to $2345) and $1268 higher in the abciximab with
standard-dose heparin group (95% CI $265 to $2406).
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Cumulative frequency distribution curves for total baseline
hospital and cumulative 6-month costs (inclusive of abciximab drug
cost) are shown in the
Figure
.
Abciximab therapy was associated with increased costs in the majority
of patients, with neutral or reduced costs in the remainder due to
prevention of adverse events.
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| Discussion |
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The baseline hospitalization costs assessed in this economic analysis represent a relevant measure of the costs experienced by hospitals operating under noncapitated payment systems. With such payment arrangements, costs incurred during the initial hospitalization are often reimbursed at a fixed level, although subsequent hospitalization costs are generally billed and reimbursed separately. Thus, for cost savings to recoup the price of a new drug therapy from a provider perspective, they must accrue during the hospitalization period in which that drug is administered, rather than as a delayed cost savings over long-term follow-up. In this regard, the findings of the EPILOG economic analysis are particularly germane, because cost offsets due to efficacy from abciximab occurred during the baseline hospitalization period. It should be noted, however, that $68 of the total $874 cost savings in the abciximab plus low-dose heparin arm were attributable to reductions in physician fees (not included in hospital payments) and therefore would not be realized by the hospital. The attenuation of the economic benefit of abciximab observed over 6-month follow-up in EPILOG due to repeat revascularization procedures would be relevant, however, to capitated payors or healthcare systems.
Baseline hospitalization cost savings with abciximab in
EPILOG arose primarily from reduction in the need for repeat
revascularization procedures, less bailout
stenting, and shortened hospital lengths of stay
(Table 3
). Interestingly, periprocedural myocardial
infarction was also associated with an estimated cost of $1180 by
regression analysis, independently of consequent use of repeat
revascularization procedures or prolonged duration
of hospitalization. Importantly, however, a major bleeding event was
estimated to cost $3295, more than any other single event except CABG
surgery, highlighting the potential for bleeding complications to
markedly attenuate any cost savings achieved through reduction in
ischemic end points.
It is thus instructive to compare the economic outcome in EPILOG to that in the prior study of abciximab during coronary intervention, the EPIC trial. As in EPILOG, clinical efficacy in EPIC was associated with a cost savings during the initial hospitalization, estimated by regression analysis to be $444 per patient compared with placebo therapy.6 However, with the increase due to abciximab in rates of major and minor bleeding, this economic savings due to efficacy was offset by a estimated $531 cost due to bleeding. Inclusive of drug cost, then, the net incremental cost of abciximab therapy during the baseline hospitalization in EPIC was $1550. In contrast, the EPILOG trial demonstrated that clinical efficacy of abciximab could be uncoupled from bleeding complications by dose reduction and weight adjustment of concurrent heparin dosing. As a result, economic savings due to reduced ischemic events were not offset by costs of bleeding complications, and the net incremental cost of abciximab therapy during the baseline hospitalization in EPILOG was $583, only 38% of that in the earlier EPIC trial. These findings establish the importance of careful heparin dosing during abciximab administration to optimize not only clinical outcome but the economic attractiveness of this therapy as well.
Outcome over the 6 months after baseline hospitalization also differed between the EPIC and EPILOG trials. In EPIC, follow-up rates of repeat revascularization and rehospitalization were reduced by abciximab,6 resulting in a $1270 cost savings over the follow-up period. This finding was not reproduced in EPILOG, where rates of elective revascularization were nonsignificantly increased in the abciximab groups. As a result, follow-up hospital costs were $355 to $653 higher among patients randomized to abciximab compared with placebo in EPILOG. Moreover, it remains unclear whether the need for late revascularization procedures and their associated economic costs were actually increased by abciximab therapy in the EPILOG trial. Such a finding may have been spurious because of statistical chance, and an excess risk for elective revascularization procedures with abciximab was not observed among patients receiving stents in the recent Evaluation of Platelet Inhibition in Stenting (EPISTENT) trial.8 Alternatively, the reduction in periprocedural myocardial infarction risk by abciximab in EPILOG might have predisposed to more frequent late revascularizations.9
Economic analyses have also been published for 2
other trials of GP IIb/IIIa blockade during
percutaneous coronary intervention. In
EPISTENT, abciximab among patients undergoing stenting was associated
with an incremental baseline hospital cost of $1305 and a cumulative
incremental cost over 1 year of
$932.10 Based on the
observed mortality benefit of abciximab, the cost-effectiveness ratio
was calculated to be $6213 per added life-year, a value that compares
favorably with other accepted medical therapies. In the Randomized
Efficacy Study of Tirofiban for Outcomes and Restenosis
(RESTORE) trial, there was no significant difference in hospital costs
among patients receiving placebo or tirofiban during coronary
angioplasty, in part because of the relatively low acquisition cost of
tirofiban (
$700).11
Importantly, however, clinical efficacy of tirofiban therapy in RESTORE
was marginal,12 because this
agent did not significantly reduce the incidence of death, myocardial
infarction, or urgent revascularization by 30 days
(24% relative risk reduction in RESTORE,
P=0.052, compared with the 56%
relative risk reduction observed in EPILOG); it is therefore difficult
to compare the economic profiles of abciximab and tirofiban in these 2
trials.
This study has several limitations. First, outpatient costs (aside from cardiac catheterization) were not considered, nor were indirect or productivity costs, such as those related to loss of employment. Such costs may have been somewhat reduced by abciximab because of fewer complications during the baseline hospitalization or increased owing to late revascularization procedures. Second, the use of summary UB 92 bill forms to estimate costs is only an approximation that has been validated in selective instances, but not in all hospitals. Moreover, owing to the large number of physicians providing care to patients in this trial, we were unable to directly collect physician bills and instead estimated professional costs using the Medicare Fee Schedule; this method of estimation captured all "big ticket" items, however, such as rehospitalizations and cardiac procedures. Third, cost-effectiveness analyses were not performed, because abciximab did not result in a statistically significant reduction in mortality in this trial, and utility was not assessed. Finally, the relevance of these findings in a trial of balloon angioplasty are unclear in the current era, in which elective stenting is the predominant means of percutaneous coronary revascularization. The reduction of clinical ischemic events by abciximab among stented patients in the EPISTENT trial was equivalent to that among patients undergoing balloon angioplasty in EPILOG,5 however, and the economic analysis in that trial suggested that this treatment strategy also has a favorable economic profile in stented patients.10
Summary
Prospective economic analysis in the EPILOG
trial demonstrates that reduction in ischemic events during the
baseline hospitalization among patients receiving abciximab offsets
more than half of the cost of the drug, resulting in a net incremental
baseline hospitalization cost of therapy with abciximab and low-dose
heparin of $583. Suppression of bleeding complications associated with
this agent by heparin dose reduction optimizes the economic
attractiveness of this treatment
strategy.
| Acknowledgments |
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| Footnotes |
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1 A complete list of the principal investigators and study coordinators of the EPILOG (Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade) Study Group can be found in N Engl J Med 1997;336:1689-1696. ![]()
Received May 25, 2000; revision received August 3, 2000; accepted August 8, 2000.
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