CLINICAL THERAPEUTICSVVOL. 23, NO.

2,200l

Cost-Minimization Analysis of Simvastatin Versus

Atorvastatin for Maintenance Therapy in Patients with
Coronary or Peripheral Vascular Disease

Ermanno Attanasio, DEc,l Pierluigi Russo, MD,2

and Shannon E. Allen, MS3
‘Department of Experimental Medicine and Pathology, 2Department of Human
Physiology and Pharmacology, University La Sapienza, Rome, Italy, and 3Department
of Statistics, Temple University, Philadelphia, Pennsylvania

ABSTRACT

Background: Previous health economic studies have demonstrated the cost-effective-

ness of simvastatin in the treatment of coronary heart disease (CHD) based on clinical re-
sults of the Scandinavian Simvastatin Survival Study. A prior analysis evaluated the “cost
of getting to goal,” but ignored all costs after titration. However, when evaluating the cost-
effectiveness of long-term therapies, it is important to consider the maintenance costs
as well.
Objective: The purpose of this study was to evaluate the maintenance costs of treat-
ment with simvastatin versus that of treatment with another more recently available statin,
atorvastatin, in a European context.
Methods: We assessed the long-term maintenance cost of simvastatin versus atorva-
statin in terms of the cost of reducing low-density lipoprotein cholesterol (LDL-C) levels
to the recommended goals based on a previously published clinical trial in patients with
CHD. The analysis focused on the patients in the original clinical trial who were ran-
domized to treatment with simvastatin or atorvastatin. Patients began therapy with 10 mg
of simvastatin or atorvastatin; the dose of study drug was titrated every 12 weeks up to
40 mg simvastatin or 80 mg atorvastatin, with the addition of up to 8 g/d of cholestyra-
mine until a modified European Atherosclerosis Society LDL-C goal (52.84 mmol/L) was
reached. As there was no significant difference between the 2 groups in resource utiliza-
tion for adverse events, only drug costs were included. The calculated average annual
maintenance cost was based on the distribution of the final daily dosing regimens and the
public drug prices for each regimen. Individual country analyses were conducted using
each local currency.
Results: There was no significant difference between groups in the percentage of pa-
tients reaching their LDL-C goal over the study period (80% for simvastatin-treated pa-

Accepted for publication December 13, 2000.

Printed in the USA. Reproduction in whole or part is not permitted.

276 0149-2918/01/$19.00
E. ATTANASIO ET AL.
tients vs 89% for atorvastatin-treated pa-
tients, P = 0.135). However, the cost of
maintaining a similar percentage of pa-
tients at their appropriate LDL-C levels
was significantly lower in the simvastatin
group compared with the atorvastatin
group in 13 of the 17 countries assessed.
In the remaining 4 countries, there was a
cost advantage for simvastatin, but it did
not reach statistical significance.
Conclusions: Across Europe there was
a significant reduction in the cost of main-
taining patients at their appropriate LDL-C
levels with simvastatin versus atorvastatin.
The results of this analysis, along with the
proven clinical benefits of simvastatin,
support the use of this drug as the treat-
ment of choice in the secondary preven-
tion of CHD.
Key words: outcomes, cost, cholesterol,
simvastatin, atorvastatin. (Clin Ther: 200 1;
23:276-283)
BACKGROUND
Cardiovascular disease accounts for ap-
proximately half of all deaths and a large
expenditure of health care resources. The
cost of treating cardiovascular disease ac-
counts for -10% to 15% of total health
care expenditures in developed countries.’
In the Scandinavian Simvastatin Survival
Study (4S),* treatment with simvastatin in
patients with preexisting coronary heart
disease (CHD) resulted in a 30% reduc-
tion in the risk of death (P c 0.001) over
a median follow-up period of 5.4 years, at-
tributable to a 42% reduction in coronary
deaths. After an additional 2 years of open-
label treatment, the reductions in mortality
were maintained, with a 30% reduction in
the risk of death (P = 0.024) and a relative
risk for coronary death of 0.62 (0.51-
0.76).3 The 4s has shown that treatment
with simvastatin for up to 8 years is well
tolerated and can produce continued sur-
vival benefit in patients with CHD.
Previous health economic studies have
demonstrated the cost-effectiveness of
simvastatin in patients with CHD, based on
the proven clinical results in 4s. Over the
5.4-year follow-up period of the study, treat-
ment with simvastatin reduced the use of
hospital services by 34% and was highly
cost-effective in this patient population.4J
The cost-effectiveness ratio, or cost per
life-year saved, of simvastatin (&5502,
corresponding to $7825 at the current ex-
change rate)5 was of the same magnitude
as that of beta-blockers in the post-
myocardial infarction setting ($360-!$17,000,
corresponding to &252-&l 1,952 at the cur-
rent exchange rate).6 Another study demon-
strated that simvastatin remained cost-
effective across all the subgroups evaluated
in 4s (by age, sex, and baseline cholesterol
levels) and that when the cost of productiv-
ity losses were included, treatment with
simvastatin was cost-saving in the young
working-age population (average age 35
years)?
More recently another statin, atorva-
statin, has become available in Europe.
The only outcomes data currently avail-
able for atorvastatin are from an 18-month
study conducted in high-risk patients tak-
ing atorvastatin 80 mg.8 The results indi-
cated a nonsignificant reduction (P =
0.048, a level = 0.045) in percutaneous
revascularizations with atorvastatin 80 mg
compared with usual care.8 Because of
the lack of data on beneficial outcomes or
long-term tolerability of atorvastatin, eco-
nomic comparisons of atorvastatin and
other statins must be limited to evalua-
tions based on surrogate efficacy mea-
sures such as reductions in low-density
lipoprotein cholesterol (LDL-C) and drug
277

prices. The Surrogate Marker Cost-Efficacy
(SMaC) study9 showed that in a primary-
prevention population, treatment with
simvastatin resulted in a similar percent-
age of patients reaching their LDL-C goal,
but at a significantly lower cost compared
with atorvastatin treatment (P < 0.001).
Over the 52-week study period, the cost
of atorvastatin treatment was 25% more
than that of simvastatin, with no signifi-
cant difference in the percentage of pa-
tients reaching their LDL-C goal.
In a recently published study by Smith
et al,‘O the cost of getting patients with
preexisting CHD and/or peripheral vascu-
lar disease (PVD) to a modified European
Atherosclerosis Society LDL-C target
with various statins was estimated. In this
54-week study, patients were randomized
to 1 of 4 statins (atorvastatin, fluvastatin,
pravastatin, or simvastatin) and the dose
was titrated every 12 weeks until patients
reached their target LDL-C level. A higher
percentage of patients who received ator-
vastatin (89%) or simvastatin (80%)
reached their LDL-C target compared with
patients who received fluvastatin (6 1%;
P < 0.001 vs atorvastatin; P = 0.018 vs
simvastatin) or pravastatin (50%; P <
0.001 vs atorvastatin and simvastatin). No
significant difference between simvastatin
and atorvastatin groups was found in the
percentage of patients who reached goal
(P= 0.135). However, the average time to
reach target LDL-C level was shorter for
patients who received starting doses of
atorvastatin. An economic evaluation
based on this study compared the costs
for physician visits, laboratory tests, and
drugs from study initiation until the visit
in which patients reached their LDL-C
target. Although atorvastatin was found to
have the lowest cost over this period, one
must also consider the costs once patients
278
CLINICAL THERAPEUTICS”
reach the goal. The authors note that the
cost advantage narrows when a common
period of 54 weeks is used to assess costs.
Payers, however, must consider not only
the initiation costs of lipid-lowering ther-
apies, but also the associated maintenance
costs.
To make the results of the study more
useful to health care payers, we used the
final dosing data from the aforementioned
clinical triali to project the annual main-
tenance cost of simvastatin versus atorva-
statin in patients with preexisting CHD
and/or PVD, in a European context. Be-
cause the clinical trial demonstrated that
both fluvastatin and pravastatin are less ef-
ficacious than atorvastatin and simvastatin,
the focus of the current analysis was a
comparison of costs between simvastatin
and atorvastatin, for which there was no
significant difference in the percentage of
patients reaching their LDL-C target.
METHODS
We performed a cost-minimization analy-
sis comparing the average annual mainte-
nance costs for simvastatin and atorva-
statin in hypercholesterolemic patients
with CHD and/or PVD in 17 western Eu-
ropean countries. We used the final dos-
ing regimen from the 54-week titration
study published by Smith et ali0 as the
maintenance dose. The average annual
maintenance cost was based on the distri-
bution of the final daily dosing regimens
and the cost for each regimen using local
pharmaceutical costs.
Only the annual maintenance treatment
costs were projected in this analysis. If
the data were available, a comprehensive
economic evaluation would include the
costs of future events, whether related to
benefits of therapy or adverse experiences.
E. ATTANASIO ET AL.
Within the clinical trial, there was no sig-
nificant difference between atorvastatin
and simvastatin in treatment-related ad-
verse events requiring medical resource
utilization (P = 0.294 for additional physi-
cian visits). Once patients reach their op-
timum dose through titration, the number
of physician visits to monitor therapy
would be expected to be the same in both
groups. However, without data on future
events and the long-term use of medical
resources for atorvastatin we were forced
to rely on the data from the published clin-
ical trial; therefore, only drug costs were
included.
Clinical Trial
The distribution of final dosing regi-
mens was taken from the published re-
sults of a 54-week, randomized, open-
label study in 336 hypercholesterolemic
patients with CHD and/or PVD. lo Patients
from 28 centers in 17 western European
countries were advised to follow a con-
trolled, low-cholesterol diet throughout
the study. During a 4-week dietary base-
line phase, patients underwent 2 fasting
lipid measurements 2 and 4 weeks before
randomization. If the average of the 2
LDL-C measurements was 8135 mg/dL
(3.49 mmol/L), patients were randomly
assigned to 1 of 4 study medications: ator-
vastatin (n = 140), simvastatin (n = 66),
fluvastatin (n = 58), or pravastatin (n =
72). The primary clinical efficacy variable
was attainment of a modified LDL-C tar-
get of ~110 mg/dL (~2.84 mmol/L).
Patients were considered to have
achieved the LDL-C target if the average
of 2 LDL-C measurements at 2 consecu-
tive visits was ~110 mg/dL (~2.84 mmol/L).
Patients received the recommended start-
ing dose of each statin (fluvastatin 20 mg,
atorvastatin 10 mg, pravastatin 20 mg, sim-
vastatin 10 mg), and the dose was titrated
upward every 12 weeks until the LDL-C
target was achieved. In each treatment arm,
cholestyramine (up to 8 g/d) was added if
the target was not reached with the high-
est recommended dose for the statin.
Maintenance Dose Distribution
To determine the distribution of the
maintenance dosing regimens, we as-
sumed that patients from the clinical trial
maintained treatment at their last recorded
dosage. In the trial, the dose was no longer
titrated for patients who reached the tar-
get LDL-C level. If a patient reached tar-
get at a given dosage, we assumed that
treatment was maintained at that level and
was not titrated to a lower dose (per pro-
tocol). If a patient did not reach target at
a given dosage, then the dose was titrated
upward until the patient either reached the
target LDL-C level or completed the
study. The distribution of patients accord-
ing to their final dosing regimen is shown
in Table I. There was a significantly
greater proportion of patients who re-
mained at the starting dose in the atorva-
statin treatment group than in the simva-
statin treatment group (55% vs 38%, P =
0.022); however, there is no evidence to
suggest that the titration distributions of
these 2 treatments differed among those
patients who were titrated 21 time.
Cost Data
Public prices for each dose of atorva-
statin, simvastatin, and cholestyramine
were used to obtain the cost for each drug
regimen; this cost was then used to calcu-
late the average annual maintenance cost.
Public prices were collected from each of
279
 CLINICAL THERAPEUTICS”

Table I. Distribution of final daily doses of simvastatin and atorvastatin.

No. (%) of Patients

Regimen Simvastatin (n = 66) Atorvastatin (n = 140)

10mg 25 (37.9) 77 (55.0)

20 mg 17 (25.8) 31 (22.1)
40 mg 9 (13.6) 14 (10.0)
80 mg NA 11 (7.9)
40 mg + cholestyramine 4 g 15 (22.7) NA
40 mg + cholestyramine 8g 0 (0) NA
80 mg + cholestyramine 4 g NA 7 (5.0)

NA = not available, by protocol design.

Adapted from Smith et al.‘O

the 17 western European countries and
were applied to the maintenance dose dis-
tribution. Public prices are inclusive of
wholesaler and pharmacy margins placed
on the ex-manufacturer price, and are
the prices generally paid by the health
authorities.
Statistical Analysis
The null hypothesis that the average
daily maintenance costs were equal for
patients treated with atorvastatin and sim-
vastatin was tested against the alternative
that they differed using a bootstrap ran-
domization test with 1000 bootstrap repli-
cates.‘l The randomization P value was
calculated as the proportion of replicates
with mean differences that were greater
than the absolute value of the observed
mean difference.
RESULTS
The average daily maintenance cost of
simvastatin was significantly lower than
that of atorvastatin in 13 of the 17 western
European countries studied (Austria, Bel-
gium, France, Germany, Greece, Ireland,
Italy, the Netherlands, Portugal, Spain,
Sweden, Switzerland, and the United
Kingdom) (Table II). In these countries,
the percentage decrease in annual mainte-
nance cost for simvastatin compared with
atorvastatin ranged from 16.0% (Sweden
and France) to 43.5% (Spain). In the re-
maining 4 countries (Denmark, Finland,
Luxembourg, and Norway), the cost of
simvastatin was lower than that of ator-
vastatin, although the difference was not
statistically significant.
DISCUSSION
These data show the relative costs and ben-
efits of therapy with simvastatin and ator-
vastatin in terms of surrogate markers of
efficacy and drug costs. There was no sig-
nificant difference between the simvastatin
and atorvastatin treatment groups in the
proportion of patients who reached target
LDL-C levels (80% for simvastatin vs 89%
for atorvastatin, P = 0.135).The level of ef-
ficacy was not inconsistent with that found
in a recent study by Pedersen et al,t2 in
which 90% of patients receiving 40 mg sim-
vastatin achieved their LDL-C goals. Al-
though both agents demonstrated similar

280
E. ATTANASIO ET AL.

Table II. Annual maintenance costs for patients taking simvastatin and atorvastatin in 17
western European countries.

Cost in Local Currency

Percent
Country Local Currency Simvastatin Atorvastatin Difference Difference P

Austria Schilling 8809 12,244 -3435 28.1 <O.ool

Belgium Belgian franc 27,055 34,330 -7275 21.2 0.012
Denmark Krone 5545 6328 -783 12.4 0.096
Finland Markka 3974 463 1 -657 14.2 0.078
France French franc 3653 4349 -696 16.0 0.045
Germany Deutsche mark 1551 1925 -374 19.4 0.022
Greece Drachma 197,391 271,214 -73,823 27.2 <O.OOl
Ireland Punt 404 485 -81 16.7 0.022
Italy Lira 1,282,277 1,832,185 -549,908 30.0 <0.001
Luxembourg Franc 3 1,908 34,330 -2422 7.1 0.471
Netherlands Guilder 1110 1423 -313 22.0 0.010
Norway Krone 5360 5988 628 10.5 0.151
Portugal Escudo 129,556 209,865 -80,309 38.3 <O.OOl
Spain Peseta 91,236 161,617 -70,38 1 43.5 <o.oo 1
Sweden Krona 4598 5475 -877 16.0 0.020
Switzerland Swiss franc 1101 1358 -257 18.9 0.023
United Kingdom Pound 358 448 -90 20.1 0.004

efficacy, we found, on an individual coun- CHD.i3 However, without published posi-

try basis, a cost advantage for simvastatin
that was numerically consistent across all
17 countries evaluated and statistically sig-
nificant in 13 countries. These results are
consistent with the results of the SMaC
study9 in primary prevention, which demon-
strated that a similar percentage of patients
achieved their LDL-C goal while taking
simvastatin at a 20% lower cost than while
taking atorvastatin (P < 0.001).
Results of the present analysis must be
viewed against the study’s limitations.
First, the analysis of benefits in this study
was based on a surrogate efficacy mea-
sure, that is, the percentage of patients
maintained at their target LDL-C level. A
number of studies have demonstrated a with CHD in most countries is 20 mg.
correlation between LDL-C level and
tive data on long-term outcomes and tol-
erability of atorvastatin, the use of LDL-C
level as a surrogate assumes that there are
no other factors that may affect coronary
events. It has been shown, however, that
raising high-density lipoprotein choles-
terol levels, in combination with lowering
LDL-C levels, is strongly correlated with
improved coronary risk.i4
Second, this study does not reflect re-
cent changes in dosage indications for
simvastatin. This is primarily a limitation
of the clinical trial on which the study
was based. The starting dose used for sim-
vastatin was 10 mg in this study, whereas
the approved starting dose for patients
Moreover, the highest dose of simvastatin

281

included in this study was 40 mg. In many
countries, however, the dose of simva-
statin can be titrated up to 80 mg. Despite
this, there was no significant difference
between simvastatin and atorvastatin
treatment groups in the percentage of pa-
tients achieving target LDL-C levels.
Third, this analysis assumes that all pa-
tients continued treatment at the dose at
which the target LDL-C level was reached.
Although it was reported that a portion of
patients originally randomized to each
treatment group did not complete the study
(7% and 11% for the atorvastatin and sim-
vast&in treatment groups, respectively), it
was not possible to determine which dose
these patients were taking before discon-
tinuation. The patients who dropped out of
the study would not incur any additional
medication costs; however, we were un-
able to account for this in the analysis.
Fourth, the sample’ sizes in the clinical
trial on which this analysis was based may
not have been adequate to show statisti-
cally significant differences between sim-
vastatin and atorvastatin. However, if we
assume that the difference was significant,
then an analysis of the differences in the
annual maintenance cost per percentage of
patients reaching the target LDL-C level
would be appropriate. In this case, the cost
per percentage of patients reaching the tar-
get LDL-C level was less for simvastatin
than for atorvastatin in all the countries
studied, with the exception of Luxembourg.
Fifth, the analysis of costs is restricted
to medications alone. Many health au-
thorities make resource allocation deci-
sions based on drug costs only, and our
analysis should provide useful informa-
tion for such decisions. Medication costs,
however, represent only 1 component of
the overall cost of care for these patients.
As demonstrated in 4S, simvastatin re-
282
CLINICAL THERAPEUTICS”
duced the use of hospital services by coro-
nary patients by 34%.3 The current analy-
sis is unable to take into account the
proven benefits of simvastatin or the po-
tential benefits of atorvastatin on health
care resource utilization, because these
end points were beyond the scope of the
clinical trial underlying this economic
evaluation. True cost-effectiveness com-
parisons based on cost per life-year saved
or cost per quality-adjusted life-year saved
would need to be based on statistical ex-
trapolation until similar results can be
demonstrated with atorvastatin.
Despite the aforementioned issues, this
study provides a useful evaluation of the
relative costs and benefits of simvastatin
and atorvastatin in terms of surrogate
markers of efficacy and drug costs. In
terms of efficacy, there was no significant
difference in the percentage of patients
reaching their target LDL-C levels. Fur-
thermore, based on this analysis there was
a significant reduction in the cost of main-
taining patients at their target LDL-C lev-
els with simvastatin treatment versus ator-
vastatin treatment in 13 of 17 western
European countries. These results should
provide information that is useful for
physicians and payers; however, addi-
tional long-term clinical trials of atorva-
statin are required to assess the drug’s tol-
erability, cost-effectiveness, and impact
on patient outcomes.
CONCLUSIONS
The cost of maintaining patients at target
LDL-C levels was significantly lower with
simvastatin than with atorvastatin in 13 of
17 western European countries. The re-
sults of this study support the use of sim-
vastatin as the treatment of choice for sec-
ondary prevention of CHD.
E. ATTANASIO ET AL.
ACKNOWLEDGMENTS
Economic analyses were supported by
Worldwide Outcomes Research, Merck &
Co, Inc, Whitehouse Station, New Jersey.
The clinical trial on which the economic
analysis was based was funded by Parke-
Davis Pharmaceutical Research, Ann Ar-
bor, Michigan.
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