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Volume 12 • Supplement 3 • 2009
VA L U E
I N
H E A LT H
Evaluation of Cost-Utility of Varenicline Compared with
Existing Smoking Cessation Therapies in South Korea
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Jung Youn Bae, BS,1 Cheol Hwan Kim, MD, PhD,2 Eui Kyung Lee, PhD1
1
Graduate School of Clinical Pharmacy, SookMyung Women’s University, Seoul, South Korea; 2Family Medicine of Seoul Paik Hospital, Seoul,
South Korea
A B S T R AC T
Objective: This study aimed to evaluate the cost-effectiveness of varenicline compared with the other smoking cessation interventions, bupropion, nicotine replacement therapy (NRT), and willpower.
Methods: The Benefits of Smoking Cessation on Outcomes model was
modified to reflect major smoking-related diseases in Korea. Transitional
probabilities, resource utilization, and costs were obtained from Korean
public data. The analysis was carried out from a societal perspective for
the lifetime period. Also, series of sensitivity analyses, including probabilistic sensitivity analysis, were performed.
Results: With the exclusion of bupropion, which is subject to extended
dominance, the incremental cost-effectiveness ratio (ICER) for varenicline
versus NRT was analyzed as $US4809 per quality-adjusted life-year
(QALY) during the lifetime. The results of sensitivity analysis are quite
stable across most of the included parameters. The acceptability curves
showed that the probability of varenicline being cost-effective was 83.3%
at the willingness to pay of $US15,000.
Conclusions: Even though the maximum willingness to pay for a QALY
has not officially been defined, varenicline can be regarded as cost-effective
because the ICER is at the 24.0% level of per capital gross domestic
product, which is an implicit reference for decision-making in Korea.
Keywords: cost-utility analysis, Markov model, pharmocoeconomics,
smoking cessation.
Introduction
Third, the smoking rate by sex in Korea is different from that
of other countries. There are similarities in the smoking rate
between the sexes in Europe and the United States. In Asian
countries including Korea, however, the female smoking rate is
much lower than the male smoking rate. According to the 2005
Korean National Health and Nutritional Survey [6], the overall
smoking rate was 27.3% (male: 52.2%, female: 3.9%). These
results showed that most smokers are males. If the costeffectiveness of smoking cessation treatment is different between
the sexes, sex difference in smoking rate among countries can
have some impact on the study results.
Given the above background, we conducted this study to
assess the cost-effectiveness of varenicline compared with the
other currently available smoking cessation drugs (NRT and
bupropion) and willpower. Then, we attempted to propose the
most cost-effective alternatives by estimating the long-term benefits of smoking cessation from a societal perspective based on
Korean PE guidelines [1].
Smoking is not simply a preferential activity but a detrimental
one, causing various physical diseases. Many smokers often fail
to quit smoking because smoking is related to nicotine dependency, which leads to chronic diseases that require repeated
therapies. There are some smoking cessation drugs that are currently available, such as nicotine replacement therapy (NRT),
bupropion SR, nortriptyline, and clonidine. A new smoking cessation drug, varenicline is also available as a prescription drug in
Korea. Nevertheless, it is not reimbursed by insurance coverage
yet. For a new drug to be reimbursed, an economic assessment
based on Korean pharmacoeconomic (PE) guidelines [1] is mandatory with the introduction of positive list system from 2007
(for more information on all the following references, see Evaluation of Cost-Utility of Varenicline Compared with Existing
Smoking Cessation Therapies in South Korea Value in Health
Supporting Information, part II at: http://www.ispor.org/
Publications/value/ViHsupplementary/ViH12s3_EKLee.asp). A
cost-effectiveness analysis of varenicline has already been performed in other countries [2–4], but the results cannot be applied
to a Korean clinical setting for the following reasons.
First, smoking-related morbidities can be different in Korea.
Unlike Western countries, stomach cancer and liver cancer rank
higher than other smoking-related cancers in Korean males.
Among Korean females, lung cancer, esophageal cancer, and
stomach cancer are the three most prevalent disease burdens [5].
Second, in Korea, per capita health-care expenditures are
relatively low compared with other Organization for Economic
Cooperation and Development (OECD) countries. New drugs are
valuable when they prevent smoking-related morbidities. In
Korea, however, the treatment cost is relatively low and the
trade-off between the drug and treatment cost can be different
from other countries.
Address correspondence to: Eui Kyung Lee, Graduate School of Clinical
Pharmacy, SookMyung Women’s University, Hyochangwongil 52,
Yongsan-Ku, Seoul 140-742, South Korea. E-mail: [email protected]
10.1111/j.1524-4733.2009.00631.x
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Methods
Model Design
A Markov model, the Benefits of Smoking Cessation on Outcomes model, was adopted to conduct a long-term cost-utility
analysis in four smoking cessation alternatives (for more information on all the following tables and figures, see Evaluation of
Cost-Utility of Varenicline Compared with Existing Smoking
Cessation Therapies in South Korea Value in Health Supporting
Information, part I at: http://www.ispor.org/Publications/value/
ViHsupplementary/ViH12s3_EKLee.asp). The time horizon was
set to the lifetime years reaching the time point when the cohort
became 100 years old. Based on Korea’s PE guidelines [1], a
discount rate of 5% was applied to both cost and effectiveness.
Smoking-Related Comorbidities
Rationales for our selection of six diseases are based on the
following reasons: First, the three cancers (lung, stomach, and
© 2009, International Society for Pharmacoeconomics and Outcomes Research (ISPOR)
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Cost-Utility Analysis of Smoking Cessations
liver cancer) are the top three cancers from the result of
multiplying the disability-adjusted life-year by the population
attributable risk (PAR) due to smoking [5]. Second, three
smoking-related chronic diseases (ischemic heart disease [IHD],
stroke, and chronic obstructive pulmonary disease [COPD]),
known to have high incidence rates among the Korean population and to be associated with smoking greatly, were the most
prevalent diseases with high PAR [7].
Model Inputs
The prevalence, incidence, and mortality rate of the six diseases
in this study were subdivided based on smoking state, sex, and
age band using the existing epidemiological data [6,8,9–11] and
the relative risk (RR) of smoking [12,13] (Table S2).
To compare the efficacy of each smoking cessation intervention, we found head-to-head trials about varenicline and bupropion, and those about varenicline and NRT. Nevertheless, there
are only two clinical trials [14,15] that compared varenicline and
bupropion, and no clinical studies have been conducted on
varenicline and NRT. For the quitting rates for the interventions,
we conducted meta-analysis of the related trials [14–18]
(Table S3).
The relapse rate for the recent quitters was obtained as 6.8%
from the previous study [19] (References 19–36 found at Evaluation of Cost-Utility of Varenicline Compared with Existing
Smoking Cessation Therapies in South Korea Value in Health
Supporting Information at: http://www.ispor.org/Publications/
value/ViHsupplementary/ViH12s3_EKLee.asp). By contrast, the
long-term quitters are those who have quitted for more than 6
years (6+ years), in whom the relapse rate was 2% during a
period ranging from 6 to 10 years and 1% after a 10-year period
[20].
We obtained utility weights based on published studies
[21–25]. On the one hand, utility weights for the cohort with no
comorbidity were specified depending on the age, sex, and
smoking status [25]. On the other hand, the utility weight for the
cohorts with a smoking-related morbidity was applied to the
model regardless of the age, sex, and smoking status based on
various data resources [21–25] (Table S4).
Table S5 shows the direct annual per capita medical costs of
six smoking-related diseases [26–28]. The direct cost for therapies includes drug [29], pharmacy dispensing, physician visit,
monitoring, and traveling cost [6]. In order to calculate the direct
medical cost, we used National Health Insurance reimbursement
fee schedule [30]. As NRT is an over-the-counter drug, only drug
cost was included (Table S5).
Sensitivity Analyses
One-way sensitivity analyses were conducted on discount rate,
efficacy of varenicline, cost, and utility weight. Also, the probabilistic sensitivity analysis (PSA) was conducted for major parameters used in the model, including effectiveness of smoking
cessation strategies and treatment cost for morbidities and utilities. For the distribution followed by each parameter, the beta
distribution was used for the quit rate and utilities, whereas the
log normal distribution was used for costs based on related study
[31].
Results
Varenicline had the lowest absolute number of cumulative lifetime incidence cases of smoking-related morbidities (Table S6),
and also have the lowest number of deaths from the included
smoking-related morbidities. Drug cost was the highest for
varenicline, whereas direct medical cost to treat the included
smoking-related morbidities was the lowest compared with the
other comparators.
The results showed that the incremental cost-effectiveness
ratio (ICER) of bupropion to NRT is $US53,241 per qualityadjusted life-year (QALY), which is higher than $US859 per
QALY, the ICER of varenicline to bupropion (Table S7). For the
remaining alternatives, NRT versus willpower is $US1956 per
QALY, and varenicline versus NRT is $US4809 per QALY. Willpower, NRT, and varenicline are placed on the kinked line of
lower slopes, and this line represents cost-effectiveness frontier
(Fig. S1). But bupropion is placed on the left side of the line,
indicating that it is dominated (by extended dominance) and
excluded from consideration.
Subgroup analysis by sex was performed, and varenicline was
a consistently dominant strategy at lifetime. The ICER of varenicline versus NRT was higher in males as $US4913 per QALY,
whereas it is $US3861 per QALY in females.
As shown in Table S8, results of the one-way sensitivity
analysis of key model parameters such as discount rate, efficacy
of varenicline, costs, and utility weights were summarized. For
discount rate, 0%, 3%, and 7.5% were used based on the Korean
PE guidelines. The result shows that the higher the discount rate,
the higher the ICER value. For efficacy, 95% confidence level
upper limit and lower limit of the quit rate of varenicline was
applied to the model. As a result, the lower limit was more
sensitive. For the costs, the ICER for the cases in which NRT was
prescribed by doctors was relatively lower. Nevertheless, other
parameters, increase of cancer cost and use of different data
source, were robust. Of those without comorbidities, when the
utility weights of smokers were applied as one of the nonsmokers, the cost was the same as the baseline analysis. But both
QALYs and ICERs increased for all alternatives. The upper limit
and lower limit of all utility weights by 0.05 did not have a big
impact on the result.
The result of the PSA can be explained with the costeffectiveness acceptability curve (Fig. S2). As shown in the figure,
this study shows that the cost-effectiveness probability of NRT
versus willpower is 80.9% with the critical value of $US5,000,
87.9% with $US10,000, and 90% with $US15,000. Meanwhile,
the cost-effectiveness probability of varenicline versus NRT is
75.2% with the critical value of $US10,000 and 83.3% with
$US15,000.
Discussion
Our results showed that varenicline dominated bupropion. For
the remaining alternatives, the ICER for NRT versus willpower
was $US1956 per QALY, whereas varenicline versus NRT was
$US4809 per QALY.
Still, in Korea, no official threshold of ICER has been
announced for decision-making. At the Drug Reimbursement
Evaluation Committee, however, a certain range of per capita
gross domestic product (GDP) is referenced as a threshold of
ICER for decision-making (Korean per capita GDP is $US20,045
in 2007). Orlewska [32] suggested the reference range as a
ratio of 0.7~2.3 times per capita GDP, which is $US14,000~
$US46,000 in Korea, but the actual criteria for decision-making
in Korea seems to be lower than the suggestions. Even though
there is no explicit range for decision-making, however, as ICERs
of varenicline and NRT are at the 24.0% and 9.8% level of per
capita GDP, respectively, we think both of them can be regarded
as cost-effective alternatives.
A one-way sensitivity analysis showed that our results were
generally robust for discount rate, utility weight, and cost.
Bae et al.
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Varenicline dominated bupropion consistently, whereas ICERs
for varenicline versus NRT ranged from $US1575 per QALY to
$US8284 per QALY. This corresponds to less than the per capita
GDP. The parameter that had the biggest impact on the result of
the sensitivity analysis was efficacy of varenicline. Even though
the assumption that efficacy of varenicline is at the 95% confidence interval lower limit is extremely conservative, ICER of
$US16,544 is still lower than GDP. Also, the PSA suggests that
the model results are consistent across multiple stochastic runs.
For the comparison of varenicline with NRT, 75.2% of the
simulations showed cost-effectiveness at $US10,000 per QALY,
whereas 83.3% at $US15,000 per QALY. The results showed
that the uncertainty around the input parameters did not influence the conclusions.
Previous studies [2–4,33] have demonstrated the costeffectiveness of varenicline, although their detailed results are
different from ours. In the current Korean study, varenicline did
not dominate and its ICER was higher than the results of other
countries.
The major reason is that the share of treatment cost for
smoking-related morbidities is lower in Korea, although the
share of drug cost is higher as compared with other countries.
For example, in Korea, the cost of varenicline accounts for
16.4% of cumulative direct cost at lifetime, while the treatment
cost for smoking-related morbidities accounted for 83.6%. In
the United States, the varenicline cost is 1.3% and the treatment cost for smoking-related morbidities is 98.7% [2]. The
value of varenicline is to reduce the treatment cost for smokingrelated morbidities. In Korea, however, the treatment cost for
smoking-related morbidities takes a relatively small share.
Accordingly, varenicline showed less favorable cost-effective
results.
Another reason is that the number of male smokers was
greater than female smokers in Korea. The share of male smokers
is 92.1% in Korea, although it is 58.4% in the United States.
Because the ICER of females is $US3862 per QALY, which is
lower than males ($US4913), the fact that the share of male
smokers is large increases the overall ICER value.
As for limitations, first, this study used outcome data from
foreign clinical studies because there are only limited references
on efficacies and utility weights domestically. To circumvent this
difficulty, PE guideline [1] recommends comparing foreign data
with local clinical and epidemiological data to cross-check for
data transferability, and then to solicit expert opinions when
published clinical or epidemiological data are not available.
Although it is not enough at all, we referred to the expert opinions on the transferability of foreign outcomes data based on the
guideline, and got a positive response.
Second, modeling the benefits of smoking cessation is challenging because multiple morbidities and related mortalities were
obtained by transformation based on the formula of the previous
studies. A lack of observable data on a population basis prevents availability of direct evidence for the model inputs. But
previous studies showed that the use of the RR of mortality as a
proxy for RR of morbidity is valid [34–36].
Third, we did not include productivity costs and the medical
costs of morbidity during the additional life-years gained, even
though it is well established nowadays that the costs for
nonsmoking-related diseases in additional life-years are substantial. Regarding future increases in health-care costs originating
from increased survival, however, there seems to be no consensus
yet among economists on the correct way of doing it. For these
debatable issues, Korean guidelines recommend that both productivity costs and unrelated health-care cost be not included in
the future for the baseline analysis [1].
For the following reasons, our results are conservative. First,
although smoking is associated with many forms of cancer, cardiovascular diseases, respiratory problems, and reproductive
problems, only the six types of diseases were included. Second,
we assumed that NRTs are purchased by consumers directly
without visiting doctors’ offices as it is a nonprescription drug.
But bupropion and varenicline, both of which are prescription
drugs, must be purchased after the visit to both doctor’s office
and pharmacy. Therefore, doctor’s fee, pharmacist’s fee, and
medical examination fee were applied for bupropion and varenicline, whereas the medical costs for NRT and willpower were
applied to a lesser extent.
Conclusions
Varenicline costs $US4809 more to gain an additional QALY
compared with NRT. To date, no maximum willingness to pay
for a QALY has officially been defined in Korea. Nevertheless,
varenicline can be regarded as a cost-effective alternative because
the ICER is at the 24.0% level of per capital GDP, which is an
implicit reference for decision-making in Korea.
Source of financial support: This study was sponsored by Pfizer, Ltd.,
Seoul, South Korea. Jung Youn Bae, Cheol Hwan Kim, and Eui Kyung Lee
have no conflicts to declare.
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