Smoking cessation in Asians: focus on varenicline
Patient Preference and Adherence
Smoking cessation in Asians: focus on varenicline
Dan Xiao 0
Shuilian Chu 0
Chen w ang 0
0 Clinical Cessation and Tobacco Medicine Research Centre, China- Japan Friendship Hospital , Beijing , People's Republic of China
Smoking is a modifiable risk factor for morbidity and mortality caused by cancer, cardiovascular diseases, respiratory diseases, and many other diseases. Given the large population size and high prevalence of smoking in Asia, successful smoking cessation could potentially prevent the large number of premature deaths in Asians. However, most dependent smokers cannot successfully quit smoking due to nicotine addiction, and they need professional help and smoking cessation therapies. Varenicline is a highly selective partial agonist for the nicotinic acetylcholine receptor α4β2 subtype, which is believed to be responsible for mediating the reinforcing properties of nicotine. This article is a narrative review, which summarizes the smoking cessation efficacy, side effects, and cost utilities of varenicline in Asians. From this review, we conclude that varenicline is an effective medication that could assist smoking cessation in the Asian populations. The adverse events of varenicline are tolerable, and the most common events were nausea and abnormal dreams. Both the efficacy and tolerance of varenicline in Asians are similar to that in Western populations. Considering the cost utilities, varenicline should be recommended for use in smoking cessation and be covered by medical insurance in most Asian countries.
*These authors are the co-first
Smoking is a modifiable risk factor for morbidity and mortality caused by cancer,
cardiovascular diseases, respiratory diseases, and many other diseases. According to
the World Health Organization, tobacco kills nearly six million people each year.1
The top ten biggest tobacco-consuming countries in the world include seven
countries in Asia, with the People’s Republic of China at number one and India at
number two.2–7 In 2010, there were an estimated 301 million current smokers in the
People’s Republic of China, with an estimated 28.1% of adult (52.9% of men and
2.4% of women) current smokers.2 In India, the prevalence of smoking among men
increased from 29.3% in 1998 to 36.
4% in 2010
, with 20.3% of women and 47.9% of
men aged 15 and above smoking cigarettes or bidis.4
Given the large population size and high prevalence of smoking in Asia,2–7 successful
abstinence could potentially prevent the large number of premature deaths in this part
of the world. Even when smokers are fully aware of the health hazards, most smokers
intend to quit but cannot successfully quit smoking due to nicotine addiction.8 Thus,
nicotine-dependent smokers need professional assistance and smoking cessation treatment
to quit successfully. Currently, smoking cessation treatments that can markedly increase
long-term abstinence rates include pharmacotherapy, smoking cessation advice, and
9 The 2008
US Guide to Quitting Smoking recommends that, except for groups
with contraindications or for whom smoking cessation drugs have uncertain efficacy
(eg, users of smokeless tobacco, light smokers, pregnant women, nursing women, and
teenagers), clinicians should encourage all smokers intending to quit smoking to take
smoking cessation medications combined with smoking cessation advice.9
Varenicline is a highly selective partial agonist for the
nicotinic acetylcholine receptor α4β2 subtype, which is
believed to be responsible for mediating the reinforcing
properties of nicotine. It has bidirectional adjustment effects
of stimulation and antagonism. After combining with nicotinic
acetylcholine receptors, varenicline works as an agonist,
stimulating the release of dopamine in the brain, which can relieve
nicotine withdrawal symptoms. Its antagonistic features can
also prevent nicotine from combining with nicotinic
acetylcholine receptors, thus reducing the satisfaction and reward of
smoking.10 It has been approved in over 100 countries
worldwide, and involved in several smoking cessation guidelines
as a first-line smoking cessation medication, including the
China Smoking Cessation Guideline.9,11 This article reviews
the smoking cessation efficacy, adverse events (AEs), and
cost utilities of varenicline in the Asian population.
ftroedhm rrspeooF iidneAntsiifaynsst.uTdhieesseevaarlcuhatcionvgevreadreJnuicnlein2e0f0o7r ttoobJauclcyo2c0e1s4sa,taionnd
included articles available online ahead of print publication.
The search strings were “varenicline”, “smoking cessation”,
“Asian”, “Chinese OR China or Taiwan”, “Japanese OR
Japan”, “Korean OR Korea”, “Indian OR India”,
“Philippines”, “Thailand”, “Vietnam”, and other Asian country
names (though these obtained no related literature). Types of
studies included meta-analysis, clinical randomized controlled
trials, observational studies, and other related studies.
The studies were required to meet the following criteria:
(i) the subjects should be Asians, (ii) the full original text
should be accessible, and (iii) the contents of the study should
include the relationship between varenicline and smoking
Efficacy of smoking cessation in Asian
Clinical trials in Western populations indicated that
varenicline could reduce the urge and desire to smoke, and
satisfaction from smoking.12–14 The results of the studies in Asians
were roughly the same as those for Western populations.15,16
In a 12-week, randomized, placebo-controlled, dose–
response study, with a 40-week follow-up, mean scores in
Japanese smokers on the Minnesota Nicotine Withdrawal
Scale (MNWS) Urge to Smoke subscale were significantly
lower with varenicline 0.25, 0.5, 1 mg twice daily compared
to placebo (P=0.01, P0.001, and P0.001), and indicated
less negative affect (P=0.046, P0.001, and P0.001) and
less restlessness (P=0.018, P0.001, and P0.001). Results
for the mean Brief Questionnaire on Smoking Urges
(QSUBrief) scores suggested a similar effect of varenicline on
the QSU-Brief total craving score to that observed by the
MNWS.15 Another trial conducted in Korea and Taiwan
obtained similar results.16
The efficacy of varenicline as a smoking cessation aid
has been reported in a number of studies.17–20 A Cochrane
meta-analysis indicated that the risk ratio of continuous
abstinence rates (CARs) of smokers taking standard doses
of varenicline for 6 months or longer was 2.27 times that
of smokers taking placebo, and 1.52 times that of smokers
taking bupropion sustained-release tablets.17 Additionally, in
studies where smokers taking varenicline could adjust the
dosage schedule18 or choose a flexible quit date approach,19
the medication remained an effective smoking cessation
aid. Prolonging treatment time with varenicline in smokers
who were abstinent for the last week of treatment during the
initial 12-week course increased the long-term smoking
cessation rate and prevented relapse.20 Studies have also found
that smoking cessation efficacy of varenicline is better than
bupropion or nicotine replacement therapy (NRT) at the end
of the treatment period.12,13,21
Clinical studies on smoking cessation efficacy of
varenicline in Asians indicate that varenicline can markedly
increase the smoking cessation rate in this population.12,15,16,22,23
In our primary clinical trial, which was a 24-week,
randomized, double-blind, placebo-controlled trial of varenicline
conducted in 333 subjects in the People’s Republic of
China, Singapore, and Thailand, 4-week continuous
abstinence was achieved by 50.3% and 31.6% of
participants in the varenicline and placebo groups,
respectively (P=0.0003). Continuous abstinence from weeks 9
to 24 was achieved by 38.2% and 25.0% of participants in the
varenicline and placebo groups, respectively (P=0.0080).22
Comparable efficacy between Japanese and the US
smokers has been reported in a study of 618 Japanese smokers.
This study reported a complete abstinence rate of 65.4% for
varenicline at weeks 9–12, which compared well to the 44%
abstinence rate reported in the US studies.12 Fagerström et al
summarized and analyzed three placebo-controlled trials
conducted in six Asian countries and found that 9–12-week CAR
(58.6% vs 34.3%, odds ratio [OR] =2.74, P0.0001) and
9–24-week CAR (41.4% vs 25.3%, OR =2.08, P0.0001)
for the varenicline group were both higher than for the
A double-blind, placebo-controlled, randomized trial in
India found that varenicline was also effective for treating
smokeless tobacco dependence. Although biochemically
confirmed abstinence was greater for varenicline vs
placebo (25.2% vs 19.5%), this was not statistically different
(adjusted OR =1.6, 95% confidence interval [CI], 0.84–3.1,
P=0.15).24 Further studies are required to confirm the
effectiveness of varenicline in this specific population.
The results of an observational study on the efficacy of
varenicline in Asians obtained similar findings as
randomized trials. An observational study in adult Filipino smokers
prescribed varenicline for the first time (during routine clinical
practice) indicated that varenicline was efficacious as an aid
for smoking cessation. At the end of week 12, 57.6% (95%
CI, 52.0%–63.0%) of participants had been abstinent in the
previous 7 days.25 A smoking cessation program for
outpatients, provided by a hospital in Southern Taiwan, found that
varenicline use in a sample of treatment-seeking dependent
smokers was associated with significantly higher abstinence
rates than the nicotine patch.26 A real-world observational study
in a smoking cessation clinic in Taiwan, which involved 587
smokers followed up at 3 years, found that 36-month sustained
abstinence rates showed a significant advantage for varenicline
than for the nicotine patch (OR =7.94, 95% CI, 1.87–33.74).27
A multicenter, prospective, non-comparative, observational
study conducted in the People’s Republic of China, India,
Philippines, and Korea demonstrated an acceptable safety profile
of varenicline, and the abstinence rates was consistent with
those of randomized controlled trials. Overall, 46.4% (95% CI,
43.73%–49.07%) of subjects successfully quit smoking by the
end of the treatment phase at week 12.28 However, the
compliance to medication use in the real world must be considered.
An observational study conducted in a pulmonary clinic in
South Korea found that although varenicline was effective in
reducing the desire to smoke, compliance with medication was
poor, and this needs to be overcome in clinical practice.29
Safety and tolerance in Asian populations
Many studies have showed that the safety and tolerance of
varenicline during clinical treatment are relatively good.
The most common AEs reported are nausea and strange
dreams.15,16,18,19 The tolerability of varenicline in Asians is
generally consistent with that of Western populations.22–28 In
our primary clinical trial, the most frequent categories of AEs
were gastrointestinal disorders, psychiatric disorders, nervous
system disorders, general disorders, and administration site
conditions, infections, and infestations. The most common
AEs reported were nausea and strange dreams.22 A
clinical trial conducted among Chinese, Thai, and Singaporean
smokers showed that the most commonly reported AEs
in the varenicline group were nausea (29.1%), dizziness
(14.5%), dry mouth (9.1%), and insomnia and drowsiness
(both 6.1%).23 The results of an observational study in adult
Filipino smokers prescribed varenicline for the first time
demonstrated that the most frequently reported AEs were
headache (5.5%), dizziness (3.9%), and nausea (3.6%).25
Some post-marketing reports have drawn attention to
neuropsychiatric AEs found in patients taking varenicline.30–
In February 2008
, the US Food and Drug Administration
announced that the psychiatric symptoms reported by patients
who took varenicline include behavioral changes, agitation,
sadness, suicidal thoughts, and suicide attempts or deaths.
Prescribing information for varenicline was subsequently
updated in the US, Europe, and the People’s Republic of
China to include warnings about neuropsychiatric events
for doctors and patients. However, data from randomized,
placebo-controlled studies, retrospective cohort studies, and
a prospective cohort study of varenicline in patients
without active mental disorders have not shown an increase in
neuropsychiatric AEs.33–38 Many randomized, double-blind,
placebo-controlled studies have reported no evidence of
exacerbation of symptoms in patients with mental disease,
and varenicline was not associated with significantly higher
smoking cessation rates vs placebo.39–42 Within the Asian
population, varenicline has not been reported to be associated
with increasing psychiatric symptoms or suicide,22–29 though
further trials are needed to confirm this.
Three systematic reviews by Singh et al, Prochaska and
Hilton, and Ware et al published between 2011 and 2013,
have evaluated serious cardiovascular AEs with varenicline
use.43–45 Even though all three reviews demonstrated that
serious cardiovascular AEs were nominally more frequent
in varenicline-treated patients when compared to placebo,
a significantly increased event rate was found only in the
review by Singh et al.43 The three reviews included similar
trials but differed in the evaluation of outcomes and
performance of summary statistic computation. In a clinical trial
conducted in 85 Japanese smokers, the researchers
evaluated the effect of varenicline-assisted smoking cessation on
vascular endothelial function assessed by flow-mediated
vasodilation (FMD). Participants were evaluated by FMD
prior to, and 3 months after, complete smoking cessation. The
researchers found that FMD was significantly increased from
4.0%±1.8% to 5.5%±2.2% (P0.01, n=22) 3 months after
complete cessation. FMD also increased during varenicline
use (from 3.7%±2.7% to 4.3%±2.8%, n=11). The
observations suggest that in ceasing smokers, varenicline and
smoking cessation do not lead to worsening of the vascular
endothelial function.46 Within the Asian population, there
have been no reports of varenicline being associated with
increasing serious cardiovascular AEs,22–29 though further
trials are needed to confirm this.
Cost efficacy of varenicline
Since in most Asian countries, smokers would purchase
varenicline themselves, the cost utility of varenicline must
be evaluated. A cost-utility analysis of two 12-week smoking
cessation interventions in Japan (smoking cessation
counseling by a physician vs varenicline in addition to
counseling) analyzed lifetime medical costs and quality-adjusted
life-years (QALYs) from the perspective of the health care
payer. It was found that varenicline would save Japanese yen
43,846 ($US 381; $US 1 = yen 11
5; October 2007
) in direct
medical costs and generate an increase of 0.094 QALYs in
male smokers. In females, the incremental cost-effectiveness
froedm rpeoF ratio was yen 346,143 per QALY gained. Varenicline was
da estimated to save yen 23.7 billion ($US 206 million) of
lonw the medical costs for tobacco-associated diseases for the
doe whole population. Overall savings were reported to be yen
rcen 9.5 billion. This study concluded that varenicline appears to
ehd be cost-effective and may contribute to future medical cost
ndA savings in Japan.47
cae Another similar study conducted in South Korea
evalufrrenee samtedokt hinegcocsets-esfafteioctniviennteesrsvoenftviaornesn,icbluinperocpomiopna,rNedRtTo,otahnedr
tenP willpower. The incremental cost-effectiveness ratio for
itaP varenicline vs NRT was reported to be $US 4,809 per QALY
over a lifetime.48
However, studies conducted in Vietnam found that
varenicline did not fall within the range of being
“costeffective” under different scenarios. They revealed that
prices of pharmaceuticals must be substantially lower than
the levels from other countries if pharmacological therapies
are to be cost-effective in Vietnam.49
Meta-analyses indicate that varenicline is more effective
than bupropion and single-form NRT for smoking cessation.
Pooled analysis and many placebo-controlled, randomized
trials and real-world studies also strongly suggest that
varenicline is an effective drug that assists in smoking cessation
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in Asians. Moreover, varenicline was recommended in the
China Smoking Cessation Guideline as a first-line smoking
cessation medication in 2007.11
The safety and tolerance of varenicline during clinical use
are relatively good, and the most common AEs in clinical
trials were nausea and abnormal dreams, which are similar to
the AEs reported in the Western population. Although several
clinical case reports suggested that varenicline might be
associated with neuropsychiatric events or serious cardiovascular
events, there is no evidence that varenicline was associated
with a higher rate of, or an exacerbation of, mental diseases,
or increasing serious cardiovascular AEs in Asians. Further
trials are needed to confirm these reports.
Half of the current Asian smokers, most of whom are
young men at present, will die prematurely due to
smokingrelated diseases in the next few decades. Given its high cost
efficacy and safety profile, varenicline should be
recommended for use in smoking cessation, and be covered by
medical insurance in most Asian countries.
Chen Wang and Dan Xiao have consulted for a number of
companies with an interest in clinical trials of medication and
medical professionals training for tobacco dependence
treatments, including Pfizer Inc., and they have been investigators
for Pfizer-sponsored clinical trials. Shuilian Chu reports no
conflicts of interest in this work.
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Patient Preference and Adherence is an international, peer-reviewed,
open access journal that focuses on the growing importance of patient
preference and adherence throughout the therapeutic continuum. Patient
satisfaction, acceptability, quality of life, compliance, persistence and their
role in developing new therapeutic modalities and compounds to optimize
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