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Doi:10.1016/s0195-668x(03)00003-4European Heart Journal (2003) 24, 946–955
Bupropion SR for smoking cessation in smokers
with cardiovascular disease: a multicentre,
S. Tonstada*, C. Farsangb, G. Klaenec, K. Lewisd, A. Manolise,
A.P. Perruchoudf, C. Silagyg, P.I. van Spiegelh, C. Astburyi, A. Hideri,
a Department of Preventative Cardiology, Ulleva˚l University Hospital, N-0407 Oslo, Norwayb St. Imre Hospital, Budapest, Hungaryc Department of Cardiology and Pneumology, Hospital AK Altona, Hamburg, Germanyd Help2Quit Centre, Royal Shrewsbury Hospital, Shrewsbury, UKe Tzannio General Hospital, Piraeus, Greecef University of Basel, Basel, Switzerlandg Monash Medical Centre, Monash Institute of Public Health Services Research, Victoria, Australiah Department of Pulmonary Medicine, Slotervaart Hospital, Amsterdam, The Netherlandsi GlaxoSmithKline Research and Development, Greenford, Middlesex, UK Received 16 December 2002; accepted 18 December 2002 KEYWORDS
Aim To investigate the safety and efficacy of bupropion sustained release (bupropion SR)
in promoting abstinence from smoking in subjects with cardiovascular disease (CVD).
Methods Six hundred twenty-nine subjects with CVD who smoked ≥10 cigarettes/day
were randomised in a double-blind, multicentre study to receive bupropion SR (150 mg twice daily) or placebo for 7 weeks, with a follow-up of 52 weeks. Primary
efficacy endpoint: continuous abstinence from smoking from weeks 4 to 7. Secondary
endpoints: continuous abstinence (weeks 4–12, 4–26 and 4–52) and weekly point
prevalence abstinence. All participants received brief motivational support. Safety
was evaluated throughout the study.
Results Continuous smoking abstinence rates from weeks 4 to 7 were significantly
higher in subjects receiving bupropion SR compared with placebo (43 vs. 19%, odds
ratio [OR]=3.27, 95% confidence interval [CI] 2.24–4.84; P<0.001). Continuous absti-
nence rates from weeks 4 to 26 and 4 to 52 continued to be more than double for
bupropion SR compared with placebo (27 vs. 11%; 22 vs. 9%, P<0.001). Weekly point
prevalence abstinence was significantly higher for participants who received bupro-
pion SR compared with placebo at weeks 3, 7, 26 and 52 (P<0.001). In both groups,
there were no clinically significant changes in blood pressure and heart rate through-
out the treatment phase. Overall, 6% of the participants (nϭ36) discontinued study
medication due to an adverse event (bupropion SR, nϭ17; placebo, nϭ19).
Conclusions After 7 weeks of bupropion SR treatment, more than twice as many
smokers with CVD had quit smoking at 1 year compared with placebo. The safety profile
of bupropion SR was similar to that previously observed in general smoking populations.
2003 The European Society of Cardiology. Published by Elsevier Science Ltd. All
* Corresponding author. Tel.: +22-11-79-39; fax: 22-11-99-75 E-mail address: email@example.com (S. Tonstad).
0195-668X/03/$ - see front matter 2003 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0195-668X(03)00003-4 Bupropion SR in smokers with cardiovascular disease Introduction
smoking using nicotine replacement therapy duringthe previous 3 months. Subjects had not made a Strong, consistent epidemiological evidence links quit attempt lasting >3 months during the previous cigarette smoking to increased cardiovascular dis- year. All participants were motivated to stop smok- ease (CVD) morbidity and mortality.1,2 In the devel- ing and had at least one of the following cardiovas- oped world, CVD (most often ischaemic heart cular conditions: myocardial infarction >3 months disease) is the most common smoking-related cause ago, interventional cardiac procedure (excluding of death, with 25% of deaths in the 35–69 years age valve replacement) >3 months ago, stable angina group being due to tobacco.3 It has been recognised pectoris, peripheral vascular disease (excluding for some time that mortality levels are significantly varicose veins and current deep vein thrombosis) higher among smokers who have experienced a or congestive heart failure (NYHA Class I or II).
myocardial infarction and continue to smoke, com- Subjects with at least one of these conditions, with pared with those who quit.4 Furthermore, the risk or without hypertension, were eligible. However, of a coronary event declines rapidly after stopping hypertension had to be controlled (i.e. <160/ smoking, and after 2–3 years of abstinence the 100 mmHg; baseline systolic and diastolic values, risk of such an event is similar to that for subjects respectively) by diet, exercise, or medication.
who have never smoked.5–7 For this reason, the Subjects were excluded if they had a predisposi- Joint British Recommendations on Prevention of tion for seizure; had a current diagnosis of severe Coronary Heart Disease in Clinical Practice state renal, hepatic, haematological, pulmonary or that stopping smoking is one of the primary lifestyle neurological disease; or had a history or current options for reducing the risk of coronary heart diagnosis of bulimia or anorexia nervosa. Subjects were also excluded if they had an acute or chronic Bupropion sustained release (bupropion SR) is a medical condition likely to impair drug absorption, non-nicotine-based treatment for use in smoking distribution, metabolism or excretion; had a history cessation. Controlled clinical studies involving or current diagnosis of panic disorder, psychosis, or approximately 8000 subjects receiving bupropion bipolar disorder; or were depressed.
SR have now demonstrated the efficacy and The protocol was approved by the appropriate tolerability of this agent.9–13 This efficacy is Independent Ethics Committee or Institutional acknowledged in smoking cessation guidelines14–16 Review Board and participants provided written and the National Institute for Clinical Excellence has recently recommended its use in smoking ces-sation.17 Bupropion SR is effective in smokers whomay be considered particularly refractory to treat- Interventions
ment.11,18 In addition, meta-analyses suggest that We performed a multicentre, randomised, double- the efficacy, tolerability and safety of bupropion blind, placebo-controlled study in subjects from 28 SR are unaffected by a previous history of serious conditions such as alcoholism and major depres- The study consisted of a 1- to 2-week screening/ sion.19 However, there have been no clinical baseline phase, a 7-week treatment phase and studies carried out to date that have assessed follow-up at 3, 6 and 12 months. Subjects set bupropion SR as an aid to smoking cessation in a target quit date for >7 but ≤14 days after base- subjects with CVD. Smokers who have survived line assessment. At baseline, smoking history a cardiac event but not quit smoking may be more and cardiovascular diagnoses were collected, and nicotine dependent or face more barriers to expiratory carbon monoxide levels were measured using a Bedfont Smokerlyser monitor. Participants We conducted a double-blind, multicentre, ran- were also weighed and two questionnaires (the domised study to assess the efficacy and safety of bupropion SR in subjects with smoking-related CVD.
Smoking Assessment Questionnaire) were com-pleted. Participants were then randomised in a 1:1 ratio to receive either bupropion SR (150 mg/day ondays 1–3; 150 mg twice daily on days 4–49) or Participants
placebo during the 7-week treatment phase.
Subjects were contacted by telephone 1 day We enrolled adults who smoked an average of before their target quit date and reminded that ≥10 cigarettes/day during the previous 12 months they were due to stop smoking the following day.
and who had not made a serious attempt to stop Three days after this date, subjects were again contacted to provide motivational support. Partici- 4-week continuous abstinence rate was 15% for subjects receiving placebo. We considered a 10% (number of cigarettes per day) on a diary card increase in the continuous abstinence rate for sub- and visited the clinic each week throughout jects receiving bupropion SR to be clinically rel- the treatment phase. At each clinic visit, subjects evant. Therefore, we assumed that 15% of subjects were weighed, vital signs and expiratory carbon receiving placebo and 25% of subjects receiving monoxide levels measured and brief motivational bupropion SR would remain continuously abstinent support (10–15 min) was given. At week 7, the during weeks 4–7 of the current study. With 620 Smoking Assessment Questionnaire was completed.
participants randomised 1:1, the study would have During follow-up, subjects were contacted at at least 85% power to detect this difference at the monthly intervals to encourage abstinence from two-sided 5% level of significance and detect a smoking and prevent relapse. At weeks 12, 26 and difference assuming that 5% of the subjects ran- 52, subjects were weighed, expiratory carbon mon- domised to placebo and 12% of those randomised to oxide levels and vital signs were measured and brief bupropion SR, remained continuously abstinent at motivational support given. Subjects who withdrew or missed a clinic visit were assumed to be smoking.
Data were analysed using sas® (v.6.12) statistical software. For continuous abstinence data, compari- Primary outcomes
son of the treatment groups was performed using anexact test according to Gart and Cox22,23 stratified The primary outcome was defined as continuous by country. For point prevalence abstinence, the abstinence from smoking for a 4-week period from treatment groups were compared using the exact the beginning of week 4 of the treatment phase.
test. Change in weight relative to baseline was Continuous abstinence was assessed by the investi- compared by analysis of covariance including gator and confirmed by the subject's self-report of terms for treatment, centre, gender and abstention not smoking and an expiratory carbon monoxide status, with baseline weight as a covariate.
level <10 ppm. Subjects with missing investigatorassessments were assumed to be smokers at thatvisit.
Secondary outcomes of efficacy included con- Six hundred and sixty-nine potential subjects were tinuous abstinence from smoking from week 4 to screened, and 629 participants were enrolled, of weeks 12, 26 and 52. In addition, weekly point whom 626 received at least one dose of study prevalence abstinence (abstinence from smoking medication (intent-to-treat population; nϭ313 in for the previous 7-day period) was assessed during each group) [Fig. 1]. After 52 weeks, 120 (38%) patients receiving bupropion SR and 155 (50%) Change in body weight relative to baseline was receiving placebo had prematurely discontinued assessed at the end of the treatment phase (week 7) and at weeks 26 and 52 of the follow-up phase.
Treatment groups were comparable in terms of At week 7, subjects were asked to evaluate age, gender, race and smoking history (Table 1).
their experience with the study medication, and This population of chronic smokers had a mean whether they would recommend it to other smokers pack-year history of 49.6 years and a mean ¨m Tolerance Questionnaire score of 6.6.
Most subjects (85%) had made at least one previous attempt to stop smoking, and 31% had made ≥5 Vital signs were recorded throughout the study, and previous cessation attempts. Overall, 27% of sub- adverse events were recorded throughout the jects had chronic obstructive pulmonary disease treatment phase and up to week 9. All serious and/or diabetes and the incidence of these adverse events were collected throughout the conditions was similar for both treatment groups treatment phase, after which only serious adverse (Table 1). Subjects entering the study presented events related to study medication were recorded.
with a range of cardiovascular diagnoses and Statistics
included 306 (49%) who had previously experienceda myocardial infarction (Fig. 2). Patients must have In the study of Tashkin et al.,11 which examined had at least one of the following to be eligible for smokers considered refractory to treatment, the the study (±controlled hypertension): myocardial Bupropion SR in smokers with cardiovascular disease infarction (>3 months ago), interventional cardiac 26, 27% (84/313) of subjects receiving bupropion SR procedure (>3 months ago), stable angina, periph- remained abstinent, compared with 11% (34/313) eral vascular disease (excluding varicose veins and of those receiving placebo (P<0.001). At week 52 current deep vein thrombosis) or congestive heart the corresponding values were 22% (68/313) and 9% (29/313) for bupropion SR vs. placebo, respectively(P<0.001).
In both treatment groups, subjects with CVD and chronic obstructive pulmonary disease and/or A significantly higher percentage of subjects diabetes had similar continuous abstinence rates for weeks 4–52 compared with CVD only (18 and abstinence from smoking for weeks 4–7 (Fig. 3) compared with those receiving placebo—43% (134/313) of subjects receiving bupropion SR remainedabstinent, compared with 19% (61/313) of those Point prevalence abstinence
receiving placebo (P<0.001, odds ratio [OR] 3.27; Weekly point prevalence abstinence for the bupro- 95% confidence interval [CI] 2.24–4.84).
pion SR group remained more than double that ofthe placebo group throughout the study. Statistical Secondary outcomes
analysis revealed significantly greater weekly pointprevalence abstinence (P<0.001) in participants Bupropion SR treatment resulted in consistently receiving bupropion SR compared with placebo at higher rates of abstinence than placebo. At week all prespecified time points (Fig. 4).
¨m Tolerance Questionnaire score [mean (SD)]a Used nicotine replacement therapy [number of subjects (%)] Chronic obstructive pulmonary disease [number of subjects (%)] Pack year history=([number of years smoking]×[number of cigarettes per day])/20.
a nϭ263 for bupropion SR and placebo.
Cardiovascular diagnoses at baseline for all subjects (nϭ626).
At weeks 7 and 26 the odds of not having smoked receiving placebo (95% CI 0.46–1.83 kg). However, during the preceding week were almost four times participants who remained abstinent at week 52 higher for bupropion SR-treated subjects compared experienced a similar overall gain in weight, with those receiving placebo (OR 3.96, 95% CI 2.74– regardless of treatment group, with bupropion SR- 5.79; OR 3.85, 95% CI 2.50–6.03, respectively).
treated subjects gaining an average of 0.9 kg moreat week 52 (95% CI −1.19 to 2.80 kg).
During the treatment phase, subjects receiving
Smoking assessment questionnaire
bupropion SR who had abstained from smoking Responses to the Smoking Assessment Question- from the beginning of week 4 to the end of week 7 naire were more positive for bupropion SR than gained an average of 1.15 kg less weight than those placebo in four of the seven questions (Fig. 5). At Bupropion SR in smokers with cardiovascular disease Continuous abstinence during the treatment and follow-up phases.
Weekly point prevalence abstinence during the treatment and follow-up phases.
the end of treatment, 61% of subjects in the felt that altered sleeping patterns were a problem bupropion SR group considered that the urge to smoke was not a problem, compared with 37% of In total, 89% of subjects in the bupropion SR those receiving placebo. Both treatment groups group stated that they would recommend their generally felt that side effects were not a problem.
study medication to other smokers, compared with However, 28% of subjects receiving bupropion SR Smoking Assessment Questionnaire responses at the end of treatment.
In total, 38 subjects (6%) reported cardiovascular adverse events (bupropion SR nϭ24; placebo nϭ14). The most common were angina pectoris (bupropion SR nϭ7; placebo nϭ4), hypertension(bupropion SR nϭ2; placebo nϭ3), and palpitations (bupropion SR nϭ4; placebo nϭ1).
A total of 36 participants (6%) discontinued from the study due to an adverse event (bupropion SR nϭ17 [5%]; placebo nϭ19 [6%]) (Table 2). Eight participants experienced a total of nine serious adverse events during the study, and five of theseoccurred during treatment (bupropion SR nϭ5, pla- cebo nϭ0). Three events were considered to be possibly a worsening of a preexisting condition, angina pectoris (nϭ2) and vascular disease (nϭ1).
Glaucoma (nϭ1) and lupus erythematodes dissemi-natus (nϭ1) were also reported. Only one of theseevents was considered possibly related to studytreatment (lupus), and none led to discontinuation of study medication. One event (worsening of con-gestive heart failure) occurred following the A total of 64% (201/313) of subjects receiving screening visit, prior to the receipt of study bupropion SR and 58% (181/313) of those receiving medication, in a patient ultimately randomised to placebo experienced at least one adverse event whilst on treatment (and 2 weeks thereafter). The Within a week of finishing treatment, three most frequently reported events were insomnia serious adverse events were reported. One subject (24% bupropion SR; 12% placebo) and dry mouth had received bupropion SR during the treatment (18% bupropion SR; 10% placebo) [Table 2]. The phase, and the event (vestibular disorder) was frequency with which these events were reported not considered to be related to study medication.
was similar regardless of disease group (CVD or CVD The two remaining events (chest pain, dyspnoea) and chronic obstructive pulmonary disease and/or were reported by one subject who had received Bupropion SR in smokers with cardiovascular disease There were four deaths during the study (two a more recent bupropion SR study11 in that both of patients receiving bupropion SR and two receiving these populations were older, less healthy, had placebo), and none was related to study medica- smoked for a longer period of time and made tion. All deaths occurred during the follow-up more quit attempts than participants in earlier phase and occurred between 66 and 313 days after studies.9,10 In addition, both study populations comprised subjects with chronic smoking historieswho continued the habit despite developing Vital signs
smoking-related diseases, and who may therefore No overall treatment effect was observed in sys- be particularly refractory to smoking-cessation tolic and diastolic blood pressure and heart rate (mean changes in beats per minute from baseline to Bupropion SR was significantly more effective week 7 were −2.15 and −0.80, for bupropion SR and than placebo as an aid to smoking cessation for placebo, respectively). No clinically significant smokers with CVD and the odds of being con- change in vital signs was seen for either treatment tinuously abstinent by week 4 and maintaining this during the follow-up phase to week 52. At week 52, until weeks 26 and 52, were around three times the mean change from baseline in systolic blood greater for bupropion SR. Weekly point prevalence pressure with bupropion SR and placebo was +1.5 analysis (continuous abstinence 7 days prior to and +3.5 mmHg, respectively. The corresponding each clinic visit) confirmed these findings, with change from baseline in diastolic blood pressure rates being more than double throughout the with bupropion SR was +0.7 mmHg compared with study for bupropion SR compared with placebo.
Notably, abstinence rates were comparable tothose found in previous clinical studies in a gen-eral smoking population9,10,12 and to that esti- Discussion
mated in a recent meta-analysis conducted by the We have conducted the first prospective study of National Institute for Clinical Excellence. This non-nicotine pharmacotherapy in a population of meta-analysis reported that treatment with bu- persistent smokers with CVD, nearly half of whom propion gave an OR of 2.16 (95% CI 1.51–3.10) for continuous abstinence compared to placebo.17 months previously. At 6 and 12 months after The institute estimated that nicotine replacement beginning treatment, subjects who had received therapy gave an OR of 1.69 (95% CI 1.57–1.82) bupropion SR were significantly more likely to have successfully stopped smoking than those The motivational support provided during this receiving placebo. Bupropion SR was well toler- study was minimal (10–15 min sessions with existing ated and the safety profile was more favour- clinical staff) and similar to that provided in previ- able than expected for a study population of this ous trials of bupropion SR. Furthermore, the weight gain in subjects treated with bupropion SR was Smokers in the present study were recruited in noticeably less than that in the placebo group while the settings of primary and secondary/tertiary care they were receiving treatment. This finding is sig- in addition to smoking cessation clinics. Thus, these nificant because individuals often start smoking smokers were clearly different from smokers again if they gain weight,24 and although the recruited to previous studies of bupropion SR con- benefit appears to be short term, bupropion SR may ducted in subjects recruited from a general smok- ing population, with the exception of one study Responses to the Smoking Assessment Question- carried out in patients with chronic obstructive naire add further support to these central efficacy pulmonary disease.11 All patients were diagnosed findings. More than half of subjects confirmed with a cardiovascular condition, over one-quarter that the urge to smoke was not a problem with were also diagnosed with chronic obstructive pul- bupropion SR, and the majority stated they monary disease and/or diabetes, and most (96%) would recommend their treatment to others. This were taking concomitant medications. Further- is in line with findings from a previous study in more, the mean pack year history (49.6 years) and 91 chronic smokers, where bupropion SR was mean number of quit attempts (5.4) were higher found to ameliorate selected nicotine withdrawal than observed in previous bupropion SR studies in effects (difficulty in concentrating, irritability and general smoking populations.9,10 However, this smoking profile was similar to that of subjects with We hypothesised that as the current study chronic obstructive pulmonary disease recruited in examined persistent smokers with serious disease, there may be an increase in the rate of adverse References
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9. Hurt RD, Sachs DP, Glover ED et al. A comparison of Acknowledgements
sustained-release bupropion and placebo for smoking
cessation. N Engl J Med 1997;337:1195–202.
We gratefully acknowledge the assistance of the 10. Jorenby DE, Leischow SJ, Nides MA et al. A controlled Principal Investigators in the Zyban® Cardiovascular clinical trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 1999;
Australia: Krum H., McKiernan M., Silagy C., 11. Tashkin D, Kanner R, Bailey W et al. Smoking cessation in Stuckey B. Austria: Irsigler K., Pilger E., Vetter patients with chronic obstructive pulmonary disease: a N. Germany: Fritz H., Kaspari S., Krause H., double-blind, placebo-controlled, randomised trial. Lancet Lindemann L., von Olshausen K. Greece: Chalkidis 2001;357:1571–5.
C., Manolis A., Vardas P. Hungary: Farsang C., 12. Tonstad S, Aaserud E, Hjalmarson A et al. on behalf of the ´czy J. Netherlands: Deckers J., Meyboom-de- Zyban Study Group. Bupropion SR is an effective and well-tolerated aid to smoking cessation in a general smoking Jong B., van Spiegel P. New Zealand: Kerr D., Rea population: an international study (ZYB40017). Poster H. Norway: Aaserud E., Tonstad S. Switzerland: presentation at SRNT Third European Conference; 2001, Perruchoud A. UK: Hajek P., Lewis K., Murphy M.
We would also like to thank Professor P. Hajek, 13. Hays JT, Hurt RD, Rigotti NA et al. Sustained-release bupro- at St. Bartholomew's and the Royal London School pion for pharmacologic relapse prevention after smokingcessation: a randomised controlled trial. Ann Intern Med of Medicine (London, UK) who developed the moti- 2001;135:423–33.
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14. West R, McNeill A, Raw M. Smoking cessation guidelines for This study was supported by an educational grant health professionals: an update. Thorax 2000;55:987–99.
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16. Lancaster T, Stead L, Silagy C et al. Effectiveness of inter- were performed by GlaxoSmithKline, however, all ventions to help people stop smoking: findings from the data were available to the authors for analysis. The Cochrane Library. BMJ 2000;321:355–8.
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Tonstad, Manolis, Perruchoud and Van Spiegel have 18. Smoking withdrawal in hospital patients: factors associated all received honoraria from GlaxoSmithKline for with outcome. Subcommittee of the Research Committee of the British Thoracic Society. Thorax 1984;39:651–6.
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20. Heatherton TF, Kozlowski LT, Frecker RC et al. The 25. Shiffman S, Johnstone JA, Khayrallah M et al. The effect ¨m Test for Nicotine Dependence: a revision of the ¨m Tolerance Questionnaire. Br J Addict 1991; Psychopharmacology 2000;148:33–40.
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5 years of postmarketing experience. 3rd European 23. Cox DR. A simple example of a comparison involving quantal Congress on Tobacco or Health; 2002 June 19–22; Warsaw, data. Biometrika 1966;53:215–20.
The Abstract Compactness Theorem revisited 1Abstract. The Abstract Compactness Theorem of Makowsky and Shelah for model the-oretic logics is shown to be an immediate consequence of a general characterization oftopological spaces having [ ; ]-compact products, when applied to spaces of structuresendowed with the natural topology induced by the de…nable classes of a logic L. In thiscontext, the n