Zyban as an Effective Smoking Cessation Aid for Patients Following an Acute Coronary Syndrome: The ZESCA Trial

Study Overview
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Brief Summary
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Patients who continue to smoke after a heart attack have a 35% increased risk of a recurrent event or death compared with those who quit. Many patients attempt to stop smoking after a heart attack, but relapse rates approach 66%. A variety of smoking cessation aids have been shown to be effective for the general population. However, bupropion is the only non-nicotine replacement therapy shown to improve abstinence rates in healthy young smokers. Furthermore, nicotine replacement therapies (NRTs) are contraindicated in the immediate period following a heart attack because of the undesirable effects of nicotine. Although bupropion has been successfully used to reduce smoking rates in healthy young populations, its efficacy and safety in the setting of patients recovering from an ACS is unknown. These patients, if they continue to smoke, are at exceptionally high risk for recurrent cardiac events. If bupropion is effective in this population, it will have a major impact on secondary prevention of recurrent clinical events in patients who suffer a heart attack.

Detailed Description
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Patients who continue smoking after ACS have a 35% increased risk of reinfarction or death compared with those who quit. Many patients attempt to stop smoking after an acute coronary syndrome (ACS), but relapse rates approach 66%. A variety of smoking cessation aids have been shown to be effective for the general population. However, physicians are reluctant to use a nicotine-based therapy because of its hemodynamic effects. Bupropion is the only non-nicotine replacement therapy shown to improve abstinence rates in healthy young smokers by approximately 50%. Although bupropion has successfully been used to reduce smoking rates in healthy young populations, its efficacy and safety in the setting of patients recovering from an ACS is unknown. The ZESCA Trial will directly compare the efficacy and safety of bupropion versus placebo as a means of reducing smoking rates in patients following an ACS. The ZESCA Trial will be a multi-center effort, coordinated from the Jewish General Hospital/McGill University (Montreal, Quebec). A total of 1500 patients will be randomized following an ACS but before hospital discharge via an Internet web site. Prior to the start of the treatment, patients in both treatment arms will receive a standard physician-administered counseling session regarding smoking cessation. Patients will begin treatment in-hospital and will be monitored in-hospital for ≥ 2 days prior to discharge. Half the patients will receive bupropion for 9 weeks and the other half will receive placebo pills for 9 weeks. Patients receiving bupropion will take 150 mg once per day for 3 days and then 150 mg twice per day for the remainder of 9 weeks. Prior to discharge, the patients will receive an information sheet listing the possible side effects of bupropion. They will be advised to consult the treating physician should they experience any listed side effects. While in-hospital, patients will have quit smoking and they will be instructed to not restart smoking when discharged. Phone calls to the patients will be made by the study nurses at weeks 1 and 2 of the 9-week treatment period. In addition, the patients will have clinic visits at weeks 4 and 9 as well as months 6 and 12. Smoking abstinence will be assessed at 4 weeks, 9 weeks, 6 months, and 12 months after randomization. Smoking abstinence will be defined as the complete abstinence in the week prior to the clinic visits and levels of exhaled carbon monoxide ≤ 10 ppm. Side effects of bupropion in patients following ACS as well as clinical events following initiation of treatment will be measured at weeks 1-8 (by telephone calls), and weeks 4 and 9 as well as months 6 and 12 (by clinic visits). Withdrawal symptoms will also be assessed by the nurses during their weekly calls. Trials previously conducted with bupropion involved young healthy smokers. The ZESCA trial will be the first to examine the utility of bupropion in a group of patients with an ACS. These patients, if they continue to smoke, are at exceptionally high risk for recurrent cardiac events. If bupropion is effective in this population, it will have a major impact on secondary prevention of recurrent clinical events in patients who suffer an ACS.

Official Title
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Zyban as an Effective Smoking Cessation Aid for Patients Following an Acute Coronary Syndrome: The ZESCA Trial

Conditions
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Acute Coronary Syndrome, Myocardial Infarction, Smoking

Intervention / Treatment
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* Drug: Bupropion HCl ER
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 18 years of age Smoke at least 10 cigarettes/day for the past year Suffered an enzyme-positive ACS Planned hospitalization of ≥24 hours Motivated to quit smoking Likely to be available for follow-up Able to understand and read English or French Exclusion Criteria: Medical condition with a prognosis of < 1 year Pregnant or lactating Current use of Wellbutrin or any other medications that contain bupropion Current use of any medical therapy for smoking cessation (e.g. BuSpar, fluoxetine, doxepin, nicotine gum, or nicotine patch) Current seizure disorder, history of seizures or predisposition to seizures (e.g. history of brain tumor, severe head trauma, or stroke) History of bulimia or anorexia nervosa Current diagnosis of major depression (requiring medication), bipolar disease, or dementia History of suicidal events (previous suicide attempt, suicidal ideation) or family history of suicide Diagnosed hepatic failure, cirrhosis, hepatitis or history of hepatic impairment (AST or ALT levels ≥ 2 times upper limit of normal prior to admission for ACS) Renal impairment with creatinine levels ≥ 2 times the upper limit of normal Excessive alcohol consumption defined as ≥ 14 alcoholic drinks per week Use of any illegal drugs in the past year (e.g. cocaine, heroin, opiates) Current use of medications that lower seizure threshold e.g. amantadine, anti-depressants, anti-malarials, anti-psychotics, levodopa, lithium, quinolone antibiotics, ritonavir, systemic steroids, theophyllin, type 1C antiarrhythmics (e.g. encainide, flecainide, propafenone) Use of MAO inhibitors or thioridazine in the past 15 days Current use of over-the-counter stimulants (e.g. ephedrine, phenylephrine) or anoretics

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: P<br>Half of patients will receive placebo for 9 weeks. | Drug: Placebo<br>* Placebo<br>|
| Active Comparator: A<br>Half of patients will receive bupropion for 9 weeks. | Drug: Bupropion HCl ER<br>* 150 mg tablets po qd for 3 days and then 150 mg po bid for remainder of 9 weeks<br>* Other names: Zyban;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Smoking Abstinence | The primary end point was 7-day point prevalence smoking abstinence at 12 months. Smoking cessation was defined as self-reported abstinence in the week before the 12-month clinic visit and a measurement of exhaled carbon monoxide less than 11 ppm. The primary end point was analyzed on an intention-to-treat (ITT) basis. Our ITT analysis assumed that those who withdrew consent or were lost to follow-up had returned to smoking at their baseline rates. This assumption is common in smoking cessation trials. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Major Adverse Cardiovascular Events (MACE) | All clinical end points were adjudicated by members of the Endpoints Evaluation Committee who were blinded to treatment assignment. Composite MACE (death, myocardial infarction, unstable angina) | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Smoking cessation, Acute coronary syndrome, Myocardial infarction, Zyban, Secondary intervention post-ACS