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

• Sponsor: Mark Eisenberg (Other)
• Overall Status: Completed
• CT.gov ID: NCT00689611
• Collaborator: Canadian Institutes of Health Research (CIHR) (Other), Heart and Stroke Foundation of Canada (Other)
• Enrollment: 392
• Locations: 38
• Arms: 2
• Duration (Months): 54
• Patients Per Site: 10.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Coronary Syndrome; Myocardial Infarction; Smoking	Drug: Bupropion HCl ER; Drug: Placebo	Phase 3

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 392 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Zyban as an Effective Smoking Cessation Aid for Patients Following an Acute Coronary Syndrome: The ZESCA Trial
• Study Start Date: Dec 1, 2005
• Actual Primary Completion Date: Jun 1, 2010
• Actual Study Completion Date: Jun 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: P Half of patients will receive placebo for 9 weeks.	Drug: Placebo; Placebo
Active Comparator: A Half of patients will receive bupropion for 9 weeks.	Drug: Bupropion HCl ER; 150 mg tablets po qd for 3 days and then 150 mg po bid for remainder of 9 weeks; Other Names: Zyban

Outcome Measures

Primary Outcome Measures

1. Smoking Abstinence [12 months]

   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.

Secondary Outcome Measures

1. Composite Major Adverse Cardiovascular Events (MACE) [12 months]

   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)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Parkview Medcial Center	Pueblo	Colorado	United States	81003
2	Central Maine Medical Center	Lewiston	Maine	United States	04240
3	Bay Regional Medical Center	Bay City	Michigan	United States
4	Bassett Healthcare	Cooperstown	New York	United States	13326
5	United Health Services	Johnson City	New York	United States	13790
6	Stony Brook Hospital and Medical Center	Stony Brook	New York	United States	11794-8167
7	Schuster Cardiology	Kettering	Ohio	United States	45429
8	Southwest Cardiology	Kettering	Ohio	United States	45429
9	DVA Medical Center	Oklahoma City	Oklahoma	United States	73104
10	Advanced Cardiology Specialists	Scranton	Pennsylvania	United States	18501
11	Medical University of South Carolina	Charleston	South Carolina	United States	29403
12	Riverside Hospital	Newport News	Virginia	United States	23601
13	Charleston Area Medical Center	South Charleston	West Virginia	United States	25309
14	National Heart Foundation of Bangladesh	Dhaka		Bangladesh
15	Peter Lougheed Centre of the Calgary General Hospital	Calgary	Alberta	Canada
16	University of Alberta Hospital	Edmonton	Alberta	Canada
17	Vancouver Coastal Health	Vancouver	British Columbia	Canada	V5M 1L9
18	Victoria General Hospital	Winnipeg	Manitoba	Canada	R3T 2E8
19	St. Boniface General Hospital	Winnipeg	Manitoba	Canada
20	New Brunswick Heart Centre	Saint Johns	New Brunswick	Canada
21	Valley Regional Hospital	Kentville	Nova Scotia	Canada
22	The Ottawa Hospital, General Campus	Ottawa	Ontario	Canada
23	St. Michael's Hospital	Toronto	Ontario	Canada
24	Hopital de la Cite de la Sante	Laval	Quebec	Canada	H7M 3L9
25	CHA Hotel-Dieu de Levis	Levis	Quebec	Canada
26	SMBD- Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2
27	Hopital Sacre-Coeur de Montreal	Montreal	Quebec	Canada
28	Hotel-Dieu	Montreal	Quebec	Canada
29	Montreal General Hospital	Montreal	Quebec	Canada
30	Hopital Fleurimont	Sherbrooke	Quebec	Canada	J1H 5N4
31	CSSS de Sorel-Tracy	Sorel	Quebec	Canada
32	CSSS de la Region de Thetford	Thetford Mines	Quebec	Canada
33	Saskatchewan Drug Research Institute	Saskatoon	Saskatchewan	Canada	S7N 0W8
34	Hopital Laval	Quebec		Canada	G1V 4G5
35	Centre for Chronic Disease Control	New Delhi		India
36	Isfahan Cardiovascular Research Centre	Isfahan	Iran	Iran, Islamic Republic of
37	InterActive Research and Development	Karachi		Pakistan
38	University Hospital F. Bourguiba	Sousse		Tunisia

Sponsors and Collaborators

• Mark Eisenberg
• Canadian Institutes of Health Research (CIHR)
• Heart and Stroke Foundation of Canada

Investigators

• Principal Investigator: Mark J Eisenberg, MD, MPH, Jewish General Hospital/ McGill University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mark Eisenberg, MD, MPH, Professor of Medicine, McGill University
• ClinicalTrials.gov Identifier: NCT00689611
• Other Study ID Numbers: ZESCA 9197; ISRCTN75356261
• First Posted: Jun 3, 2008
• Last Update Posted: Apr 23, 2015
• Last Verified: Apr 1, 2015

• Keywords provided by Mark Eisenberg, MD, MPH, Professor of Medicine, McGill University: Acute coronary syndrome; Myocardial infarction; Smoking cessation; Zyban; Secondary intervention post-ACS
• Additional relevant MeSH terms: Myocardial Infarction; Acute Coronary Syndrome; Syndrome; Infarction; Bupropion

Study Results

Participant Flow

Arm/Group Title	Placebo	Bupropion
Arm/Group Description	Participants received placebo for 9 weeks.	Participants received bupropion for 9 weeks. Bupropion HCl ER: 150 mg tablets po qd for 3 days and then 150 mg po bid for remainder of 9 weeks.
Period Title: Overall Study
STARTED	200	192
COMPLETED	159	146
NOT COMPLETED	41	46

Baseline Characteristics

Arm/Group Title	Placebo	Bupropion	Total
Arm/Group Description	participants received placebo for 9 weeks. Placebo: Placebo	participants received bupropion for 9 weeks. Bupropion HCl ER: 150 mg tablets po qd for 3 days and then 150 mg po bid for remainder of 9 weeks	Total of all reporting groups
Overall Participants	200	192	392
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.4 (10.3)	54.5 (10.4)	53.9 (10.3)
Sex: Female, Male (Count of Participants)
Female	34 17%	31 16.1%	65 16.6%
Male	166 83%	161 83.9%	327 83.4%
Region of Enrollment (participants) [Number]
United States	35 17.5%	33 17.2%	68 17.3%
Pakistan	18 9%	18 9.4%	36 9.2%
Canada	101 50.5%	96 50%	197 50.3%
Iran, Islamic Republic of	31 15.5%	31 16.1%	62 15.8%
Tunisia	6 3%	4 2.1%	10 2.6%
India	9 4.5%	10 5.2%	19 4.8%
No. of years smoked (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.6 (11.9)	33.2 (13.0)	32.9 (12.4)
No. of cigarettes/day (past year) (cigarettes/day) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cigarettes/day]	23.2 (10.4)	23.2 (10.8)	23.2 (10.6)
Index admission was for ST-segment elevation myocardial infarction [STEMI] (participants) [Number]
Number [participants]	133 66.5%	121 63%	254 64.8%
Cardiac catheterization during index admission (participants) [Number]
Number [participants]	136 68%	128 66.7%	264 67.3%
Percutaneous coronary intervention during index admission (participants) [Number]
Number [participants]	104 52%	93 48.4%	197 50.3%
Coronary artery bypass graft during index admission (participants) [Number]
Number [participants]	15 7.5%	10 5.2%	25 6.4%

Outcome Measures

1. Primary Outcome

Title	Smoking Abstinence
Description	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.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Bupropion
Arm/Group Description	Participants received placebo for 9 weeks.	Participants received bupropion for 9 weeks. Bupropion HCl ER: 150 mg tablets po qd for 3 days and then 150 mg po bid for remainder of 9 weeks
Measure Participants	194	183
Number [percentage of participants]	32.0 16%	37.2 19.4%

2. Secondary Outcome

Title	Composite Major Adverse Cardiovascular Events (MACE)
Description	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)
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Bupropion
Arm/Group Description	Participants received placebo for 9 weeks.	Participants received bupropion for 9 weeks. Bupropion HCl ER: 150 mg tablets po qd for 3 days and then 150 mg po bid for remainder of 9 weeks
Measure Participants	200	192
Number [percentage of participants]	11.0 5.5%	13.0 6.8%

Adverse Events

Arm/Group Title	Placebo		Bupropion
Arm/Group Description	Participants received placebo for 9 weeks.		Participants received bupropion for 9 weeks. Bupropion HCl ER: 150 mg tablets po qd for 3 days and then 150 mg po bid for remainder of 9 weeks
All Cause Mortality
	Placebo		Bupropion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Bupropion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/200 (18.5%)		34/192 (17.7%)
Cardiac disorders
Myocardial Infarction	5/200 (2.5%)	5	5/192 (2.6%)	5
Unstable Angina	11/200 (5.5%)	11	12/192 (6.3%)	12
General disorders
Death	6/200 (3%)	6	9/192 (4.7%)	9
Other	17/200 (8.5%)	17	9/192 (4.7%)	9
Psychiatric disorders
Psychiatric event	1/200 (0.5%)	1	2/192 (1%)	2
Vascular disorders
Stroke	1/200 (0.5%)	1	0/192 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Bupropion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	48/200 (24%)		58/192 (30.2%)
Gastrointestinal disorders
Constipation	12/200 (6%)	12	14/192 (7.3%)	14
General disorders
Dry mouth	18/200 (9%)	18	26/192 (13.5%)	26
Dizziness	17/200 (8.5%)	17	15/192 (7.8%)	15
Dysgeusia	13/200 (6.5%)	13	16/192 (8.3%)	16
Dream abnormality	17/200 (8.5%)	17	7/192 (3.6%)	7
Pruritus	8/200 (4%)	8	5/192 (2.6%)	5
Nervous system disorders
Insomnia	36/200 (18%)	36	43/192 (22.4%)	43

Limitations/Caveats

Relatively high number who withdrew or were lost to follow-up (22.2%), but within expectations for smoking cessation trials; Relatively small numbers of serious adverse events occurred, limiting power to examine secondary safety end points.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.