Transcript A Randomized Controlled Trial

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The Efficacy and Safety of Varenicline, a Selective
α4β2 Nicotinic Receptor Partial Agonist, for
Smoking Cessation in Patients Hospitalized with
Acute Coronary Syndrome:
A Randomized Controlled Trial
Mark J. Eisenberg, Sarah B. Windle, Nathalie Roy, Wayne Old, François Grondin,
Iqbal Bata, Ayman Iskander, Claude Lauzon, Nalin Srivastava, Adam Clarke, Daniel
Cassavar, Danielle Dion, Herbert Haught, Shamir Mehta, Jean-François Baril, Charles
Lambert, Mina Madan, Beth L. Abramson, and Payam Dehghani
for the Evaluation of Varenicline in Smoking Cessation for Patients Post-Acute
Coronary Syndrome (EVITA) Trial Investigators
Embargoed Until 10:45 a.m. ET, Monday, Nov. 9, 2015
Disclosures
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• Drs. Eisenberg, Dehghani and Madan received honoraria
from Pfizer Inc. for providing continuing medical education
on smoking cessation
• Dr. Eisenberg received funding and study drug/placebo from
Pfizer Inc., to perform the Evaluation of Varenicline in
Smoking Cessation for Patients Post-Acute Coronary
Syndrome [EVITA] Trial; NCT00794573).
Background
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• Morbidity and mortality substantially increased among
patients who continue to smoke following ACS
• Less than 1/3 remain abstinent after discharge
• Nicotine replacement therapies (NRTs) – frequently
prescribed in-hospital but no RCTs
• Bupropion (non-NRT) – 3 RCTs and not found to be
efficacious
• Varenicline (non-NRT) – efficacious in healthy smokers and
stable CVD patients
• Little is known about varenicline’s efficacy in ACS patients
References: JAMA 2003;290:86-97. Am J Cardiol 2011;108:804-8. How Tobacco Smoking Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon
General, 2010. The Health Consequences of Smoking: A Report of the Surgeon General, 2004. J Am Coll Cardiol 2013; 61:524-32. Arch Intern Med 2011;171:1055-60. Am J Med 2006;119:1080-7.
JAMA 2015;313:687-94. JAMA 2006;296:56-63. Circulation. 2010; 121:221-9.
Objective
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To assess the efficacy of varenicline
in smokers hospitalized with ACS
Study Design
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• Multicenter
• 40 Canadian and US centers
• Double-blind
• Randomized
• Placebo-controlled
• Investigator-initiated
• Funding & study drug/placebo from Pfizer Inc.
• No role in design, conduct, analysis, or reporting
The complete EVITA Trial methodology is available in:
Windle SB et al. Am Heart J 2015;170:635-40.e1
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Trial Schematic
Smokers Hospitalized for ACS
Informed Consent & Eligibility Assessment
Randomization
Varenicline for 12 Weeks
Placebo for 12 Weeks
Baseline Visit & 1st Dose In-Hospital
Follow-Up Visits
Telephone: Weeks 1, 2 & 8
Clinic: Weeks 4, 12 & 24
Primary Endpoint
Smoking abstinence at Week 24
Low-Intensity Counselling at Baseline & All Follow-Up Contacts
Inclusion/Exclusion
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• Main Inclusion Criteria
• Age ≥ 18 years and motivated to quit smoking
• Smoke ≥ 10 cigarettes/day on average in the past year
• Hospitalized with ACS
• Main Exclusion Criteria
• History of neuropsychiatric disorders
• Prior varenicline use, or use of smoking cessation
pharmacotherapy at the time of ACS
• Cardiogenic shock or renal impairment at randomization
• Hepatic impairment prior to ACS
• Excessive alcohol use, or current use of: marijuana, noncigarette tobacco products, OTC stimulants or anorectics
Endpoints
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• Primary Endpoint (ITT)
• 7-day point prevalence abstinence at week 24
• Self-reported abstinence in past week and exhaled CO ≤ 10 ppm
• Secondary Endpoints (ITT)
• Continuous abstinence at week 24
• Self-reported abstinence since baseline and exhaled CO ≤ 10 ppm
at all follow-up visits up to and including week 24
• ≥ 50% reduction in daily cigarette consumption at week 24
• Safety Endpoints
• Side effects, SAEs, MACE, neuropsychiatric events
• SAEs adjudicated by an EEC (blinded to treatment status)
• Trial monitored by an external DSMB
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Trial Flow
Patients Randomized
n=302
Varenicline n=151
Placebo n=151
Treatment
Weeks
1-12
Died n=2
Withdrew Consent n=9
Lost to Follow-Up n=16
Died n=0
Withdrew Consent n=10
Lost to Follow-Up n=18
Follow-Up
Weeks
13-24
Died n=1
Withdrew Consent n=0
Lost to Follow-Up n=5
Died n=0
Withdrew Consent n=2
Lost to Follow-Up n=7
Smoking Status for ITT Analysis*
n=148
Smoking Status for ITT Analysis*
n=151
Week
24
* Assumed that patients who withdrew or who were lost to follow-up returned
to smoking at their baseline rate
Patient Characteristics
Varenicline
(n = 151)
Varenicline
(n = 151)
Placebo
(n = 151)
STEMI
57
55
NSTEMI
35
40
Unstable angina
8
5
Cardiac catheterization
99
98
PCI
83
85
CABG
9
3
CHF
7
5
Recurrent ischemia
5
1
Ventricular arrhythmia
6
8
Median Length of Stay (d)
3
3
Median Time from
Admission to 1st Dose of
Study Medication (d)
2
2
Placebo
(n = 151)
Reason for Admission (%)
Demographics
Age (y)
55 ± 8
55 ± 10
74
76
69 vs. 31
64 vs. 36
Male (%)
Canada vs. US (%)
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Procedures (%)
Smoking (mean ± SD)
Years smoked
35 ± 11
37 ± 12
Cigarettes/day
at baseline
22 ± 11
21 ± 10
Clinical/Medical History (%)
Complications (%)
Hyperlipidemia
64
70
Hypertension
52
46
Diabetes
22
17
Prior use of
antidepressants
11
6
Prior MI
17
19
Prior PCI
12
19
Prior CABG
3
3
Prior TIA or CVA
2
4
Index Hospitalization
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Primary Endpoint
Varenicline
Placebo
100
80
7-Day Point
60
Prevalence
Smoking
Abstinence 40
(%)
p<0.001
60.0
p<0.001
NNT: 6.8
↓
p=0.012
57.7
47.3
37.7
36.4
32.5
20
0
4 weeks
12 weeks
24 weeks
Primary Endpoint
Secondary Endpoints
Varenicline
Placebo
100
80
Continuous 60
Smoking
Abstinence
40
(%)
p<0.001
p=0.013
52.0
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NNT: 10.0
↓
p=0.081
44.3
32.5
29.8
35.8
25.8
Varenicline
Placebo
20
p=0.009
0
4 weeks
12 weeks
24 weeks
p=0.004
100
87.2
80
≥ 50%
Reduction
in Daily
60
Cigarette
Consumption
from Baseline 40
(%)
74.8
NNT: 8.5
↓
P<0.05
77.7
61.6
67.4
55.6
20
0
4 weeks
12 weeks
24 weeks
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Safety Endpoints
Varenicline
(n = 151)
Placebo
(n = 151)
P-Value
18 (11.9)
17 (11.3)
>0.99
Composite MACE
6 (4.0)
7 (4.6)
>0.99
Death
2 (1.3)
0
0.50
Myocardial infarction
3 (2.0)
3 (2.0)
1.00
Unstable angina
1 (0.7)
5 (3.3)
0.21
Other cardiovascular events
3 (2.0)
2 (1.3)
>0.99
0
0
----
1 (0.7)
0
>0.99
9 (6.0)
8 (5.3)
>0.99
Insomnia
27 (17.9)
19 (12.6)
0.26
Nausea
21 (13.9)
13 (8.6)
0.20
Abnormal dreams
23 (15.2)
7 (4.6)
<0.01
SAEs Within 30 Days of Treatment Discontinuation, n (%)
Patients with any SAE
Neuropsychiatric events
Seizure, suicidal ideation
Other
Other
Most Common Side Effects – 12-Week Cumulative, n (%)
Conclusions
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• Varenicline, initiated in-hospital following ACS, and in
conjunction with low-intensity counseling, is efficacious for
smoking cessation
• Without smoking cessation therapy, less than 1/3 of
smokers hospitalized with ACS remain abstinent after
discharge
• Future studies are needed to establish safety in these
patients
For more details on the EVITA Trial, please refer to our
simultaneous publication in Circulation
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Investigators
Steering Committee
Mark Eisenberg (Chair)
Jewish General Hospital/McGill
University, Montreal, QC
Trial Coordinator
Beth L. Abramson
St. Michael's Hospital,
Toronto, ON
Iqbal Bata
Queen Elizabeth II Health Sciences
Centre, Halifax, NS
Mina Madan
Sunnybrook Health Sciences Centre,
Toronto, ON
Sarah Windle
Jewish General Hospital,
Montreal, QC
Jean-François Baril
Dr. Georges-L.-Dumont University
Hospital Centre, Moncton, NB
Danielle Dion
CISSS de Chaudière Appalaches site
Hôpital St-Georges, Beauce, QC
Thao Huynh
Montréal General Hospital,
Montréal, QC
Shamir R. Mehta
McMaster University & Hamilton
Health Sciences, Hamilton, ON
Neville Suskin
London Health Sciences Centre,
London, ON
Qiangjun Cai
McFarland Clinic PC,
Ames, IA
Naim Farhat
North Ohio Research,
Elyria, OH
Ayman Iskander
SJH Cardiology Associates and St.
Joseph's Hospital, Liverpool, NY
Wayne Old
Sentara Cardiovascular Research
Institute, Norfolk, VA
Mohamed Turki
St. Luke's University Hospital,
Bethlehem, PA
Daniel Cassavar
ProMedica Toledo Hospital,
oledo, OH
Nancy Fillion
L’Hôtel-Dieu de Québec,
Québec, QC
Smadar Kort
Stony Brook University,
Stony Brook, NY
Michael Peters
Heart Consultants,
Omaha, NE
Andrew Weeks
Norfolk General Hospital,
Simcoe, ON
Suresh Chandrasekaran
The Oklahoma Heart Hospital Research
Foundation, Oklahoma City, OK
Eve Gillespie
Glacier View Research Institute,
Kalispell, MT
Charles Lambert
Florida Hospital Pepin Heart
Institute, Tampa, FL
Nathalie Roy
CSSS de Chicoutimi,
Chicoutimi, QC
Brian Wong
Sudbury Regional Hospital,
Sudbury, ON
Mohamed Chebaclo
Altru Health System,
Grand Forks, ND
François R. Grondin
CISSS Chaudière-Appalaches,
Hôtel-Dieu de Lévis Site, QC
John Larry
Ohio State University,
Columbus, OH
Manohara Senaratne
Grey Nuns Community Hospital,
Edmonton, AB
Adam Clarke
Valley Regional Hospital,
Kentville, NS
Herbert Haught
Heart Center Research,
Huntsville, AL
Claude Lauzon
CISSS - Chaudière-Appalaches,
Thetford Mines, QC
Jeffrey Shanes
Consultants in Cardiovascular
Medicine, Melrose Park, IL
David Cleveland
Penticton Regional Hospital,
Penticton, BC
John Henry
Heart Consultants,
Omaha, NE
Pedro Lozano
VA Medical Center,
Oklahoma City, OK
Satyendra Sharma
St. Boniface General Hospital,
Winnipeg, MB
Payam Dehghani
Prairie Vascular Research Network,
University of Saskatchewan, Regina, SK
Michael Hong
Buffalo Heart Group,
Buffalo, NY
Peter McCullough &Thomas Anan
Providence Park Hospital,
Novi, MI
Nalin Srivastava
Spartanburg Regional Medical
Center, Spartanburg, SC
Endpoints Evaluation Committee
Data Safety Monitoring Board
Vidal Essebag
Montreal General Hospital,
Montreal, QC
Jafna Cox (Chair)
Dalhousie University,
Halifax, NS
Peter Faris
University of Calgary,
Calgary, AB
Nadia Kahn
University of British Columbia,
Vancouver, BC
Site Investigators
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Sample Size Calculation
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• Assumptions:
• 7-day PPA rate of 24% at 24 weeks in placebo-treated patients
• ≥ 15% absolute increase in abstinence rates with varenicline
• > 80% power and two-tailed α of 0.05
• 150 patients per study arm (n=300) needed
• Not powered to examine safety endpoints
Limitations
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• Only enrolled patients motivated to quit smoking
• Smoking abstinence rates likely optimistic vs. real-world
• Small sample size
• Limits ability to definitively address the cardiovascular safety
of varenicline
• Smokers represent a challenging patient population
• As with other smoking cessation trials, a not insubstantial
number of patients withdrew or were lost to follow-up
• Low-intensity counseling
• High-intensity counselling could have improved quit rates