www.mghcme.org
A. Eden Evins, MD, MPH Director, Center for Addiction Medicine
Massachusetts General Hospital Associate Professor of Psychiatry
Harvard Medical School
Treatment of Tobacco and Cocaine Use Disorders
www.mghcme.org
A. Eden Evins, MD, MPH
My spouse/partner and I have the following relevant financial relationship with a commercial interest to disclose: Research Support (to institution): Forum Pharmaceuticals, Pfizer Inc. Advisory Board: Reckitt Benckizer
www.mghcme.org
• Nearly 68 million smokers in the US
• 3 million tobacco-related deaths annually worldwide-- 440,000 in the US
• 19% of Americans currently smoke
• 25% of Americans are former smokers
• 54% of those with SMI smoke
• Numbers of smokers are INCREASING
• 100 million people died in the last century from smoking related causes Anticipated that 1 billion smokers worldwide will die from smoking related causes in this century – WHO
Public Health Burden of Tobacco
Dependence
MD-4
Potential public health impact of improved,
integrated addiction treatment in a chronic care
model
• Opioid overdoses killed more than 29,000 people
in 2014, more than any prior year.
• Over 88,000 alcohol related deaths per year and
increasing.
• Over 430,000 tobacco related deaths per year and
not decreasing.
• Approx. 18,000 illicit drug overdose deaths
www.mghcme.org
Smoking Kills
www.mghcme.org
Quitting Helps
www.mghcme.org
Illustration of the effects of a 3-fold difference in annual death rates on mortality at ages 35-79 *
78%
47%
Adapted from the One Million Women Study
Pirie, Peto, et al., Lancet 2013
www.mghcme.org
THE MILLION WOMEN STUDY
Pirie, Lancet, 2013
Quitting by age 50 cuts mortality in half
www.mghcme.org
50 Years after the first Surgeon General’s report of an association between smoking and cancer, adult smoking has declined 55% in the general US population. Smoking prevalence among adults with SMI in the US today is 53%.
This is higher than in the US general population in 1964.
www.mghcme.org
• In those with one or more lifetime hospitalizations for schizophrenia, bipolar disorder, or MDD,
• HALF died from to 1 of 19 diseases identified by CDC as causally linked to tobacco use
Smoking-Related Mortality in Those with
Psychiatric Disorders
Callaghan, 2014
www.mghcme.org
• Death
• MI
• Stroke
• Progression of atherosclerosis
• Bronchitis
• Diabetes Morbidity
• Cancer Risk
• Progression of COPD
Quitting Reduces
www.mghcme.org
• 26 studies
• Change in psychiatric symptoms was compared between continuing smokers and successful quitters
• Depression, anxiety, stress and quality of life improved among those who quit smoking significantly compared to those who continued smoking.
• It did not matter whether one had a pre-existing psychiatric diagnosis or not!!!
• Effect sizes comparable to those observed for antidepressant medications!!!
META-ANALYSIS CONFIRMS: SMOKING CESSATION IMPROVES
PSYCHIATRIC SYMPTOMS, QUALITY OF LIFE
Taylor et al. BMJ 2014
Smoking Cessation
Is Associated
with Improved Psychiatric Symptoms
Taylor et al., BMJ, 2014
Evins, MGH CAM
www.mghcme.org
•Acetylcholine stimulates nicotinic cholinergic receptors on dopaminergic and glutamatergic neurons in hippocampus prefrontal cortical areas as well as nucleus accumbens and other reward areas
•Nicotine stimulates a4b2, a7 and other nAChRs in brain
•Therapies target Nicotinic Receptors: NRT, Varenicline
•Or downstream targets such as dopaminergic targets: Bupropion, agents specific for subtypes of dopaminergic receptors under development
•Glutamatergic agents under development
•Exception: Nicotine stimulation upregulates receptor expression, especially high-affinity a4b2 receptors
Addiction to Nicotine:
Mechanism and Therapeutic Targets
www.mghcme.org
Cessation Works: Pharmacotherapy + Behavioral Therapy Doubles to
Triples Abstinence Rates
Cahill et al., JAMA 2014
www.mghcme.org
Cessation Works: Pharmacotherapy + Behavioral Therapy Doubles to Triples Abstinence Rates
First Line Tx: 1a. Varenicline, Dual NRT,
1b. Bupropion, Single NRT
1c. Varenicline + NRT (single study)
Cahill et al., JAMA, 2014
Varenicline & Dual NRT superior to bupropion & single NRT
Cahill et al., JAMA, 2014
Varenicline + NRT more effective than placebo + varenicline
Koegelenberg et al., JAMA, 2014
www.mghcme.org
For tobacco dependence: average of 5 attempts at abstinence before long-term abstinence achieved
Treatments double to triple abstinence rates and are Underutilized!
With Sustained Treatment Efforts, Addictive Disorders for which Treatments are Available are Good Prognosis Disorders
Addiction Treatment Works: Expect and Treat Relapses
www.mghcme.org
Repeat Cessation Attempts Are Effective
Gonzales, Clin Pharmacol Ther, 2014
Varenicline, 12-week trial, was associated with significantly higher quit rates than placebo in those who had failed one or more prior varenicline trials.
www.mghcme.org
Consider Maintenance Treatment: Point Prevalence Abstinence During One Year Maintenance Treatment
***
**
Evins, Cather, et al., JAMA. 2014
247 enrolled, 203 started open treatment, 87 (43%) attained abstinence at week 12 and were randomized to 40 weeks maintenance therapy
www.mghcme.org
Maintenance Treatment Extends Continuous
Abstinence Even More in Those with SMI
Evins, et al., under review, Evins, et al., 2014, JAMA; Tonstad, et al., 2006 JAMA
www.mghcme.org
• Pharmacotherapy + Behavioral Tx Doubles to Triples Quit Rates over placebo and are Universally Recommended in those without psychiatric illness and increases success rates over 5-fold in those with SMI
• Pharmacotherapy – First line:
• 1a. varenicline, dual NRT (short- + long-acting NRT)
• 1b. Bupropion, single NRT – Second line: nortriptyline
• Behavioral Treatment – Brief advice, individ/group tx, set a quit date, use “quit lines”
– Web, phone, in person, printed materials
– Example: http://www.trytostop.org/ Mass
• Multiple quit attempts are usual and
should be expected.
Treatment for Nicotine Dependence
www.mghcme.org
• Advise all your patients who smoke to quit
• Review health risks of tobacco use
• Educate about effective available treatments, choose and prescribe a pharmacotherapy
• Emphasize past successes, even if small, and encourage repeat attempts
• Set a quit date
• Refer for peer group support and or Quit Line
• Refer for or perform behavioral relapse prevention – CBT
• Brief advice to quit smoking has a significant impact on abstinence rates at 6 months
– Brief advice alone decreases fatal coronary artery disease, lung cancer, and total mortality
Give Brief Physician Advice to Quit
Lancaster and Stead, 2005a
www.mghcme.org
• Treatment guidelines recommend physician advice to quit at every visit, and physician recommendation for cessation plan for all smokers.
• But physicians document smoking status at 70% of visits; counsel to quit at 30% of visits; prescribe medications at <1% of visits
• No improvement since 1990
• Psychiatrists rarely offer counseling to quit smoking. In one study, only 12.4% of smoking patients were advised to quit.
Treatment is effective in the long run and is underprescribed!
Effective Treatments: Underutilized!
Himloch and Daumit, 2003; Thorndike, 2001.
www.mghcme.org
• Selective, partial a4 b2 and full a7 NAChR agonist
• FDA approved 2006 as an aid for smoking cessation
• Reduces nicotine withdrawal symptoms
– Stimulates NAChRs
• Reduces nicotine-induced dopamine release and reward
– Blocks binding of nicotine at NAChRs
• Superior efficacy vs placebo (and bupropion and NRT)
• Well tolerated from a psychiatric standpoint in all controlled studies to date as well as all large epidemiologic studies.
Varenicline (Chantix)
www.mghcme.org
Case Reports: Irritability, Impulsive Behavior, Depressed Mood, Suicidal Behavior
NOT seen in controlled trials to date in smokers with or without co-morbid psychiatric illness
Varenicline : Safety
www.mghcme.org
Observational Studies of Varenicline & NPS
Study Sample Outcome Adj. HR*
Meyer 2013 Addiction 35,800 US MHS 2006-2007
NPS hospital. (prim diag) 30 days
NPS hospital. (any diag) 30 days
NPS outpt visits
1.14 (0.56, 2.34)
0.79 (0.50, 1.24)
0.71 (0.60, 0.84)
Thomas 2013 BMJ
112,805 UK NHS 2006-2011
Fatal/nonfatal self-harm 90 days
Initiated antidepressant 90 days
0.88 (0.52, 1.49)
0.75 (0.65, 0.87)
Kotz 2015 Lancet Resp Med
158,209 UK NHS 2007-2012
Depression
Fatal/nonfatal self-harm 6 mo
0.65 (0.61, 0.68)
0.60 (0.48, 0.76)
Cunningham 2016 Addiction
15,255 US VA 2006-2007
NPS hospital. (prim diag) 30 days
NPS outpt visit in 30 days
0.15 – 2.00 all NS
Signif for Schiz only 1.27 (1.07, 1.51)
+5 visits per 100 yrs tx
Molero 2015 BMJ
69,757 Sweden (self-controlled) 2006-2009
Hospital or outpt specialist psychoses, mood, or anxiety
Fatal/nonfatal self-harm
1.18 (1.05, 1.31) (Specific to mood or
anxiety tx in Psych-HX)
1.00 (0.72, 1.37)
Pasternak 2013 Addiction
77,726 Denmark 2007-2010
NPS ER visit or hosp. in 30 days (vs. bupropion)
0.85 (0.55, 1.30)
*All analyses used statistical adjustment to control for confounds, effect is a hazard ratio
www.mghcme.org
Observational Studies of Varenicline & NPS
*All analyses used statistical adjustment to control for confounds, effect is a hazard ratio
Study Sample Outcome Adj. HR*
Meyer 2013 Addiction 35,800 US MHS 2006-2007
NPS hospital. (prim diag) 30 days
NPS hospital. (any diag) 30 days
NPS outpt visits
1.14 (0.56, 2.34)
0.79 (0.50, 1.24)
0.71 (0.60, 0.84)
Thomas 2013 BMJ
112,805 UK NHS 2006-2011
Fatal/nonfatal self-harm 90 days
Initiated antidepressant 90 days
0.88 (0.52, 1.49)
0.75 (0.65, 0.87)
Kotz 2015 Lancet Resp Med
158,209 UK NHS 2007-2012
Depression
Fatal/nonfatal self-harm 6 mo
0.65 (0.61, 0.68)
0.60 (0.48, 0.76)
Cunningham 2016 Addiction
15,255 US VA 2006-2007
NPS hospital. (prim diag) 30 days
NPS outpt visit in 30 days
0.15 – 2.00 all NS
Signif for Schiz only 1.27 (1.07, 1.51)
+5 visits per 100 yrs tx
Molero 2015 BMJ
69,757 Sweden (self-controlled) 2006-2009
Hospital or outpt specialist psychoses, mood, or anxiety
Fatal/nonfatal self-harm
1.18 (1.05, 1.31) (Specific to mood or
anxiety tx in Psych-HX)
1.00 (0.72, 1.37)
Pasternak 2013 Addiction
77,726 Denmark 2007-2010
NPS ER visit or hosp. in 30 days (vs. bupropion)
0.85 (0.55, 1.30)
www.mghcme.org
Observational Studies of Varenicline & NPS
*All analyses used statistical adjustment to control for confounds, effect is a hazard ratio
Study Sample Outcome Adj. HR*
Meyer 2013 Addiction 35,800 US MHS 2006-2007
NPS hospital. (prim diag) 30 days
NPS hospital. (any diag) 30 days
NPS outpt visits
1.14 (0.56, 2.34)
0.79 (0.50, 1.24)
0.71 (0.60, 0.84)
Thomas 2013 BMJ
112,805 UK NHS 2006-2011
Fatal/nonfatal self-harm 90 days
Initiated antidepressant 90 days
0.88 (0.52, 1.49)
0.75 (0.65, 0.87)
Kotz 2015 Lancet Resp Med
158,209 UK NHS 2007-2012
Depression
Fatal/nonfatal self-harm 6 mo
0.65 (0.61, 0.68)
0.60 (0.48, 0.76)
Cunningham 2016 Addiction
15,255 US VA 2006-2007
NPS hospital. (prim diag) 30 days
NPS outpt visit in 30 days
0.15 – 2.00 all NS
Signif for Schiz only 1.27 (1.07, 1.51)
+5 visits per 100 yrs tx
Molero 2015 BMJ
69,757 Sweden (self-controlled) 2006-2009
Hospital or outpt specialist psychoses, mood, or anxiety
Fatal/nonfatal self-harm
1.18 (1.05, 1.31) (Specific to mood or
anxiety tx in Psych-HX)
1.00 (0.72, 1.37)
Pasternak 2013 Addiction
77,726 Denmark 2007-2010
NPS ER visit or hosp. in 30 days (vs. bupropion)
0.85 (0.55, 1.30)
www.mghcme.org
Observational Studies of Varenicline & NPS
*All analyses used statistical adjustment to control for confounds, effect is a hazard ratio
Study Sample Outcome Adj. HR*
Meyer 2013 Addiction 35,800 US MHS 2006-2007
NPS hospital. (prim diag) 30 days
NPS hospital. (any diag) 30 days
NPS outpt visits
1.14 (0.56, 2.34)
0.79 (0.50, 1.24)
0.71 (0.60, 0.84)
Thomas 2013 BMJ
112,805 UK NHS 2006-2011
Fatal/nonfatal self-harm 90 days
Initiated antidepressant 90 days
0.88 (0.52, 1.49)
0.75 (0.65, 0.87)
Kotz 2015 Lancet Resp Med
158,209 UK NHS 2007-2012
Depression
Fatal/nonfatal self-harm 6 mo
0.65 (0.61, 0.68)
0.60 (0.48, 0.76)
Cunningham 2016 Addiction
15,255 US VA 2006-2007
NPS hospital. (prim diag) 30 days
NPS outpt visit in 30 days
0.15 – 2.00 all NS
Signif for Schiz only 1.27 (1.07, 1.51)
+5 visits per 100 yrs tx
Molero 2015 BMJ
69,757 Sweden (self-controlled) 2006-2009
Hospital or outpt specialist psychoses, mood, or anxiety
Fatal/nonfatal self-harm
1.18 (1.05, 1.31) (Specific to mood or
anxiety tx in Psych-HX)
1.00 (0.72, 1.37)
Pasternak 2013 Addiction
77,726 Denmark 2007-2010
NPS ER visit or hosp. in 30 days (vs. bupropion)
0.85 (0.55, 1.30)
www.mghcme.org
Observational Studies of Varenicline & NPS
*All analyses used statistical adjustment to control for confounds, effect is a hazard ratio
Study Sample Outcome Adj. HR*
Meyer 2013 Addiction 35,800 US MHS 2006-2007
NPS hospital. (prim diag) 30 days
NPS hospital. (any diag) 30 days
NPS outpt visits
1.14 (0.56, 2.34)
0.79 (0.50, 1.24)
0.71 (0.60, 0.84)
Thomas 2013 BMJ
112,805 UK NHS 2006-2011
Fatal/nonfatal self-harm 90 days
Initiated antidepressant 90 days
0.88 (0.52, 1.49)
0.75 (0.65, 0.87)
Kotz 2015 Lancet Resp Med
158,209 UK NHS 2007-2012
Depression
Fatal/nonfatal self-harm 6 mo
0.65 (0.61, 0.68)
0.60 (0.48, 0.76)
Cunningham 2016 Addiction
15,255 US VA 2006-2007
NPS hospital. (prim diag) 30 days
NPS outpt visit in 30 days
0.15 – 2.00 all NS
Signif for Schiz only 1.27 (1.07, 1.51)
+5 visits per 100 yrs tx
Molero 2015 BMJ
69,757 Sweden (self-controlled) 2006-2009
Hospital or outpt specialist psychoses, mood, or anxiety
Fatal/nonfatal self-harm
1.18 (1.05, 1.31) (Specific to mood or
anxiety tx in Psych-HX)
1.00 (0.72, 1.37)
Pasternak 2013 Addiction
77,726 Denmark 2007-2010
NPS ER visit or hosp. in 30 days (vs. bupropion)
0.85 (0.55, 1.30)
www.mghcme.org
Observational Studies of Varenicline & NPS
*All analyses used statistical adjustment to control for confounds, effect is a hazard ratio
Study Sample Outcome Adj. HR*
Meyer 2013 Addiction 35,800 US MHS 2006-2007
NPS hospital. (prim diag) 30 days
NPS hospital. (any diag) 30 days
NPS outpt visits
1.14 (0.56, 2.34)
0.79 (0.50, 1.24)
0.71 (0.60, 0.84)
Thomas 2013 BMJ
112,805 UK NHS 2006-2011
Fatal/nonfatal self-harm 90 days
Initiated antidepressant 90 days
0.88 (0.52, 1.49)
0.75 (0.65, 0.87)
Kotz 2015 Lancet Resp Med
158,209 UK NHS 2007-2012
Depression
Fatal/nonfatal self-harm 6 mo
0.65 (0.61, 0.68)
0.60 (0.48, 0.76)
Cunningham 2016 Addiction
15,255 US VA 2006-2007
NPS hospital. (prim diag) 30 days
NPS outpt visit in 30 days
0.15 – 2.00 all NS
Signif for Schiz only 1.27 (1.07, 1.51)
+5 visits per 100 yrs tx
Molero 2015 BMJ
69,757 Sweden (self-controlled) 2006-2009
Hospital or outpt specialist psychoses, mood, or anxiety
Fatal/nonfatal self-harm
1.18 (1.05, 1.31) (Specific to mood or
anxiety tx in Psych-HX)
1.00 (0.72, 1.37)
Pasternak 2013 Addiction
77,726 Denmark 2007-2010
NPS ER visit or hosp. in 30 days (vs. bupropion)
0.85 (0.55, 1.30)
www.mghcme.org
Observational Studies of Varenicline & NPS
*All analyses used statistical adjustment to control for confounds, effect is a hazard ratio
Study Sample Outcome Adj. HR*
Meyer 2013 Addiction 35,800 US MHS 2006-2007
NPS hospital. (prim diag) 30 days
NPS hospital. (any diag) 30 days
NPS outpt visits
1.14 (0.56, 2.34)
0.79 (0.50, 1.24)
0.71 (0.60, 0.84)
Thomas 2013 BMJ
112,805 UK NHS 2006-2011
Fatal/nonfatal self-harm 90 days
Initiated antidepressant 90 days
0.88 (0.52, 1.49)
0.75 (0.65, 0.87)
Kotz 2015 Lancet Resp Med
158,209 UK NHS 2007-2012
Depression
Fatal/nonfatal self-harm 6 mo
0.65 (0.61, 0.68)
0.60 (0.48, 0.76)
Cunningham 2016 Addiction
15,255 US VA 2006-2007
NPS hospital. (prim diag) 30 days
NPS outpt visit in 30 days
0.15 – 2.00 all NS
Signif for Schiz only 1.27 (1.07, 1.51)
+5 visits per 100 yrs tx
Molero 2015 BMJ
69,757 Sweden (self-controlled) 2006-2009
Hospital or outpt specialist psychoses, mood, or anxiety
Fatal/nonfatal self-harm
1.18 (1.05, 1.31) (Specific to mood or
anxiety tx in Psych-HX)
1.00 (0.72, 1.37)
Pasternak 2013 Addiction
77,726 Denmark 2007-2010
NPS ER visit or hosp. in 30 days (vs. bupropion)
0.85 (0.55, 1.30)
www.mghcme.org
Observational Studies of Varenicline & NPS
*All analyses used statistical adjustment to control for confounds, effect is a hazard ratio
Study Sample Outcome Adj. HR*
Meyer 2013 Addiction 35,800 US MHS 2006-2007
NPS hospital. (prim diag) 30 days
NPS hospital. (any diag) 30 days
NPS outpt visits
1.14 (0.56, 2.34)
0.79 (0.50, 1.24)
0.71 (0.60, 0.84)
Thomas 2013 BMJ
112,805 UK NHS 2006-2011
Fatal/nonfatal self-harm 90 days
Initiated antidepressant 90 days
0.88 (0.52, 1.49)
0.75 (0.65, 0.87)
Kotz 2015 Lancet Resp Med
158,209 UK NHS 2007-2012
Depression
Fatal/nonfatal self-harm 6 mo
0.65 (0.61, 0.68)
0.60 (0.48, 0.76)
Cunningham 2016 Addiction
15,255 US VA 2006-2007
NPS hospital. (prim diag) 30 days
NPS outpt visit in 30 days
0.15 – 2.00 all NS
Signif for Schiz only 1.27 (1.07, 1.51)
+5 visits per 100 yrs tx
Molero 2015 BMJ
69,757 Sweden (self-controlled) 2006-2009
Hospital or outpt specialist psychoses, mood, or anxiety
Fatal/nonfatal self-harm
1.18 (1.05, 1.31) (Specific to mood or
anxiety tx in Psych-HX)
1.00 (0.72, 1.37)
Pasternak 2013 Addiction
77,726 Denmark 2007-2010
NPS ER visit or hosp. in 30 days (vs. bupropion)
0.85 (0.55, 1.30)
www.mghcme.org
Observational Studies of Varenicline & NPS
*All analyses used statistical adjustment to control for confounds, effect is a hazard ratio
Study Sample Outcome Adj. HR*
Meyer 2013 Addiction 35,800 US MHS 2006-2007
NPS hospital. (prim diag) 30 days
NPS hospital. (any diag) 30 days
NPS outpt visits
1.14 (0.56, 2.34)
0.79 (0.50, 1.24)
0.71 (0.60, 0.84)
Thomas 2013 BMJ
112,805 UK NHS 2006-2011
Fatal/nonfatal self-harm 90 days
Initiated antidepressant 90 days
0.88 (0.52, 1.49)
0.75 (0.65, 0.87)
Kotz 2015 Lancet Resp Med
158,209 UK NHS 2007-2012
Depression
Fatal/nonfatal self-harm 6 mo
0.65 (0.61, 0.68)
0.60 (0.48, 0.76)
Cunningham 2016 Addiction
15,255 US VA 2006-2007
NPS hospital. (prim diag) 30 days
NPS outpt visit in 30 days
0.15 – 2.00 all NS
Signif for Schiz only 1.27 (1.07, 1.51)
+5 visits per 100 yrs tx
Molero 2015 BMJ
69,757 Sweden (self-controlled) 2006-2009
Hospital or outpt specialist psychoses, mood, or anxiety
Fatal/nonfatal self-harm
1.18 (1.05, 1.31) (Specific to mood or
anxiety tx in Psych-HX)
1.00 (0.72, 1.37)
Pasternak 2013 Addiction
77,726 Denmark 2007-2010
NPS ER visit or hosp. in 30 days (vs. bupropion)
0.85 (0.55, 1.30)
www.mghcme.org
Observational Studies of Varenicline & NPS
*All analyses used statistical adjustment to control for confounds, effect is a hazard ratio
Study Sample Outcome Adj. HR*
Meyer 2013 Addiction 35,800 US MHS 2006-2007
NPS hospital. (prim diag) 30 days
NPS hospital. (any diag) 30 days
NPS outpt visits
1.14 (0.56, 2.34)
0.79 (0.50, 1.24)
0.71 (0.60, 0.84)
Thomas 2013 BMJ
112,805 UK NHS 2006-2011
Fatal/nonfatal self-harm 90 days
Initiated antidepressant 90 days
0.88 (0.52, 1.49)
0.75 (0.65, 0.87)
Kotz 2015 Lancet Resp Med
158,209 UK NHS 2007-2012
Depression
Fatal/nonfatal self-harm 6 mo
0.65 (0.61, 0.68)
0.60 (0.48, 0.76)
Cunningham 2016 Addiction
15,255 US VA 2006-2007
NPS hospital. (prim diag) 30 days
NPS outpt visit in 30 days
0.15 – 2.00 all NS
Signif for Schiz only 1.27 (1.07, 1.51)
+5 visits per 100 yrs tx
Molero 2015 BMJ
69,757 Sweden (self-controlled) 2006-2009
Hospital or outpt specialist psychoses, mood, or anxiety
Fatal/nonfatal self-harm
1.18 (1.05, 1.31) (Specific to mood or
anxiety tx in Psych-HX)
1.00 (0.72, 1.37)
Pasternak 2013 Addiction
77,726 Denmark 2007-2010
NPS ER visit or hosp. in 30 days (vs. bupropion)
0.85 (0.55, 1.30)
www.mghcme.org
Fatal/Non-Fatal Self-Harm
Endpoint Author
Varenicline
# Events/ Sample Size
Comparator
# Events/ Sample Size
Hazard Ratio
95% CI
Lower Limit
Upper Limit
Suicide attempt Cunningham 0 / 11,774 0 / 23,548 NA NA NA
Suicide Thomas 2 / 30,352 6 / 78,407 NA NA NA
Fatal Or Non Fatal Self Harm
Thomas 19 / 30,352 69 / 78,407 0.88 0.52 1.49
Kotz 119 / 51,450 540 / 106,759 0.56 0.46 0.68
Molero 657 / 69,757 NA 1.00 0.72 1.37
www.mghcme.org
Summary: Observational Studies
Multiple outcomes assessed and most not significant
Fatal and nonfatal self-harm events are rare
No evidence of an increased risk for the most severe NPS events in varenicline users
www.mghcme.org
Pooled Analysis of ALL Psychiatric Adverse Effects in 17 RCT’s of Varenicline
Varenicline increased incidence of nausea but not psychiatric adverse events while increasing abstinence rates by 124% vs placebo and 22% vs. bupropion
Having a psychiatric illness increased the risk for psychiatric adverse events in smokers trying to quit and did so equally in those assigned to varenicline and placebo
In a large observational study in 35,800 outpatients trying to quit smoking, there were fewer psychiatric adverse events in those prescribed varenicline than those prescribed NRT
Results replicated now in multiple studies in different practice populations: DoD, VA, UK NHS
Varenicline Safety in 17 Randomized
Controlled Trials:
Gibbons and Mann 2013; Tonstad et al., 2010; Kotz et al., 2015
www.mghcme.org
EAGLES: Study Design
• Design: Prospective, randomized, double-blind, 24-week trial
• Treatments: varenicline, bupropion, NRT patch, placebo – Triple dummy design – All subjects received smoking cessation counseling
• Duration: 12 weeks treatment; 12 weeks non-treatment follow-up
• Target Sample Size: 8000 randomized subjects – 2000 per treatment (1000 with and 1000 without psychiatric
disorder)
• Primary comparisons: varenicline vs. placebo and bupropion vs. placebo
Author: Larry Samuels Reference: A3051123 Study protocol
www.mghcme.org
EAGLES: Primary Objectives
• Assess risk of clinically significant neuropsychiatric (NPS) adverse events (AEs) in subjects using varenicline, bupropion, nicotine replacement therapy (NRT), or placebo
• Determine whether subjects with prior history of psychiatric disorders are at greater risk for development of clinically significant NPS AEs compared to subjects without such history while using varenicline or bupropion as aids to smoking cessation
Author: Larry Samuels Reference: A3051123 Study protocol
AE=Adverse Event
www.mghcme.org
EAGLES: Study Diagram
BL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Study
Contacts
(Week)
Varenicline
Bupropion
Nicotine Patch (NRT)
Placebo
Screening
Visit
Baseline
Randomization
Vertical ticks represent subject clinic visits
BID=Twice Daily; BL=Baseline; QD=Once Daily
Treatment Phase Non-Treatment Follow-Up
Target Quit
Date
Begin dosing: varenicline (0.5 mg QD)
Begin 0.5 mg BID Day 4
Begin 1 mg BID Day 8
Begin dosing: bupropion (150 mg QD)
Begin 150 mg BID Day 4
Begin 21 mg QD (7 weeks) 14 mg QD
7 mg QD
Author: Larry Samuels Reference: CSR
Primary Safety Endpoint
www.mghcme.org
EAGLES: Study Diagram
BL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Study
Contacts
(Week)
Varenicline
Bupropion
Nicotine Patch (NRT)
Placebo
Screening
Visit
Baseline
Randomization
Vertical ticks represent subject clinic visits
BID=Twice Daily; BL=Baseline; QD=Once Daily
Treatment Phase Non-Treatment Follow-Up
Target Quit
Date
Begin dosing: varenicline (0.5 mg QD)
Begin 0.5 mg BID Day 4
Begin 1 mg BID Day 8
Begin dosing: bupropion (150 mg QD)
Begin 150 mg BID Day 4
Begin 21 mg QD (7 weeks) 14 mg QD
7 mg QD
Author: Larry Samuels Reference: CSR
Primary Safety Endpoint
www.mghcme.org
EAGLES: Study Diagram
BL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Study
Contacts
(Week)
Varenicline
Bupropion
Nicotine Patch (NRT)
Placebo
Screening
Visit
Baseline
Randomization
Vertical ticks represent subject clinic visits
BID=Twice Daily; BL=Baseline; QD=Once Daily
Treatment Phase Non-Treatment Follow-Up
Target Quit
Date
Begin dosing: varenicline (0.5 mg QD)
Begin 0.5 mg BID Day 4
Begin 1 mg BID Day 8
Begin dosing: bupropion (150 mg QD)
Begin 150 mg BID Day 4
Begin 21 mg QD (7 weeks) 14 mg QD
7 mg QD
Author: Larry Samuels Reference: CSR
Primary Safety Endpoint
www.mghcme.org
Study Population
• Included: Smokers age 18 to 75 years; average ≥10 cigarettes/day
• Excluded: Subjects with imminent suicidal risk or those engaging in self-injurious behaviors
• Psychiatric diagnosis confirmed by Structured Clinical Interview for DSM-IV Disorders (SCID) administered by trained mental health professionals
Author: Larry Samuels Reference: Study A3051123 protocol
www.mghcme.org
Study Population
Author: Larry Samuels Reference: Study A3051123 protocol
• Non-Psychiatric cohort: No current or past psychiatric diagnosis • Psychiatric cohort: One or more clinically stable, current or past
diagnosis
Mood Disorders Major depressive disorder (MDD), bipolar I, bipolar II
Anxiety Disorders Panic disorder with or without agoraphobia, post-traumatic stress disorder, obsessive-compulsive disorder, social phobia, generalized anxiety disorder
Psychotic Disorders Schizophrenia, schizoaffective disorder
Personality Disorders Limited to past history of borderline personality disorder
www.mghcme.org
Development of Composite NPS Safety Endpoint
• Broad range of NPS AEs reported in the postmarketing experience for varenicline and reflected in the label
• A composite of NPS events provides for increased sensitivity of the endpoint
• Included only moderate to severe NPS events to increase specificity and minimize inclusion of less clinically significant events and events associated with nicotine withdrawal
Author: Larry Samuels Source:
www.mghcme.org
Primary Safety Endpoint Designed to Capture Serious NPS AEs
Primary Safety Endpoint: Percent of subjects reporting one or more of the following during treatment and up to 30 days after last dose:
Anxiety
Depression
Feeling abnormal
Hostility
Agitation
Aggression
Delusions
Hallucinations
Homicidal ideation
Mania
Panic
Paranoia
Psychosis
Suicidal ideation
Suicidal behavior
Suicide*
Classified as Moderate
or Severe
Classified as Severe
Severity assessment
Moderate = interferes to some extent with subject’s usual function
Severe = interferes significantly with subject’s usual function * Includes completed suicide and depression suicidal
Author: Larry Samuels Reference: Study A3051123 protocol
www.mghcme.org
Study Size
• In agreement with FDA, EAGLES was sized to attain an adequate level of precision in the estimation of the risk difference in the NPS composite endpoint
• An Independent Data Monitoring Committee reviewed un-blinded safety data every 4 months to monitor safety and at 50% and 75% of available data to ensure that the target sample size was correct
• For an attributable risk difference corresponding to an increase on a relative risk scale of 75% in the incidence of the primary safety endpoint vs. placebo
Cohort N Width of 95% CI
Non-Psychiatric 4000 ±1.9%
Psychiatric 4000 ±2.6%
Overall Study 8000 ±1.6%
CI=Confidence Interval
www.mghcme.org
Key Secondary Safety Endpoints
• Percentage of subjects with severe NPS AEs in the primary composite endpoint by cohort
• Analyses of the individual components of the primary endpoint
• Psychiatric rating scales
– Columbia - Suicide Severity Rating Scale (C-SSRS)
– Hospital Anxiety and Depression Scale (HADS)
– Clinical Global Impression of Improvement (CGI-I)
Author: Larry Samuels Reference: Study A3051123 Protocol
Author: Larry Samuels Reference: Study A3051123 Protocol
www.mghcme.org
Subject Disposition
Screened=11,186 Number (%) of Subjects
Varenicline Placebo NRT Bupropion Total
Non-Psychiatric Cohort
All randomized (ITT), n 1005 1009 1013 1001 4028
All treated (safety), n 990 999 1006 989 3984
Completed study, n (%) 787 (79.5) 787 (78.8) 767 (76.2) 783 (79.2)
Did not complete study, n 203 212 239 206
Psychiatric Cohort
All randomized (ITT), n 1032 1026 1025 1033 4116
All treated (safety), n 1026 1015 1016 1017 4074
Completed study, n (%) 811 (79.0) 765 (75.4) 790 (77.8) 803 (79.0)
Did not complete study, n 215 250 226 214
ITT=Intent-To-Treat population (efficacy analysis). All Treated population (safety analysis): received at least one dose of study drug
Author: Thomas McRae Source:
www.mghcme.org
Subject Disposition
Screened=11,186 Number (%) of Subjects
Varenicline Placebo NRT Bupropion Total
Non-Psychiatric Cohort
All randomized (ITT), n 1005 1009 1013 1001 4028
All treated (safety), n 990 999 1006 989 3984
Completed study, n (%) 787 (79.5) 787 (78.8) 767 (76.2) 783 (79.2)
Did not complete study, n 203 212 239 206
Psychiatric Cohort
All randomized (ITT), n 1032 1026 1025 1033 4116
All treated (safety), n 1026 1015 1016 1017 4074
Completed study, n (%) 811 (79.0) 765 (75.4) 790 (77.8) 803 (79.0)
Did not complete study, n 215 250 226 214
ITT=Intent-To-Treat population (efficacy analysis). All Treated population (safety analysis): received at least one dose of study drug
Author: Thomas McRae Source:
www.mghcme.org
Baseline Characteristics
Non-Psychiatric Cohort N=3984
Psychiatric Cohort N=4074
Demographic Characteristics
Male, % 50.2 38.0
Age, years 46.0 47.1
Smoking Characteristics
FTNDa score, mean 5.5 6.0
Duration of smoking, years 28.1 28.6
Suicidality (Measured by C-SSRS)
Lifetime suicide ideation, % 4.8 33.8
Lifetime suicide behavior, % 0.7 12.6
Hospital Anxiety and Depression Scale (HADS)
Anxiety, mean 2.7 5.2
Depression, mean 1.5 3.2
a. Fagerstrom Test for Nicotine Dependence
Author: Thomas McRae Source:
www.mghcme.org
Baseline Characteristics
Non-Psychiatric Cohort N=3984
Psychiatric Cohort N=4074
Demographic Characteristics
Male, % 50.2 38.0
Age, years 46.0 47.1
Smoking Characteristics
FTNDa score, mean 5.5 6.0
Duration of smoking, years 28.1 28.6
Suicidality (Measured by C-SSRS)
Lifetime suicide ideation, % 4.8 33.8
Lifetime suicide behavior, % 0.7 12.6
Hospital Anxiety and Depression Scale (HADS)
Anxiety, mean 2.7 5.2
Depression, mean 1.5 3.2
a. Fagerstrom Test for Nicotine Dependence
Author: Thomas McRae Source:
www.mghcme.org
Baseline Characteristics
Non-Psychiatric Cohort N=3984
Psychiatric Cohort N=4074
Demographic Characteristics
Male, % 50.2 38.0
Age, years 46.0 47.1
Smoking Characteristics
FTNDa score, mean 5.5 6.0
Duration of smoking, years 28.1 28.6
Suicidality (Measured by C-SSRS)
Lifetime suicide ideation, % 4.8 33.8
Lifetime suicide behavior, % 0.7 12.6
Hospital Anxiety and Depression Scale (HADS)
Anxiety, mean 2.7 5.2
Depression, mean 1.5 3.2
a. Fagerstrom Test for Nicotine Dependence
Author: Thomas McRae Source:
www.mghcme.org
Baseline Characteristics: Psychiatric Cohort
Psychiatric Cohort N=4074
%
Primary Diagnosis (SCID)
Mood disorders 70.7
Anxiety disorders 19.2
Psychotic disorders 9.5
Personality disorder 0.6
Psychotropic Medication Use at Baseline
Received psychotropic medication at enrollment 49.0
Antidepressants 33.8
Anxiolytics, hypnotics and other sedatives 15.3
Antipsychotics 16.0
Mood stabilizers 2.0
Author: Thomas McRae Source:
Author: Larry Samuels Reference:
www.mghcme.org
Baseline Characteristics: Psychiatric Cohort
Psychiatric Cohort N=4074
%
Primary Diagnosis (SCID)
Mood disorders 70.7
Anxiety disorders 19.2
Psychotic disorders 9.5
Personality disorder 0.6
Psychotropic Medication Use at Baseline
Received psychotropic medication at enrollment 49.0
Antidepressants 33.8
Anxiolytics, hypnotics and other sedatives 15.3
Antipsychotics 16.0
Mood stabilizers 2.0
Author: Thomas McRae Source:
Author: Larry Samuels Reference:
www.mghcme.org
Perspectives on Smoking Cessation
• Challenging to disentangle NPS AEs without placebo control – Tobacco withdrawal symptoms and signs – Potential drug-related adverse event – Emergence or recurrence of psychiatric symptoms – Another medication’s side effect – Stress of quitting smoking
• EAGLES results shed light on this diagnostic dilemma • Unintended consequences of the Boxed Warning
– Contributes to misattribution of symptoms and “a rush to judgment”
– Another hurdle for those already facing many barriers
www.mghcme.org
Primary Neuropsychiatric AE Composite Endpoint: Observed incidence
4.0
1.3
6.5
4.5
2.2
6.7
3.9
2.5
5.3
3.7
2.4
4.9
0
1
2
3
4
5
6
7
8
9
10
OverallN=8058
Non-Psychiatric N=3984
PsychiatricN=4074
Ob
se
rve
d I
nc
ide
nc
e o
f E
ve
nt,
%
Varenicline Bupropion NRT Placebo
Author: Cristina Russ Source: Pfizer BD Table 10 QC: Chetna Bhattacharyya
n 80 90 79 74 13 22 25 24 67 68 54 50 N 2016 2006 2022 2014 990 989 1006 999 1026 1017 1016 1015
Treatment + 30 days; Anthenelli RM, Benowitz NL, West R, St. Aubin L, McRae T, Lawrence D, Ascher J, Russ C, Krishen A, Evins AE. Effects of varenicline and bupropion in smokers with and without psychiatric disorders. Lancet. 2016 Apr 22
• Similar across treatment arms for overall study population • Non-psychiatric< psychiatric, regardless of treatment • Difference in varenicline vs. placebo may differ by cohort
www.mghcme.org
Primary NPS Endpoint: Risk Difference vs. Placebo - Overall Study Population
Treatment Comparisons Risk Difference
(95% CI)
Varenicline vs. placebo 0.16 (-0.99, 1.30)
Bupropion vs. placebo 0.85 (-0.35, 2.05)
NRT vs. placebo 0.12 (-1.04, 1.28)
-5 -4 -3 -2 -1 0 1 2 3 4 5
Risk Difference (95% CI)
Author: Cristina Russ Source: Pfizer BD Table 11 And Figure 2 QC: Chetna Bhattacharyya
Anthenelli RM, Benowitz NL, West R, St. Aubin L, McRae T, Lawrence D, Ascher J, Russ C, Krishen A, Evins AE. Effects of varenicline and bupropion in smokers with and without psychiatric disorders. Lancet. 2016 Apr 22
www.mghcme.org
Primary NPS Endpoint: Risk Differences vs. Placebo Non-Psychiatric and Psychiatric Cohort
Non-Psychiatric Cohort N=3984
Risk Difference (95% CI)
Varenicline vs. placebo -1.28 (-2.40, -0.15)
Bupropion vs. placebo -0.08 (-1.37, 1.21)
NRT vs. placebo -0.21 (-1.54, 1.12)
Psychiatric Cohort N=4074
Risk Difference (95% CI)
Varenicline vs. placebo 1.59 (-0.42, 3.59)
Bupropion vs. placebo 1.78 (-0.24, 3.81)
NRT vs. placebo 0.37 (-1.53, 2.26)
-5 -4 -3 -2 -1 0 1 2 3 4 5
Risk Difference (95% CI)
Small numerical decrease in the non-psychiatric cohort and small numerical
increase (95% CI includes 0) in the psychiatric cohort for varenicline vs. placebo
Author: Cristina Russ Source: Pfizer BD Table 11 QC: Chetna Bhattacharyya
www.mghcme.org
67
14
68
14
54
14
50
13
0
10
20
30
40
50
60
70
80
Total Severe Adverse Events
Nu
mb
er
of
Su
bje
cts
wit
h E
ve
nts
Varenicline Bupropion NRT Placebo
Author: Cristina Russ Source: Pfizer BD Table 14 QC: Marianna Bruno
NPS Primary Endpoint – Subjects with Any Event and with Severe Events - Psychiatric Cohort
Treatment + 30 days
www.mghcme.org
67
26
68
21
54
19
50
23
0
10
20
30
40
50
60
70
80
Total Combined
Nu
mb
er
of
Su
bje
cts
wit
h E
ve
nts
Varenicline Bupropion NRT Placebo
Author: Cristina Russ Source: Pfizer BD Table 14 QC: Marianna Bruno
NPS Primary Endpoint – Subjects with Severe, Serious Adverse Events or Events Leading to Treatment Discontinuation - Psychiatric Cohort
Severe Events and/or Serious Adverse Events and/or
Events Leading to Treatment Discontinuation
Treatment + 30 days
www.mghcme.org
NPS Primary Endpoint: Frequency of Components Non-Psychiatric Cohort
0
5
10
15
20
25
30
Nu
mb
er
of
su
bje
cts
wit
h a
dve
rse
eve
nts
in
a c
ert
ain
co
mp
on
en
t
Varenicline Bupropion NRT Placebo
Author: Cristina Russ QC: Kevin Booth Source: Pfizer BD Table 12
Treatment + 30 days
www.mghcme.org
NPS Primary Endpoint: Frequency of Components Psychiatric Cohort
0
5
10
15
20
25
30
Nu
mb
er
of
su
bje
cts
wit
h a
dve
rse
eve
nts
in
a c
ert
ain
co
mp
on
en
t
Varenicline Bupropion NRT Placebo
Author: Cristina Russ QC: Kevin Booth Source: Pfizer BD Table 13
Treatment + 30 days
www.mghcme.org
Columbia Suicide Severity Rating Scale (C-SSRS)
Non-Psychiatric Cohort
N=3984 Psychiatric Cohort
N=4074
Varenicline n (%)
Bupropion n (%)
NRT n (%)
Placebo n (%)
Varenicline n (%)
Bupropion n (%)
NRT n (%)
Placebo n (%)
During Treatment + 30 Days
Assessed, n 988 983 996 995 1017 1012 1006 1006
Suicidal behavior 0 1 (0.1) 1 (0.1) 1 (0.1)a 1 (0) 1 (0.1) 0 2 (0.2)
Suicidal ideation (without behavior)
9 (0.9) 4 (0.4) 4 (0.4) 7 (0.7) 29 (2.9) 16 (1.7) 23 (2.4) 26 (2.8)
a. Completed suicide
Author: Cristina Russ QC: Sarah Dubrava Source: SCSa3050686a Subject on NRT 10571010 cut wrist - excluded vs programatic table – verbatim husband May 25; last dose March 9 Non psych behavior NRT – 10161040 – cut left wrist Pb – 11441029 completed suicide Bp 11101153 gun in mouth – was added with new algorithm Psych Var – 10091085 hallucination – jumping in front of bus Bup – 10881338 – gas from lighter Pb – 12081087 – overdose in endpoint Pb – 10071005 – overdose with study drug, not in endpoint
www.mghcme.org
Columbia Suicide Severity Rating Scale (C-SSRS)
Non-Psychiatric Cohort
N=3984 Psychiatric Cohort
N=4074
Varenicline n (%)
Bupropion n (%)
NRT n (%)
Placebo n (%)
Varenicline n (%)
Bupropion n (%)
NRT n (%)
Placebo n (%)
During Treatment + 30 Days
Assessed, n 988 983 996 995 1017 1012 1006 1006
Suicidal behavior 0 1 (0.1) 1 (0.1) 1 (0.1)a 1 (0) 1 (0.1) 0 2 (0.2)
Suicidal ideation (without behavior)
9 (0.9) 4 (0.4) 4 (0.4) 7 (0.7) 29 (2.9) 16 (1.7) 23 (2.4) 26 (2.8)
Author: Cristina Russ QC: Sarah Dubrava Source: SCSa3050686a Subject on NRT 10571010 cut wrist - excluded vs programatic table – verbatim husband May 25; last dose March 9 Non psych behavior NRT – 10161040 – cut left wrist Pb – 11441029 completed suicide Bp 11101153 gun in mouth – was added with new algorithm Psych Var – 10091085 hallucination – jumping in front of bus Bup – 10881338 – gas from lighter Pb – 12081087 – overdose in endpoint Pb – 10071005 – overdose with study drug, not in endpoint
a. Completed suicide
www.mghcme.org
Columbia Suicide Severity Rating Scale (C-SSRS)
Non-Psychiatric Cohort
N=3984 Psychiatric Cohort
N=4074
Varenicline n (%)
Bupropion n (%)
NRT n (%)
Placebo n (%)
Varenicline n (%)
Bupropion n (%)
NRT n (%)
Placebo n (%)
During Treatment + 30 Days
Assessed, n 988 983 996 995 1017 1012 1006 1006
Suicidal behavior 0 1 (0.1) 1 (0.1) 1 (0.1)a 1 (0) 1 (0.1) 0 2 (0.2)
Suicidal ideation (without behavior)
9 (0.9) 4 (0.4) 4 (0.4) 7 (0.7) 29 (2.9) 16 (1.7) 23 (2.4) 26 (2.8)
with intent and or plan
0 1 0 0 0 0 1 2
Author: Cristina Russ QC: Sarah Dubrava Source: SCSa3050686a Subject on NRT 10571010 cut wrist - excluded vs programatic table – verbatim husband May 25; last dose March 9 Non psych behavior NRT – 10161040 – cut left wrist Pb – 11441029 completed suicide Bp 11101153 gun in mouth – was added with new algorithm Psych Var – 10091085 hallucination – jumping in front of bus Bup – 10881338 – gas from lighter Pb – 12081087 – overdose in endpoint Pb – 10071005 – overdose with study drug, not in endpoint
a. Completed suicide
www.mghcme.org
Non-Psychiatric Cohort
N=3984 Psychiatric Cohort
N=4074
Varenicline n (%)
Bupropion n (%)
NRT n (%)
Placebo n (%)
Varenicline n (%)
Bupropion n (%)
NRT n (%)
Placebo n (%)
During Treatment + 30 Days
Assessed, n 988 983 996 995 1017 1012 1006 1006
Suicidal behavior 0 1 (0.1) 1 (0.1) 1 (0.1)a 1 (0) 1 (0.1) 0 2 (0.2)
Suicidal ideation (without behavior)
9 (0.9) 4 (0.4) 4 (0.4) 7 (0.7) 29 (2.9) 16 (1.7) 23 (2.3) 26 (2.8)
Suicidal ideation and/or behavior
9 (0.9) 5 (0.5) 5 (0.5) 8 (0.8) 30 (2.9) 17 (1.7) 23 (2.3) 28 (2.8)
Columbia Suicide Severity Rating Scale (C-SSRS)
Author: Cristina Russ QC: Sarah Dubrava Source: SCSa3050686a Subject on NRT 10571010 cut wrist - excluded vs programatic table – verbatim husband May 25; last dose March 9 Non psych behavior NRT – 10161040 – cut left wrist Pb – 11441029 completed suicide Bp 11101153 gun in mouth – was added with new algorithm Psych Var – 10091085 hallucination – jumping in front of bus Bup – 10881338 – gas from lighter Pb – 12081087 – overdose in endpoint Pb – 10071005 – overdose with study drug, not in endpoint
a. Completed suicide
www.mghcme.org
Hospital Anxiety and Depression Scale (HADS): Anxiety Worsening of Category of Severity vs. Baselinea
5.3
2.1
7.3
3.1
7.5
3.2
7.3
2.7
0
10
20
Any worsening of category Increase from below 11 to ≥11
Su
bje
cts
, %
14.1
8.1
17.9
9.2
15.8
8.3
15.7
8.8
0
10
20
Any worsening of category Increase from below 11 to ≥11
Su
bje
cts
, %
Author: Cristina Russ QC: David Lawrence Source: SCSa3050673c Please confirm manual calculations
Non-Psychiatric Cohort
Psychiatric Cohort
a. At any time during treatment + 30 days
Varenicline Bupropion NRT Placebo
Scores 0-7: Normal 8-10: Suggestive 11- 21: Probable
www.mghcme.org
Hospital Anxiety and Depression Scale (HADS): Depression
Worsening of Category of Severity vs. Baselinea
6.3
1.4
5.3
1.5
4.4
1.4
5.6
1.6
0
10
20
Any worsening of category Increase from below 11 to ≥11
Su
bje
cts
, %
15.7
7.2
15.6
7
17.3
7.6
15.9
6.5
0
10
20
Any worsening of category Increase from below 11 to ≥11
Su
bje
cts
, %
Author: Cristina Russ QC: David Lawrence Source: SCSa3050673c
a. At any time during treatment + 30 days
Varenicline Bupropion NRT Placebo
Non-Psychiatric Cohort
Psychiatric Cohort
Scores 0-7: Normal 8-10: Suggestive 11- 21: Probable
www.mghcme.org
Clinical Global Impression of Improvement (CGI-I) Worsening vs. Baselinea
7.5
1.3 0.1
7
1.1 0
7
0.8 0.1
7.5
1.3 0
0
5
10
15
20
Minimally Worse Much Worse Very Much Worse
Su
bje
cts
, %
Varenicline Bupropion NRT Placebo
Author: Cristina Russ QC: Kevin Booth Source: SCSa3050672c
Non-Psychiatric Cohort
Psychiatric Cohort
14.5
3.4
0.2
16
2.6 0.3
15.9
2.3 0
14
3
0.3 0
5
10
15
20
Minimally Worse Much Worse Very Much Worse
Su
bje
cts
, %
a. At any time during treatment + 30 days
www.mghcme.org
Efficacy: Continuous Abstinence Rates (ITT) Non-Psychiatric Cohort
38.0
26.1 26.4
13.7
0
5
10
15
20
25
30
35
40
Weeks 9–12
Co
nti
nu
ou
s A
bs
tin
en
ce
Ra
te, %
Varenicline (N=1005)
Bupropion (N=1001)
NRT (N=1013)
Placebo (N=1009)
Author: Cristina Russ QC: Larry Samuels Source: Pfizer BD Table 28 and Figure 9
Odds Ratios CAR Weeks 9-12 Main Efficacy Measure
OR (95% CI)
Varenicline vs. placebo 4.00 (3.20, 5.00)
Varenicline vs. NRT 1.74 (1.43, 2.10)
Varenicline vs. bupropion 1.77 (1.46, 2.14)
www.mghcme.org
Efficacy: Continuous Abstinence Rates (ITT) Non-Psychiatric Cohort
38.0
25.5 26.1
18.8
26.4
18.5
13.7
10.5
0
5
10
15
20
25
30
35
40
Weeks 9–12 Weeks 9–24
Co
nti
nu
ou
s A
bs
tin
en
ce
Ra
te, %
Varenicline (N=1005)
Bupropion (N=1001)
NRT (N=1013)
Placebo (N=1009)
Author: Cristina Russ QC: Larry Samuels Source: Pfizer BD Table 28 and Figure 9
Odds Ratios CAR Weeks 9-12 Main Efficacy Measure
OR (95% CI)
Varenicline vs. placebo 4.00 (3.20, 5.00)
Varenicline vs. NRT 1.74 (1.43, 2.10)
Varenicline vs. bupropion 1.77 (1.46, 2.14)
Odds Ratios CAR Weeks 9-24
OR (95% CI)
Varenicline vs. placebo 2.99 (2.33, 3.83)
Varenicline vs. NRT 1.52 (1.23, 1.89)
Varenicline vs. bupropion 1.49 (1.20, 1.85)
Anthenelli RM, Benowitz NL, West R, St. Aubin L, McRae T, Lawrence D, Ascher J, Russ C, Krishen A, Evins AE. Effects of varenicline and bupropion in smokers with and without psychiatric disorders. Lancet. 2016.
www.mghcme.org
Efficacy: Continuous Abstinence Rates (ITT) Psychiatric Cohort
29.2
18.3 19.3
13.7
20.4
13 11.4
8.3
0
5
10
15
20
25
30
35
40
Weeks 9–12 Weeks 9–24
Co
nti
nu
ou
s A
bs
tin
en
ce
Ra
te,
%
Varenicline (N=1032)
Bupropion (N=1033)
NRT (N=1025)
Placebo (N=1026)
Author: Cristina Russ QC: Larry Samuels Source: Pfizer BD Table 28 and Figure 9
Odds Ratios CAR Weeks 9-12 Main Efficacy Measure
OR (95% CI)
Varenicline vs. placebo 3.24 (2.56, 4.11)
Varenicline vs. NRT 1.62 (1.32, 1.99)
Varenicline vs. bupropion 1.74 (1.41, 2.14)
Odds Ratios CAR Weeks 9-24
OR (95% CI)
Varenicline vs. placebo 2.50 (1.90, 3.29)
Varenicline vs. NRT 1.51 (1.19, 1.93)
Varenicline vs. bupropion 1.41 (1.11, 1.79)
Anthenelli RM, Benowitz NL, West R, St. Aubin L, McRae T, Lawrence D, Ascher J, Russ C, Krishen A, Evins AE. Effects of varenicline and bupropion in smokers with and without psychiatric disorders. Lancet. 2016.
www.mghcme.org
EAGLES Conclusions
• Results did no show an increased risk of NPS AEs in the composite primary endpoint in the overall study population for varenicline or bupropion vs. placebo or vs. NRT patch
• In all treatment arms, including placebo, incidence of the primary NPS endpoint was higher in the psychiatric vs non-psychiatric cohort
• Risk differences for varenicline vs. placebo – Non-psychiatric cohort: AE Rate No Effect for Treatments than Placebo – Psychiatric cohort: No Effect of Treatment
» Did not reach statistical significance (95% CIs include 0) » Were not driven by events that were severe, or serious adverse events,
or led to treatment discontinuation, or resulted in harm to self or others
• Sensitivity analysis of expanded endpoint consistent with primary analysis
• Psychiatric scales (C-SSRS, HADs, and CGI-I) did not show an increased neuropsychiatric risk for varenicline vs. placebo or vs. NRT
• In both cohorts: Varenicline > Bupropion and single NRT > placebo
Author: Cristina Russ QC: Larry Samuels
www.mghcme.org
EAGLES is a Landmark Study of Clinical and Public Health Importance
• The EAGLES trial is the first:
– To compare safety and efficacy of all 3 FDA approved smoking cessation therapies in large samples of patients with and without a history of psychiatric disorder
– To allow for comparison of safety and efficacy of smoking cessation aids in smokers with different mental illnesses
M
D
-
7
6
www.mghcme.org
EAGLES is a Landmark Study of Clinical and Public Health Importance
• Study population is representative of patients seen in primary care and in community mental health settings
• Psychiatric Cohort – Stable but symptomatic,
– Half on psychotropic medication at baseline
– Half with major depressive disorder had recurrent depression
– One third had a second psychiatric diagnosis / comorbidity
– One fourth had a prior substance use disorder
– One eighth had made a prior suicide attempt
www.mghcme.org
EAGLES is a Confirmatory Trial for Efficacy
• Efficacy conclusions replicate and extend findings from smaller trials and meta-analyses in those with and without mental illness
• The efficacy data are clear
Varenicline > bupropion and nicotine patch > placebo
• Agreement with overall, growing body of evidence, raising confidence in the findings
www.mghcme.org
EAGLES Quantifies NPS Risk Across Treatment and Cohort
• Greater risk of NPS AE’s in Psych group versus Non-Psych group, independent of treatment – ~2% NPS AE rate in smokers without mental illness
– ~5-7% NPS AE rate in smokers with mental illness
• NPS AE rates in smokers during a cessation attempt are not different by treatment
• No pattern of NPS AE’s – No pattern in the most worrisome NPS AE’s
– No psychiatric subgroup appears to be at increased risk
Anthenelli RM, Benowitz NL, West R, St. Aubin L, McRae T, Lawrence D, Ascher J, Russ C, Krishen A, Evins AE. Effects of varenicline and bupropion in smokers with and without psychiatric disorders. Lancet. 2016 Apr 22
www.mghcme.org
38.0
26.1 26.4
13.7
0
5
10
15
20
25
30
35
40
Co
nti
nu
ou
s A
bs
tin
en
ce
Ra
te, %
Varenicline (N=2037) Bupropion (N=2034)
NRT (N=2038) Placebo (N=2035)
1.3 2.2 2.5 2.4
0
5
10
15
Ob
se
rve
d I
nc
ide
nc
e o
f E
ve
nt,
%
EAGLES Allows Comparison of Neuropsychiatric Safety and Efficacy in Those without Psychiatric Illness
Anthenelli RM, Benowitz NL, West R, St. Aubin L, McRae T, Lawrence D, Ascher J, Russ C, Krishen A, Evins AE. Effects of varenicline and bupropion in smokers with and without psychiatric disorders. Lancet. 2016 Apr 22
Primary NPS Composite
Safety Endpoint
CARs Week 9-12
www.mghcme.org
EAGLES Allows Comparison of Neuropsychiatric Safety and Efficacy in Those with Psychiatric Illness
a
Adapted from Evins, et al., Society for Research on Nicotine and Tobacco 2016; Chicago
a. One additional participant (NRT group/mood subcohort) who reported suicide ideation was identified after clinical database lock and was not
included in the analysis
6.3 5.7 6.8 6.3 8.0 6.4 5.1 4.6 5.5 6.3 5.7 4.6
05
101520253035
Psychotic Disorder Anxiety Disorder Mood Disorder
Ob
se
rve
d R
ate
o
f N
PS
Eve
nts
, %
Varenicline Bupropion NRT Placebo
23.2 27.0
30.4
11.2 13.9
21.7
13.1
21.9 21.2
4.1 8.0
13.2
0
5
10
15
20
25
30
35
Psychotic Disorder Anxiety Disorder Mood Disorder
Ob
se
rve
d
CA
Rs
, %
Primary NPS Composite Safety Endpoints by Treatment for Those with
Primary Psychotic, Anxiety and Mood Disorders
CARs Week 9-12 by Treatment and Psychiatric Diagnosis
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Neuropsychiatric Adverse Event Rate During Smoking Cessation is Independent of Treatment
• NPS AEs are seen in trials regardless of treatment
• Clinicians who prescribe a treatment and observe a NPS AE likely attribute this AE to the treatment.
• This happened in our large maintenance treatment trial of varenicline, in trials of bupropion, and in clinical practice.
Evins, et al., JAMA 2014; Evins, et al., J Clin Psychopharm 2007
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Why Might There be Significant NPS AEs Among Smokers, Independent of Treatment
(and Abstinence)?
• Smoking is an addiction; like all drug addictions, there are: – Well documented brain changes
– Increased neuropsychiatric events, e.g. suicide
– Suicide risk reduced in smokers who quit
• People with psychiatric illness are more likely to smoke
• Attempts to quit smoking are not risk free, with or without pharmacologic support and independent of abstinence – Well replicated in smokers with history of depression
Volkow et al., Am. J. Psych, 1999; Fehr et al., Am J Psych 2008; Li, et al., J Psych Res 2012; Berlin et al., NTR 2011;
Brown 1996; Tsoh, et al., Am J Psych 2000; Torres, et al., Psychol Med 2010; Evins, et al., JAMA 2014
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Implication of EAGLES: Offer Treatment to All Smokers, Including Those with Stable Mental Illness
• EAGLES trial shows NPS safety and efficacy of smoking cessation treatments for smokers with mental illness, a group that is:
– More likely to smoke, to smoke heavily, and be dependent
– Less likely to quit without a cessation aid
– More likely to relapse after discontinuation of cessation aids
– Likely to benefit from maintenance treatment
– Less likely to receive advice to quit from a medical provider
– Less likely to receive cessation aid
• Smokers with mental illness are less likely to receive a pharmacotherapeutic cessation aid from a medical provider
– This contributes to the 25 year mortality gap in those with mental illness, secondary to diseases causally related to tobacco smoking
www.mghcme.org
Risk/Benefit Considerations for Varenicline
• Physicians overestimate the risk of NPS AEs with varenicline
• Physicians underestimate the benefit of varenicline on improving quit rates
• It is imperative we find ways to increase use of the most effective smoking cessation treatment for our patients who try time and again to quit smoking
www.mghcme.org
• Dosing: 0.5 and 1.0 mg tabs
– 0.5 mg/d x 3 d
– 0.5 mg bid x 4 d
– 1.0 mg bid x 11 weeks
– Additional 12 weeks Tx recommended in those who achieve abstinence
– 12-month safety data published: well tolerated
• Renal excretion
• No significant drug-drug interactions or effect on cytochrome enzymes
• Nausea-common, headache, insomnia/dreams
Varenicline (Chantix)
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• Antidepressant acting via dopaminergic & noradrenergic mechanism; also a competitive NAChR inhibitor
• First-line (1b) treatment
• Doubles odds of long-term abstinence
• Independent of depressive symptoms
• 40-44% abstinence at end of treatment
• Approx 50% relapse at 12 months
Bupropion SR
Hurt et al. NEJM. 1996; Cox et al, 2004; USPHS, 2004; Hughes et al, 2005.
www.mghcme.org
• Treatment with Varenicline (n=696) and Bupropion (n=671) Significantly Improved Self Rated Quality of Life Over Placebo (n=685) at 12, 24, and 52 Weeks
• Significant positive association between smoking cessation and self rating of vitality, self-control, anxiety, and overall mental health profile
• Replication of several studies demonstrating reduced self report of anxiety after smoking cessation…
Varenicline and Bupropion Improved Health Related Quality of Life
Hays et al., 2010
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• First-line (Dual NRT 1a, single NRT 1b)
• Doubles odds of abstinence over placebo
• Helpful with or without counseling
• All forms appear equally effective overall
• In heavy smokers, there is a dose-response curve with gum favoring higher dose (4 mg)
• Dose: 20-30 mg/day; may be a benefit to increased doses of NRT and to combinations of NRT forms
– Long acting: transdermal patch
– Short acting: gum, inhaler, nasal spray
– Proper use of gum is critical
– Combination use is most common
Nicotine Replacement Therapy (NRT)
Silagy et al, 2005.
www.mghcme.org
May improve abstinence rates
For smokers who have relapsed after treatment with single agent, consider maintenance treatment or combination treatment:
• NRT: long acting (patch) + short acting (gum, inhaler or nasal spray ) + CBT
• Bupropion 150 mg bid + NRT + CBT
• Varenicline + NRT
Combination Pharmacotherapy for Nicotine Dependence
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• Current guidelines recommend behavioral tx + pharmacotherapy – Motivational enhancement
– Relapse prevention
– Partner support
• Guidelines are based on several large meta-analyses of controlled trials
• Telephone counseling provides a modest benefit in quit rates vs minimal intervention – www.trytostop.org or 1-800-TRY-TO-STOP
• Physical exercise can decrease cravings and attenuate weight gain
Behavioral Interventions
USPHS, 2000; Stead et al, 2003.
www.mghcme.org
• Peaks in 4 days
• Lasts for several weeks
• Can be severe, not life threatening
– Anxiety
– Awakening during sleep
– Depression
– Difficulty concentrating
– Impatience
– Irritability/anger
– Restlessness
– Decreased heart rate
– Weight gain
Withdrawal Syndrome:
Nicotine
www.mghcme.org
• Smoking speeds hepatic metabolism of many medications
• Serum concentrations of medications that are stable in smokers may rise following abstinence
• CYP 1A1, 1A2, and 2E1
– Abstinence associated with 30-42% reduction in 1A2 activity over the first 1-3 days of abstinence
– Therapeutic drug monitoring and 10% dose reduction has been recommended
• Take care when prescribing bupropion to those on clozapine because of additive seizure risk
Tobacco Abstinence: Effects on Metabolism
Seppala NH, et al.,1999. Desai HD, et al., 2001. Faber & Fuhr, 2004.
www.mghcme.org
• Give physician advice to quit smoking
• Develop a “quit day” plan, teach coping skills, build in self-rewards, and provide written cues to reinforce abstinence
• Treat with combined behavioral treatment and pharmacotherapy
• Long-term NRT or non nicotine treatment may be warranted, both to sustain abstinence and to improve symptoms
Summary – Nicotine Dependence
Evins AE and MGH Center for Addiction Medicine.
www.mghcme.org
• Major epidemic since 1980
• Availability of cheap, high-potency drug
• New forms: freebase/crack
• 30 million in US have used cocaine
• < 20% become regular users
• 17% risk of dependence (NCS)
• Increasing incidence of lacing with Levamisole
– Up to 80% of samples
– 3-13% risk of agranulocytosis with sustained exposure
Cocaine Dependence
www.mghcme.org
• Dopamine stimulation of neurons in nucleus accumbens normally limited by dopamine reuptake
• Cocaine blocks dopamine reuptake
• Assoc. with excessive dopamine stimulation in reward system of brain - “HIGH”
• Also assoc. with depletion of dopamine in the nerve terminals of the dopaminergic neurons involved - “LOW”
• Compensatory down-regulation of post-synaptic dopamine receptors
• Protracted syndrome of refractoriness to reward
Pharmacology of Cocaine Dependence
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• Binge symptoms:
– Intense euphoria
– Increased anxiety, dysphoria, tremor, hyperactivity
– Long-lasting craving
– Paranoid ideations, delusions
– Panic attacks, depression, mania
• Withdrawal:
– Onset: <24 hrs, peak: 2-4 days
– Duration: 7-10 days
– Protracted depression, craving: 1-3 months
Cocaine Use Patterns
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• Acute cocaine intoxication:
– Onset: seconds
– Duration: 30-60 min
– Dysphoria: within hours
– Recovery: < 48 hrs
– OD requires life support, airway
• Cocaine delusional disorder
– Diazepam for agitation
– Antipsychotics for delusions
• Hospitalize if suicidal or delusional
Treating Cocaine Intoxication
www.mghcme.org
• Pharmacotherapy not required in mild withdrawal states
• For severe cocaine withdrawal: • Amantadine – indirect dopamine agonist, increases dopamine levels
• Propranolol – B-adrenergic blocker reduces anxiety / severe adrenergic symptoms - 1 mg IV q min, up to 8 min
• Seizures: IV diazepam
Treating Cocaine Withdrawal
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Relapse prevention: Pharmacotherapy
• Disulfiram effective in 3 trials
• Inhibits DA-beta hydroxylase
• Reduced craving & relapse
• Baclofen – GABA-B agonist: 20 mg tid
• Topiramate increases GABA & inhibits glutamate: 25 mg po qd, slowly increase to 200 mg qd (Kampman, 2004)
• Modafinil enhances glutamate levels: 200-400 mg po qd
• However, Overall:
• Disulfiram: evidence not supportive
• Topiramate, other anticonvulsants: evidence not supportive
• Anticonvulsants: evidence not supportive
• Antipsychotics: evidence not supportive
Treating Cocaine Dependence
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Relapse prevention: Psychotherapy
– Contingency Management
– Manual-guided CBT
– 12-step facilitation
– Individual plus group therapy
– Behavioral reinforcement:
• Urine testing with contingencies
• Restrict access to money & friends
– High-intensity support to disrupt binge cycles
Treating Cocaine Dependence
www.mghcme.org
As with any substance use disorder, treat anxiety and depressive symptoms in those suspected of having an independent mood or anxiety disorder, especially if these symptoms appear to be interfering with attainment of abstinence
Co-morbid depression: – SSRIs – effective if depressed
– “May” also reduce cocaine use
– Avoid TCAs, may be associated with cardiac arrhythmia when combined with cocaine
Co-morbid bipolar disorder: No adequate med trials – Consider combination therapy if rapid cycling
Treating Cocaine Dependence
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