CTRI Webinar:
Combination Medication
Effectiveness
June 9, 2010
Stevens S. Smith, Ph.D.
Megan E. Piper, Ph.D.
Center for Tobacco Research & Intervention
UW School of Medicine and Public Health
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Combination Medication Effectiveness
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Rationale
PHS Guideline medication recommendations
Overview of UW-CTRI Transdisciplinary Tobacco
Use Research Center (TTURC2) studies
TTURC2 Effectiveness Study in primary care clinics
TTURC2 Randomized Clinical Trial (Efficacy Study)
Conclusions
Questions and answers
Rationale
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Tobacco dependence – chronic, relapsing disease
Most smokers want to quit; about 40% try each year
70% visit a primary care physician each year
Effective treatments exist
2008 Public Health Service Guideline provides
specific evidence-based treatment recommendations
How do we optimize cessation success with
medications?
2008 PHS Guideline
Printed version
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Online version – a printable pdf
of full guideline
The "5 A's" Model for Treating Tobacco
Use and Dependence - 2008
ASK
Do you currently use
tobacco?
YES
NO
ASK
ADVISE to quit
Have you ever used tobacco?
Medication
And
Counseling
YES
NO
ASSESS
ASSESS
Are you willing to quit now?
Have you recently quit?
Any challenges?
YES
ASSIST
Provide appropriate
tobacco dependence
treatment
YES
NO
ASSIST
ASSIST
ASSIST
Intervene to
increase motivation
to quit
Provide relapse
prevention
Encourage
continued
abstinence
ARRANGE FOLLOW-UP
5
NO
Guideline Recommendation:
FDA-Approved Cessation Medications
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Clinicians should encourage medication for all patients
attempting to quit smoking
–
–
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EXCEPT when medically contraindicated
EXCEPT when there is insufficient evidence of effectiveness (i.e.,
pregnant women, smokeless tobacco users, light smokers and
adolescents)
The combination of counseling and medication is more effective
for smoking cessation than either medication or counseling
alone. Therefore, whenever feasible and appropriate, both
counseling and medication should be provided to patients trying
to quit smoking.
Guideline Recommendation:
FDA-Approved Cessation Medications
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Seven first-line medications (5 nicotine and 2 nonnicotine) reliably increase long-term smoking
abstinence rates
- Bupropion SR
- Nicotine lozenge*
- Nicotine inhaler
- Varenicline
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- Nicotine gum*
- Nicotine nasal spray
- Nicotine patch*
Clinicians should also consider the use of certain
combinations of medications identified as effective in
this Guideline
*Available without a prescription
Selected Medication Options:
Monotherapy and Combination Therapy
Number
of arms
Estimated
odds ratio
(95% C.I.)
Estimated
abstinence rate
(95% C.I.)
Nicotine Patch
32
1.9
(1.7 - 2.2)
23.4%
(21.3 – 25.8)
Bupropion SR
26
2.0
(1.8 – 2.2)
24.2%
(22.2 – 26.4)
Varenicline
5
3.1
(2.5 – 3.8)
33.2%
(28.9 - 37.8)
Patch (>14 wks)
+ NRT (gum or spray)
3
3.6
(2.5 – 5.2)
36.5%
(28.6 – 45.3)
Patch + Bupropion SR
3
2.5
(1.9 – 3.4)
28.9%
(23.5 – 35.1)
Medication
8
Relative Efficacy
Number
of arms
Estimated
odds ratio
(95% C. I.)
Nicotine Patch (reference group)
32
1.0
Varenicline (2 mg/day)
5
1.6
(1.3, 2.0)
Patch (>14 weeks) + NRT (gum
or spray)
3
1.9
(1.3, 2.7)
Patch + Bupropion SR
3
1.3
(1.0, 1.8)
Medication
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2008 PHS Guideline: Combination
Medication Recommendation
Recommendation: Certain combinations of first-line
medications have been shown to be effective smoking cessation
treatments. Therefore, clinicians should consider using these
combinations of medications with their patients who are willing to
quit. Effective combination medications are:
* Long-term (> 14 weeks) nicotine patch + other NRT
(gum and spray)
* The nicotine patch + the nicotine inhaler
* The nicotine patch + bupropion SR.
(Strength of Evidence = A)
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UW-CTRI Transdisciplinary Tobacco Use
Research Center (TTURC2) Studies
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Funded by NIH
Two independent samples of smokers attempting cessation
Effectiveness study (Stevens will discuss)
Efficacy study (Megan will discuss)
Five active pharmacotherapy treatments in each study:
 Nicotine patch
 Nicotine lozenge
 Bupropion SR
 Nicotine patch + Nicotine lozenge
 Bupropion SR + Nicotine lozenge
 Placebo (Efficacy study only)
TTURC2 Studies
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Effectiveness Study
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1346 smokers recruited in 12 primary care clinics
Enrollment offered during regular primary care visits
Efficacy Study (Randomized Clinical Trial)
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1504 smokers
Participants - smokers motivated to quit recruited from
community
In-depth multi-method assessments of their smoking, physical
health, mental health and life context
Agreed to be followed up for at least 3 years
Effectiveness Study
Primary care patients presenting
to 12 primary care clinics
Randomization
N = 1346
Bupropion
Nicotine
Lozenge
Nicotine
Patch
Bupropion
+ Lozenge
Patch
+ Lozenge
N = 256
N = 261
N = 282
N = 268
N = 279
Effectiveness Study: Treatment Model
•
•
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Clinic Medical Assistant Asks, Assesses and Offers
a smoking cessation study
Physician encourages and clears for medications
Research staff enrolls, provides Rx and quitline
referral
Clinic pharmacist dispenses meds with instructions
Quitline staff provide 4 phone counseling sessions
Effectiveness Study: Participants
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1346 smokers
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Mean age = 44.3, SD = 12.1
56% female
87% Caucasian
Representative of the demographics of the
population of smokers in the clinics
Effectiveness Study: Cessation Rates
(% Abstinent at 6 Months)
Bupropion
(N=256)
Lozenge
(N=261)
Patch
(N=282)
Bupropion +
Lozenge
(N=268)
Patch +
Lozenge
(N=279)
6 Month
% Abstinent
16.8%
19.9%
17.7%
29.9%
26.9%
OR – Bup+Loz
as reference
.46
p<.001
.56
p<.01
.48
p<.001
-
-
OR – Patch+Loz
as reference
.54
p<.01
.67
p=.06
.56
p<.01
-
-
Total N=1346
Effectiveness Study: Cessation Rates
Figure 2. Abstinence rates
70
Bupropion
Lozenge
60
Patch
Bupropion+Lozenge
50
Percent Abstinent
Patch+Lozenge
40
30
20
10
0
Week 1
Week 8
Post-Quit Study Endpoints
Six Months
Efficacy Study CONSORT Figure
N = 8526
Expressed interest
n = 2010
Unreachable
n = 1418
Declined
n = 1331
Withdrew
Patch
n = 261
Lozenge
n = 260
n = 2027
Failed screen
n = 1504
Randomized
Bupropion
SR
n = 266
n = 3153
Passed phone screen
n = 318
Excluded
Patch +
Lozenge
n = 267
Bupropion SR
+ Lozenge
n = 261
Placebo
n = 189
Efficacy Study Participants
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N = 1504 (628 men, 876 women)
Ethnicity
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1258 (83.9%) White
204 (13.6%) African-American
42 (2.8%) parents of Hispanic origin
21.9% had a 4-year college degree
Mean age = 44.67 (SD = 11.08)
Mean cigs. smoked/day = 21.43 (SD = 8.93)
Mean number of quit attempts = 5.72 (SD = 9.65)
Efficacy Study Treatments
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All participants received 6 brief (10-20 min) individual
counseling sessions
Bupropion SR
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Nicotine patch
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150 mg bid for 9 weeks
24-hour patch; 21, 14, and 7mg; titrated down over 8 weeks
post-quit
Nicotine lozenge
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2 or 4 mg, based on dependence level per package
instructions, for 12 weeks post-quit
Efficacy Study Outcomes: %
Abstinent for Active Conditions vs.
Placebo
Placebo
Bupropion
Lozenge
Patch
Bupropion
+ Lozenge
Patch +
Lozenge
Initial
cessation
65.5
78.9
77.2
86.3
82.0
89.8
OR = 2.04
OR = 1.91
OR = 3.14
OR = 2.40
OR = 4.73
8 weeks
30.2
40.2
40.4
44.7
50.4
53.6
OR = 1.55
OR = 1.57
OR = 1.87
OR = 2.35
OR = 2.67
31.8
33.5
34.4
33.2
40.1
OR = 1.63
OR = 1.76
OR = 1.83
OR = 1.74
OR = 2.34
6 months
22.2
= p < .05
= p < .005
Efficacy Study: Latency to Relapse
Patch + Lozenge
Patch/Bupropion
+ Lozenge
Lozenge/Bupropion
Placebo
Efficacy Study Adverse Events
Patch +
Lozenge
(n = 262)
Placebo
(n = 189)
Bupropion
(n = 262)
Nausea
16 (4.4)
20 (3.8)
44 (7.8)
25 (4.3)
33 (5.0)
55 (7.9)
Skin irritation
10 (2.7)
14 (2.7)
3 (1.0)
86 (14.7)
14 (2.1)
62 (8.9)
12 (3.3)
11 (2.1)
38 (6.7)
11 (1.9)
15 (2.3)
40 (5.7)
2 (1.0)
8 (1.5)
1 (0.2)
0 (0.0)
9 (1.4)
0 (0.0)
20 (5.6)
88 (16.8)
18 (3.2)
66 (11.3)
69 (10.6)
63 (9.0)
Hiccups
1 (0.3)
0 (0.0)
35 (6.2)
0 (0.0)
7 (1.1)
22 (3.2)
Headaches
24 (6.7)
23 (4.4)
29 (5.1)
26 (4.4)
30 (4.6)
34 (4.9)
359
524
566
585
654
697
Mouth/throat
irritation
Alteration of
taste
Sleep
disturbance/
abnormal
dreams
Total adverse
events
Lozenge
Patch
(n = 260) (n = 264)
Bupropion
+ Lozenge
(n = 267)
Analyses with Combined Efficacy and
Effectiveness Samples
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Gender
Race
Education
Demographic Comparisons for Both Studies
Age
Gender (%female)
Effectiveness Study
Milwaukee
n=815
44.1 (11.8)
55%
Efficacy Study
Milwaukee
n=883
45.5 (10.7)
56.7%
Race/Ethnicity
% Caucasian
% Afr.Amer.
% Other
Cigarettes/day
FTND
83%
13.9%
3.0%
19.7 (8.7)
5.0 (2.1)
75.9%
21.1%
2.9%
21.9 (9.3)
5.5 (2.1)
Household income
<$35,000
$35-49,999
>$50,000
Education <HS
HS
>HS
35.5%
20.5%
44%
13.7%
46.6%
39.6%
40%
19.3%
40.7%
8.1%
25.3%
66.5%
Treatment Impact by Gender on 6-month Outcome
Treatment Impact by Race on 6-month Outcome
Treatment Impact by Education on 6-month Outcome
Conclusions
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The combination therapies (bupropion + nicotine lozenge and
nicotine patch + nicotine lozenge) produced the highest longterm abstinence rates in the Effectiveness Study
The combination of nicotine patch + lozenge produced the
highest long-term abstinence rates in the Efficacy Study
Efficacy Study data supports safety and patient acceptance of
combination NRT
These results agree with 2008 PHS Guideline that both single
and combination pharmacotherapies are effective, with
combination NRT therapy being particularly effective.
The nicotine patch remains a highly efficacious
pharmacotherapy for helping smokers quit.
Conclusions
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For women, combination therapy produced the
highest long-term abstinence rates relative to
monotherapies.
For African-American smokers, combination therapy
did not appear to have any added benefit over and
above monotherapies.
For smokers with <high school education,
combination therapy produced significantly higher
abstinence rates relative to monotherapies.
Acknowledgements
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These studies were conducted at the University of Wisconsin
and supported by NIH Grant # P50-DA0197. Dr. Piper was
supported by an Institutional Clinical and Translational Science
Award (UW-Madison; KL2 Grant # 1KL2RR025012-01).
Medication was provided to patients at no cost under a
research agreement with GlaxoSmithKline.
Tanya R. Schlam, Ph.D.
Michael C. Fiore, M.D., M.P.H.
Douglas E. Jorenby, Ph.D.
David Fraser, M.S.
Timothy B. Baker, Ph.D.
Madison and Milwaukee Study Staff
www.ctri.wisc.edu
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