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CTRI Webinar:Combination Medication

Effectiveness

June 9, 2010

Stevens S. Smith, Ph.D.Megan E. Piper, Ph.D.Center for Tobacco Research & InterventionUW School of Medicine and Public Health

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Combination Medication Effectiveness

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

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Rationale

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?

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2008 PHS Guideline

Printed version Online version – a printable pdf of full guideline

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The "5 A's" Model for Treating Tobacco Use and Dependence - 2008

ASK

Do you currently use

tobacco?

ASSESS

Have you recently quit?

Any challenges?

ASSIST

Provide appropriate tobacco dependence

treatment

ASSIST

Intervene to increase motivation

to quit

ASSIST

Provide relapse prevention

ASSIST

Encourage continuedabstinence

YES

NO

YES NONO

YES

ADVISE to quit

ASK

Have you ever used tobacco?

YES NO

ARRANGE FOLLOW-UP

ASSESSAre you willing to quit now?

MedicationAnd

Counseling

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Guideline Recommendation:FDA-Approved Cessation Medications

Clinicians should encourage medication for all patients attempting to quit smoking

– 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

Seven first-line medications (5 nicotine and 2 non-nicotine) reliably increase long-term smoking abstinence rates- Bupropion SR - Nicotine gum*

- Nicotine lozenge* - Nicotine nasal spray

- Nicotine inhaler - Nicotine patch*

- Varenicline

Clinicians should also consider the use of certain combinations of medications identified as effective in this Guideline

7 *Available without a prescription

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MedicationNumberof arms

Estimatedodds ratio(95% C.I.)

Estimatedabstinence rate

(95% C.I.)

Nicotine Patch 321.9

(1.7 - 2.2)23.4%

(21.3 – 25.8)

Bupropion SR 262.0

(1.8 – 2.2)24.2%

(22.2 – 26.4)

Varenicline 53.1

(2.5 – 3.8)33.2%

(28.9 - 37.8)

Patch (>14 wks)+ NRT (gum or spray)

33.6

(2.5 – 5.2)36.5%

(28.6 – 45.3)

Patch + Bupropion SR 32.5

(1.9 – 3.4)28.9%

(23.5 – 35.1)

Selected Medication Options:Monotherapy and Combination Therapy

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Relative Efficacy

MedicationNumber of arms

Estimated odds ratio (95% C. I.)

Nicotine Patch (reference group) 32 1.0

Varenicline (2 mg/day) 51.6

(1.3, 2.0)

Patch (>14 weeks) + NRT (gum or spray)

31.9

(1.3, 2.7)

Patch + Bupropion SR 31.3

(1.0, 1.8)

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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)

UW-CTRI Transdisciplinary Tobacco Use Research Center (TTURC2) Studies

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

• Effectiveness Study – 1346 smokers recruited in 12 primary care clinics– Enrollment offered during regular primary care visits

• Efficacy Study (Randomized Clinical Trial)– 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

Bupropion Nicotine Lozenge

Nicotine Patch

Bupropion + Lozenge

Patch+ Lozenge

RandomizationN = 1346

N = 256 N = 261 N = 282 N = 268 N = 279

Primary care patients presentingto 12 primary care clinics

Effectiveness Study: Treatment Model

• 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

1346 smokers – Mean age = 44.3, SD = 12.1– 56% female– 87% Caucasian

Representative of the demographics of the population of smokers in the clinics

Total N=1346 Bupropion

(N=256)

Lozenge

(N=261)

Patch

(N=282)

Bupropion + Lozenge

(N=268)

Patch + Lozenge

(N=279)

6 Month

% Abstinent16.8% 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- -

Effectiveness Study: Cessation Rates (% Abstinent at 6 Months)

Figure 2. Abstinence rates

0

10

20

30

40

50

60

70

Week 1 Week 8 Six Months

Post-Quit Study Endpoints

Per

cen

t A

bst

inen

t

Bupropion

Lozenge

Patch

Bupropion+Lozenge

Patch+Lozenge

Effectiveness Study: Cessation Rates

Efficacy Study CONSORT Figure

N = 8526Expressed interest

n = 1418Declined

n = 2010Unreachable

n = 2027Failed screen

n = 3153Passed phone screen

n = 1331Withdrew

n = 1504Randomized

n = 318Excluded

Lozengen = 260

Patchn = 261

Bupropion SR

n = 266

Patch +Lozengen = 267

Bupropion SR + Lozenge

n = 261

Placebon = 189

Efficacy Study Participants

N = 1504 (628 men, 876 women) Ethnicity

– 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

All participants received 6 brief (10-20 min) individual counseling sessions

Bupropion SR – 150 mg bid for 9 weeks

Nicotine patch – 24-hour patch; 21, 14, and 7mg; titrated down over 8 weeks

post-quit Nicotine lozenge

– 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 78.9OR = 2.04

77.2OR = 1.91

86.3OR = 3.14

82.0OR = 2.40

89.8OR = 4.73

8 weeks 30.2 40.2OR = 1.55

40.4OR = 1.57

44.7OR = 1.87

50.4OR = 2.35

53.6OR = 2.67

6 months 22.2 31.8OR = 1.63

33.5OR = 1.76

34.4OR = 1.83

33.2OR = 1.74

40.1OR = 2.34

= p < .05 = p < .005

Efficacy Study: Latency to Relapse

Placebo

Lozenge/Bupropion

Patch + Lozenge

Patch/BupropionBupropion + Lozenge+ Lozenge

Efficacy Study Adverse Events

Placebo (n = 189)

Bupropion (n = 262)

Lozenge (n = 260)

Patch

(n = 264)

Bupropion + Lozenge (n = 267)

Patch + Lozenge (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)

Mouth/throat irritation 12 (3.3) 11 (2.1) 38 (6.7) 11 (1.9) 15 (2.3) 40 (5.7)

Alteration of taste 2 (1.0) 8 (1.5) 1 (0.2) 0 (0.0) 9 (1.4) 0 (0.0)

Sleep disturbance/ abnormal dreams

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)

Total adverse events 359 524 566 585 654 697

Analyses with Combined Efficacy and Effectiveness Samples

Gender Race Education

Effectiveness Study Milwaukee

n=815

Efficacy Study Milwaukee

n=883

AgeGender (%female)

44.1 (11.8)55%

45.5 (10.7)56.7%

Race/Ethnicity % Caucasian% Afr.Amer.% Other

83%13.9%3.0%

75.9%21.1%2.9%

Cigarettes/dayFTND

19.7 (8.7)5.0 (2.1)

21.9 (9.3)5.5 (2.1)

Household income<$35,000$35-49,999>$50,000

35.5%20.5%44%

40%19.3%40.7%

Education <HS HS

>HS

13.7%46.6%39.6%

8.1%25.3%66.5%

Demographic Comparisons for Both Studies

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

The combination therapies (bupropion + nicotine lozenge and nicotine patch + nicotine lozenge) produced the highest long-term 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.

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.

Conclusions

Acknowledgements

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

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www.ctri.wisc.edu