1 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

2 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

3 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?

PHS Guideline Printed version Online version – a printable pdf of full guideline

5 The "5 A's" Model for Treating Tobacco Use and Dependence Medication And Counseling

6 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

8 Medication Number of arms Estimated odds ratio (95% C.I.) Estimated abstinence rate (95% C.I.) Nicotine Patch ( ) 23.4% (21.3 – 25.8) Bupropion SR (1.8 – 2.2) 24.2% (22.2 – 26.4) Varenicline (2.5 – 3.8) 33.2% ( ) Patch (>14 wks) + NRT (gum or spray) (2.5 – 5.2) 36.5% (28.6 – 45.3) Patch + Bupropion SR (1.9 – 3.4) 28.9% (23.5 – 35.1) Selected Medication Options: Monotherapy and Combination Therapy

9 99 Relative Efficacy Medication Number of arms Estimated odds ratio (95% C. I.) Nicotine Patch (reference group)321.0 Varenicline (2 mg/day)5 1.6 (1.3, 2.0) Patch (>14 weeks) + NRT (gum or spray) (1.3, 2.7) Patch + Bupropion SR3 1.3 (1.0, 1.8)

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 BupropionNicotine Lozenge Nicotine Patch Bupropion + Lozenge Patch + Lozenge Randomization N = 1346 N = 256N = 261N = 282N = 268N = 279 Primary care patients presenting to 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 % Abstinent 16.8%19.9%17.7%29.9%26.9% OR – Bup+Loz as reference.46 p< p< p< OR – Patch+Loz as reference.54 p< p= p< Effectiveness Study: Cessation Rates (% Abstinent at 6 Months)

Effectiveness Study: Cessation Rates

Efficacy Study CONSORT Figure N = 8526 Expressed interest n = 1418 Declined n = 2010 Unreachable n = 2027 Failed screen n = 3153 Passed phone screen n = 1331 Withdrew n = 1504 Randomized n = 318 Excluded Lozenge n = 260 Patch n = 261 Bupropion SR n = 266 Patch + Lozenge n = 267 Bupropion SR + Lozenge n = 261 Placebo n = 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 = (SD = 11.08) Mean cigs. smoked/day = (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 PlaceboBupropionLozengePatchBupropion + Lozenge Patch + Lozenge Initial cessation OR = OR = OR = OR = OR = weeks OR = OR = OR = OR = OR = months OR = OR = OR = OR = OR = 2.34 = p <.05= p <.005

Efficacy Study: Latency to Relapse Placebo Lozenge/Bupropion Patch + Lozenge Bupropion + Lozenge Patch/Bupropion + Lozenge

Efficacy Study Adverse Events

Analyses with Combined Efficacy and Effectiveness Samples Gender Race Education

Effectiveness Study Milwaukee n=815 Efficacy Study Milwaukee n=883 Age Gender (%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/day FTND 19.7 (8.7) 5.0 (2.1) 21.9 (9.3) 5.5 (2.1) Household income <$35,000 $35-49,999 >$50, % 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 # 1KL2RR ). 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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