1. ABSTINENCE AND RELAPSE AMONG SMOKERS WHO USE VARENICLINE FOR QUITTING—A POOLED ANALYSIS OF RANDOMIZED CONTROLLED TRIALS Shade Agboola, Ann McNeill, Tim Coleman and Jo Leonardi-Bee UK Centre for Tobacco and Alcohol Studies University of Nottingham Institute of Psychiatry, Psychology & Neuroscience King’s College London

2. Introduction Varenicline is a nicotine receptor partial agonist that increases the likelihood of long term abstinence following a quit attempt. It is typically administered for 12 weeks It has been suggested that part of it’s benefit arises from recruiting into abstinence smokers who are not able to stop on their target quit date Also suggested that rate of relapse is common after treatment discontinuation

3. What we know Effective cessation treatments show an advantage over control treatments very soon after the target quit date* After the target quit date, relapse curves/abstinence patterns from treatments and control groups tend to be parallel. *Piasecki M(2006). Relapse to smoking. Clinical Psychology review (26:196-251)

4. What we don’t know We don’t know the patterns of abstinence and relapse amongst users of varenicline We don’t know if varenicline works by “recruiting into abstinence” smokers who are not able to quit on their target quit date We don’t know if relapse to smoking in those who have used varenicline is greater after treatment discontinuation, even though abstinence rates compared to placebo remain higher

5. Research Questions How does abstinence change over time following the end of treatment and up to 52weeks following the target quit date? What is the relapse pattern following the end of treatment and up to 52 weeks following the target quit date?

6. Study methods We used the most up-to-date Cochrane review of nicotine receptor partial agonists to identify RCTs assessing the effectiveness of varenicline Data extracted from all varenicline trials with minimum follow- up of six months that reported either point prevalence (PPA) or continuous abstinence Data pooled at six follow-up points for studies that reported PPA - two, three, four, 12, 24, and 52 weeks Data pooled at three time periods for studies that reported continuous abstinence 9-12 weeks, 9-24 weeks and 9-52 weeks

7. Why we pooled data separately Smoking cessation trials report abstinence as either PPA or continuous/prolonged abstinence We wanted to construct a true relapse (survival) curve, which ideally should measure time to occurrence of an event (in this case relapse) But data reported in trials insufficient to do this. PPA cannot be used to construct relapse curves, because smoking status is known only at the particular point that it’s reported Therefore, PPA at similar time points were pooled to derive abstinence patterns Continuous abstinence at similar time periods were pooled to derive a relapse curve

8. Statistical methods We calculated proportions of abstainers at specific time points/periods by extracting the numbers of abstainers and dividing by the total number of participants randomized to treatment. We performed meta analyses using StatsDirect to estimate pooled proportions of abstinence at each follow- up time-points in studies reporting PPA Meta analyses was also performed to estimate pooled proportions of abstinence at three time-periods for studies reporting continuous abstinence

9. Findings –Abstinence after Target Quit Date 19 studies compared effectiveness of varenicline with placebo Follow- up Week2 (11 trials) Week3 (11 trials) Week4 (13 trials) Week 12 (16 trials) Week 24 (16 trials) Week 52 (9 trials) VAR32%43% 54%39%35% PLB16%18%20%24%19%13% Abstinence observed for the pooled estimates for point prevalence abstinence appeared to rise steadily from week 2, peak at week 12 with a sharp decline in proportion abstinent by week 24, followed by a steady decline until week 52

10. Abstinence pattern -PPA

11. Findings –Relapse after TQD Follow-upWeek 9-12 (14 trials) Week 9-24(13 trials) Week 9-52(9 trials) VAR49%33%22% PLB17%14%8% Relapse rate between weeks 9-12 to week 24= 33%(Varenicline); 18%(Placebo) Relapse rate between weeks 9-12 to week 52 = 55%(Varenicline); 53%(Placebo)

12. Relapse Curve

13. Summary of main findings Pooled analysis of point prevalence abstinence estimates suggest that varenicline appears to recruit smokers into abstinence during the course of treatment supporting the view that part of its action may be through blockade of nicotinic ACh receptors Relapse from end of treatment to 52 weeks was similar in varenicline-treated and placebo-treated participants.

14. Study limitations Varenicline only – there’s a need to explore the abstinence patterns in users of bupropion and NRT No sub-group analysis. This was beyond the scope of the paper as it would have required individual patient data from original articles High levels of heterogeneity anticipated and observed because we pooled absolute percentages from the trials – hence modelling of heterogeneity using random effect

15. Implications From a clinical perspective, findings indicate that smokers using varenicline should be advised to continue with their quit attempt and to use the drug even after lapsing. The relapse rate following varenicline treatment discontinuation suggests that there may be smokers who may benefit from a longer course of treatment

16. Special thanks to Professor Robert West for his comments and alterations to the paper

17. Questions