Controversies and evidence in smoking cessation

Transcription

1 Controversies and evidence in smoking cessation Robert West University College London June 2016

2 Declaration of competing interests I undertake research and consultancy for companies that develop and manufacture smoking cessahon medicines (Pfizer, GSK, J&J) but not e- cigare<es My salary is funded by the charity, Cancer Research UK I am an advisor to the UK s NaHonal Centre for Smoking CessaHon and Training

3 Addiction science has a problem IdenHfying and quanhfying causal associahons is very challenging and involves uncertainty Moral judgements and vested interests are important sources of bias Uncertainty nurtures bias Bias is leading to misleading informahon being presented in the research literature and mass media

4 The cases of varenicline and e-cigarettes Strong claims are being made The smoking cessahon medicine, varenicline, causes serious neuropsychiatric side- effects Use of electronic- cigare<es undermines smoking cessahon

5 How is a causal association established? We can infer that variable A causally influences variable B when we observe a reliable stahshcal associahon and can rule out alternahve explanahons The confidence we should have in our conclusions depends on The reliability with which the associahon is observed The confidence with which we can rule out alternahve explanahons A B Causality: A influences B

6 Possible explanations that can be addressed by high quality RCTs 1. A B Reverse causality: B influences A 3. C Confounding: C influences A and B A B 4. A C B Coincidence: C is by chance coincident with A and causes B

7 Possible explanations that can be addressed by high quality RCTs 1. A B Reverse causality: B influences A 2. C Confounding: C influences A and B A B 4. A C B Coincidence: C is by chance coincident with A and causes B

8 Possible explanations that can be addressed by high quality RCTs 1. A B Reverse causality: B influences A 2. C Confounding: C influences A and B A B 3. A C B Coincidence: C is by chance coincident with A and causes B

9 Possible explanations that are not addressed by RCTs 4. A C B Co- occurrence: C, that o`en co- occurs with A, influences B 6. A D B Moderated causality: A influences B to a degree dependent on C 7. (A) (B) Limited causality: A influences B within a limited range or type of A and/or B

10 Possible explanations that are not addressed by RCTs 4. A C B Co- occurrence: C, that o`en co- occurs with A, influences B 5. A D B Moderated causality: A influences B to a degree dependent on D 6. (A) (B) Limited causality: A influences B within a limited range or type of A and/or B

11 Template for evaluating explanations Explana'on Reverse causality Made less likely by A preceding B; Implausible mechanism for B causing A Confounding StaHsHcal adjustment for C; Matching on C; RandomisaHon Coincidence Co- occurrence Moderated causality Limited causality Repeated co- occurrence of A and B at above chance level ConHnued associahon between A and B even when C is not present Consistent associahon between A and B despite varying values of D Consistent associahon between A and B over varying values of A and B

12 Claims about varenicline side effects Reports in media and to medicine regulators of serious neuropsychiatric events (suicide, aggression, depression) in users

13 Explanations Possible explana'on Reverse causality Unlikely No plausible mechanism for reverse causality Confounding Likely No increased risk in RCTs or comparahve studies a`er adjushng for other variables Coincidence Likely Rate is no greater than expected by chance in smokers trying to stop; excess in spontaneous report appears to be shmulated by publicity Co- occurrence Possible Could be partly due to nicohne withdrawal symptoms Moderated influence Possible ConflicHng evidence for an interachon with pre- exishng psychiatric disorder Limited causality Unknown Limited informahon on dose response

14 Appropriate conclusion Serious neuropsychiatric events have been observed in people taking varenicline. Evidence from mulhple randomised controlled trials and large comparahve observahonal studies have found no evidence of an increased risk in people using varenicline so it is unlikely that varenicline is the cause. However, a very small increase in risk cannot be ruled out. If there is a small increased risk in neuropsychiatric events caused by varenicline, part of the increase could be due to the effects of stopping smoking and it is probably only in smokers with a pre- exishng psychiatric disorder.

15 Illustrative findings

16 EAGLES RCT: Suicidal ideation and ParHcipants reporhng (%) behaviour Non- psychiatric (N = 3984) Psychiatric (N = 4074) 0,7 0,4 0,3 0,6 0,1 0,1 2,7 2,5 2,7 2,5 0,7 0,4 0,3 0,7 1,5 2,0 0,1 0,2 1,5 2,0 SI SB SI and/or SB SI SB SI and/or SB Varenicline Bupropion NRT Placebo C- SSRS, Columbia Suicide Severity RaHng Scale; SI, suicide ideahon; SB, suicide behavior. Lancet 2016 Apr 22. pii: S (16) doi: /S (16)

17 Swedish population study: overall results BMJ 2015;350:h2388 doi: /bmj.h2388

18 Swedish population study: moderation results

19 Claims about e-cigarettes... quimng smoking is one of the main reasons both adults and kids use e- cigare<es, but the overall effect is less, not more, quimng, Stanton A. Glantz, PhD, UCSF professor of medicine and director of the UCSF Center for Tobacco Control Research and EducaHon.... the most dangerous thing about e- cigare<es is that they keep people smoking convenhonal cigare<es. h<p://hnyurl.com/gwv3kfe

20 The basis for the claim The UCSF team reviewed 38 studies assessing the associahon between e- cigare<e use and cigare<e cessahon among adult smokers. They then combined the results of the 20 studies that had control groups of smokers not using e- cigare<es in a meta- analysis that concluded that the odds of quimng smoking were 28 percent lower in smokers who used e- cigare<es compared to those who did not The authors undertook a number of sensihvity analyses to assess the impact of varying the inclusion criteria and other factors. Lancet Respir Med Feb;4(2): doi: /S (15)

21 Explanations Possible explana'on Reverse causality Unlikely Several studies were prospechve with e- cigare<e use predahng period when quimng was canvassed Confounding Likely Strong correlahons between cigare<e addichon and both use of e- cigare<es and failure to quit Coincidence Unlikely The associahon is consistent Co- occurrence Unlikely No evidence for co- occurring causes Moderated influence Unknown No evidence on moderators Limited causality Likely Depends on whether e- cigare<e is used in a quit a<empt, type of e- cigare<e, and frequency of use

22 Confounding Confounding The ability to adjust for confounding was very limited available measures of addichon were weak and o`en retrospechve. Could not rule out that more addicted smokers were more likely to use e- cigare<es, having tried and failed with other methods of quimng

23 Limited causality Limited causality Only one study looked at smokers using an e- cigare<e as part of a quit a<empt. This was a large study that found a posi've associahon with quimng. In addihon, the combined results of two RCTs show a posihve effect on quit success compared with placebo AddicHon Sep;109(9): doi: /add One study found a negahve associahon only with non- daily e- cigare<e use or 1 st generahon products AddicHon Jul;110(7): doi: /add

24 Appropriate conclusion Use of electronic cigare<es in the past or while smoking is associated with a reduced likelihood of stopping smoking. This associahon may not be causal, may depend on the type of electronic cigare<e and the frequency of use, and does not appear to generalise to use of electronic cigare<es in a quit a<empt which has been found to have a posihve associahon with quit success.

25 Conclusions AddicHon science is complex and findings are o`en uncertain and need to be qualified. We need a structure to evaluate alternahve explanahon to simple causal ones and require all claims to be evaluated using that structure Conclusions must reflect a careful and objechve evaluahon of alternahve explanahons and the wording should be appropriate to the level of uncertainty