1. Electronic Cigarettes: An Opportunity or a Threat to Health? Chris Bullen MBChB, MPH, PhD Charles R Drew University of Medicine and Science 11 th Drug Abuse Research Symposium August 5 th 2016

2. Declaration of interests Affiliations  Employee of the University of Auckland. Disclosures  Principal Investigator of the ASCEND e-cigarette trial, a study funded in full by the Health Research Council of NZ  Co-Investigator of the ASCEND II e-cigarette trial and STATUS trial, funded in full by the Health Research Council of NZ  Co-Director of the Tobacco Control Research Turanga, a programme that supports several e-cigarette research projects  Consultant on two TCORS progammes that are investigating e- cigarettes  I have not received any benefits from the manufacturers/retailers of e-cigarettes nor the tobacco industry.

3. My context  New Zealand (NZ) has a national goal of ‘smokefree nation’ by 2025, (prevalence ≤ 5% for all NZers  Nicotine regulated as a medicine, except in tobacco  E-cigarettes without nicotine can be sold; e-cigarettes with nicotine can only be imported for personal use  This regulation is being reviewed  Oral tobacco is illegal

4. Outline

5. What are e-cigarettes? “Devices whose function is to vaporise and deliver to the lungs of the user a chemical mixture typically composed of nicotine, propylene glycol and other chemicals” - World Health Organisation

6. Evolution of e-cigarettes Herbert A Gilbert 1963 Hon Lik 2003

7. Recent products ‘3 rd gen’

9. Evolution and Growth 2004: 1 brand (Ruyan) and a few models 2012-2014: 11 new brands/month 2014: 466 brands  Differ in nicotine content - content of fluid in cartridge, or fluid in reservoir  Huge array of flavors: 7764 unique flavours in Jan 2014; 242 new flavours per month between 2012-14  Rapidly evolving designs and features Goniewicz 2012; Goniewicz, Hajek & McRobbie 2014; Zhu et al, 2014; Vansickel 2012, Hitchman et al, 2015

10. Rapid uptake by smokers – why? As a cigarette substitute Health concerns with smoking Convenience Affordability Supportive subculture Online information ‘Viral’ movement Hobby Regulatory vacuum

11. Individuals: Prevent would-be smokers from taking up smoking Help smokers quit tobacco smoking Help smokers cut down tobacco smoking to levels that reduce harms Populations: Reduce tobacco smoking initiation and increase quitting Reduce smoking prevalence Reduce exposure to SHS Opportunity for health?

12. Assessing e-cigarettes not easy  Hundreds of different brands and models of e- cigarette available. 466 in Jan 2014, 11 new brands/month between 2012-14  All vaporise propylene glycol and glycerol as a carriage medium for nicotine and flavours  Differ in nicotine content - content of fluid in cartridge, or fluid in reservoir  7764 unique flavours in Jan 2014; 242 new flavours per month between 2012-14  User experience is important Goniewicz 2012; Goniewicz, Hajek & McRobbie 2014; Zhu et al, 2014; Vansickel 2012

13. Bullen et al, Tob Control 2010 E-cigarettes reduce urge to smoke

14. Nicotine delivery varies by brand 2.4% 18mg Source: Goniewicz, Hajek & McRobbie, 2014

15. Variation with models: 1 st gen, 2 nd /3 rd gen Farsalinos et al, Sci. Rep. 2014 http://dx.doi.org/10.1038/srep0413

16. Substitution is possible Goniewicz et al, in preparation

17. Biomarkers of tobacco smoke exposure before & after e-cig use Goniewicz et al, in preparation

18. Surveys e.g.  Etter & Bullen (2014) Internet survey; 46% quit by 1 year  Brown et al. (2014) UK Smokers survey  Biener & Hargraves (2015) - daily use for > 1 month  Vickerman et al. (2013) – State Quitline callers Prospective studies e.g.  Smokers unwilling to quit  Polosa et al (2011 and 2013) – 13%-15% validated abstinence at 1 year Mixed evidence from surveys and cohort studies

19. Cochrane review

20. Published RCTs with a primary endpoint of quitting Caponnetto (2013) (PlosOne) Bullen (2013) (Lancet) PopulationUnmotivated to quitMotivated to quit Inclusion criteria ≥10cpd for at least 5 years, 18-70 years ≥10cpd for last year, ≥18 years BrandCategoriaElusion Sample size300657 Arms7.2 mg E-cig 7.2-5.4 mg E-cig 0 mg E-cig No behavioural support 16mg E-cig 21mg NRT patch 0mg E-cig Minimal behavioural support Intervention period 12 weeks13 weeks (includes one week pre-quit) Follow-up12 months6 months Power75%80% Primary outcome Verified continuous abstinence at 6 months Verified continuous abstinence at 6 months

21. Cessation - Nicotine EC vs NRT StudyNicotine ECNicotine PatchRR (95% CI) Bullen 20137% (21/289)6% (17/295)1.26 (0.68 – 2.34) Post hoc non inferiority analysis: nicotine ECs as at least as effective as patches

22. Cessation – Nicotine vs Non-Nicotine EC  No significant statistical heterogeneity  RR 2.29 (1.05-5.96) StudyNicotine ECPlacebo ECRR (95% CI) Bullen 20137% (21/289)4% (3/73)1.77 (0.54 – 5.77) Caponnetto 201311% (22/200)4% (4/100)2.75 (0.97 – 7.76) Total9% (43/489)4% (7/173)2.29 (1.05 – 4.96)

23. RCTs: ≥ 50% reduction StudyNicotine ECPlacebo ECRR (95% CI) Bullen 201362% (165/268)47% (33/70)1.31 (1.00 – 1.70) Caponnetto 201316% (29/178)13% (12/96)1.30 (0.70 – 2.44) Total43% (194/446)27% (45/166)1.31 (1.02 – 1.68) StudyNicotine ECNicotine PatchRR (95% CI) Bullen 201362% (165/268)44% (121/278)1.41 (1.20 – 1.67)

24. Duelling systematic reviews WHO review (2014) - pooled data from 5 studies (4 longitudinal and 1 cross-sectional) reporting e-cigarette use associated with a significantly lower chance of quitting smoking (OR=0.61; 95% CI: 0.50-0.75). The Cochrane review - did not include 3 of the studies in the WHO review (Adkison 2013; Popova 2013; Vickerman 2013) but included Grana 2014 and Choi 2014 - neither of these detected significant differences in cessation between smokers that used or did not use e-cigarettes at baseline. Kalkhoran and Glantz (2016) - reported a lower chance of quitting Concerns re. quality of many of the included studies

25. UK ‘real-world’ effectiveness adj OR=1.61 (95% CI: 1.19-2.18) adj OR=1.63 (95% CI: 1.17- 2.27) Brown et al. Addiction. 2014 May 20. doi: 10.1111/add.12623. 5863 adults who had smoked within the previous 12 months and made at least one quit attempt during that period with either an e-cigarette only (n=464), NRT bought over-the- counter only (n=1922) or no aid in their most recent quit attempt (n=3477)

26. UK smokers are using ECs for smoking cessation www.smokinginengland.info/latest-statistic “Aids used in most recent quit attempt” N=11695 adults who smoke and tried to stop or who stopped in the past year

27. Prevalence reduction? West et al 2016 N=9783 adults who smoke and tried to stop or who stopped in the past year; 2009 is Jul to Dec ECs have grown the use of moderately effective* aids to cessation from 24% in 2010 to 40+% in 2014; use of most effective* methods has decreased from 4% to 3% over same time. Assuming a stable quit attempt rate of 37% this contributed ~20,000 additional ex-smokers (0.05% to the decreased prevalence) *Approx. odds of success relative to nothing and NRT-OTC: 1.5 Moderately effective 3.0 Most effective

28. Health improvements in e-cigarette users Campagna et al, 2016 N=264, RCT

29. Individuals Reduce or delay quitting smoking Exposure to more/new toxicants than if they had continued smoking Create other harms in excess of those from continued smoking Use by never smokers Populations Second-hand exposure Increase smoking prevalence Re-normalise smoking behaviour Distract from key tobacco control efforts Threat to health?

30.  “ECs reduce most of the harms from tobacco smoking and to that extent they are effective”  Short-term use appears to be safe with few AEs reported in trials  Many studies on toxicology of vapour and a few biomarker studies  Effects of long-term frequent use unknown  Second-hand exposure risks minimal  Abuse liability potential Hazardous exposures?

31. Constituents and toxicants in vapour Sleiman et al, 2016 Environmental Science & Technology.

32. Toxicants relative to tobacco and guidelines Chen and Bullen, 2015

33. Other exposures and potential harms Hua and Talbot, 2016

34. Assessing harms Nutt et al, 2014

35. Relative harmfulness Nutt et al, 2014

36. Perceptions of Harm: US and UK Sources: NCI, ASH UK; http://rodutobaccotruth.blogspot.co.nz/2016/07/uk-e-cigarette-perceptions-more.html

37. Population health impact of E-cigarette initiation in the US Levy et al, 2016

38. California youth use of e-cigarettes Barrington-Trimis et al, 2016

39. Smoking trends in US youth

40. Regulation Need regulations that balance benefits with potential harms at individual and population levels. e.g. Controls on sales and marketing and use in some settings; Quality standards for devices and e- liquid. However  Products already available in the marketplace including on-line  Limited information available  Diverse products and use patterns  Tobacco Industry involvement

41. Opportunity or threat? Opportunity: possibility of genuine tobacco harm reduction, an option for smokers who want to quit and reduce harms to their health, and a leap forward for tobacco control if mass substitution occurs. Threat: as yet unknown health harms, ‘dual use’, ‘gateway’, smoking re-normalisation, tobacco industry reinvigorated, tobacco control sector divided and distracted.

42. E-cigarettes are a ‘disruptive’ technology presenting both opportunities and threats to the health of individuals and populations The jury is still out on the long-term health harms but most experts agree they are less harmful for individuals than smoking - the balance of population harms vs. benefits hinges in large part on how we regulate them Monitoring and research essential Respectful, constructive discussion and debate, based on high-quality data, is essential to achieve our common goal of ending the tobacco smoking epidemic. Conclusions

43. Professor Christopher Bullen Director, National Institute for Health Innovation (NIHI), School of Population Health, The University of Auckland, Auckland, New Zealand. c.bullen@auckland.ac.nz www.nihi.auckland.ac.nz