E-cigarettes Evidence Brief: March 2018

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What are E-cigarettes? Originally introduced in China in 2003, electronic nicotine delivery devices (e-cigarettes) entered the U.S. and European markets in 2006 and have grown into a multibillion dollar industry with over 466 brands and 7,764 flavors (Liberman, 2017). E-cigarettes deliver nicotine rapidly to the brain without burning tobacco. The e-cigarette heats a liquid solution of nicotine via a battery-powered device producing nicotine-containing vapor for inhalation (Liberman, 2017). Prevalence/Trends Among adults in the United States, awareness of e-cigarettes increased from 41% in 2010 to 80% in 2013. In this same time frame, prevalence of ever use increased from 10% to 37% among smokers; from 3% to 10% among former smokers. Among never smokers, prevalence of use remained unchanged at 1% between 2010 and 2014 (King, 2014). According to the Centers for Disease Control and Prevention (CDC) 2015 survey, 13.5% of middle school and 37.7% of high school students had ever used e-cigarettes while past 30-day use was at 5.3% for middle school students and 16% for high school students. Both ever and past 30-day rates among middle and high school students have more than tripled since 2011 (USDHHS, 2016). Another CDC survey found that in 2013-2014, e-cigarette use among young adults surpassed that of adults for both ever and current use. In young adults, ever use was at 35.8% compared to 16.4% in adults. Current use was 13.6% in young adults and 5.7% in adults (USDHHS, 2016). Tobacco Cessation There is insufficient evidence to support e-cigarettes as effective aids for smoking cessation compared to standard FDA approved therapies. The U.S. Preventive Services Task Force (USPSTF) did not find sufficient evidence to recommend electronic nicotine delivery systems (ENDS) for tobacco cessation in adults, including pregnant women. Instead, they recommended that clinicians direct patients who smoke tobacco to other cessation interventions with established effectiveness and safety (USPSTF, 2015). A 2016 meta-analysis of 2 randomized controlled trials, 15 cohort studies and 3 cross-sectional studies found that smokers using e-cigarettes (irrespective of intent to quit smoking) were not more likely to quit smoking than those who did not use e-cigarettes (Kalkhoran, 2016). A more recent 2017 meta-analysis of 3 randomized controlled trials and 9 cohort studies confirmed these findings. It did find evidence from cohort studies of a possible reduction in quit rates with the use of nicotine e-cigarettes compared with alternatives (nicotine replacement therapy, cigarette use, behavioral interventions, no nicotine e-cigarette use) (El Dib, 2017). The evidence (randomized controlled trials, cohort and cross-sectional studies) on which these systematic reviews and meta-analyses are based on have methodological issues and only few randomized controlled trials Copyright 2018 by Institute for Clinical Systems Improvement 1

are available. Overall quality of evidence is either low or very low. No trials (only observational studies) compared the direct effects of e-cigarette use on smoking cessation to standard therapies such as nicotine replacement therapy. The trials that are available studied the efficacy of nicotine e-cigarettes vs. placebos e-cigarettes. These trials showed mixed results, and because of the low quality evidence, no clear inferences can be drawn (Hartmann-Boyce, 2016; Khoudigian, 2016, El Dib, 2017). Safety Because e-cigarettes contain lower levels of toxins than conventional cigarettes, they are considered by some as a safer alternative. A 2017 health risk assessment found that compared with e-cigarettes, conventional cigarettes had more contaminants with exposure levels higher than the international guideline levels (Chen, 2017). A systematic review of 687 articles found that conventional cigarette smokers who report switching to e-cigarettes have been shown to have positive outcomes such as reduced blood pressure, improved lung function, and improved lung disease symptoms (Glasser, 2017). A 2016 systematic review of 3 randomized controlled trials and 21 cohort studies found no serious adverse events from e-cigarette with irritation of the mouth and throat reported as the most common side effects (Hartmann-Boyce, 2016). Additional side effects may include nausea, headache, and dry cough (Gualano, 2014, Glasser, 2017; Hajek 2014). However, there is also concern that they are not a harm-free alternative (Chen, 2017; Glasser, 2017; Fernandez, 2015; Hajek 2014, Hess 2016). There is conflicting literature regarding particular substances in e-cigarettes and the potential for toxicity and harm (Chen, 2017; Burstyn, 2014). Further complicating this issue of toxins is the variability of the delivery systems. Most e-cigarettes share a similar basic design, with common components including an aerosol generator, a flow sensor, a battery, and a liquid solution storage area (Brown, 2014). Yet, there is significant variability in configuration and functionality which therefore leads to varied nicotine delivery and variable exposure to other substances (Brown, 2014; Cheng, 2014). The effect of e-cigarettes on bystanders is not fully understood. While the exposure to toxins is much less than with conventional cigarettes, the risk is unclear. A systematic review by Hess et. al (2016) found that passive exposure to e-cigarette vapor had the potential to lead to adverse health events because of elevated levels of chemicals such as nicotine, particulate matter, glycerine, proplylene glycol, formaldehyde, acetaldehyde, polycyclic aromatic hydrocarbons, and metals (Hess, 2016). Abidin (2017) found that current studies were inconsistent in methodology and findings on indoor air quality related to e-cigarettes. (Abidin, 2017) In youth, a 2018 study on 103 adolescents with an average age of 16.4 years old found significantly higher levels of toxic chemicals, including carcinogens, in those who used both e-cigarettes and traditional cigarettes compared to e-cigarette use alone as well as significantly higher levels in those youths who used e-cigarettes alone compared to those who never used e-cigarettes or traditional cigarettes. The harmful toxins were found in both nicotine and non-nicotine e-cigarettes. (Rubinstein, 2018) Other safety issues of e-cigarettes include accidental poisoning, explosions, and vaping of other substances (Glasser 2017, Brown 2014). Between 2012 and 2015, e-cigarettes accounted for 14.2% of the nicotine singleexposure calls among children five years old and under (Glasser, 2017). There were 92 reports of overheating, 2

fire, or explosion events from 2012 to 2015 in the United States, with about 50% of those resulting in injuries (Glasser, 2017). There is also concern that the e-cigarette apparatus may be used to vaporize other chemical substances (Brown, 2014). Many of the flavorings are in the same class of flavorings that have been shown to cause bronchiolitis obliterans (Kreiss, 2008). Caution should be exercised when using flavoring products. Youth: Potential Gateway to Addiction According to the 2016 U.S. Surgeon General Report on e-cigarettes, nicotine exposure during adolescence can cause addiction and harm brain development (USDHHS, 2016). Low to moderate evidence from systematic reviews and meta-analyses of observational studies suggests that young adults who use e-cigarettes may be at higher risk for future cigarette smoking. A 2016 meta-analysis of six studies (91,051 participants, including 1452 with ever e-cigarettes use) found that never-smoking adolescents and young adults who used e-cigarettes had higher likelihood of increased intent to smoke cigarettes in the future (Zhong, 2016). A 2017 systematic review and meta-analysis of 9 studies of 17,389 adolescents and young adults found that never cigarette smokers who used e-cigarettes in the past 30 days had higher likelihood for subsequent cigarette smoking initiation (Soneji, 2017). Discussing E-Cigarettes with Patients - Key Takeaways Adapted from Ebbert, 2015: Counseling Patients on the Use of Electronic Cigarettes (Mayo Clinic Proceedings) 1. They are not demonstrably superior to FDA-approved medications for smoking cessation. 2. They may not be effective for smoking cessation and dual use (i.e., using e-cigarettes and continuing to smoke) will prolong exposure to tobacco. 3. They are not FDA-approved for the treatment of tobacco dependence. 4. The long-term health risk of exposure to e-cigarette constituent chemicals is unknown. 5. No regulatory oversight, such as requirements for good manufacturing practices, is currently in place for e-cigarette devices. 6. For adolescents, use of e-cigarettes may increase likelihood of use of conventional cigarettes. 7. The safety of flavorings have not been documented and there is some evidence that it could be hazardous. References Abidin ZN, Abidin EZ, et al. Electronic cigarettes and indoor air quality: a review of studies using human volunteers. Rev Environ Health 2017 Sep 26;32(3):235-244. Brown CJ, Cheng JM. Electronic cigarettes: product characterisation and design considerations. Tob Control. 2014 May;23 Suppl 2:ii4-10. doi: 10.1136/tobaccocontrol-2013-051476. Burstyn I. Peering through the mist: systematic review of what the chemistry of contaminants in electroniccigarettes tells us about health risks. BMC Public Health 2014 Jan 9;14:18. doi: 10.1186/1471-2458-14-18. 3

Chen J, Bullen C, Dirks K. A Comparative Health Risk Assessment of Electronic Cigarettes and Conventional Cigarettes. Int J Environ Res Public Health 2017 Apr 5;14(4). pii: E382. doi: 10.3390/ijerph14040382. Cheng T. Chemical evaluation of electronic cigarettes. Tob Control 2014 May;23 Suppl 2:ii11-7. doi: 10.1136/ tobaccocontrol-2013-051482. Ebbert, JO et al. Counseling Patients on the Use of Electronic Cigarettes. Mayo Clin Proc 2015;90(1):128-134. El Dib R, Suzumura EA, et al. Electronic nicotine delivery systems and/or electronic non-nicotine delivery systems for tobacco smoking cessation or reduction: a systematic review and meta-analysis BMJ Open. 2017 Feb 23;7(2):e012680. doi: 10.1136/bmjopen-2016-012680. Hartmann-Boyce J, McRobbie H, Bullen C, Begh R, Stead LF, Hajek P. Electronic cigarettes for smoking cessation. Cochrane Database of Systematic Reviews 2016, Issue 9. Art. No.: CD010216. DOI: 10.1002/14651858. CD010216.pub3. Fernández E, Ballbè M, et al. Particulate Matter from Electronic Cigarettes and Conventional Cigarettes: a Systematic Review and Observational Study. Curr Environ Health Rep 2015 Dec;2(4):423-9. doi: 10.1007/ s40572-015-0072-x. Glasser AM, Collins L et al. Overview of Electronic Nicotine Delivery Systems: A Systematic Review. Am J Prev Med 2017 Feb;52(2):e33-e66. doi: 10.1016/j.amepre.2016.10.036. Epub 2016 Nov 30. Gualano MR, Passi S, et al. Electronic cigarettes: assessing the efficacy and the adverse effects through a systematic review of published studies. J Public Health (Oxf) 2015 Sep;37(3):488-97. doi: 10.1093/pubmed/ fdu055. Epub 2014 Aug 9. Hajek P, Etter JF, et al. Electronic cigarettes: review of use, content, safety, effects on smokers and potential for harm and benefit. Addiction 2014 Nov;109(11):1801-10. doi: 10.1111/add.12659. Epub 2014 Jul 31. Hess IM, Lachireddy K, Capon A. A systematic review of the health risks from passive exposure to electronic cigarette vapour. Public Health Res Pract 2016 Apr 15;26(2). pii: 2621617. doi: 10.17061/phrp2621617. Kalkhoran S, Glantz SA. E-cigarettes and smoking cessation in real-world and clinical settings: a systematic review and meta-analysis. Lancet Respir Med 2016 Feb;4(2):116-28. doi: 10.1016/S2213-2600(15)00521-4. Epub 2016 Jan 14. Khoudigian S, Devji T. The efficacy and short-term effects of electronic cigarettes as a method for smoking cessation: a systematic review and a meta-analysis. Int J Public Health 2016 Mar;61(2):257-67. doi: 10.1007/ s00038-016-0786-z. Epub 2016 Jan 29. King BA, Patel R, Nguyen KH, Dube SR. Trends in awareness and use of electronic cigarettes among US adults, 2010-2013. Nicotine Tob Res 2015 Feb;17(2):219-27. doi: 10.1093/ntr/ntu191. Epub 2014 Sep 19. Kreiss K, Gomaa A, et al. Clinical bronchiolitis obliterans in workers at a microwave-popcorn plant. N Engl J Med 2002 Aug 1;347(5):330-8. Liberman J, Wann S. E-Cigarettes-What a Practicing Cardiologist Needs to Know. Am J Cardiol 2017 Feb 15;119(4):681-686. doi: 10.1016/j.amjcard.2016.11.011. Epub 2016 Nov 19. 4

Rubinstein ML, Delucchi K, Benowitz NL, et al. Adolescent Exposure to Toxic Volatile Organic Chemicals From E-Cigarettes. Pediatrics 2018;141(4):e20173557. Siu AL; U.S. Preventive Services Task Force. Behavioral and Pharmacotherapy Interventions for Tobacco Smoking Cessation in Adults, Including Pregnant Women: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2015 Oct 20;163(8):622-34. doi: 10.7326/M15-2023. Epub 2015 Sep 22. Soneji S, Barrington-Trimis JL, et al. Association Between Initial Use of e-cigarettes and Subsequent Cigarette Smoking Among Adolescents and Young Adults: A Systematic Review and Meta-analysis. JAMA Pediatr 2017 Aug 1;171(8):788-797. doi: 10.1001/jamapediatrics.2017.1488. U.S. Department of Health and Human Services. E-Cigarette Use Among Youth and Young Adults. A Report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2016. Zhong J, Cao S, et al. Electronic Cigarettes Use and Intention to Cigarette Smoking among Never-Smoking Adolescents and Young Adults: A Meta-Analysis. Int J Environ Res Public Health 2016 May 3;13(5). pii: E465. doi: 10.3390/ijerph13050465. Work Group Authors Courtney Baechler, MD, Allina Health, Minneapolis, MN Christine Danner, PhD, LP, University of Minnesota Physicians, Minneapolis, MN Kristin Erickson, MS, APHN-BC, BC, Ottertail County Public Health, Fergus Falls, MN Thomas Kottke, MD, MSPH, HealthPartners (work group leader) Patrick O Connor, MD, HealthPartners, Bloomington, MN Rebecca Straub, RD, LD, HealthPartners, Bloomington, MN John Wilkinson, MD, Mayo Clinic, Rochester, MN Institute for Clinical Systems Improvement Staff Jodie Dvorkin, MD, MPH Senka Hadzic, MPH 5