Disclosures Dr. Benowitz has been a consultant to pharmaceutical - PDF document

12/7/19 Cardiovascular Effects of Vaping Neal L Benowitz MD Professor of Medicine University of California San Francisco UCSF Heart Disease Dec 7, 2019 1 Disclosures Dr. Benowitz has been a consultant to pharmaceutical companies that market smoking cessation products, including Pfizer and Achieve Life Sciences and a paid expert in litigation against tobacco companies 2 1

12/7/19 Clinical Vignette A 75 year old man with severe CAD, hypertension and HFrEF is a lifelong smoker. He would like to quit smoking but has been unable to do so with approved medications. He would like to try e-cigarettes and asks your advice about whether to do so. 3 Your response? (1) I recommend the approach (2) I wouldn’t recommend the approach, but it is up to you (3) Don’t use electronic cigarettes to quit smoking Nickels, AnnalsATS 2017 4 2

12/7/19 The Public Health Question • Cigarette smoking remains a major preventable cause of disease and premature death. Most of the harms of smoking are caused by tobacco combustion products. • The harms and risks of electronic cigarettes, which deliver nicotine without combustion products, are an essential consideration in assessing the public health impact of nicotine-based harm reduction. • What do we know about the cardiovascular safety of electronic cigarettes? 5 Other Related Clinical Questions • Should the patient who has switched from cigarette smoking to e-cigarettes be counseled to quit vaping? • What are the cardiovascular health risks of persistent e-cigarette use in never-smokers? • In light of recent cases of vaping related acute lung injury, how should we advise people who vape? 6 3

12/7/19 Brief Summary • E-cigarette use, while not harmless, is most likely much less harmful than cigarette smoking • There are many different e-cigarette devices and liquids, and their health effects are likely to be quite different • The cardiovascular harms of long term use of e-cigarettes have not been determined and need to be studied 7 Overall Impact of Cigarette Smoking on CVD in the U.S. • 21% of all CV deaths • 56% of ischemic heart disease deaths in people less than 65 8 4

12/7/19 Getting smokers to quit as soon as possible is essential for public health 9 Projected Global Mortality from Smoking 2000-2050 Cumulative Deaths (millions) Year Henningfield and Slade, FDLI, 1998 10 5

12/7/19 Hajek et al, NEJM, 2019 11 CO-verified smoking abstinence at one 18.0 year 20 % Pragmatic trial, UK NHS 15 9.9% - 866 participants 10 - ECig Starter kit vs. Choice of NRT - Behavioral Support for 4 weeks - 80% ECig use in Quitters at 1 year 5 0 E-Cigarettes NRT Hajek et al, NEJM, 2019 12 6

12/7/19 Despite extraordinary progress in tobacco control and prevention, tobacco use remains the leading cause of preventable disease and death in the United States. Combustible cigarettes cause the overwhelming majority of tobacco-related disease and are responsible for more than 480,000 U.S. deaths each year. Indeed, when used as intended, combustible cigarettes kill half of all long-term users. 1 With the tools provided to the Food and Drug Administration (FDA) under the Family Smoking Prevention and Tobacco Control Act of 2009, the agency has taken consequential steps to prevent sales of tobacco products to children, expand the science base for understanding traditional and newer tobacco products, and conduct public education campaigns. But the agency needs to do more to protect Americans; Gottlieb and Zeller, NEJM, 2016 13 Continuum of Risk Addictiveness/Appeal Toxicity 14 7

12/7/19 As for smoking, teenagers now won’t go near a cigarette, but they do vape. 15 National Youth Tobacco Survey Past 30-Day Product Use by High School Students (9th - 12th Grade ) 30 25 20 Prevalence (%) 15 10 5 0 2011 2012 2013 2014 2015 2016 2017 2018 2019 Cigarettes E-Cigarettes 16 8

12/7/19 What is an Electronic Cigarette? 17 What is an electronic cigarette? Heats a nicotine solution to create a vapor for inhalation • Clearomizer Battery 18 9

12/7/19 Schematic drawing of ENDS operation mouth end aerosol liquid coil wick air battery end 19 C’est une E-cigarette 20 10

12/7/19 iQOS 21 Main components of EC aerosol • Nicotine Propylene glycol (PG) • • Vegetable glycerine (VG) Flavorants • Particles • • Oxidants Various thermal degradation products (carbonyls) • • Metals (nickel, chromium, lead) 22 11

12/7/19 E-cigarette Voltage and Aldehyde Emissions (Sleiman et al. Envir Sci Tech 2016) 23 Pathophysiology of Smoking-induced Cardiovacular Disease 24 12

12/7/19 Tobacco Smoke Chemicals That May Contribute to Cardiovascular Disease • Oxidizing chemicals • Carbon monoxide • Particulates • Nicotine • Polycyclic aromatic hydrocarbons • Acrolein and other volatile organic chemicals • Cadmium & other metals 25 Mechanisms of Smoking-Induced Cardiovascular Disease • Hemodynamic* • Endothelial Dysfunction* • Hypercoagulable State • Inflammation* • Insulin Resistance* • Hyperlipidemia* • Arrhythmogenesis* * Nicotine may contribute 26 13

12/7/19 Acute myocardial infarction in smokers: a major role of thrombotic events The smoker’s paradox 27 28 14

12/7/19 29 Mechanisms of Smoking Induced Acute CV Events Oxidant chemicals Nicotine Particulates Carbon Other combustion monoxide products Sympathetic nervous system Inflammation Reduced activation oxygen availability Platelet Increased heart rate Endothelial activation/ Coronary Increased blood dysfunction pressure thrombosis Vasoconstrictio Increased myocardial n contractility Increased Reduced myocardial Myocardial blood, oxygen, and demand for oxygen nutrient supply and nutrients Coronary occlusion Myocardial i schemia Myocardial infarction Sudden death 30 15

12/7/19 Cardiovascular Safety of Electronic Cigarettes 31 Types of evidence • Nature and toxicity of constituents (emissions) • Levels of exposure • Mechanisms and toxicology in experimental models • Human experimental studies • Human epidemiology • Human switching studies 32 16

12/7/19 Caveats in interpreting studies of EC cardiovascular toxicity ECs are highly variable in emissions, including nicotine and • thermal degradation products. Some products probably more harmful than others • Preclinical EC studies do not accurately replicate human dosing or duration Acute effects of EC on biomarkers of CVD risk might not be • useful predictors of future events • Epidemiologic studies of CV events difficult to interpret because most EC users current or former smokers, most EC users are young so there are small numbers of events, unclear timing between EC use and CV events, high prevalence of dual use, diagnosis of MI by self-report and other confounders. 33 Constituents of Tobacco Smoke and EC aerosol that could contribute to CVD Oxidizing chemicals # • Carbon monoxide * • Acrolein and other volatile organic compounds # • Particulates • Heavy metals # • Nicotine • * Not present in EC aerosol # Present at much lower levels - levels depend on coil heating temperature 34 17

12/7/19 Reduced toxicant exposure after switching from tobacco to electronic cigarettes Acrolein Carbon Monoxide 40 2000 1500 3 HPMA (µg/g) ppm (exhaled) 20 1000 500 0 0 Baseline Week 1 Week 2 Baseline Week 1 Week 2 Benzene Acrylonitrile 600 2000 CNEMA (µg/g) 1500 SPMA (ng/g) 400 1000 200 500 0 0 Baseline Week 1 Week 2 Baseline Week 1 Week 2 Goniewicz et al. NTR 2016 35 Cardiovascular Toxicity of Cigarette Smoking and E-cigarettes: What Role Nicotine? 36 18

12/7/19 E-Liquid nicotine concentrations do not predict daily nicotine exposure Nicotine Blood/saliva Concentration Cotinine 4.1 mg/ml 430 ng/ml 22.5 mg/ml 316 ng/ml 172 ng/ml 59 mg/ml (50 – 313) 37 Nicotine and JUUL 38 19

12/7/19 JUUL liquid • Nicotine 3.0 and 5.0% by weight (latter 59 mg/ml) • Nicotine as benzoate salt: benzoic acid 45 mg/ml; molar ratio 0.97 to 1 • pH 5.8 – easier to inhale! • Flavors: tobacco, menthol 39 Nicotine Pharmacologic Mechanisms 40 20

12/7/19 Nicotine Mimics the Neurotransmitter Acetylcholine: Both Bind to “Nicotinic Cholinergic Receptors” 41 Pharmacologic Effects of Nicotine • Facilitates neurotransmitter release (e.g. dopamine) • Sympathetic neural stimulation • Immune suppression • Oxidant stress • Endothelial dysfunction • Inhibition of apoptosis • Promotes cell growth, including angiogenesis 42 21

12/7/19 CV Actions of Nicotine and Probable Contribution to Smoking-induced CVD Action Probable Contribution • Hemodynamic • Probable • Endothelial Dysfunction • Possible • Thrombogenesis • Unlikely • Inflammation • Unlikely • Arrhythmogenesis • Probable • Lipid Abnormalities • Possible • Insulin Resistance/Diabetes • Possible • Myocardial Effects • Possible 43 Hemodynamic Effects of Nicotine Increased heart rate and BP • Increased myocardial • contractility and myocardial work Coronary vasoconstriction & • Reduced coronary flow reserve Cutaneous vasoconstriction • Skeletal muscle vasodilation • 44 22