Electronic Nicotine Delivery Systems (ENDS):

Friends or Foes in Smoking Cessation to Reduce Risk of ASCVD?

Pamela B. Morris, MDFACC, FAHA, FASPC, FNLA

Chair, ACC Prevention of Cardiovascular Disease Leadership Council and Section

The Medical University of South CarolinaCharleston, SC

Disclosures Advisory board/Consultant: Amgen, AstraZeneca, Sanofi Regeneron

Do you remember… Mindset pre-1950’s?

How could a behavior as widespread as cigarette smoking with so little apparent acute toxicity, cause major chronic health problems?

Oh, so glamorous….

And so rugged…

50% of doctors were smoking cigarettes in 1950…

• 1964: Publication of first USPHS Surgeon General’s report on smoking more than half a century ago.

• Identified tobacco smoking as a principle cause of lung and laryngeal cancer and major contributing factor in CHD, PAD, HTN.

• Heralded one of the most successful public health campaigns in the 20th century.

https://www.cdc.gov/statesystem/cigaretteuseadult.html.https://www.cdc.gov/statesystem/cigaretteuseyouth.html.

Worldwide cigarette consumption is still increasing…

http://www.tobaccoatlas.org/topic/cigarette-use-globally/

Enter new, rapidly evolving, disruptive technology…

Introduction of the e-cig or Electronic Nicotine Delivery System (ENDS)

First patented by Mr. Hon Lik in 2003 and first commercially marketed e-cigarette introduced in Chinese market in 2004

Available in the U.S. in 2007 Initially via internet Then mall kiosks Then tobacco retail outlets Print advertisements

Awareness of e-cigarettes

Doubled among adults and adolescents from 2008 to 2012

In US awareness is higher among men but trying e-cigs is more prevalent among women.

Highest e-cig use is among current smokers, followed by formers smokers, with little use among non-smokers.

U.S. Sales

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600

800

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Source: UBS, Wells Fargo (Feb 2015)

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% U

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Overall Prevalence

Source: McMillen et al. (2015). NTR. 17:1195.

https://www.cdc.gov/nchs/data/databriefs/db217.pdf

https://www.cdc.gov/nchs/data/databriefs/db217.pdf

Prevalence of Electronic Cigarette Use: Smoking Status

Source: McMillen et al. (2015). Nicotine & Tobacco Research, 17 (10), 1195-1202

EVER Use Past 30 Day Use

0102030405060708090

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2010 2011 2012 2013

% U

se

Never SmokerFormer SmokerNonDaily SmokerDaily Smoker

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2010 2011 2012 2013

% U

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In 2015 (CDC)

• 58.5% of users also use tobacco cigarettes (dual users)

• 29.8% former smokers

• 11.4% never smoked

https://www.cdc.gov/nchs/data/databriefs/db217.pdf

E-cigarettes

Rapid market penetration

“Smoke-like” inhaled aerosol imitates tobacco smoke visually

Replicates sensation in mouth and throat

Same hand-to-mouth behaviors

E-cigarettes and marketing

Tobacco advertising banned on TV/radio since 1970s

Celebrities used to market e-cigs since 2009

Claims Healthier than cigarettes Cheaper than cigarettes Cleaner than cigarettes Smoke anywhere Circumvent smoke-free policies No secondhand smoke Modern Cessation claims Harmless water vapor

2014 Sports Illustrated swimsuit issue (February 2014)

Magazine Advertising

blu e-cigarettes, Car and Driver (April 2015), Men's Journal (April & May 2015, Playboy (April & June 2015), Maxim (June/July 2015), http://trinketsandtrash.org/detail.php?artifactid=9859&page=1; http://trinketsandtrash.org/detail.php?artifactid=9882&page=1

blu e-cigarettes, Car and Driver, Playboy (May 2015); Men's Journal and Popular Mechanics (June 2015), http://trinketsandtrash.org/detail.php?artifactid=9993&page=1; Also appeared in Cosmopolitan (April 2015)

Magazine Advertising with actors

2. Magazine Advertisements Like old cigarette ads, e-cigarette magazine ads feature rugged men ...

... and glamorous women…and glamorous women

Billboard on I-95 South in Miami, FL, December 2013

Billboard Advertisements

Sports/event sponsorships

Bank of America 500, Charlotte, NC, October 2014

Mistic Facebook Post, May 10, 2014 https://www.facebook.com/MisticElectronicCigarettes/photos/a.511099415652844.1073741825.350217771741010/603283403101111/?type=3&theater

Point of Sale / Sales Near Candy

E-cigarette counter display near candy. Taken January 20, 2014 in Yanceyville, NC E-cigarette counter display near candy. Taken

August 2, 2013 in Denver, CO

ENDS: an infinite number of new questions

What are ENDS?

What harms do ENDS pose to users and bystanders?

Can ENDS help tobacco smokers quit?

Are ENDS a gateway to tobacco smoking, addicting new users, particularly the young, to nicotine?

Should ENDS be tolerated or even favored over tobacco, as a less harmful substitute for those unable to stop smoking?

US Patent Application

“An electronic atomization cigarette that functions as substitute for quitting smoking and cigarette substitute” (patent No. 8,490,628 B2)

Grana, et al. Circulation. 2014;129:1972-86

Basic Anatomy of ENDS

Image Sources: Legacy Factsheet

Indicator Tip

Battery

Vaporizer

Mouthpiece

Devices Manufactured mainly in China Wide variability in product engineering Varying solutions used to generate nicotine aerosol

Volume of solution Carrier compounds (usually propylene glycol with or without

glycerin/glycerol) Additives Flavors

Varying battery voltage Users can modify products (eg, to deliver marijuana) Variability in heating, conversion of nicotine solution to

aerosol, levels of nicotine and other chemicals delivered to use and environment

Four generations First generation:

cigalikes Heavier than tobacco

cigarettes LED light simulates

when inhaling Some disposable,

some rechargeable Cheap, easy to use Battery and cartridge

with atomizer

Four generations

Second generation:Mid-size electronic cigarettes

Larger Look like pens or laser pointers Pre-filled or refillable cartridge Push “fire” button when you

inhale (regulate length/frequency of puffs)

Improved battery capacity (1-2 days)

Four generations Third generation:Advanced personal vaping device

Favorite of advanced users Large, refillable cartridge Can easily modify voltage,

wattage output Design more effective

delivery of desired vapor Manual “fire” button Much larger

Four generations

Fourth generation:Innovative regulated mods Automatic temperature

control Adjustable and dual

air-flow

ENDS liquids

Basic Ingredients of e-liquid:• Water• Humectant(s)

• Propylene Glycol (base or carrier for nicotine and flavorings)• Vegetable Glycerin (base or carrier for nicotine and

flavorings)• Nicotine

• Various concentrations• 0-36 mg/mL in cartridges/cartomizers• Up to 100 mg/mL in refill fluids

• Flavoring agents (food flavorings to create specific taste)

http://www.veppocig.com/how-to-choose-nicotine-strength/

ENDS liquids: propylene glycol

Wieslander et al. 2001, Occup Environ MedVardavas et al. 2012, Chest

Choi et al. 2010, PlosOne

Inhalation exposure Short-term: eye, throat, airway irritation Long-term: can result in asthma in children

Used in theatrical fog/smoke machines Respiratory, throat, nose irritation

Supports possible respiratory irritation in some individuals

ENDS liquid: glycerin Humectant used instead of or in combination

with propylene glycol for aerosol production Most common is vegetable glycerin

Material Safety Data Sheet Slightly hazardous in case of skin or eye contact,

ingestion, and inhalation Prolonged exposure may cause organ damage

http://www.sciencelab.com/msds.php?msdsId=9927350

ENDS liquid:

http://www.sciencelab.com/msds.php?msdsId=9926222

• Large amounts of nicotine are lethal.• Is also insecticide and toxicant• 60 mg adult• 6 mg children

• Some ENDS manufacturers include caution labels for nicotine use.

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Nicotine Delivery Potential to deliver nicotine directly to

pulmonary system for rapid absorption (unlike NRT)

Nicotine delivery varies By product Less nicotine is delivered in original ENDS than

tobacco cigarettes, but newer options improve delivery Experience with the product Differential nicotine delivery novice vs. experienced users

Nicotine content of cartridge e-liquid had poor concordance of labeled and actual nicotine content

Secondhand exposure

ENDS do not burn or smolder Do not emit side-stream smoke

Bystanders are exposed to aerosol exhaled by user Low levels of nicotine, toxins, metals Much lower levels compared with

conventional cigarette emissions Particulate matter also exhaled Not “harmless water vapor”

ENDS: aerosol

ENDS vapor contains known carcinogens and toxic chemicals (formaldehyde and acetaldehyde), Also potentially toxic metal nanoparticles from the vaporizing

mechanism

Minor adverse events Headache, chest pain, nausea, cough, mouth irritation

Major adverse events Singular case reports of hospitalizations for pneumonia,

congestive heart failure, seizure, rapid heart rate, burns

Bottom line Long term risks largely unknown--more research needed

~trace levels of∧

Toxic compound Conventional cigarette [µg]

Electronic cigarette[µg per 15 puffs]

Conventional vs. electronic cigarette

Formaldehyde 1.6-52 0.20-5.61 9

Acetaldehyde 52-140 0.11-1.36 130

Acrolein 4.6-14 0.07-4.19 4

Toluene 6.4-9.0 0.02-0.63 23

NNN 0.012-0.37 0.00008-0.00043 145

NNK 0.009-0.08 0.00011-0.00283 30

Cd 0.03-0.35 0.001-0.022 16

Ni 0.003-0.60 0.011-0.029 15

Toxicants in vapor

Goniewicz et al., 2013, Tob Control

Health risks of tobacco products

Highly addictive

Cancers

Cardiovascular disease

Respiratory disease

Harm to others

Addictiveness dependent on delivery

Theoretical, no evidence

Risk low in those without CVD, but some risk in those with CVD

No

No

Adverse reproductive effects Some risk, but likely less than smoking

CIGARETTE SMOKE • >7000 different chemicals• >69 cause cancer• Many others are toxic

NICOTINE• 1 chemical• Neuroadaptive effects• Very high levels (>500 mg)

can be fatal

Calls to poison control centers

http://www.tobaccoatlas.org/topic/cigarette-use-globally/

Summary: not an obvious answer…….

Effects on youth…

Primary Concerns:1. Stem cell pulmonary cytotoxicity2. Nicotine initiation3. Gateway to other tobacco use4. Renormalizing smoking behavior

E-Cig Use among Adolescents: Concerning Trend?

In 2014, more high school seniors used e-cigarettes (17.1%) than traditional cigarettes (13.6%)

Among those who had used e-cigarettes, 20.3%reported never smoking conventional cigarettes

Dual use with conventional cigarettes is most common: 61% in MS, 80% in HS students

Johnson et al., 2015

0

5

10

15

20

25

30

35

6 Month Follow-up 12 Month Follow-up 6 Month Follow-up 12 Month Follow-up

%

% Ecig Never Use

% Ecig Ever Use

Risk difference = 22.7 (95% CI: 16.4 - 28.9)

Risk difference = 15.9 (95% CI: 10.0 - 21.8)

Risk difference = 6.7 (95% CI: 2.7 -

10.7) Risk difference = 4.7 (95% CI: 1.0 -

8.4)

Does E-Cigarette Use Lead to Other Tobacco Use?Prevalence of Combustible Tobacco Product Use During Past 6 Months Among Baseline E-cig (Non)Users

Overall Follow-Up AOR = 2.73 (95% CI: 2.00 - 3.73)

Overall Follow-Up AOR = 1.75(95% CI: 1.10 - 2.77)

Leventhal et al. (2015). Association of Electronic Cigarette Use With Initiation of Combustible Tobacco Product Smoking in Early Adolescence. JAMA, 314(7), 700-707.

New tools in the tobacco control intervention toolbox:

What is the role of e-cigs?

Two Different Approaches

Less Harm Nicotine is the highly

addictive component of tobacco smoke

Not the primary ingredient in tobacco that causes cancer, respiratory, and cardiovascular diseases

End the Addiction Risks of maintaining nicotine

addiction

Uncertain long-term personal and public health consequences

Unproven efficacy as cessation aid

versus

Show me the evidence…

ENDS in smoking cessation: clinical trials

Four clinical trials 2 very small sample sizes 3 did not have control group One compared e-cig to SOC with 21 mg

nicotine patch None with behavioral support Early generation devices that are no longer

widely used

Pragmatic RCT in Auckland, NZ (2011-2013)

657 smokers who wanted to quit

Randomized 4:4:1 ratio 16 mg nicotine e-cigs 21 mg nicotine patch daily Placebo e-cigs Low intensity behavioral

support with voluntary telephone counseling

Outcome: biochemically verified abstinence at 6 months

Bullen, et al. Lancet. 2013;382:1629-37

Results Very low rates of abstinence overall Insufficient power to conclude superiority of

nicotine e-cigarettes to patches or to placebo e-cigarettes.

No significant differences in adverse events

ECLAT (Italy)

Prospective 12-month RCT of 300 smokers not intending to quit

2 nicotine strengths of a popular e-cigarette model (‘Categoria’; Arbi Group Srl, Italy) compared to its non-nicotine choice. Group A (n = 100): 7.2 mg nicotine cartridges for 12 weeks; Group B (n = 100): 6-weeks 7.2 mg nicotine cartridges followed

by 6-weeks 5.4 mg nicotine cartridges Group C (n = 100): no-nicotine cartridges for 12 weeks

PLOS ONE. 2013;8:e66317

Cochrane Review 2014McRobbie et al

• Two trials suggest that ECs may help smokersto stop smoking long-term

• Small number of trials, low event rates, andwide confidence intervals

• Lack of biochemical assessment of actualreduction in smoke intake

• No evidence emerged that short-term ECuse is associated with health risk.

• Lack of difference between the effect ofECs compared with nicotine patches

USPSTF Recommendation Statement: 10/2015

Identified only 2 RCTs that evaluated the effect of e-cigs on smoking abstinence and found mixed results.

Neither reported adverse events.

How they may affect fetus is unknown.

Annals of Internal Medicine. 2015;163:622-34

USPSTF Recommendation Statement: 10/2015

“The USPSTF concludes that the current evidence is insufficient to recommend ENDS for tobacco cessation in adults, including pregnant women.”

“The USPSTF recommends that clinicians direct patients who smoke tobacco to other cessation interventions with established effectiveness and safety.”

Annals of Internal Medicine. 2015;163:622-34

2016 Cochrane Review Update Combined results from two studies, involving

662 people, showed that using an EC containing nicotine increased the chances of stopping smoking in the long term compared to using an EC without nicotine.

We could not determine if EC was better than a nicotine patch in helping people stop smoking, because the number of participants in the study was low. More studies are needed to evaluate this effect.

None of the studies found that smokers who used EC short- to mid-term (for two years or less) had an increased health risk compared to smokers who did not use ECs.

E-Cigs in real world: Systematic review and meta-analysis (Kalkhoran, Glantz)

38 studies included in systematic review 20 with control groups included in meta-

analysis Odds of quitting conventional cigarettes were

28% LOWER in those who used e-cigs compared with those who did not OR 0.72 (95% CI 0.57 to 0.91)

No difference in studies of smokers interested in smoking cessation

Lancet Respir Med. 2016;4:116-28

E-Cigs in real world: Systematic review and meta-analysis

Lancet Respir Med. 2016;4:116-28

As currently being used, e-cigarettes are associated

with significantly less quitting among smokers.

Review new tobacco products not yet on the market Registering manufacturing establishments and providing product

listings to the FDA Report ingredients, and harmful and potentially harmful constituents Requires premarket review and authorization of new tobacco products

by the FDA Places health warnings on product packages and advertisements Requires age verification by photo ID for purchase; No sales under

age 18 Disallows vending machine sales Disallows free samples

This final rule went into effect on August 8, 2016.

FDA and ENDS regulation

Public Health:Hope or Caution?

Effects on Individual Pros

Decrease toxicant exposure

Promote quitting? Cons

Dual Use Maintenance of long term

nicotine dependence

Effects on Population Pros

Lower smoking prevalence

Reduced healthcare burden of disease

Cons Youth initiation Undermine smoking

restrictions Renormalizing smoking

What to tell patients… Support a smoker’s quit attempt Ask, advise, assess, assist, arrange If appropriate, consider conventional smoking

cessation medications. Safest, most proven are

Varenicline Bupropion NRT

Referral to QUIT line Counseling support program

What to tell patients… If patient fails initial treatment, intolerant or refuses

conventional smoking cessation medication, and wishes to try e-cigs to aid quitting, it is reasonable to support the attempt.

Explain Likely much less toxic Unregulated Contain toxic chemicals Not proven Quit conventional cigarettes as soon as possible Do not use indoors or around children because others

exposed to nicotine and other toxins Urge to set quite date for e-cigs, do not use indefinitely