2015 Prof. Riccardo Polosa

Electronic cigarette use and harm reversal: emerging evidence in health and disease Prof. Riccardo Polosa Institute of Internal Medicine University of Catania ITALY

Exhaled CO in ECIG users R. Polosa et al. BMC Public Health 2011 7 ppm BoE

ECs have a more favorable toxicity profile than tobacco cigarettes Carcinogen metabolites levels in the urine of EC users and cigarette smokers (adjusted for age and sex) pmol/mL pmol/mL ND BoE Hect SS, et al. Nicotine Tob Res 2015

Change in 3-HPMA (ng/mg creatinine) at baseline and after 4 wks of EC use BoE McRobbie et al. Cancer Prev Res; 8(9) September 2015

Nicotine containing products: risk estimates E-cig 4 DJ Nutt, LD Phillips, D Balfour, HV Curran, M Dockrell, J Foulds, K Fagerstrom, K Letlape, A Milton, R Polosa, J Ramsey, D Sweanor. Estimating the harms of nicotine-containing products using the MCDA approach. Eur J Addiction 2014



ECs: from risk reduction to harm reversal 1. Impossibility to provide long term evidence for THR for many years 2. Evidence for risk reduction can be derived from snus data 3. Direct evidence for harm reversal in health and disease can be shown (focus on biomarkers used as proxy for risk prediction in respiratory, cardiovascular and metabolic disease)

XXI Century Emerging THR approaches NCP that are enjoyable

ECs: from risk reduction to harm reversal • Direct evidence for harm reversal in health (i.e. early changes are detectable in ‘healthy’ smokers switching to vaping) • Direct evidence for harm reversal in disease (i.e. changes are detectable in EC users with preexisting disease)

Randomised Controlled Trials • ‘Categoria’ 24mg nicotine EC vs. 18mg nicotine EC vs. no nicotine EC • 300 smokers (unwilling to quit) • 1 year abstinence rates: 13%, 9% and 4% • good tolerability (Caponnetto et al. Plos One 2013) • ‘Elusion’ 16mg nicotine EC vs. nicotine patch vs. no nicotine EC • 657 smokers (motivated to quit) • 6 month abstinence rates: 7.3%, 5.8% and 4.1% • good tolerability (Bullen et al. Lancet 2013)

Exploring ECs harm reversal potential (e.g. reduction in biomarkers used as proxy for risk prediction in CVD) STUDY ASSESSMENTS Procedure BL Wk2 Wk4 Wk6 Wk8 Wk10 Wk12 Wk24 Wk52 Visit Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Informed consent X Sociodemografic factors X S Medical history X M O Drug history X K Physical examination X X X X E Vital signs – HR & BP X X X X X X X X X C Weight - Kg X X X X H Smoking Hx X A BDI and BAI X R T FTND X eCO X X X X X X X X X GN-SBQ X NO and spirometry X X X X X X Saliva collection for cotinine X X Give Study Diary X X X X X X Collect Study Diary X X X X X X Craving/VAS X X X X X X X X X MNWS (past 2 weeks) X X X X X X X X X MNWS (past 24 hrs) X X X X X X X X X Adverse events X X X X X X X X X E-cig training X and dispense of E-cig kit Dispense study cartridges X X X X X X Cartridges use record X X X X X X Smokers’ preference X X X

Long-term effect of reduced smoking on BP in smokers switching to ECs Systolic BP changes at Week 52 from baseline Harm Reversal!

BLOOD PRESSURE CONTROL IN E-CIG USERS K. Farsalinos et al. Int. J. Environ. Res. Public Health 2014 Dual users Single users (N = 2162)

Exploring ECs harm reversal potential (e.g. reduction in biomarkers used as proxy for risk prediction in CVD and metabolic diseases) STUDY ASSESSMENTS Procedure BL Wk2 Wk4 Wk6 Wk8 Wk10 Wk12 Wk24 Wk52 Visit Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Informed consent X Sociodemografic factors X S Medical history X M O Drug history X K Physical examination X X X X E Vital signs – HR & BP X X X X X X X X X C Weight - Kg X X X X H Smoking Hx X A BDI and BAI X R T FTND X eCO X X X X X X X X X GN-SBQ X NO and spirometry X X X X X X Saliva collection for cotinine X X Give Study Diary X X X X X X Collect Study Diary X X X X X X Craving/VAS X X X X X X X X X MNWS (past 2 weeks) X X X X X X X X X MNWS (past 24 hrs) X X X X X X X X X Adverse events X X X X X X X X X E-cig training X and dispense of E-cig kit Dispense study cartridges X X X X X X Cartridges use record X X X X X X Smokers’ preference X X X

Effect of smoking abstinence/reduction on weight changes in smokers switching to ECs Post Cessation Weight Gain Russo C. et al. Sci Rep 2015 (in press)

Post Cessation Weight Gain in Quitters: Cochrane vs ECLAT Quitters’ weight Quitters’ weight in Kg 4,7 4.7 4,2 4.2 Cochrane review of 62 studies 2.9 2.9 2.9 2.9 ECLAT study Weight in kg 2.4 2.4 2.5 2.5 Wk-12 Wk-24 Wk-52 Week-12 62 previous studies Our study Week-52 Week-24

Exploring ECs harm reversal potential (e.g. reduction in biomarkers used as proxy for risk prediction in COAD) STUDY ASSESSMENTS Procedure BL Wk2 Wk4 Wk6 Wk8 Wk10 Wk12 Wk24 Wk52 Visit Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Informed consent X Sociodemografic factors X S Medical history X M O Drug history X K Physical examination X X X X E Vital signs – HR & BP X X X X X X X X X C Weight - Kg X X X X H Smoking Hx X A BDI and BAI X R T FTND X eCO X X X X X X X X X GN-SBQ X NO and spirometry X X X X X X Saliva collection for cotinine X X Give Study Diary X X X X X X Collect Study Diary X X X X X X Craving/VAS X X X X X X X X X MNWS (past 2 weeks) X X X X X X X X X MNWS (past 24 hrs) X X X X X X X X X Adverse events X X X X X X X X X E-cig training X and dispense of E-cig kit Dispense study cartridges X X X X X X Cartridges use record X X X X X X Smokers’ preference X X X

Chronic effect of abstinence/reduction on spirometry in smokers switching to ECs

Exploring ECs harm reversal potential (e.g. reduction in biomarkers used as proxy for risk prediction in COAD) STUDY ASSESSMENTS Procedure BL Wk2 Wk4 Wk6 Wk8 Wk10 Wk12 Wk24 Wk52 Visit Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Informed consent X Sociodemografic factors X S Medical history X M O Drug history X K Physical examination X X X X E Vital signs – HR & BP X X X X X X X X X C Weight - Kg X X X X H Smoking Hx X A BDI and BAI X R T FTND X eCO X X X X X X X X X GN-SBQ X NO and spirometry X X X X X X Saliva collection for cotinine X X Give Study Diary X X X X X X Collect Study Diary X X X X X X Craving/VAS X X X X X X X X X MNWS (past 2 weeks) X X X X X X X X X MNWS (past 24 hrs) X X X X X X X X X Adverse events X X X X X X X X X E-cig training X and dispense of E-cig kit Dispense study cartridges X X X X X X Cartridges use record X X X X X X Smokers’ preference X X X

Chronic effect of abstinence/reduction on eCO and FeNO in smokers switching to ECs CHANGES IN BREATHOMICS FROM A 1-YEAR RANDOMIZED SMOKING CESSATION TRIAL OF ECs Davide Campagna, Fabio Cibella, Pasquale Caponnetto, et al. eCO FeNO Between subject effects: p<0.0001 Between subject effects: p<0.0001 30 Failures 20 Failures 25 Reducers Reducers Quitters Quitters 20 15 ppm 15 ppb 10 10 5 5 0 0 BL W-12 W-24 W-52 BL W-12 W-24 W-52

ECs: from risk reduction to harm reversal • Direct evidence for harm reversal in health (i.e. early changes are detectable in ‘healthy’ smokers switching to vaping) • Direct evidence for harm reversal in disease (i.e. changes are detectable in EC users with preexisting disease)

 Increased prevalence of asthma  More incident asthma  Increased asthma morbidity and mortality  Greater asthma severity  More uncontrolled asthma  Accelerated decline in lung function  Persistent airway obstruction  Corticosteroid insensitivity

• ECs are effective and safe in RCTs of healthy smokers • No data about EC use in smokers with pre-existing disease • We investigated subjective and objective asthma outcomes as well as safety in smoking asthmatics who switched to EC

FEV1 Improvement from baseline to 24 months 3.8 Forced Expiratory Volume in 1 second (L) p=0.005 3.6 ** mean increase of 100mls Harm  Reversal! 3.4 3.2 Regular EC use 3.0 Pre- Baseline 1st F/up 2nd F/up 3rd F/up Polosa et al. Baseline Visit Visit Visit Discov Med 2015 (in press) Assessment Timepoints

FEF25-75 Improvement from baseline to 24 months 3.4 p=0.001 *** 3.2 p=0.006 ** mean increase of 360mls/sec mean increase of 250mls/sec  Harm FEF25-75 (L/sec) 3.0 Reversal! 2.8 2.6 Regular EC use 2.4 Pre- Baseline 1st F/up 2nd F/up 3rd F/up Polosa et al. Baseline Visit Visit Visit Discov Med 2015 (in press) Assessment Timepoints

Methacholine PC20 Improvement from baseline to 24 months p=0.003 3.5 ** mean increase of 1.2 DD  Harm Methacholine PC20 (mg/mL) 3.0 Reversal! 2.5 2.0 1.5 1.0 Regular EC use Pre- Baseline 1st F/up 2nd F/up 3rd F/up Polosa et al. Baseline Visit Visit Visit Discov Med 2015 (in press) Assessment Timepoints

Juniper’s ACQ Improvement from baseline to 24 months 2.4 2.2 Harm 2.0 Reversal! ACQ scores 1.8 1.6 p=0.001 *** p=0.001 mean decrease of 0.43 *** mean decrease of 0.56 1.4  1.2 Regular EC use Pre- Baseline 1st F/up 2nd F/up 3rd F/up Polosa et al. Baseline Visit Visit Visit Discov Med 2015 (in press) Assessment Timepoints

Vaping and asthma exacerbations st Parameter Baseline 1 follow-up visit 2 follow-up visit 3 follow-up visit nd nd w/o relapsers (6 months) (12 months ) (24 months) N=18 N=18 N=18 N=16 p value to p value to p value to Baseline Baseline Baseline Cigarettes/day 21.9 5.0 (±2.6) <0.001 3.9 (±1.0) <0.001 3.5 (±1.22) <0.001 (±4.5) Exacerbations 1.17 0.87 (±0.7) 0.296 0.78 (±0.7) 0.153 0.81 (±0.66) 0.190 (±0.9) Frequent exacerbators (≥ 2 exacerbations; n=6) halved their exacerbations Exacerbation rate increased at both follow-up visits from 0 at 12 months to 2 at 24 months in the two patients relapsing to tobacco smoking

RESPIRATORY SYMPTOMS IN E-CIG USERS K. Farsalinos et al. Int. J. Environ. Res. Public Health 2014 Dual users Single users (N = 1173) (N = 1062)

BLOOD PRESSURE CONTROL IN SMOKERS WITH ARTERIAL HYPERTENSION WHO SWITCH TO ELECTRONIC CIGARETTES Polosa et al. (submitted for publication) • ECs are effective and safe in RCTs of “healthy” smokers • No data about EC use in smokers with pre-existing disease • We investigated changes in blood pressure and BP control in smoking hypertensive patients who switched to EC

Changes in daily smoking from baseline EC users Controls 30 Mean Conventional Cigarettes/day 25 20 15 10 P<0.001 5 P<0.001 0 Baseline Visit 1 Visit 2 Baseline ≈ 6 months ≈ 12 months Visits

Changes in SBP from baseline EC users Controls Mean Systolic Blood Pressure (mmHg) 160 150 140 130 P<0.001 average decrease of 10 mmHg 120 Baseline Visit 1 Visit 2 Baseline ≈ 6 months ≈ 12 months Visits

Changes in DBP from baseline EC users 100 Controls Mean Diastolic Blood Pressure (mmHg) 90 80 P=0.006 average decrease of 6 mmHg 70 Baseline Visit 1 Visit 2 Baseline ≈ 6 months ≈ 12 months Visits

Proportion of BP grading throughout the study 80 Normal BP 80 70 Pre-Hypertension 70 60 Grade 1 60 50 Grade 2 50 % 40 Normal 40 [2013 ESH/ESC Guidelines] Pre-Hypertension Grade 1 Grade 2 30 30 20 20 10 10 0 0 V1 V1 V2 V2 BL BL Baseline Baseline ≈ 6 months ≈ 6 months ≈ 12 months ≈ 12 months Control Gp Control Gp E-Cig Gp E-Cig Gp E-Cig Gp Control Gp EC Group Ctrl Group EC Group Ctrl Group EC Group Ctrl Group

Proportion of good and poor BP control throughout the study 90 90 80 80 70 70 Good Control 60 60 Poor Control 50 50 % 40 Good Control criteria: Good Poor 40 systolic BP <140 mmHg and 30 diastolic BP <90 mmHg 30 (<130/80 mmHg for patients 20 with diabetes, chronic kidney 20 disease or CV disease [2013 ESH/ESC Guidelines] 10 10 0 0 V2 V2 BL V1 BL V1 Baseline Baseline ≈ 6 months ≈ 6 months ≈ 12 months ≈ 12 months Control Gp E-Cig Gp Control Gp E-Cig Gp E-Cig Gp Control Gp EC Group Ctrl Group EC Group Ctrl Group EC Group Ctrl Group

Take Home Message • Improved lung function, respiratory symptoms, subjective/objective asthma outcomes; • Improved BP and BP control in hypertensive patients; • Improvements also reported in dual users; • Exposure to e-vapour in vulnerable populations (i.e. asthma, hypertension) does not trigger acute symptoms; • A safe alternative to cigarettes. even in smokers with chronic diseases.