Supplementary material 6 to: Electronic cigarettes for smoking cessation

Lindson N, Livingstone-Banks J, Butler AR, McRobbie H, Bullen CR, Hajek P, Wu AD, Begh R, Theodoulou A, Ma C, Notley C, Rigotti NA, Turner T, Fanshawe T, Hartmann-Boyce J
https://doi.org/10.1002/14651858.CD010216.pub11

The material in this section has been supplied by the author(s) for publication under a Licence for Publication and the author(s) are solely responsible for the material. Cochrane has reviewed this material, but Cochrane has not copyedited, formatted or proofread. Cochrane accordingly gives no representations or warranties of any kind in relation to, and accepts no liability for any reliance on or use of, such material.

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Analyses

Analysis group 1: Nicotine EC versus NRT

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1.1 Smoking cessation - subgrouped by pregnancy status114114Risk Ratio (IV, Random, 95% CI)1.61 [1.23, 2.12]
1.1.1 Not selected on pregnancy103795Risk Ratio (IV, Random, 95% CI)1.61 [1.20, 2.16]
1.1.2 Pregnant population1319Risk Ratio (IV, Random, 95% CI)1.78 [0.45, 6.97]
1.2 Smoking cessation - subgrouped by combined vs. single NRT114114Risk Ratio (IV, Random, 95% CI)1.61 [1.23, 2.12]
1.2.1 Combination NRT41503Risk Ratio (IV, Random, 95% CI)1.58 [0.56, 4.44]
1.2.2 Single-form NRT52019Risk Ratio (IV, Random, 95% CI)2.01 [1.21, 3.34]
1.2.3 Unclear2592Risk Ratio (IV, Random, 95% CI)1.34 [0.99, 1.81]
1.3 Adverse events83107Risk Ratio (M-H, Random, 95% CI)0.95 [0.72, 1.24]
1.4 Serious adverse events104045Risk Difference (M-H, Random, 95% CI)0.01 [−0.01, 0.02]
1.5 Carbon monoxide (ppm)5385Mean Difference (IV, Random, 95% CI)−1.98 [−3.78, −0.18]
1.5.1 Absolute values at follow-up1110Mean Difference (IV, Random, 95% CI)−1.87 [−5.15, 1.41]
1.5.2 Change from baseline4275Mean Difference (IV, Random, 95% CI)−2.93 [−6.20, 0.34]
1.6 Heart rate (bpm)2166Mean Difference (IV, Random, 95% CI)0.53 [−1.76, 2.83]
1.6.1 Absolute values at follow-up1111Mean Difference (IV, Random, 95% CI)−0.74 [−5.17, 3.69]
1.6.2 Change from baseline155Mean Difference (IV, Random, 95% CI)1.00 [−1.69, 3.69]
1.7 Systolic blood pressure2166Mean Difference (IV, Random, 95% CI)−1.62 [−3.59, 0.36]
1.7.1 Absolute values at follow-up1111Mean Difference (IV, Random, 95% CI)1.00 [−4.54, 6.54]
1.7.2 Change from baseline155Mean Difference (IV, Random, 95% CI)−2.00 [−4.11, 0.11]
1.8 Blood oxygen saturation2165Mean Difference (IV, Random, 95% CI)−0.14 [−0.59, 0.30]
1.8.1 Absolute values at follow-up1110Mean Difference (IV, Random, 95% CI)−0.20 [−0.72, 0.32]
1.8.2 Change from baseline155Mean Difference (IV, Random, 95% CI)0.00 [−0.83, 0.83]
1.9 NNAL (pmol/mg creatinine)1Mean Difference (IV, Random, 95% CI)Totals not selected
1.9.1 Absolute values at follow-up1Mean Difference (IV, Random, 95% CI)Totals not selected
1.10 3-HPMA (pmol/mg creatinine)1Mean Difference (IV, Random, 95% CI)Totals not selected
1.10.1 Absolute values at follow-up1Mean Difference (IV, Random, 95% CI)Totals not selected
1.11 2-HPMA (pmol/mg creatinine)1Mean Difference (IV, Random, 95% CI)Totals not selected
1.11.1 Absolute values at follow-up1Mean Difference (IV, Random, 95% CI)Totals not selected
1.12 HMPMA (pmol/mg creatinine)1Mean Difference (IV, Random, 95% CI)Totals not selected
1.12.1 Absolute values at follow-up1Mean Difference (IV, Random, 95% CI)Totals not selected
1.13 PheT (pmol/mg creatinine)1Mean Difference (IV, Random, 95% CI)Totals not selected
1.13.1 Absolute values at follow-up1Mean Difference (IV, Random, 95% CI)Totals not selected
1.14 CEMA (pmol/mg creatinine)1Mean Difference (IV, Random, 95% CI)Totals not selected
1.14.1 Absolute values at follow-up1Mean Difference (IV, Random, 95% CI)Totals not selected
1.15 AAMA (pmol/mg creatinine)1Mean Difference (IV, Random, 95% CI)Totals not selected
1.15.1 Absolute values at follow-up1Mean Difference (IV, Random, 95% CI)Totals not selected
1.16 FEV12Std. Mean Difference (IV, Random, 95% CI)Totals not selected
1.16.1 Change from baseline2Std. Mean Difference (IV, Random, 95% CI)Totals not selected
1.17 FEV1/FVC (%)2Mean Difference (IV, Random, 95% CI)Subtotals only
1.17.1 Change from baseline281Mean Difference (IV, Random, 95% CI)10.15 [−24.36, 44.67]
1.18 PEF (L/min)1Mean Difference (IV, Random, 95% CI)Totals not selected
1.18.1 Change from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected
1.19 Product use at 6+ months6Risk Ratio (M-H, Random, 95% CI)Totals not selected
1.20 EC use with no combustible tobacco use52776Risk Ratio (M-H, Random, 95% CI)4.40 [1.27, 15.28]
1.21 No EC or combustible tobacco use52776Risk Ratio (M-H, Random, 95% CI)0.49 [0.26, 0.91]
1.22 EC + combustible tobacco use4Risk Ratio (M-H, Random, 95% CI)Totals not selected
1.23 Combustible tobacco use with no EC use42543Risk Ratio (M-H, Random, 95% CI)0.76 [0.58, 1.01]

Analysis group 2: Nicotine EC versus varenicline

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
2.1 Smoking cessation1Risk Ratio (M-H, Random, 95% CI)Totals not selected
2.2 Serious adverse events1Risk Difference (M-H, Random, 95% CI)Totals not selected

Analysis group 3: Nicotine EC versus non-nicotine EC + varenicline

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
3.1 Smoking cessation1Risk Ratio (M-H, Random, 95% CI)Totals not selected
3.2 Serious adverse events1Risk Difference (M-H, Random, 95% CI)Totals not selected

Analysis group 4: Nicotine EC versus cytisine

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
4.1 Smoking cessation1Risk Ratio (M-H, Random, 95% CI)Totals not selected
4.2 Adverse events1Risk Ratio (M-H, Random, 95% CI)Totals not selected
4.3 Serious adverse events1Risk Difference (M-H, Random, 95% CI)Totals not selected

Analysis group 5: Nicotine EC versus NRT + bupropion

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
5.1 Smoking cessation1Risk Ratio (M-H, Random, 95% CI)Totals not selected

Analysis group 6: Nicotine EC versus heated tobacco

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
6.1 Adverse events1Risk Ratio (M-H, Random, 95% CI)Totals not selected
6.2 SAEs1Risk Difference (M-H, Random, 95% CI)Totals not selected
6.3 Carbon monoxide (ppm)2267Mean Difference (IV, Random, 95% CI)1.00 [−1.04, 3.03]
6.3.1 Absolute values at 12 weeks1217Mean Difference (IV, Random, 95% CI)1.90 [−0.71, 4.51]
6.3.2 Change at 1 month150Mean Difference (IV, Random, 95% CI)−0.20 [−3.23, 2.83]
6.4 VO2 Max at 12 weeks1Mean Difference (IV, Random, 95% CI)Totals not selected

Analysis group 7: Nicotine EC versus oral nicotine pouches

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
7.1 Serious adverse events1Risk Difference (M-H, Random, 95% CI)Totals not selected
7.2 Carbon monoxide (ppm)1Mean Difference (IV, Random, 95% CI)Totals not selected
7.2.1 Change from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected

Analysis group 8: Nicotine EC versus non-nicotine EC

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
8.1 Smoking cessation71918Risk Ratio (M-H, Random, 95% CI)1.34 [1.05, 1.69]
8.2 Adverse events6909Risk Ratio (M-H, Random, 95% CI)1.01 [0.95, 1.08]
8.3 Serious adverse events111786Risk Difference (M-H, Random, 95% CI)0.00 [−0.01, 0.01]
8.4 Carbon monoxide (ppm)7Mean Difference (IV, Random, 95% CI)Totals not selected
8.4.1 Change from baseline3Mean Difference (IV, Random, 95% CI)Totals not selected
8.4.2 Absolute values at follow-up4Mean Difference (IV, Random, 95% CI)Totals not selected
8.5 Heart rate2Mean Difference (IV, Random, 95% CI)Subtotals only
8.5.1 Absolute values at follow-up2401Mean Difference (IV, Random, 95% CI)−1.23 [−3.55, 1.08]
8.6 Systolic blood pressure3Mean Difference (IV, Random, 95% CI)Subtotals only
8.6.1 Absolute values at follow-up3470Mean Difference (IV, Random, 95% CI)2.28 [−0.41, 4.97]
8.7 NNAL (pmol/mg creatinine)3Mean Difference (IV, Random, 95% CI)Totals not selected
8.7.1 Change from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected
8.7.2 Absolute values at follow-up2Mean Difference (IV, Random, 95% CI)Totals not selected
8.8 FEV1 (l)3Std. Mean Difference (IV, Random, 95% CI)Subtotals only
8.8.1 Absolute values at follow-up3417Std. Mean Difference (IV, Random, 95% CI)−0.01 [−0.68, 0.66]
8.9 FEV1/FVC2Mean Difference (IV, Random, 95% CI)Subtotals only
8.9.1 Absolute values at follow-up2348Mean Difference (IV, Random, 95% CI)−0.14 [−1.76, 1.47]
8.10 FVC (l)1Std. Mean Difference (IV, Random, 95% CI)Totals not selected
8.10.1 Absolute values at follow-up1Std. Mean Difference (IV, Random, 95% CI)Totals not selected
8.11 PEF (l/s)1Std. Mean Difference (IV, Random, 95% CI)Totals not selected
8.11.1 Absolute values at follow-up1Std. Mean Difference (IV, Random, 95% CI)Totals not selected
8.12 FEF 25-75 (l/s)1Std. Mean Difference (IV, Random, 95% CI)Totals not selected
8.12.1 Absolute values at follow-up1Std. Mean Difference (IV, Random, 95% CI)Totals not selected
8.13 FeNO (ppb)1Mean Difference (IV, Random, 95% CI)Totals not selected
8.13.1 Change from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected
8.14 Product use at 6+ months3874Risk Ratio (M-H, Random, 95% CI)1.14 [0.77, 1.69]
8.15 EC use with no combustible tobacco use2458Risk Ratio (M-H, Random, 95% CI)5.38 [0.43, 66.54]
8.16 No EC or combustible tobacco use2458Risk Ratio (M-H, Random, 95% CI)1.59 [0.46, 5.51]
8.17 EC + combustible tobacco use2458Risk Ratio (M-H, Random, 95% CI)0.88 [0.71, 1.09]
8.18 Combustible tobacco use with no EC use1Risk Ratio (M-H, Random, 95% CI)Totals not selected
8.19 Adverse events (with Robinson)71247Risk Ratio (IV, Random, 95% CI)1.01 [0.95, 1.08]
8.20 Serious adverse events (with Robinson)122124Risk Difference (IV, Random, 95% CI)0.00 [−0.01, 0.01]

Analysis group 9: Nicotine EC versus behavioural support only/no support

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
9.1 Smoking cessation117214Risk Ratio (M-H, Random, 95% CI)1.75 [1.39, 2.20]
9.2 Adverse events112801Risk Ratio (M-H, Random, 95% CI)1.22 [1.00, 1.49]
9.3 Serious adverse events185032Risk Difference (M-H, Random, 95% CI)0.00 [−0.00, 0.01]
9.4 Carbon monoxide (ppm)14Mean Difference (IV, Random, 95% CI)Totals not selected
9.4.1 Change from baseline5Mean Difference (IV, Random, 95% CI)Totals not selected
9.4.2 Absolute values at follow-up9Mean Difference (IV, Random, 95% CI)Totals not selected
9.5 Heart rate (bpm)2Mean Difference (IV, Random, 95% CI)Subtotals only
9.5.1 Absolute values at follow-up2111Mean Difference (IV, Random, 95% CI)1.72 [−3.34, 6.78]
9.6 Systolic blood pressure4319Mean Difference (IV, Random, 95% CI)−2.23 [−5.38, 0.92]
9.6.1 Change from baseline1168Mean Difference (IV, Random, 95% CI)−2.68 [−4.38, −0.98]
9.6.2 Absolute values at follow-up3151Mean Difference (IV, Random, 95% CI)0.24 [−10.05, 10.52]
9.7 Blood oxygen saturation1Mean Difference (IV, Random, 95% CI)Totals not selected
9.7.1 Absolute values at follow-up1Mean Difference (IV, Random, 95% CI)Totals not selected
9.8 NNAL (SMD)6Std. Mean Difference (IV, Random, 95% CI)Totals not selected
9.8.1 Absolute values at follow-up3Std. Mean Difference (IV, Random, 95% CI)Totals not selected
9.8.2 Change from baseline3Std. Mean Difference (IV, Random, 95% CI)Totals not selected
9.9 3-HPMA (SMD)2474Std. Mean Difference (IV, Random, 95% CI)−0.46 [−0.66, −0.26]
9.9.1 Absolute values at follow-up190Std. Mean Difference (IV, Random, 95% CI)−0.30 [−0.74, 0.13]
9.9.2 Change from baseline1384Std. Mean Difference (IV, Random, 95% CI)−0.50 [−0.73, −0.27]
9.10 2-HPMA (pmol/mg creatinine)1Mean Difference (IV, Random, 95% CI)Totals not selected
9.10.1 Absolute values at follow-up1Mean Difference (IV, Random, 95% CI)Totals not selected
9.11 HMPMA (pmol/mg creatinine)1Mean Difference (IV, Random, 95% CI)Totals not selected
9.11.1 Absolute values at follow-up1Mean Difference (IV, Random, 95% CI)Totals not selected
9.12 PheT (pmol/mg creatinine)1Mean Difference (IV, Random, 95% CI)Totals not selected
9.12.1 Absolute values at follow-up1Mean Difference (IV, Random, 95% CI)Totals not selected
9.13 CEMA (pmol/mg creatinine)1Mean Difference (IV, Random, 95% CI)Totals not selected
9.13.1 Absolute values at follow-up1Mean Difference (IV, Random, 95% CI)Totals not selected
9.14 AAMA (pmol/mg creatinine)1Mean Difference (IV, Random, 95% CI)Totals not selected
9.14.1 Absolute values at follow-up1Mean Difference (IV, Random, 95% CI)Totals not selected
9.15 S-PMA (nanograms)1Mean Difference (IV, Random, 95% CI)Totals not selected
9.15.1 Change from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected
9.16 FEV1 (SMD)5781Std. Mean Difference (IV, Random, 95% CI)0.12 [−0.10, 0.34]
9.16.1 Change from baseline3744Std. Mean Difference (IV, Random, 95% CI)0.12 [−0.39, 0.62]
9.16.2 Absolute values at follow-up237Std. Mean Difference (IV, Random, 95% CI)0.10 [−0.74, 0.95]
9.17 FEV1/FVC2348Mean Difference (IV, Random, 95% CI)1.02 [−0.47, 2.50]
9.17.1 Change from baseline1327Mean Difference (IV, Random, 95% CI)1.72 [0.74, 2.70]
9.17.2 Value at follow-up121Mean Difference (IV, Random, 95% CI)0.20 [−1.08, 1.48]
9.18 FVC (SMD)237Std. Mean Difference (IV, Random, 95% CI)0.11 [−0.56, 0.77]
9.18.1 Change from baseline121Std. Mean Difference (IV, Random, 95% CI)0.09 [−0.77, 0.95]
9.18.2 Absolute values at follow-up116Std. Mean Difference (IV, Random, 95% CI)0.13 [−0.92, 1.19]
9.19 FEF 25-75 (litres/second))3571Mean Difference (IV, Random, 95% CI)−0.05 [−0.43, 0.34]
9.19.1 Change from baseline2555Mean Difference (IV, Random, 95% CI)−0.03 [−1.55, 1.49]
9.19.2 Absolute values at follow-up116Mean Difference (IV, Random, 95% CI)−0.24 [−1.05, 0.57]
9.20 PEF (litres/minute)1Mean Difference (IV, Random, 95% CI)Totals not selected
9.20.1 Absolute values at follow-up1Mean Difference (IV, Random, 95% CI)Totals not selected
9.21 PEF 25-75 (litres/minute)1Mean Difference (IV, Random, 95% CI)Totals not selected
9.21.1 Change from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected
9.22 FeNo (ppb)1Mean Difference (IV, Random, 95% CI)Totals not selected
9.22.1 Absolute values at follow-up1Mean Difference (IV, Random, 95% CI)Totals not selected
9.23 EC use with no combustible tobacco use31784Risk Ratio (M-H, Random, 95% CI)4.69 [0.21, 105.12]
9.24 No EC or combustible tobacco use3Risk Ratio (M-H, Random, 95% CI)Totals not selected
9.25 EC + combustible tobacco use31986Risk Ratio (M-H, Random, 95% CI)4.45 [3.54, 5.61]
9.26 Combustible tobacco use with no EC use32169Risk Ratio (M-H, Random, 95% CI)0.46 [0.30, 0.72]

Analysis group 10: Higher versus lower nicotine content

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
10.1 Smoking cessation1Risk Ratio (M-H, Random, 95% CI)Totals not selected
10.2 Adverse events1Risk Ratio (M-H, Random, 95% CI)Totals not selected
10.3 Serious adverse events2239Risk Difference (M-H, Random, 95% CI)0.01 [−0.03, 0.05]
10.4 Carbon monoxide (ppm)3348Mean Difference (IV, Random, 95% CI)−0.92 [−1.71, −0.13]
10.4.1 Change from baseline2309Mean Difference (IV, Random, 95% CI)−0.90 [−1.70, −0.10]
10.4.2 Absolute values at follow-up139Mean Difference (IV, Random, 95% CI)−1.66 [−6.65, 3.33]
10.5 Heart rate2408Mean Difference (IV, Random, 95% CI)0.36 [−1.91, 2.62]
10.5.1 Change from baseline1148Mean Difference (IV, Random, 95% CI)−0.50 [−1.63, 0.63]
10.5.2 Absolute values at follow-up1260Mean Difference (IV, Random, 95% CI)1.92 [−0.89, 4.73]
10.6 Systolic blood pressure2408Mean Difference (IV, Random, 95% CI)0.86 [−0.77, 2.48]
10.6.1 Change from baseline1148Mean Difference (IV, Random, 95% CI)0.80 [−0.99, 2.59]
10.6.2 Absolute values at follow-up1260Mean Difference (IV, Random, 95% CI)1.13 [−2.76, 5.02]
10.7 NNAL (pg/mg creatinine) at 24 weeks1Mean Difference (IV, Random, 95% CI)Totals not selected
10.7.1 Change from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected
10.8 FEV1 (l)2350Mean Difference (IV, Random, 95% CI)0.05 [−0.10, 0.20]
10.8.1 Change from baseline190Mean Difference (IV, Random, 95% CI)−0.01 [−0.11, 0.09]
10.8.2 Absolute values at follow-up1260Mean Difference (IV, Random, 95% CI)0.15 [−0.04, 0.34]
10.9 FVC (l)2350Mean Difference (IV, Random, 95% CI)−0.05 [−0.16, 0.06]
10.9.1 Change from baseline190Mean Difference (IV, Random, 95% CI)−0.03 [−0.15, 0.09]
10.9.2 Absolute values at follow-up1260Mean Difference (IV, Random, 95% CI)−0.12 [−0.36, 0.12]
10.10 FEV1/FVC2350Mean Difference (IV, Random, 95% CI)0.91 [0.18, 1.64]
10.10.1 Change from baseline190Mean Difference (IV, Random, 95% CI)0.91 [0.15, 1.67]
10.10.2 Absolute values at follow-up1260Mean Difference (IV, Random, 95% CI)0.89 [−1.56, 3.34]
10.11 PEF (l/s)1Std. Mean Difference (IV, Random, 95% CI)Totals not selected
10.11.1 Absolute values at follow-up1Std. Mean Difference (IV, Random, 95% CI)Totals not selected
10.12 FEF 25-75 (l/s)1Std. Mean Difference (IV, Random, 95% CI)Totals not selected
10.12.1 Absolute values at follow-up1Std. Mean Difference (IV, Random, 95% CI)Totals not selected
10.13 FeNO (ppb)1Mean Difference (IV, Random, 95% CI)Totals not selected
10.13.1 Change from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected
10.14 Product use at 6+ months1Risk Ratio (M-H, Random, 95% CI)Totals not selected
10.15 EC use with no combustible tobacco use1Risk Ratio (M-H, Random, 95% CI)Totals not selected
10.16 No EC or combustible tobacco use1Risk Ratio (M-H, Random, 95% CI)Totals not selected
10.17 EC + combustible tobacco use1Risk Ratio (M-H, Random, 95% CI)Totals not selected

Analysis group 11: Choice of flavours versus tobacco flavour only

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
11.1 Smoking cessation1Risk Ratio (M-H, Random, 95% CI)Totals not selected
11.2 Adverse events (EC as adjunct to VLNC)1Risk Ratio (M-H, Random, 95% CI)Totals not selected
11.3 Serious adverse events (EC as adjunct to VLNC)1Risk Difference (M-H, Random, 95% CI)Totals not selected
11.4 Carbon monoxide (ppm; as adjunct to VLNC)1Mean Difference (IV, Random, 95% CI)Totals not selected
11.4.1 Change from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected
11.5 NNAL (pmol/mg creatinine; as adjunct to VLNC)1Mean Difference (IV, Random, 95% CI)Totals not selected
11.5.1 Change from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected
11.6 Product use at 6+ months1Risk Ratio (M-H, Random, 95% CI)Totals not selected

Analysis group 12: Choice of flavour vs. usual cigarette flavour (tobacco/menthol)

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
12.1 Adverse events1Risk Ratio (IV, Random, 95% CI)Totals not selected
12.2 Serious adverse events1Risk Difference (IV, Random, 95% CI)Totals not selected
12.3 Carbon monoxide (ppm)1Mean Difference (IV, Random, 95% CI)Totals not selected
12.3.1 Absolute values at follow-up1Mean Difference (IV, Random, 95% CI)Totals not selected
12.4 Heart rate1Mean Difference (IV, Random, 95% CI)Totals not selected
12.4.1 Absolute values at follow-up1Mean Difference (IV, Random, 95% CI)Totals not selected
12.5 Systolic blood pressure1Mean Difference (IV, Random, 95% CI)Totals not selected
12.5.1 Absolute values at follow-up1Mean Difference (IV, Random, 95% CI)Totals not selected

Analysis group 13: Tobacco versus menthol flavour

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
13.1 Serious adverse events1Risk Difference (M-H, Random, 95% CI)Totals not selected
13.2 NNAL (ng/g)1Mean Difference (IV, Random, 95% CI)Totals not selected
13.2.1 Change from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected
13.3 FEV1 (% predicted)1Mean Difference (IV, Random, 95% CI)Totals not selected
13.3.1 Change from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected
13.4 FEV1/FVC1Mean Difference (IV, Random, 95% CI)Totals not selected
13.4.1 Change from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected

Analysis group 14: Refillable versus cartridge

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
14.1 Carbon monoxide (ppm)1Mean Difference (IV, Random, 95% CI)Totals not selected
14.1.1 Absolute values at follow-up1Mean Difference (IV, Random, 95% CI)Totals not selected

Analysis group 15: Nicotine salt EC versus free-base nicotine EC

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
15.1 Smoking cessation1Risk Ratio (M-H, Random, 95% CI)Totals not selected
15.2 Product use at 6+ months1Risk Ratio (M-H, Random, 95% CI)Totals not selected

Analysis group 16: Higher versus lower wattage

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
16.1 Smoking cessation1Risk Ratio (M-H, Random, 95% CI)Totals not selected
16.2 Adverse events1Risk Ratio (M-H, Random, 95% CI)Totals not selected
16.3 Serious adverse events1Risk Difference (M-H, Random, 95% CI)Totals not selected

Analysis group 17: Non-nicotine EC versus NRT

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
17.1 Smoking cessation2314Risk Ratio (M-H, Random, 95% CI)0.99 [0.64, 1.54]
17.2 Adverse events1Risk Ratio (M-H, Random, 95% CI)Totals not selected
17.3 Serious adverse events1Risk Difference (M-H, Random, 95% CI)Totals not selected
17.4 Carbon monoxide (ppm)1Mean Difference (IV, Random, 95% CI)Totals not selected
17.4.1 Change from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected

Analysis group 18: Non-nicotine EC versus behavioural support only/no support

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
18.1 Smoking cessation2388Risk Ratio (M-H, Random, 95% CI)1.59 [0.80, 3.19]
18.2 Adverse events1Risk Ratio (M-H, Random, 95% CI)Totals not selected
18.3 Serious adverse events2388Risk Difference (M-H, Random, 95% CI)0.00 [−0.02, 0.03]

Analysis group 19: Non-nicotine EC + NRT versus NRT

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
19.1 Smoking cessation1Risk Ratio (M-H, Random, 95% CI)Totals not selected
19.2 Adverse events1Risk Ratio (M-H, Random, 95% CI)Totals not selected
19.3 Serious adverse events1Risk Difference (M-H, Random, 95% CI)Totals not selected

Analysis group 20: Advice to use e-cigarettes versus no advice to use e-cigarettes

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
20.1 Smoking cessation22652Risk Ratio (M-H, Random, 95% CI)1.02 [0.88, 1.19]
20.2 Adverse events1Risk Ratio (M-H, Random, 95% CI)Totals not selected
20.3 Serious adverse events152Risk Difference (M-H, Random, 95% CI)0.00 [−0.07, 0.07]
20.4 EC use with no combustible tobacco use1Risk Ratio (M-H, Random, 95% CI)Totals not selected
20.5 No EC or combustible tobacco use1Risk Ratio (M-H, Random, 95% CI)Totals not selected
20.6 EC + combustible tobacco use2Risk Ratio (M-H, Random, 95% CI)Totals not selected
20.7 Combustible tobacco use with no EC use1Risk Ratio (M-H, Random, 95% CI)Totals not selected

Analysis group 21: Nicotine EC + NRT versus non-nicotine EC + NRT

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
21.1 Smoking cessation21039Risk Ratio (M-H, Random, 95% CI)1.77 [1.07, 2.94]
21.2 Adverse events2677Risk Ratio (M-H, Random, 95% CI)1.11 [0.93, 1.32]
21.3 Serious adverse events21069Risk Difference (M-H, Random, 95% CI)−0.02 [−0.04, 0.01]
21.4 Carbon monoxide (ppm)2Mean Difference (IV, Random, 95% CI)Subtotals only
21.4.1 Change from baseline270Mean Difference (IV, Random, 95% CI)−4.62 [−12.07, 2.82]
21.5 FeNO (ppb)1Mean Difference (IV, Random, 95% CI)Totals not selected
21.5.1 Change from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected
21.6 FEV1 (%)1Mean Difference (IV, Random, 95% CI)Totals not selected
21.6.1 Change from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected
21.7 FVC (%)1Mean Difference (IV, Random, 95% CI)Totals not selected
21.7.1 Change from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected
21.8 Study product use at 6+ months1Risk Ratio (M-H, Random, 95% CI)Totals not selected
21.9 EC use with no combustible tobacco use1Risk Ratio (M-H, Random, 95% CI)Totals not selected
21.10 No EC or combustible tobacco use1Risk Ratio (M-H, Random, 95% CI)Totals not selected
21.11 EC + combustible tobacco use2708Risk Ratio (M-H, Random, 95% CI)0.55 [0.11, 2.74]
21.12 Combustible tobacco use with no EC use1Risk Ratio (M-H, Random, 95% CI)Totals not selected

Analysis group 22: Nicotine EC + NRT versus NRT

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
22.1 Smoking cessation2980Risk Ratio (M-H, Random, 95% CI)3.57 [1.96, 6.51]
22.2 Adverse events4Risk Ratio (M-H, Random, 95% CI)Totals not selected
22.3 Serious adverse events52352Risk Difference (M-H, Random, 95% CI)0.00 [−0.00, 0.00]
22.4 No EC or combustible tobacco use1Risk Ratio (M-H, Random, 95% CI)Totals not selected
22.5 EC + combustible tobacco use1Risk Ratio (M-H, Random, 95% CI)Totals not selected

Analysis group 23: Nicotine EC + varenicline versus varenicline

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
23.1 Adverse events1Risk Ratio (M-H, Random, 95% CI)Totals not selected
23.2 Serious adverse events1Risk Difference (M-H, Random, 95% CI)Totals not selected

Analysis group 24: Nicotine EC + cytisine versus cytisine

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
24.1 Smoking cessation1Risk Ratio (M-H, Random, 95% CI)Totals not selected
24.2 Adverse events1Risk Ratio (M-H, Random, 95% CI)Totals not selected
24.3 Serious adverse events1Risk Difference (M-H, Random, 95% CI)Totals not selected

Analysis group 25: Nicotine EC + VLNC versus VLNC

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
25.1 Adverse events1Risk Ratio (M-H, Random, 95% CI)Totals not selected
25.2 Serious adverse events1Risk Difference (M-H, Random, 95% CI)Totals not selected
25.3 Carbon monoxide (ppm)1Mean Difference (IV, Random, 95% CI)Totals not selected
25.3.1 Change from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected
25.4 Heart rate1Mean Difference (IV, Random, 95% CI)Totals not selected
25.4.1 Change from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected
25.5 Systolic blood pressure1Mean Difference (IV, Random, 95% CI)Totals not selected
25.5.1 Change from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected
25.6 Blood oxygen saturation1Mean Difference (IV, Random, 95% CI)Totals not selected
25.6.1 Change from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected
25.7 NNAL (pmol/mg creatinine)1Mean Difference (IV, Random, 95% CI)Totals not selected
25.7.1 Change from baseline1Mean Difference (IV, Random, 95% CI)Totals not selected

Figures and tables

Analysis 1.1: Smoking cessation - subgrouped by pregnancy status

Study or Subgroup 1.1.1 Not selected on pregnancy Bonevski 2025 Bullen 2013 Courtney 2025 Hajek 2019 Klonizakis 2022 Kouroutzoglou 2024 Lee 2018 Myers-Smith 2022 Russell 2021* a Russell 2021* b Vojjala 2025 Subtotal (HKSJ c ) Total events: Test for overall effect: T = 3.59, df = 10 (P = 0.005) Heterogeneity: Tau² (DL d ) = 0.11; Chi² = 24.57, df = 10 (P = 0.006); I² = 59% 1.1.2 Pregnant population Hajek 2022 e Subtotal Total events: Test for overall effect: Z = 0.82 (P = 0.41) Heterogeneity: Not applicable Total (HKSJ c ) Total events: Test for overall effect: T = 3.88, df = 11 (P = 0.003) Test for subgroup differences: Chi² = 0.02, df = 1 (P = 0.89), I² = 0% Heterogeneity: Tau² (DL d ) = 0.10; Chi² = 24.57, df = 11 (P = 0.01); I² = 55% EC Events 19 21 148 79 36 8 5 13 34 44 7 414 6 6 420 Total 179 289 524 438 84 19 20 68 140 145 63 1969 169 169 2138 NRT Events 18 17 50 44 25 5 1 2 15 15 7 199 3 3 202 Total 184 295 524 446 82 19 10 67 70 71 58 1826 150 150 1976 Weight 9.3% 9.2% 14.9% 14.0% 12.7% 5.7% 1.6% 2.8% 10.5% 10.9% 5.2% 96.9% 3.1% 3.1% 100.0% Risk Ratio IV, Random, 95% CI 1.09 [0.59 , 2.00] 1.26 [0.68 , 2.34] 2.96 [2.20 , 3.98] 1.83 [1.30 , 2.58] 1.41 [0.93 , 2.12] 1.60 [0.64 , 4.01] 2.50 [0.34 , 18.63] 6.40 [1.50 , 27.30] 1.13 [0.66 , 1.94] 1.44 [0.86 , 2.40] 0.92 [0.34 , 2.47] 1.61 [1.20 , 2.16] 1.78 [0.45 , 6.97] 1.78 [0.45 , 6.97] 1.61 [1.23 , 2.12] Risk Ratio IV, Random, 95% CI 0.01 0.1 1 10 100 Favours NRT Favours EC Risk of Bias A + + + + + ? + + ? ? + + B ? + + + + ? + + ? ? − + C + + + + + + + + + + + + D − + + + + ? + + + + − + E + + + + + ? + + + + + + F + + + + ? ? + + ? ? + + G + Footnotes a FBNPs EC arm; control group split to avoid double-counting b NSP EC arm; control group split to avoid double-counting c CI calculated by Hartung-Knapp-Sidik-Jonkman (HKSJ) method. d Tau² calculated by DerSimonian and Laird method. e This is a subset of data from participants followed up for 6 months or longer Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 1.2: Smoking cessation - subgrouped by combined vs. single NRT

Study or Subgroup 1.2.1 Combination NRT Bonevski 2025 Hajek 2019 Myers-Smith 2022 Vojjala 2025 Subtotal (HKSJ a ) Total events: Test for overall effect: T = 1.40, df = 3 (P = 0.26) Heterogeneity: Tau² (DL b ) = 0.16; Chi² = 6.84, df = 3 (P = 0.08); I² = 56% 1.2.2 Single-form NRT Bullen 2013 Courtney 2025 Hajek 2022 c Kouroutzoglou 2024 Lee 2018 Subtotal (HKSJ a ) Total events: Test for overall effect: T = 3.81, df = 4 (P = 0.02) Heterogeneity: Tau² (DL b ) = 0.11; Chi² = 7.01, df = 4 (P = 0.14); I² = 43% 1.2.3 Unclear Klonizakis 2022 Russell 2021* d Russell 2021* e Subtotal (HKSJ a ) Total events: Test for overall effect: T = 4.15, df = 2 (P = 0.05) Heterogeneity: Tau² (DL b ) = 0.00; Chi² = 0.50, df = 2 (P = 0.78); I² = 0% Total (HKSJ a ) Total events: Test for overall effect: T = 3.88, df = 11 (P = 0.003) Test for subgroup differences: Chi² = 4.45, df = 2 (P = 0.11), I² = 55.1% Heterogeneity: Tau² (DL b ) = 0.10; Chi² = 24.57, df = 11 (P = 0.01); I² = 55% EC Events 19 79 13 7 118 21 148 6 8 5 188 36 44 34 114 420 Total 179 438 68 63 748 289 524 169 19 20 1021 84 145 140 369 2138 NRT Events 18 44 2 7 71 17 50 3 5 1 76 25 15 15 55 202 Total 184 446 67 58 755 295 524 150 19 10 998 82 71 70 223 1976 Weight 9.3% 14.0% 2.8% 5.2% 31.3% 9.2% 14.9% 3.1% 5.7% 1.6% 34.5% 12.7% 10.9% 10.5% 34.1% 100.0% Risk Ratio IV, Random, 95% CI 1.09 [0.59 , 2.00] 1.83 [1.30 , 2.58] 6.40 [1.50 , 27.30] 0.92 [0.34 , 2.47] 1.58 [0.56 , 4.44] 1.26 [0.68 , 2.34] 2.96 [2.20 , 3.98] 1.78 [0.45 , 6.97] 1.60 [0.64 , 4.01] 2.50 [0.34 , 18.63] 2.01 [1.21 , 3.34] 1.41 [0.93 , 2.12] 1.44 [0.86 , 2.40] 1.13 [0.66 , 1.94] 1.34 [0.99 , 1.81] 1.61 [1.23 , 2.12] Risk Ratio IV, Random, 95% CI 0.01 0.1 1 10 100 Favours NRT Favours EC Risk of Bias A + + + + + + + ? + + ? ? B ? + + − + + + ? + + ? ? C + + + + + + + + + + + + D − + + − + + + ? + + + + E + + + + + + + ? + + + + F + + + + + + + ? + ? ? ? G + Footnotes a CI calculated by Hartung-Knapp-Sidik-Jonkman (HKSJ) method. b Tau² calculated by DerSimonian and Laird method. c This is a subset of data from participants followed up for 6 months or longer d NSP EC arm; control group split to avoid double-counting e FBNPs EC arm; control group split to avoid double-counting Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 1.3: Adverse events

Study or Subgroup Bullen 2013 Courtney 2025 Hajek 2022 Lee 2018 a Myers-Smith 2022 Piper 2025 b Smith 2025 Wagener 2023 Total (HKSJ c ) Total events: Test for overall effect: T = 0.48, df = 7 (P = 0.65) Heterogeneity: Tau² (DL d ) = 0.04; Chi² = 24.82, df = 7 (P = 0.0008); I² = 72% Nicotine EC Events 107 237 124 7 4 53 8 93 633 Total 241 449 556 19 60 108 18 175 1626 NRT Events 96 278 118 5 2 16 10 87 612 Total 215 417 554 10 47 53 10 175 1481 Weight 18.3% 21.3% 17.6% 4.2% 1.3% 10.2% 8.8% 18.3% 100.0% Risk Ratio M-H, Random, 95% CI 0.99 [0.81 , 1.22] 0.79 [0.71 , 0.88] 1.05 [0.84 , 1.31] 0.74 [0.31 , 1.73] 1.57 [0.30 , 8.19] 1.63 [1.03 , 2.56] 0.47 [0.28 , 0.79] 1.07 [0.87 , 1.31] 0.95 [0.72 , 1.24] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours EC Favours NRT Risk of Bias A + + + + + + ? ? B + + + + + ? ? ? C + + + + + − + ? D + + + + + − + ? E + + + + + + + ? F + + + + + + + ? G + ? Footnotes a Data at 4 weeks post-operation; time from baseline not defined and likely to differ between participants b Intervention arm contains data from EC + placebo patch and EC + no patch study arms c CI calculated by Hartung-Knapp-Sidik-Jonkman (HKSJ) method. d Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 1.4: Serious adverse events

Study or Subgroup Bonevski 2025 Bullen 2013 Courtney 2025 Hajek 2019 Hajek 2022 Lee 2018 a Myers-Smith 2022 Piper 2025 b Smith 2025 Wagener 2023 Total (HKSJ c ) Total events: Test for overall effect: T = 1.29, df = 9 (P = 0.23) Heterogeneity: Tau² (DL d ) = 0.00; Chi² = 7.70, df = 9 (P = 0.56); I² = 0% EC Events 11 24 38 27 31 0 0 0 0 18 149 Total 114 241 449 356 564 19 60 108 18 175 2104 NRT Events 11 14 26 19 37 0 0 0 1 10 118 Total 115 215 417 342 557 10 47 53 10 175 1941 Weight 3.0% 6.9% 14.4% 12.8% 22.1% 0.9% 12.9% 21.2% 0.4% 5.4% 100.0% Risk Difference M-H, Random, 95% CI 0.00 [-0.08 , 0.08] 0.03 [-0.02 , 0.08] 0.02 [-0.01 , 0.06] 0.02 [-0.02 , 0.06] -0.01 [-0.04 , 0.02] 0.00 [-0.14 , 0.14] 0.00 [-0.04 , 0.04] 0.00 [-0.03 , 0.03] -0.10 [-0.32 , 0.12] 0.05 [-0.01 , 0.10] 0.01 [-0.01 , 0.02] Risk Difference M-H, Random, 95% CI -1 -0.5 0 0.5 1 Favours EC Favours NRT Risk of Bias A + + + + + + + + ? ? B ? + + + + + + ? ? ? C + + + + + + + − + ? D − + + + + + + − + ? E + + + + + + + + + ? F + + + + + + + + + ? G + ? Footnotes a Data at 4 weeks post-operation; time from baseline not defined and likely to differ between participants b Intervention arm contains data from EC + placebo patch and EC + no patch study arms c CI calculated by Hartung-Knapp-Sidik-Jonkman (HKSJ) method. d Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 1.5: Carbon monoxide (ppm)

Study or Subgroup 1.5.1 Absolute values at follow-up Hatsukami 2020 Subtotal Test for overall effect: Z = 1.12 (P = 0.26) Heterogeneity: Not applicable 1.5.2 Change from baseline Kerr 2020 Klonizakis 2022 Lee 2018 Smith 2025 Subtotal (Wald a ) Test for overall effect: Z = 1.75 (P = 0.08) Heterogeneity: Tau² (REML b ) = 3.45; Chi² = 4.01, df = 3 (P = 0.26); I² = 29% Total (Wald a ) Test for overall effect: Z = 2.15 (P = 0.03) Test for subgroup differences: Chi² = 0.20, df = 1 (P = 0.65), I² = 0% Heterogeneity: Tau² (REML b ) = 0.00; Chi² = 4.01, df = 4 (P = 0.40); I² = 0% Nicotine EC Mean 11.02 -10 -9 -2.1 -19.4 SD 8.96 10 9.35 12.2 19.9 Total 58 58 28 84 18 18 148 206 NRT Mean 12.89 -7 -8 7.1 -11.9 SD 8.59 10 6.93 11 8.4 Total 52 52 27 82 8 10 127 179 Weight 30.1% 30.1% 11.6% 51.8% 3.6% 2.9% 69.9% 100.0% Mean Difference IV, Random, 95% CI -1.87 [-5.15 , 1.41] -1.87 [-5.15 , 1.41] -3.00 [-8.29 , 2.29] -1.00 [-3.50 , 1.50] -9.20 [-18.68 , 0.28] -7.50 [-18.07 , 3.07] -2.93 [-6.20 , 0.34] -1.98 [-3.78 , -0.18] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours EC Favours NRT Risk of Bias A ? + + + ? B ? + + + ? C ? + + + + D + + + + + E + + + + + F + + ? + + G Footnotes a CI calculated by Wald-type method. b Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 1.6: Heart rate (bpm)

Study or Subgroup 1.6.1 Absolute values at follow-up Hatsukami 2020 Subtotal Test for overall effect: Z = 0.33 (P = 0.74) Heterogeneity: Not applicable 1.6.2 Change from baseline Kerr 2020 Subtotal Test for overall effect: Z = 0.73 (P = 0.47) Heterogeneity: Not applicable Total (Wald a ) Test for overall effect: Z = 0.45 (P = 0.65) Test for subgroup differences: Chi² = 0.43, df = 1 (P = 0.51), I² = 0% Heterogeneity: Tau² (REML b ) = 0.00; Chi² = 0.43, df = 1 (P = 0.51); I² = 0% Nicotine EC Mean 74.81 0 SD 13.91 6 Total 58 58 28 28 86 NRT Mean 75.55 -1 SD 9.72 4 Total 53 53 27 27 80 Weight 26.8% 26.8% 73.2% 73.2% 100.0% Mean Difference IV, Random, 95% CI -0.74 [-5.17 , 3.69] -0.74 [-5.17 , 3.69] 1.00 [-1.69 , 3.69] 1.00 [-1.69 , 3.69] 0.53 [-1.76 , 2.83] Mean Difference IV, Random, 95% CI -4 -2 0 2 4 Favours EC Favours NRT Risk of Bias A ? + B ? + C ? + D + + E + + F + + G Footnotes a CI calculated by Wald-type method. b Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 1.7: Systolic blood pressure

Study or Subgroup 1.7.1 Absolute values at follow-up Hatsukami 2020 Subtotal Test for overall effect: Z = 0.35 (P = 0.72) Heterogeneity: Not applicable 1.7.2 Change from baseline Kerr 2020 Subtotal Test for overall effect: Z = 1.85 (P = 0.06) Heterogeneity: Not applicable Total (Wald a ) Test for overall effect: Z = 1.61 (P = 0.11) Test for subgroup differences: Chi² = 0.98, df = 1 (P = 0.32), I² = 0% Heterogeneity: Tau² (REML b ) = 0.00; Chi² = 0.98, df = 1 (P = 0.32); I² = 0% Nicotine EC Mean 123.1 -4 SD 13.3 4 Total 58 58 28 28 86 NRT Mean 122.1 -2 SD 16.2 4 Total 53 53 27 27 80 Weight 12.7% 12.7% 87.3% 87.3% 100.0% Mean Difference IV, Random, 95% CI 1.00 [-4.54 , 6.54] 1.00 [-4.54 , 6.54] -2.00 [-4.11 , 0.11] -2.00 [-4.11 , 0.11] -1.62 [-3.59 , 0.36] Mean Difference IV, Random, 95% CI -10 -5 0 5 10 Favours EC Favours NRT Risk of Bias A ? + B ? + C ? + D + + E + + F + + G Footnotes a CI calculated by Wald-type method. b Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 1.8: Blood oxygen saturation

Study or Subgroup 1.8.1 Absolute values at follow-up Hatsukami 2020 Subtotal Test for overall effect: Z = 0.75 (P = 0.45) Heterogeneity: Not applicable 1.8.2 Change from baseline Kerr 2020 Subtotal Test for overall effect: Z = 0.00 (P = 1.00) Heterogeneity: Not applicable Total (Wald a ) Test for overall effect: Z = 0.63 (P = 0.53) Test for subgroup differences: Chi² = 0.16, df = 1 (P = 0.69), I² = 0% Heterogeneity: Tau² (REML b ) = 0.00; Chi² = 0.16, df = 1 (P = 0.69); I² = 0% Nicotine EC Mean 98.1 0 SD 1.5 2 Total 57 57 28 28 85 NRT Mean 98.3 0 SD 1.3 1 Total 53 53 27 27 80 Weight 71.6% 71.6% 28.4% 28.4% 100.0% Mean Difference IV, Random, 95% CI -0.20 [-0.72 , 0.32] -0.20 [-0.72 , 0.32] 0.00 [-0.83 , 0.83] 0.00 [-0.83 , 0.83] -0.14 [-0.59 , 0.30] Mean Difference IV, Random, 95% CI -4 -2 0 2 4 Favours NRT Favours EC Risk of Bias A ? + B ? + C ? + D + + E + + F + + G Footnotes a CI calculated by Wald-type method. b Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 1.9: NNAL (pmol/mg creatinine)

Study or Subgroup 1.9.1 Absolute values at follow-up Hatsukami 2020 Nicotine EC Mean 1.2 SD 1.7 Total 57 NRT Mean 1.2 SD 1.1 Total 53 Mean Difference IV, Random, 95% CI 0.00 [-0.53 , 0.53] Mean Difference IV, Random, 95% CI -1 -0.5 0 0.5 1 Favours EC Favours NRT Risk of Bias A ? B ? C ? D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 1.10: 3-HPMA (pmol/mg creatinine)

Study or Subgroup 1.10.1 Absolute values at follow-up Hatsukami 2020 Nicotine EC Mean 4612 SD 4263 Total 58 NRT Mean 5419 SD 5076 Total 53 Mean Difference IV, Random, 95% CI -807.00 [-2559.47 , 945.47] Mean Difference IV, Random, 95% CI -1000 -500 0 500 1000 Favours EC Favours NRT Risk of Bias A ? B ? C ? D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 1.11: 2-HPMA (pmol/mg creatinine)

Study or Subgroup 1.11.1 Absolute values at follow-up Hatsukami 2020 Nicotine EC Mean 733.2 SD 855.6 Total 58 NRT Mean 842.2 SD 1083.7 Total 53 Mean Difference IV, Random, 95% CI -109.00 [-474.52 , 256.52] Mean Difference IV, Random, 95% CI -500 -250 0 250 500 Favours EC Favours NRT Risk of Bias A ? B ? C ? D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 1.12: HMPMA (pmol/mg creatinine)

Study or Subgroup 1.12.1 Absolute values at follow-up Hatsukami 2020 Nicotine EC Mean 3959 SD 3633 Total 58 NRT Mean 4834 SD 3999 Total 53 Mean Difference IV, Random, 95% CI -875.00 [-2300.93 , 550.93] Mean Difference IV, Random, 95% CI -1000 -500 0 500 1000 Favours EC Favours NRT Risk of Bias A ? B ? C ? D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 1.13: PheT (pmol/mg creatinine)

Study or Subgroup 1.13.1 Absolute values at follow-up Hatsukami 2020 Nicotine EC Mean 2.9 SD 2.8 Total 56 NRT Mean 2.5 SD 2.9 Total 53 Mean Difference IV, Random, 95% CI 0.40 [-0.67 , 1.47] Mean Difference IV, Random, 95% CI -4 -2 0 2 4 Favours EC Favours NRT Risk of Bias A ? B ? C ? D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 1.14: CEMA (pmol/mg creatinine)

Study or Subgroup 1.14.1 Absolute values at follow-up Hatsukami 2020 Nicotine EC Mean 512 SD 443 Total 58 NRT Mean 475 SD 409 Total 53 Mean Difference IV, Random, 95% CI 37.00 [-121.50 , 195.50] Mean Difference IV, Random, 95% CI -200 -100 0 100 200 Favours EC Favours NRT Risk of Bias A ? B ? C ? D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 1.15: AAMA (pmol/mg creatinine)

Study or Subgroup 1.15.1 Absolute values at follow-up Hatsukami 2020 Nicotine EC Mean 495.2 SD 390.9 Total 58 NRT Mean 463.2 SD 361.8 Total 51 Mean Difference IV, Random, 95% CI 32.00 [-109.35 , 173.35] Mean Difference IV, Random, 95% CI -200 -100 0 100 200 Favours EC Favours NRT Risk of Bias A ? B ? C ? D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 1.16: FEV1

Study or Subgroup 1.16.1 Change from baseline Kerr 2020 Lee 2018 Nicotine EC Mean -0.04 292 SD 0.14 503 Total 28 18 NRT Mean 0.03 -300 SD 0.14 549 Total 27 8 Std. Mean Difference IV, Random, 95% CI -0.49 [-1.03 , 0.04] 1.11 [0.21 , 2.00] Std. Mean Difference IV, Random, 95% CI -2 -1 0 1 2 Favours NRT Favours nicotine EC Risk of Bias A + + B + + C + + D + + E + + F + + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 1.17: FEV1/FVC (%)

Study or Subgroup 1.17.1 Change from baseline Kerr 2020 Lee 2018 Subtotal (Wald a ) Test for overall effect: Z = 0.58 (P = 0.56) Heterogeneity: Tau² (REML b ) = 416.58; Chi² = 2.05, df = 1 (P = 0.15); I² = 51% Test for subgroup differences: Not applicable Nicotine EC Mean -0.2 2 SD 2.6 10.5 Total 28 18 46 NRT Mean 0 -38.1 SD 3.6 79.2 Total 27 8 35 Weight 74.3% 25.7% 100.0% Mean Difference IV, Random, 95% CI -0.20 [-1.86 , 1.46] 40.10 [-15.00 , 95.20] 10.15 [-24.36 , 44.67] Mean Difference IV, Random, 95% CI -100 -50 0 50 100 Favours NRT Favours nicotine EC Risk of Bias A + + B + + C + + D + + E + + F + + G Footnotes a CI calculated by Wald-type method. b Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 1.18: PEF (L/min)

Study or Subgroup 1.18.1 Change from baseline Kerr 2020 Nicotine EC Mean 2 SD 49 Total 28 NRT Mean 5 SD 42 Total 27 Mean Difference IV, Random, 95% CI -3.00 [-27.09 , 21.09] Mean Difference IV, Random, 95% CI -50 -25 0 25 50 Favours NRT Favours nicotine EC Risk of Bias A + B + C + D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 1.19: Product use at 6+ months

Study or Subgroup Bullen 2013 Courtney 2025 Hajek 2019 Lee 2018 Myers-Smith 2022 Russell 2021* a Russell 2021* b EC Events 71 253 173 3 32 48 62 Total 241 449 356 18 59 103 124 NRT Events 17 129 19 2 7 28 28 Total 215 417 342 9 47 60 61 Risk Ratio M-H, Random, 95% CI 3.73 [2.27 , 6.12] 1.82 [1.54 , 2.15] 8.75 [5.58 , 13.72] 0.75 [0.15 , 3.72] 3.64 [1.77 , 7.50] 1.00 [0.71 , 1.40] 1.09 [0.79 , 1.51] Risk Ratio M-H, Random, 95% CI 0.05 0.2 1 5 20 Higher with NRT Higher with EC Risk of Bias A + + + + + ? ? B + + + + + ? ? C + + + + + + + D + + + + + + + E + + + + + + + F + + + + + ? ? G + Footnotes a FBNP EC arm; control group split to avoid double-counting. Study product use and numbers at follow up by correspondence. b NSP EC arm; control arm split to avoid double-counting. Study product use and numbers at  follow up by correspondence. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 1.20: EC use with no combustible tobacco use

Study or Subgroup Bonevski 2025 Bullen 2013 Hajek 2019 Hajek 2022 Lee 2018 Total (HKSJ a ) Total events: Test for overall effect: T = 3.30, df = 4 (P = 0.03) Heterogeneity: Tau² (DL b ) = 0.91; Chi² = 18.23, df = 4 (P = 0.001); I² = 78% EC Events 25 8 71 29 1 134 Total 179 241 438 515 18 1391 NRT Events 18 1 12 2 0 33 Total 184 251 446 495 9 1385 Weight 28.9% 14.2% 28.6% 19.9% 8.4% 100.0% Risk Ratio M-H, Random, 95% CI 1.43 [0.81 , 2.52] 8.33 [1.05 , 66.12] 6.02 [3.32 , 10.95] 13.94 [3.34 , 58.10] 1.58 [0.07 , 35.32] 4.40 [1.27 , 15.28] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with NRT Higher with EC Risk of Bias A + + + + + B ? + + + + C + + + + + D − + + + + E + + + + + F + + + + + G Footnotes a CI calculated by Hartung-Knapp-Sidik-Jonkman (HKSJ) method. b Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 1.21: No EC or combustible tobacco use

Study or Subgroup Bonevski 2025 Bullen 2013 Hajek 2019 Hajek 2022 Lee 2018 Total (HKSJ a ) Total events: Test for overall effect: T = 3.21, df = 4 (P = 0.03) Heterogeneity: Tau² (DL b ) = 0.08; Chi² = 5.79, df = 4 (P = 0.22); I² = 31% EC Events 11 13 8 10 2 44 Total 179 241 438 515 18 1391 NRT Events 21 16 32 23 1 93 Total 184 251 446 495 9 1385 Weight 25.2% 24.8% 22.6% 23.8% 3.7% 100.0% Risk Ratio M-H, Random, 95% CI 0.54 [0.27 , 1.08] 0.85 [0.42 , 1.72] 0.25 [0.12 , 0.55] 0.42 [0.20 , 0.87] 1.00 [0.10 , 9.61] 0.49 [0.26 , 0.91] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with NRT Higher with EC Risk of Bias A + + + + + B ? + + + + C + + + + + D − + + + + E + + + + + F + + + + + G Footnotes a CI calculated by Hartung-Knapp-Sidik-Jonkman (HKSJ) method. b Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 1.22: EC + combustible tobacco use

Study or Subgroup Bullen 2013 Hajek 2019 Hajek 2022 Lee 2018 EC Events 63 164 164 2 Total 241 438 571 18 NRT Events 16 90 47 2 Total 251 446 569 9 Risk Ratio M-H, Random, 95% CI 4.10 [2.44 , 6.89] 1.86 [1.49 , 2.31] 3.48 [2.57 , 4.71] 0.50 [0.08 , 2.99] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with NRT Higher with EC Risk of Bias A + + + + B + + + + C + + + + D + + + + E + + + + F + + + + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 1.23: Combustible tobacco use with no EC use

Study or Subgroup Bullen 2013 Hajek 2019 Hajek 2022 Lee 2018 Total (HKSJ a ) Total events: Test for overall effect: T = 3.08, df = 3 (P = 0.05) Heterogeneity: Tau² (DL b ) = 0.02; Chi² = 17.28, df = 3 (P = 0.0006); I² = 83% EC Events 157 195 368 12 732 Total 241 438 571 18 1268 NRT Events 182 312 497 6 997 Total 251 446 569 9 1275 Weight 29.9% 29.8% 33.7% 6.6% 100.0% Risk Ratio M-H, Random, 95% CI 0.90 [0.80 , 1.01] 0.64 [0.56 , 0.72] 0.74 [0.69 , 0.79] 1.00 [0.57 , 1.76] 0.76 [0.58 , 1.01] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with NRT Higher with EC Risk of Bias A + + + + B + + + + C + + + + D + + + + E + + + + F + + + + G Footnotes a CI calculated by Hartung-Knapp-Sidik-Jonkman (HKSJ) method. b Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 2.1: Smoking cessation

Study or Subgroup Ioakeimidis 2018 Nicotine EC Events 4 Total 27 Varenicline Events 13 Total 27 Risk Ratio M-H, Random, 95% CI 0.31 [0.11 , 0.82] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours varenicline Favours nicotine EC Risk of Bias A ? B ? C + D + E ? F ? G − Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 2.2: Serious adverse events

Study or Subgroup Ioakeimidis 2018 a Nicotine EC Events 0 Total 27 Varenicline Events 0 Total 27 Risk Difference M-H, Random, 95% CI 0.00 [-0.07 , 0.07] Risk Difference M-H, Random, 95% CI -1 -0.5 0 0.5 1 Favours EC Favours varenicline Risk of Bias A ? B ? C + D + E ? F ? G − Footnotes a n followed up not reported; n randomized used as denominators Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 3.1: Smoking cessation

Study or Subgroup Tuisku 2024 a EC Events 42 Total 152 non-nicotine EC + varenicline Events 58 Total 153 Risk Ratio M-H, Random, 95% CI 0.73 [0.53 , 1.01] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours non-nicotine EC + varenicline Favours EC Risk of Bias A + B + C + D + E + F + G Footnotes a The EC group also received placebo 'varenicline' pills Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 3.2: Serious adverse events

Study or Subgroup Tuisku 2024 a EC Events 2 Total 152 non-nicotine EC + varenicline Events 0 Total 153 Risk Difference M-H, Random, 95% CI 0.01 [-0.01 , 0.04] Risk Difference M-H, Random, 95% CI -1 -0.5 0 0.5 1 Favours EC Favours non-nicotine EC + varenicline Risk of Bias A + B + C + D + E + F + G Footnotes a The EC group also received placebo 'varenicline' pills Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 4.1: Smoking cessation

Study or Subgroup Walker 2023 EC Events 44 Total 207 Cytisine Events 41 Total 301 Risk Ratio M-H, Random, 95% CI 1.56 [1.06 , 2.30] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours cytisine Favours nicotine EC Risk of Bias A + B ? C + D + E + F ? G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 4.2: Adverse events

Study or Subgroup Walker 2023 a EC Events 104 Total 207 Cytisine Events 150 Total 301 Risk Ratio M-H, Random, 95% CI 1.01 [0.84 , 1.20] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours nicotine EC Favours cytisine Risk of Bias A + B ? C + D + E + F ? G Footnotes a Denominator based on number randomised Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 4.3: Serious adverse events

Study or Subgroup Walker 2023 a EC Events 8 Total 207 Cytisine Events 8 Total 301 Risk Difference M-H, Random, 95% CI 0.01 [-0.02 , 0.04] Risk Difference M-H, Random, 95% CI -1 -0.5 0 0.5 1 Favours nicotine EC Favours cytisine Risk of Bias A + B ? C + D + E + F ? G Footnotes a Denominators based on numbers randomised Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 5.1: Smoking cessation

Study or Subgroup Kouroutzoglou 2024 EC Events 8 Total 19 NRT + bupropion Events 9 Total 19 Risk Ratio M-H, Random, 95% CI 0.89 [0.44 , 1.81] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours NRT + bupropion Favours EC Risk of Bias A ? B ? C + D ? E ? F ? G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 6.1: Adverse events

Study or Subgroup Caponnetto 2023* Nicotine EC Events 56 Total 110 Heated tobacco Events 65 Total 110 Risk Ratio M-H, Random, 95% CI 0.86 [0.68 , 1.10] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours nicotine EC Favours heated tobacco Risk of Bias A + B + C − D + E + F − G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 6.2: SAEs

Study or Subgroup Caponnetto 2023* Nicotine EC Events 0 Total 110 Heated tobacco Events 0 Total 110 Risk Difference M-H, Random, 95% CI 0.00 [-0.02 , 0.02] Risk Difference M-H, Random, 95% CI -1 -0.5 0 0.5 1 Favours nicotine EC Favours heated tobacco Risk of Bias A + B + C − D + E + F − G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 6.3: Carbon monoxide (ppm)

Study or Subgroup 6.3.1 Absolute values at 12 weeks Caponnetto 2023* Subtotal Test for overall effect: Z = 1.43 (P = 0.15) Heterogeneity: Not applicable 6.3.2 Change at 1 month Ikonomidis 2024 Subtotal Test for overall effect: Z = 0.13 (P = 0.90) Heterogeneity: Not applicable Total (Wald a ) Test for overall effect: Z = 0.96 (P = 0.34) Test for subgroup differences: Chi² = 1.06, df = 1 (P = 0.30), I² = 5.6% Heterogeneity: Tau² (REML b ) = 0.12; Chi² = 1.06, df = 1 (P = 0.30); I² = 6% Nicotine EC Mean 10.1 -7.9 SD 11.3 5.1 Total 107 107 25 25 132 Heated tobacco Mean 8.2 -7.7 SD 8 5.8 Total 110 110 25 25 135 Weight 56.9% 56.9% 43.1% 43.1% 100.0% Mean Difference IV, Random, 95% CI 1.90 [-0.71 , 4.51] 1.90 [-0.71 , 4.51] -0.20 [-3.23 , 2.83] -0.20 [-3.23 , 2.83] 1.00 [-1.04 , 3.03] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours nicotine EC Favours heated tobacco Risk of Bias A + ? B + ? C − + D + + E + ? F − ? G Footnotes a CI calculated by Wald-type method. b Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 6.4: VO2 Max at 12 weeks

Study or Subgroup Caponnetto 2023* Nicotine EC Mean 50.9 SD 31.9 Total 101 Heated tobacco Mean 44.7 SD 28.7 Total 110 Mean Difference IV, Random, 95% CI 6.20 [-2.01 , 14.41] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours heated tobacco Favours nicotine EC Risk of Bias A + B + C − D + E + F − G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 7.1: Serious adverse events

Study or Subgroup Avila 2024 Nicotine EC Events 0 Total 14 ONP Events 0 Total 12 Risk Difference M-H, Random, 95% CI 0.00 [-0.14 , 0.14] Risk Difference M-H, Random, 95% CI -1 -0.5 0 0.5 1 Favours nicotine  EC Favours ONP Risk of Bias A + B + C + D + E + F − G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 7.2: Carbon monoxide (ppm)

Study or Subgroup 7.2.1 Change from baseline Avila 2024 Nicotine EC Mean [ppm] -15.36 SD [ppm] 22.7 Total 14 ONP Mean [ppm] -2.92 SD [ppm] 19.9 Total 12 Mean Difference IV, Random, 95% CI [ppm] -12.44 [-28.82 , 3.94] Mean Difference IV, Random, 95% CI [ppm] -50 -25 0 25 50 Favours nicotine EC Favours ONP Risk of Bias A + B + C + D + E + F − G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 8.1: Smoking cessation

Study or Subgroup Bullen 2013 Caponnetto 2013* Cobb 2021 a Cobb 2021 b Eisenberg 2020 Klonizakis 2022 Lucchiari 2022 Tuisku 2024 Total (Wald c ) Total events: Test for overall effect: Z = 2.40 (P = 0.02) Heterogeneity: Tau² (DL d ) = 0.00; Chi² = 6.04, df = 7 (P = 0.54); I² = 0% Nicotine EC Events 21 22 10 4 4 36 15 42 154 Total 289 200 130 130 128 84 70 152 1183 Non-nicotine EC Events 3 4 1 0 3 30 15 30 86 Total 73 100 65 65 127 82 70 153 735 Weight 4.0% 5.2% 1.4% 0.7% 2.6% 39.3% 13.9% 33.0% 100.0% Risk Ratio M-H, Random, 95% CI 1.77 [0.54 , 5.77] 2.75 [0.97 , 7.76] 5.00 [0.65 , 38.22] 4.53 [0.25 , 82.96] 1.32 [0.30 , 5.79] 1.17 [0.80 , 1.71] 1.00 [0.53 , 1.89] 1.41 [0.93 , 2.13] 1.34 [1.05 , 1.69] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours non-nicotine EC Favours nicotine EC Risk of Bias A + + + + + + + + B + + + + + + + + C + + + + + + + + D + + + + + + + + E + + + + + + + + F + ? + + + ? − + G Footnotes a 36 mg/mL arm; control group split to avoid double-counting b 8 mg/mL arm; control group split to avoid double-counting c CI calculated by Wald-type method. d Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 8.2: Adverse events

Study or Subgroup Bullen 2013 Eisenberg 2020 Meier 2017 NCT03625986 Okuyemi 2022 Rose 2023* a Total (Wald b ) Total events: Test for overall effect: Z = 0.32 (P = 0.75) Heterogeneity: Tau² (DL c ) = 0.00; Chi² = 1.02, df = 4 (P = 0.91); I² = 0% Nicotine EC Events 107 120 3 11 0 4 245 Total 241 128 24 35 109 11 548 Non-nicotine EC Events 26 118 2 8 0 4 158 Total 57 127 24 34 106 13 361 Weight 4.1% 94.8% 0.1% 0.7% 0.3% 100.0% Risk Ratio M-H, Random, 95% CI 0.97 [0.71 , 1.34] 1.01 [0.94 , 1.08] 1.50 [0.27 , 8.19] 1.34 [0.61 , 2.91] Not estimable 1.18 [0.38 , 3.66] 1.01 [0.95 , 1.08] Risk Ratio M-H, Random, 95% CI 0.05 0.2 1 5 20 Favours nicotine EC Favours non-nicotine EC Risk of Bias A + + ? ? ? ? B + + ? + ? ? C + + + + + + D + + + + + + E + + ? + + + F + + + + + + G + Footnotes a All participants receiving placebo patch b CI calculated by Wald-type method. c Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 8.3: Serious adverse events

Study or Subgroup Bullen 2013 Caponnetto 2013* Cobb 2021 a Cobb 2021 b Eisenberg 2020 George 2019 Lucchiari 2022 Meier 2017 NCT03625986 Okuyemi 2022 Rose 2023* c Tuisku 2024 Total (Wald d ) Total events: Test for overall effect: Z = 0.02 (P = 0.99) Heterogeneity: Tau² (DL e ) = 0.00; Chi² = 3.09, df = 11 (P = 0.99); I² = 0% Nicotine EC Events 24 0 8 5 3 0 0 0 1 0 1 2 44 Total 241 72 86 81 128 37 70 24 35 109 11 152 1046 Non-nicotine EC Events 4 0 3 4 5 0 0 0 0 0 0 2 18 Total 57 45 37 37 127 37 70 24 34 106 13 153 740 Weight 2.1% 9.5% 1.0% 0.9% 6.5% 4.6% 15.8% 2.0% 2.1% 36.8% 0.3% 18.4% 100.0% Risk Difference M-H, Random, 95% CI 0.03 [-0.05 , 0.11] 0.00 [-0.04 , 0.04] 0.01 [-0.10 , 0.12] -0.05 [-0.16 , 0.07] -0.02 [-0.06 , 0.03] 0.00 [-0.05 , 0.05] 0.00 [-0.03 , 0.03] 0.00 [-0.08 , 0.08] 0.03 [-0.05 , 0.10] 0.00 [-0.02 , 0.02] 0.09 [-0.12 , 0.30] 0.00 [-0.03 , 0.03] 0.00 [-0.01 , 0.01] Risk Difference M-H, Random, 95% CI -1 -0.5 0 0.5 1 Favours nicotine EC Favours non-nicotine EC Risk of Bias A + + + + + + + ? ? ? ? + B + + + + + + + ? + ? ? + C + + + + + ? + + + + + + D + + + + + − + + + + + + E + + + + + ? + ? + + + + F + ? + + + + − + + + + + G + Footnotes a 36 mg/mL; control group split to avoid double counting b 8 mg/mL; control group split to avoid double counting c All participants receiving placebo patch d CI calculated by Wald-type method. e Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 8.4: Carbon monoxide (ppm)

Study or Subgroup 8.4.1 Change from baseline Cobb 2021 a Klonizakis 2022 Rose 2023* b 8.4.2 Absolute values at follow-up Caponnetto 2013* c Felicione 2019 NCT03625986 Okuyemi 2022 Nicotine EC Mean -5.53 -9 -11.1 9.5 26.2 10.7 14.2 SD 2.7 9.35 16.6 4.2 11 18.8 8 Total 80 84 7 49 14 35 116 Non-nicotine EC Mean -3.88 -6 -2.2 7.3 20.4 13.8 15.4 SD 3.1 9.24 13 3.2 7.4 11.5 8 Total 69 82 10 41 11 34 114 Mean Difference IV, Random, 95% CI -1.65 [-2.59 , -0.71] -3.00 [-5.83 , -0.17] -8.90 [-23.60 , 5.80] 2.20 [0.67 , 3.73] 5.80 [-1.43 , 13.03] -3.10 [-10.43 , 4.23] -1.20 [-3.27 , 0.87] Mean Difference IV, Random, 95% CI -50 -25 0 25 50 Favours nicotine EC Favours non-nicotine EC Risk of Bias A + + ? + ? ? ? B + + ? + ? + ? C + + + + ? + + D + + + + ? + + E + + + + + + + F + ? + ? ? + + G + Footnotes a Data are for 36 mg/mL arm. In 8 mg/mL arm, -4.4, SD 3.1, n = 74 b Comparison: Nicotine pod + placebo patch vs. non-nicotine pod + placebo patch c Data are 2.4% nicotine compared to no-nicotine; 1.8% nicotine arm reported elsewhere Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 8.5: Heart rate

Study or Subgroup 8.5.1 Absolute values at follow-up Caponnetto 2013* a Cobb 2021 b Subtotal (Wald c ) Test for overall effect: Z = 1.04 (P = 0.30) Heterogeneity: Tau² (REML d ) = 0.00; Chi² = 0.48, df = 1 (P = 0.49); I² = 0% Test for subgroup differences: Not applicable Nicotine EC Mean 77.5 79.33 SD 12.2 11.65 Total 73 130 203 Non-nicotine EC Mean 79.8 79.93 SD 10.8 12.38 Total 68 130 198 Weight 37.2% 62.8% 100.0% Mean Difference IV, Random, 95% CI -2.30 [-6.10 , 1.50] -0.60 [-3.52 , 2.32] -1.23 [-3.55 , 1.08] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours nicotine EC Favours non-nicotine EC Risk of Bias A + + B + + C + + D + + E + + F ? + G Footnotes a Data are 2.4% nicotine compared to no-nicotine; 1.8% nicotine arm reported elsewhere b Comparing highest (36mg) dose EC arm to no-nicotine EC arm; N at follow-up not provided, so N at baseline used c CI calculated by Wald-type method. d Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 8.6: Systolic blood pressure

Study or Subgroup 8.6.1 Absolute values at follow-up Caponnetto 2013* a Cobb 2021 b NCT03625986 Subtotal (Wald c ) Test for overall effect: Z = 1.66 (P = 0.10) Heterogeneity: Tau² (REML d ) = 0.00; Chi² = 0.48, df = 2 (P = 0.79); I² = 0% Test for subgroup differences: Not applicable Nicotine EC Mean 124.1 125.85 125.91 SD 17.7 14.82 15.74 Total 73 130 35 238 Non-nicotine EC Mean 122.9 122.74 124.74 SD 13.6 14.56 12.13 Total 68 130 34 232 Weight 26.8% 56.7% 16.5% 100.0% Mean Difference IV, Random, 95% CI 1.20 [-3.99 , 6.39] 3.11 [-0.46 , 6.68] 1.17 [-5.45 , 7.79] 2.28 [-0.41 , 4.97] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours nicotine EC Favours non-nicotine EC Risk of Bias A + + ? B + + + C + + + D + + + E + + + F ? + + G Footnotes a Data are 2.4% nicotine compared to no-nicotine; 1.8% nicotine arm reported elsewhere b Comparing highest (36mg) dose EC arm to no-nicotine EC arm; N at follow-up not provided, so N at baseline used c CI calculated by Wald-type method. d Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 8.7: NNAL (pmol/mg creatinine)

Study or Subgroup 8.7.1 Change from baseline Cobb 2021 a 8.7.2 Absolute values at follow-up NCT03625986 Okuyemi 2022 Nicotine EC Mean -4.23 151.6 1.95 SD 72.48 235.1 1.47 Total 79 33 109 Non-nicotine EC Mean -19.5 338.2 1.98 SD 52.7 270.1 1.74 Total 69 32 106 Mean Difference IV, Random, 95% CI 15.27 [-4.98 , 35.52] -186.60 [-309.86 , -63.34] -0.03 [-0.46 , 0.40] Mean Difference IV, Random, 95% CI -500 -250 0 250 500 Favours nicotine EC Favours non-nicotine EC Risk of Bias A + ? ? B + + ? C + + + D + + + E + + + F + + + G Footnotes a Data for 36 mg/mL arm. 8 mg/mL arm -141.46 (SD 259.14), n = 73 Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 8.8: FEV1 (l)

Study or Subgroup 8.8.1 Absolute values at follow-up Caponnetto 2013* a Cobb 2021 b NCT03625986 Subtotal (HKSJ c ) Test for overall effect: T = 0.06, df = 2 (P = 0.96) Heterogeneity: Tau² (REML d ) = 0.04; Chi² = 4.55, df = 2 (P = 0.10); I² = 55% Test for subgroup differences: Not applicable Nicotine EC Mean 3.2 2.67 2.7 SD 0.9 0.81 0.8 Total 47 130 35 212 Non-nicotine EC Mean 3.5 2.52 2.7 SD 0.9 0.71 0.8 Total 41 130 34 205 Weight 29.4% 44.5% 26.1% 100.0% Std. Mean Difference IV, Random, 95% CI -0.33 [-0.75 , 0.09] 0.20 [-0.05 , 0.44] 0.00 [-0.47 , 0.47] -0.01 [-0.68 , 0.66] Std. Mean Difference IV, Random, 95% CI -1 -0.5 0 0.5 1 Favours non-nicotine EC Favours nicotine EC Risk of Bias A + + ? B + + + C + + + D + + + E + + + F ? + + G Footnotes a Data are 2.4% nicotine compared to no-nicotine; 1.8% nicotine arm reported elsewhere b Comparing highest (36mg) dose EC arm to no-nicotine EC arm; N at follow-up not provided, so N at baseline used c CI calculated by Hartung-Knapp-Sidik-Jonkman (HKSJ) method. d Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 8.9: FEV1/FVC

Study or Subgroup 8.9.1 Absolute values at follow-up Caponnetto 2013* a Cobb 2021 b Subtotal (Wald c ) Test for overall effect: Z = 0.17 (P = 0.86) Heterogeneity: Tau² (REML d ) = 0.00; Chi² = 0.48, df = 1 (P = 0.49); I² = 0% Test for subgroup differences: Not applicable Nicotine EC Mean 80.3 78.65 SD 7.2 8.86 Total 47 130 177 Non-nicotine EC Mean 81.2 78.36 SD 5.6 7.73 Total 41 130 171 Weight 36.3% 63.7% 100.0% Mean Difference IV, Random, 95% CI -0.90 [-3.58 , 1.78] 0.29 [-1.73 , 2.31] -0.14 [-1.76 , 1.47] Mean Difference IV, Random, 95% CI -4 -2 0 2 4 Favours non-nicotine EC Favours nicotine EC Risk of Bias A + + B + + C + + D + + E + + F ? + G Footnotes a Data are 2.4% nicotine compared to no-nicotine; 1.8% nicotine arm reported elsewhere b Comparing highest (36mg) dose EC arm to no-nicotine EC arm; N at follow-up not provided, so N at baseline used c CI calculated by Wald-type method. d Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 8.10: FVC (l)

Study or Subgroup 8.10.1 Absolute values at follow-up Cobb 2021 a Nicotine EC Mean 3.38 SD 0.9 Total 130 Non-nicotine EC Mean 3.21 SD 0.82 Total 130 Std. Mean Difference IV, Random, 95% CI 0.20 [-0.05 , 0.44] Std. Mean Difference IV, Random, 95% CI -1 -0.5 0 0.5 1 Favours non-nicotine EC Favours nicotine EC Risk of Bias A + B + C + D + E + F + G Footnotes a Comparing highest (36mg) dose EC arm to no-nicotine EC arm; N at follow-up not provided, so N at baseline used Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 8.11: PEF (l/s)

Study or Subgroup 8.11.1 Absolute values at follow-up Cobb 2021 a Nicotine EC Mean 6.26 SD 1.66 Total 130 Non-nicotine EC Mean 5.91 SD 1.65 Total 130 Std. Mean Difference IV, Random, 95% CI 0.21 [-0.03 , 0.45] Std. Mean Difference IV, Random, 95% CI -1 -0.5 0 0.5 1 Favours non-nicotine EC Favours nicotine EC Risk of Bias A + B + C + D + E + F + G Footnotes a Comparing highest (36mg) dose EC arm to no-nicotine EC arm; N at follow-up not provided, so N at baseline used Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 8.12: FEF 25-75 (l/s)

Study or Subgroup 8.12.1 Absolute values at follow-up Cobb 2021 a Nicotine EC Mean 2.6 SD 1.24 Total 130 Non-nicotine EC Mean 2.4 SD 1.04 Total 130 Std. Mean Difference IV, Random, 95% CI 0.17 [-0.07 , 0.42] Std. Mean Difference IV, Random, 95% CI -1 -0.5 0 0.5 1 Favours non-nicotine EC Favours nicotine EC Risk of Bias A + B + C + D + E + F + G Footnotes a Comparing highest (36mg) dose EC arm to no-nicotine EC arm; N at follow-up not provided, so N at baseline used Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 8.13: FeNO (ppb)

Study or Subgroup 8.13.1 Change from baseline Caponnetto 2013* a Nicotine EC Mean 2.8 SD 1.7 Total 49 Non-nicotine EC Mean 0.45 SD 1 Total 41 Mean Difference IV, Random, 95% CI 2.35 [1.78 , 2.92] Mean Difference IV, Random, 95% CI -4 -2 0 2 4 Favours nicotine EC Favours non-nicotine EC Risk of Bias A + B + C + D + E + F ? G Footnotes a Data are 2.4% nicotine compared to no-nicotine; 1.8% nicotine arm reported elsewhere Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 8.14: Product use at 6+ months

Study or Subgroup Bullen 2013 Cobb 2021 a Cobb 2021 b Eisenberg 2020 Total (HKSJ c ) Total events: Test for overall effect: T = 1.08, df = 3 (P = 0.36) Heterogeneity: Tau² (DL d ) = 0.02; Chi² = 4.30, df = 3 (P = 0.23); I² = 30% Nicotine EC Events 71 49 62 37 219 Total 241 130 130 100 601 Non-nicotine EC Events 20 23 24 21 88 Total 57 65 65 86 273 Weight 24.9% 25.5% 28.5% 21.2% 100.0% Risk Ratio M-H, Random, 95% CI 0.84 [0.56 , 1.26] 1.07 [0.72 , 1.58] 1.29 [0.90 , 1.86] 1.52 [0.96 , 2.38] 1.14 [0.77 , 1.69] Risk Ratio M-H, Random, 95% CI 0.05 0.2 1 5 20 Higher in non-nicotine EC Higher in nicotine EC Risk of Bias A + + + + B + + + + C + + + + D + + + + E + + + + F + + + + G Footnotes a 8 mg/mL; control group split to avoid double-counting. Data provided as ITT with n randomized as denominator; those not followed up assumed to be not using study product b 36 mg/mL; control group split to avoid double-counting. Data provided as ITT with n randomized as denominator; those not followed up assumed to be not using study product c CI calculated by Hartung-Knapp-Sidik-Jonkman (HKSJ) method. d Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 8.15: EC use with no combustible tobacco use

Study or Subgroup Bullen 2013 Cobb 2021 a Total (Wald b ) Total events: Test for overall effect: Z = 1.31 (P = 0.19) Heterogeneity: Tau² (DL c ) = 1.78; Chi² = 2.13, df = 1 (P = 0.14); I² = 53% EC Events 8 12 20 Total 241 86 327 Non-nicotine EC Events 1 0 1 Total 57 74 131 Weight 57.1% 42.9% 100.0% Risk Ratio M-H, Random, 95% CI 1.89 [0.24 , 14.83] 21.55 [1.30 , 357.89] 5.38 [0.43 , 66.54] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours EC Favours non-nicotine EC Risk of Bias A + + B + + C + + D + + E + + F + + G Footnotes a Using data from 36mg nicotine arm b CI calculated by Wald-type method. c Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 8.16: No EC or combustible tobacco use

Study or Subgroup Bullen 2013 Cobb 2021 a Total (Wald b ) Total events: Test for overall effect: Z = 0.73 (P = 0.47) Heterogeneity: Tau² (DL c ) = 0.00; Chi² = 0.01, df = 1 (P = 0.94); I² = 0% EC Events 13 2 15 Total 241 86 327 Non-nicotine EC Events 2 1 3 Total 57 74 131 Weight 72.6% 27.4% 100.0% Risk Ratio M-H, Random, 95% CI 1.54 [0.36 , 6.62] 1.72 [0.16 , 18.60] 1.59 [0.46 , 5.51] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours non-nicotine EC Favours EC Risk of Bias A + + B + + C + + D + + E + + F + + G Footnotes a Using data from 36mg nicotine arm b CI calculated by Wald-type method. c Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 8.17: EC + combustible tobacco use

Study or Subgroup Bullen 2013 Cobb 2021 a Total (Wald b ) Total events: Test for overall effect: Z = 1.17 (P = 0.24) Heterogeneity: Tau² (DL c ) = 0.00; Chi² = 0.40, df = 1 (P = 0.53); I² = 0% EC Events 63 50 113 Total 241 86 327 Non-nicotine EC Events 19 47 66 Total 57 74 131 Weight 25.6% 74.4% 100.0% Risk Ratio M-H, Random, 95% CI 0.78 [0.51 , 1.20] 0.92 [0.71 , 1.17] 0.88 [0.71 , 1.09] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours EC Favours non-nicotine EC Risk of Bias A + + B + + C + + D + + E + + F + + G Footnotes a Using data from 36mg nicotine arm b CI calculated by Wald-type method. c Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 8.18: Combustible tobacco use with no EC use

Study or Subgroup Bullen 2013 EC Events 157 Total 241 Non-nicotine EC Events 35 Total 57 Risk Ratio M-H, Random, 95% CI 1.06 [0.85 , 1.33] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours EC Favours non-nicotine EC Risk of Bias A + B + C + D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 8.19: Adverse events (with Robinson)

Study or Subgroup Bullen 2013 Eisenberg 2020 Meier 2017 NCT03625986 Okuyemi 2022 Robinson 2025 Rose 2023* Total (Wald a ) Test for overall effect: Z = 0.38 (P = 0.70) Heterogeneity: Tau² (REML b ) = 0.00; Chi² = 1.32, df = 5 (P = 0.93); I² = 0% log[RR] -0.02701337 0.008963941 0.4054651 0.2894662 0 0.2876821 0.1670541 SE 0.1615986 0.03348722 0.8660254 0.3973989 0 0.396746 0.57634 Nicotine EC Total 241 128 24 35 109 169 11 717 Non-nicotine EC Total 57 127 24 34 106 169 13 530 Weight 4.0% 94.2% 0.1% 0.7% 0.7% 0.3% 100.0% Risk Ratio IV, Random, 95% CI 0.97 [0.71 , 1.34] 1.01 [0.94 , 1.08] 1.50 [0.27 , 8.19] 1.34 [0.61 , 2.91] Not estimable 1.33 [0.61 , 2.90] 1.18 [0.38 , 3.66] 1.01 [0.95 , 1.08] Risk Ratio IV, Random, 95% CI 0.01 0.1 1 10 100 Favours nicotine EC Favours non-nicotine EC Risk of Bias A + + ? ? ? ? ? B + + ? + ? + ? C + + + + + + + D + + + + + + + E + + ? + + + + F + + + + + + + G + Footnotes a CI calculated by Wald-type method. b Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 8.20: Serious adverse events (with Robinson)

Study or Subgroup Bullen 2013 Caponnetto 2013* Cobb 2021 a Cobb 2021 b Eisenberg 2020 George 2019 Lucchiari 2022 Meier 2017 NCT03625986 Okuyemi 2022 Robinson 2025 Rose 2023* c Tuisku 2024 Total (Wald d ) Test for overall effect: Z = 0.01 (P = 0.99) Heterogeneity: Tau² (DL e ) = 0.00; Chi² = 3.05, df = 12 (P = 1.00); I² = 0% RD 0.02940962 0 0.01194217 -0.04637971 -0.01593258 0 0 0 0.02857143 0 0 0.09090909 0 SE 0.03894634 0.01808065 0.05472428 0.05762815 0.02183139 0.02614209 0.01403483 0.03959798 0.0388782 0.009197953 0.005847953 0.1075848 0.01302868 Nicotine EC Total 241 72 86 81 128 37 70 24 35 109 169 11 152 1215 Non-nicotine EC Total 57 45 37 37 127 37 70 24 34 106 169 13 153 909 Weight 1.1% 5.0% 0.5% 0.5% 3.4% 2.4% 8.3% 1.0% 1.1% 19.3% 47.7% 0.1% 9.6% 100.0% Risk Difference IV, Random, 95% CI 0.03 [-0.05 , 0.11] 0.00 [-0.04 , 0.04] 0.01 [-0.10 , 0.12] -0.05 [-0.16 , 0.07] -0.02 [-0.06 , 0.03] 0.00 [-0.05 , 0.05] 0.00 [-0.03 , 0.03] 0.00 [-0.08 , 0.08] 0.03 [-0.05 , 0.10] 0.00 [-0.02 , 0.02] 0.00 [-0.01 , 0.01] 0.09 [-0.12 , 0.30] 0.00 [-0.03 , 0.03] 0.00 [-0.01 , 0.01] Risk Difference IV, Random, 95% CI -0.5 -0.25 0 0.25 0.5 Favours nicotine EC Favours non-nicotine EC Risk of Bias A + + + + + + + ? ? ? ? ? + B + + + + + + + ? + ? + ? + C + + + + + ? + + + + + + + D + + + + + − + + + + + + + E + + + + + ? + ? + + + + + F + ? + + + + − + + + + + + G + Footnotes a 36 mg/mL; control group split to avoid double counting b 8 mg/mL; control group split to avoid double counting c All participants receiving placebo patch d CI calculated by Wald-type method. e Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.1: Smoking cessation

Study or Subgroup Auer 2024 a Begh 2021 Carpenter 2023 Cox 2022 Eisenberg 2020 Halpern 2018 Holliday 2019 b Lucchiari 2022 Pope 2024 Pratt 2022 Xu 2023* Total (HKSJ c ) Total events: Test for overall effect: T = 5.41, df = 10 (P = 0.0003) Heterogeneity: Tau² (DL d ) = 0.02; Chi² = 11.45, df = 10 (P = 0.32); I² = 13% Nicotine EC Events 141 7 58 5 4 4 6 15 35 6 91 372 Total 622 164 427 239 128 1199 40 70 484 120 566 4059 Usual care Events 102 3 17 4 0 0 2 10 20 2 14 174 Total 624 161 211 236 121 813 40 70 488 120 271 3155 Weight 40.3% 2.6% 14.5% 2.7% 0.6% 0.6% 2.0% 8.0% 13.6% 1.9% 13.3% 100.0% Risk Ratio M-H, Random, 95% CI 1.39 [1.10 , 1.74] 2.29 [0.60 , 8.70] 1.69 [1.01 , 2.82] 1.23 [0.34 , 4.54] 8.51 [0.46 , 156.44] 6.11 [0.33 , 113.24] 3.00 [0.64 , 13.98] 1.50 [0.72 , 3.11] 1.76 [1.03 , 3.01] 3.00 [0.62 , 14.57] 3.11 [1.81 , 5.36] 1.75 [1.39 , 2.20] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours usual care Favours nicotine EC Risk of Bias A + + + + + ? + + + + + B + + + + + ? + + + + + C − − − + + − − + − − − D + + − + + + + + + + − E + + + − + − + + + + + F + + + + + + + − + ? ? G Footnotes a As NRT was not provided by the study, we classed this comparator arm as "behavioural support only." b Although participants were given a choice of nicotine concentration including 0 mg, none of the participants chose the non-nicotine e-liquid c CI calculated by Hartung-Knapp-Sidik-Jonkman (HKSJ) method. d Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.2: Adverse events

Study or Subgroup Auer 2024 Carpenter 2017 a Carpenter 2023 Cioe 2025 Cox 2022 Cravo 2016* Eisenberg 2020 Holliday 2019 b Kale 2025 NCT05278065 Piper 2025 Total (HKSJ c ) Total events: Test for overall effect: T = 2.22, df = 9 (P = 0.05) Heterogeneity: Tau² (DL d ) = 0.02; Chi² = 21.65, df = 9 (P = 0.01); I² = 58% Nicotine EC Events 272 20 180 0 3 271 120 5 12 1 34 918 Total 575 34 292 13 162 306 128 29 15 11 54 1619 Usual care Events 229 8 86 0 0 80 88 0 10 0 8 509 Total 556 16 163 14 111 102 121 29 12 5 53 1182 Weight 20.8% 4.4% 18.1% 0.2% 22.2% 21.7% 0.2% 8.8% 0.2% 3.3% 100.0% Risk Ratio M-H, Random, 95% CI 1.15 [1.01 , 1.31] 1.18 [0.67 , 2.07] 1.17 [0.98 , 1.39] Not estimable 4.81 [0.25 , 92.21] 1.13 [1.01 , 1.26] 1.29 [1.15 , 1.45] 11.00 [0.64 , 190.26] 0.96 [0.67 , 1.37] 1.50 [0.07 , 31.57] 4.17 [2.13 , 8.16] 1.22 [1.00 , 1.49] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours nicotine EC Favours usual care Risk of Bias A + ? + + + + + + + ? + B + ? + + + + + + + − ? C − − − − + − + − − − − D + − − + + − + + + + − E + + + + − + + + + + + F + ? + + + + + + + ? + G + Footnotes a 24 mg EC arm included here; 16 mg data reported elsewhere b Participants offered choice of nicotine or no-nicotine EC; all chose nicotine-containing EC c CI calculated by Hartung-Knapp-Sidik-Jonkman (HKSJ) method. d Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.3: Serious adverse events

Study or Subgroup Auer 2024 Avila 2024 Begh 2021 Carpenter 2017 a Carpenter 2023 Cioe 2025 Cox 2022 Cravo 2016* Edmiston 2022* b Eisenberg 2020 George 2019 Holliday 2019 c Kale 2025 NCT05278065 Piper 2025 Pope 2024 Pratt 2022 Pulvers 2020 Total (Wald d ) Total events: Test for overall effect: Z = 0.60 (P = 0.55) Heterogeneity: Tau² (DL e ) = 0.00; Chi² = 9.50, df = 17 (P = 0.92); I² = 0% Nicotine EC Events 25 0 11 0 1 0 1 5 0 3 0 0 0 0 0 25 2 0 73 Total 575 14 148 34 292 13 162 306 300 128 37 29 15 11 54 484 120 115 2837 Usual care Events 31 0 6 0 0 0 0 0 0 4 0 0 0 0 0 25 7 0 73 Total 566 7 144 16 163 14 111 102 150 121 40 29 12 5 53 488 120 54 2195 Weight 5.4% 0.1% 1.2% 0.4% 24.8% 0.2% 9.3% 8.5% 32.5% 2.0% 1.4% 0.8% 0.2% 0.1% 2.7% 4.4% 1.5% 4.4% 100.0% Risk Difference M-H, Random, 95% CI -0.01 [-0.04 , 0.01] 0.00 [-0.19 , 0.19] 0.03 [-0.02 , 0.09] 0.00 [-0.09 , 0.09] 0.00 [-0.01 , 0.02] 0.00 [-0.13 , 0.13] 0.01 [-0.01 , 0.03] 0.02 [-0.00 , 0.04] 0.00 [-0.01 , 0.01] -0.01 [-0.05 , 0.03] 0.00 [-0.05 , 0.05] 0.00 [-0.06 , 0.06] 0.00 [-0.13 , 0.13] 0.00 [-0.25 , 0.25] 0.00 [-0.04 , 0.04] 0.00 [-0.03 , 0.03] -0.04 [-0.09 , 0.01] 0.00 [-0.03 , 0.03] 0.00 [-0.00 , 0.01] Risk Difference M-H, Random, 95% CI -1 -0.5 0 0.5 1 Favours nicotine EC Favours usual care Risk of Bias A + + + ? + + + + ? + + + + ? + + + + B + + + ? + + + + ? + + + + − ? + + + C − + − − − − + − − + ? − − − − − − − D + + + − − + + − ? + − + + + − + + + E + + + + + + − + + + ? + + + + + + + F + − + ? + + + + + + + + + ? + + ? + G + Footnotes a Data from 24 mg arm (0 events in 16 mg arm as well) b Menthol and tobacco flavour arms were combined c Participants offered choice of nicotine or no-nicotine EC; all chose nicotine-containing EC d CI calculated by Wald-type method. e Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.4: Carbon monoxide (ppm)

Study or Subgroup 9.4.1 Change from baseline Avila 2024 Holliday 2019 Ikonomidis 2024 Piper 2025 a Pulvers 2020 9.4.2 Absolute values at follow-up Adriaens 2014 Begh 2021 Carpenter 2017 Cioe 2025 Hatsukami 2020 Ikonomidis 2020a Ikonomidis 2020b Ozga-Hess 2019 Pratt 2022 Nicotine EC Mean -15.36 -12 -7.9 -8.91 -8.13 6.4 25.3 22.4 17.9 11.02 5.6 5.9 18.3 21.8 SD 22.7 11 5.1 10.1 2.75 1.6 13.8 15.2 12.8 8.96 3.8 0.7 15.9 8.7 Total 14 29 25 54 114 31 148 42 14 58 20 20 18 108 Usual care Mean 8.72 -5.8 1.2 -6.81 -0.37 14.7 23.8 32.9 16.4 16.96 10.2 13.6 19.7 21.9 SD 26.3 12.3 4.8 9.57 3.59 1.6 10.8 16.9 10.8 9.94 3.8 1.3 13.5 8.4 Total 7 29 50 53 54 15 144 19 16 32 20 20 16 105 Mean Difference IV, Random, 95% CI -24.08 [-46.90 , -1.26] -6.20 [-12.21 , -0.19] -9.10 [-11.50 , -6.70] -2.10 [-5.83 , 1.63] -7.76 [-8.84 , -6.68] -8.30 [-9.29 , -7.31] 1.50 [-1.34 , 4.34] -10.50 [-19.38 , -1.62] 1.50 [-7.04 , 10.04] -5.94 [-10.08 , -1.80] -4.60 [-6.96 , -2.24] -7.70 [-8.35 , -7.05] -1.40 [-11.28 , 8.48] -0.10 [-2.40 , 2.20] Mean Difference IV, Random, 95% CI -50 -25 0 25 50 Favours EC Favours usual care Risk of Bias A + + ? + + + + ? + ? + ? ? + B + + ? ? + ? + ? + ? ? ? ? + C + − + − − + − − − ? ? − − − D + + + − + + + − + + + ? + + E + + ? + + + + + + + + ? − + F − + ? + + ? + ? + + ? − + ? G + Footnotes a Data provided by author. Values collapse NRT active and placebo conditions (authors report no interaction found). Values are at the end of 'Switch Week 1 Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.5: Heart rate (bpm)

Study or Subgroup 9.5.1 Absolute values at follow-up Hatsukami 2020 Katz 2025 Subtotal (Wald a ) Test for overall effect: Z = 0.67 (P = 0.51) Heterogeneity: Tau² (REML b ) = 0.00; Chi² = 0.29, df = 1 (P = 0.59); I² = 0% Test for subgroup differences: Not applicable Nicotine EC Mean 74.81 83.2 SD 13.91 18.4 Total 58 10 68 Usual care Mean 73.64 77.9 SD 11.81 13.4 Total 32 11 43 Weight 86.7% 13.3% 100.0% Mean Difference IV, Random, 95% CI 1.17 [-4.27 , 6.61] 5.30 [-8.58 , 19.18] 1.72 [-3.34 , 6.78] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours EC Favours usual care Risk of Bias A ? ? B ? ? C ? ? D + + E + ? F + ? G Footnotes a CI calculated by Wald-type method. b Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.6: Systolic blood pressure

Study or Subgroup 9.6.1 Change from baseline Pulvers 2020 Subtotal Test for overall effect: Z = 3.09 (P = 0.002) Heterogeneity: Not applicable 9.6.2 Absolute values at follow-up Hatsukami 2020 Ikonomidis 2020a Katz 2025 Subtotal (HKSJ a ) Test for overall effect: T = 0.10, df = 2 (P = 0.93) Heterogeneity: Tau² (REML b ) = 0.00; Chi² = 1.89, df = 2 (P = 0.39); I² = 0% Total (HKSJ a ) Test for overall effect: T = 2.25, df = 3 (P = 0.11) Test for subgroup differences: Chi² = 1.31, df = 1 (P = 0.25), I² = 23.9% Heterogeneity: Tau² (REML b ) = 0.40; Chi² = 3.14, df = 3 (P = 0.37); I² = 4% Nicotine EC Mean 1.07 123.1 128.7 121.5 SD 5.68 13.3 19.9 20.8 Total 114 114 58 20 10 88 202 Usual care Mean 3.75 123.1 123.5 129.6 SD 5.03 13.2 15.1 14.9 Total 54 54 32 20 11 63 117 Weight 84.5% 84.5% 10.9% 3.1% 1.5% 15.5% 100.0% Mean Difference IV, Random, 95% CI -2.68 [-4.38 , -0.98] -2.68 [-4.38 , -0.98] 0.00 [-5.71 , 5.71] 5.20 [-5.75 , 16.15] -8.10 [-23.71 , 7.51] 0.24 [-10.05 , 10.52] -2.23 [-5.38 , 0.92] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours EC Favours usual care Risk of Bias A + ? + ? B + ? ? ? C − ? ? ? D + + + + E + + + ? F + + ? ? G Footnotes a CI calculated by Hartung-Knapp-Sidik-Jonkman (HKSJ) method. b Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.7: Blood oxygen saturation

Study or Subgroup 9.7.1 Absolute values at follow-up Hatsukami 2020 Nicotine EC Mean 98.1 SD 1.5 Total 57 Usual care Mean 97.9 SD 0.9 Total 32 Mean Difference IV, Random, 95% CI 0.20 [-0.30 , 0.70] Mean Difference IV, Random, 95% CI -1 -0.5 0 0.5 1 Favours usual care Favours EC Risk of Bias A ? B ? C ? D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.8: NNAL (SMD)

Study or Subgroup 9.8.1 Absolute values at follow-up Carpenter 2017 a Hatsukami 2020 b Pratt 2022 c 9.8.2 Change from baseline Cravo 2016* d Edmiston 2022* e Pulvers 2020 f Nicotine EC Mean 151.8 1.2 1.4 -76 -172.1 -65.91 SD 158.1 1.7 1.095 189.2 158 39.41 Total 41 57 120 284 232 114 Usual care Mean 156.9 1.2 1.73 6 -6.3 14.23 SD 125.8 1 1.295 163.3 205.8 39.62 Total 19 31 120 100 128 54 Std. Mean Difference IV, Random, 95% CI -0.03 [-0.58 , 0.51] 0.00 [-0.44 , 0.44] -0.27 [-0.53 , -0.02] -0.45 [-0.68 , -0.22] -0.94 [-1.16 , -0.71] -2.02 [-2.41 , -1.63] Std. Mean Difference IV, Random, 95% CI -2 -1 0 1 2 Favours EC Favours usual care Risk of Bias A ? ? + + ? + B ? ? + + ? + C − ? − − − − D − + + − ? + E + + + + + + F ? + ? + + + G + Footnotes a Measured as pg/mL b Measured as pmol/mg creatinine c Measured as pmol/mg creatinine; n is those randomized, n followed up not available by arm d Measured as nanograms e ng/g f pg/mL Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.9: 3-HPMA (SMD)

Study or Subgroup 9.9.1 Absolute values at follow-up Hatsukami 2020 a Subtotal Test for overall effect: Z = 1.38 (P = 0.17) Heterogeneity: Not applicable 9.9.2 Change from baseline Cravo 2016* b Subtotal Test for overall effect: Z = 4.28 (P < 0.0001) Heterogeneity: Not applicable Total (Wald c ) Test for overall effect: Z = 4.42 (P < 0.00001) Test for subgroup differences: Chi² = 0.63, df = 1 (P = 0.43), I² = 0% Heterogeneity: Tau² (REML d ) = 0.00; Chi² = 0.63, df = 1 (P = 0.43); I² = 0% Nicotine EC Mean 4612 -530 SD 4263 1272.5 Total 58 58 284 284 342 Usual care Mean 5926 96 SD 4298 1142.9 Total 32 32 100 100 132 Weight 22.0% 22.0% 78.0% 78.0% 100.0% Std. Mean Difference IV, Random, 95% CI -0.30 [-0.74 , 0.13] -0.30 [-0.74 , 0.13] -0.50 [-0.73 , -0.27] -0.50 [-0.73 , -0.27] -0.46 [-0.66 , -0.26] Std. Mean Difference IV, Random, 95% CI -2 -1 0 1 2 Favours EC Favours usual care Risk of Bias A ? + B ? + C ? − D + − E + + F + + G Footnotes a Measured as pmol/mg creatinine b Measured as micrograms c CI calculated by Wald-type method. d Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.10: 2-HPMA (pmol/mg creatinine)

Study or Subgroup 9.10.1 Absolute values at follow-up Hatsukami 2020 Nicotine EC Mean 733.2 SD 855.6 Total 58 Usual care Mean 1013.1 SD 1887.6 Total 32 Mean Difference IV, Random, 95% CI -279.90 [-969.98 , 410.18] Mean Difference IV, Random, 95% CI -1000 -500 0 500 1000 Favours EC Favours usual care Risk of Bias A ? B ? C ? D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.11: HMPMA (pmol/mg creatinine)

Study or Subgroup 9.11.1 Absolute values at follow-up Hatsukami 2020 Nicotine EC Mean 3959 SD 3633 Total 58 Usual care Mean 5631 SD 5701 Total 32 Mean Difference IV, Random, 95% CI -1672.00 [-3857.37 , 513.37] Mean Difference IV, Random, 95% CI -5000 -2500 0 2500 5000 Favours EC Favours usual care Risk of Bias A ? B ? C ? D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.12: PheT (pmol/mg creatinine)

Study or Subgroup 9.12.1 Absolute values at follow-up Hatsukami 2020 Nicotine EC Mean 2.9 SD 2.8 Total 56 Usual care Mean 4.2 SD 8 Total 32 Mean Difference IV, Random, 95% CI -1.30 [-4.17 , 1.57] Mean Difference IV, Random, 95% CI -10 -5 0 5 10 Favours EC Favours usual care Risk of Bias A ? B ? C ? D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.13: CEMA (pmol/mg creatinine)

Study or Subgroup 9.13.1 Absolute values at follow-up Hatsukami 2020 Nicotine EC Mean 512 SD 443 Total 58 Usual care Mean 509 SD 358 Total 32 Mean Difference IV, Random, 95% CI 3.00 [-165.47 , 171.47] Mean Difference IV, Random, 95% CI -200 -100 0 100 200 Favours EC Favours usual care Risk of Bias A ? B ? C ? D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.14: AAMA (pmol/mg creatinine)

Study or Subgroup 9.14.1 Absolute values at follow-up Hatsukami 2020 Nicotine EC Mean 495.2 SD 390.9 Total 58 Usual care Mean 563.1 SD 328.2 Total 32 Mean Difference IV, Random, 95% CI -67.90 [-219.73 , 83.93] Mean Difference IV, Random, 95% CI -500 -250 0 250 500 Favours EC Favours usual care Risk of Bias A ? B ? C ? D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.15: S-PMA (nanograms)

Study or Subgroup 9.15.1 Change from baseline Cravo 2016* Nicotine EC Mean -1340 SD 3426.3 Total 284 Usual care Mean 31 SD 2451.5 Total 100 Mean Difference IV, Random, 95% CI -1371.00 [-1995.23 , -746.77] Mean Difference IV, Random, 95% CI -1000 -500 0 500 1000 Favours EC Favours usual care Risk of Bias A + B + C − D − E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.16: FEV1 (SMD)

Study or Subgroup 9.16.1 Change from baseline Cioe 2025 Cravo 2016* Edmiston 2022* Subtotal (HKSJ a ) Test for overall effect: T = 1.01, df = 2 (P = 0.42) Heterogeneity: Tau² (REML b ) = 0.02; Chi² = 3.86, df = 2 (P = 0.15); I² = 51% 9.16.2 Absolute values at follow-up Katz 2025 NCT05278065 Subtotal (HKSJ a ) Test for overall effect: T = 1.57, df = 1 (P = 0.36) Heterogeneity: Tau² (REML b ) = 0.00; Chi² = 0.04, df = 1 (P = 0.84); I² = 0% Total (HKSJ a ) Test for overall effect: T = 1.54, df = 4 (P = 0.20) Test for subgroup differences: Chi² = 0.01, df = 1 (P = 0.92), I² = 0% Heterogeneity: Tau² (REML b ) = 0.02; Chi² = 3.91, df = 4 (P = 0.42); I² = 29% Nicotine EC Mean 1.8 -0.1 -0.7 -2.1 2.32 SD 0.74 0.9 6.2 1.1 0.93 Total 14 286 212 512 10 11 21 533 Usual care Mean 1.9 -0.1 -2.5 -2.3 2.3 SD 0.7 0.8 5.7 1.3 0.57 Total 16 101 115 232 11 5 16 248 Weight 8.2% 41.0% 40.8% 90.0% 6.0% 4.0% 10.0% 100.0% Std. Mean Difference IV, Random, 95% CI -0.14 [-0.85 , 0.58] 0.00 [-0.23 , 0.23] 0.30 [0.07 , 0.53] 0.12 [-0.39 , 0.62] 0.16 [-0.70 , 1.02] 0.02 [-1.03 , 1.08] 0.10 [-0.74 , 0.95] 0.12 [-0.10 , 0.34] Std. Mean Difference IV, Random, 95% CI -1 -0.5 0 0.5 1 Favours usual care Favours nicotine EC Risk of Bias A + + ? ? ? B + + ? ? − C − − − ? − D + − ? + + E + + + ? + F + + + ? ? G Footnotes a CI calculated by Hartung-Knapp-Sidik-Jonkman (HKSJ) method. b Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.17: FEV1/FVC

Study or Subgroup 9.17.1 Change from baseline Edmiston 2022* Subtotal Test for overall effect: Z = 3.44 (P = 0.0006) Heterogeneity: Not applicable 9.17.2 Value at follow-up Katz 2025 Subtotal Test for overall effect: Z = 0.31 (P = 0.76) Heterogeneity: Not applicable Total (Wald a ) Test for overall effect: Z = 1.34 (P = 0.18) Test for subgroup differences: Chi² = 3.41, df = 1 (P = 0.06), I² = 70.6% Heterogeneity: Tau² (REML b ) = 0.82; Chi² = 3.41, df = 1 (P = 0.06); I² = 71% Nicotine EC Mean 0.36 -2.1 SD 4.5 1.4 Total 212 212 10 10 222 Usual care Mean -1.36 -2.3 SD 4.21 1.6 Total 115 115 11 11 126 Weight 53.9% 53.9% 46.1% 46.1% 100.0% Mean Difference IV, Random, 95% CI 1.72 [0.74 , 2.70] 1.72 [0.74 , 2.70] 0.20 [-1.08 , 1.48] 0.20 [-1.08 , 1.48] 1.02 [-0.47 , 2.50] Mean Difference IV, Random, 95% CI -10 -5 0 5 10 Favours usual care Favours nicotine EC Risk of Bias A ? ? B ? ? C − ? D ? + E + ? F + ? G Footnotes a CI calculated by Wald-type method. b Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.18: FVC (SMD)

Study or Subgroup 9.18.1 Change from baseline Katz 2025 a Subtotal Test for overall effect: Z = 0.21 (P = 0.83) Heterogeneity: Not applicable 9.18.2 Absolute values at follow-up NCT05278065 b Subtotal Test for overall effect: Z = 0.25 (P = 0.80) Heterogeneity: Not applicable Total (Wald c ) Test for overall effect: Z = 0.32 (P = 0.75) Test for subgroup differences: Chi² = 0.00, df = 1 (P = 0.95), I² = 0% Heterogeneity: Tau² (REML d ) = 0.00; Chi² = 0.00, df = 1 (P = 0.95); I² = 0% Nicotine EC Mean -1 3.13 SD 1.1 1.16 Total 10 10 11 11 21 Usual care Mean -1.1 2.98 SD 1 0.74 Total 11 11 5 5 16 Weight 60.4% 60.4% 39.6% 39.6% 100.0% Std. Mean Difference IV, Random, 95% CI 0.09 [-0.77 , 0.95] 0.09 [-0.77 , 0.95] 0.13 [-0.92 , 1.19] 0.13 [-0.92 , 1.19] 0.11 [-0.56 , 0.77] Std. Mean Difference IV, Random, 95% CI -4 -2 0 2 4 Favours usual care Favours nicotine EC Risk of Bias A ? ? B ? − C ? − D + + E ? + F ? ? G Footnotes a reported as Z scores b litres c CI calculated by Wald-type method. d Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.19: FEF 25-75 (litres/second))

Study or Subgroup 9.19.1 Change from baseline Cravo 2016* Pulvers 2020 Subtotal (HKSJ a ) Test for overall effect: T = 0.26, df = 1 (P = 0.84) Heterogeneity: Tau² (REML b ) = 0.02; Chi² = 3.68, df = 1 (P = 0.06); I² = 73% 9.19.2 Absolute values at follow-up NCT05278065 Subtotal Test for overall effect: Z = 0.58 (P = 0.56) Heterogeneity: Not applicable Total (HKSJ a ) Test for overall effect: T = 0.51, df = 2 (P = 0.66) Test for subgroup differences: Chi² = 0.24, df = 1 (P = 0.63), I² = 0% Heterogeneity: Tau² (REML b ) = 0.02; Chi² = 3.86, df = 2 (P = 0.14); I² = 53% Nicotine EC Mean -0.1 -0.11 1.88 SD 0.4 0.43 0.98 Total 286 114 400 11 11 411 Usual care Mean -0.2 0.03 2.12 SD 1 0.44 0.64 Total 101 54 155 5 5 160 Weight 41.9% 52.0% 93.9% 6.1% 6.1% 100.0% Mean Difference IV, Random, 95% CI 0.10 [-0.10 , 0.30] -0.14 [-0.28 , 0.00] -0.03 [-1.55 , 1.49] -0.24 [-1.05 , 0.57] -0.24 [-1.05 , 0.57] -0.05 [-0.43 , 0.34] Mean Difference IV, Random, 95% CI -2 -1 0 1 2 Favours usual care Favours nicotine EC Risk of Bias A + + ? B + + − C − − − D − + + E + + + F + + ? G Footnotes a CI calculated by Hartung-Knapp-Sidik-Jonkman (HKSJ) method. b Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.20: PEF (litres/minute)

Study or Subgroup 9.20.1 Absolute values at follow-up NCT05278065 Nicotine EC Mean 6.68 SD 2.91 Total 11 Usual care Mean 5.69 SD 1.69 Total 5 Mean Difference IV, Random, 95% CI 0.99 [-1.28 , 3.26] Mean Difference IV, Random, 95% CI -4 -2 0 2 4 Favours usual care Favours nicotine EC Risk of Bias A ? B − C − D + E + F ? G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.21: PEF 25-75 (litres/minute)

Study or Subgroup 9.21.1 Change from baseline Cravo 2016* Nicotine EC Mean 11.7 SD 75.9 Total 286 Usual care Mean 18.8 SD 103.6 Total 101 Mean Difference IV, Random, 95% CI -7.10 [-29.14 , 14.94] Mean Difference IV, Random, 95% CI -50 -25 0 25 50 Favours usual care Favours nicotine EC Risk of Bias A + B + C − D − E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.22: FeNo (ppb)

Study or Subgroup 9.22.1 Absolute values at follow-up NCT05278065 Nicotine EC Mean 10.9 SD 8.96 Total 11 Usual care Mean 7.75 SD 2.36 Total 5 Mean Difference IV, Random, 95% CI 3.15 [-2.53 , 8.83] Mean Difference IV, Random, 95% CI -10 -5 0 5 10 Favours nicotine EC Favours usual care Risk of Bias A ? B − C − D + E + F ? G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.23: EC use with no combustible tobacco use

Study or Subgroup Auer 2024 Carpenter 2023 Cox 2022 Total (HKSJ a ) Total events: Test for overall effect: T = 2.14, df = 2 (P = 0.17) Heterogeneity: Tau² (DL b ) = 1.46; Chi² = 17.88, df = 2 (P = 0.0001); I² = 89% EC Events 267 39 4 310 Total 552 292 162 1006 Usual care Events 15 7 2 24 Total 504 163 111 778 Weight 37.9% 35.7% 26.4% 100.0% Risk Ratio M-H, Random, 95% CI 16.25 [9.80 , 26.95] 3.11 [1.42 , 6.79] 1.37 [0.26 , 7.35] 4.69 [0.21 , 105.12] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with usual care Higher with EC Risk of Bias A + + + B + + + C − − + D + − + E + + − F + + + G Footnotes a CI calculated by Hartung-Knapp-Sidik-Jonkman (HKSJ) method. b Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.24: No EC or combustible tobacco use

Study or Subgroup Auer 2024 Carpenter 2023 Cox 2022 EC Events 62 34 1 Total 552 292 162 Usual care Events 179 13 0 Total 504 163 111 Risk Ratio M-H, Random, 95% CI 0.32 [0.24 , 0.41] 1.46 [0.79 , 2.69] 2.06 [0.08 , 50.14] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with usual care Higher with EC Risk of Bias A + + + B + + + C − − + D + − + E + + − F + + + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.25: EC + combustible tobacco use

Study or Subgroup Auer 2024 Carpenter 2023 Cox 2022 a Total (Wald b ) Total events: Test for overall effect: Z = 12.72 (P < 0.00001) Heterogeneity: Tau² (DL c ) = 0.00; Chi² = 1.91, df = 2 (P = 0.38); I² = 0% EC Events 101 194 123 418 Total 552 292 239 1083 Usual care Events 16 23 32 71 Total 504 163 236 903 Weight 20.1% 35.3% 44.6% 100.0% Risk Ratio M-H, Random, 95% CI 5.76 [3.45 , 9.63] 4.71 [3.20 , 6.94] 3.80 [2.69 , 5.36] 4.45 [3.54 , 5.61] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with usual care Higher with EC Risk of Bias A + + + B + + + C − − + D + − + E + + − F + + + G Footnotes a Denominator is N randomised as investigators assumed those lost to follow-up were continuing to smoke b CI calculated by Wald-type method. c Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 9.26: Combustible tobacco use with no EC use

Study or Subgroup Auer 2024 Carpenter 2023 a Cox 2022 b Total (HKSJ c ) Total events: Test for overall effect: T = 7.49, df = 2 (P = 0.02) Heterogeneity: Tau² (DL d ) = 0.03; Chi² = 10.32, df = 2 (P = 0.006); I² = 81% EC Events 122 160 111 393 Total 552 427 239 1218 Usual care Events 294 168 202 664 Total 504 211 236 951 Weight 31.6% 34.4% 34.0% 100.0% Risk Ratio M-H, Random, 95% CI 0.38 [0.32 , 0.45] 0.47 [0.41 , 0.54] 0.54 [0.47 , 0.63] 0.46 [0.30 , 0.72] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with usual care Higher with EC Risk of Bias A + + + B + + + C − − + D + − + E + + − F + + + G Footnotes a Denominator is n randomized b Denominator is N randomised as investigators assumed those lost to follow-up were continuing to smoke c CI calculated by Hartung-Knapp-Sidik-Jonkman (HKSJ) method. d Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 10.1: Smoking cessation

Study or Subgroup Cobb 2021 a Higher nicotine Events 10 Total 130 Lower nicotine Events 4 Total 130 Risk Ratio M-H, Random, 95% CI 2.50 [0.80 , 7.77] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours lower nicotine Favours higher nicotine Risk of Bias A + B + C + D + E + F + G Footnotes a 36 v 8 mg/mL Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 10.2: Adverse events

Study or Subgroup Kanobe 2022* Higher Events 17 Total 33 Lower Events 20 Total 35 Risk Ratio M-H, Random, 95% CI 0.90 [0.58 , 1.40] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours higher Favours lower Risk of Bias A + B + C − D + E + F − G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 10.3: Serious adverse events

Study or Subgroup Caponnetto 2013* Cobb 2021 a Total (Wald b ) Total events: Test for overall effect: Z = 0.42 (P = 0.68) Heterogeneity: Tau² (DL c ) = 0.00; Chi² = 0.71, df = 1 (P = 0.40); I² = 0% Higher nicotine content Events 0 8 8 Total 35 86 121 Lower nicotine content Events 0 5 5 Total 37 81 118 Weight 70.1% 29.9% 100.0% Risk Difference M-H, Random, 95% CI 0.00 [-0.05 , 0.05] 0.03 [-0.05 , 0.11] 0.01 [-0.03 , 0.05] Risk Difference M-H, Random, 95% CI -1 -0.5 0 0.5 1 Favours higher Favours lower Risk of Bias A + + B + + C + + D + + E + + F ? + G Footnotes a 36 v 8 mg/mL b CI calculated by Wald-type method. c Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 10.4: Carbon monoxide (ppm)

Study or Subgroup 10.4.1 Change from baseline Caponnetto 2013* Cobb 2021 Subtotal (Wald a ) Test for overall effect: Z = 2.21 (P = 0.03) Heterogeneity: Tau² (REML b ) = 0.00; Chi² = 0.95, df = 1 (P = 0.33); I² = 0% 10.4.2 Absolute values at follow-up Kimber 2021 Subtotal Test for overall effect: Z = 0.65 (P = 0.51) Heterogeneity: Not applicable Total (Wald a ) Test for overall effect: Z = 2.28 (P = 0.02) Test for subgroup differences: Chi² = 0.09, df = 1 (P = 0.77), I² = 0% Heterogeneity: Tau² (REML b ) = 0.00; Chi² = 1.04, df = 2 (P = 0.59); I² = 0% higher dose Mean -6 -5.53 10.55 SD 6.4 2.7 7.97 Total 76 80 156 20 20 176 lower dose Mean -5.8 -4.4 12.21 SD 3.4 3.1 7.94 Total 79 74 153 19 19 172 Weight 23.8% 73.7% 97.5% 2.5% 2.5% 100.0% Mean Difference IV, Random, 95% CI -0.20 [-1.82 , 1.42] -1.13 [-2.05 , -0.21] -0.90 [-1.70 , -0.10] -1.66 [-6.65 , 3.33] -1.66 [-6.65 , 3.33] -0.92 [-1.71 , -0.13] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours higher dose Favours lower dose Risk of Bias A + + + B + + ? C + + + D + + + E + + − F ? + − G Footnotes a CI calculated by Wald-type method. b Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 10.5: Heart rate

Study or Subgroup 10.5.1 Change from baseline Caponnetto 2013* Subtotal Test for overall effect: Z = 0.87 (P = 0.38) Heterogeneity: Not applicable 10.5.2 Absolute values at follow-up Cobb 2021 a Subtotal Test for overall effect: Z = 1.34 (P = 0.18) Heterogeneity: Not applicable Total (Wald b ) Test for overall effect: Z = 0.31 (P = 0.76) Test for subgroup differences: Chi² = 2.46, df = 1 (P = 0.12), I² = 59.4% Heterogeneity: Tau² (REML c ) = 1.74; Chi² = 2.46, df = 1 (P = 0.12); I² = 59% higher dose Mean -1.7 79.33 SD 3.4 11.65 Total 73 73 130 130 203 lower dose Mean -1.2 77.41 SD 3.6 11.43 Total 75 75 130 130 205 Weight 64.7% 64.7% 35.3% 35.3% 100.0% Mean Difference IV, Random, 95% CI -0.50 [-1.63 , 0.63] -0.50 [-1.63 , 0.63] 1.92 [-0.89 , 4.73] 1.92 [-0.89 , 4.73] 0.36 [-1.91 , 2.62] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours higher dose Favours lower dose Risk of Bias A + + B + + C + + D + + E + + F ? + G Footnotes a N at follow-up not provided, so N at baseline used b CI calculated by Wald-type method. c Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 10.6: Systolic blood pressure

Study or Subgroup 10.6.1 Change from baseline Caponnetto 2013* Subtotal Test for overall effect: Z = 0.88 (P = 0.38) Heterogeneity: Not applicable 10.6.2 Absolute values at follow-up Cobb 2021 a Subtotal Test for overall effect: Z = 0.57 (P = 0.57) Heterogeneity: Not applicable Total (Wald b ) Test for overall effect: Z = 1.03 (P = 0.30) Test for subgroup differences: Chi² = 0.02, df = 1 (P = 0.88), I² = 0% Heterogeneity: Tau² (REML c ) = 0.00; Chi² = 0.02, df = 1 (P = 0.88); I² = 0% higher dose Mean -3.9 125.85 SD 5.7 14.82 Total 73 73 130 130 203 lower dose Mean -4.7 124.72 SD 5.4 17.08 Total 75 75 130 130 205 Weight 82.5% 82.5% 17.5% 17.5% 100.0% Mean Difference IV, Random, 95% CI 0.80 [-0.99 , 2.59] 0.80 [-0.99 , 2.59] 1.13 [-2.76 , 5.02] 1.13 [-2.76 , 5.02] 0.86 [-0.77 , 2.48] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours higher dose Favours lower dose Risk of Bias A + + B + + C + + D + + E + + F ? + G Footnotes a N at follow-up not provided, so N at baseline used b CI calculated by Wald-type method. c Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 10.7: NNAL (pg/mg creatinine) at 24 weeks

Study or Subgroup 10.7.1 Change from baseline Cobb 2021 Higher nicotine Mean -155.35 SD 266.1 Total 79 Lower nicotine Mean -141.46 SD 259.14 Total 73 Mean Difference IV, Random, 95% CI -13.89 [-97.42 , 69.64] Mean Difference IV, Random, 95% CI -100 -50 0 50 100 Favours higher nicotine Favours lower nicotine Risk of Bias A + B + C + D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 10.8: FEV1 (l)

Study or Subgroup 10.8.1 Change from baseline Caponnetto 2013* Subtotal Test for overall effect: Z = 0.19 (P = 0.85) Heterogeneity: Not applicable 10.8.2 Absolute values at follow-up Cobb 2021 a Subtotal Test for overall effect: Z = 1.59 (P = 0.11) Heterogeneity: Not applicable Total (Wald b ) Test for overall effect: Z = 0.66 (P = 0.51) Test for subgroup differences: Chi² = 2.18, df = 1 (P = 0.14), I² = 54.0% Heterogeneity: Tau² (REML c ) = 0.01; Chi² = 2.18, df = 1 (P = 0.14); I² = 54% higher dose Mean 0 2.67 SD 0.3 0.81 Total 47 47 130 130 177 lower dose Mean 0.01 2.52 SD 0.2 0.71 Total 43 43 130 130 173 Weight 61.9% 61.9% 38.1% 38.1% 100.0% Mean Difference IV, Random, 95% CI -0.01 [-0.11 , 0.09] -0.01 [-0.11 , 0.09] 0.15 [-0.04 , 0.34] 0.15 [-0.04 , 0.34] 0.05 [-0.10 , 0.20] Mean Difference IV, Random, 95% CI -2 -1 0 1 2 Favours lower dose Favours higher dose Risk of Bias A + + B + + C + + D + + E + + F ? + G Footnotes a N at follow-up not provided, so N at baseline used b CI calculated by Wald-type method. c Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 10.9: FVC (l)

Study or Subgroup 10.9.1 Change from baseline Caponnetto 2013* Subtotal Test for overall effect: Z = 0.47 (P = 0.64) Heterogeneity: Not applicable 10.9.2 Absolute values at follow-up Cobb 2021 a Subtotal Test for overall effect: Z = 0.97 (P = 0.33) Heterogeneity: Not applicable Total (Wald b ) Test for overall effect: Z = 0.87 (P = 0.39) Test for subgroup differences: Chi² = 0.42, df = 1 (P = 0.52), I² = 0% Heterogeneity: Tau² (REML c ) = 0.00; Chi² = 0.42, df = 1 (P = 0.52); I² = 0% higher dose Mean -0.02 3.38 SD 0.3 0.9 Total 47 47 130 130 177 lower dose Mean 0.01 3.5 SD 0.3 1.08 Total 43 43 130 130 173 Weight 79.1% 79.1% 20.9% 20.9% 100.0% Mean Difference IV, Random, 95% CI -0.03 [-0.15 , 0.09] -0.03 [-0.15 , 0.09] -0.12 [-0.36 , 0.12] -0.12 [-0.36 , 0.12] -0.05 [-0.16 , 0.06] Mean Difference IV, Random, 95% CI -2 -1 0 1 2 Favours lower dose Favours higher dose Risk of Bias A + + B + + C + + D + + E + + F ? + G Footnotes a N at follow-up not provided, so N at baseline used b CI calculated by Wald-type method. c Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 10.10: FEV1/FVC

Study or Subgroup 10.10.1 Change from baseline Caponnetto 2013* Subtotal Test for overall effect: Z = 2.33 (P = 0.02) Heterogeneity: Not applicable 10.10.2 Absolute values at follow-up Cobb 2021 a Subtotal Test for overall effect: Z = 0.71 (P = 0.48) Heterogeneity: Not applicable Total (Wald b ) Test for overall effect: Z = 2.44 (P = 0.01) Test for subgroup differences: Chi² = 0.00, df = 1 (P = 0.99), I² = 0% Heterogeneity: Tau² (REML c ) = 0.00; Chi² = 0.00, df = 1 (P = 0.99); I² = 0% higher dose Mean 0.96 78.65 SD 2 8.86 Total 47 47 130 130 177 lower dose Mean 0.05 77.76 SD 1.7 11.14 Total 43 43 130 130 173 Weight 91.1% 91.1% 8.9% 8.9% 100.0% Mean Difference IV, Random, 95% CI 0.91 [0.15 , 1.67] 0.91 [0.15 , 1.67] 0.89 [-1.56 , 3.34] 0.89 [-1.56 , 3.34] 0.91 [0.18 , 1.64] Mean Difference IV, Random, 95% CI -10 -5 0 5 10 Favours lower dose Favours higher dose Risk of Bias A + + B + + C + + D + + E + + F ? + G Footnotes a N at follow-up not provided, so N at baseline used b CI calculated by Wald-type method. c Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 10.11: PEF (l/s)

Study or Subgroup 10.11.1 Absolute values at follow-up Cobb 2021 a Higher dose Mean 6.26 SD 1.66 Total 130 Lower dose Mean 6.15 SD 1.86 Total 130 Std. Mean Difference IV, Random, 95% CI 0.06 [-0.18 , 0.31] Std. Mean Difference IV, Random, 95% CI -1 -0.5 0 0.5 1 Favours lower dose Favours higher dose Risk of Bias A + B + C + D + E + F + G Footnotes a N at follow-up not provided, so N at baseline used Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 10.12: FEF 25-75 (l/s)

Study or Subgroup 10.12.1 Absolute values at follow-up Cobb 2021 a Higher dose Mean 2.6 SD 1.24 Total 130 Lower dose Mean 2.62 SD 1.27 Total 130 Std. Mean Difference IV, Random, 95% CI -0.02 [-0.26 , 0.23] Std. Mean Difference IV, Random, 95% CI -1 -0.5 0 0.5 1 Favours lower dose Favours higher dose Risk of Bias A + B + C + D + E + F + G Footnotes a N at follow-up not provided, so N at baseline used Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 10.13: FeNO (ppb)

Study or Subgroup 10.13.1 Change from baseline Caponnetto 2013* higher dose Mean 2.8 SD 1.7 Total 49 lower dose Mean 2.5 SD 1.6 Total 44 Mean Difference IV, Random, 95% CI 0.30 [-0.37 , 0.97] Mean Difference IV, Random, 95% CI -10 -5 0 5 10 Favours higher dose Favours lower dose Risk of Bias A + B + C + D + E + F ? G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 10.14: Product use at 6+ months

Study or Subgroup Cobb 2021 Higher nicotine Events 62 Total 130 Lower nicotine Events 49 Total 130 Risk Ratio M-H, Random, 95% CI 1.27 [0.95 , 1.68] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher use with lower nicotine Higher use with higher nicotine Risk of Bias A + B + C + D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 10.15: EC use with no combustible tobacco use

Study or Subgroup Cobb 2021 Higher nicotine content Events 12 Total 86 Lower nicotine content Events 5 Total 81 Risk Ratio M-H, Random, 95% CI 2.26 [0.83 , 6.13] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with lower nicotine Higher with higher nicotine Risk of Bias A + B + C + D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 10.16: No EC or combustible tobacco use

Study or Subgroup Cobb 2021 Higher nicotine Events 2 Total 86 Lower nicotine Events 1 Total 81 Risk Ratio M-H, Random, 95% CI 1.88 [0.17 , 20.38] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with lower nicotine Higher with higher nicotine Risk of Bias A + B + C + D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 10.17: EC + combustible tobacco use

Study or Subgroup Cobb 2021 Higher nicotine content Events 50 Total 86 Lower nicotine content Events 44 Total 81 Risk Ratio M-H, Random, 95% CI 1.07 [0.82 , 1.40] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with lower nicotine Higher with higher nicotine Risk of Bias A + B + C + D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 11.1: Smoking cessation

Study or Subgroup Xu 2023* Choice of flavours Events 40 Total 281 Tobacco flavour Events 51 Total 285 Risk Ratio M-H, Random, 95% CI 0.80 [0.54 , 1.16] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours tobacco flavour Favours choice of flavours Risk of Bias A + B + C − D − E + F ? G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 11.2: Adverse events (EC as adjunct to VLNC)

Study or Subgroup Higgins 2024 Choice of flavour Events 72 Total 84 Tobacco flavour Events 63 Total 74 Risk Ratio M-H, Random, 95% CI 1.01 [0.88 , 1.15] Risk Ratio M-H, Random, 95% CI 0.2 0.5 1 2 5 Favours choice of flavour Favours tobacco flavour Risk of Bias A ? B + C + D + E + F + G ? Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 11.3: Serious adverse events (EC as adjunct to VLNC)

Study or Subgroup Higgins 2024 Choice of flavour Events 2 Total 84 Tobacco flavour Events 4 Total 74 Risk Difference M-H, Random, 95% CI -0.03 [-0.09 , 0.03] Risk Difference M-H, Random, 95% CI -1 -0.5 0 0.5 1 Favours choice of flavour Favours tobacco flavour Risk of Bias A ? B + C + D + E + F + G ? Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 11.4: Carbon monoxide (ppm; as adjunct to VLNC)

Study or Subgroup 11.4.1 Change from baseline Higgins 2024 Choice of flavours Mean -6.42 SD 20.67 Total 69 Tobacco flavour Mean -1.9 SD 16.48 Total 55 Mean Difference IV, Random, 95% CI -4.52 [-11.06 , 2.02] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours choice of flavours Favours tobacco flavour Risk of Bias A ? B + C + D + E + F + G ? Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 11.5: NNAL (pmol/mg creatinine; as adjunct to VLNC)

Study or Subgroup 11.5.1 Change from baseline Higgins 2024 Choice of flavours Mean -0.5 SD 3.73 Total 53 Tobacco flavour Mean -0.41 SD 2.1 Total 47 Mean Difference IV, Random, 95% CI -0.09 [-1.26 , 1.08] Mean Difference IV, Random, 95% CI -4 -2 0 2 4 Favours choice of flavours Favours tobacco flavour Risk of Bias A ? B + C + D + E + F + G ? Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 11.6: Product use at 6+ months

Study or Subgroup Xu 2023* Choice of flavours Events 91 Total 261 Tobacco flavour Events 83 Total 261 Risk Ratio M-H, Random, 95% CI 1.10 [0.86 , 1.40] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with tobacco flavour Higher with choice of flavours Risk of Bias A + B + C − D − E + F ? G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 12.1: Adverse events

Study or Subgroup NCT03277495 Choice of flavour Events 16 Total 22 Usual cigarette flavour (tobacco/menthol) Events 17 Total 19 Risk Ratio IV, Random, 95% CI 0.81 [0.60 , 1.10] Risk Ratio IV, Random, 95% CI 0.01 0.1 1 10 100 Favours flavour choice Favours usual flavour Risk of Bias A ? B ? C + D + E + F + G − Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 12.2: Serious adverse events

Study or Subgroup NCT03277495 Choice of flavour Events 2 Total 22 Usual cigarette flavour (tobacco/menthol) Events 1 Total 19 Risk Difference IV, Random, 95% CI 0.04 [-0.12 , 0.19] Risk Difference IV, Random, 95% CI -1 -0.5 0 0.5 1 Favours flavour choice Favours usual flavour Risk of Bias A ? B ? C + D + E + F + G − Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 12.3: Carbon monoxide (ppm)

Study or Subgroup 12.3.1 Absolute values at follow-up NCT03277495 Choice of flavour Mean [ppm] 10.05 SD [ppm] 12.51 Total 22 Usual cigarette flavour (tobacco/menthol) Mean [ppm] 9.58 SD [ppm] 10.47 Total 19 Mean Difference IV, Random, 95% CI [ppm] 0.47 [-6.56 , 7.50] Mean Difference IV, Random, 95% CI [ppm] -20 -10 0 10 20 Favours choice Favours usual flavour Risk of Bias A ? B ? C + D + E + F + G − Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 12.4: Heart rate

Study or Subgroup 12.4.1 Absolute values at follow-up NCT03277495 Choice of flavour Mean [ppm] 77.12 SD [ppm] 10.58 Total 22 Usual cigarette flavour (tobacco/menthol) Mean [ppm] 80.11 SD [ppm] 12.78 Total 19 Mean Difference IV, Random, 95% CI [ppm] -2.99 [-10.24 , 4.26] Mean Difference IV, Random, 95% CI [ppm] -20 -10 0 10 20 Favours choice Favours usual flavour Risk of Bias A ? B ? C + D + E + F + G − Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 12.5: Systolic blood pressure

Study or Subgroup 12.5.1 Absolute values at follow-up NCT03277495 Choice of flavour Mean [ppm] 120.84 SD [ppm] 13.67 Total 22 Usual cigarette flavour (tobacco/menthol) Mean [ppm] 120.18 SD [ppm] 15.13 Total 19 Mean Difference IV, Random, 95% CI [ppm] 0.66 [-8.22 , 9.54] Mean Difference IV, Random, 95% CI [ppm] -20 -10 0 10 20 Favours choice Favours usual flavour Risk of Bias A ? B ? C + D + E + F + G − Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 13.1: Serious adverse events

Study or Subgroup Edmiston 2022* Tobacco Events 0 Total 150 Menthol Events 0 Total 150 Risk Difference M-H, Random, 95% CI 0.00 [-0.01 , 0.01] Risk Difference M-H, Random, 95% CI -1 -0.5 0 0.5 1 Favours tobacco flavour Favours menthol flavour Risk of Bias A ? B ? C − D ? E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 13.2: NNAL (ng/g)

Study or Subgroup 13.2.1 Change from baseline Edmiston 2022* Tobacco Mean -185.6 SD 157.8 Total 112 Menthol Mean -159.5 SD 157.8 Total 120 Mean Difference IV, Random, 95% CI -26.10 [-66.73 , 14.53] Mean Difference IV, Random, 95% CI -100 -50 0 50 100 Favours tobacco Favours menthol Risk of Bias A ? B ? C − D ? E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 13.3: FEV1 (% predicted)

Study or Subgroup 13.3.1 Change from baseline Edmiston 2022* Tobacco Mean -1.04 SD 6.2 Total 100 Menthol Mean -0.37 SD 6.2 Total 112 Mean Difference IV, Random, 95% CI -0.67 [-2.34 , 1.00] Mean Difference IV, Random, 95% CI -10 -5 0 5 10 Favours menthol Favours tobacco Risk of Bias A ? B ? C − D ? E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 13.4: FEV1/FVC

Study or Subgroup 13.4.1 Change from baseline Edmiston 2022* Tobacco Mean 0.12 SD 4.47 Total 100 Menthol Mean 0.58 SD 4.47 Total 112 Mean Difference IV, Random, 95% CI -0.46 [-1.67 , 0.75] Mean Difference IV, Random, 95% CI -4 -2 0 2 4 Favours menthol Favours tobacco Risk of Bias A ? B ? C − D ? E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 14.1: Carbon monoxide (ppm)

Study or Subgroup 14.1.1 Absolute values at follow-up Kimber 2021 a Refillable Mean 10.6 SD 8 Total 20 Cartridge Mean 9.9 SD 7.9 Total 12 Mean Difference IV, Random, 95% CI 0.70 [-4.98 , 6.38] Mean Difference IV, Random, 95% CI -10 -5 0 5 10 Favours refillable Favours cartridge Risk of Bias A + B ? C + D + E − F − G Footnotes a This is using data from the 'Tank18' (higher nicotine) refillable arm. Exhaled CO was higher in the 'Tank6' (lower nicotine) arm (12.2, SD 7.9). Result not sensitive to choice of arm. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 15.1: Smoking cessation

Study or Subgroup Russell 2021* Nicotine salt Events 44 Total 145 Free-base nicotine Events 34 Total 140 Risk Ratio M-H, Random, 95% CI 1.25 [0.85 , 1.83] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours free-base Favours nicotine salt Risk of Bias A ? B ? C + D + E + F ? G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 15.2: Product use at 6+ months

Study or Subgroup Russell 2021* NSP Events 62 Total 124 FBNP Events 48 Total 103 Risk Ratio M-H, Random, 95% CI 1.07 [0.82 , 1.41] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with FBNP Higher with NSP Risk of Bias A ? B ? C + D + E + F ? G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 16.1: Smoking cessation

Study or Subgroup NCT03113136 Higher wattage Events 8 Total 134 Lower wattage Events 11 Total 133 Risk Ratio M-H, Random, 95% CI 0.72 [0.30 , 1.74] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours lower wattage Favours higher wattage Risk of Bias A + B ? C + D + E − F ? G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 16.2: Adverse events

Study or Subgroup NCT03113136 Higher wattage Events 95 Total 134 Lower wattage Events 103 Total 133 Risk Ratio M-H, Random, 95% CI 0.92 [0.79 , 1.06] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours higher wattage Favours lower wattage Risk of Bias A + B ? C + D + E − F ? G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 16.3: Serious adverse events

Study or Subgroup NCT03113136 Higher wattage Events 2 Total 134 Lower wattage Events 2 Total 133 Risk Difference M-H, Random, 95% CI -0.00 [-0.03 , 0.03] Risk Difference M-H, Random, 95% CI -1 -0.5 0 0.5 1 Favours higher wattage Favours lower wattage Risk of Bias A + B ? C + D + E − F ? G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 17.1: Smoking cessation

Study or Subgroup Klonizakis 2022 Lee 2019 a Total (Wald b ) Total events: Test for overall effect: Z = 0.03 (P = 0.98) Heterogeneity: Tau² (DL c ) = 0.04; Chi² = 1.57, df = 1 (P = 0.21); I² = 36% Non-nicotine EC Events 30 16 46 Total 82 75 157 NRT Events 25 21 46 Total 82 75 157 Weight 58.3% 41.7% 100.0% Risk Ratio M-H, Random, 95% CI 1.20 [0.78 , 1.85] 0.76 [0.43 , 1.34] 0.99 [0.64 , 1.54] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours NRT Favours non-nicotine EC Risk of Bias A + + B + + C + + D + + E + + F ? + G Footnotes a 0.01 mg/mL of nicotine in e-liquid b CI calculated by Wald-type method. c Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 17.2: Adverse events

Study or Subgroup Lee 2019 a Non-nicotine EC Events 5 Total 71 NRT Events 13 Total 61 Risk Ratio M-H, Random, 95% CI 0.33 [0.12 , 0.87] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours non-nicotine EC Favours NRT Risk of Bias A + B + C + D + E + F + G Footnotes a 0.01 mg/mL of nicotine in e-liquid; length of follow-up not defined but presumably over study period Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 17.3: Serious adverse events

Study or Subgroup Lee 2019 a Non-nicotine EC Events 0 Total 71 NRT Events 0 Total 61 Risk Difference M-H, Random, 95% CI 0.00 [-0.03 , 0.03] Risk Difference M-H, Random, 95% CI -1 -0.5 0 0.5 1 Favours non-nicotine EC Favours NRT Risk of Bias A + B + C + D + E + F + G Footnotes a 0.01 mg/mL of nicotine in e-liquid; length of follow-up not defined but presumably over study period Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 17.4: Carbon monoxide (ppm)

Study or Subgroup 17.4.1 Change from baseline Klonizakis 2022 Non-nicotine EC Mean -6 SD 9.24 Total 82 NRT Mean -8 SD 6.93 Total 82 Mean Difference IV, Random, 95% CI 2.00 [-0.50 , 4.50] Mean Difference IV, Random, 95% CI -10 -5 0 5 10 Favours non-nicotine EC Favours NRT Risk of Bias A + B + C + D + E + F ? G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 18.1: Smoking cessation

Study or Subgroup Eisenberg 2020 Lucchiari 2022 Total (Wald a ) Total events: Test for overall effect: Z = 1.32 (P = 0.19) Heterogeneity: Tau² (DL b ) = 0.00; Chi² = 0.29, df = 1 (P = 0.59); I² = 0% Non-nicotine EC Events 3 15 18 Total 127 70 197 Usual care Events 1 10 11 Total 121 70 191 Weight 9.5% 90.5% 100.0% Risk Ratio M-H, Random, 95% CI 2.86 [0.30 , 27.10] 1.50 [0.72 , 3.11] 1.59 [0.80 , 3.19] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours usual care Favours non-nicotine EC Risk of Bias A + + B + + C + + D + + E + + F + − G Footnotes a CI calculated by Wald-type method. b Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 18.2: Adverse events

Study or Subgroup Eisenberg 2020 Non-nicotine EC Events 118 Total 127 behavioural support only/no support Events 88 Total 121 Risk Ratio M-H, Random, 95% CI 1.28 [1.13 , 1.44] Risk Ratio M-H, Random, 95% CI 0.1 0.2 0.5 1 2 5 10 Favours non-nicotine Favours behavioural Risk of Bias A + B + C + D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 18.3: Serious adverse events

Study or Subgroup Eisenberg 2020 Lucchiari 2022 Total (Wald a ) Total events: Test for overall effect: Z = 0.14 (P = 0.89) Heterogeneity: Tau² (DL b ) = 0.00; Chi² = 0.09, df = 1 (P = 0.76); I² = 0% Non-nicotine EC Events 5 0 5 Total 127 70 197 behavioural support only/no support Events 4 0 4 Total 121 70 191 Weight 26.0% 74.0% 100.0% Risk Difference M-H, Random, 95% CI 0.01 [-0.04 , 0.05] 0.00 [-0.03 , 0.03] 0.00 [-0.02 , 0.03] Risk Difference M-H, Random, 95% CI -1 -0.5 0 0.5 1 Favours non-nicotine Favours behavioural Risk of Bias A + + B + + C + + D + + E + + F + − G Footnotes a CI calculated by Wald-type method. b Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 19.1: Smoking cessation

Study or Subgroup Walker 2020 a Non-nicotine EC + NRT Events 20 Total 499 NRT Events 3 Total 125 Risk Ratio M-H, Random, 95% CI 1.67 [0.50 , 5.53] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours NRT alone Favours EC + NRT Risk of Bias A + B + C − D + E + F ? G Footnotes a this represents an EC + patch versus patch only comparison Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 19.2: Adverse events

Study or Subgroup Walker 2020 Non-nicotine EC + NRT Events 116 Total 290 NRT Events 31 Total 54 Risk Ratio M-H, Random, 95% CI 0.70 [0.53 , 0.91] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours non-nicotine EC + NRT Favours NRT Risk of Bias A + B + C − D + E + F ? G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 19.3: Serious adverse events

Study or Subgroup Walker 2020 Non-nicotine EC + NRT Events 27 Total 499 NRT Events 4 Total 125 Risk Difference M-H, Random, 95% CI 0.02 [-0.01 , 0.06] Risk Difference M-H, Random, 95% CI -1 -0.5 0 0.5 1 Favours non-nicotine EC+NRT Favours NRT Risk of Bias A + B + C − D + E + F ? G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 20.1: Smoking cessation

Study or Subgroup Elling 2023 Martinez 2021 Total (Wald a ) Total events: Test for overall effect: Z = 0.32 (P = 0.75) Heterogeneity: Tau² (DL b ) = 0.00; Chi² = 0.28, df = 1 (P = 0.60); I² = 0% Advice to use EC to quit Events 28 249 277 Total 157 1167 1324 Advice does not include EC Events 34 237 271 Total 174 1154 1328 Weight 10.9% 89.1% 100.0% Risk Ratio M-H, Random, 95% CI 0.91 [0.58 , 1.43] 1.04 [0.89 , 1.22] 1.02 [0.88 , 1.19] Risk Ratio M-H, Random, 95% CI 0.85 0.9 1 1.1 1.2 Favours no EC advice Favours EC advice Risk of Bias A ? + B ? + C ? + D − + E + + F + + G Footnotes a CI calculated by Wald-type method. b Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 20.2: Adverse events

Study or Subgroup Vickerman 2022 Advice to use EC to quit Events 14 Total 26 Advice does not include EC Events 11 Total 26 Risk Ratio M-H, Random, 95% CI 1.27 [0.72 , 2.26] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours EC advice Favours no EC advice Risk of Bias A + B + C ? D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 20.3: Serious adverse events

Study or Subgroup Vickerman 2022 Total Total events: Test for overall effect: Z = 0.00 (P = 1.00) Heterogeneity: Not applicable Advice to use EC to quit Events 0 0 Total 26 26 Advice does not include EC Events 0 0 Total 26 26 Weight 100.0% 100.0% Risk Difference M-H, Random, 95% CI 0.00 [-0.07 , 0.07] 0.00 [-0.07 , 0.07] Risk Difference M-H, Random, 95% CI -1 -0.5 0 0.5 1 Favours EC advice Favours no EC advice Risk of Bias A + B + C ? D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 20.4: EC use with no combustible tobacco use

Study or Subgroup Martinez 2021 Advice to use EC to quit Events 209 Total 640 Advice does not include EC Events 222 Total 619 Risk Ratio M-H, Random, 95% CI 0.91 [0.78 , 1.06] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with no EC advice Higher with EC advice Risk of Bias A + B + C + D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 20.5: No EC or combustible tobacco use

Study or Subgroup Martinez 2021 Advice to use EC to quit Events 104 Total 640 Advice does not include EC Events 89 Total 619 Risk Ratio M-H, Random, 95% CI 1.13 [0.87 , 1.47] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with no EC advice Higher with EC advice Risk of Bias A + B + C + D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 20.6: EC + combustible tobacco use

Study or Subgroup Elling 2023 Martinez 2021 Advice to use EC to quit Events 5 209 Total 139 640 Advice does not include EC Events 11 192 Total 138 619 Risk Ratio M-H, Random, 95% CI 0.45 [0.16 , 1.26] 1.05 [0.90 , 1.24] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with no EC advice Higher with EC advice Risk of Bias A ? + B ? + C ? + D − + E + + F + + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 20.7: Combustible tobacco use with no EC use

Study or Subgroup Martinez 2021 Advice to use EC to quit Events 118 Total 640 Advice does not include EC Events 116 Total 619 Risk Ratio M-H, Random, 95% CI 0.98 [0.78 , 1.24] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with no EC advice Higher with EC advice Risk of Bias A + B + C + D + E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 21.1: Smoking cessation

Study or Subgroup Baldassarri 2018 a Walker 2020 a Total (Wald b ) Total events: Test for overall effect: Z = 2.21 (P = 0.03) Heterogeneity: Tau² (DL c ) = 0.00; Chi² = 0.03, df = 1 (P = 0.87); I² = 0% Nicotine EC + NRT Events 4 35 39 Total 20 500 520 Non-nicotine EC + NRT Events 2 20 22 Total 20 499 519 Weight 10.3% 89.7% 100.0% Risk Ratio M-H, Random, 95% CI 2.00 [0.41 , 9.71] 1.75 [1.02 , 2.98] 1.77 [1.07 , 2.94] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours non-nicotine EC Favours nicotine EC Risk of Bias A + + B ? + C + − D + + E − + F + ? G Footnotes a this represents an EC + patch versus non-nicotine EC + patch comparison b CI calculated by Wald-type method. c Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 21.2: Adverse events

Study or Subgroup Rose 2023* Walker 2020 Total (Wald a ) Total events: Test for overall effect: Z = 1.16 (P = 0.24) Heterogeneity: Tau² (DL b ) = 0.00; Chi² = 0.29, df = 1 (P = 0.59); I² = 0% Nicotine EC + NRT Events 21 138 159 Total 37 317 354 Non-nicotine EC + NRT Events 15 116 131 Total 33 290 323 Weight 14.0% 86.0% 100.0% Risk Ratio M-H, Random, 95% CI 1.25 [0.78 , 1.99] 1.09 [0.90 , 1.31] 1.11 [0.93 , 1.32] Risk Ratio M-H, Random, 95% CI 0.1 0.2 0.5 1 2 5 10 Favours nicotine EC Favours non-nicotine EC Risk of Bias A ? + B ? + C + − D + + E + + F + ? G + Footnotes a CI calculated by Wald-type method. b Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 21.3: Serious adverse events

Study or Subgroup Rose 2023* Walker 2020 Total (Wald a ) Total events: Test for overall effect: Z = 1.47 (P = 0.14) Heterogeneity: Tau² (DL b ) = 0.00; Chi² = 0.09, df = 1 (P = 0.77); I² = 0% Nicotine EC + NRT Events 2 18 20 Total 37 500 537 Non-nicotine EC + NRT Events 3 27 30 Total 33 499 532 Weight 4.2% 95.8% 100.0% Risk Difference M-H, Random, 95% CI -0.04 [-0.16 , 0.09] -0.02 [-0.04 , 0.01] -0.02 [-0.04 , 0.01] Risk Difference M-H, Random, 95% CI -1 -0.5 0 0.5 1 Favours nicotine EC Favours non-nicotine EC Risk of Bias A ? + B ? + C + − D + + E + + F + ? G + Footnotes a CI calculated by Wald-type method. b Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 21.4: Carbon monoxide (ppm)

Study or Subgroup 21.4.1 Change from baseline Baldassarri 2018 Rose 2023* Subtotal (Wald a ) Test for overall effect: Z = 1.22 (P = 0.22) Heterogeneity: Tau² (REML b ) = 22.69; Chi² = 4.26, df = 1 (P = 0.04); I² = 77% Test for subgroup differences: Not applicable Nicotine EC + NRT Mean -9.5 -11.1 SD 3.9 12.8 Total 13 26 39 Non-nicotine EC + NRT Mean -8.1 -2 SD 3.4 10.2 Total 12 19 31 Weight 58.1% 41.9% 100.0% Mean Difference IV, Random, 95% CI -1.40 [-4.26 , 1.46] -9.10 [-15.83 , -2.37] -4.62 [-12.07 , 2.82] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours nicotine EC Favours non-nicotine EC Risk of Bias A + ? B ? ? C + + D + + E − + F + + G + Footnotes a CI calculated by Wald-type method. b Tau² calculated by Restricted Maximum-Likelihood method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 21.5: FeNO (ppb)

Study or Subgroup 21.5.1 Change from baseline Baldassarri 2018 Nicotine EC Mean 2.75 SD 10.5 Total 12 Non-nicotine EC Mean 3.11 SD 7.45 Total 18 Mean Difference IV, Random, 95% CI -0.36 [-7.23 , 6.51] Mean Difference IV, Random, 95% CI -10 -5 0 5 10 Favours nicotine EC Favours non-nicotine EC Risk of Bias A + B ? C + D + E − F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 21.6: FEV1 (%)

Study or Subgroup 21.6.1 Change from baseline Baldassarri 2018 Nicotine EC Mean 0.0085 SD 0.057 Total 13 Non-nicotine EC Mean -0.037 SD 0.097 Total 19 Mean Difference IV, Random, 95% CI 0.05 [-0.01 , 0.10] Mean Difference IV, Random, 95% CI -0.1 -0.05 0 0.05 0.1 Favours non-nicotine EC Favours nicotine EC Risk of Bias A + B ? C + D + E − F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 21.7: FVC (%)

Study or Subgroup 21.7.1 Change from baseline Baldassarri 2018 Nicotine EC Mean 0.0108 SD 0.065 Total 13 Non-nicotine EC Mean -0.0216 SD 0.103 Total 19 Mean Difference IV, Random, 95% CI 0.03 [-0.03 , 0.09] Mean Difference IV, Random, 95% CI -0.1 -0.05 0 0.05 0.1 Favours non-nicotine EC Favours nicotine EC Risk of Bias A + B ? C + D + E − F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 21.8: Study product use at 6+ months

Study or Subgroup Baldassarri 2018 Nicotine EC Events 2 Total 4 Non-nicotine EC Events 2 Total 5 Risk Ratio M-H, Random, 95% CI 1.25 [0.29 , 5.35] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with non nicotine EC Higher with nicotine EC Risk of Bias A + B ? C + D + E − F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 21.9: EC use with no combustible tobacco use

Study or Subgroup Baldassarri 2018 Nicotine EC + NRT Events 2 Total 13 Non-nicotine EC + NRT Events 1 Total 19 Risk Ratio M-H, Random, 95% CI 2.92 [0.29 , 28.99] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with non-nicotine EC+NRT Higher with nicotine EC+NRT Risk of Bias A + B ? C + D + E − F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 21.10: No EC or combustible tobacco use

Study or Subgroup Baldassarri 2018 Nicotine EC + NRT Events 2 Total 13 Non-nicotine EC + NRT Events 1 Total 19 Risk Ratio M-H, Random, 95% CI 2.92 [0.29 , 28.99] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with non-nicotine EC+NRT Higher with nicotine EC+NRT Risk of Bias A + B ? C + D + E − F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 21.11: EC + combustible tobacco use

Study or Subgroup Baldassarri 2018 Walker 2020 Total (Wald a ) Total events: Test for overall effect: Z = 0.73 (P = 0.47) Heterogeneity: Tau² (DL b ) = 0.92; Chi² = 2.68, df = 1 (P = 0.10); I² = 63% Nicotine EC + NRT Events 1 18 19 Total 13 339 352 Non-nicotine EC + NRT Events 8 18 26 Total 19 337 356 Weight 34.9% 65.1% 100.0% Risk Ratio M-H, Random, 95% CI 0.18 [0.03 , 1.29] 0.99 [0.53 , 1.88] 0.55 [0.11 , 2.74] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with non-nicotine EC+NRT Higher with nicotine EC+NRT Risk of Bias A + + B ? + C + − D + + E − + F + ? G Footnotes a CI calculated by Wald-type method. b Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 21.12: Combustible tobacco use with no EC use

Study or Subgroup Baldassarri 2018 Nicotine EC + NRT Events 8 Total 13 Non-nicotine EC + NRT Events 9 Total 19 Risk Ratio M-H, Random, 95% CI 1.30 [0.69 , 2.46] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with non-nicotine EC+NRT Higher with nicotine EC+NRT Risk of Bias A + B ? C + D + E − F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 22.1: Smoking cessation

Study or Subgroup Morphett 2022b a Walker 2020 b Total (Wald c ) Total events: Test for overall effect: Z = 4.16 (P < 0.0001) Heterogeneity: Tau² (DL d ) = 0.00; Chi² = 0.16, df = 1 (P = 0.69); I² = 0% Nicotine EC + NRT Events 36 35 71 Total 181 500 681 NRT Events 9 3 12 Total 174 125 299 Weight 73.4% 26.6% 100.0% Risk Ratio M-H, Random, 95% CI 3.85 [1.91 , 7.74] 2.92 [0.91 , 9.33] 3.57 [1.96 , 6.51] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours NRT Favours nicotine EC + NRT Risk of Bias A ? + B ? + C + − D + + E ? + F ? ? G Footnotes a Based on quit data at 6 months (prior to study cross-over). NRT arm includes patch and gum/lozenge; EC arm includes patch and EC. b This represents an EC + patch versus patch only c CI calculated by Wald-type method. d Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 22.2: Adverse events

Study or Subgroup Bonevski 2021 a Morphett 2022a b Piper 2025 Walker 2020 Nicotine EC + NRT Events 15 146 31 138 Total 25 619 54 317 NRT Events 10 225 16 31 Total 25 944 53 54 Risk Ratio M-H, Random, 95% CI 1.50 [0.84 , 2.67] 0.99 [0.82 , 1.19] 1.90 [1.19 , 3.04] 0.76 [0.58 , 0.99] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours EC + NRT Favours NRT Risk of Bias A + + + + B + + ? + C − + − − D − − − + E + + + + F + + + ? G Footnotes a NRT not matched between arms b Two NRT only arms combined for comparator Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 22.3: Serious adverse events

Study or Subgroup Bonevski 2021 a Morphett 2022a b NCT02918630 Piper 2025 Walker 2020 Total (Wald c ) Total events: Test for overall effect: Z = 0.04 (P = 0.97) Heterogeneity: Tau² (DL d ) = 0.00; Chi² = 2.19, df = 4 (P = 0.70); I² = 0% Nicotine EC + NRT Events 1 0 0 0 18 19 Total 25 619 3 54 500 1201 NRT Events 0 0 0 0 4 4 Total 25 944 4 53 125 1151 Weight 0.1% 98.8% 0.0% 0.6% 0.6% 100.0% Risk Difference M-H, Random, 95% CI 0.04 [-0.06 , 0.14] 0.00 [-0.00 , 0.00] 0.00 [-0.42 , 0.42] 0.00 [-0.04 , 0.04] 0.00 [-0.03 , 0.04] 0.00 [-0.00 , 0.00] Risk Difference M-H, Random, 95% CI -1 -0.5 0 0.5 1 Favours EC+NRT Favours NRT Risk of Bias A + + ? + + B + + ? ? + C − + ? − − D − − ? − + E + + ? + + F + + − + ? G ? Footnotes a NRT not matched between arms b Two NRT only arms combined for comparator c CI calculated by Wald-type method. d Tau² calculated by DerSimonian and Laird method. Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 22.4: No EC or combustible tobacco use

Study or Subgroup Morphett 2022a Nicotine EC + NRT Events 23 Total 448 NRT Events 21 Total 457 Risk Ratio M-H, Random, 95% CI 1.12 [0.63 , 1.99] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with NRT Higher with nicotine EC+NRT Risk of Bias A + B + C + D − E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 22.5: EC + combustible tobacco use

Study or Subgroup Morphett 2022a Nicotine EC + NRT Events 40 Total 448 NRT Events 13 Total 457 Risk Ratio M-H, Random, 95% CI 3.14 [1.70 , 5.79] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher with NRT Higher with nicotine EC+NRT Risk of Bias A + B + C + D − E + F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 23.1: Adverse events

Study or Subgroup Tattan-Birch 2023 Nicotine EC + varenicline Events 31 Total 48 Varenicline Events 24 Total 44 Risk Ratio M-H, Random, 95% CI 1.18 [0.84 , 1.67] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours EC + varenicline Favours varenicline Risk of Bias A + B + C + D + E − F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 23.2: Serious adverse events

Study or Subgroup Tattan-Birch 2023 Nicotine EC + varenicline Events 0 Total 48 Varenicline Events 0 Total 44 Risk Difference M-H, Random, 95% CI 0.00 [-0.04 , 0.04] Risk Difference M-H, Random, 95% CI -1 -0.5 0 0.5 1 Favours EC + varenicline Favours varenicline Risk of Bias A + B + C + D + E − F + G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 24.1: Smoking cessation

Study or Subgroup Walker 2023 Nicotine EC + cytisine Events 56 Total 296 Cytisine Events 41 Total 301 Risk Ratio M-H, Random, 95% CI 1.39 [0.96 , 2.01] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours cytisine Favours nicotine EC+cytisine Risk of Bias A + B ? C + D + E + F ? G Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 24.2: Adverse events

Study or Subgroup Walker 2023 a Nicotine EC + cytisine Events 171 Total 296 Cytisine Events 150 Total 301 Risk Ratio M-H, Random, 95% CI 1.16 [1.00 , 1.35] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours nicotine EC+cytisine Favours cytisine Risk of Bias A + B ? C + D + E + F ? G Footnotes a Denominator based on number randomised Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 24.3: Serious adverse events

Study or Subgroup Walker 2023 a Nicotine EC + cytisine Events 13 Total 296 Cytisine Events 8 Total 301 Risk Difference M-H, Random, 95% CI 0.02 [-0.01 , 0.05] Risk Difference M-H, Random, 95% CI -1 -0.5 0 0.5 1 Favours nicotine EC+cytisine Favours cytisine Risk of Bias A + B ? C + D + E + F ? G Footnotes a Denominators based on numbers randomised Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 25.1: Adverse events

Study or Subgroup Higgins 2024 a Nicotine EC + VLNC Events 135 Total 158 VLNC Events 75 Total 85 Risk Ratio M-H, Random, 95% CI 0.97 [0.88 , 1.07] Risk Ratio M-H, Random, 95% CI 0.2 0.5 1 2 5 Favours EC + VLNC Favours VLNC Risk of Bias A ? B + C + D + E + F + G ? Footnotes a EC arm combines data from preferred flavour and tobacco flavour arms Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 25.2: Serious adverse events

Study or Subgroup Higgins 2024 a Nicotine EC + VLNC Events 6 Total 158 VLNC Events 4 Total 85 Risk Difference M-H, Random, 95% CI -0.01 [-0.06 , 0.04] Risk Difference M-H, Random, 95% CI -1 -0.5 0 0.5 1 Favours EC + VLNC Favours VLNC Risk of Bias A ? B + C + D + E + F + G ? Footnotes a EC arm combines data from preferred flavour and tobacco flavour arms Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 25.3: Carbon monoxide (ppm)

Study or Subgroup 25.3.1 Change from baseline Higgins 2024 a EC + VLNC Mean -6.42 SD 20.67 Total 69 VLNC Mean 0.73 SD 13.6 Total 63 Mean Difference IV, Random, 95% CI -7.15 [-13.07 , -1.23] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours EC + VLNC Favours VLNC Risk of Bias A ? B + C + D + E + F + G ? Footnotes a The EC + VLNC data comes from the preferred flavour study arm only (i.e. excluding the tobacco flavour arm data) Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 25.4: Heart rate

Study or Subgroup 25.4.1 Change from baseline Higgins 2024 a EC + VLNC Mean -0.1 SD 11.3 Total 70 VLNC Mean 3.2 SD 10 Total 66 Mean Difference IV, Random, 95% CI -3.30 [-6.88 , 0.28] Mean Difference IV, Random, 95% CI -10 -5 0 5 10 Favours EC + VLNC Favours VLNC Risk of Bias A ? B + C + D + E + F + G ? Footnotes a The EC + VLNC data comes from the preferred flavour study arm only (i.e. excluding the tobacco flavour arm data) Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 25.5: Systolic blood pressure

Study or Subgroup 25.5.1 Change from baseline Higgins 2024 a EC + VLNC Mean -2.3 SD 14.9 Total 70 VLNC Mean -1 SD 12.7 Total 66 Mean Difference IV, Random, 95% CI -1.30 [-5.94 , 3.34] Mean Difference IV, Random, 95% CI -10 -5 0 5 10 Favours EC + VLNC Favours VLNC Risk of Bias A ? B + C + D + E + F + G ? Footnotes a The EC + VLNC data comes from the preferred flavour study arm only (i.e. excluding the tobacco flavour arm data) Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 25.6: Blood oxygen saturation

Study or Subgroup 25.6.1 Change from baseline Higgins 2024 a EC + VLNC Mean -0.1 SD 1.2 Total 70 VLNC Mean -0.1 SD 1.5 Total 66 Mean Difference IV, Random, 95% CI 0.00 [-0.46 , 0.46] Mean Difference IV, Random, 95% CI -10 -5 0 5 10 Favours VLNC Favours EC + VLNC Risk of Bias A ? B + C + D + E + F + G ? Footnotes a The EC + VLNC data comes from the preferred flavour study arm only (i.e. excluding the tobacco flavour arm data) Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias

Analysis 25.7: NNAL (pmol/mg creatinine)

Study or Subgroup 25.7.1 Change from baseline Higgins 2024 a EC + VLNC Mean -0.5 SD 3.73 Total 53 VLNC Mean -0.79 SD 7.21 Total 57 Mean Difference IV, Random, 95% CI 0.29 [-1.83 , 2.41] Mean Difference IV, Random, 95% CI -10 -5 0 5 10 Favours EC + VLNC Favours VLNC Risk of Bias A ? B + C + D + E + F + G ? Footnotes a The EC + VLNC data comes from the preferred flavour study arm only (i.e. excluding the tobacco flavour arm data) Risk of bias legend (A) Random sequence generation (selection bias) (B) Allocation concealment (selection bias) (C) Blinding of participants and personnel (performance bias) (D) Blinding of outcome assessment (detection bias) (E) Incomplete outcome data (attrition bias) (F) Selective reporting (reporting bias) (G) Other bias