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, Notley C, Rigotti NA, Turner T, Fanshawe T, Hartmann-Boyce J
https://doi.org/10.1002/14651858.CD010216.pub10

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 cessation92703Risk Ratio (M-H, Fixed, 95% CI)1.55 [1.28, 1.88]
1.1.1 Not selected on pregnancy82384Risk Ratio (M-H, Fixed, 95% CI)1.55 [1.28, 1.87]
1.1.2 Pregnant population1319Risk Ratio (M-H, Fixed, 95% CI)1.78 [0.45, 6.97]
1.2 Adverse events72241Risk Ratio (M-H, Random, 95% CI)1.00 [0.73, 1.37]
1.3 Serious adverse events82950Risk Ratio (M-H, Random, 95% CI)1.22 [0.73, 2.03]
1.4 Carbon monoxide (ppm)5385Mean Difference (IV, Random, 95% CI)−1.98 [−3.78, −0.18]
1.4.1 Absolute values at follow-up1110Mean Difference (IV, Random, 95% CI)−1.87 [−5.15, 1.41]
1.4.2 Change from baseline4275Mean Difference (IV, Random, 95% CI)−2.93 [−6.20, 0.34]
1.5 Heart rate (bpm)2166Mean Difference (IV, Random, 95% CI)0.53 [−1.76, 2.83]
1.5.1 Absolute values at follow-up1111Mean Difference (IV, Random, 95% CI)−0.74 [−5.17, 3.69]
1.5.2 Change from baseline155Mean Difference (IV, Random, 95% CI)1.00 [−1.69, 3.69]
1.6 Systolic blood pressure2166Mean Difference (IV, Random, 95% CI)−1.62 [−3.59, 0.36]
1.6.1 Absolute values at follow-up1111Mean Difference (IV, Random, 95% CI)1.00 [−4.54, 6.54]
1.6.2 Change from baseline155Mean Difference (IV, Random, 95% CI)−2.00 [−4.11, 0.11]
1.7 Blood oxygen saturation2165Mean Difference (IV, Random, 95% CI)−0.14 [−0.59, 0.30]
1.7.1 Absolute values at follow-up1110Mean Difference (IV, Random, 95% CI)−0.20 [−0.72, 0.32]
1.7.2 Change from baseline155Mean Difference (IV, Random, 95% CI)0.00 [−0.83, 0.83]
1.8 3-HPMA (pmol/mg creatinine)1111Mean Difference (IV, Random, 95% CI)−807.00 [−2559.47, 945.47]
1.8.1 Absolute values at follow-up1111Mean Difference (IV, Random, 95% CI)−807.00 [−2559.47, 945.47]
1.9 NNAL (pmol/mg creatinine)1110Mean Difference (IV, Random, 95% CI)0.00 [−0.53, 0.53]
1.9.1 Absolute values at follow-up1110Mean Difference (IV, Random, 95% CI)0.00 [−0.53, 0.53]
1.10 2-HPMA (pmol/mg creatinine)1111Mean Difference (IV, Random, 95% CI)−109.00 [−474.52, 256.52]
1.10.1 Absolute values at follow-up1111Mean Difference (IV, Random, 95% CI)−109.00 [−474.52, 256.52]
1.11 HMPMA (pmol/mg creatinine)1111Mean Difference (IV, Random, 95% CI)−875.00 [−2300.93, 550.93]
1.11.1 Absolute values at follow-up1111Mean Difference (IV, Random, 95% CI)−875.00 [−2300.93, 550.93]
1.12 PheT (pmol/mg creatinine)1109Mean Difference (IV, Random, 95% CI)0.40 [−0.67, 1.47]
1.12.1 Absolute values at follow-up1109Mean Difference (IV, Random, 95% CI)0.40 [−0.67, 1.47]
1.13 CEMA (pmol/mg creatinine)1111Mean Difference (IV, Random, 95% CI)37.00 [−121.50, 195.50]
1.13.1 Absolute values at follow-up1111Mean Difference (IV, Random, 95% CI)37.00 [−121.50, 195.50]
1.14 AAMA (pmol/mg creatinine)1109Mean Difference (IV, Random, 95% CI)32.00 [−109.35, 173.35]
1.14.1 Absolute values at follow-up1109Mean Difference (IV, Random, 95% CI)32.00 [−109.35, 173.35]
1.15 FEV12Std. Mean Difference (IV, Random, 95% CI)Totals not selected
1.15.1 Change from baseline2Std. Mean Difference (IV, Random, 95% CI)Totals not selected
1.16 FEV1/FVC (%)281Mean Difference (IV, Random, 95% CI)10.15 [−24.36, 44.67]
1.16.1 Change from baseline281Mean Difference (IV, Random, 95% CI)10.15 [−24.36, 44.67]
1.17 PEF (L/min)155Mean Difference (IV, Random, 95% CI)−3.00 [−27.09, 21.09]
1.17.1 Change from baseline155Mean Difference (IV, Random, 95% CI)−3.00 [−27.09, 21.09]
1.18 Product use at 6+ months5Risk Ratio (M-H, Random, 95% CI)Totals not selected

Analysis group 2: Nicotine EC versus varenicline

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
2.1 Smoking cessation154Risk Ratio (M-H, Random, 95% CI)0.31 [0.11, 0.82]
2.2 Serious adverse events154Risk Ratio (M-H, Random, 95% CI)Not estimable

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

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
3.1 Smoking cessation1305Risk Ratio (M-H, Random, 95% CI)0.73 [0.53, 1.01]
3.2 Serious adverse events1305Risk Ratio (M-H, Random, 95% CI)5.03 [0.24, 103.97]

Analysis group 4: Nicotine EC versus NRT + bupropion

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
4.1 Smoking cessation138Risk Ratio (M-H, Random, 95% CI)0.89 [0.44, 1.81]

Analysis group 5: Nicotine EC versus heated tobacco

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
5.1 Adverse events1220Risk Ratio (M-H, Random, 95% CI)0.86 [0.68, 1.10]
5.2 SAEs1220Risk Ratio (M-H, Random, 95% CI)Not estimable
5.3 Carbon monoxide (ppm)2267Mean Difference (IV, Random, 95% CI)1.00 [−1.04, 3.03]
5.3.1 Absolute values at 12 weeks1217Mean Difference (IV, Random, 95% CI)1.90 [−0.71, 4.51]
5.3.2 Change at 1 month150Mean Difference (IV, Random, 95% CI)−0.20 [−3.23, 2.83]
5.4 VO2 Max at 12 weeks1211Mean Difference (IV, Random, 95% CI)6.20 [−2.01, 14.41]

Analysis group 6: Nicotine EC versus oral nicotine pouches

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
6.1 Serious adverse events126Risk Ratio (M-H, Random, 95% CI)Not estimable
6.2 Carbon monoxide (ppm)126Mean Difference (IV, Random, 95% CI)−12.44 [−28.82, 3.94]
6.2.1 Change from baseline126Mean Difference (IV, Random, 95% CI)−12.44 [−28.82, 3.94]

Analysis group 7: Nicotine EC versus non-nicotine EC

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
7.1 Smoking cessation71918Risk Ratio (M-H, Random, 95% CI)1.34 [1.06, 1.70]
7.2 Adverse events5840Risk Ratio (M-H, Random, 95% CI)1.01 [0.95, 1.08]
7.3 Serious adverse events101717Risk Ratio (M-H, Random, 95% CI)0.98 [0.55, 1.73]
7.4 Carbon monoxide (ppm)6Mean Difference (IV, Random, 95% CI)Totals not selected
7.4.1 Change from baseline3Mean Difference (IV, Random, 95% CI)Totals not selected
7.4.2 Absolute values at follow-up3Mean Difference (IV, Random, 95% CI)Totals not selected
7.5 Heart rate2401Mean Difference (IV, Random, 95% CI)−1.23 [−3.55, 1.08]
7.5.1 Absolute values at follow-up2401Mean Difference (IV, Random, 95% CI)−1.23 [−3.55, 1.08]
7.6 Systolic blood pressure2401Mean Difference (IV, Random, 95% CI)2.50 [−0.45, 5.44]
7.6.1 Absolute values at follow-up2401Mean Difference (IV, Random, 95% CI)2.50 [−0.45, 5.44]
7.7 NNAL (pmol/mg creatinine)2363Mean Difference (IV, Random, 95% CI)4.13 [−9.21, 17.48]
7.7.1 Change from baseline1148Mean Difference (IV, Random, 95% CI)15.27 [−4.98, 35.52]
7.7.2 Absolute values at follow-up1215Mean Difference (IV, Random, 95% CI)−0.03 [−0.46, 0.40]
7.8 FeNO (ppb)190Mean Difference (IV, Random, 95% CI)2.35 [1.78, 2.92]
7.8.1 Change from baseline190Mean Difference (IV, Random, 95% CI)2.35 [1.78, 2.92]
7.9 FEV1 (l)2Std. Mean Difference (IV, Random, 95% CI)Totals not selected
7.9.1 Absolute values at follow-up2Std. Mean Difference (IV, Random, 95% CI)Totals not selected
7.10 FEV1/FVC2348Mean Difference (IV, Random, 95% CI)−0.14 [−1.76, 1.47]
7.10.1 Absolute values at follow-up2348Mean Difference (IV, Random, 95% CI)−0.14 [−1.76, 1.47]
7.11 FVC (l)1260Std. Mean Difference (IV, Random, 95% CI)0.20 [−0.05, 0.44]
7.11.1 Absolute values at follow-up1260Std. Mean Difference (IV, Random, 95% CI)0.20 [−0.05, 0.44]
7.12 PEF (l/s)1260Std. Mean Difference (IV, Random, 95% CI)0.21 [−0.03, 0.45]
7.12.1 Absolute values at follow-up1260Std. Mean Difference (IV, Random, 95% CI)0.21 [−0.03, 0.45]
7.13 FEF 25-75 (l/s)1260Std. Mean Difference (IV, Random, 95% CI)0.17 [−0.07, 0.42]
7.13.1 Absolute values at follow-up1260Std. Mean Difference (IV, Random, 95% CI)0.17 [−0.07, 0.42]
7.14 Product use at 6+ months3874Risk Ratio (M-H, Random, 95% CI)1.14 [0.77, 1.69]

Analysis group 8: Nicotine EC versus behavioural support only/no support

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
8.1 Smoking cessation116819Risk Ratio (M-H, Random, 95% CI)1.78 [1.42, 2.25]
8.2 Adverse events82485Risk Ratio (M-H, Random, 95% CI)1.22 [0.96, 1.55]
8.3 Serious adverse events154716Risk Ratio (M-H, Random, 95% CI)0.93 [0.67, 1.29]
8.4 Carbon monoxide (ppm)14Mean Difference (IV, Random, 95% CI)Totals not selected
8.4.1 Change from baseline5Mean Difference (IV, Random, 95% CI)Totals not selected
8.4.2 Absolute values at follow-up9Mean Difference (IV, Random, 95% CI)Totals not selected
8.5 Heart rate (bpm)190Mean Difference (IV, Random, 95% CI)1.17 [−4.27, 6.61]
8.5.1 Absolute values at follow-up190Mean Difference (IV, Random, 95% CI)1.17 [−4.27, 6.61]
8.6 Systolic blood pressure3298Mean Difference (IV, Random, 95% CI)−1.64 [−7.97, 4.70]
8.6.1 Change from baseline1168Mean Difference (IV, Random, 95% CI)−2.68 [−4.38, −0.98]
8.6.2 Absolute values at follow-up2130Mean Difference (IV, Random, 95% CI)1.11 [−25.99, 28.21]
8.7 Blood oxygen saturation189Mean Difference (IV, Random, 95% CI)0.20 [−0.30, 0.70]
8.7.1 Absolute values at follow-up189Mean Difference (IV, Random, 95% CI)0.20 [−0.30, 0.70]
8.8 3-HPMA (SMD)2474Std. Mean Difference (IV, Random, 95% CI)−0.46 [−0.66, −0.26]
8.8.1 Absolute values at follow-up190Std. Mean Difference (IV, Random, 95% CI)−0.30 [−0.74, 0.13]
8.8.2 Change from baseline1384Std. Mean Difference (IV, Random, 95% CI)−0.50 [−0.73, −0.27]
8.9 NNAL (SMD)5Std. Mean Difference (IV, Random, 95% CI)Totals not selected
8.9.1 Absolute values at follow-up2Std. Mean Difference (IV, Random, 95% CI)Totals not selected
8.9.2 Change from baseline3Std. Mean Difference (IV, Random, 95% CI)Totals not selected
8.10 2-HPMA (pmol/mg creatinine)190Mean Difference (IV, Random, 95% CI)−279.90 [−969.98, 410.18]
8.10.1 Absolute values at follow-up190Mean Difference (IV, Random, 95% CI)−279.90 [−969.98, 410.18]
8.11 HMPMA (pmol/mg creatinine)190Mean Difference (IV, Random, 95% CI)−1672.00 [−3857.37, 513.37]
8.11.1 Absolute values at follow-up190Mean Difference (IV, Random, 95% CI)−1672.00 [−3857.37, 513.37]
8.12 PheT (pmol/mg creatinine)188Mean Difference (IV, Random, 95% CI)−1.30 [−4.17, 1.57]
8.12.1 Absolute values at follow-up188Mean Difference (IV, Random, 95% CI)−1.30 [−4.17, 1.57]
8.13 CEMA (pmol/mg creatinine)190Mean Difference (IV, Random, 95% CI)3.00 [−165.47, 171.47]
8.13.1 Absolute values at follow-up190Mean Difference (IV, Random, 95% CI)3.00 [−165.47, 171.47]
8.14 AAMA (pmol/mg creatinine)190Mean Difference (IV, Random, 95% CI)−67.90 [−219.73, 83.93]
8.14.1 Absolute values at follow-up190Mean Difference (IV, Random, 95% CI)−67.90 [−219.73, 83.93]
8.15 S-PMA (nanograms)1384Mean Difference (IV, Random, 95% CI)−1371.00 [−1995.23, −746.77]
8.15.1 12 weeks1384Mean Difference (IV, Random, 95% CI)−1371.00 [−1995.23, −746.77]
8.16 FEV1 (SMD)2714Std. Mean Difference (IV, Random, 95% CI)0.15 [−0.14, 0.44]
8.16.1 Change from baseline2714Std. Mean Difference (IV, Random, 95% CI)0.15 [−0.14, 0.44]
8.17 FEF 25-75 (litres/second))2555Mean Difference (IV, Random, 95% CI)−0.03 [−0.27, 0.20]
8.17.1 Change from baseline2555Mean Difference (IV, Random, 95% CI)−0.03 [−0.27, 0.20]
8.18 PEF 25-75 (litres/minute)1387Mean Difference (IV, Random, 95% CI)−7.10 [−29.14, 14.94]
8.18.1 Change from baseline1387Mean Difference (IV, Random, 95% CI)−7.10 [−29.14, 14.94]
8.19 FEV1/FVC1327Mean Difference (IV, Random, 95% CI)1.72 [0.74, 2.70]
8.19.1 Change from baseline1327Mean Difference (IV, Random, 95% CI)1.72 [0.74, 2.70]

Analysis group 9: Higher versus lower nicotine content

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
9.1 Smoking cessation1260Risk Ratio (M-H, Random, 95% CI)2.50 [0.80, 7.77]
9.2 Adverse events168Risk Ratio (M-H, Random, 95% CI)0.90 [0.58, 1.40]
9.3 Serious adverse events2239Risk Ratio (M-H, Random, 95% CI)1.51 [0.51, 4.42]
9.4 Carbon monoxide (ppm)3348Mean Difference (IV, Random, 95% CI)−0.92 [−1.71, −0.13]
9.4.1 Change from baseline2309Mean Difference (IV, Random, 95% CI)−0.90 [−1.70, −0.10]
9.4.2 Absolute values at follow-up139Mean Difference (IV, Random, 95% CI)−1.66 [−6.65, 3.33]
9.5 Heart rate2408Mean Difference (IV, Random, 95% CI)0.36 [−1.91, 2.62]
9.5.1 Change from baseline1148Mean Difference (IV, Random, 95% CI)−0.50 [−1.63, 0.63]
9.5.2 Absolute values at follow-up1260Mean Difference (IV, Random, 95% CI)1.92 [−0.89, 4.73]
9.6 Systolic blood pressure2408Mean Difference (IV, Random, 95% CI)0.86 [−0.77, 2.48]
9.6.1 Change from baseline1148Mean Difference (IV, Random, 95% CI)0.80 [−0.99, 2.59]
9.6.2 Absolute values at follow-up1260Mean Difference (IV, Random, 95% CI)1.13 [−2.76, 5.02]
9.7 FeNO (ppb)193Mean Difference (IV, Random, 95% CI)0.30 [−0.37, 0.97]
9.7.1 12 weeks193Mean Difference (IV, Random, 95% CI)0.30 [−0.37, 0.97]
9.8 FEV1 (l)2350Mean Difference (IV, Random, 95% CI)0.05 [−0.10, 0.20]
9.8.1 Change from baseline190Mean Difference (IV, Random, 95% CI)−0.01 [−0.11, 0.09]
9.8.2 Absolute values at follow-up1260Mean Difference (IV, Random, 95% CI)0.15 [−0.04, 0.34]
9.9 FVC (l)2350Mean Difference (IV, Random, 95% CI)−0.05 [−0.16, 0.06]
9.9.1 Change from baseline190Mean Difference (IV, Random, 95% CI)−0.03 [−0.15, 0.09]
9.9.2 Absolute values at follow-up1260Mean Difference (IV, Random, 95% CI)−0.12 [−0.36, 0.12]
9.10 FEV1/FVC2350Mean Difference (IV, Random, 95% CI)0.91 [0.18, 1.64]
9.10.1 Change from baseline190Mean Difference (IV, Random, 95% CI)0.91 [0.15, 1.67]
9.10.2 Absolute values at follow-up1260Mean Difference (IV, Random, 95% CI)0.89 [−1.56, 3.34]
9.11 PEF (l/s)1260Std. Mean Difference (IV, Random, 95% CI)0.06 [−0.18, 0.31]
9.11.1 Absolute values at follow-up1260Std. Mean Difference (IV, Random, 95% CI)0.06 [−0.18, 0.31]
9.12 FEF 25-75 (l/s)1260Std. Mean Difference (IV, Random, 95% CI)−0.02 [−0.26, 0.23]
9.12.1 Absolute values at follow-up1260Std. Mean Difference (IV, Random, 95% CI)−0.02 [−0.26, 0.23]
9.13 NNAL (pg/mg creatinine) at 24 weeks1152Mean Difference (IV, Random, 95% CI)−13.89 [−97.42, 69.64]
9.14 Product use at 6+ months1260Risk Ratio (M-H, Random, 95% CI)1.27 [0.95, 1.68]

Analysis group 10: Choice of flavours vs. tobacco flavour only

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
10.1 Smoking cessation1566Risk Ratio (M-H, Random, 95% CI)0.80 [0.54, 1.16]
10.2 Product use at 6+ months1522Risk Ratio (M-H, Random, 95% CI)1.10 [0.86, 1.40]
10.3 Adverse events (EC as adjunct to VLNC)1158Risk Ratio (M-H, Random, 95% CI)1.01 [0.88, 1.15]
10.4 Serious adverse events (EC as adjunct to VLNC)1158Risk Ratio (M-H, Random, 95% CI)0.44 [0.08, 2.34]
10.5 Change in carbon monoxide (ppm; as adjunct to VLNC)1124Mean Difference (IV, Random, 95% CI)−4.52 [−11.06, 2.02]
10.6 Change in NNAL (pmol/mg creatinine; as adjunct to VLNC)1100Mean Difference (IV, Random, 95% CI)−0.09 [−1.26, 1.08]

Analysis group 11: Tobacco vs. menthol flavour

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
11.1 Serious adverse events1300Risk Ratio (M-H, Random, 95% CI)Not estimable
11.2 NNAL (ng/g)1232Mean Difference (IV, Random, 95% CI)−26.10 [−66.73, 14.53]
11.2.1 Change from baseline1232Mean Difference (IV, Random, 95% CI)−26.10 [−66.73, 14.53]
11.3 FEV1 (% predicted)1212Mean Difference (IV, Random, 95% CI)−0.67 [−2.34, 1.00]
11.3.1 Change from baseline1212Mean Difference (IV, Random, 95% CI)−0.67 [−2.34, 1.00]
11.4 FEV1/FVC1212Mean Difference (IV, Random, 95% CI)−0.46 [−1.67, 0.75]
11.4.1 Change from baseline1212Mean Difference (IV, Random, 95% CI)−0.46 [−1.67, 0.75]

Analysis group 12: Refillable versus cartridge

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
12.1 Exhaled CO132Mean Difference (IV, Random, 95% CI)0.70 [−4.98, 6.38]

Analysis group 13: Nicotine salt EC versus free-base nicotine EC

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
13.1 Smoking cessation1285Risk Ratio (M-H, Random, 95% CI)1.25 [0.85, 1.83]
13.2 Product use at 6+ months1227Risk Ratio (M-H, Random, 95% CI)1.07 [0.82, 1.41]

Analysis group 14: Higher versus lower wattage

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
14.1 Smoking cessation1267Risk Ratio (M-H, Random, 95% CI)0.72 [0.30, 1.74]
14.2 Adverse events1267Risk Ratio (M-H, Random, 95% CI)0.92 [0.79, 1.06]
14.3 Serious adverse events1267Risk Ratio (M-H, Random, 95% CI)0.99 [0.14, 6.94]

Analysis group 15: Non-nicotine EC versus behavioural support only/no support

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
15.1 Smoking cessation2388Risk Ratio (M-H, Random, 95% CI)1.59 [0.80, 3.19]
15.2 Adverse events1248Risk Ratio (M-H, Random, 95% CI)1.28 [1.13, 1.44]
15.3 Serious adverse events2388Risk Ratio (M-H, Random, 95% CI)1.19 [0.33, 4.33]

Analysis group 16: Non-nicotine EC + NRT versus NRT

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
16.1 Smoking cessation1624Risk Ratio (M-H, Random, 95% CI)1.67 [0.50, 5.53]
16.2 Adverse events1344Risk Ratio (M-H, Random, 95% CI)0.70 [0.53, 0.91]
16.3 Serious adverse events1624Risk Ratio (M-H, Random, 95% CI)1.69 [0.60, 4.74]

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 events1132Risk Ratio (M-H, Random, 95% CI)0.33 [0.12, 0.87]
17.3 Serious adverse events1132Risk Ratio (M-H, Random, 95% CI)Not estimable
17.4 Change in carbon monoxide (ppm) at 6 months1164Mean Difference (IV, Random, 95% CI)2.00 [−0.50, 4.50]

Analysis group 18: Advice to use e-cigarettes compared to no advice to use e-cigarettes

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
18.1 Smoking cessation22652Risk Ratio (M-H, Random, 95% CI)1.02 [0.88, 1.19]
18.2 Adverse events152Risk Ratio (M-H, Random, 95% CI)1.27 [0.72, 2.26]
18.3 Serious adverse events152Risk Ratio (M-H, Random, 95% CI)Not estimable
18.4 Product use at 6+ months1331Risk Ratio (M-H, Random, 95% CI)1.77 [0.83, 3.79]

Analysis group 19: Nicotine EC + NRT versus non-nicotine EC + NRT

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
19.1 Smoking cessation21039Risk Ratio (M-H, Random, 95% CI)1.77 [1.07, 2.94]
19.2 Adverse events2677Risk Ratio (M-H, Random, 95% CI)1.11 [0.93, 1.32]
19.3 Serious adverse events21069Risk Ratio (M-H, Random, 95% CI)0.66 [0.38, 1.14]
19.4 Carbon monoxide (ppm)270Mean Difference (IV, Random, 95% CI)−4.62 [−12.07, 2.82]
19.4.1 change from baseline270Mean Difference (IV, Random, 95% CI)−4.62 [−12.07, 2.82]
19.5 FeNO (ppb)130Mean Difference (IV, Random, 95% CI)−0.36 [−7.23, 6.51]
19.5.1 6 months130Mean Difference (IV, Random, 95% CI)−0.36 [−7.23, 6.51]
19.6 FEV1 (%)132Mean Difference (IV, Random, 95% CI)0.05 [−0.01, 0.10]
19.6.1 6 months132Mean Difference (IV, Random, 95% CI)0.05 [−0.01, 0.10]
19.7 FVC (%)132Mean Difference (IV, Random, 95% CI)0.03 [−0.03, 0.09]
19.7.1 6 months132Mean Difference (IV, Random, 95% CI)0.03 [−0.03, 0.09]
19.8 Study product use at 6+ months19Risk Ratio (M-H, Random, 95% CI)1.25 [0.29, 5.35]

Analysis group 20: Nicotine EC + NRT versus NRT

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
20.1 Smoking cessation2980Risk Ratio (M-H, Random, 95% CI)3.57 [1.96, 6.51]
20.2 Adverse events4Risk Ratio (M-H, Random, 95% CI)Totals not selected
20.3 Serious adverse events52352Risk Ratio (M-H, Random, 95% CI)1.24 [0.45, 3.41]

Analysis group 21: Nicotine EC + varenicline vs. varenicline

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
21.1 Adverse events192Risk Ratio (M-H, Random, 95% CI)1.18 [0.84, 1.67]
21.2 Serious adverse events192Risk Ratio (M-H, Random, 95% CI)Not estimable

Analysis group 22: Nicotine EC + VLNC versus VLNC

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
22.1 Adverse events1243Risk Ratio (M-H, Random, 95% CI)0.97 [0.88, 1.07]
22.2 Serious adverse events1243Risk Ratio (M-H, Random, 95% CI)0.81 [0.23, 2.78]
22.3 Change in carbon monoxide1132Mean Difference (IV, Random, 95% CI)−7.15 [−13.07, −1.23]
22.4 Change in NNAL (pmol/mg creatinine)1110Mean Difference (IV, Random, 95% CI)0.29 [−1.83, 2.41]

Figures and tables

Analysis 1.1: Smoking cessation

Study or Subgroup 1.1.1 Not selected on pregnancy Bullen 2013 Hajek 2019 Klonizakis 2022 Kouroutzoglou 2024 Lee 2018 Myers-Smith 2022 Russell 2021* a Russell 2021* b Vojjala 2025 Subtotal Total events: Test for overall effect: Z = 4.47 (P < 0.00001) Heterogeneity: Chi² = 7.89, df = 8 (P = 0.44); I² = 0% 1.1.2 Pregnant population Hajek 2022 c Subtotal Total events: Test for overall effect: Z = 0.82 (P = 0.41) Heterogeneity: Not applicable Total Total events: Test for overall effect: Z = 4.55 (P < 0.00001) Test for subgroup differences: Chi² = 0.04, df = 1 (P = 0.85), I² = 0% Heterogeneity: Chi² = 7.95, df = 9 (P = 0.54); I² = 0% EC Events 21 79 36 8 5 13 34 44 7 247 6 6 253 Total 289 438 84 19 20 68 140 145 63 1266 169 169 1435 NRT Events 17 44 25 5 1 2 15 15 7 131 3 3 134 Total 295 446 82 19 10 67 70 71 58 1118 150 150 1268 Weight 11.6% 30.1% 17.5% 3.5% 0.9% 1.4% 13.8% 13.9% 5.0% 97.8% 2.2% 2.2% 100.0% Risk Ratio M-H, Fixed, 95% CI 1.26 [0.68 , 2.34] 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] 1.55 [1.28 , 1.87] 1.78 [0.45 , 6.97] 1.78 [0.45 , 6.97] 1.55 [1.28 , 1.88] Risk Ratio M-H, Fixed, 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 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: Adverse events

Study or Subgroup Bullen 2013 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 = 0.02, df = 6 (P = 0.98) Heterogeneity: Tau² (DL d ) = 0.04; Chi² = 14.13, df = 6 (P = 0.03); I² = 58% Nicotine EC Events 107 124 7 4 53 8 93 396 Total 241 556 19 60 108 18 175 1177 NRT Events 96 118 5 2 16 10 87 334 Total 215 554 10 47 53 10 175 1064 Weight 23.7% 22.8% 5.0% 1.5% 12.6% 10.6% 23.8% 100.0% Risk Ratio M-H, Random, 95% CI 0.99 [0.81 , 1.22] 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] 1.00 [0.73 , 1.37] 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 1.3: Serious adverse events

Study or Subgroup Bullen 2013 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 = 1.06, df = 4 (P = 0.35) Heterogeneity: Tau² (DL d ) = 0.05; Chi² = 5.70, df = 4 (P = 0.22); I² = 30% EC Events 24 27 31 0 0 0 0 18 100 Total 241 356 564 19 60 108 18 175 1541 NRT Events 14 19 37 0 0 0 1 10 81 Total 215 342 557 10 47 53 10 175 1409 Weight 22.4% 25.8% 32.7% 1.3% 17.8% 100.0% Risk Ratio M-H, Random, 95% CI 1.53 [0.81 , 2.88] 1.37 [0.77 , 2.41] 0.83 [0.52 , 1.31] Not estimable Not estimable Not estimable 0.19 [0.01 , 4.34] 1.80 [0.86 , 3.79] 1.22 [0.73 , 2.03] 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: Carbon monoxide (ppm)

Study or Subgroup 1.4.1 Absolute values at follow-up Hatsukami 2020 Subtotal Test for overall effect: Z = 1.12 (P = 0.26) Heterogeneity: Not applicable 1.4.2 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 Footnotes a CI calculated by Wald-type method. b Tau² calculated by Restricted Maximum-Likelihood method.

Analysis 1.5: Heart rate (bpm)

Study or Subgroup 1.5.1 Absolute values at follow-up Hatsukami 2020 Subtotal Test for overall effect: Z = 0.33 (P = 0.74) Heterogeneity: Not applicable 1.5.2 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 Footnotes a CI calculated by Wald-type method. b Tau² calculated by Restricted Maximum-Likelihood method.

Analysis 1.6: Systolic blood pressure

Study or Subgroup 1.6.1 Absolute values at follow-up Hatsukami 2020 Subtotal Test for overall effect: Z = 0.35 (P = 0.72) Heterogeneity: Not applicable 1.6.2 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 -4 -2 0 2 4 Favours EC Favours NRT Footnotes a CI calculated by Wald-type method. b Tau² calculated by Restricted Maximum-Likelihood method.

Analysis 1.7: Blood oxygen saturation

Study or Subgroup 1.7.1 Absolute values at follow-up Hatsukami 2020 Subtotal Test for overall effect: Z = 0.75 (P = 0.45) Heterogeneity: Not applicable 1.7.2 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 -0.5 -0.25 0 0.25 0.5 Favours NRT Favours EC Footnotes a CI calculated by Wald-type method. b Tau² calculated by Restricted Maximum-Likelihood method.

Analysis 1.8: 3-HPMA (pmol/mg creatinine)

Study or Subgroup 1.8.1 Absolute values at follow-up Hatsukami 2020 Subtotal Test for overall effect: Z = 0.90 (P = 0.37) Heterogeneity: Not applicable Total Test for overall effect: Z = 0.90 (P = 0.37) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 4612 SD 4263 Total 58 58 58 NRT Mean 5419 SD 5076 Total 53 53 53 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI -807.00 [-2559.47 , 945.47] -807.00 [-2559.47 , 945.47] -807.00 [-2559.47 , 945.47] Mean Difference IV, Random, 95% CI -1000 -500 0 500 1000 Favours EC Favours NRT

Analysis 1.9: NNAL (pmol/mg creatinine)

Study or Subgroup 1.9.1 Absolute values at follow-up Hatsukami 2020 Subtotal Test for overall effect: Z = 0.00 (P = 1.00) Heterogeneity: Not applicable Total Test for overall effect: Z = 0.00 (P = 1.00) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 1.2 SD 1.7 Total 57 57 57 NRT Mean 1.2 SD 1.1 Total 53 53 53 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI 0.00 [-0.53 , 0.53] 0.00 [-0.53 , 0.53] 0.00 [-0.53 , 0.53] Mean Difference IV, Random, 95% CI -1 -0.5 0 0.5 1 Favours EC Favours NRT

Analysis 1.10: 2-HPMA (pmol/mg creatinine)

Study or Subgroup 1.10.1 Absolute values at follow-up Hatsukami 2020 Subtotal Test for overall effect: Z = 0.58 (P = 0.56) Heterogeneity: Not applicable Total Test for overall effect: Z = 0.58 (P = 0.56) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 733.2 SD 855.6 Total 58 58 58 NRT Mean 842.2 SD 1083.7 Total 53 53 53 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI -109.00 [-474.52 , 256.52] -109.00 [-474.52 , 256.52] -109.00 [-474.52 , 256.52] Mean Difference IV, Random, 95% CI -200 -100 0 100 200 Favours EC Favours NRT

Analysis 1.11: HMPMA (pmol/mg creatinine)

Study or Subgroup 1.11.1 Absolute values at follow-up Hatsukami 2020 Subtotal Test for overall effect: Z = 1.20 (P = 0.23) Heterogeneity: Not applicable Total Test for overall effect: Z = 1.20 (P = 0.23) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 3959 SD 3633 Total 58 58 58 NRT Mean 4834 SD 3999 Total 53 53 53 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI -875.00 [-2300.93 , 550.93] -875.00 [-2300.93 , 550.93] -875.00 [-2300.93 , 550.93] Mean Difference IV, Random, 95% CI -1000 -500 0 500 1000 Favours EC Favours NRT

Analysis 1.12: PheT (pmol/mg creatinine)

Study or Subgroup 1.12.1 Absolute values at follow-up Hatsukami 2020 Subtotal Test for overall effect: Z = 0.73 (P = 0.46) Heterogeneity: Not applicable Total Test for overall effect: Z = 0.73 (P = 0.46) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 2.9 SD 2.8 Total 56 56 56 NRT Mean 2.5 SD 2.9 Total 53 53 53 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI 0.40 [-0.67 , 1.47] 0.40 [-0.67 , 1.47] 0.40 [-0.67 , 1.47] Mean Difference IV, Random, 95% CI -1 -0.5 0 0.5 1 Favours EC Favours NRT

Analysis 1.13: CEMA (pmol/mg creatinine)

Study or Subgroup 1.13.1 Absolute values at follow-up Hatsukami 2020 Subtotal Test for overall effect: Z = 0.46 (P = 0.65) Heterogeneity: Not applicable Total Test for overall effect: Z = 0.46 (P = 0.65) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 512 SD 443 Total 58 58 58 NRT Mean 475 SD 409 Total 53 53 53 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI 37.00 [-121.50 , 195.50] 37.00 [-121.50 , 195.50] 37.00 [-121.50 , 195.50] Mean Difference IV, Random, 95% CI -100 -50 0 50 100 Favours EC Favours NRT

Analysis 1.14: AAMA (pmol/mg creatinine)

Study or Subgroup 1.14.1 Absolute values at follow-up Hatsukami 2020 Subtotal Test for overall effect: Z = 0.44 (P = 0.66) Heterogeneity: Not applicable Total Test for overall effect: Z = 0.44 (P = 0.66) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 495.2 SD 390.9 Total 58 58 58 NRT Mean 463.2 SD 361.8 Total 51 51 51 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI 32.00 [-109.35 , 173.35] 32.00 [-109.35 , 173.35] 32.00 [-109.35 , 173.35] Mean Difference IV, Random, 95% CI -500 -250 0 250 500 Favours EC Favours NRT

Analysis 1.15: FEV1

Study or Subgroup 1.15.1 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

Analysis 1.16: FEV1/FVC (%)

Study or Subgroup 1.16.1 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% Total (Wald a ) Test for overall effect: Z = 0.58 (P = 0.56) Test for subgroup differences: Not applicable Heterogeneity: Tau² (REML b ) = 416.58; Chi² = 2.05, df = 1 (P = 0.15); I² = 51% Nicotine EC Mean -0.2 2 SD 2.6 10.5 Total 28 18 46 46 NRT Mean 0 -38.1 SD 3.6 79.2 Total 27 8 35 35 Weight 74.3% 25.7% 100.0% 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] 10.15 [-24.36 , 44.67] Mean Difference IV, Random, 95% CI -50 -25 0 25 50 Favours NRT Favours nicotine EC Footnotes a CI calculated by Wald-type method. b Tau² calculated by Restricted Maximum-Likelihood method.

Analysis 1.17: PEF (L/min)

Study or Subgroup 1.17.1 Change from baseline Kerr 2020 Subtotal Test for overall effect: Z = 0.24 (P = 0.81) Heterogeneity: Not applicable Total Test for overall effect: Z = 0.24 (P = 0.81) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 2 SD 49 Total 28 28 28 NRT Mean 5 SD 42 Total 27 27 27 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI -3.00 [-27.09 , 21.09] -3.00 [-27.09 , 21.09] -3.00 [-27.09 , 21.09] Mean Difference IV, Random, 95% CI -100 -50 0 50 100 Favours NRT Favours nicotine EC

Analysis 1.18: Product use at 6+ months

Study or Subgroup Bullen 2013 Hajek 2019 Lee 2018 Myers-Smith 2022 Russell 2021* a Russell 2021* b EC Events 71 173 3 32 62 48 Total 241 356 18 59 124 103 NRT Events 17 19 2 7 28 28 Total 215 342 9 47 61 60 Risk Ratio M-H, Random, 95% CI 3.73 [2.27 , 6.12] 8.75 [5.58 , 13.72] 0.75 [0.15 , 3.72] 3.64 [1.77 , 7.50] 1.09 [0.79 , 1.51] 1.00 [0.71 , 1.40] Risk Ratio M-H, Random, 95% CI 0.05 0.2 1 5 20 Higher with NRT Higher with EC Footnotes a NSP EC arm; control arm split to avoid double-counting. Study product use and numbers at  by follow up correspondence. b FBNP EC arm; control group split to avoid double-counting. Study product use and numbers at follow up by correspondence.

Analysis 2.1: Smoking cessation

Study or Subgroup Ioakeimidis 2018 Total Total events: Test for overall effect: Z = 2.34 (P = 0.02) Heterogeneity: Not applicable Nicotine EC Events 4 4 Total 27 27 Varenicline Events 13 13 Total 27 27 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 0.31 [0.11 , 0.82] 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 Total Total events: Test for overall effect: Not applicable Heterogeneity: Not applicable Nicotine EC Events 0 0 Total 27 27 Varenicline Events 0 0 Total 27 27 Weight Risk Ratio M-H, Random, 95% CI Not estimable Not estimable Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours EC Favours varenicline Footnotes a n followed up not reported; n randomized used as denominators

Analysis 3.1: Smoking cessation

Study or Subgroup Tuisku 2024 a Total Total events: Test for overall effect: Z = 1.89 (P = 0.06) Heterogeneity: Not applicable EC Events 42 42 Total 152 152 non-nicotine EC + varenicline Events 58 58 Total 153 153 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 0.73 [0.53 , 1.01] 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 Footnotes a The EC group also received placebo 'varenicline' pills

Analysis 3.2: Serious adverse events

Study or Subgroup Tuisku 2024 a Total Total events: Test for overall effect: Z = 1.05 (P = 0.30) Heterogeneity: Not applicable EC Events 2 2 Total 152 152 non-nicotine EC + varenicline Events 0 0 Total 153 153 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 5.03 [0.24 , 103.97] 5.03 [0.24 , 103.97] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours EC Favours non-nicotine EC + varenicline Footnotes a The EC group also received placebo 'varenicline' pills

Analysis 4.1: Smoking cessation

Study or Subgroup Kouroutzoglou 2024 Total Total events: Test for overall effect: Z = 0.33 (P = 0.74) Heterogeneity: Not applicable EC Events 8 8 Total 19 19 NRT + bupropion Events 9 9 Total 19 19 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 0.89 [0.44 , 1.81] 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

Analysis 5.1: Adverse events

Study or Subgroup Caponnetto 2023* Total Total events: Test for overall effect: Z = 1.21 (P = 0.22) Heterogeneity: Not applicable Nicotine EC Events 56 56 Total 110 110 Heated tobacco Events 65 65 Total 110 110 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 0.86 [0.68 , 1.10] 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

Analysis 5.2: SAEs

Study or Subgroup Caponnetto 2023* Total Total events: Test for overall effect: Not applicable Heterogeneity: Not applicable Nicotine EC Events 0 0 Total 110 110 Heated tobacco Events 0 0 Total 110 110 Weight Risk Ratio M-H, Random, 95% CI Not estimable Not estimable Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours nicotine EC Favours heated tobacco

Analysis 5.3: Carbon monoxide (ppm)

Study or Subgroup 5.3.1 Absolute values at 12 weeks Caponnetto 2023* Subtotal Test for overall effect: Z = 1.43 (P = 0.15) Heterogeneity: Not applicable 5.3.2 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 Footnotes a CI calculated by Wald-type method. b Tau² calculated by Restricted Maximum-Likelihood method.

Analysis 5.4: VO2 Max at 12 weeks

Study or Subgroup Caponnetto 2023* Total Test for overall effect: Z = 1.48 (P = 0.14) Heterogeneity: Not applicable Nicotine EC Mean 50.9 SD 31.9 Total 101 101 Heated tobacco Mean 44.7 SD 28.7 Total 110 110 Weight 100.0% 100.0% Mean Difference IV, Random, 95% CI 6.20 [-2.01 , 14.41] 6.20 [-2.01 , 14.41] Mean Difference IV, Random, 95% CI -100 -50 0 50 100 Favours heated tobacco Favours nicotine EC

Analysis 6.1: Serious adverse events

Study or Subgroup Avila 2024 Total Total events: Test for overall effect: Not applicable Heterogeneity: Not applicable Nicotine EC Events 0 0 Total 14 14 ONP Events 0 0 Total 12 12 Weight Risk Ratio M-H, Random, 95% CI Not estimable Not estimable Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours nicotine  EC Favours ONP

Analysis 6.2: Carbon monoxide (ppm)

Study or Subgroup 6.2.1 Change from baseline Avila 2024 Subtotal Test for overall effect: Z = 1.49 (P = 0.14) Heterogeneity: Not applicable Total Test for overall effect: Z = 1.49 (P = 0.14) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean [ppm] -15.36 SD [ppm] 22.7 Total 14 14 14 ONP Mean [ppm] -2.92 SD [ppm] 19.9 Total 12 12 12 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI [ppm] -12.44 [-28.82 , 3.94] -12.44 [-28.82 , 3.94] -12.44 [-28.82 , 3.94] Mean Difference IV, Random, 95% CI [ppm] -100 -50 0 50 100 Favours nicotine EC Favours ONP

Analysis 7.1: Smoking cessation

Study or Subgroup Bullen 2013 Caponnetto 2013a* Cobb 2021 a Cobb 2021 b Eisenberg 2020 Klonizakis 2022 Lucchiari 2022 Tuisku 2024 Total (Wald c ) Total events: Test for overall effect: Z = 2.46 (P = 0.01) Heterogeneity: Tau² (DL d ) = 0.00; Chi² = 6.14, df = 7 (P = 0.52); I² = 0% Nicotine EC Events 21 22 10 4 5 36 15 42 155 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% 1.3% 0.7% 2.8% 39.2% 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] 1.65 [0.40 , 6.77] 1.17 [0.80 , 1.71] 1.00 [0.53 , 1.89] 1.41 [0.93 , 2.13] 1.34 [1.06 , 1.70] 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 7.2: Adverse events

Study or Subgroup Bullen 2013 Eisenberg 2020 Meier 2017 Okuyemi 2022 Rose 2023* a Total (Wald b ) Total events: Test for overall effect: Z = 0.26 (P = 0.79) Heterogeneity: Tau² (DL c ) = 0.00; Chi² = 0.34, df = 3 (P = 0.95); I² = 0% Nicotine EC Events 107 120 3 0 4 234 Total 241 128 24 109 11 513 Non-nicotine EC Events 26 118 2 0 4 150 Total 57 127 24 106 13 327 Weight 4.1% 95.4% 0.1% 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] 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 7.3: Serious adverse events

Study or Subgroup Bullen 2013 Caponnetto 2013a* Cobb 2021 a Cobb 2021 b Eisenberg 2020 George 2019 Lucchiari 2022 Meier 2017 Okuyemi 2022 Rose 2023* c Tuisku 2024 Total (Wald d ) Total events: Test for overall effect: Z = 0.07 (P = 0.95) Heterogeneity: Tau² (DL e ) = 0.00; Chi² = 2.41, df = 5 (P = 0.79); I² = 0% Nicotine EC Events 24 0 8 5 3 0 0 0 0 1 2 43 Total 241 72 86 81 128 37 70 24 109 11 152 1011 Non-nicotine EC Events 4 0 3 4 5 0 0 0 0 0 2 18 Total 57 45 37 37 127 37 70 24 106 13 153 706 Weight 31.2% 20.1% 20.5% 16.3% 3.4% 8.5% 100.0% Risk Ratio M-H, Random, 95% CI 1.42 [0.51 , 3.93] Not estimable 1.15 [0.32 , 4.08] 0.57 [0.16 , 2.00] 0.60 [0.15 , 2.44] Not estimable Not estimable Not estimable Not estimable 3.50 [0.16 , 78.19] 1.01 [0.14 , 7.05] 0.98 [0.55 , 1.73] Risk Ratio M-H, 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 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 7.4: Carbon monoxide (ppm)

Study or Subgroup 7.4.1 Change from baseline Cobb 2021 a Klonizakis 2022 Rose 2023* b 7.4.2 Absolute values at follow-up Caponnetto 2013a* c Felicione 2019 Okuyemi 2022 Nicotine EC Mean -5.53 -9 -11.1 9.5 26.2 14.2 SD 2.7 9.35 16.6 4.2 11 8 Total 80 84 7 49 14 116 Non-nicotine EC Mean -3.88 -6 -2.2 7.3 20.4 15.4 SD 3.1 9.24 13 3.2 7.4 8 Total 69 82 10 41 11 114 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] -1.20 [-3.27 , 0.87] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours nicotine EC Favours non-nicotine EC 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

Analysis 7.5: Heart rate

Study or Subgroup 7.5.1 Absolute values at follow-up Caponnetto 2013a* 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% Total (Wald c ) Test for overall effect: Z = 1.04 (P = 0.30) Test for subgroup differences: Not applicable Heterogeneity: Tau² (REML d ) = 0.00; Chi² = 0.48, df = 1 (P = 0.49); I² = 0% Nicotine EC Mean 77.5 79.33 SD 12.2 11.65 Total 73 130 203 203 Non-nicotine EC Mean 79.8 79.93 SD 10.8 12.38 Total 68 130 198 198 Weight 37.2% 62.8% 100.0% 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] -1.23 [-3.55 , 1.08] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours nicotine EC Favours non-nicotine EC 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.

Analysis 7.6: Systolic blood pressure

Study or Subgroup 7.6.1 Absolute values at follow-up Caponnetto 2013a* a Cobb 2021 b Subtotal (Wald c ) Test for overall effect: Z = 1.66 (P = 0.10) Heterogeneity: Tau² (REML d ) = 0.00; Chi² = 0.35, df = 1 (P = 0.55); I² = 0% Total (Wald c ) Test for overall effect: Z = 1.66 (P = 0.10) Test for subgroup differences: Not applicable Heterogeneity: Tau² (REML d ) = 0.00; Chi² = 0.35, df = 1 (P = 0.55); I² = 0% Nicotine EC Mean 124.1 125.85 SD 17.7 14.82 Total 73 130 203 203 Non-nicotine EC Mean 122.9 122.74 SD 13.6 14.56 Total 68 130 198 198 Weight 32.1% 67.9% 100.0% 100.0% Mean Difference IV, Random, 95% CI 1.20 [-3.99 , 6.39] 3.11 [-0.46 , 6.68] 2.50 [-0.45 , 5.44] 2.50 [-0.45 , 5.44] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours nicotine EC Favours non-nicotine EC 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.

Analysis 7.7: NNAL (pmol/mg creatinine)

Study or Subgroup 7.7.1 Change from baseline Cobb 2021 a Subtotal Test for overall effect: Z = 1.48 (P = 0.14) Heterogeneity: Not applicable 7.7.2 Absolute values at follow-up Okuyemi 2022 Subtotal Test for overall effect: Z = 0.14 (P = 0.89) Heterogeneity: Not applicable Total (Wald b ) Test for overall effect: Z = 0.61 (P = 0.54) Test for subgroup differences: Chi² = 2.19, df = 1 (P = 0.14), I² = 54.4% Heterogeneity: Tau² (REML c ) = 63.65; Chi² = 2.19, df = 1 (P = 0.14); I² = 54% Nicotine EC Mean -4.23 1.95 SD 72.48 1.47 Total 79 79 109 109 188 Non-nicotine EC Mean -19.5 1.98 SD 52.7 1.74 Total 69 69 106 106 175 Weight 27.2% 27.2% 72.8% 72.8% 100.0% Mean Difference IV, Random, 95% CI 15.27 [-4.98 , 35.52] 15.27 [-4.98 , 35.52] -0.03 [-0.46 , 0.40] -0.03 [-0.46 , 0.40] 4.13 [-9.21 , 17.48] Mean Difference IV, Random, 95% CI -50 -25 0 25 50 Favours nicotine EC Favours non-nicotine EC Footnotes a Data for 36 mg/mL arm. 8 mg/mL arm -141.46 (SD 259.14), n = 73 b CI calculated by Wald-type method. c Tau² calculated by Restricted Maximum-Likelihood method.

Analysis 7.8: FeNO (ppb)

Study or Subgroup 7.8.1 Change from baseline Caponnetto 2013a* a Subtotal Test for overall effect: Z = 8.14 (P < 0.00001) Heterogeneity: Not applicable Total Test for overall effect: Z = 8.14 (P < 0.00001) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 2.8 SD 1.7 Total 49 49 49 Non-nicotine EC Mean 0.45 SD 1 Total 41 41 41 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI 2.35 [1.78 , 2.92] 2.35 [1.78 , 2.92] 2.35 [1.78 , 2.92] Mean Difference IV, Random, 95% CI -4 -2 0 2 4 Favours nicotine EC Favours non-nicotine EC Footnotes a Data are 2.4% nicotine compared to no-nicotine; 1.8% nicotine arm reported elsewhere

Analysis 7.9: FEV1 (l)

Study or Subgroup 7.9.1 Absolute values at follow-up Caponnetto 2013a* a Cobb 2021 b Nicotine EC Mean 3.2 2.67 SD 0.9 0.81 Total 47 130 Non-nicotine EC Mean 3.5 2.52 SD 0.9 0.71 Total 41 130 Std. Mean Difference IV, Random, 95% CI -0.33 [-0.75 , 0.09] 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 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

Analysis 7.10: FEV1/FVC

Study or Subgroup 7.10.1 Absolute values at follow-up Caponnetto 2013a* 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% Total (Wald c ) Test for overall effect: Z = 0.17 (P = 0.86) Test for subgroup differences: Not applicable Heterogeneity: Tau² (REML d ) = 0.00; Chi² = 0.48, df = 1 (P = 0.49); I² = 0% Nicotine EC Mean 80.3 78.65 SD 7.2 8.86 Total 47 130 177 177 Non-nicotine EC Mean 81.2 78.36 SD 5.6 7.73 Total 41 130 171 171 Weight 36.3% 63.7% 100.0% 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] -0.14 [-1.76 , 1.47] Mean Difference IV, Random, 95% CI -4 -2 0 2 4 Favours non-nicotine EC Favours nicotine EC 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.

Analysis 7.11: FVC (l)

Study or Subgroup 7.11.1 Absolute values at follow-up Cobb 2021 a Subtotal Test for overall effect: Z = 1.58 (P = 0.11) Heterogeneity: Not applicable Total Test for overall effect: Z = 1.58 (P = 0.11) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 3.38 SD 0.9 Total 130 130 130 Non-nicotine EC Mean 3.21 SD 0.82 Total 130 130 130 Weight 100.0% 100.0% 100.0% Std. Mean Difference IV, Random, 95% CI 0.20 [-0.05 , 0.44] 0.20 [-0.05 , 0.44] 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 Footnotes a Comparing highest (36mg) dose EC arm to no-nicotine EC arm; N at follow-up not provided, so N at baseline used

Analysis 7.12: PEF (l/s)

Study or Subgroup 7.12.1 Absolute values at follow-up Cobb 2021 a Subtotal Test for overall effect: Z = 1.70 (P = 0.09) Heterogeneity: Not applicable Total Test for overall effect: Z = 1.70 (P = 0.09) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 6.26 SD 1.66 Total 130 130 130 Non-nicotine EC Mean 5.91 SD 1.65 Total 130 130 130 Weight 100.0% 100.0% 100.0% Std. Mean Difference IV, Random, 95% CI 0.21 [-0.03 , 0.45] 0.21 [-0.03 , 0.45] 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 Footnotes a Comparing highest (36mg) dose EC arm to no-nicotine EC arm; N at follow-up not provided, so N at baseline used

Analysis 7.13: FEF 25-75 (l/s)

Study or Subgroup 7.13.1 Absolute values at follow-up Cobb 2021 a Subtotal Test for overall effect: Z = 1.40 (P = 0.16) Heterogeneity: Not applicable Total Test for overall effect: Z = 1.40 (P = 0.16) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 2.6 SD 1.24 Total 130 130 130 Non-nicotine EC Mean 2.4 SD 1.04 Total 130 130 130 Weight 100.0% 100.0% 100.0% Std. Mean Difference IV, Random, 95% CI 0.17 [-0.07 , 0.42] 0.17 [-0.07 , 0.42] 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 Footnotes a Comparing highest (36mg) dose EC arm to no-nicotine EC arm; N at follow-up not provided, so N at baseline used

Analysis 7.14: 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 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.

Analysis 8.1: Smoking cessation

Study or Subgroup Auer 2024 a Begh 2021 Carpenter 2023 Dawkins 2020 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 = 5.58, df = 10 (P = 0.0002) Heterogeneity: Tau² (DL d ) = 0.02; Chi² = 11.47, df = 10 (P = 0.32); I² = 13% Nicotine EC Events 141 7 58 3 5 4 6 15 35 6 91 371 Total 622 164 427 48 128 1199 40 70 484 120 566 3868 Usual care Events 102 3 17 0 1 0 2 10 20 2 14 171 Total 624 161 211 32 121 813 40 70 488 120 271 2951 Weight 40.6% 2.7% 14.8% 0.6% 1.1% 0.6% 2.0% 8.2% 13.9% 1.9% 13.6% 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] 4.71 [0.25 , 88.30] 4.73 [0.56 , 39.88] 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] 1.78 [1.42 , 2.25] 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 8.2: Adverse events

Study or Subgroup Auer 2024 Carpenter 2017 a Carpenter 2023 Eisenberg 2020 Holliday 2019 b Kale 2025 Piper 2025 Walele 2018* Total (HKSJ c ) Total events: Test for overall effect: T = 1.95, df = 7 (P = 0.09) Heterogeneity: Tau² (DL d ) = 0.02; Chi² = 20.64, df = 7 (P = 0.004); I² = 66% Nicotine EC Events 272 20 180 120 5 12 34 271 914 Total 575 34 292 128 29 15 54 306 1433 Usual care Events 229 8 86 88 0 10 8 80 509 Total 556 16 163 121 29 12 53 102 1052 Weight 20.7% 4.6% 18.2% 21.6% 0.2% 9.1% 3.5% 22.1% 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] 1.29 [1.15 , 1.45] 11.00 [0.64 , 190.26] 0.96 [0.67 , 1.37] 4.17 [2.13 , 8.16] 1.13 [1.01 , 1.26] 1.22 [0.96 , 1.55] 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 8.3: Serious adverse events

Study or Subgroup Auer 2024 Avila 2024 Begh 2021 Carpenter 2017 a Carpenter 2023 Edmiston 2022* b Eisenberg 2020 George 2019 Holliday 2019 c Kale 2025 Piper 2025 Pope 2024 Pratt 2022 Pulvers 2020 Walele 2018* Total (Wald d ) Total events: Test for overall effect: Z = 0.45 (P = 0.65) Heterogeneity: Tau² (DL e ) = 0.00; Chi² = 5.55, df = 6 (P = 0.48); I² = 0% Nicotine EC Events 25 0 11 0 1 0 3 0 0 0 0 25 2 0 5 72 Total 575 14 148 34 292 300 128 37 29 15 54 484 120 115 306 2651 Usual care Events 31 0 6 0 0 0 4 0 0 0 0 25 7 0 0 73 Total 566 7 144 16 163 150 121 40 29 12 53 488 120 54 102 2065 Weight 40.4% 11.4% 1.0% 4.9% 36.6% 4.4% 1.3% 100.0% Risk Ratio M-H, Random, 95% CI 0.79 [0.47 , 1.33] Not estimable 1.78 [0.68 , 4.70] Not estimable 1.68 [0.07 , 40.98] Not estimable 0.71 [0.16 , 3.10] Not estimable Not estimable Not estimable Not estimable 1.01 [0.59 , 1.73] 0.29 [0.06 , 1.35] Not estimable 3.69 [0.21 , 66.17] 0.93 [0.67 , 1.29] 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 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 8.4: Carbon monoxide (ppm)

Study or Subgroup 8.4.1 Change from baseline Avila 2024 Holliday 2019 Ikonomidis 2024 Piper 2025 a Pulvers 2020 8.4.2 Absolute values at follow-up Adriaens 2014 Begh 2021 Carpenter 2017 Dawkins 2020 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 16.8 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 12.1 8.96 3.8 0.7 15.9 8.7 Total 14 29 25 54 114 31 148 42 39 58 20 20 18 108 Usual care Mean 8.72 -5.8 1.2 -6.81 -0.37 14.7 23.8 32.9 18.1 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 9.5 9.94 3.8 1.3 13.5 8.4 Total 7 29 50 53 54 15 144 19 21 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] -1.30 [-6.86 , 4.26] -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 -20 -10 0 10 20 Favours EC Favours usual care 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

Analysis 8.5: Heart rate (bpm)

Study or Subgroup 8.5.1 Absolute values at follow-up Hatsukami 2020 Subtotal Test for overall effect: Z = 0.42 (P = 0.67) Heterogeneity: Not applicable Total Test for overall effect: Z = 0.42 (P = 0.67) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 74.81 SD 13.91 Total 58 58 58 Usual care Mean 73.64 SD 11.81 Total 32 32 32 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI 1.17 [-4.27 , 6.61] 1.17 [-4.27 , 6.61] 1.17 [-4.27 , 6.61] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours EC Favours usual care

Analysis 8.6: Systolic blood pressure

Study or Subgroup 8.6.1 Change from baseline Pulvers 2020 Subtotal Test for overall effect: Z = 3.09 (P = 0.002) Heterogeneity: Not applicable 8.6.2 Absolute values at follow-up Hatsukami 2020 Ikonomidis 2020a Subtotal (HKSJ a ) Test for overall effect: T = 0.52, df = 1 (P = 0.69) Heterogeneity: Tau² (REML b ) = 0.00; Chi² = 0.68, df = 1 (P = 0.41); I² = 0% Total (HKSJ a ) Test for overall effect: T = 1.11, df = 2 (P = 0.38) Test for subgroup differences: Chi² = 2.71, df = 1 (P = 0.10), I² = 63.2% Heterogeneity: Tau² (REML b ) = 2.16; Chi² = 2.62, df = 2 (P = 0.27); I² = 23% Nicotine EC Mean 1.07 123.1 128.7 SD 5.68 13.3 19.9 Total 114 114 58 20 78 192 Usual care Mean 3.75 123.1 123.5 SD 5.03 13.2 15.1 Total 54 54 32 20 52 106 Weight 73.5% 73.5% 20.1% 6.4% 26.5% 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] 1.11 [-25.99 , 28.21] -1.64 [-7.97 , 4.70] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours EC Favours usual care Footnotes a CI calculated by Hartung-Knapp-Sidik-Jonkman (HKSJ) method. b Tau² calculated by Restricted Maximum-Likelihood method.

Analysis 8.7: Blood oxygen saturation

Study or Subgroup 8.7.1 Absolute values at follow-up Hatsukami 2020 Subtotal Test for overall effect: Z = 0.79 (P = 0.43) Heterogeneity: Not applicable Total Test for overall effect: Z = 0.79 (P = 0.43) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 98.1 SD 1.5 Total 57 57 57 Usual care Mean 97.9 SD 0.9 Total 32 32 32 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI 0.20 [-0.30 , 0.70] 0.20 [-0.30 , 0.70] 0.20 [-0.30 , 0.70] Mean Difference IV, Random, 95% CI -0.5 -0.25 0 0.25 0.5 Favours usual care Favours EC

Analysis 8.8: 3-HPMA (SMD)

Study or Subgroup 8.8.1 Absolute values at follow-up Hatsukami 2020 a Subtotal Test for overall effect: Z = 1.38 (P = 0.17) Heterogeneity: Not applicable 8.8.2 Change from baseline Walele 2018* 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 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.

Analysis 8.9: NNAL (SMD)

Study or Subgroup 8.9.1 Absolute values at follow-up Carpenter 2017 a Hatsukami 2020 b 8.9.2 Change from baseline Edmiston 2022* c Pulvers 2020 d Walele 2018* e Nicotine EC Mean 151.8 1.2 -172.1 -65.91 -76 SD 158.1 1.7 158 39.41 189.2 Total 41 57 232 114 284 Usual care Mean 156.9 1.2 -6.3 14.23 6 SD 125.8 1 205.8 39.62 163.3 Total 19 31 128 54 100 Std. Mean Difference IV, Random, 95% CI -0.03 [-0.58 , 0.51] 0.00 [-0.44 , 0.44] -0.94 [-1.16 , -0.71] -2.02 [-2.41 , -1.63] -0.45 [-0.68 , -0.22] Std. Mean Difference IV, Random, 95% CI -2 -1 0 1 2 Favours EC Favours usual care Footnotes a Measured as pg/mL b Measured as pmol/mg creatinine c ng/g d pg/mL e Measured as nanograms

Analysis 8.10: 2-HPMA (pmol/mg creatinine)

Study or Subgroup 8.10.1 Absolute values at follow-up Hatsukami 2020 Subtotal Test for overall effect: Z = 0.79 (P = 0.43) Heterogeneity: Not applicable Total Test for overall effect: Z = 0.79 (P = 0.43) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 733.2 SD 855.6 Total 58 58 58 Usual care Mean 1013.1 SD 1887.6 Total 32 32 32 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI -279.90 [-969.98 , 410.18] -279.90 [-969.98 , 410.18] -279.90 [-969.98 , 410.18] Mean Difference IV, Random, 95% CI -1000 -500 0 500 1000 Favours EC Favours usual care

Analysis 8.11: HMPMA (pmol/mg creatinine)

Study or Subgroup 8.11.1 Absolute values at follow-up Hatsukami 2020 Subtotal Test for overall effect: Z = 1.50 (P = 0.13) Heterogeneity: Not applicable Total Test for overall effect: Z = 1.50 (P = 0.13) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 3959 SD 3633 Total 58 58 58 Usual care Mean 5631 SD 5701 Total 32 32 32 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI -1672.00 [-3857.37 , 513.37] -1672.00 [-3857.37 , 513.37] -1672.00 [-3857.37 , 513.37] Mean Difference IV, Random, 95% CI -1000 -500 0 500 1000 Favours EC Favours usual care

Analysis 8.12: PheT (pmol/mg creatinine)

Study or Subgroup 8.12.1 Absolute values at follow-up Hatsukami 2020 Subtotal Test for overall effect: Z = 0.89 (P = 0.37) Heterogeneity: Not applicable Total Test for overall effect: Z = 0.89 (P = 0.37) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 2.9 SD 2.8 Total 56 56 56 Usual care Mean 4.2 SD 8 Total 32 32 32 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI -1.30 [-4.17 , 1.57] -1.30 [-4.17 , 1.57] -1.30 [-4.17 , 1.57] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours EC Favours usual care

Analysis 8.13: CEMA (pmol/mg creatinine)

Study or Subgroup 8.13.1 Absolute values at follow-up Hatsukami 2020 Subtotal Test for overall effect: Z = 0.03 (P = 0.97) Heterogeneity: Not applicable Total Test for overall effect: Z = 0.03 (P = 0.97) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 512 SD 443 Total 58 58 58 Usual care Mean 509 SD 358 Total 32 32 32 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI 3.00 [-165.47 , 171.47] 3.00 [-165.47 , 171.47] 3.00 [-165.47 , 171.47] Mean Difference IV, Random, 95% CI -500 -250 0 250 500 Favours EC Favours usual care

Analysis 8.14: AAMA (pmol/mg creatinine)

Study or Subgroup 8.14.1 Absolute values at follow-up Hatsukami 2020 Subtotal Test for overall effect: Z = 0.88 (P = 0.38) Heterogeneity: Not applicable Total Test for overall effect: Z = 0.88 (P = 0.38) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 495.2 SD 390.9 Total 58 58 58 Usual care Mean 563.1 SD 328.2 Total 32 32 32 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI -67.90 [-219.73 , 83.93] -67.90 [-219.73 , 83.93] -67.90 [-219.73 , 83.93] Mean Difference IV, Random, 95% CI -500 -250 0 250 500 Favours EC Favours usual care

Analysis 8.15: S-PMA (nanograms)

Study or Subgroup 8.15.1 12 weeks Walele 2018* Subtotal Test for overall effect: Z = 4.30 (P < 0.0001) Heterogeneity: Not applicable Total Test for overall effect: Z = 4.30 (P < 0.0001) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean -1340 SD 3426.3 Total 284 284 284 Usual care Mean 31 SD 2451.5 Total 100 100 100 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI -1371.00 [-1995.23 , -746.77] -1371.00 [-1995.23 , -746.77] -1371.00 [-1995.23 , -746.77] Mean Difference IV, Random, 95% CI -1000 -500 0 500 1000 Favours EC Favours usual care

Analysis 8.16: FEV1 (SMD)

Study or Subgroup 8.16.1 Change from baseline Edmiston 2022* Walele 2018* Subtotal (Wald a ) Test for overall effect: Z = 1.00 (P = 0.32) Heterogeneity: Tau² (REML b ) = 0.03; Chi² = 3.29, df = 1 (P = 0.07); I² = 70% Total (Wald a ) Test for overall effect: Z = 1.00 (P = 0.32) Test for subgroup differences: Not applicable Heterogeneity: Tau² (REML b ) = 0.03; Chi² = 3.29, df = 1 (P = 0.07); I² = 70% Nicotine EC Mean -0.7 -0.1 SD 6.2 0.9 Total 212 286 498 498 Usual care Mean -2.5 -0.1 SD 5.7 0.8 Total 115 101 216 216 Weight 49.9% 50.1% 100.0% 100.0% Std. Mean Difference IV, Random, 95% CI 0.30 [0.07 , 0.53] 0.00 [-0.23 , 0.23] 0.15 [-0.14 , 0.44] 0.15 [-0.14 , 0.44] Std. Mean Difference IV, Random, 95% CI -0.5 -0.25 0 0.25 0.5 Favours usual care Favours nicotine EC Footnotes a CI calculated by Wald-type method. b Tau² calculated by Restricted Maximum-Likelihood method.

Analysis 8.17: FEF 25-75 (litres/second))

Study or Subgroup 8.17.1 Change from baseline Pulvers 2020 Walele 2018* Subtotal (Wald a ) Test for overall effect: Z = 0.26 (P = 0.80) Heterogeneity: Tau² (REML b ) = 0.02; Chi² = 3.68, df = 1 (P = 0.06); I² = 73% Total (Wald a ) Test for overall effect: Z = 0.26 (P = 0.80) Test for subgroup differences: Not applicable Heterogeneity: Tau² (REML b ) = 0.02; Chi² = 3.68, df = 1 (P = 0.06); I² = 73% Nicotine EC Mean -0.11 -0.1 SD 0.43 0.4 Total 114 286 400 400 Usual care Mean 0.03 -0.2 SD 0.44 1 Total 54 101 155 155 Weight 54.6% 45.4% 100.0% 100.0% Mean Difference IV, Random, 95% CI -0.14 [-0.28 , 0.00] 0.10 [-0.10 , 0.30] -0.03 [-0.27 , 0.20] -0.03 [-0.27 , 0.20] Mean Difference IV, Random, 95% CI -4 -2 0 2 4 Favours usual care Favours nicotine EC Footnotes a CI calculated by Wald-type method. b Tau² calculated by Restricted Maximum-Likelihood method.

Analysis 8.18: PEF 25-75 (litres/minute)

Study or Subgroup 8.18.1 Change from baseline Walele 2018* Subtotal Test for overall effect: Z = 0.63 (P = 0.53) Heterogeneity: Not applicable Total Test for overall effect: Z = 0.63 (P = 0.53) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 11.7 SD 75.9 Total 286 286 286 Usual care Mean 18.8 SD 103.6 Total 101 101 101 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI -7.10 [-29.14 , 14.94] -7.10 [-29.14 , 14.94] -7.10 [-29.14 , 14.94] Mean Difference IV, Random, 95% CI -100 -50 0 50 100 Favours usual care Favours nicotine EC

Analysis 8.19: FEV1/FVC

Study or Subgroup 8.19.1 Change from baseline Edmiston 2022* Subtotal Test for overall effect: Z = 3.44 (P = 0.0006) Heterogeneity: Not applicable Total Test for overall effect: Z = 3.44 (P = 0.0006) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 0.36 SD 4.5 Total 212 212 212 Usual care Mean -1.36 SD 4.21 Total 115 115 115 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI 1.72 [0.74 , 2.70] 1.72 [0.74 , 2.70] 1.72 [0.74 , 2.70] Mean Difference IV, Random, 95% CI -4 -2 0 2 4 Favours control Favours nicotine EC

Analysis 9.1: Smoking cessation

Study or Subgroup Cobb 2021 a Total Total events: Test for overall effect: Z = 1.58 (P = 0.11) Heterogeneity: Not applicable Higher nicotine Events 10 10 Total 130 130 Lower nicotine Events 4 4 Total 130 130 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 2.50 [0.80 , 7.77] 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 Footnotes a 36 v 8 mg/mL

Analysis 9.2: Adverse events

Study or Subgroup Kanobe 2022* Total Total events: Test for overall effect: Z = 0.46 (P = 0.64) Heterogeneity: Not applicable Higher Events 17 17 Total 33 33 Lower Events 20 20 Total 35 35 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 0.90 [0.58 , 1.40] 0.90 [0.58 , 1.40] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours higher Favours lower

Analysis 9.3: Serious adverse events

Study or Subgroup Caponnetto 2013a* Cobb 2021 a Total Total events: Test for overall effect: Z = 0.75 (P = 0.45) Heterogeneity: Not applicable Higher nicotine content Events 0 8 8 Total 35 86 121 Lower nicotine content Events 0 5 5 Total 37 81 118 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI Not estimable 1.51 [0.51 , 4.42] 1.51 [0.51 , 4.42] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours higher Favours lower Footnotes a 36 v 8 mg/mL

Analysis 9.4: Carbon monoxide (ppm)

Study or Subgroup 9.4.1 Change from baseline Caponnetto 2013a* 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% 9.4.2 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 -2 -1 0 1 2 Favours higher dose Favours lower dose Footnotes a CI calculated by Wald-type method. b Tau² calculated by Restricted Maximum-Likelihood method.

Analysis 9.5: Heart rate

Study or Subgroup 9.5.1 Change from baseline Caponnetto 2013a* Subtotal Test for overall effect: Z = 0.87 (P = 0.38) Heterogeneity: Not applicable 9.5.2 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 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.

Analysis 9.6: Systolic blood pressure

Study or Subgroup 9.6.1 Change from baseline Caponnetto 2013a* Subtotal Test for overall effect: Z = 0.88 (P = 0.38) Heterogeneity: Not applicable 9.6.2 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 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.

Analysis 9.7: FeNO (ppb)

Study or Subgroup 9.7.1 12 weeks Caponnetto 2013a* Subtotal Test for overall effect: Z = 0.88 (P = 0.38) Heterogeneity: Not applicable Total Test for overall effect: Z = 0.88 (P = 0.38) Test for subgroup differences: Not applicable Heterogeneity: Not applicable higher dose Mean 2.8 SD 1.7 Total 49 49 49 lower dose Mean 2.5 SD 1.6 Total 44 44 44 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI 0.30 [-0.37 , 0.97] 0.30 [-0.37 , 0.97] 0.30 [-0.37 , 0.97] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours higher dose Favours lower dose

Analysis 9.8: FEV1 (l)

Study or Subgroup 9.8.1 Change from baseline Caponnetto 2013a* Subtotal Test for overall effect: Z = 0.19 (P = 0.85) Heterogeneity: Not applicable 9.8.2 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 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.

Analysis 9.9: FVC (l)

Study or Subgroup 9.9.1 Change from baseline Caponnetto 2013a* Subtotal Test for overall effect: Z = 0.47 (P = 0.64) Heterogeneity: Not applicable 9.9.2 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 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.

Analysis 9.10: FEV1/FVC

Study or Subgroup 9.10.1 Change from baseline Caponnetto 2013a* Subtotal Test for overall effect: Z = 2.33 (P = 0.02) Heterogeneity: Not applicable 9.10.2 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 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.

Analysis 9.11: PEF (l/s)

Study or Subgroup 9.11.1 Absolute values at follow-up Cobb 2021 a Subtotal Test for overall effect: Z = 0.50 (P = 0.62) Heterogeneity: Not applicable Total Test for overall effect: Z = 0.50 (P = 0.62) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Higher dose Mean 6.26 SD 1.66 Total 130 130 130 Lower dose Mean 6.15 SD 1.86 Total 130 130 130 Weight 100.0% 100.0% 100.0% Std. Mean Difference IV, Random, 95% CI 0.06 [-0.18 , 0.31] 0.06 [-0.18 , 0.31] 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 Footnotes a N at follow-up not provided, so N at baseline used

Analysis 9.12: FEF 25-75 (l/s)

Study or Subgroup 9.12.1 Absolute values at follow-up Cobb 2021 a Subtotal Test for overall effect: Z = 0.13 (P = 0.90) Heterogeneity: Not applicable Total Test for overall effect: Z = 0.13 (P = 0.90) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Higher dose Mean 2.6 SD 1.24 Total 130 130 130 Lower dose Mean 2.62 SD 1.27 Total 130 130 130 Weight 100.0% 100.0% 100.0% Std. Mean Difference IV, Random, 95% CI -0.02 [-0.26 , 0.23] -0.02 [-0.26 , 0.23] -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 Footnotes a N at follow-up not provided, so N at baseline used

Analysis 9.13: NNAL (pg/mg creatinine) at 24 weeks

Study or Subgroup Cobb 2021 Total Test for overall effect: Z = 0.33 (P = 0.74) Heterogeneity: Not applicable Higher nicotine Mean -155.35 SD 266.1 Total 79 79 Lower nicotine Mean -141.46 SD 259.14 Total 73 73 Weight 100.0% 100.0% Mean Difference IV, Random, 95% CI -13.89 [-97.42 , 69.64] -13.89 [-97.42 , 69.64] Mean Difference IV, Random, 95% CI -100 -50 0 50 100 Favours higher nicotine Favours lower nicotine

Analysis 9.14: Product use at 6+ months

Study or Subgroup Cobb 2021 Total Total events: Test for overall effect: Z = 1.62 (P = 0.11) Heterogeneity: Not applicable Higher nicotine Events 62 62 Total 130 130 Lower nicotine Events 49 49 Total 130 130 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 1.27 [0.95 , 1.68] 1.27 [0.95 , 1.68] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Higher use in lower nicotine Higher use in higher nicotine

Analysis 10.1: Smoking cessation

Study or Subgroup Xu 2023* Total Total events: Test for overall effect: Z = 1.18 (P = 0.24) Heterogeneity: Not applicable Choice of flavours Events 40 40 Total 281 281 Tobacco flavour Events 51 51 Total 285 285 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 0.80 [0.54 , 1.16] 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

Analysis 10.2: Product use at 6+ months

Study or Subgroup Xu 2023* Total Total events: Test for overall effect: Z = 0.74 (P = 0.46) Heterogeneity: Not applicable Choice of flavours Events 91 91 Total 261 261 Tobacco flavour Events 83 83 Total 261 261 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 1.10 [0.86 , 1.40] 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

Analysis 10.3: Adverse events (EC as adjunct to VLNC)

Study or Subgroup Higgins 2024 Total Total events: Test for overall effect: Z = 0.10 (P = 0.92) Heterogeneity: Not applicable Choice of flavour Events 72 72 Total 84 84 Tobacco flavour Events 63 63 Total 74 74 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 1.01 [0.88 , 1.15] 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

Analysis 10.4: Serious adverse events (EC as adjunct to VLNC)

Study or Subgroup Higgins 2024 Total Total events: Test for overall effect: Z = 0.96 (P = 0.34) Heterogeneity: Not applicable Choice of flavour Events 2 2 Total 84 84 Tobacco flavour Events 4 4 Total 74 74 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 0.44 [0.08 , 2.34] 0.44 [0.08 , 2.34] Risk Ratio M-H, Random, 95% CI 0.02 0.1 1 10 50 Favours choice of flavour Favours tobacco flavour

Analysis 10.5: Change in carbon monoxide (ppm; as adjunct to VLNC)

Study or Subgroup Higgins 2024 Total Test for overall effect: Z = 1.35 (P = 0.18) Heterogeneity: Not applicable Choice of flavours Mean -6.42 SD 20.67 Total 69 69 Tobacco flavour Mean -1.9 SD 16.48 Total 55 55 Weight 100.0% 100.0% Mean Difference IV, Random, 95% CI -4.52 [-11.06 , 2.02] -4.52 [-11.06 , 2.02] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours choice of flavours Favours tobacco flavour

Analysis 10.6: Change in NNAL (pmol/mg creatinine; as adjunct to VLNC)

Study or Subgroup Higgins 2024 Total Test for overall effect: Z = 0.15 (P = 0.88) Heterogeneity: Not applicable Choice of flavours Mean -0.5 SD 3.73 Total 53 53 Tobacco flavour Mean -0.41 SD 2.1 Total 47 47 Weight 100.0% 100.0% Mean Difference IV, Random, 95% CI -0.09 [-1.26 , 1.08] -0.09 [-1.26 , 1.08] Mean Difference IV, Random, 95% CI -10 -5 0 5 10 Favours choice of flavours Favours tobacco flavour

Analysis 11.1: Serious adverse events

Study or Subgroup Edmiston 2022* Total Total events: Test for overall effect: Not applicable Heterogeneity: Not applicable Tobacco Events 0 0 Total 150 150 Menthol Events 0 0 Total 150 150 Weight Risk Ratio M-H, Random, 95% CI Not estimable Not estimable Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours tobacco Favours menthol

Analysis 11.2: NNAL (ng/g)

Study or Subgroup 11.2.1 Change from baseline Edmiston 2022* Subtotal Test for overall effect: Z = 1.26 (P = 0.21) Heterogeneity: Not applicable Total Test for overall effect: Z = 1.26 (P = 0.21) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Tobacco Mean -185.6 SD 157.8 Total 112 112 112 Menthol Mean -159.5 SD 157.8 Total 120 120 120 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI -26.10 [-66.73 , 14.53] -26.10 [-66.73 , 14.53] -26.10 [-66.73 , 14.53] Mean Difference IV, Random, 95% CI -100 -50 0 50 100 Favours tobacco Favours menthol

Analysis 11.3: FEV1 (% predicted)

Study or Subgroup 11.3.1 Change from baseline Edmiston 2022* Subtotal Test for overall effect: Z = 0.79 (P = 0.43) Heterogeneity: Not applicable Total Test for overall effect: Z = 0.79 (P = 0.43) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Tobacco Mean -1.04 SD 6.2 Total 100 100 100 Menthol Mean -0.37 SD 6.2 Total 112 112 112 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI -0.67 [-2.34 , 1.00] -0.67 [-2.34 , 1.00] -0.67 [-2.34 , 1.00] Mean Difference IV, Random, 95% CI -100 -50 0 50 100 Favours menthol Favours tobacco

Analysis 11.4: FEV1/FVC

Study or Subgroup 11.4.1 Change from baseline Edmiston 2022* Subtotal Test for overall effect: Z = 0.75 (P = 0.45) Heterogeneity: Not applicable Total Test for overall effect: Z = 0.75 (P = 0.45) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Tobacco Mean 0.12 SD 4.47 Total 100 100 100 Menthol Mean 0.58 SD 4.47 Total 112 112 112 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI -0.46 [-1.67 , 0.75] -0.46 [-1.67 , 0.75] -0.46 [-1.67 , 0.75] Mean Difference IV, Random, 95% CI -4 -2 0 2 4 Favours menthol Favours tobacco

Analysis 12.1: Exhaled CO

Study or Subgroup Kimber 2021 a Total Test for overall effect: Z = 0.24 (P = 0.81) Heterogeneity: Not applicable Refillable Mean 10.6 SD 8 Total 20 20 Cartridge Mean 9.9 SD 7.9 Total 12 12 Weight 100.0% 100.0% Mean Difference IV, Random, 95% CI 0.70 [-4.98 , 6.38] 0.70 [-4.98 , 6.38] Mean Difference IV, Random, 95% CI -100 -50 0 50 100 Favours refillable Favours cartridge 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.

Analysis 13.1: Smoking cessation

Study or Subgroup Russell 2021* Total Total events: Test for overall effect: Z = 1.14 (P = 0.25) Heterogeneity: Not applicable Nicotine salt Events 44 44 Total 145 145 Free-base nicotine Events 34 34 Total 140 140 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 1.25 [0.85 , 1.83] 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

Analysis 13.2: Product use at 6+ months

Study or Subgroup Russell 2021* Total Total events: Test for overall effect: Z = 0.51 (P = 0.61) Heterogeneity: Not applicable NSP Events 62 62 Total 124 124 FBNP Events 48 48 Total 103 103 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 1.07 [0.82 , 1.41] 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

Analysis 14.1: Smoking cessation

Study or Subgroup NCT03113136 Total Total events: Test for overall effect: Z = 0.73 (P = 0.47) Heterogeneity: Not applicable Higher wattage  Events 8 8 Total 134 134 Lower wattage Events 11 11 Total 133 133 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 0.72 [0.30 , 1.74] 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

Analysis 14.2: Adverse events

Study or Subgroup NCT03113136 Total Total events: Test for overall effect: Z = 1.22 (P = 0.22) Heterogeneity: Not applicable Higher wattage Events 95 95 Total 134 134 Lower wattage Events 103 103 Total 133 133 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 0.92 [0.79 , 1.06] 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

Analysis 14.3: Serious adverse events

Study or Subgroup NCT03113136 Total Total events: Test for overall effect: Z = 0.01 (P = 0.99) Heterogeneity: Not applicable Higher wattage Events 2 2 Total 134 134 Lower wattage Events 2 2 Total 133 133 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 0.99 [0.14 , 6.94] 0.99 [0.14 , 6.94] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours higher wattage Favours lower wattage

Analysis 15.1: 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 Footnotes a CI calculated by Wald-type method. b Tau² calculated by DerSimonian and Laird method.

Analysis 15.2: Adverse events

Study or Subgroup Eisenberg 2020 Total Total events: Test for overall effect: Z = 4.03 (P < 0.0001) Heterogeneity: Not applicable Non-nicotine EC Events 118 118 Total 127 127 behavioural support only/no support Events 88 88 Total 121 121 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 1.28 [1.13 , 1.44] 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

Analysis 15.3: Serious adverse events

Study or Subgroup Eisenberg 2020 Lucchiari 2022 Total Total events: Test for overall effect: Z = 0.27 (P = 0.79) Heterogeneity: Not applicable 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 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 1.19 [0.33 , 4.33] Not estimable 1.19 [0.33 , 4.33] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours non-nicotine Favours behavioural

Analysis 16.1: Smoking cessation

Study or Subgroup Walker 2020 a Total Total events: Test for overall effect: Z = 0.84 (P = 0.40) Heterogeneity: Not applicable Non-nicotine EC + NRT Events 20 20 Total 499 499 NRT Events 3 3 Total 125 125 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 1.67 [0.50 , 5.53] 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 Footnotes a this represents an EC + patch versus patch only comparison

Analysis 16.2: Adverse events

Study or Subgroup Walker 2020 Total Total events: Test for overall effect: Z = 2.63 (P = 0.009) Heterogeneity: Not applicable Non-nicotine EC + NRT Events 116 116 Total 290 290 NRT Events 31 31 Total 54 54 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 0.70 [0.53 , 0.91] 0.70 [0.53 , 0.91] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours EC + NRT Favours NRT

Analysis 16.3: Serious adverse events

Study or Subgroup Walker 2020 Total Total events: Test for overall effect: Z = 1.00 (P = 0.32) Heterogeneity: Not applicable Non-nicotine EC + NRT Events 27 27 Total 499 499 NRT Events 4 4 Total 125 125 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 1.69 [0.60 , 4.74] 1.69 [0.60 , 4.74] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours EC+NRT Favours NRT

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 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.

Analysis 17.2: Adverse events

Study or Subgroup Lee 2019 a Total Total events: Test for overall effect: Z = 2.23 (P = 0.03) Heterogeneity: Not applicable Non-nicotine EC Events 5 5 Total 71 71 NRT Events 13 13 Total 61 61 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 0.33 [0.12 , 0.87] 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 Footnotes a 0.01 mg/mL of nicotine in e-liquid; length of follow-up not defined but presumably over study period

Analysis 17.3: Serious adverse events

Study or Subgroup Lee 2019 a Total Total events: Test for overall effect: Not applicable Heterogeneity: Not applicable Non-nicotine EC Events 0 0 Total 71 71 NRT Events 0 0 Total 61 61 Weight Risk Ratio M-H, Random, 95% CI Not estimable Not estimable Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours non-nicotine EC Favours NRT Footnotes a 0.01 mg/mL of nicotine in e-liquid; length of follow-up not defined but presumably over study period

Analysis 17.4: Change in carbon monoxide (ppm) at 6 months

Study or Subgroup Klonizakis 2022 Total Test for overall effect: Z = 1.57 (P = 0.12) Heterogeneity: Not applicable Non-nicotine EC Mean -6 SD 9.24 Total 82 82 NRT Mean -8 SD 6.93 Total 82 82 Weight 100.0% 100.0% Mean Difference IV, Random, 95% CI 2.00 [-0.50 , 4.50] 2.00 [-0.50 , 4.50] Mean Difference IV, Random, 95% CI -10 -5 0 5 10 Favours non-nicotine EC Favours NRT

Analysis 18.1: 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 Footnotes a CI calculated by Wald-type method. b Tau² calculated by DerSimonian and Laird method.

Analysis 18.2: Adverse events

Study or Subgroup Vickerman 2022 Total Total events: Test for overall effect: Z = 0.83 (P = 0.41) Heterogeneity: Not applicable Advice to use EC to quit Events 14 14 Total 26 26 Advice does not include EC Events 11 11 Total 26 26 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 1.27 [0.72 , 2.26] 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

Analysis 18.3: Serious adverse events

Study or Subgroup Vickerman 2022 Total Total events: Test for overall effect: Not applicable 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 Risk Ratio M-H, Random, 95% CI Not estimable Not estimable Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours EC advice Favours no EC advice

Analysis 18.4: Product use at 6+ months

Study or Subgroup Elling 2023 Total Total events: Test for overall effect: Z = 1.48 (P = 0.14) Heterogeneity: Not applicable Advice to use EC to quit Events 16 16 Total 157 157 Advice does not include EC Events 10 10 Total 174 174 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 1.77 [0.83 , 3.79] 1.77 [0.83 , 3.79] Risk Ratio M-H, Random, 95% CI 0.1 0.2 0.5 1 2 5 10 Higher with no EC-advice Higher with EC advice

Analysis 19.1: 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 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.

Analysis 19.2: 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 Footnotes a CI calculated by Wald-type method. b Tau² calculated by DerSimonian and Laird method.

Analysis 19.3: Serious adverse events

Study or Subgroup Rose 2023* Walker 2020 Total (Wald a ) Total events: Test for overall effect: Z = 1.49 (P = 0.14) Heterogeneity: Tau² (DL b ) = 0.00; Chi² = 0.01, df = 1 (P = 0.90); 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 10.2% 89.8% 100.0% Risk Ratio M-H, Random, 95% CI 0.59 [0.11 , 3.34] 0.67 [0.37 , 1.19] 0.66 [0.38 , 1.14] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours nicotine EC Favours non-nicotine EC Footnotes a CI calculated by Wald-type method. b Tau² calculated by DerSimonian and Laird method.

Analysis 19.4: Carbon monoxide (ppm)

Study or Subgroup 19.4.1 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% Total (Wald a ) Test for overall effect: Z = 1.22 (P = 0.22) Test for subgroup differences: Not applicable Heterogeneity: Tau² (REML b ) = 22.69; Chi² = 4.26, df = 1 (P = 0.04); I² = 77% Nicotine EC + NRT Mean -9.5 -11.1 SD 3.9 12.8 Total 13 26 39 39 Non-nicotine EC + NRT Mean -8.1 -2 SD 3.4 10.2 Total 12 19 31 31 Weight 58.1% 41.9% 100.0% 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] -4.62 [-12.07 , 2.82] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours nicotine EC Favours non-nicotine EC Footnotes a CI calculated by Wald-type method. b Tau² calculated by Restricted Maximum-Likelihood method.

Analysis 19.5: FeNO (ppb)

Study or Subgroup 19.5.1 6 months Baldassarri 2018 Subtotal Test for overall effect: Z = 0.10 (P = 0.92) Heterogeneity: Not applicable Total Test for overall effect: Z = 0.10 (P = 0.92) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 2.75 SD 10.5 Total 12 12 12 Non-nicotine EC Mean 3.11 SD 7.45 Total 18 18 18 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI -0.36 [-7.23 , 6.51] -0.36 [-7.23 , 6.51] -0.36 [-7.23 , 6.51] Mean Difference IV, Random, 95% CI -10 -5 0 5 10 Favours nicotine EC Favours non-nicotine EC

Analysis 19.6: FEV1 (%)

Study or Subgroup 19.6.1 6 months Baldassarri 2018 Subtotal Test for overall effect: Z = 1.67 (P = 0.10) Heterogeneity: Not applicable Total Test for overall effect: Z = 1.67 (P = 0.10) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 0.0085 SD 0.057 Total 13 13 13 Non-nicotine EC Mean -0.037 SD 0.097 Total 19 19 19 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI 0.05 [-0.01 , 0.10] 0.05 [-0.01 , 0.10] 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

Analysis 19.7: FVC (%)

Study or Subgroup 19.7.1 6 months Baldassarri 2018 Subtotal Test for overall effect: Z = 1.09 (P = 0.28) Heterogeneity: Not applicable Total Test for overall effect: Z = 1.09 (P = 0.28) Test for subgroup differences: Not applicable Heterogeneity: Not applicable Nicotine EC Mean 0.0108 SD 0.065 Total 13 13 13 Non-nicotine EC Mean -0.0216 SD 0.103 Total 19 19 19 Weight 100.0% 100.0% 100.0% Mean Difference IV, Random, 95% CI 0.03 [-0.03 , 0.09] 0.03 [-0.03 , 0.09] 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

Analysis 19.8: Study product use at 6+ months

Study or Subgroup Baldassarri 2018 Total Total events: Test for overall effect: Z = 0.30 (P = 0.76) Heterogeneity: Not applicable Nicotine EC Events 2 2 Total 4 4 Non-nicotine EC Events 2 2 Total 5 5 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 1.25 [0.29 , 5.35] 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

Analysis 20.1: 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 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.

Analysis 20.2: 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 0.2 0.5 1 2 5 Favours EC + NRT Favours NRT Footnotes a NRT not matched between arms b Two NRT only arms combined for comparator

Analysis 20.3: 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 = 0.42 (P = 0.67) Heterogeneity: Tau² (DL d ) = 0.00; Chi² = 0.33, df = 1 (P = 0.56); 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 10.2% 89.8% 100.0% Risk Ratio M-H, Random, 95% CI 3.00 [0.13 , 70.30] Not estimable Not estimable Not estimable 1.13 [0.39 , 3.27] 1.24 [0.45 , 3.41] Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours EC+NRT Favours NRT 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.

Analysis 21.1: Adverse events

Study or Subgroup Tattan-Birch 2023 Total Total events: Test for overall effect: Z = 0.97 (P = 0.33) Heterogeneity: Not applicable Nicotine EC + varenicline Events 31 31 Total 48 48 Varenicline Events 24 24 Total 44 44 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 1.18 [0.84 , 1.67] 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

Analysis 21.2: Serious adverse events

Study or Subgroup Tattan-Birch 2023 Total Total events: Test for overall effect: Not applicable Heterogeneity: Not applicable Nicotine EC + varenicline Events 0 0 Total 48 48 Varenicline Events 0 0 Total 44 44 Weight Risk Ratio M-H, Random, 95% CI Not estimable Not estimable Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favours EC + varenicline Favours varenicline

Analysis 22.1: Adverse events

Study or Subgroup Higgins 2024 a Total Total events: Test for overall effect: Z = 0.63 (P = 0.53) Heterogeneity: Not applicable Nicotine EC + VLNC Events 135 135 Total 158 158 VLNC Events 75 75 Total 85 85 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 0.97 [0.88 , 1.07] 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 Footnotes a EC arm combines data from preferred flavour and tobacco flavour arms

Analysis 22.2: Serious adverse events

Study or Subgroup Higgins 2024 a Total Total events: Test for overall effect: Z = 0.34 (P = 0.73) Heterogeneity: Not applicable Nicotine EC + VLNC Events 6 6 Total 158 158 VLNC Events 4 4 Total 85 85 Weight 100.0% 100.0% Risk Ratio M-H, Random, 95% CI 0.81 [0.23 , 2.78] 0.81 [0.23 , 2.78] Risk Ratio M-H, Random, 95% CI 0.2 0.5 1 2 5 Favours EC + VLNC Favours VLNC Footnotes a EC arm combines data from preferred flavour and tobacco flavour arms

Analysis 22.3: Change in carbon monoxide

Study or Subgroup Higgins 2024 a Total Test for overall effect: Z = 2.37 (P = 0.02) Heterogeneity: Not applicable EC + VLNC Mean -6.42 SD 20.67 Total 69 69 VLNC Mean 0.73 SD 13.6 Total 63 63 Weight 100.0% 100.0% Mean Difference IV, Random, 95% CI -7.15 [-13.07 , -1.23] -7.15 [-13.07 , -1.23] Mean Difference IV, Random, 95% CI -20 -10 0 10 20 Favours EC + VLNC Favours VLNC Footnotes a The EC + VLNC data comes from the preferred flavour study arm only (i.e. excluding the tobacco flavour arm data)

Analysis 22.4: Change in NNAL (pmol/mg creatinine)

Study or Subgroup Higgins 2024 a Total Test for overall effect: Z = 0.27 (P = 0.79) Heterogeneity: Not applicable EC + VLNC Mean -0.5 SD 3.73 Total 53 53 VLNC Mean -0.79 SD 7.21 Total 57 57 Weight 100.0% 100.0% Mean Difference IV, Random, 95% CI 0.29 [-1.83 , 2.41] 0.29 [-1.83 , 2.41] Mean Difference IV, Random, 95% CI -10 -5 0 5 10 Favours EC + VLNC Favours VLNC Footnotes a The EC + VLNC data comes from the preferred flavour study arm only (i.e. excluding the tobacco flavour arm data)