Values are mean (SD) or n (percentage). Percentages may not add to 100 due to rounding.

NRTnicotine replacement therapyENDelectronic nicotine delivery (e-cigarette)BMIbody mass index = (weight (kg)/height2 (m2))COPDchronic obstructive pulmonary diseaseCOcarbon monoxideFEV1forced expiratory volume in first secondFVCforced vital capacity

aOther surgery includes ophthalmology, urology, otolaryngology, plastics, gynecology and podiatry.

bHeart disease defined as coronary artery disease, congestive heart failure, or arrhythmia.

Smoking cessation outcomes

Smoking cessation outcomes are presented in Table 2. There were no statistically significant differences between smoking cessation or reduction rates between NRT and END groups at any time point. However, there was a trend towards improved outcomes in the END group at the 8 week follow-up visit. Biochemically verified smoking cessation for 2 days preoperatively was achieved in 20% (n = 2) of the NRT group, which was similar to the 15% (n = 3) in the END group (p = 1.0). At 8-week follow-up, no participants in the NRT group had biochemically verified smoking cessation, while the END group had three participants (15%) that achieved 7-day point-prevalence abstinence (p = 0.53). When including both those that quit and those that reduced cigarette consumption by at least 50%, 70% of the END group (n = 14) was able to reduce or quit compared to 40% of the NRT group (n = 4), but this difference was not statistically significant (p = 0.14). The number of cigarettes per day smoked by group at baseline, day of surgery, 30-days postoperatively and 8-week follow-up are represented graphically in Fig. S2. Both NRT and END groups reduced their cigarette consumption over time, with median cigarette consumption decreasing from 12.5 [IQR = 8-20] at baseline to 3 [IQR =0.3-9.5] at 8-week follow-up in the END group (p = 0.0001) and from 7.8 [IQR = 6-20] to 5 [IQR = 3-8] in the NRT group (p = 0.01). There were no statistically significant differences between groups in percentage of smoking reduction at any time point (Table 3).

Smoking cessation outcomes.

NRTnicotine replacement therapyENDelectronic nicotine delivery (e-cigarette)

Cessation on the day of surgery was determined based on 48-hour point prevalence abstinence. Cessation at all other time points was determined by 7-day point-prevalence abstinence. Smoking reduction includes those that quit.

aSmoking cessation verified by exhaled carbon monoxide 10ppm or less.

bSmoking reduction is defined by reduction of 50% or more cigarettes per day compared to baseline, including smoking cessation. Analysis by intention-to-treat—those lost to follow-up were assumed to have continued smoking.

cRelative risk undefined due to no quitters in the NRT group, risk difference = 15% (95% CI [−6.5%-+ 30.6%]).

Values are n (percentage). p-values from Fisher's exact test.

aAll participants had a web-based referral confirmed by the study team. However, the California Smokers' Helpline did not locate the referral for two patients in the NRT group and one patient in the END group.

Satisfaction outcomes

The acceptability of nicotine patches and e-cigarettes were assessed on the day of surgery and 8-weeks after randomization. Regular (daily or most days) use of the product was not statistically significantly different between NRT and END groups (p = 0.71), with about half reporting regular usage on the day of surgery. Usage increased by 8-week follow-up, particularly in the END group, which reported 80% (n = 16) regular use compared with 67% (n = 6) in the NRT group, although the difference was not statistically significant (p = 0.64).

Satisfaction was also similar at both time points between NRT and END groups, with both groups being at least somewhat satisfied with the products they were given, as shown in Table 5. More in-depth explorations of how each product was used, patient attitudes towards smoking cessation in relation to the assigned products, and satisfaction with the products were conducted in qualitative interviews at 8-weeks follow-up and will be reported separately.

Feasibility of study processes

As a pilot study, feasibility of study processes were also analyzed. As with prior perioperative smoking cessation studies (Lee et al., 2013), potential research participants were successfully identified by chart review in the preoperative period, although similarly, more than half of smokers chose not to participate in the research study despite meeting eligibility criteria (Fig. 1). Recruitment may have been further reduced in this trial compared to prior perioperative smoking cessation studies due to the use of non-standard treatments (ENDs) compared to other perioperative studies that used NRT or varenicline (Moller et al., 2002; Thomsen, Tonnesen & Moller, 2009; Wong et al., 2017). Blinding of research staff was successful, although it was not feasible to have participants blinded given the nature of the treatment. Follow-up was nearly complete, with losses to follow-up for the primary outcome occurring only due to cancelled surgeries. Future studies may wish to select a fixed date follow-up (such as 8-weeks post-randomization) for the primary outcome, regardless of surgical date, to maintain consistency between participants and reduce losses due to cancelled and postponed surgeries.

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Discussion

In this pilot randomized trial of END versus NRT initiated in the preoperative period, we found that e-cigarettes were a feasible and acceptable intervention to veterans around the time of surgery and had similar smoking cessation rates compared to transdermal nicotine replacement. Given the current need for more controlled data with respect to the use of e-cigarettes for smoking cessation (Hartmann-Boyce et al., 2016) (a practice already popular amongst preoperative patients (Kadimpati, Nolan & Warner, 2015)), this trial has demonstrated important groundwork for future studies.

Our findings are consistent with those of the largest randomized controlled trial of e-cigarettes versus NRT to date (Bullen et al., 2013) and several recent systematic reviews (Hartmann-Boyce et al., 2016; Malas et al., 2016), which also found that e-cigarettes were modestly effective in helping smokers quit compared to NRT. Our protocol differed in its shorter duration of therapy (6-weeks) and tapering nicotine dose in both NRT and END groups, suggesting that a shorter duration of therapy may still be effective in assisting patients in quitting smoking. Similar to prior e-cigarette studies (Hartmann-Boyce et al., 2016), none of our participants experienced serious adverse events, although mild and moderate headache, nausea, cough and throat irritation were common. Quit rates in this study (30% in NRT group and 25% in the END group at 30-days postoperatively) were similar to those found in another pragmatic perioperative smoking cessation study using NRT (Lee et al., 2013) (quit rate at 30-days postoperatively in the NRT group was 29% versus usual care 11%), indicating that both e-cigarettes and NRT are probably more effective than no intervention and can be useful tools to assist patients in quitting smoking at a time when they are highly motivated to quit due to impending or recent surgery.

The differential in exposure time to END versus NRT products prior to the day of surgery (average of 16 versus 11 days) may have introduced some difficulty in interpreting the primary outcome. Future studies may choose a fixed time interval post-randomization (similar to our 8-week follow-up visit) rather than the day of surgery as a primary outcome to standardize this variable between groups.

The improvements in spirometry, for example the increased FEV1 and FEV1/FVC in the END group may indicate that e-cigarette vapor is less harmful than continued cigarette smoking, a claim that is often marketed (Grana & Ling, 2014) despite some controversy in the literature (Konstantinos & Riccardo, 2014; Palazzolo, 2013). These results are especially impressive in light of the fact that baseline characteristics show that the END group was imbalanced towards heavier, more dependent smokers with worse baseline spirometry values. The results could also be explained by a higher baseline prevalence of COPD in the END group in addition to the possible increased smoking reduction and cessation in the END group. Given the small sample size and effort-dependence of spirometry, further studies would be needed to verify the consistency of the spirometry findings.

As is typical of pilot studies, our study was limited by small sample size, such that we were underpowered to detect all but the largest of differences between groups. Nevertheless, we were able to demonstrate the acceptability of e-cigarettes for perioperative smoking cessation, as evidenced by similar satisfaction scores between END and NRT groups, with most patients in the END group indicating that the product was helpful in their quit attempt and that they would recommend the product.

Participants were given a set 6-week supply based on baseline cigarettes per day of either END (per manufacturer's recommendation) or NRT (daily use) upon enrollment to the study. NRT patients were directed to use the patches daily, while END patients were asked to use the e-cigarette devices ad libitum, with the further instruction that if they ran out of a particular strength of product, they should move on to the next product. A limitation to the study may be that the set amount of product given to the END group may not have been truly ad libitum due to the limited supply. Nevertheless, most participants (15/20 (75%) of the END group) had leftover e-cigarettes and therefore did achieve true ad libitum use.

Another limitation to this study was the inconsistent use of behavioral support. While most referrals were appropriately received by the California Smokers' Helpline, a large proportion were unable to connect with counselling support. It is likely that with better adherence to telephone counselling, quit rates in both groups may have been higher. Future studies may benefit from tighter control of access and use of smoking cessation counselling, including face-to-face counselling and improved follow-up counselling, which might improve smoking cessation rates in both arms, as intensive smoking cessation counselling has previously been shown to be effective in the perioperative period (Thomsen, Villebro & Moller, 2014).

Conclusions

E-cigarettes were found to be a feasible and acceptable aid for perioperative smoking cessation with quit rates comparable to nicotine replacement patch. Spirometry may be improved with e-cigarette use. A large, adequately powered study is recommended to determine if the results from this pilot study can be duplicated.

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