Articles
Nicotine patches used in combination with e-cigarettes (with and without nicotine) for smoking cessation: a pragmatic, randomised trial

https://doi.org/10.1016/S2213-2600(19)30269-3Get rights and content

Summary

Background

Combination nicotine replacement therapy shows additive cessation benefits. We aimed to find out the effectiveness of combining nicotine patches with an e-cigarette (with and without nicotine) on six-month smoking abstinence.

Methods

We did a pragmatic, three-arm, parallel-group trial in New Zealand in adult smokers who were e-cigarette naive and motivated to quit smoking. Participants were recruited from the general population using national media advertising. Participants were randomly assigned (1:4:4), with the use of stratified block randomisation, to receive 14 weeks (2 weeks before the agreed quit date) of 21 mg, 24h nicotine patches, patches plus an 18 mg/L nicotine e-cigarette, or patches plus a nicotine-free e-cigarette. We advised participants to use one patch daily, with e-cigarette use as and when necessary or desired. Participants and researchers were masked to e-liquid nicotine content. We offered 6 weeks of telephone-delivered behavioural support. The primary outcome was exhaled carbon monoxide (CO)-verified continuous smoking abstinence 6 months after the agreed quit date. Primary analysis was by intention to treat, with sensitivity analysis by per protocol, treatment adherence, varying CO cutoffs, and complete case analysis. This paper presents the main analyses and is registered with ClinicalTrials.gov, NCT02521662.

Findings

Between March 17, 2016 and Nov 30, 2017, 1124 people were assigned to nicotine patches (patches only group, n=125), patches plus a nicotine e-cigarette (patches plus nicotine e-cigarette group, n=500), or patches plus a nicotine-free e-cigarette (patches plus nicotine-free e-cigarette group, n=499). 62 (50%) of 125 participants in the patches only group withdrew or were lost to follow-up by 6 months compared with 161 (32%) of 500 in the patches plus nicotine e-cigarette group and 162 (33%) of 499 in the patches plus nicotine-free e-cigarette group. 35 (7%) participants in the patches plus nicotine e-cigarette group had CO-verified continuous abstinence at 6 months compared with 20 (4%) in the patches plus nicotine-free e-cigarette group (risk difference [RD] 2·99 [95% CI 0·17–5·81]), and three (2%) people in the patches only group (RD 4·60 [1·11–8·09]). 18 serious adverse events occurred in 16 people in the patches plus nicotine e-cigarette group compared with 27 events in 22 people in the patches plus nicotine-free e-cigarette group and four events in three people in the patches only group. In the patches plus nicotine e-cigarette group, two life-threatening serious adverse events were reported (two separate heart attacks in the one participant). In the patches plus nicotine-free e-cigarette group, one death occurred (accidental drug overdose) and one life-threatening serious adverse event (heart attack). No significant between-group differences were noted for serious adverse events, and none were treatment-related.

Interpretation

Combining reduced-harm nicotine products, such as nicotine patches with a nicotine e-cigarette, can lead to a modest improvement in smoking cessation over and above that obtained from using patches plus a nicotine-free e-cigarette (or patches alone), with no indication of any serious harm in the short-term. Future e-cigarette trials should focus on their use alone or in combination with usual smoking cessation support, given issues with differential loss to follow-up and withdrawal if a usual care group is used as a comparator.

Funding

Health Research Council of New Zealand.

Introduction

Nicotine replacement therapy (NRT) helps reduce the nicotine withdrawal symptoms experienced by people when they quit smoking. However, no NRT product currently available matches the nicotine concentrations and rapid delivery achieved with smoking. In contrast, contemporary nicotine e-cigarettes enable users to obtain nicotine as rapidly, and potentially in as high concentrations, as that from cigarettes.1 E-cigarettes, mostly with nicotine, are used by smokers in many countries as an aid to quit smoking.2 To date, seven clinical trials3, 4, 5, 6, 7, 8, 9 (total N=8222; range n=68 to 6006) have investigated the efficacy and effectiveness of e-cigarettes for smoking cessation and overall suggest a net benefit. However, only four trials (N=7849; n=300 to 6006) had 6-month abstinence as a primary outcome3, 4, 8, 9 and only two trials (total N=6892)8, 9 tested a second-generation e-cigarette (capable of delivering nicotine more effectively than first-generation devices).10

Research in context

Evidence before this study

The Cochrane review of e-cigarettes for smoking cessation sought studies published between 2004 and January, 2016. Two trials (N=953) were identified that measured smoking abstinence rates after 6 months or more, and both tested ad libitum use of first-generation e-cigarettes. Combined data from the trials showed that using a nicotine e-cigarette significantly increased smoking abstinence at 6 months compared with using a nicotine-free e-cigarette, although absolute quit rates were low (9% vs 4%). No serious adverse events were reported. Confidence in the findings was low given the “small number of trials, low event rates and wide confidence intervals around the estimates”. We sought to identify e-cigarette trials that measured smoking abstinence rates at 6 months or more, published between Jan 1, 2016, and June 30, 2019. We searched MEDLINE, Embase, and PsycINFO using the same search terms as the Cochrane Review (e-cig$ OR electr$ cigar$ OR electronic nicotine OR [vape or vaper or vapers or vaping]) plus “Randomized Controlled Trial” (Publication Type). We identified 48 articles, of which two were trials. The first trial (N=54 US companies, 6006 employees and their spouses) tested the effectiveness of four smoking cessation interventions (involving cessation medications, nicotine e-cigarettes, and financial rewards) against usual care (behavioural support). The verified continuous smoking abstinence rate at 6 months in the usual care plus e-cigarette group was higher, but not significantly different, to that observed in the usual care plus cessation medication group (1·0% vs 0·5%) or usual care alone (1·0% vs 0·1%). The second trial, done within the UK national stop smoking services, tested the effectiveness of second-generation e-cigarettes plus moderate level face-to-face behavioural support for smoking cessation (N=886). Self-reported continuous smoking abstinence rates at 6 months were higher in the 18 mg nicotine e-cigarette group (35·4%) than in those allocated 3 months of nicotine replacement therapy (NRT) (25·1%).

Added value of this study

Our study adds to the scarce trial evidence base on e-cigarettes as a smoking cessation tool and, to our knowledge, is the first to investigate the effectiveness and safety of combining nicotine patches and second-generation e-cigarettes (with and without nicotine) on smoking abstinence. We did the trial in a country with strong tobacco control measures, where advertising is restricted, use of e-cigarettes is low, and there was a ban on the sale of nicotine e-cigarettes. The findings may therefore be generalisable to countries with similar policy backgrounds. For example, Canada, Costa Rica, Ecuador, Japan, and Mexico had similar advertising restrictions on e-cigarettes at the time of the study and Australia, Canada, Costa Rica, Jamaica, Japan, Malaysia, Mexico, and Switzerland prohibited the sale of nicotine e-cigarettes. The research questions addressed in our trial have informed tobacco control policy being developed by the New Zealand Ministry of Health.

Implications of all the available evidence

All five published trials on e-cigarettes for smoking cessation are pragmatic in design, suggesting that under real-world conditions, e-cigarettes (with and without nicotine) could help some people quit smoking but the tobacco control policy environment within which they are available might affect cessation rates. E-cigarettes should be offered as one of the many smoking cessation aids available to people wanting to quit, but do not appear to be a solution for all. People using e-cigarettes should be encouraged to fully switch away from tobacco to e-cigarettes, with the aim of eventually also stopping vaping (if possible) given the lack of any long-term safety data for these devices. Future e-cigarette trials should consider carefully which comparator intervention(s) to use given the high likelihood of differential loss to follow-up (or withdrawal) when only usual care or NRT is offered.

In 2015, we did a trial11 to assess the effectiveness and safety of combining nicotine patches with second-generation e-cigarettes (with and without nicotine liquid [e-liquid]) on smoking abstinence. Moderate intensity behavioural support was available by phone for all participants, given its additional benefit.12 The trial was done throughout New Zealand, a country with strong tobacco-control policies and an adult smoking prevalence of 16%.13 When the trial began, it was illegal for nicotine e-liquid to be advertised or sold in New Zealand, but a 3-month supply of nicotine e-liquid could be imported for personal use and nicotine-free e-liquid could be sold. Against this policy background, the prevalence of current e-cigarette use (used at least once a day, week, or month) was low at 3% of adults aged 15 years and older.14

The case for maintaining the status-quo for access to nicotine-free e-cigarettes was founded on trial evidence that nicotine-free e-cigarettes help reduce cravings to smoke tobacco and increase quitting in some people;3, 4, 15 and if a person wanted to use nicotine, they could use medicinal NRT in addition to nicotine-free e-cigarette use. This argument formed the basis of our primary hypothesis, namely NRT (in this case, patches) plus a nicotine e-cigarette would be more effective at helping smokers quit than patches plus a nicotine-free e-cigarette. Our secondary hypothesis that patches plus a nicotine e-cigarette (combination therapy) would be more effective than patches alone (monotherapy) was based on evidence that combining nicotine patches with faster-acting oral NRT products increases quit rates compared with patches alone.16

Section snippets

Study design and participants

We did a parallel group, community-based, pragmatic, three-arm, randomised trial in New Zealand. The published protocol describes procedures in detail.11 In brief, people were eligible if they were living in New Zealand, were aged 18 years or older, smoked tobacco (amount not specified), were motivated to quit in the next 2 weeks, were able to provide verbal consent, were prepared to use any of the trial treatments, and had access to a telephone. We excluded pregnant or breastfeeding women,

Results

Between March 17, 2016, and Nov 30, 2017, 1623 people were screened, of whom 1124 (69%) were eligible and randomly assigned to the patches only group (n=125), the patches plus nicotine e-cigarette group (n=500), or the patches plus nicotine-free e-cigarette group (n=499; figure). This sample size was less than planned, as the trial ran out of time and funding to continue recruitment due to delays in sourcing nicotine e-liquid and slower than anticipated recruitment.

Last follow-up occurred on

Discussion

This effectiveness trial found that a combination of nicotine patches plus a nicotine e-cigarette was superior to patches plus a nicotine-free e-cigarette for 6 month smoking abstinence among dependent smokers motivated to quit. For the patches plus nicotine e-cigarette versus patches plus nicotine-free e-cigarette comparison, as well as for the patches plus nicotine e-cigarette versus patches only comparison, self-reported, self-reported quit rates at all timepoints were in favour of patches

Data sharing

Requests for de-identified individual participant data or study documents will be considered where the proposed use aligns with public good purposes, does not conflict with other requests or planned use by the trial steering committee, and the requestor is willing to sign a data access agreement. Contact is through the corresponding author.

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