nicotine replacement therapy

Research question

In adult combustible cigarette smokers, do nicotine electronic cigarettes compared to nicotine replacement therapy increase success rates of smoking cessation.

Introduction

Smoking is a leading modifiable risk factor for death and disease, responsible for 13% of all deaths and 8.6% of disease burden in Australia (Australian Bureau of Statistics [ABS], 2022). Combustible cigarettes contain nicotine and burn tobacco, exposing the smoker to thousands of harmful chemicals. They are highly addictive, and many smokers find quitting difficult, making smoking cessation a public health priority (Department of Health, 2019). One smoking cessation method is the use of nicotine replacement therapy (NRT) which delivers nicotine via patches, gum, lozenges, sprays, or inhalers. Another method is the use of nicotine electronic cigarettes (ECs), in which the user inhales nicotine as a vapour. ECs are increasing in popularity with 9.3% of Australian adults having used ECs (ABS, 2022). ECs are minimally regulated, however since October 2021, ECs containing nicotine are only available in Australia via prescription (Therapeutic Goods Administration, 2021). An annotated bibliography of four relevant research articles will be followed by an evaluation of this evidence on the effectiveness of nicotine ECs compared to NRT for smoking cessation.

Annotated bibliography

Bullen, C. D., Howe, C. P., Laugesen, M. M., McRobbie, H. M., Parag, V. M., Williman, J. P., & Walker, N. P. (2013). Electronic cigarettes for smoking cessation: a randomised controlled trial. The Lancet (British edition), 382(9905), 1629-1637. https://doi.org/10.1016/S0140-6736(13)61842-5

Bullen et al. used a quantitative research method to compare nicotine ECs, nicotine patches, and placebo ECs on continuous abstinence from combustible smoking. The authors argue that while there is a rapid increase in EC sales, there is a lack of reliable evidence to support their use in smoking cessation programs. This New Zealand pragmatic randomised controlled trial (RCT) had 657 eligible participants willing to quit, with 289 randomised to nicotine ECs, 295 to nicotine patches and 73 to nicotine-free ECs. Baseline characteristics were similar across all groups. Those in both EC groups were blinded to whether they received nicotine EC or nicotine-free EC. It was not possible to blind participants to EC or NRT given their method of delivery. All participants were given access to behavioural support with Quitline. The 144 participants who were lost to follow-up or discontinued were assumed to have continued smoking. At 6 months, continuous abstinence from combustible cigarette smoking was verified biochemically.

The results were not statistically significant, with 7.3% in the nicotine EC group, 5.8% in the nicotine patches group and 4.1% in the placebo EC group remaining abstinent from combustible cigarette smoking. The authors noted that continuous abstinence at 1 month was significantly higher at 23.2% in the nicotine EC group and 15.9% in the NRT group, suggesting relapse rates are high. Despite this, the authors argue that there is still the potential for improved health outcomes, as 57% in the nicotine EC group had decreased the number of combustible cigarettes per day by at least 50%. This may be due to the potential for ECs to mimic the sensorimotor aspects of smoking; however, this data appears to be relevant for those who are motivated to quit and may not be generalised to the entire combustible cigarette smoking population.

The strengths of this study include its pragmatic design pertinent to real-world effectiveness. Block and stratified randomisation to ensure even distribution among groups was evident. Both inclusion and exclusion criteria were clearly stated. There are, however, several limitations present. While a robust trial design was used to attempt to mitigate bias, there are some concerns with the overall risk of bias for this study. One author had previously received funding from a manufacturer of ECs. There is also evidence of attrition bias as the number of lost to follow-up or discontinued participants was significantly higher in the NRT group, with the authors postulating that some participants who were randomised to NRT initially joined the trial to try ECs. The authors also relied on self-reported abstinence with no evidence to suggest adherence to study protocol. It is evident that further research with larger, multi-centre trials with homogeneity of trial products is required.

Chan, G. C. K., Stjepanovic, D., Lim, C., Sun, T., Shanmuga Anandan, A., Connor, J. P., Gartner, C., Hall, W. D., & Leung, J. (2021). A systematic review of randomized controlled trials and network meta-analysis of e-cigarettes for smoking cessation. Addictive Behaviors, 119, 106912. https://doi.org/10.1016/j.addbeh.2021.106912

Chan et al. used a quantitative study method to examine the effectiveness of ECs on smoking cessation compared to NRTs, placebo, or usual care. The authors argue that the majority of evidence examining the effectiveness of ECs are from observational cohort and cross-sectional studies that have a moderate or high risk of bias. They undertook a systematic review and network meta-analysis of RCTs, which involved a direct comparison of nicotine ECs with NRT, and an indirect comparison of nicotine ECs with nicotine-free control, and indirect comparison of NRT with nicotine-free control.

Meeting the eligibility criteria were 16 trials with a total of 11,754 participants. The aim of this method was to expand the available data to assess the effect that ECs have on smoking cessation. The pooled results of this network meta-analysis showed that nicotine ECs were more effective than both NRT and nicotine-free control. The authors claimed that one potential reason for this is that ECs can not only provide a nicotine substitute for combustible cigarette smoking, but also a behavioural one.

The strengths of this review include the restricted focus on only RCTs with greater than 6 months of follow-up. The pooled data from indirect comparisons between the two treatments allowed for a much greater sample size from which to gather data. There are, however, several limitations. Many of the EC trials had a moderate or high risk of bias, and four of the included trials had a sample size of fewer than 100 participants, rendering the results of those trials inconclusive. The authors caution that there is moderate heterogeneity amongst the trials used in this meta-analysis, which may be due to the different models of ECs and NRT products used. It is therefore difficult to measure whether this impacted on the results. Follow-up duration of the included studies varied, and the nicotine-free controls differed considerably, with some studies comparing nicotine-free ECs and others only phone consultation. Chan et al. also highlight a major issue with the carbon monoxide biomarker test in that it has a very short half-life, so it may only detect combustible cigarette smoking that has occurred within the previous 2 days. The applicability to long-term smoking cessation is therefore questionable.

Hajek, P., Phillips-Waller, A., Przulj, D., Pesola, F., Myers Smith, K., Bisal, N., Li, J., Parrott, S., Sasieni, P., Dawkins, L., Ross, L., Goniewicz, M., Wu, Q., & McRobbie, H. J. (2019). A Randomized Trial of E-Cigarettes versus Nicotine-Replacement Therapy. New England Journal of Medicine, 380(7), 629-637. https://doi.org/10.1056/NEJMoa1808779

The multi-centre pragmatic randomised controlled trial by Hajek et al. utilised a quantitative method to examine the effectiveness of ECs compared with NRT in smoking cessation. The authors reason that there is limited evidence available comparing the two treatments. A reasonable sample size of 886 participants attending the U.K. National Health Service stop-smoking services were randomly assigned to EC or NRT, with even distribution across the two therapy groups. The 439 participants assigned to EC were provided with a starter pack with product education, and if required to purchase further e-liquid replacements. The 447 participants assigned to NRT were informed on the range of NRT products available and provided with 3 months of NRT, selecting their preferred products with combination use encouraged. Both groups were provided with behavioural support for at least four weeks. Hajek et al. concluded with statistical significance (P<0.001) that ECs were more effective (18%) for smoking cessation than NRT (9.9%).

The strengths of this study include the restriction of participation to those who had no strong preference between the two treatment arms, limiting potential bias. Furthermore, while participants were not blinded due to therapy types, data analysts were, and bias is considered low given the concealed and random allocation to each treatment arm. Follow-up was at one year, suggesting the potential for long-term combustible cigarette abstinence. With its robust study design, it is one of a few studies that directly compares ECs to NRT, providing a valuable contribution to the evidence base supporting the use of ECs in smoking cessation treatment. There are, however, several limitations. Participants were dependent smokers who had a desire to quit, and they were also provided with behavioural support, so data may not be generalised outside of the UK National Health Service. Data relied on self-reporting, and although chemically tested, the method used only detects smoking in the previous 24-48hours, so there is potential for false negative results. The starter kits that EC participants were provided with only had a small supply of e-liquid, and they were advised to purchase further e-liquids themselves. This indicates that the strength of the e-liquids amongst participants were diverse, and the type of EC models used differed. Overall, this study is an important contribution to the growing body of research supporting the use of ECs, however more research through large multi-centre RCTs addressing the above limitations is required to corroborate these results.

Hartmann-Boyce, J., McRobbie, H., Butler, A. R., Lindson, N., Bullen, C., Begh, R., Theodoulou, A., Notley, C., Rigotti, N. A., Turner, T., Fanshawe, T. R., & Hajek, P. (2021). Electronic cigarettes for smoking cessation. Cochrane Database Syst Rev, 9, CD010216. https://doi.org/10.1002/14651858.CD010216.pub6

Hartmann-Boyce et al. used a quantitative method to investigate the safety and effectiveness of nicotine ECs for combustible cigarette smokers in smoking cessation. The authors claim that the rationale behind the lack of promotion of ECs as a quit smoking aid is due to insufficient evidence on the safety and effectiveness of these devices. This Cochrane systematic review looked at a number of different comparators to ECs and included RCTs, randomised cross-over trials and uncontrolled intervention studies.

The relevance to the research question in this annotated bibliography are the four RCTs with 1924 participants that compared ECs with NRT. Only trials that undertook at least 6-months of follow-up were included in this systematic review. The results provide moderate certainty evidence that nicotine ECs are more effective for smoking cessation. Between 9-14% of nicotine EC users are likely to achieve smoking abstinence compared to 6% for NRT users. The authors also evaluated the safety of each treatment, determining that adverse events were rare and equivalent across the nicotine EC and NRT groups.

There are several strengths to this systematic review. Multiple relevant databases were searched, and monthly searches continue to be performed, making this a living systematic review that seeks out new evidence. Meta-analyses were conducted with a rigorous review process. With regards to the primary outcomes, statistical heterogeneity was low, and the included studies had an overall low risk of bias. Several limitations must also be acknowledged. Firstly, the evidence is limited by imprecision, with only a small number of trials that meet the inclusion criteria. Data collection varied, as did follow-up duration. Only smokers motivated to quit participated in the included trials, so the results may not be generalised to the wider smoking population. The authors state that several RCTs in this field are currently underway, so future updates of this living systematic review may provide more reliable evidence to guide practice.

Literature Evaluation

All of the studies included in the above annotated bibliography are unanimous that there is a paucity of reliable data available on the efficacy and safety of nicotine ECs compared to NRT in smoking cessation. All studies only included smokers who were motivated to quit, and both treatment arms were also provided with a degree of behavioural support, so it is difficult to generalise this data beyond this sample population, as it may not be applicable to the general population who do not typically have this level of support (Hajek et al., 2019).

Despite ECs showing a higher success rate over NRT, the overall effectiveness at achieving smoking abstinence is still relatively low, with the highest being that recorded by Hajek et al. (2019) at 18%. However, EC technology is rapidly changing, with current models of ECs showing improved nicotine delivery, which may result in an increase in the effectiveness of this treatment on smoking cessation (Bullen et al., 2013). The combination of both a short-acting and long-acting NRT has also been shown to improve smoking cessation success, so future studies should feature this comparator with newer models of ECs or newer ECs compared to leading pharmacotherapies to gain a clearer picture of their place in smoking cessation programs (Hartmann-Boyce et al., 2013). One such comparator is the nicotine receptor partial agonist varenicline, which is the preferred pharmacotherapy option in Australia (Royal Australian College of General Practitioners, 2021). Evidence of varenicline use in smoking cessation is considered robust and reliable (Cahill et al., 2016), so a comparison of ECs to this first-line therapy or as an adjunct is warranted.

Results show that EC use significantly reduces smoke and toxin intake compared to combustible cigarettes, so there is the potential that ECs may provide an overall improvement to public health (Hartmann-Boyce et al., 2021). In addition, Bullen et al. (2013) describe that ECs are more widely accepted by smokers than NRT and have a comparable risk of adverse events. However, as Chan et al. (2021) infer, it may be decades before the long-term impact on population health is evident. Concerns were also raised that a significant proportion of participants randomised to the nicotine EC arm continued to use ECs beyond the follow-up period, suggesting long-term use and the importance of long-term safety data (Hartmann-Boyce et al., 2021). The Australian Government are cautious about active promotion of nicotine ECs given the lack of conclusive evidence on smoking cessation, long-term harm, and the increased uptake of ECs by the younger population (Australian Institute of Health and Welfare, 2021). As Chan et al. (2021) argue, the aim should be to avoid the use of either ECs or combustible cigarettes.

Conclusion

There is a paucity of evidence comparing the efficacy of nicotine ECs to NRT. The limited evidence available shows that ECs are more effective than NRT for smoking cessation, with an equivalent degree of safety. Further research into these comparators, as well as the long-term safety of ECs, is required before these devices can be promoted as a quit smoking aid.

References

Australian Bureau of Statistics. (2022, March 21). Smoking, 2020-21 financial year. https://www.abs.gov.au/statistics/health/health-conditions-and-risks/smoking/latest-release

Australian Institute of Health and Welfare. (2021). Tobacco smoking.

https://www.aihw.gov.au/reports/australias-health/tobacco-smoking

Cahill, K., Lindson‐Hawley, N., Thomas, K. H., Fanshawe, T. R., & Lancaster, T. (2016). Nicotine receptor partial agonists for smoking cessation. Cochrane Database of Systematic Reviews(5). https://doi.org/10.1002/14651858.CD006103.pub7

Department of Health. (2019). What is smoking and tobacco? Retrieved April 11, 2022 from

https://www.health.gov.au/health-topics/smoking-and-tobacco/about-smoking-and-tobacco/what-is-smoking-and-tobacco#chemicals-in-tobacco-smoke

Royal Australian College of General Practitioners. (2021). Supporting smoking cessation. A guide for health professionals (2nd ed.). https://www.racgp.org.au/clinical-resources/clinical-guidelines/key-racgp-guidelines/view-all-racgp-guidelines/supporting-smoking-cessation/pharmacotherapy-for-smoking-cessation

Therapeutic Goods Administration. (2021). Guidance for the use of nicotine vaping products for smoking cessation. Retrieved April 11, 2022 from https://www.tga.gov.au/node/939881

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