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

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Clinical Question

In a patient who wants to quit smoking, would the combination therapy of nicotine patches and a nicotine e-cigarette be as safe and effective in aiding in smoking cessation, compared to nicotine patches alone?

Bottom Line

In an adult patient who wants to quit smoking,the combination of nicotine patches and e-cigarettes is not more effective than the use of nicotine patches alone.

Major Points

E-cigarettes are devices used by many individuals as an alternative to traditional cigarettes. E-cigarettes, with and without nicotine, have been studied in clinical trials to determine efficacy in being a successful therapy for smoking cessation compared to other methods such as nicotine replacement therapy (NRT). NRT reduces the patient’s withdrawal symptoms while quitting smoking. However nicotine containing e-cigarettes allows users to obtain nicotine as quickly and at similar concentrations to traditional cigarette smoking.

The study randomly assigned 1124 participants across New Zealand, with participants assigned to nicotine patches, patches plus a nicotine e-cigarette, or patches plus a nicotine-free e-cigarette. Behavioral support was provided to participants weekly for up to six weeks. The study was a parallel group, community-based, pragmatic, three-arm, randomized trial. This study included adults 18 years or older that smoked tobacco and were motivated to quit within 2 weeks and who could provide verbal consent.

The primary outcome of the trial was quit rate (verified through measuring Carbon Monoxide levels) at 6 months for patches + nicotine e-cigarettes (7%), patches and nicotine free e-cigarettes (4%), and for patches only (2%). The patches and nicotine e-cigarette group showed the highest abstinence rate at the end of the 6 months. However, when analyzing the p-value (0.05) and confidence interval (0.91-9.33) of the data, the reported result is not statistically significant. Therefore, using a nicotine patch with a nicotine e-cigarette is not statistically significant in aiding in smoking cessation over patches alone or nicotine patches and nicotine free e-cigarettes.

The trial conducted assessed the safety and efficacy of combining nicotine patches with e-cigarettes (with and without nicotine) in promoting smoking abstinence. In a Cochrane Review, combined data from several 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 for both groups. All five of the currently published trials on e-cigarettes for smoking cessation suggest e-cigarettes (with and without nicotine) could help some people quit smoking. E-cigarettes should be offered as one of the many smoking cessation aids to people wanting to quit, but do not appear to be a solution for everyone. It is difficult to generalize the true result of the studies based on the policy and restrictions on e-cigarette use in certain regions.

Guidelines

Per New Zealand Guidelines on quitting smoking: Nicotine replacement therapy (NRT)

  • NRT provides some of the nicotine that a person would have otherwise received from tobacco, and in doing so reduces the person’s urge to smoke.
  • There are five different NRT products available in New Zealand, including the patch, gum, lozenges, inhalator and mouth spray.
  • Using two NRT products (for example, patches and gum) is more effective than using one
  • If the person is not ready to stop smoking straight away, NRT can be used to help reduce their smoking before they stop.
  • The approved stop-smoking medicines that are available in New Zealand are:
    • Nicotine replacement therapy (NRT), bupropion, nortriptyline, varenicline.
  • All of these medicines ease tobacco withdrawal symptoms, which makes quitting easier.

Per the CDC Guidelines on quitting smoking: Medications for quitting that have been found to be effective include the following:

  • Nicotine replacement products
  • Over-the-counter options
    • Nicotine patch, gum, lozenge
  • Prescription options
    • Nicotine patch, inhaler, nasal spray
  • Prescription non-nicotine medications:
    • bupropion SR (Zyban®), varenicline tartrate (Chantix®)
  • NRT helps to reduce withdrawal symptoms by giving you a small controlled amount of nicotine
  • This small amount of nicotine helps to satisfy the craving for nicotine and reduce smoking urges
  • NRT can be an important part of almost every smoker’s strategy to quit smoking
  • A single quitting option is not the best for everyone, it is very patient specific

Per the American Lung Association: E-Cigarette Safety

  • Two main components of e-cigarette e-liquid, propylene glycol and vegetable glycerin, are toxic to cells; the more ingredients in the e-liquid, the greater the toxicity.
  • E-cigarettes, when smoked, create many dangerous chemicals such as acetaldehyde, acrolein, and formaldehyde.
  • Aldehydes can cause lung and cardiovascular disease
  • Acrolein, which is a herbicide that may cause acute lung injury, COPD, asthma and lung cancer
  • The U.S. Surgeon General and the National Academies of Science, Engineering and Medicine have issued warnings regarding secondhand e-cigarette emission inhalation, stating the emissions themselves can contain nicotine as well as other harmful chemicals.
  • The Food and Drug Administration currently does not find any available e-cigarettes safe and effective in helping smokers quit.


Design

  • Parallel group, community-based pragmatic, three-arm randomized trial
  • N= 1124 randomized
  • Patches only: n= 125
  • Patches plus nicotine e-cigarette: n=500
  • Patches plus nicotine-free e-cigarette: n=499
  • Setting: community-based across New Zealand
  • Enrollment: March 17, 2016- November 30, 2017
  • Mean follow-up: 6 months
  • Analysis: Intention to treat Analysis, Per-protocol, and complete case analysis
  • Primary outcome: continuous smoking abstinence 6 months after the agreed quit date (self-reported abstinence since quit date, allowing five or fewer cigarettes in total).


Population

Inclusion Criteria

  • Adults 18 years or older that smoked tobacco and were motivated to quit within 2 weeks and who could provide verbal consent


Exclusion Criteria

  • Women currently pregnant or breastfeeding
  • People who have previously used an e-cigarette for smoking cessation for more than 1 week within the previous year before the trial
  • People currently on smoking cessation medication
  • People currently enrolled in another smoking cessation program or study
  • People who have self-reported history of severe allergies, poorly controlled asthma, or a cardiovascular event in the 2 weeks before enrollment


Baseline Characteristics

  • Gender
    • Women: 768
    • Men: 355
  • Median Age: 41.2-42.3
  • Number of cigarettes smoked per day: 17.3
  • Number of years smoked: 22.5
  • At least one attempt to quit in the past 12 months: 507
  • Previously used nicotine patches to quit: 147
  • Mood Disorder
    • Depression: 137
    • Anxiety: 111
    • Other: 41


Interventions

Randomization and Masking:

  • Eligible participants were randomly allocated by computer to patches, patches

plus a nicotine e-cigarette, or patches plus a nicotine-free e-cigarette in a 1:4:4 ratio using stratified block randomization.

  • Participants and researchers collecting outcome data were masked to the nicotine content of the e-liquid.
  • Moderate-intensity behavioral support was available for all participants immediately after randomization

Nicotine Patches:

  • Patches were started two weeks before quit date

E-cigarettes:

  • Participants were given a KangerTech e-cigarette Electronic Vapor on Demand (eVOD) starter kit with two batteries, two refillable tanks, one charging kit, one carry case, and five atomizers.
  • Participants chose from two tobacco e-liquid flavors—one that resembled the taste of smoke roll-your-own tobacco and one resembling the taste of smoke factory-made cigarettes.
  • E-liquid had a nicotine content of either 0 mg/mL or 18 mg/mL.


Outcomes

Comparisons are intensive therapy vs. standard therapy.

Primary Outcomes

Primary: The primary outcome was continuous smoking abstinence 6 months after the agreed quit date (self-reported abstinence since quit date, allowing five or fewer cigarettes in total).

  • CO-verified quit rate at 6 months patches + nicotine e-cigarettes ( 7%) compared to patches only (2%)
    • P-value = 0.05
    • Confidence interval = 0.91 - 9.33
    • NNT = 21.7
  • CO-verified quit rate at 6 months patches + nicotine free e-cigarettes (4%) compared to patches + nicotine e-cigarettes (7%)
    • P-value = 0.038
    • Confidence interval = 1.02-2.98
    • NNT = 33.4
  • Overall - Based on the information from the primary outcomes, using the patches and the nicotine free e-cigarettes were more effective than patches alone or patches and nicotine e-cigarettes when trying to quit smoking.


Secondary Outcomes

There were no significant differences in the secondary outcomes.

Subgroup Analysis

The researchers assessed the consistency of effects for the primary outcome for ethnicity, age, sex, education, level of cigarette dependence, motivation to quit, and e-liquid batch using tests for heterogeneity. They did a post-hoc subgroup analysis for Māori and non-Māori women. Per-protocol analysis excluded participants with missing 6-months of data and major protocol violations.

Adverse Events

  • Patches only - 3%
    • 3 hospitalizations
  • Patches + nicotine e-cigarettes - 4%
    • 2 life threatening (two separate heart attacks in one participant)
    • 11 hospitalizations
    • 1 significant disability
    • 4 other
  • Patches + nicotine free e-cigarettes - 5%
    • 1 death (accidental drug overdose)
    • 1 life threatening (heart attack)
    • 19 hospitalizations
    • 6 other
  • No significant differences were noted for serious adverse events, and none were treatment-related.


Criticisms

  • 385 participants were lost to follow-up at 6 months (those with a low level of education and high cigarette dependence were more likely to be lost to follow-up)
  • 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.
  • The findings are not generalizable given the multitude of e-cigarette brands and delivery systems available worldwide with different amounts of nicotine content from that used in this trial.
  • There were a lot less participants in the patches only group, compared to the other two groups.
  • It is difficult to generalize the true result of this study due to policy and restrictions on e-cigarette use in New Zealand
    • When the trial began, nicotine-containing e-liquid was illegal in New Zealand
    • However, a 3-month supply of nicotine e-liquid could be imported for personal use
    • In March 2018, once the study had already begun, New Zealand legalized nicotine e-cigarettes to be sold to adults only
      • 15% of patches only group crossed over and use nicotine e-cigarettes during the trial
      • 11% of the patches + nicotine free e-cigarettes crossed over and used the nicotine e-cigarettes
  • The patients were allowed to pick between 2 different flavors of e-cigarettes and this could affect the quit rate, if the patient picked something that they may have liked or if they ended up enjoying very much, they might not have wanted to stop


Funding

  • This RCT was funded by the Health Research Council of New Zealand.


Further Reading


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