A Randomized Trial of E-Cigarettes versus Nicotine-Replacement Therapy

Hajek Peter, et al. (2019). A Randomized Trial of E-Cigarettes versus Nicotine-Replacement Therapy. New England Journal of Medicine, 380(7), 629-637.

Clinical Question

In patients that are trying to quit smoking, is the use of e-cigarettes in comparison to conventional nicotine replacement therapy as effective in helping patients to quit smoking?

Bottom Line

In adult patients trying to quit smoking, e-cigarettes are more effective than conventional nicotine replacement therapy.

Major Points

Over the past few years, e-cigarettes have become an alternative to traditional combustible cigarettes. E-cigarettes are battery-powered devices that contain nicotine-based liquid that is used to simulate the effects of smoking traditional cigarettes. Use of e-cigarettes as a smoking cessation tool has recently become a discussion regarding their efficacy compared to alternative smoking cessation methods such as nicotine replacement therapy.

The study randomly assigned 886 adults attending U.K. National Health Service stop-smoking services to either nicotine-replacement products of their choice, provided for up to 3 months, or an e-cigarette starter pack with a recommendation to purchase further e- liquids of the flavor and strength. The study was an individually randomized, multicenter, controlled trial. For at least four weeks weekly behavioral support was provided to the participants. Inclusion criteria for the trial consisted of non-pregnant and non-breastfeeding adult smokers with no strong preference for nicotine-replacement therapy or e-cigarettes, and people currently not using either product. Adult smokers with no preference for nicotine-replacement therapy or e-cigarettes.

This trial evaluated the efficacy of one year use of refillable e-cigarettes compared to nicotine-replacement therapy both combines with behavioral support. In a Cochrane review e- cigarettes containing nicotine were shown to be more effective than e-cigarettes that did not contain nicotine. A comparison trial between nicotine replacement and e-cigarettes for smoking cessation used cartridge e-cigarettes with low nicotine delivery and no face-to-face contact. For both treatments similar efficacy was observed.

The primary outcome was sustained abstinence from cigarette smoking which was validated biochemically for one year. The 1-year abstinence rate was 18.0% in the e-cigarette group, compared with 9.9% in the nicotine-replacement group. E-cigarettes were more effective for smoking cessation than nicotine-replacement therapy, when both were accompanied by behavioral support. Overall, e-cigarettes were more effective for smoking cessation than nicotine-replacement therapy; when both were accompanied with behavioral support.

Guidelines

2018 ACC Expert Consensus Decision Pathway on Tobacco Cessation Treatment

• Scientific evidence is insufficient to allow reliable conclusions to be made about the long-term health effects of e-cigarettes
• A clinician should advise cigarette smokers seeking to quit to use evidence-based, FDA-approved, safe, and effective smoking cessation pharmacotherapies as first-line treatments in preference to e-cigarettes.
• Although there are no data yet to show that behavioral support enhances the potential effectiveness of e-cigarettes for cessation, it is reasonable to encourage e-cigarette users to use the standard resources for behavioral support.

National guidelines for smoking cessation in primary care: a literature review and evidence analysis

• E-cigarettes were not included in national guidelines as an FDA-approved smoking cessation tool
• Lack of inclusion primarily due to rapid rise of e-cigarettes on the market after development of guidelines included in this study

Design

• Individually randomized, multicenter, controlled trial
• N=886 randomized
• E-cigarettes:  n=439
• Nicotine Replacement Therapy: n=447
• Setting: 3 service enters in the UK
• Enrollment: May 2015- Feb 2018
• Mean follow-up: 1 year
• Analysis: Intention to Treat Analysis
• Primary outcome: 1-year sustained “smoking” abstinence

Population

Inclusion Criteria

• Non-pregnant and non-breastfeeding adult smokers with no strong preference for nicotine-replacement therapy or e-cigarettes, and currently not using either product
• Adult smokers with no preference for nicotine-replacement therapy or e-cigarette

Exclusion Criteria

• Adult smokers currently using either nicotine-replacement therapy or e-cigarettes

Baseline Characteristics

• Median age of 41 years: 33-52
• Female sex: 48
• Employed: 69.6
• Entitled to free prescriptions: 40.7
• Median of 15 cigarettes per day: 10-20
• Median level of 20 ppm expired carbon monoxide: 13-28
• Score on the Fagerstrom Test for Cigarette Dependence: 4.6 + 2.4 on 10 point scale, with higher score indicating higher dependence
• Past use of nicotine replacement: 74.9
• Past use of e-cigarettes: 41.5

Interventions

Randomization

• All eligible patients were randomized on the quit date of their choosing to limit differential dropout
• Product use began right after randomization
• Both groups signed commitment not to use non-assigned treatment for at least 4 weeks after their quit date

Nicotine-replacement

• Nicotine-replacement including: patches, gum, lozenges, nasal sprays, inhalators, mouth sprays, mouth strips, and microtabs were provided for 3 months

E-cigarettes

• E-cigarette group: starter pack One Kit for initial use (during trial this kit was discontinued by manufacturer; One Kit 2016 was used instead), or a different device based on patient preference

Other treatment

• Behavioral therapy for both groups for 4 weeks

Outcomes

Primary Outcomes

• E-Cigarette 1-Year Abstinence: 18%
• Nicotine replacement group 1-Year Abstinence Rate: 9.9%
• Confidence Interval: 1.30-2.58
• P<0.001
• NNT: 12
• Overall: E-cigarettes were more effective in sustaining 1 year abstinence from smoking compared to nicotine replacement therapy when both were combined with behavioral support.

Secondary Outcomes

Abstinence between week 26 and week 52:

• E-Cigarettes: 93 (21.2%)
• Nicotine Replacement: 53 (11.9%)
• Primary Analysis Relative Risk (95% CI): 1.79 (1.32 - 2.44)

Abstinence at 4 week after target quit date:

• E-Cigarettes: 192 (43.8%)
• Nicotine Replacement: 134 (30.0%)
• Primary Analysis Relative Risk (95% CI): 1.45 (1.22 - 1.74)

Abstinence at 26 week after target quit date:

• E-Cigarettes: 155 (35.4%)
• Nicotine Replacement: 53 (25.1%)
• Primary Analysis Relative Risk (95% CI): 1.79 (1.14 - 2.72)

Other Secondary Outcomes Observed

Urge to smoke with Abstinence at 1 week and 4 weeks after quit date: 1 week after quit date - frequency of urge

• E-Cigarette (158): 2.5
• Nicotine Replacement: 2.8
• Mean Difference (95% CI): -0.4(-0.6 to -0.1)

1 week after quit date - strength of urge

• E-Cigarette (131): 2.7
• Nicotine Replacement: 3.2
• Mean Difference (95% CI): -0.5(-0.7 to -0.2)

4 weeks after quit date - frequency of urge

• E-Cigarette (186): 1.9
• Nicotine Replacement: 2.2
• Mean Difference (95% CI): -0.3(-0.5 to -0.1)

4 weeks after quit date - strength of urge

• E-Cigarette (132): 2.1
• Nicotine Replacement: 2.4
• Mean Difference (95% CI): -0.3(-0.6 to -0.1)

These results show a significant decrease in both the frequency and the strength of the urge to smoke in participants in both groups, however participants in the E-cigarette group had smaller urges and less frequency when compared to those receiving nicotine replacement.

Respiratory Symptoms: Relative Risk (95% CI)

• Shortness of Breath: 0.9 (0.7-1.1)
• Wheezing: 1.1 (0.8-1.4)
• Cough: 0.8 (0.6-0.9)
• Phlegm: 0.7 (0.6-0.9)

Cough and Phlegm were the two respiratory symptoms to have a significant difference in both groups. Researchers found that significant more participants in the E-cigarette group were symptom free at the 52 week mark compared to those in the nicotine replacement.

Subgroup Analysis

The researchers completed a post-hoc test of participants who completed 1 year abstinence, but eliminated those that were using unassigned products. In the E-cigarette group two of 79 were eliminated for using nicotine replacement and nine of the 44 in the nicotine replacement were eliminated for using an E-cigarette. The result of a 1 year abstinence rate of mono therapy treatment of 17.7% for the E-cigarette group and 8.0% for the nicotine replacement group; 95% CI {1.52 to 3.22}

Additionally, researchers examined relapse at 52 weeks in participants that had sustained abstinence at 4 weeks. The results were insignificant between each group with time of relapse 95% CI of 0.96 to 1.34 and relative risk of relapse at 52 weeks 95% CI of 0.93 to 1.73

Adverse Events

• In the e-cigarette group there was one death caused by ischemic heart disease and 27 adverse effects.
• The nicotine replacement group had one death cause by traumatic spine injury and 22 other adverse effects.
• The trial clinician deemed no adverse effects were caused by the products used in the trials.
• The most common adverse effects were:
  • Nausea: 37.9% in the Nicotine Replacement vs. 31.3% in the E-Cigarette o
  • Sleep Disturbances: 68% in the Nicotine Replacement vs. 64% in the E-Cigarette
  • Throat or Mouth Irritation: 51.2% in the Nicotine Replacement vs. 65.3% in the E-Cigarette
  • Severe Nausea: 6.5% in the Nicotine Replacement vs. 6.6% in the E-Cigarette
  • Severe Sleep Disturbances: 13% in the Nicotine Replacement vs. 13% in the E- Cigarette
  • Severe Throat or Mouth Irritation: 3.9% in the Nicotine Replacement vs. 5.9% in the E-Cigarette

Criticisms

• Participants could not be blinded from there product assignment. If participants felt that their product was the lesser of the two, they may have put less effort in trying to quit. This could have an uncontrolled influence on the results, more specifically if the nicotine replacement group felt that their treatment was lesser than that of an e-cigarette.
• Carbon monoxide validation can detect CO levels from the past 24 hours so there was a possibility of false negatives. CO levels were tested to validate reduction of smoking but this test could not inform the researchers about an smoking that occurred 24 hours or more before the test. If participants were not honest, this test could not catch a lie.
• Embarrassment from failure to quit can cause lack of face to face follow up with participants. Lack of follow up can influence the results if only those who actually remained abstinent were the ones who reported back to the surveyors.

Funding

The RCT was funded by a grant provided by the Cancer Research UK Prevention Trials Unit and supported by the National Institute for Health Research Health Technology Assessment Programme.