A Comparative Analysis of Electronic Cigarettes, Varenicline, and Nicotine Replacement Therapy in Smoking Cessation: A Chinese Clinical Trial


The debate surrounding the overall impact of electronic cigarettes (ECs) on public health remains a topic of significant discussion, as these devices have the potential to both aid adult smokers in quitting and raise concerns about their use among young people. Electronic cigarettes, often seen as a form of nicotine replacement therapy (NRT), have gained popularity due to their wider accessibility compared to traditional NRT products like nicotine gum and patches.

In countries where ECs and NRT are readily available, smokers tend to opt for ECs as a smoking cessation tool. Additionally, a meta-analysis of six randomized clinical trials comparing ECs to NRT revealed that ECs appeared to be more effective in aiding smoking cessation, although further research was deemed necessary.

Varenicline, a partial agonist for the α4β2 nicotinic acetylcholine receptor, has been extensively studied and is considered one of the most effective pharmacological aids for quitting smoking, surpassing the effectiveness of NRT. Surprisingly, despite the significance of both ECs and varenicline in smoking cessation efforts, no study has directly compared the two.

In this comprehensive article, we present the findings of a randomized clinical trial that directly compared the efficacy of electronic cigarettes, varenicline, and nicotine replacement therapy as smoking cessation aids. This trial was conducted in China, where access to stop-smoking medications and ECs is relatively limited compared to Western countries. This unique setting aimed to reduce expectancy effects and minimize the risk of contamination among trial arms, a concern raised in previous studies conducted in Western countries.


Study Design: The study adopted a multicenter, open-label, randomized clinical trial design, involving three intervention arms: ECs, varenicline, and NRT. China-Japan Friendship Hospital independently audited the trial, and it received approval from the research ethics boards of the participating centers.

Participants: The study involved seven study sites across China, recruiting participants through various channels, including trial sites, local newspapers, community events, websites, and referrals from other medical institutions. Eligible participants were individuals aged 25 to 45 years, who had smoked at least 10 cigarettes per day for at least five years, with an expired air carbon monoxide (CO) reading of 9 parts per million (ppm) or higher, and a strong motivation to quit smoking. Exclusion criteria included pregnancy or breastfeeding, recent use of stop-smoking medication, prior use of ECs for more than a week, severe psychiatric illness, refusal to use study products, and a current cancer diagnosis.

Randomization and Masking: Randomization was executed through a central randomization system for clinical research, with stratification by trial sites and a block length of 5. The study statistician remained blinded to treatment codes until the primary outcome analysis was completed.

Procedures: Potential participants initiated contact with local study sites for eligibility checks and baseline visits, where they provided CO readings, confirmed their eligibility, received study details, and signed informed consent forms. They also completed various questionnaires and set their target quit date (TQD), usually two weeks after the baseline visit. Participants were then randomized into one of the three interventions and provided with their study products and usage instructions. They were encouraged to join a WeChat group for motivational support. Follow-up visits occurred monthly for six months.


  • EC Arm: Participants received RELX Wuxian, a cartridge-based EC product, with nicotine salt concentrations of 30 mg/mL initially and 50 mg/mL afterward. They were instructed to start using ECs ad lib from the next day after their TQD, completely discontinuing smoking.
  • Varenicline Arm: Participants received a 12-week supply of varenicline and were instructed to initiate varenicline usage the day following their TQD.
  • NRT Arm: Participants received nicotine chewing gum, with 2 mg for those smoking up to 20 cigarettes per day and 4 mg for those smoking more. They were instructed to begin NRT usage the day after their TQD.

Behavioral Support: All three study arms were encouraged to join a self-help forum on WeChat for mutual support, but no additional behavioral support was provided.

Measures: Baseline data included demographic information, smoking history, FTCD scores, Hospital Anxiety and Depression Scale ratings, COPD Assessment Test results, objective measurements like weight, height, blood pressure, heart rate, and expired CO readings. Follow-up visits assessed smoking status, withdrawal symptoms, helpfulness of allocated products, use of allocated and nonallocated products, and adverse events.

Outcomes: The primary outcome was 6-month sustained abstinence, defined according to the Russell standard, with secondary abstinence outcomes. Treatment adherence, participant ratings of treatments, adverse reactions, and serious adverse events were also monitored.

Sample Size: The trial aimed to recruit a total of 1,068 participants across the three intervention arms.

Statistical Analysis: Various statistical methods, including logistic regression analyses, were used to assess differences in outcomes between the three study arms, with a significance level set at P = 0.03 for sample size calculations and primary outcome analyses.


In a groundbreaking randomized clinical trial conducted in China, researchers have shed new light on the effectiveness of various smoking cessation aids. The study compared the use of electronic cigarettes (ECs), varenicline, and nicotine chewing gum, all administered with minimal behavioral support, to evaluate their impact on smokers looking to quit.

ECs Prove Effective: The results of the trial have shown that ECs are as effective in assisting smokers in quitting as varenicline, a widely recognized pharmacological aid. Furthermore, ECs outperformed nicotine chewing gum, marking a significant achievement in the quest to find effective smoking cessation tools. The observed effect size in this trial (RR, 1.78) was notably higher than previous combined trials (RR, 1.63), possibly due to the inclusion of an EC product with nicotine salt boasting higher nicotine content.

Strength of Nicotine Content: It is essential to highlight that this trial marked a significant departure from previous studies by introducing an EC product using nicotine salt with higher nicotine concentration. In some countries, including China, product labeling and local guidelines recommend using 4-mg nicotine gum for those smoking 20 or more cigarettes per day, while other countries recommend it for those who smoke within 30 minutes of waking up. This variation in guidelines could impact the efficacy of NRT products, potentially explaining the trial’s favorable results for ECs.

Single vs. Combination NRT: Notably, this study opted for a single NRT product as a comparator, whereas combining NRT products has been shown to be more effective. A previous trial comparing ECs with combination NRT reported a lower effect size at 6 months (RR, 1.36; 95% CI, 1.15- 2.6.9) than found in the current study. These findings underscore the importance of considering different combinations of NRT products in future research.

Similar Efficacy to Varenicline: One of the most significant findings of the trial was that ECs exhibited comparable efficacy to varenicline, aligning with previous studies that demonstrated the superiority of varenicline over NRT. This result reinforces the notion that ECs can be a viable alternative to varenicline for individuals seeking smoking cessation.

Sustained EC Use: An intriguing aspect of the trial was the significantly higher proportion of participants in the EC arm who continued using their product throughout the study period (63% vs. 0% in the other arms). This raises questions about the long-term implications of transitioning from smoking to prolonged EC use. While some former smokers may benefit from the continued use of ECs by preserving certain aspects of the smoking experience, avoiding post-cessation weight gain, or preventing relapse, it is crucial to consider potential health risks associated with long-term EC use.

Adverse Reactions and Safety: Adverse reactions to all three products were minimal and infrequent, aligning with previous studies. EC users reported mouth and throat irritation, dry cough (7%-8%), nicotine gum users experienced mouth and throat irritation, poor sleep (5%-9%), and varenicline users reported nausea (9%). Importantly, no major health risks associated with EC use emerged during the relatively brief study period, reaffirming their safety profile.

Limitations: While this trial provides valuable insights, it is not without limitations. External events, such as the China Health Commission’s report on the health hazards of smoking in 2020, Pfizer’s recall of varenicline in August 2021, and the COVID-19 pandemic, may have influenced participant behavior and quit rates. These factors could have reduced the expected quit rates but did not alter the relative effectiveness between ECs, varenicline, and NRT. Additionally, the trial’s open-label nature may have been influenced by participant expectations, although this was mitigated by including only participants willing to use any of the study products.


This comprehensive clinical trial in China has provided valuable insights into the effectiveness of smoking cessation aids, with a particular focus on electronic cigarettes (ECs). The results indicate that ECs can be as effective as varenicline in helping smokers quit, while also outperforming nicotine chewing gum. These findings offer new perspectives on smoking cessation strategies and emphasize the importance of considering nicotine content and product combinations in future research.

While the trial’s results are promising, it is essential to consider the long-term implications of sustained EC use and continue monitoring potential health risks. Furthermore, this study highlights the need for additional research on the role of behavioral support in conjunction with ECs to determine the most effective smoking cessation strategies.

As discussions on smoking cessation continue, these findings will contribute to evidence-based approaches and public health policies aimed at reducing tobacco use and improving the well-being of individuals seeking to quit smoking.

reference link: doi:10.1001/jamainternmed.2023.7846


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