Almost all the randomized controlled trials of e-cigarettes as clinical interventions for smoking cessation have compared e-cigarettes to nicotine replacement therapy. Varenicline, which is a prescription medication that works by blocking nicotine receptors rather than replacing the nicotine that cigarettes provide, is more effective than NRT. Anna Tsiku and colleagues new paper “Electronic Cigarettes vs Varenicline for Smoking Cessation in Adults: A Randomized Clinical Trial,” contributes to the literature by doing a comparison of nicotine e-cigarettes with varenicline, both combined with 12 weeks of counselling, as clinical smoking cessation interventions among heavy smokers interested in quitting. They find “that varenicline and nicotine-containing [e-cigarettes] were both effective in helping individuals in quitting smoking conventional cigarettes for up to 6 months.”
Because of the way they designed their RCT (see below), a more precise statement of their conclusion would be “combined with 12 weeks of counselling, nicotine e-cigarettes were as effective as varenicline plus non-nicotine e-cigarettes compared to non-nicotine e-cigarettes as clinical cigarette smoking cessation interventions among heavy smokers interested in quitting.
This wording of the conclusion is a little different from the way the authors characterize their conclusions, where they just refer to e-cigarettes vs varenicline, without specifying that everyone received some form of e-cigarette (nicotine or non-nicotine). The reason for this is that the authors wanted to do comparisons against placebo to account for the fact that sometimes people getting a treatment – even if it has no effect – can affect the results. For this reason, they provided all participants with a pill (varenicline or an inert placebo pill) and an e-cigarette (nicotine or non-nicotine). This is a fine and careful design, but to draw a conclusion about nicotine e-cigarettes vs (just) varenicline, they would have needed a varenicline only group as well as a second control group that only received placebo pills.
At 52 weeks, varenicline does better than placebo but nicotine e-cigarettes do not (although the nicotine e-cigarette difference is close to conventional statistical significance pf p=0.05). In addition, the between varenicline plus non-nicotine e-cigs vs nicotine e-cigs does not quite reach conventional statistical significance (p is about 0.075 vs the conventional 0.05 cutoff).
The larger context
In presenting this study, it is important to stress that the conclusions apply to an intensive clinical intervention, not e-cigarettes as consumer products. (See discussion in Wang et al for the importance of this distinction.)
The biggest limitation: Not reporting ongoing e-cigarette use as an adverse event
The big limitation of the paper is that, like all the other RCTs, it assumes that e-cigarettes are so much safer than cigarettes the authors don’t need to consider continuing use of e-cigarettes as an adverse event. As a result, they do not report e-cigarette and dual use at the end of the study period.
This is wrong; our meta-analysis published a couple months ago (also attached) shows that for several disease, e-cigarettes pose risks indistinguishable from cigarettes and for others, while lower, the risks are still substantial.
The authors also do not report continuing dual use as an adverse event. This is important because dual use is more dangerous than just smoking and, in one RCT of giving people free e-cigarettes for every smoker who stopped cigarettes, 2.7 became dual users.
Considering these adverse events, it is likely that providing nicotine e-cigarettes as a cessation medication would actually increase disease risk, making it unlikely that the benefit/risk ratio would be favorable enough to justify a medicines authority like the US FDA from approving e-cigarettes as cessation medicines.
As far as I know, no e-cigarette company has submitted their e-cigarettes as therapeutic interventions anywhere in the world. In any event, none have been approved. Medical providers should not be recommending e-cigarettes as cessation therapy until the FDA or other comparable authority approves them as cessation therapies.
Here is the abstract:
Importance. Little is known about the relative effectiveness of nicotine-containing electronic cigarettes (ECs) compared with varenicline as smoking cessation aids.
Objective. To determine the relative effectiveness of ECs in smoking cessation.
Design, Setting, and Participants. This randomized placebo-controlled single-center trial was conducted in northern Finland. Participants aged 25 to 75 years who smoked daily and had volunteered to quit smoking were recruited from August 1, 2018, to February 20, 2020, via local media. The trial included 52 weeks of follow-up. All data analyses were conducted from September 1, 2022, to January 15, 2024. The participants, study nurses, and researchers were masked to group assignment.
Intervention. The participants were assigned by block randomization to receive 18 mg/mL of nicotine-containing ECs together with placebo tablets, varenicline with standard dosing together with nicotine-free ECs, or placebo tablets together with nicotine-free ECs, all combined with a motivational interview, with the intervention phase lasting for 12 weeks.
Main Outcome and Measure. The primary outcome was self-reported 7-day conventional cigarette smoking abstinence as confirmed by the exhaled carbon monoxide level on week 26. The analysis followed the intent-to-treat principle.
Results. Of the 561 recruited participants, 458 (81.6%) eligible participants (257 women [56%]; 201 men [44%]; mean [SD] age, 51 [11.6] years) were randomized. The primary outcome occurred in 61 of 152 participants (40.4%) in the EC group, 67 of 153 (43.8%) in the varenicline group, and 30 of 153 (19.7%) in the placebo group (P < .001). In the pairwise comparison, placebo differed statistically significantly from ECs (risk difference [RD], 20.7%; 95% CI, 10.4-30.4; P < .001) and varenicline (RD, 24.1%; 95% CI, 13.7-33.7; P < .001), but the difference was statistically insignificant between ECs and varenicline (RD, 3.4%; 95% CI, −7.6 to 14.3; P = .56). No serious adverse events were reported.
Conclusions. This randomized clinical trial found that varenicline and nicotine-containing ECs were both effective in helping individuals in quitting smoking conventional cigarettes for up to 6 months.
The citation is: Tuisku A, Rahkola M, Nieminen P, Toljamo T. Electronic Cigarettes vs Varenicline for Smoking Cessation in Adults: A Randomized Clinical Trial. JAMA Intern Med. Published online June 17, 2024. doi:10.1001/jamainternmed.2024.1822. It is available here.
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