Editors' Note: The trial of e-cigarettes that we wrote about in this edition of the EBM Focus has been retracted. The authors report there were “significant coding errors that are difficult to rectify…and discrepancies in the calculation process that cast doubt on the accuracy and reliability of the reported findings.” While the trial results should be completely disregarded, we stand by our advice as stated in the Focus, which was “to [still] recommend varenicline as the first line."
Reference: JAMA Intern Med. 2024 Jan 29 early online
Practice Point: Electronic cigarettes appear more likely to replace smoking than to help people quit.
EBM Pearl: In contrast to superiority trials, per-protocol analysis is the more conservative and preferred analysis for noninferiority trials.
Doctors used to recommend Lucky Strike. Now the way things are going, it looks like doctors might be recommending electronic cigarettes (ECs) too—for smoking cessation, at least. We can’t help but to have a sense of déjà vu when we look back at old magazine ads where doctors said, “Smoking is good for you!” before we knew how that story ended. ECs have been touted as a good way to quit smoking, but recent evidence suggests most people just trade out one addiction for another.
A recent trial in JAMA evaluated ECs for smoking cessation, comparing them to varenicline and nicotine replacement therapy (NRT) in the form of nicotine gum. Recruited participants were 25-45 years old living in China, smoked at least 10 cigarettes/day for ≥ 5 years, and were motivated to quit. After randomization to one of the three treatment arms, all participants were asked to come up with their own quit date about two weeks after beginning treatment. They also received minor behavioral support including a texting app. Quit rates were assessed with monthly surveys and carbon monoxide detection tests to verify smoking status for six months. The treatments were provided free of charge for three months, but patients were allowed to continue if they wished and were provided info on how to obtain the therapy on their own.
This trial was the first to compare ECs and varenicline head-to-head, so it could not be assumed whether ECs would be better or worse than varenicline. For that reason, the study would either have had to have been powered for a two-tailed superiority assessment (more participants) or for noninferiority (fewer participants) for the comparison of EC vs varenicline. They went with noninferiority. However, because prior trials had demonstrated that ECs were better than NRT, investigators chose a superiority analysis for that comparison because the direction of effect was known (assumed). The different comparisons required different statistics. Also as part of the power calculations, investigators calculated the needed sample size based on an anticipated quit rate of about 40%. (This seems generous.) Ultimately, they came up short of the planned enrollment and ended up randomizing 1,068 smokers in total, 409 to ECs, 409 to varenicline, and 250 to NRT. (Failure to meet enrollment goals can lead to a study being underpowered to detect a difference if a difference truly exists. However, if significant differences are found, this becomes a moot point.)
By the end of six months, quit rates were 15.7% for ECs, 14.2% for varenicline, and 8.8% for NRT. The differences between ECs and the other therapies were each significant based on intention-to-treat analyses, with an absolute risk reduction compared to varenicline of 1.47% (95% Cl -1.41% to 4.34%) and an odds ratio of 1.92 compared to NRT (95% CI 1.15-3.21, NNT 15). Importantly, 62.8% of participants in the EC arm continued to use ECs after six months, compared to no continuation in the other groups. We want to note that omitting a per-protocol analysis for the noninferiority comparison could make it easier to demonstrate noninferiority. This is not ideal from an EBM standpoint, but because the EC effect surpassed the varenicline effect, we think this is unlikely to significantly affect the validity of the results.
Overall, there are several key takeaways from the study. 1) ECs do seem to be reasonably effective for helping people stop smoking cigarettes. 2) People who quit smoking using ECs are more likely than not to continue using ECs, essentially swapping one addiction for another. 3) It is really hard to quit smoking. These participants were motivated to quit, given pharmacologic and behavioral support, and yet only 16% succeeded using ECs, and two thirds of them were still vaping at 6 months. The odds of truly quitting any type of inhaled nicotine aren’t looking great, especially for patients who aren’t particularly inclined to quit. We also can’t forget that we still don’t know the long, long-term consequences of vaping, and that makes the idea of recommending them uncomfortable. Doctors really, truly used to recommend cigarette smoking to patients, and look how that turned out. So while we are pretty sure that ECs are less harmful than regular cigarettes, they still can’t be good for you. We suppose the bottom line may be that ECs are a reasonable method of harm reduction for those that can’t or won’t use other methods, but our advice is still to recommend varenicline as the first line.
For more information, see the topic Nicotine Replacement Therapy for Tobacco Cessation in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia. Edited by Alan Ehrlich, MD, FAAFP, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Dan Randall, MD, MPH, FACP, Deputy Editor at DynaMed; Nicole Jensen, MD, Family Physician at WholeHealth Medical; Vincent Lemaitre, PhD, Medical Editor at DynaMed; Hannah Ekeh, MA, Senior Associate Editor at DynaMed; and Jennifer Wallace, BA, Associate Editor at DynaMed.