Richard Wang, Sudha Bhadriraju and I just published a comprehensive meta-analysis of the association between e-cigarette use and smoking cessation, “E-Cigarette Use and Adult Cigarette Smoking Cessation: A Meta-Analysis,” in American Journal of Public Health. Unlisk earlier meta-analyses, we made a distinction between population observational studies, which are valuable for assessing the effects of e-cigarettes as consume products used in the real world, and clinical trials, which are useful for assessing the effects of e-cigarettes used as a smoking cessation aid under medical supervision. This is an important distinction because it is the population level effects that the FDA should be considering when assessing whether allowing the sale of e-cigarettes is “appropriate for the protection of public health,” the standard in the law.
What we found was that:
- When considering all users, e-cigarette user was not associated with quitting cigarettes.
- Among people motivated to quit smoking, e-cigarette use was not associated with quitting cigarettes.
- Daily e-cig users were more likely to quit and non-daily users were less likely to quit with the overall effect nonsignificant.
These are important findings for the FDA Center for Tobacco Products because if, overall, e-cigarette users do not quit smoking the whole “complete switching: hypothesis the FDA still clings too falls apart and there is no way that approving e-cigs would be appropriate for the protection of public health.
This is particularly true given the emerging evidence that dual use (continuing to smoke while using e-cigarettes) is more dangerous than just smoking.
And then there is the huge “gateway effect” of youth initiating nicotine addiction with e-cigs and going on to add cigarettes.
In contrast, the evidence from the smaller number of randomized clinical trials does show that e-cigarettes provided free to people under medical supervision is associated with more quitting. This suggests that, if e-cigarettes can be shown to have a favorable risk/benefit profile, the FDA Center for Drug Evaluation and Research — the part of FDA that deals with medicines and medical devices — might approve e-cigarettes as a prescription smoking cessation aid.
As far as I know, no tobacco company has submitted an application for approval.
This distinction in the questions answered by the observational studies and RCTs is particularly important because most of the meta-analyses published to date, including the one the Institute of Medicine published a few years ago in its report on e-cigs, rely on RCTs and discount or dismiss observational studies as low quality or unreliable. It is true that, when assessing medicines, RCTs are the gold standard. But a e-cigarette picked up at a corner grocery, vape shop, or even a Walgreens, is not a medicine, it is a consume product.
Here is the summary of implications from our paper:
If e-cigarette consumer product use is not associated with more smoking cessation, there is no population-level health benefit for allowing them to be marketed to adults who smoke, regardless of the relative harm of e-cigarettes compared with conventional cigarettes. Moreover, to the extent that people who smoke simply add e-cigarettes to their cigarette smoking (becoming so-called dual users), their risk of heart disease, lung disease, and cancer could increase compared with smoking alone. The other 2 questions [the FDA Center for Tobacco Products], CTP is mandated to consider—the direct toxicity of e-cigarettes and the potential that e-cigarette availability increases smoking rates among the youths—are also important and not included in our meta-analysis. The fact that e-cigarettes have attracted millions of youths to nicotine, many of whom would have been unlikely to initiate nicotine use with conventional cigarettes, further undermines the idea that allowing the marketing of e-cigarettes would be “appropriate for the protection of public health.” Evidence of toxicity of e-cigarettes is also growing, including myocardial infarction and other heart disease, lung disease, and cancer.
In contrast, the RCTs suggest that specific e-cigarettes may meet the [FDA Center for Drug Evaluation and Research] CDER standard as therapeutic interventions to be delivered to specific classes of patients at specified doses under medical supervision. Among the 9 RCTs in this meta-analysis, provision of free e-cigarettes significantly increased smoking cessation compared with conventional therapies, including nicotine replacement therapy. … Approval of e-cigarettes as a cessation therapy, however, also requires that they be “safe,” meaning that the benefit-to-risk ratio must be favorable. As noted previously, recent evidence links e-cigarette use to heart disease, lung disease, and cancer; this evidence raises questions about whether the benefit-to-risk ratio would be favorable enough for approval as a medication. The fact that 80% of people who smoked in the e-cigarette arm of 1 of the RCTs were still using e-cigarettes a year later compared with 9% of nicotine replacement therapy users reinforces this concern. In addition, while outperforming nicotine replacement therapy, the efficacy of e-cigarettes was similar to or below that of FDA-approved therapies including bupropion and varenicline. If approved as a medication, e-cigarettes should be only available under prescription because of their high abuse potential, similar to prescription-only nicotine inhalers that have been approved as cessation medications. [citations omitted]
Here is the abstract:
Objectives. To determine the association between e-cigarette use and smoking cessation.
Methods. We searched PubMed, Web of Science Core Collection, and EMBASE and computed the association of e-cigarette use with quitting cigarettes using random effects meta-analyses.
Results. We identified 64 papers (55 observational studies and 9 randomized clinical trials [RCTs]). In observational studies of all adult smokers (odds ratio [OR] = 0.947; 95% confidence interval [CI] = 0.772, 1.160) and smokers motivated to quit smoking (OR = 0.851; 95% CI = 0.684, 1.057), e-cigarette consumer product use was not associated with quitting. Daily e-cigarette use was associated with more quitting (OR = 1.529; 95% CI = 1.158, 2.019) and less-than-daily use was associated with less quitting (OR = 0.514; 95% CI = 0.402, 0.665). The RCTs that compared quitting among smokers who were provided e-cigarettes to smokers with conventional therapy found e-cigarette use was associated with more quitting (relative risk = 1.555; 95% CI = 1.173, 2.061).
Conclusions. As consumer products, in observational studies, e-cigarettes were not associated with increased smoking cessation in the adult population. In RCTs, provision of free e-cigarettes as a therapeutic intervention was associated with increased smoking cessation.
Public Health Implications. E-cigarettes should not be approved as consumer products but may warrant consideration as a prescription therapy. (Am J Public Health. Published online ahead of print December 22, 2020: e1–e17. https://doi.org/10.2105/AJPH.2020.305999)
The full citation is:
Richard J. Wang, Sudhamayi Bhadriraju, Stanton A. Glantz, “E-Cigarette Use and Adult Cigarette Smoking Cessation: A Meta-Analysis”, American Journal of Public Health , no. (): pp. e1-e17. Epub ahead of print 22 Dec 2020. https://doi.org/10.2105/AJPH.2020.305999. It is available for free here.
UCSF put out a press release on the paper:
FOR IMMEDIATE RELEASE
Tuesday, December 22, 2020Media contact: Nicholas Weiler | nicholas.weiler@ucsf.edu
E-Cigarettes, as Consumer Products, Do Not Help People Quit Smoking, Study Finds
E-cigarette use has risen steeply and mostly without regulation over the past decade. The devices have diversified into a dizzying array of vape pens, tank systems, “mods,” and more, mass-marketed and sold to the public. The U.S. Food and Drug Administration (FDA) is in the midst of considering whether to approve thousands of pre-market applications for the sale of e-cigarettes as consumer products.
In these applications and related advertisements, the owners of e-cigarette brands claim that their products help smokers quit and can therefore be considered “appropriate for the protection of public health,” as stipulated by law. But a new systematic review by UC San Francisco researchers of the scientific literature on this topic puts those claims to the test.
In the new study, published December 22, 2020 in the American Journal of Public Health, a team led by UCSF’s Richard Wang, MD, MAS, surveyed the scientific community’s understanding of e-cigarettes and found that, in the form of mass-marketed consumer products, they do not lead smokers to quit.
In their paper, the authors write, “If e-cigarette consumer product use is not associated with more smoking cessation, there is no population-level health benefit for allowing them to be marketed to adults who smoke, regardless of the relative harm of e-cigarettes compared with conventional cigarettes. Moreover, to the extent that people who smoke simply add e-cigarettes to their cigarette smoking (becoming so-called dual users), their risk of heart disease, lung disease, and cancer could increase compared with smoking alone.”
“The question we explored is of both scientific interest and public health interest,” said Wang, assistant professor of medicine, “and we hope that the FDA will pay attention to our study as they try to make these decisions.” Wang was joined in the study by co–first author Sudhamayi Bhadriraju, MD, a former UCSF postdoctoral fellow who is now a pulmonologist at Kaiser Permanente in Redwood City, Calif., and senior author Stanton A. Glantz, PhD, professor of medicine.
The authors searched the literature, compiling results from 64 studies to answer this question. The studies selected for formal analysis encompassed observational studies, in which participants were surveyed, but not directed, about their use of e-cigarettes, as well as clinical trials in which smokers who were trying to quit were given free e-cigarettes under medical supervision.
This distinction mattered for their analysis, Wang noted. “In observational studies, you’re basically asking people ‘out in the wild’ about their use of e-cigarettes that they’ve purchased themselves from a corner store, without specific guidance to quit. But in a randomized trial you’re testing a product, treating it like a therapy — a medicine — to see if an e-cigarette or some other product is more conducive to quitting.”
In their analysis of observational studies that involved groups of people who already smoked and used e-cigarettes, whether or not they wanted to quit, the team found no appreciable effect of e-cigarettes on participants’ ability to quit. In the next group of studies, which surveyed smokers using e-cigarettes who did indicate a desire to quit, the researchers also found no effect.
Then the team tried to tease apart the effects of frequency of use — whether people who used e-cigarettes daily might quit at different rates than people who used them less often. The researchers found that daily users quit at a higher rate than more infrequent users, although they cautioned that most participants in U.S. studies fall into the second category.
Finally, they examined nine clinical trials, which provided some type of e-cigarette, for free, to participants who were specifically encouraged to use the devices to help them quit. Though the devices and the controls employed in the studies differed, Wang concluded that being provided with certain e-cigarette products in a clinical trial context led to more quitting than some other therapies.
The 2009 Family Smoking Prevention and Tobacco Control Act (TCA) charges the FDA with only allowing e-cigarettes on the market when manufacturers can prove their tobacco-based products are “appropriate for the protection of public health.” But the FDA delayed enforcing the law until a federal court order required companies to submit pre-market approval applications to the agency before September 2020 in order to continue selling e-cigarettes to consumers. The FDA is now evaluating thousands of such applications to sell e-cigarettes.
“It’s important to recognize that in clinical trials, when certain e-cigarette devices are treated more like medicine, there may actually be an effect on quitting smoking,” said Wang. “But that needs to be balanced against the risks of using these devices. Also, only seven e-cigarette devices were studied in the clinical trials. Whether the effect observed with these seven devices is the same or different than that of the thousands of different e-cigarette products available for sale is unknown.”
In addition, he said, the new study does not analyze the increase in youth and teen smoking as a result of e-cigarette marketing and availability, nor does it compare the negative health effects of e-cigarettes to traditional tobacco products.
With regard to the current decision before the FDA, Wang said, “The standards that the FDA has to apply to approve e-cigarettes as consumer products or therapeutic devices are fundamentally different.”
Funding: The work was supported by National Heart, Lung, and Blood Institute (F32HL144063, K12HL143961, T32HL007185, and cooperative agreement U54HL147127 from the National Heart, Lung, and Blood Institute and the Food and Drug Administration Center for Tobacco Products.Disclosures: The authors report no conflicts of interest.
About UCSF: The University of California, San Francisco (UCSF) is exclusively focused on the health sciences and is dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. UCSF Health, which serves as UCSF’s primary academic medical center, includes top-ranked specialty hospitals and other clinical programs, and has affiliations throughout the Bay Area. Learn more at ucsf.edu, or see our Fact Sheet.
###
American Journal of Public Health published four editorials with the paper. You can read them here:
Should E-Cigarette Regulation Be Based on Randomized Trials or Observational Studies? Evan Mayo-Wilson
Is Good Enough Good Enough? E-Cigarettes, Evidence, and Policy Amy Lauren Fairchild
E-Cigarettes: A Public Health Threat, Not a Population Health Intervention Rebekah E. Gee, William R. Boles and Dean G. Smith
Reporting Certainty of Evidence on E-Cigarette Use for Adult Smoking Cessation Sean Grant
Stanton Glantz blog 