Safety and tolerability of electronic cigarettes to reduce cigarette smoking: Secondary analysis from a randomized placebo-controlled trial

Background The clinical safety profile of e-cigarette use for smoking reduction remains poorly characterized. This study compared the relative safety and tolerability of nicotine e-cigarette use with non-nicotine e-cigarettes or a non-aerosol cigarette substitute (CS) among adults interested in reducing their smoking. Methods We conducted a secondary analysis of adverse events (AEs) reported in a 6-month, double-blind RCT involving 520 participants assigned to either e-cigarettes with 0, 8, or 36 mg/mL nicotine or a CS. AEs were coded using CTCAE V4.0 and assessed for frequency, severity, seriousness and relatedness across groups. Cumulative incidence was calculated over 24 weeks. We estimated risk differences (RDs) and 95% confidence intervals (CIs) for frequently reported AEs (>=1% of participants overall) comparing e-cigarette vs. CS and nicotine versus non-nicotine e-cigarette groups. Fisher's exact test, with adjustment for multiple comparisons, was used to assess statistical significance. Results Most study-related AEs (those rated as possibly, probably, or definitely related by medical monitor) were mild in severity and none were classified as serious. At 24 weeks, cumulative incidence of first study-related AE was highest in the 36 mg/mL (37.0%) and 8 mg/mL (35.2%) e-cigarette groups, followed by 0 mg/mL (23.4%), and lowest in CS group (2.5%). E-cigarette users experienced significantly greater risks of cough (RD [95%CI]: 8.5% [5.6-11.3]), headache (RD [95%CI]: 5.4% [3.3-7.6]) and sore throat (RD [95%CI]: 5.4% [3.2-7.6]) as compared with the CS group. Cough was also more common in those randomized to nicotine versus non-nicotine e-cigarettes (RD [95%CI]: 8.1% [3.4-12.8]). Conclusion All study products were generally well-tolerated; however, AEs were more common in e-cigarette groups, especially with nicotine. Findings highlight the need to monitor common symptoms such as cough, headache, and sore throat in clinical and regulatory evaluations of e-cigarette safety.