Nicotine Patches Used in Combination with E-cigarettes

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Article Citation: Walker N, et al. (2019). Nicotine patches used in combination with e-cigarettes (with and without nicotine) for smoking cessation: a pragmatic, randomised trial. The Lancet. Respiratory medicine, 8(1), 54–64.

Clinical Question:

In patients trying to quit smoking, will nicotine patches and e-cigarettes, compared to nicotine patches alone, be more efficacious for smoking cessation without increasing adverse effects?

Bottom Line: In patients trying to quit smoking, combination therapy of nicotine patches and e-cigarettes appears to provide moderate improvement in smoking cessation without increasing major adverse effects, compared to monotherapy with nicotine patches.

Major Points: There is increasing evidence to support the use of combination nicotine therapy for smoking cessation due to its additive benefits, yet there exists a lack of data regarding the efficacy of e-cigarettes. The primary goal of this randomized pragmatic trial is to determine the effectiveness of the combination therapy of nicotine patches and e-cigarettes (nicotine and non-nicotine) on six-month smoking cessation. The study design is a randomized, three-armed trial, with nicotine masking in the e-cigarettes group. Aside from the 14-week supplies for their no-cost allocated treatment, patients also received 6 weeks of complementary moderate-intensity behavior support via telephone. More participants in the patches plus nicotine e-cigarette group reduced the number of cigarettes they smoked per day compared with people in the patches plus non-nicotine e-cigarette group at the 3-month mark (54% vs 46%; p=0·012) but the difference lessened by the 6-month mark (44% vs 38%; p=0·08). Additionally, while data favored the nicotine plus nicotine e-cigarette group, there is no statistical significance in the continuous abstinence rates when comparing the three groups of patches plus nicotine e-cigarette [ n=3 (2%)], patches only [ n=35 (7%); CI (0·91 to 9·33); NNT 21.7], and the patches plus non-nicotine e-cigarette [n=20 (4%); CI 0·17–5·81] . No significance was noted in serious adverse events between the therapy groups (4% vs 3% vs 5%) and none of the serious adverse events were deemed as treatment-related. Due to the minimal additive efficacy of e-cigarettes when used in combination with nicotine replacement therapy, more studies must be conducted to determine whether e-cigarette would be worth the additive expense in smoke cessation therapy. Because there does not appear to be any additional adverse side effects when adding e-cigarettes to the nicotine patch therapy, e-cigarette should be considered as a supplement therapy in patients trying to quit smoking.

Guidelines: United States Department of Health and Human Services/Public Health Service Clinical Practice Guideline on Treating Tobacco Use and Dependence 2008 E-cigarettes are not a part of the treatment therapy for smoking cessation based on the currently published guideline.

Study Design: Trial type: parallel-group, pragmatic, 3- arm randomized control trial (1:4:4 ratio) N: 1124 Patches only group: n=125. Patches and nicotine e-cigarettes: n=500 Patches and non-nicotine e-cigarettes: n=499 Setting: New Zealand Enrolment period: March 17, 2016 to November 30, 2017 Follow-up: 6 months Analysis: Intention to treat analysis Primary outcome: exhaled carbon monoxide-verified continuous smoking abstinence at 6 months

Population:

Baseline Demographics: From the nicotine patches and nicotine e-cigarette group. Groups were similar.

Average Age: 41-years-old Gender: women Ethnicity: Māori Education below year 12 or no qualification Daily smokers Number of cigarettes smoked per day: ~18 At least one quit attempt in the past 12 months Cut down the number of cigarettes smoked in the past 12 months Lives with people who use-cigarettes Current mental health problem Medical conditions: Asthma COPD

Inclusion: Residents of New Zealand 18 years or older Smoked tobacco (any quantity) Motivated to quit in the next 14 days Access to telephone Prepared to use any of the trial treatment Verbal consent ability

Exclusion: Pregnant and lactating female population Patients who used an e-cigarette for more than one week anytime in the past year Currently on smoking cessation medication Enrolled in another cessation program or had household member enrolled in this trial Self-reported, allergies, poorly controlled asthma or a CV event in the weeks before enrolment Not willing for random assignment

Intervention(s): Three different interventions: Nicotine patches nicotine patches plus non-nicotine e-cigarette nicotine patches plus nicotine e-cigarettes The participants received a 14-week supply of 21 mg nicotine patches and used one patch daily two weeks prior to their quit date. A second-generation eVOD starter kit, containing two batteries, two refillable tanks, one charging kit, one carry case, and five (2·2 mL, 1·8 OHM) atomisers were used and participants had the option of two tobacco e-liquid flavors. The e-liquid had a nicotine content of either 0 mg/mL or 18 mg/mL. The e-cigarette participants used the device as directed by the manufacturer or as desired.

Outcomes (Primary, Secondary, Subgroup, Adverse Events):

Primary outcome: Nicotine patches plus nicotine e-cigarette 6-month smoking abstinence: 35 (7%) Nicotine patches plus non-nicotine e-cigarette 6-month smoking abstinence: 20 (4%) Relative risk (95% CI):1.75 (1.02 to 2.98) Risk difference (95% CI): 2.99 (0.17 to 5.81) P-value: 0.038 NNT: 33.4 Overall: nicotine patches plus nicotine e-cigarettes were more effective in obtaining 6-month abstinence compared to nicotine patches plus non-nicotine e-cigarettes.

Secondary outcomes: Self-reported quit rate at 1 month: P-value: 0.005 Self-reported quit rate at 3 months: P-value < 0.001 Self-reported quit rate at 6 months: P-value: 0.001 7-day point prevalence abstinence at 1 month: P-value < 0.001 7-day point prevalence abstinence at 3 months: P-value: 0.001 7-day point prevalence abstinence at 6 months: P-value: 0.002

Subgroup:

No statistical significance was found in posthoc subgroup analyses of baseline characteristics.

Adverse Events: 18 serious adverse events occurred in the patches plus nicotine e-cigarette group compared to... 27 events in the patches plus non-nicotine e-cigarette group (IRR 0·66 [95% CI 0·36–1·20]; p=0·18) 4 events in the patches only group (IRR 0·86 [95% CI 0·29–2·53]; p=0·78) Serious adverse event: Death: 1 (patches plus non-nicotine e-cigarette) Life-threatening: 2 ( patches plus nicotine e-cigarette) vs 1 (patches plus non-nicotine e-cigarette) Hospitalization: 3 vs 11 vs 19 (patches only, patches plus nicotine e-cigarette, patches plus non-nicotine e-cigarette) Persistent, significant disability, or incapacity: 1 (patches plus nicotine e-cigarette) Otherwise medically important: 1 vs 4 vs 6 (patches only, patches plus nicotine e-cigarette, patches plus non-nicotine e-cigarette)

No serious adverse events were deemed to be treatment-related

Criticism: There was a high number of participants (N=385) who either withdrew or were lost in follow-up at the 6-month mark, leading to potential errors in the data results. It was noted that the self-reported quit rates were always higher in the dual nicotine therapy group yet the data showed no statistical significance for smoking cessation. Limitations of the study are as follow: Bias due to lack of double-blinding No placebo patches and no one e-cigarette group Detection bias- some patients can tell if they had the nicotine e-cigarette despite masking attempts. Prescriber bias- Behavioral support calls varied based on group All data were collected through self-reporting with no way to verify the authenticity

Funding: Funded by the Health Research Council of New Zealand. The e-cigarettes and e-liquids were provided by third parties with no affiliation to the nicotine company, while the patches were provided by the New Zealand government through Novartis.

References: Tobacco Use and Dependence Guideline Panel. Treating Tobacco Use and Dependence: 2008 Update. National Center for Biotechnology Information. U.S. National Library of Medicine; 2008.