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The number needed to treat (NNT) and cost per responder for pharmacological interventions for smoking cessation

Additional information

5.3.2024

Elisa Rissanen, Pasi Kekkonen and Eila Kankaanpää

This additional information describes in detail the effectiveness evidence and cost information on pharmacological interventions for smoking cessation. The selection of the effectiveness evidence had following steps: the literature search and selection of effectiveness evidence and quality appraisal. We chose the network meta-analysis by Shang et al. (2022) as the base of the effectiveness evidence. «Shang X, Guo K, E F, ym. Pharmacological interventions on smoking cessation: A systematic review and network meta-analysis. Front Pharmacol 2022;13():1012433 »1

Source of the effectiveness evidence: Shang X, Guo K, E F, Deng X, Wang Y, Wang Z, Wu Y, Xu M, Yang C, Li X, Yang K. Pharmacological interventions on smoking cessation: A systematic review and network meta-analysis. Front Pharmacol. 2022 Oct 24;13:1012433. doi: 10.3389/fphar.2022.1012433.

Literature search and selection

The literature search included network meta-analyses, meta-analyses and systematic reviews of pharmacological interventions for smoking cessation. Information specialist conducted the literature searches in October 2022. The timeframe for the search was years 2018–2022. The search found 90 references. An additional hand search found one reference of network meta-analysis for pharmacological interventions on smoking cessation (Shang et al. 2022) «Shang X, Guo K, E F, ym. Pharmacological interventions on smoking cessation: A systematic review and network meta-analysis. Front Pharmacol 2022;13():1012433 »1 which was published after the literature search. We searched for the most recent evidence by viewing only network meta-analyses published in 2022 and 2021, if satisfactory number of comprehensive studies were found. A total of six network meta-analyses were published in 2022 and 2021 « Description of the network meta-analyses of pharmacological interventions for smoking cessation published in 2021 and 2022»1.

Table 1. Description of the network meta-analyses of pharmacological interventions for smoking cessation published in 2021 and 2022
Citation	Research aim	Number of trials, date of literature search	Outcome measures	Interventions	Comments
NRT= nicotine replacement therapy
Guo et al. 2022 «Guo K, Wang S, Shang X, ym. The effect of Varenicline and Bupropion on smoking cessation: A network meta-analysis of 20 randomized controlled trials. Addict Behav 2022;131():107329 »2	To investigate the effect of varenicline (VAR), bupropion (BUP), and nicotine replacement therapy (NRT) on smoking cessation.	20 RCTs. May 2021.	The number of people who quit smoking	bupropion, nicotine replacement therapy, varenicline	Did not include nortriptyline.
Thomas et al. 2022 «Thomas KH, Dalili MN, López-López JA, ym. Comparative clinical effectiveness and safety of tobacco cessation pharmacotherapies and electronic cigarettes: a systematic review and network meta-analysis »3	To determine how varenicline, bupropion, nicotine replacement therapy (NRT) and electronic cigarettes compare with respect to their clinical effectiveness and safety.	363 RCTs. February 2019.	Sustained abstinence, prolonged abstinence, any abstinence, 7-day point prevalence abstinence (PPA).	bupropion, e-cigarette, NRT patch (16 hours), NRT patch (24 hours), NRT gum, NRT nasal spray, NRT month spray, NRT lozenge, NRT sublingual tablet, NRT inhalator, varenicline	Did not include nortriptyline.
Mishra et al. 2021 «Mishra A, Maiti R, Mishra BR, ym. Comparative efficacy and safety of pharmacological interventions for smoking cessation in healthy adults: A network meta-analysis. Pharmacol Res 2021;166():105478 »4	To evaluate and compare different pharmacological interventions with or without behavioural therapy used for smoking cessation in healthy adult	97 RCTs. September 2020.	Biochemically confirmed (carbon monoxide or cotinine confirmed) continuous or prolonged abstinence rates at six months or 24–26 weeks	behavioural therapy, bupropion, clonidine, lobeline, naltrexone (opioid receptor antagonist), nicotine replacement therapy, other antidepressants (nortriptyline, duloxetine, MAO-B inhibitor), partial agonists at nicotine receptor (NRA) includes varenicline, dianicline or cytisine.	Comprehensive, includes all selected interventions. Still, varenicline was evaluated together with other partial agonists at nicotine receptors (NRA) namely dianicline and cytisine. Additional analysis evaluated nicotine replacement therapies (NRT) by type.
Chan et al. 2021 «Chan GCK, Stjepanović D, Lim C, ym. Gateway or common liability? A systematic review and meta-analysis of studies of adolescent e-cigarette use and future smoking initiation. Addiction 2021;116(4):743»5	To compare the effectiveness of nicotine e-cigarettes for smoking cessation with licensed nicotine replacement therapies and nicotine-free based control conditions by using network meta-analysis.	7 RCTs. April 2020	Smoking abstinence at the end of the study (unless the study specified a follow-up time as the primary measurement time point.	nicotine e-cigarettes, nicotine replacement therapy (e.g., nicotine patches, nicotine gums, etc), nicotine-free e- cigarettes.	Did not include selected interventions.
Thomas et al. 2021 «Thomas KH, Dalili MN, López-López JA, ym. Smoking cessation medicines and e-cigarettes: a systematic review, network meta-analysis and cost-effectiveness analysis. Health Technol Assess 2021;25(59):1-»6	To determine the clinical effectiveness, safety and cost-effectiveness of smoking cessation medicines and e-cigarettes.	363 RCTs. February 2019.	Sustained (or continuous) abstinence, prolonged abstinence, any abstinence at 6 months, and 7-day point prevalence abstinence (PPA)	bupropion, e-cigarette therapies, nicotine replacement therapy, varenicline.	Did not include nortriptyline.
Shang et al. 2022 «Shang X, Guo K, E F, ym. Pharmacological interventions on smoking cessation: A systematic review and network meta-analysis. Front Pharmacol 2022;13():1012433 »1	To investigate the effects of pharmacological interventions on smoking cessation.	159 RCTs. June 2022.	Overall abstinence rate, continuous abstinence rate, 7-point continuous abstinence rate.	bupropion, clonidine, cytisine, fluoxetine, naltrexone, nicotine replacement therapy, nortriptyline, mecamylamine, selegiline, topiramate, varenicline.	Comprehensive, includes all selected interventions.

We selected two studies «Shang X, Guo K, E F, ym. Pharmacological interventions on smoking cessation: A systematic review and network meta-analysis. Front Pharmacol 2022;13():1012433 »1, «Mishra A, Maiti R, Mishra BR, ym. Comparative efficacy and safety of pharmacological interventions for smoking cessation in healthy adults: A network meta-analysis. Pharmacol Res 2021;166():105478 »4 for further examination of the effectiveness of pharmacological interventions. Shang et al. (2022) «Shang X, Guo K, E F, ym. Pharmacological interventions on smoking cessation: A systematic review and network meta-analysis. Front Pharmacol 2022;13():1012433 »1 was the most recent, comprehensive, and included all selected pharmacological interventions. Mishra et al. (2021) «Mishra A, Maiti R, Mishra BR, ym. Comparative efficacy and safety of pharmacological interventions for smoking cessation in healthy adults: A network meta-analysis. Pharmacol Res 2021;166():105478 »4 was also recently published, comprehensive, included all selected pharmacological interventions and behavioural intervention. However, varenicline was evaluated only together with other partial agonists at nicotine receptors (NRA) namely dianicline and cytisine. The network meta-analysis had an additional analysis to evaluate nicotine replacement therapies (NRT) by type.

Quality of the selected network meta-analyses

We evaluated the quality of the Mishra et al. (2021) «Mishra A, Maiti R, Mishra BR, ym. Comparative efficacy and safety of pharmacological interventions for smoking cessation in healthy adults: A network meta-analysis. Pharmacol Res 2021;166():105478 »4 and Shang et al. (2022) «Shang X, Guo K, E F, ym. Pharmacological interventions on smoking cessation: A systematic review and network meta-analysis. Front Pharmacol 2022;13():1012433 »1 network meta-analyses by using AMSTAR 2 «Shea BJ, Reeves BC, Wells G, ym. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 2017;358():j4008»7. The results of the quality appraisal are shown in Table 2 « Critical appraisal of selected network meta-analyses by using AMSTAR 2 »2.

Table 2. Critical appraisal of selected network meta-analyses by using AMSTAR 2 «Shea BJ, Reeves BC, Wells G, ym. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 2017;358():j4008»7
Question	Mishra et al. 2021 «Mishra A, Maiti R, Mishra BR, ym. Comparative efficacy and safety of pharmacological interventions for smoking cessation in healthy adults: A network meta-analysis. Pharmacol Res 2021;166():105478 »4		Shang et al. 2022 «Shang X, Guo K, E F, ym. Pharmacological interventions on smoking cessation: A systematic review and network meta-analysis. Front Pharmacol 2022;13():1012433 »1
RoB = Risk of Bias
	Answer	Comments	Answer	Comments
1. Did the research questions and inclusion criteria for the review include the components of PICO?	Yes		Yes
2. Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol?	Partial Yes	No justifications for deviations from the protocol	No	No written protocol or guide cited.
3. Did the review authors explain their selection of the study designs for inclusion in the review?	Yes		Yes
4. Did the review authors use a comprehensive literature search strategy?	Yes		Partial yes	Did not search trial/study registers
5. Did the review authors perform study selection in duplicate?	Yes		Yes
6. Did the review authors perform data extraction in duplicate?	Yes		Yes
7. Did the review authors provide a list of excluded studies and justify the exclusions?	Partial yes	No reference list of excluded studies with justification for exclusion. Justifications for exclusions reported in the PRISMA diagram.	Partial yes	No reference list of excluded studies with justification for exclusion. Justifications for exclusions reported in the PRISMA diagram.
8. Did the review authors describe the included studies in adequate detail?	Partial yes	Study did not describe sample sizes by trial arms.	Yes
9. Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review?	Yes		Yes
10. Did the review authors report on the sources of funding for the studies included in the review?	No	Study did not report the sources of funding of the included studies.	No	Study did not report the sources of funding of the included studies.
11. If meta-analysis was performed did the review authors use appropriate methods for statistical combination of results?	Yes		Yes
12. If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis?	No	Did not include only low risk of bias RCTs or perform analyses to investigate possible impact of the RoB on summary estimates of effects	No	Did not include only low risk of bias RCTs or perform analyses to investigate possible impact of the RoB on summary estimates of effects
13. Did the review authors account for RoB in individual studies when interpreting/ discussing the results of the review?	Yes		Yes
14. Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review?	Yes		Yes
15. If they performed quantitative synthesis, did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review?	No	Did not perform graphical or statistical tests for publication bias and discuss the likelihood and magnitude of impact of publication bias.	No	Did not perform graphical or statistical tests for publication bias and discuss the likelihood and magnitude of impact of publication bias.
16. Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review?	Yes		Yes
Summary of the quality	Yes n=10 Partial yes n=3 No n=3		Yes n=10 Partial yes n=2 No n=4

We chose the network meta-analysis by Shang et al. (2022) «Shang X, Guo K, E F, ym. Pharmacological interventions on smoking cessation: A systematic review and network meta-analysis. Front Pharmacol 2022;13():1012433 »1 as the base of our effectiveness estimates as it was the most recent and comprehensive study by including all the selected interventions separately. Shang et al. (2022) «Shang X, Guo K, E F, ym. Pharmacological interventions on smoking cessation: A systematic review and network meta-analysis. Front Pharmacol 2022;13():1012433 »1 included RCTs regardless the participants age and health condition to represent the effectiveness of interventions in heterogenous population.

The effectiveness evidence

Network meta-analysis by Shang et al. (2022) «Shang X, Guo K, E F, ym. Pharmacological interventions on smoking cessation: A systematic review and network meta-analysis. Front Pharmacol 2022;13():1012433 »1 included 159 RCTs with 60 285 smokers. The characteristics of original RCTs are presented in Supplementary table 2 of Shang et al. (2022) «Shang X, Guo K, E F, ym. Pharmacological interventions on smoking cessation: A systematic review and network meta-analysis. Front Pharmacol 2022;13():1012433 »1. Shortly, most of the trials studied normal population (104 RCTs). Total of 20 trials included smokers with alcohol dependence, 10 with mental disease, 7 with cardiovascular disease, 5 with chronic obstructive pulmonary disease, 3 with pregnancy, 2 with posttraumatic stress disorder, 2 with substance use disorder, 2 with cancer, one with AIDS, one with asthma, one with tuberculosis and one with medical disease. The most common average number of cigarettes smoked per day was over 10 in the trials.

The study reported odds ratios (OR) and 95%CI for the Current Care working group's selected interventions compared to placebo. The smoking cessation was defined overall abstinence rate which included continuous abstinence rate or point abstinence rate generally confirmed with biochemical validation based on the self-reported smoking status at 24 weeks (39 RCTs), 26 weeks (10 RCTs), 48 weeks (28 RCTs) or 53 weeks (34 RCTs). We converted the ORs to NNTs «Schünemann HJ, Vist GE, Higgins JPT, Santesso N, Deeks JJ, Glasziou P, Akl EA, Guyatt GH. Chapter 15: Interpreting results and drawing conclusions. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, L»8. Assumed comparator risk (5%) was the pooled result of the 58 RCT's minimal intervention or no intervention groups' smoking cessation in 6-months «Hartmann-Boyce J, Livingstone-Banks J, Ordóñez-Mena JM, ym. Behavioural interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev 2021;1():CD013229 »9.

Costs of medicines

Costs of the prescription medicines used in smoking cessation are from drug database available at Terveysportti health portal (Duodecim Publishing Company Ltd) «https://www.terveysportti.fi/terveysportti/koti»1. Costs of the nicotine replacement therapies are from websites of pharmacies. To calculate the costs of the medicines, we used the shortest duration and the lowest dosing of the treatment. Then, we used retail prices of the cheapest product to calculate the costs. In some cases, the dose was slightly under or over the required dose level due to limited sizes of medical packages. Any other direct or indirect costs or reimbursements were not considered.

References

Shang X, Guo K, E F, ym. Pharmacological interventions on smoking cessation: A systematic review and network meta-analysis. Front Pharmacol 2022;13():1012433 «PMID: 36353488»PubMed
Guo K, Wang S, Shang X, ym. The effect of Varenicline and Bupropion on smoking cessation: A network meta-analysis of 20 randomized controlled trials. Addict Behav 2022;131():107329 «PMID: 35397262»PubMed
Thomas KH, Dalili MN, López-López JA, ym. Comparative clinical effectiveness and safety of tobacco cessation pharmacotherapies and electronic cigarettes: a systematic review and network meta-analysis of randomized controlled trials. Addiction 2022;117(4):861-876 «PMID: 34636108»PubMed
Mishra A, Maiti R, Mishra BR, ym. Comparative efficacy and safety of pharmacological interventions for smoking cessation in healthy adults: A network meta-analysis. Pharmacol Res 2021;166():105478 «PMID: 33549729»PubMed
Chan GCK, Stjepanović D, Lim C, ym. Gateway or common liability? A systematic review and meta-analysis of studies of adolescent e-cigarette use and future smoking initiation. Addiction 2021;116(4):743-756 «PMID: 32888234»PubMed
Thomas KH, Dalili MN, López-López JA, ym. Smoking cessation medicines and e-cigarettes: a systematic review, network meta-analysis and cost-effectiveness analysis. Health Technol Assess 2021;25(59):1-224 «PMID: 34668482»PubMed
Shea BJ, Reeves BC, Wells G, ym. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 2017;358():j4008 «PMID: 28935701»PubMed
Schünemann HJ, Vist GE, Higgins JPT, Santesso N, Deeks JJ, Glasziou P, Akl EA, Guyatt GH. Chapter 15: Interpreting results and drawing conclusions. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane, 2022. Available from www.training.cochrane.org/handbook.
Hartmann-Boyce J, Livingstone-Banks J, Ordóñez-Mena JM, ym. Behavioural interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev 2021;1():CD013229 «PMID: 33411338»PubMed