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Cytisinicline for Smoking Cessation: The ORCA Phase 3 Replication Randomized Clinical Trial

Author/s: 
Nancy A Rigotti, Neal L Benowitz, Judith J Prochaska, Mark Rubinstein, Anthony Clarke, Brent Blumenstein, Daniel F Cain, Cindy Jacobs

Importance: New smoking cessation medication options are needed. Cytisinicline, a partial agonist at α4β2 nicotinic acetylcholine receptors, has demonstrated smoking cessation efficacy in 1 US trial. Additional evidence is needed.

Objective: To reproduce the findings of the efficacy and tolerability of cytisinicline compared with placebo for smoking cessation and to test its effect on nicotine craving as a mechanism of action.

Design, settings, and participants: This was a 3-group double-blind, placebo-controlled phase 3 replication randomized clinical trial (ORCA-3) conducted at 20 clinical trial sites in the US from January 2022 to March 2023. It compared 6 and 12 weeks of a novel cytisinicline regimen to placebo among adults who smoked 10 or more cigarettes daily and sought to quit. Participants were randomized (1:1:1) to 3-mg cytisinicline 3 times daily for 12 weeks; 3-mg cytisinicline 3 times daily for 6 weeks followed by placebo for 6 weeks; or placebo 3 times daily for 12 weeks. The follow-up period was 24 weeks, and all groups received behavioral support. Data analyses were performed from May 3, 2023, to March 20, 2024.

Interventions: Cytisinicline, 3 mg, 3 times daily for 12 weeks; cytisinicline, 3 mg, 3 times daily for 6 weeks followed by placebo for 6 weeks; or placebo 3 times daily for 12 weeks.

Main outcomes and measures: Biochemically verified (carbon monoxide <10 ppm) continuous smoking abstinence during the last 4 weeks of 6- and 12-week treatments (primary outcome) and from end of treatment to 24 weeks (secondary outcome); Questionnaire of Smoking Urges; incidence of adverse events.

Results: Of 792 participants randomized (mean [SD] age, 52.0 [11.8] years; 439 [55.4%] female; mean [SD] cigarettes/d, 20.4 [7.5]), 628 (79.3%) completed the trial. Primary and secondary outcomes were significantly higher for both cytisinicline groups vs placebo. For 6-week treatment, 39 cytisinicline participants (14.8%) vs 16 placebo participants (6.0%) were abstinent during weeks 3 to 6 (odds ratio [OR], 2.9; 95% CI, 1.5-5.6; P < .001). For 12-week treatment, 80 cytisinicline participants (30.3%) vs 25 placebo participants (9.4%) were abstinent during weeks 9 to 12 (OR, 4.4; 95% CI, 2.6-7.3; P < .001). Continuous abstinence rates for the 6-week treatment were 6.8% (cytisinicline) vs 1.1% (placebo) from weeks 3 to 24 . Continuous abstinence rates for the 12-week treatment were 20.5% (cytisinicline) vs 4.2% (placebo) for weeks 9 to 24. Reduction in craving at week 6 was greater for cytisinicline than placebo (-15.2 points [95% CI, -16.4 to -14.0] vs -12.0 points [95% CI, -13.5 to -10.5]; P < .001). Cytisinicline was well tolerated with no treatment-related serious adverse events.

Conclusions and relevance: The findings of the ORCA phase 3 trial reaffirms the efficacy and tolerability of cytisinicline at both 6- and 12-week treatment for smoking cessation, with benefits extending through 24 weeks. As a mechanism of effect, cytisinicline mitigated nicotine craving.

Trial registration: ClinicalTrials.gov Identifier: NCT05206370.

Keywords 
smoking cessation medication smoking cessation smoking Cytisinicline

Electronic Cigarettes vs Varenicline for Smoking Cessation in Adults: A Randomized Clinical Trial

Author/s: 
Anna Tuisku, Mikko Rahkola, Pentti Nieminen, Tuula Toljamo

Importance: Little is known about the relative effectiveness of nicotine-containing electronic cigarettes (ECs) compared with varenicline as smoking cessation aids.

Objective: To determine the relative effectiveness of ECs in smoking cessation.

Design, setting, and participants: This randomized placebo-controlled single-center trial was conducted in northern Finland. Participants aged 25 to 75 years who smoked daily and had volunteered to quit smoking were recruited from August 1, 2018, to February 20, 2020, via local media. The trial included 52 weeks of follow-up. All data analyses were conducted from September 1, 2022, to January 15, 2024. The participants, study nurses, and researchers were masked to group assignment.

Intervention: The participants were assigned by block randomization to receive 18 mg/mL of nicotine-containing ECs together with placebo tablets, varenicline with standard dosing together with nicotine-free ECs, or placebo tablets together with nicotine-free ECs, all combined with a motivational interview, with the intervention phase lasting for 12 weeks.

Main outcome and measure: The primary outcome was self-reported 7-day conventional cigarette smoking abstinence as confirmed by the exhaled carbon monoxide level on week 26. The analysis followed the intent-to-treat principle.

Results: Of the 561 recruited participants, 458 (81.6%) eligible participants (257 women [56%]; 201 men [44%]; mean [SD] age, 51 [11.6] years) were randomized. The primary outcome occurred in 61 of 152 participants (40.4%) in the EC group, 67 of 153 (43.8%) in the varenicline group, and 30 of 153 (19.7%) in the placebo group (P < .001). In the pairwise comparison, placebo differed statistically significantly from ECs (risk difference [RD], 20.7%; 95% CI, 10.4-30.4; P < .001) and varenicline (RD, 24.1%; 95% CI, 13.7-33.7; P < .001), but the difference was statistically insignificant between ECs and varenicline (RD, 3.4%; 95% CI, -7.6 to 14.3; P = .56). No serious adverse events were reported.

Conclusions: This randomized clinical trial found that varenicline and nicotine-containing ECs were both effective in helping individuals in quitting smoking conventional cigarettes for up to 6 months.

Keywords 
e-cigarettes cigarettes Varenicline smoking smoking cessation

Association of Smoking Cessation and Cardiovascular, Cancer, and Respiratory Mortality

Author/s: 
Blake Thomson, Farhad Islami

There were an estimated 28 million current cigarette smokers in the US, and approximately twice as many former smokers, in 2021.1 Smoking cessation is associated with large reductions in excess mortality compared with continued smoking,2 but the timescale over which cause-specific mortality benefits of cessation may develop is unclear.3-6 Quantifying excess cause-specific mortality among former smokers by years since quitting may inform clinical decision-making and screening programs.

Keywords 
tobacco e-cigarettes smoking cessation lifestyle behaviors

Mobile phone text messaging and app-based interventions for smoking cessation

Author/s: 
Whittaker, Robyn, McRobbie, Hayden, Bullen, Chris, Rodgers, Anthony, Gu, Yulong, Dobson, Rosie

Background: Mobile phone-based smoking cessation support (mCessation) offers the opportunity to provide behavioural support to those who cannot or do not want face-to-face support. In addition, mCessation can be automated and therefore provided affordably even in resource-poor settings. This is an update of a Cochrane Review first published in 2006, and previously updated in 2009 and 2012.

Objectives: To determine whether mobile phone-based smoking cessation interventions increase smoking cessation rates in people who smoke.

Search methods: For this update, we searched the Cochrane Tobacco Addiction Group's Specialised Register, along with clinicaltrials.gov and the ICTRP. The date of the most recent searches was 29 October 2018.

Selection criteria: Participants were smokers of any age. Eligible interventions were those testing any type of predominantly mobile phone-based programme (such as text messages (or smartphone app) for smoking cessation. We included randomised controlled trials with smoking cessation outcomes reported at at least six-month follow-up.

Data collection and analysis: We used standard methodological procedures described in the Cochrane Handbook for Systematic Reviews of Interventions. We performed both study eligibility checks and data extraction in duplicate. We performed meta-analyses of the most stringent measures of abstinence at six months' follow-up or longer, using a Mantel-Haenszel random-effects method, pooling studies with similar interventions and similar comparators to calculate risk ratios (RR) and their corresponding 95% confidence intervals (CI). We conducted analyses including all randomised (with dropouts counted as still smoking) and complete cases only.

Main results: This review includes 26 studies (33,849 participants). Overall, we judged 13 studies to be at low risk of bias, three at high risk, and the remainder at unclear risk. Settings and recruitment procedures varied across studies, but most studies were conducted in high-income countries. There was moderate-certainty evidence, limited by inconsistency, that automated text messaging interventions were more effective than minimal smoking cessation support (RR 1.54, 95% CI 1.19 to 2.00; I2 = 71%; 13 studies, 14,133 participants). There was also moderate-certainty evidence, limited by imprecision, that text messaging added to other smoking cessation interventions was more effective than the other smoking cessation interventions alone (RR 1.59, 95% CI 1.09 to 2.33; I2 = 0%, 4 studies, 997 participants). Two studies comparing text messaging with other smoking cessation interventions, and three studies comparing high- and low-intensity messaging, did not show significant differences between groups (RR 0.92 95% CI 0.61 to 1.40; I2 = 27%; 2 studies, 2238 participants; and RR 1.00, 95% CI 0.95 to 1.06; I2 = 0%, 3 studies, 12,985 participants, respectively) but confidence intervals were wide in the former comparison. Five studies compared a smoking cessation smartphone app with lower-intensity smoking cessation support (either a lower-intensity app or non-app minimal support). We pooled the evidence and deemed it to be of very low certainty due to inconsistency and serious imprecision. It provided no evidence that smartphone apps improved the likelihood of smoking cessation (RR 1.00, 95% CI 0.66 to 1.52; I2 = 59%; 5 studies, 3079 participants). Other smartphone apps tested differed from the apps included in the analysis, as two used contingency management and one combined text messaging with an app, and so we did not pool them. Using complete case data as opposed to using data from all participants randomised did not substantially alter the findings.

Authors' conclusions: There is moderate-certainty evidence that automated text message-based smoking cessation interventions result in greater quit rates than minimal smoking cessation support. There is moderate-certainty evidence of the benefit of text messaging interventions in addition to other smoking cessation support in comparison with that smoking cessation support alone. The evidence comparing smartphone apps with less intensive support was of very low certainty, and more randomised controlled trials are needed to test these interventions.

Keywords 
Text Messaging cell phone smoking cessation tobacco Smokers

Interventions for Tobacco Smoking Cessation in Adults, Including Pregnant Persons: US Preventive Services Task Force Recommendation Statement

Author/s: 
US Preventative Services task Force

Tobacco use is the leading preventable cause of disease, disability, and death in the US. In 2014, it was estimated that 480 000 deaths annually are attributed to cigarette smoking, including second hand smoke exposure. Smoking during pregnancy can increase the risk of numerous adverse pregnancy outcomes (eg, miscarriage and congenital anomalies) and complications in the offspring (including sudden infant death syndrome and impaired lung function in childhood). In 2019, an estimated 50.6 million US adults (20.8% of the adult population) used tobacco; 14.0% of the US adult population currently smoked cigarettes and 4.5% of the adult population used electronic cigarettes (e-cigarettes). Among pregnant US women who gave birth in 2016, 7.2% reported smoking cigarettes while pregnant

Keywords 
tobacco tobacco use smoking smoking cessation Adults Pregnancy Pregnant Persons Recommendation Statement

Mobile phone text messaging and app-based interventions for smoking cessation

Author/s: 
Whittaker, R, McRobbie, H, Bullen, C, Rodgers, A, Gu, Y, Dobson, R

Abstract

Background

Mobile phone‐based smoking cessation support (mCessation) offers the opportunity to provide behavioural support to those who cannot or do not want face‐to‐face support. In addition, mCessation can be automated and therefore provided affordably even in resource‐poor settings. This is an update of a Cochrane Review first published in 2006, and previously updated in 2009 and 2012.

Objectives

To determine whether mobile phone‐based smoking cessation interventions increase smoking cessation rates in people who smoke.

Search methods

For this update, we searched the Cochrane Tobacco Addiction Group's Specialised Register, along with clinicaltrials.gov and the ICTRP. The date of the most recent searches was 29 October 2018.

Selection criteria

Participants were smokers of any age. Eligible interventions were those testing any type of predominantly mobile phone‐based programme (such as text messages (or smartphone app) for smoking cessation. We included randomised controlled trials with smoking cessation outcomes reported at at least six‐month follow‐up.

Data collection and analysis

We used standard methodological procedures described in the Cochrane Handbook for Systematic Reviews of Interventions. We performed both study eligibility checks and data extraction in duplicate. We performed meta‐analyses of the most stringent measures of abstinence at six months' follow‐up or longer, using a Mantel‐Haenszel random‐effects method, pooling studies with similar interventions and similar comparators to calculate risk ratios (RR) and their corresponding 95% confidence intervals (CI). We conducted analyses including all randomised (with dropouts counted as still smoking) and complete cases only.

Main results

This review includes 26 studies (33,849 participants). Overall, we judged 13 studies to be at low risk of bias, three at high risk, and the remainder at unclear risk. Settings and recruitment procedures varied across studies, but most studies were conducted in high‐income countries. There was moderate‐certainty evidence, limited by inconsistency, that automated text messaging interventions were more effective than minimal smoking cessation support (RR 1.54, 95% CI 1.19 to 2.00; I2 = 71%; 13 studies, 14,133 participants). There was also moderate‐certainty evidence, limited by imprecision, that text messaging added to other smoking cessation interventions was more effective than the other smoking cessation interventions alone (RR 1.59, 95% CI 1.09 to 2.33; I2 = 0%, 4 studies, 997 participants). Two studies comparing text messaging with other smoking cessation interventions, and three studies comparing high‐ and low‐intensity messaging, did not show significant differences between groups (RR 0.92 95% CI 0.61 to 1.40; I2 = 27%; 2 studies, 2238 participants; and RR 1.00, 95% CI 0.95 to 1.06; I2 = 0%, 3 studies, 12,985 participants, respectively) but confidence intervals were wide in the former comparison. Five studies compared a smoking cessation smartphone app with lower‐intensity smoking cessation support (either a lower‐intensity app or non‐app minimal support). We pooled the evidence and deemed it to be of very low certainty due to inconsistency and serious imprecision. It provided no evidence that smartphone apps improved the likelihood of smoking cessation (RR 1.00, 95% CI 0.66 to 1.52; I2 = 59%; 5 studies, 3079 participants). Other smartphone apps tested differed from the apps included in the analysis, as two used contingency management and one combined text messaging with an app, and so we did not pool them. Using complete case data as opposed to using data from all participants randomised did not substantially alter the findings.

Authors' conclusions

There is moderate‐certainty evidence that automated text message‐based smoking cessation interventions result in greater quit rates than minimal smoking cessation support. There is moderate‐certainty evidence of the benefit of text messaging interventions in addition to other smoking cessation support in comparison with that smoking cessation support alone. The evidence comparing smartphone apps with less intensive support was of very low certainty, and more randomised controlled trials are needed to test these interventions.

Plain Language Summary

Can programmes delivered by mobile phones help people to stop smoking?

Background

Tobacco smoking is a leading cause of preventable death. Mobile phones can be used to support people who want to quit smoking. In this review, we have focused on programmes that use text messages or smartphone apps to do so.

Search date

We searched for published and unpublished studies in October 2018.

Study characteristics

We included 26 randomised controlled studies (involving over 33,000 people) that compared smoking quit rates in people who received text messages or smartphone apps to help them quit, with people who did not receive these programmes. We were interested in studies that measured smoking for six months or longer.

Key results

We found that text messaging programmes may be effective in supporting people to quit, increasing quit rates by 50% to 60%. This was the case when they were compared to minimal support or were tested as an addition to other forms of stop‐smoking support. There was not enough evidence to determine the effect of smartphone apps.

Quality and completeness of the evidence

Most of the studies were of high quality, although three studies had high drop out rates. We are moderately confident in the results of the text messaging interventions, but there were some issues with unexplained differences between study findings and for some comparisons there was not much data. We have low confidence in the results concerning smartphone apps, and more studies are needed in this field.

Keywords 
smoking cessation mobile phone tobacco tobacco use text message

Health Benefits of Smoking Cessation

Author/s: 
World Health Organization

There are immediate and long-term health benefits of quitting for all smokers.

Beneficial health changes that take place:

  • Within 20 minutes, your heart rate and blood pressure drop.
  • 12 hours, the carbon monoxide level in your blood drops to normal.
  • 2-12 weeks, your circulation improves and your lung function increases.
  • 1-9 months, coughing and shortness of breath decrease.
  • 1 year, your risk of coronary heart disease is about half that of a smoker's.
  • 5 years, your stroke risk is reduced to that of a nonsmoker 5 to 15 years after quitting.
  • 10 years, your risk of lung cancer falls to about half that of a smoker and your risk of cancer of the mouth, throat, esophagus, bladder, cervix, and pancreas decreases.
  • 15 years, the risk of coronary heart disease is that of a nonsmoker's.
Keywords 
smoking smoking cessation

Smoking Cessation in Primary Care

Author/s: 
Braun, Stephen, Block, Jason, Fischer, MIchael, Mather, Arielle

Choose a treatment plan that fits the patient.

A comprehensive approach to cessation is more successful than any one mode of therapy. For patients ready to commit to quitting, use both behavioral interventions and pharmacologic therapy. Good evidence suggests that each of the following pharmacotherapies can effectively support smoking cessation, unless contraindications are present: 

• Nicotine replacement therapy (gum, lozenges, patches, inhalers, and nasal spray)

• Bupropion (a norepinephrine/dopamine reuptake inhibitor and nicotinic acetylcholine receptor antagonist)

• Varenicline (a partial agonist of the alpha-4/beta-2 nicotinic acetylcholine receptor)

Keywords 
smoking cessation clinical decision aid
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