SMOKING CESSATION PHARMACOTHERAPY (SCT)

HOW MANY DRUGS? HOW MANY TRIES?

Choosing Wisely Fall Refresher

October 26, 2019

Pam McLean-Veysey

Dr. Maureen Allen

DISCLOSURE

Pam McLean-Veysey, Team Leader Drug Evaluation Unit

DEU funded by the Drug Evaluation Alliance of NS. (DEANS).

DEU prepares Drug Evaluation Reports for the Atlantic Common Drug Review (ACDR)

Has no conflicts of interest

OBJECTIVES

To review evidence to address the following clinical questions

1. What is the most effective monotherapy for SC?

2. Do combinations of SCT improve quit rates?

3. Does extended or retreatment improve quit rates?

4. What is the role of vaping/ e-cigarettes in smoking cessation

A CIGARETTE

A sophisticated drug delivery instrument to facilitate the rapid delivery of nicotine and the thousands of accompanying toxins, 50 carcinogens and CO2 via the pulmonary circulation to the left

ventricle and the arterial circulation.

NICOTINE-THE MOST TENACIOUSLY ADDICTIVE DRUG ENCOUNTERED IN GENERAL COMMUNITY…

Increases mortality 2-3 fold.

One of the most important modifiable CV risk factors.

Smokers typically lose 1 decade of life expectancy.

Continued smoking diminishes the impact of the management of hypertension and dyslipidemia

interventions we consistently and assiduously address in the management of a cardiac patient.

Smoking is a leading cause of COPD

IMPACT OF SMOKING CESSATION

… is superior to any other proven CV intervention.

65% of smokers want to quit

Of the 50% who try, < 5% result in long term abstinence. Reid CMAJ 2016

< 1/3 of adult smokers attempting to quit seek help, and even fewer use the most effective treatments Up to date

Quitting smoking before age 35 associated with a mortality rate similar to that of never smokers. Patnode

SOME GOOD NEWSSMOKING CESSATION

AND SUBSEQUENT RISK OF CV DISEASE DUNCAN JAMA 2019 322 (7)

Retrospective analysis of prospectively collected data (Framingham Heart Study)

No baseline CVD; N= 8770 (original and offspring cohort)

CVD risk current smoking vs. quitting within 5 years: rates per 1000 person-years

• Current smoking, 11.56 (95%CI, 10.30-12.98)

• Quitting 6.94 (95%CI, 5.61-8.59) Statistically significant difference

CVD risk in never smokers vs cessation after 10 - 15 years: rates per 1000 person-years:

• Never smoking, 5.09 (95%CI, 4.52-5.74)

• Quitting 10 to <15 years 6.31 (95% CI, 4.93-8.09) Not significantly different

https://www150.statcan.gc.ca/n1/pub/82-625-x/2017001/article/54864-eng.htm

SOME DISTURBING STATS -CIHIHTTPS://YOURHEALTHSYSTEM.CIHI.CA/HSP/INBRIEF?LANG=EN#!/INDICATOR S/009/SMOKING/;MAPC1;MAPLEVEL2 ;/

CASE: TIM

35-year-old

25–pack-year smoking history

Currently smokes one pack of cigarettes a day.

Eager to quit smoking - soon having his first child.

Past attempts: Currently trying to cut back. In 20’s tried a “cold turkey” approach which lasted two months and then he restarted.

He asks about the drugs to help him quit.

Medical History: No cardiovascular issues, no history of seizures, no prescription medications.

On and off antidepressants since early 20’s but currently not taking any medications.

WHAT ARE TIM’S OPTIONS?

Cold Turkey

Pharmacotherapy

Nicotine Replacement Therapy (NRT)

Varenicline

Bupropion

Combination therapy

E cigs?

REMOVED PICTURE ON MECHANISM OF ACTION FOR NRT

Varenicline MOA Bupropion MOA

REMOVED PICTURES ON MECHANISM OF ACTION

QUESTION 1 WHICH PHARMACOTHERAPY IS MOST EFFECTIVE FOR TIM?

Quit rates monotherapy vs. placebo Type of Therapy

N =

Mean Absolute

Quit Rates

ABSOLUTE BENEFIT

INCREASE (ABI)

NNT

Nicotine RT

N=50,000

17% vs 10 % 7% 14

Bupropion SR

N=13,000

19.7% vs 11.5% 8.2% 12

Varenicline

N=6,166

28% vs 12% 16% 6

Reference AHRQ

Cochrane Review (Cahill Network meta analysis) 2013; 6-12 month follow-up

Cahill network meta analysis 2013

QUESTION 2 WILL A COMBO OF DRUGS IMPROVE TIM’S CHANCES?

Combinations

Type of Therapy

N =

Mean Absolute

Quit Rates

ABSOLUTE BENEFIT

INCREASE (ABI) or

Odds ratio

NNT

Bupropion +NRT vs

bupropion N=1991

Small benefit

OR 1.24 (1.06-1.45)

Bupropion +NRT vs

NRT

Insufficient evidence(Hughes Cochrane Review 2014)

No significant benefit

Combo NRT vs Single

form of NRT N=4,664

20.6% vs 15.6% 5% 20

Varenicline + NRT

Reviewed on separate slidesBupropion +

varenicline

CAHILL NETWORK META ANALYSIS 2013

C-NRT vs NRT

ABI 5% -NNT 20

2018 UPDATENRT MONO AND COMBO 6 + MONTH FOLLOW-UP

BAKER 2016 RANDOMIZED, OPEN LABEL COMBINATION NRT VS. PATCH VS. VARENICLINE N=1086; 12 WKS

Adherence < 50% at 8 weeks

More adverse effects with varenicline

COMBINING VARENICLINE + NRT?

Chang Meta Analysis

Abstinence rates

Varenicline +NRT

Patch vs varenicline

OR (95% CI)

ABI

NNT

Early outcome

Up to 12 wks.

3 studies N=904

44.4% vs 35.1 % OR = 1.50 (1.14-1.97)

ABI 9.3%11

Late outcome

Up to 24 wks.

2 studies N=787

32.4% vs 23.1% OR = 1.62 (1.18 -2.23)

ABI 9.3% 11

Adverse events No difference between groups

Chang et al. BMC Public Health (2015) 15:689

VARENICLINE (CHAMPIX) PRODUCT MONOGRAPH 2019

“The concomitant use of NRT with CHAMPIX (varenicline tartrate) may result in an increase in adverse reactions.”

A clinical drug interaction study (N=24), increased incidences of nausea, headache, vomiting, dizziness, dyspepsia and fatigue for the combination of NRT and varenicline than for NRT alone.

“The safety and efficacy of the combination treatment with CHAMPIX and NRT have not been studied. Due to the proposed mechanism of action of varenicline, it is not anticipated that co-administration with NRT would confer additional benefit compared with CHAMPIX alone.”

COMBINING BUPROPION + NRT? Cahill 2013 reported the combination was not more effective than NRT alone

Smith et al – open label N=1346 Self reported abstinence

NRT combo vs Bup

+NRT NNT 33

COMBINATION BUPROPION + VARENICLINE (B+V) VS VARENICLINE (V);12 WEEKS, RCT N=506 EBBERT 2014

Outcome of Prolonged abstinence i.e., no smoking from 2 weeks after TQD

B+V vs V ABI NNT/NNH

12 wks. 53% vs 43.2% 9.8% 10

26 wks. 36.6% vs 27.6% 9% 11

52 wks. 30.9% vs 24.5% 6.4% Not stat sign

7 day point

prevalence not statistically significant at any time frame

Adverse events

Anxiety NNH 24

Depressive sx NNH 36

Patnode CP et al Behavioral Counseling and Pharmacotherapy Interventions for Tobacco Cessation in Adults, Including Interventions for Tobacco

Cessation in Adults ii Kaiser Permanente Research Affiliates EPC Pregnant Women: A Review of Reviews for the U.S. Preventive Services Task Force.

Evidence Synthesis No. 134. AHRQ Publication No. 14-05200-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2015 (209 pages)

DECISION TIME FOR TIM…

Monotherapy

Bupropion, varenicline and NRT improve

abstinence rates after 12 weeks for

monotherapy

Quit rates 17-28%; NNTs 6-14.

Varenicline most efficacious therapy

NNT=6

Bupropion and NRT similar efficacy NNT

=12-14

Benefits decline over time but still generally

> placebo

Combination Therapy

Combination therapy: long acting nicotine patch and a short acting product such as gum: similar efficacy as varenicline. NNT =20

Other combinations (bupropion or varenicline with NRT or bupropion + varenicline): contradictory evidence for efficacy.

Varenicline product monograph states it should not be used in combination with NRT.

HOW LONG?RETREATMENT/ RELAPSE PREVENTION

TONSTAD 2006 ADDITIONAL 12 WEEKS OF VARENICLINETonstad et al Effect of maintenance therapy with varenicline on smoking cessation JAMA 2006 296:64

N=1927; open label; varenicline titrated to 1 mg bid x 12 weeks;

N=1210 (62.8%) with no nicotine in last week randomized to additional 12 weeks of varenicline or placebo

Outcome: continuous abstinence (CO2 confirmed)

Abstinence

Weeks 13-24

Abstinence

Weeks 13-52

Varenicline additional 12 weeks 70.5% 43.6%

Placebo 49.6% 36.9%

OR 2.48 95% CI, 1.95-3.16 P<0.001

ABI 20.9% NNT 5 (95% CI, 4-7)

OR, 1.34; 95% CI, 1.06-1.69 p=0.02

ABI 6.7% NNT 14 (95% CI, 8-71)

(wide CI)

No difference in adverse events between varenicline and placebo in the double blind phase

NRT EXTENDED AND MAINTENANCE THERAPY

Schnoll et al. 8 vs 24 vs 52 weeks NRT Patch assessed at 24 and 52 weeks

Abstinence at 24 and 52

weeks

8 weeks

(Standard)

24 weeks

(Extended)

52 weeks

(Maintenance)

24 week 21.7% 27.2%† -

52 weeks 21.7%* 26%* 20.3%*

† statistically significant vs standard treatment

*No significant difference between groups;

No increased efficacy beyond 24 weeks

Schnoll et al JAMA Intern Med. 2015;175(4):504-511.

LONG TERM NRT (PATCH +GUM) IN COPD PTS.AMONG CONTINUING SMOKERS, ONGOING USE OF NRT WAS NOT ASSOCIATED

WITH REDUCTIONS IN SMOKE EXPOSURE.

N= 398 COPD patients; unblinded RCT

Comparison 10 weeks vs 12 months of combo NRT (Patch + gum)

Quit rates at 12 months NOT statistically different

Standard treatment: 23 of 197 (11.7%)

Long term nicotine: 24 of 197 (12.2%)

Ellerbeck E, et al Effect of Long-term Nicotine Replacement Therapy vs Standard Smoking Cessation for Smokers With Chronic Lung Disease A Randomized Clinical Trial JAMA Network Open. 2018;1(5):e181843

RELAPSE PREVENTION WITH EXTENDED THERAPYLIVINGSTONE-BANKS 2019

Varenicline 2 Studies (assisted abstainers) N= 1297

1 study additional 12 weeks; 2nd study up to 52 weeks, (following cessation with standard therapy.)

Risk ratio (RR) 1.23, 95% CI 1.08 to 1.41, (moderate certainty evidence)

Nicotine replacement therapy (NRT) (varied lengths of extension 8 – 52 weeks)

2 studies, n = 2261, RR 1.24, 95% Cl 1.04 to 1.47) – unassisted abstainers

Analysis in assisted abstainers was not statistically significant. (low certainty of evidence)

Bupropion or combinations of bupropion with NRT (52 weeks)

Bupropion RR1.15 (0.98- 1.35) moderate certainty evidence (Not statistically significant)

Bupropion + NRT RR 1.18 (0.75 to 1.87) low certainty of evidence

LINDSON 2019 LONGER VS SHORTER COMBINATION NRT

LindsonN, et al Different doses, durations and modes of delivery of nicotine replacement therapy for smoking cessation. Cochrane Database of Systematic Reviews 2019, Issue 4.

GONZALES 2014 ABSTINENCE RATES - RETREATMENT WITH VARENICLINE R,DB,PC, MC VS. PLACEBO

Brief counselling; ≥1 prior quit attempt (≥2 weeks) using varenicline

No quit attempts in ≤3 months.

Intervention: 12 weeks varenicline (n = 251) or placebo (n = 247) plus 40 weeks non treatment

Weeks 9-12 (45% vs 11.8%) NNT 3

Weeks 9-24 (28.9% vs 7.8%) NNT 5

Weeks 9-52 (20.1% vs 3.3%) NNT 6.

AEs - 75.5% varenicline group

63.3% in the placebo group NNH 8.

Gonzales et al 2014 Retreatment with varenicline for smoking cessation in smokers who have

previously taken varenicline. Clinical Pharmacology and Therapeutics 2014;96 (3):390- 96

CUPERTINO 2009 REPEATED CYCLES LONGITUDINAL COHORT N=726

Odds of quitting increased with additional offers of pharmacotherapy Bupropion 7 wk. course or NRT 6 week course offered q6month over 2 years

First cycle 464 (63.9%) took smoking cessation pharmacotherapy OR 2.56 vs. non-user

2nd cycle 52.7% of 383

OR 1.83 vs non-user

3rd cycle 45.8% of 177

OR 1.85 vs non -user

4th cycle 64.7% of 68

OR 3.08 vs non-user

Cupertino, A.P., Wick, J.A., Richter, K.P., Mussulman, L., et al The impact of repeated cycles of

pharmacotherapy on smoking cessation: a longitudinal cohort study. Arch. Intern. Med. 169, 1928–1930 2009

RETREATMENT WITH BUPROPION

Gonzales 2001 Retreatment with bupropion 12 weeks, R, DB,PC N=450

Continuous Abstinence (All comparisons p<0.001) Weeks Bupropion SR Placebo NNT

4-7 27% 5% 4-5

9-12 28% 9% 5

4-26 12% 2% 10

Gonzales, D.H. et al. Bupropion SR as an aid to smoking cessation in smokers treated previously with

bupropion: a randomized placebo-controlled study. Clin. Pharmacol. Ther. 69, 438–444 (2001).

REDUCTION IN SMOKINGTHE USE OF NICOTINE REPLACEMENT PRODUCTS TO REDUCE SMOKING

FOR THOSE WHO DO NOT QUIT

CADTH 2014 Review NRT for cessation or reduction

SR of 7 RCTS

Abstinence: 7% of smokers receiving NRT for six months, Twice the rate of those receiving placebo

RR 2.06; 95% CI, 1.34 to 3.15

NNT 29

Smoking Reduction defined as less than 50% of baseline vs placebo NRT from week 6 to the end of follow-up (up to 26 months)

RR 3.84 (2.32 to 6.35) in favor of NRT

CADTH: Pharmacological agents for smoking cessation: clinical effectiveness and cost -effectiveness. Ottawa: 2017 Nov.

SUMMARY EXTENDED THERAPY AND RETREATMENT

Extended therapy to prevent relapses:

Varenicline: Most consistent evidence for benefit of extended (additional 12 weeks) Tonstad (moderate certainty of evidence)

NRT - evidence for benefit up to 24 weeks. Schnoll

Mixed results for longer therapy with NRT (low certainty of evidence) Livingstone-Banks, Lindson

May decrease cigs per day. CADTH 2014

Extended bupropion plus NRT or bupropion alone – no evidence of benefit. (low certainty of evidence)Livingstone-Banks

Retreatment with SCT

Abstinence rates and NNTs similar to original trial with standard treatment. Gonzales 2014, 2011, Cupertino,

Adverse effects require consideration.

VAPING, E-CIGARETTE

AN E-CIGARETTE (WIKIPEDIA)

An electronic cigarette or e-cigarette is a handheld battery-powered vaporizer that simulates smoking and provides some of the behavioral aspects of smoking, including the hand-to-mouth action of smoking, but without burning tobacco.

Instead of cigarette smoke, the user inhales an aerosol, commonly called vapor.

E-liquids usually contain propylene glycol, glycerin, nicotine, flavorings, additives, and differing amounts of contaminants.

https://en.wikipedia.org/wiki/Electronic_cigarette

PREVALENCE OF VAPING IN CANADANational samples recruited from commercial panels in Canada (n=7891)

Table 2 | Changes in prevalence of smoking and vaping between 2017 and 2018 among adolescents aged 16-19 years. Values are weighted percentages (numbers) unless stated otherwise.

Hammond, D., et al. (2019). Prevalence of vaping and smoking among adolescents in

Canada, England, and the United States: repeat national cross sectional surveys. BMJ,

l2219.

PREVALENCE OF VAPING IN CANADA

Authors Conclusions: Between 2017 and 2018, among 16 to 19 year olds the prevalence of vaping and

smoking increased in Canada

VAPING IN NOVA SCOTIA ON THE RISE

NS Students grades 7-12: 36.8% "ever tried" an e-cigarette vs. Canadian students: 22.8%

Use in the past 30 daysGrades 7-12: 20.9% used e-cigarettes in the past 30 days Vs Canadian average 10%.

Vaping more common as students get older.

Grades 10-12: 49% reported using an e-cigarette at least once.

Nova Scotia Lung Association

https://ns.lung.ca/lung-health/vaping-and-nova-scotia-youth

2019 RCT OF E-CIGARETTESVS. NICOTINE-REPLACEMENT THERAPY

Hajek, P., et al. (2019). New England Journal Of Medicine, 380(7), 629-637.

ACP Journal Club Annals of Internal Medicine 21 May 2019

JAMA Intern Med. 2019;179(9):1193-1200

https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2019/70919a-eng.php

SX OF VAPI OR EVAPI

Respiratory illness within 90 days of vaping

GI symptoms nausea, vomiting, and diarrhea

Fever and malaise; and/or respiratory symptoms:

Shortness of breath, cough, or pleuritic chest pain.

Infiltrates, hypoxia elevated leukocyte count in the absence of an identifiable infectious source.

Pulmonary manifestations may progress rapidly: hospitalization, intensive care, and mechanical ventilatory support

Pneumonitis - acute eosinophilic pneumonia, organizing pneumonia, lipoid pneumonia, diffuse alveolar hemorrhage, and hypersensitivity pneumonitis

Etc. Randol W. Hooper II Ann Intern Med. doi:10.7326/M19-2908

NOT THE END OF THIS STORY…

The outbreak of lung injuries in the US among people using electronic cigarettes should not deter UK smokers

from using them, a panel of experts told a briefing at the Science Media Centre in London. The danger, they

said, was less from vaping than from the fear of vaping, which could discourage smokers from using the best

currently available aid to quitting.

Analysis of a subset of the US cases has indicated that around three quarters of those affected had used their

vaping gear to inhale cannabis products. John Britton, director of the Centre for Tobacco and Alcohol Studies at

the University of Nottingham, told the London briefing: “It looks as if it’s a cannabis vaping problem. It’s not

happening here. It’s a US specific problem.”

https://www.bmj.com/content/367/bmj.l6027

Health Canada may allow e-cigarette companies to advertise the harm-reduction benefits of their products, despite mounting concerns about the long-term risks of vaping. Last fall, in a closed consultation, the regulator proposed promotional statements to industry and health g

CMAJ | October 18, 2019

WHAT TO CHOOSE FOR TIM?

Monotherapy:

NRT, Varenicline, Bupropion?

Combination therapy - Which combination?

E cigs

Considerations – efficacy, safety, mental health issues, cost, insurance coverage, second hand smoke (baby)

CDC - SECONDHAND SMOKE CONTAINS MORE THAN 7,000 CHEMICALS. HUNDREDS ARE TOXIC AND ABOUT 70 CAN CAUSE CANCER

https://www.cdc.gov/tobacco/data_statistics/fact_sheets/secondhand_smoke/health_effects/index.htm

CHOOSING WISELY CANADA

No explicit statements on smoking cessation other than in related conditions where smoking cessation part of treatment (E.g., PAD)

BIBLIOGRAPHY

ACP Journal Club Varenicline, combination NRT, and nicotine patch did not differ for smoking cessation at 6 mo. Annals of Internal Medicine 17 May 2016

Anthenelli RM, Benowitz NL, West R, et al Neuropsychiatric safety and efficacy of varenicline,bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet. 2016 Jun 18;387(10037):2507-20.

Baker TB et al Effects of Nicotine Patch vs Varenicline vs Combination Nicotine Replacement Therapy on Smoking Cessation at 26 Weeks: A Randomized Clinical Trial. JAMA. 2016 Jan 26;315(4):371-9.

Bupropion HCL SR (Zyban 150 mg) Product Monograph https://pdf.hres.ca/dpd_pm/00036009.PDF

Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database of Systematic Reviews 2013, Issue 5.

CADTH: Pharmacological agents for smoking cessation: clinical effectiveness and cost -effectiveness. Ottawa: 2017 Nov.

CAMH Can-ADAPTT Pharmacotherapy Guidelines https://www.nicotinedependenceclinic.com/English/CANADAPTT/Guideline/Pharmacotherapy.aspx

Chang et al. Combination therapy of varenicline with nicotine replacement therapy is better than varenicline alone: a systematic review and meta-analysis of randomized controlled trials BMC Public Health (2015) 15:689

Cupertino, A.P., Wick, J.A., Richter, K.P., Mussulman, L., et al The impact of repeated cycles of pharmacotherapy on smoking cessation: a longitudinal cohort study. Arch. Intern. Med. 169, 1928–1930 (2009)

Duncan MS et al Association of Smoking Cessation With Subsequent Risk of Cardiovascular Disease JAMA. 2019;322(7):642-650. doi:10.1001/jama.2019.10298

Ebbert JO JAMA. Combination Varenicline and Bupropion SR for Tobacco-Dependence Treatment in Cigarette Smokers 2014; 311(2):155-163

Ellerbeck E, Nollen N, Hutcheson TD Effect of Long-term Nicotine Replacement Therapy vs Standard Smoking Cessation for Smokers With Chronic Lung Disease A Randomized Clinical Trial JAMA Network Open. 2018;1(5):e181843

Evins AE, et al Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder: a randomized clinical trial. JAMA. 2014 Jan 8; 311(2):145-54

Gonzales et al 2014 Retreatment with varenicline for smoking cessation in smokers who have previously taken varenicline. Clinical Pharmacology and Therapeutics 2014;96 (3):390- 96

Gonzales, D.H. et al. Bupropion SR as an aid to smoking cessation in smokers treated previously with bupropion: a randomized placebo-controlled study. Clin. Pharmacol. Ther. 69, 438–444 (2001).

Gomajee R, El-Khoury F, Goldberg M, et al Association Between Electronic Cigarette Use and Smoking Reduction in France. JAMA Intern Med. 2019 Jul 15. doi: 10.1001/jamainternmed.2019.1483.

Gourlay, S.G., Forbes, A., Marriner, T., Pethica, D. & McNeil, J.J. Double blind trial of repeated treatment with transdermal nicotine for relapsed smokers. BMJ 311, 363–366 (1995).

Hammond, D., et al. (2019). Prevalence of vaping and smoking among adolescents in Canada, England, and the United States: repeat national cross sectional surveys. BMJ, l2219.

Hajek, P., et al. (2019). New England Journal Of Medicine, 380(7), 629-637. (ACP Journal Club Annals of Internal Medicine 21 May 2019 )

BIBLIOGRAPHY

Hartmann-Boyce J, Chepkin SC, Ye W, Bullen C, Lancaster T. Nicotine replacement therapy versus control for smoking cessation. Cochrane Database of Systematic Reviews 2018, Issue 5. Art. No.: CD000146

Health Canada Smoking statistics https://www.canada.ca/en/health-canada/services/publications/healthy-living/canadian-tobacco-use-monitoring-survey-ctums-2012.html

Hughes JR, Stead LF, Hartmann-Boyce J, Cahill K, Lancaster T. Antidepressants for smoking cessation. Cochrane Database of Systematic Reviews 2014, Issue 1

Lindson N,Chepkin SC, YeW, Fanshawe TR, BullenC,Hartmann-Boyce J.Different doses, durations andmodes of delivery of nicotine replacement therapy for smoking cessation. Cochrane Database of Systematic Reviews 2019, Issue 4. Art. No.: CD013308. DOI: 10.1002/14651858.CD013308.

Livingstone-Banks J, Norris E, Hartmann-Boyce J,West R, JarvisM, Hajek P. Relapse prevention interventions for smoking cessation. Cochrane Database of Systematic Reviews 2019, Issue 2.

NS Lung Association Vaping https://ns.lung.ca/lung-health/vaping-and-nova-scotia-youth

Nicotine replacement therapy (various forms) product monographs available on-line.

Ottawa smoking cessation model https://ottawamodel.ottawaheart.ca/

Patnode CP et al Behavioral Counseling and Pharmacotherapy Interventions for Tobacco Cessation in Adults, Including Interventions for Tobacco Cessation in Adults ii Kaiser Permanente Research Affiliates EPC Pregnant Women: A Review of Reviews for the U.S. Preventive Services Task Force. Evidence Synthesis No. 134. AHRQ Publication No. 14-05200-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2015 (209 pages)

Pekham et al Smoking Cessation in severe mental ill health: What works? An updated systematic review and meta-analysis BMC Psychiatry 2017; 17;252

Pipe AL and Reid RD 2018 Smoking Cessation and Cardiac Rehabilitation: A Priority! Canadian Journal of Cardiology 34 (2018) S247eS251

Ramon J, Morchon S, Baena A, Masuet-Aumatel Combining varenicline and nicotine patches: a randomized controlled trial study in smoking cessation BMC Medicine 2014, 12:172

Reid RD, Pritchard G, Walker K et al Managing smoking cessation CMAJ, December 6, 2016, 188(17–18)

Schnoll R, Leone F, Veluz-Wilkins A et al A randomized controlled trial of 24 weeks of varenicline for tobacco use among cancer patients: Efficacy, safety, and adherence. Psychooncology. 2019 Jan 24.

Schnoll RA et al Long term Nicotine Replacement Therapy. JAMA Intern Med 2015 175(4):504-11

Smith et a Comparative Effectiveness of 5 Smoking Cessation Pharmacotherapies in Primary Care Clinicsl Arch Intern Med. 2009;169(22):2148-2155

Stats Can https://www150.statcan.gc.ca/n1/pub/82-625-x/2017001/article/54864-eng.htm

Tonstad et al Effect of maintenance therapy with varenicline on smoking cessation JAMA 2006 296:64

US Centre for Disease Prevention and Health Promotion 2014 The Health Consequences of Smoking—50 Years of Progress A Report of the Surgeon General https://www.cdc.gov/

Varenicline (Champix) product monograph: https://www.pfizer.ca/sites/g/files/g10050796/f/201902/Champix_PM_221214_22Jan2019_EN.pdf