What Are the Effects of Varenicline Compared With Nicotine Replacement Therapy on Long Term Smoking Cessation and Clinically Important Outcomes?

NCT02681848 | Unknown DMC

• 1 other identifier: 14/49/94
• Study Type: observational
• Target: 180,000
• Locations: 0 countries
• Sites: N/A

Brief Summary

Introduction: Smoking is a major avoidable cause of ill-health and premature death. Treatments that help patients successfully quit smoking have an important effect on health and life expectancy. Varenicline is a medication that can help smokers successfully quit smoking. However, there are concerns that it may cause adverse effects, such as increase in the occurrence of depression, self-harm and suicide and cardiovascular disease. In this study the investigators aim to examine the effects of varenicline versus other smoking cessation pharmacotherapies on smoking cessation, health service use, all-cause and cause-specific mortality and physical and mental health conditions. Methods: In this project the investigators will investigate the effects of varenicline compared to nicotine replacement therapies on: (1) long-term smoking cessation and whether these effects differ by area level deprivation; and (2) the following clinically-important outcomes: rate of general practice and hospital attendance; all-cause mortality and death due to diseases of the respiratory system and cardiovascular disease; and a primary care diagnosis of respiratory illness, myocardial infarction or depression and anxiety. The study is based on a cohort of patients prescribed these smoking cessation medications from the Clinical Practice Research Datalink (CPRD). The investigators will use three methods to overcome confounding: multivariable adjusted Cox regression, propensity score matched Cox regression, and instrumental variable regression. The total expected sample size for analysis will be at least 180 000. Follow-up will end with the earliest of either an 'event' or censoring due to the end of registration or death. Ethics and dissemination: Ethics approval was not required for this study. This project has been approved by the CPRD's Independent Scientific Advisory Committee (ISAC). The investigators will disseminate the findings via publications in international peer-reviewed journals and presentations at international conferences.

Conditions

Smoking Cessation; Cardiovascular Disease; Respiratory Disease; Myocardial Infarction; Depression; Anxiety

Keywords

Primary care attendance; All-cause; Cause specific; Hospital attendance

Outcome Measures

Primary Outcomes (1)

• Smoking abstinence

  Number of patients who successfully abstain from smoking after treatment. The investigators will define a patient as relapsed on the day they have their first record indicating that the patient is a current smoker after their first prescription of a smoking cessation therapy.

  24 months after first prescription

Other Outcomes (7)

• Primary care attendance

  3, 6, 9, 12, 24 and 48 months after first prescription

• All-cause and cause specific mortality

  3, 6, 9, 12, 24 and 48 months after first prescription

• Respiratory illness

  3, 6, 9, 12, 24 and 48 months after first prescription

Interventions

Varenicline DRUG

Smoking cessation medication

Also known as: Champix, Chantix

Nicotine replacement therapy DRUG

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The investigators will use the CPRD to conduct a cohort study of all patients prescribed varenicline or nicotine replacement products. The study type is "Hypothesis testing". Exposure will be defined as the first prescription of either varenicline or nicotine replacement therapy. Setting/Context: Prescriptions of smoking cessation medications issued in primary care. Target population: All smokers aged over 18 prescribed smoking cessation treatment in eligible primary care centres contributing to the CPRD after the 1st of September 2006. Sampling method: The investigators will sample all individuals prescribed smoking cessation medication at any point after 1st of September 2006 to the most recent release of the CPRD data. Study population: The investigators will use patients prescribed other smoking cessation products such as nicotine patches as controls for patients prescribed varenicline.

You may qualify if:

• Patients:
• With CPRD records aged 18 and over.
• Who were prescribed medicines in BNF category 4.10.2 from 1st September 2006, when varenicline was introduced to the UK, to the present.
• With records that were classified as 'acceptable' by the CPRD from all up to standard practices at least 18 months prior to date of entry of each cohort (1st March 2005).
• Who have data defined as "acceptable" by the CPRD if they meet minimum quality control standards, for example their registration period with their GP is valid. "Up to standard" practices are GP practices defined by the CPRD to be providing data of sufficient quality for research purposes.

You may not qualify if:

• Patients who registered at a practice less than 365 days before the first recorded prescription to allow for high quality assessment of baseline data and possible confounders.
• Patients prescribed bupropion in the year before their index prescription will be excluded from the analysis. It is relatively rare for patients to be prescribed both NRT and varenicline on the same day. In the investigators' previous study this only occurred for 0.248% of all prescription events. In the primary analysis for this study the investigators will exclude patients initially prescribed both NRT and varenicline.
• Follow-up
• \* Follow-up will end with the earliest of either an "event" or censoring due to the end of registration or death.

Sponsors & Collaborators

• University of Bristol: lead

Related Publications (43)

• Brookhart MA, Wang PS, Solomon DH, Schneeweiss S. Evaluating short-term drug effects using a physician-specific prescribing preference as an instrumental variable. Epidemiology. 2006 May;17(3):268-75. doi: 10.1097/01.ede.0000193606.58671.c5.

  PMID: 16617275 BACKGROUND

• Davies NM, Smith GD, Windmeijer F, Martin RM. COX-2 selective nonsteroidal anti-inflammatory drugs and risk of gastrointestinal tract complications and myocardial infarction: an instrumental variable analysis. Epidemiology. 2013 May;24(3):352-62. doi: 10.1097/EDE.0b013e318289e024.

  PMID: 23532054 BACKGROUND

• Peto R, Darby S, Deo H, Silcocks P, Whitley E, Doll R. Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case-control studies. BMJ. 2000 Aug 5;321(7257):323-9. doi: 10.1136/bmj.321.7257.323.

  PMID: 10926586 BACKGROUND

• Jha P, Peto R. Global effects of smoking, of quitting, and of taxing tobacco. N Engl J Med. 2014 Jan 2;370(1):60-8. doi: 10.1056/NEJMra1308383. No abstract available.

  PMID: 24382066 BACKGROUND

• D. of Health, Smoking kills: a White Paper on tobacco (1998), (available at http://webarchive.nationalarchives.gov.uk/+/www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_4006684).

  BACKGROUND

• Ratschen E, Britton J, McNeill A. The smoking culture in psychiatry: time for change. Br J Psychiatry. 2011 Jan;198(1):6-7. doi: 10.1192/bjp.bp.110.081372.

  PMID: 21200069 BACKGROUND

• Allender S, Balakrishnan R, Scarborough P, Webster P, Rayner M. The burden of smoking-related ill health in the UK. Tob Control. 2009 Aug;18(4):262-7. doi: 10.1136/tc.2008.026294. Epub 2009 Jun 9.

  PMID: 19509003 BACKGROUND

• Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev. 2013 May 31;2013(5):CD009329. doi: 10.1002/14651858.CD009329.pub2.

  PMID: 23728690 BACKGROUND

• Thomas KH, Martin RM, Davies NM, Metcalfe C, Windmeijer F, Gunnell D. Smoking cessation treatment and risk of depression, suicide, and self harm in the Clinical Practice Research Datalink: prospective cohort study. BMJ. 2013 Oct 11;347:f5704. doi: 10.1136/bmj.f5704.

  PMID: 24124105 BACKGROUND

• Joffe MM. Confounding by indication: the case of calcium channel blockers. Pharmacoepidemiol Drug Saf. 2000 Jan;9(1):37-41. doi: 10.1002/(SICI)1099-1557(200001/02)9:13.0.CO;2-U.

  PMID: 19025800 BACKGROUND

• McMahon AD. Approaches to combat with confounding by indication in observational studies of intended drug effects. Pharmacoepidemiol Drug Saf. 2003 Oct-Nov;12(7):551-8. doi: 10.1002/pds.883.

  PMID: 14558178 BACKGROUND

• Hernan MA, Robins JM. Instruments for causal inference: an epidemiologist's dream? Epidemiology. 2006 Jul;17(4):360-72. doi: 10.1097/01.ede.0000222409.00878.37.

  PMID: 16755261 BACKGROUND

• Hiscock R, Bauld L, Amos A, Fidler JA, Munafo M. Socioeconomic status and smoking: a review. Ann N Y Acad Sci. 2012 Feb;1248:107-23. doi: 10.1111/j.1749-6632.2011.06202.x. Epub 2011 Nov 17.

  PMID: 22092035 BACKGROUND

• Action on Smoking and Health, Smoking statistics who smokes and how much (2014), (available at http://www.ash.org.uk/files/documents/ASH_106.pdf).

  BACKGROUND

• Brown T, Platt S, Amos A. Equity impact of European individual-level smoking cessation interventions to reduce smoking in adults: a systematic review. Eur J Public Health. 2014 Aug;24(4):551-6. doi: 10.1093/eurpub/cku065. Epub 2014 Jun 1.

  PMID: 24891458 BACKGROUND

• Douglas L, Szatkowski L. Socioeconomic variations in access to smoking cessation interventions in UK primary care: insights using the Mosaic classification in a large dataset of primary care records. BMC Public Health. 2013 Jun 5;13:546. doi: 10.1186/1471-2458-13-546.

  PMID: 23738743 BACKGROUND

• Kotz D, West R. Explaining the social gradient in smoking cessation: it's not in the trying, but in the succeeding. Tob Control. 2009 Feb;18(1):43-6. doi: 10.1136/tc.2008.025981. Epub 2008 Oct 20.

  PMID: 18936053 BACKGROUND

• Drug Safety and Availability > FDA Drug Safety Communication: Safety review update of Chantix (varenicline) and risk of neuropsychiatric adverse events, (available at http://www.fda.gov/Drugs/DrugSafety/ucm276737.htm).

  BACKGROUND

• The Pharmacovigilance Expert Advisory Group, Summary report based on the minutes of the Pharmacovigilance Expert Advisory Group meeting held on Wednesday 3 July 2013 (2013), (available at http://www.mhra.gov.uk/home/groups/l-cs-el/documents/committeedocument/con322356.pdf).

  BACKGROUND

• Langley TE, Szatkowski L, Gibson J, Huang Y, McNeill A, Coleman T, Lewis S. Validation of The Health Improvement Network (THIN) primary care database for monitoring prescriptions for smoking cessation medications. Pharmacoepidemiol Drug Saf. 2010 Jun;19(6):586-90. doi: 10.1002/pds.1960.

  PMID: 20535756 BACKGROUND

• Hernan MA, Alonso A, Logan R, Grodstein F, Michels KB, Willett WC, Manson JE, Robins JM. Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease. Epidemiology. 2008 Nov;19(6):766-79. doi: 10.1097/EDE.0b013e3181875e61.

  PMID: 18854702 BACKGROUND

• Marston L, Carpenter JR, Walters KR, Morris RW, Nazareth I, White IR, Petersen I. Smoker, ex-smoker or non-smoker? The validity of routinely recorded smoking status in UK primary care: a cross-sectional study. BMJ Open. 2014 Apr 23;4(4):e004958. doi: 10.1136/bmjopen-2014-004958.

  PMID: 24760355 BACKGROUND

• Booth HP, Prevost AT, Gulliford MC. Validity of smoking prevalence estimates from primary care electronic health records compared with national population survey data for England, 2007 to 2011. Pharmacoepidemiol Drug Saf. 2013 Dec;22(12):1357-61. doi: 10.1002/pds.3537.

  PMID: 24243711 BACKGROUND

• Van Staa TP, Abenhaim L, Cooper C, Zhang B, Leufkens HG. The use of a large pharmacoepidemiological database to study exposure to oral corticosteroids and risk of fractures: validation of study population and results. Pharmacoepidemiol Drug Saf. 2000 Sep;9(5):359-66. doi: 10.1002/1099-1557(200009/10)9:53.0.CO;2-E.

  PMID: 19025840 BACKGROUND

• Herrett E, Thomas SL, Schoonen WM, Smeeth L, Hall AJ. Validation and validity of diagnoses in the General Practice Research Database: a systematic review. Br J Clin Pharmacol. 2010 Jan;69(1):4-14. doi: 10.1111/j.1365-2125.2009.03537.x.

  PMID: 20078607 BACKGROUND

• Quint JK, Mullerova H, DiSantostefano RL, Forbes H, Eaton S, Hurst JR, Davis K, Smeeth L. Validation of chronic obstructive pulmonary disease recording in the Clinical Practice Research Datalink (CPRD-GOLD). BMJ Open. 2014 Jul 23;4(7):e005540. doi: 10.1136/bmjopen-2014-005540.

  PMID: 25056980 BACKGROUND

• Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-83. doi: 10.1016/0021-9681(87)90171-8.

  PMID: 3558716 BACKGROUND

• Khan NF, Perera R, Harper S, Rose PW. Adaptation and validation of the Charlson Index for Read/OXMIS coded databases. BMC Fam Pract. 2010 Jan 5;11:1. doi: 10.1186/1471-2296-11-1.

  PMID: 20051110 BACKGROUND

• Cole SR, Platt RW, Schisterman EF, Chu H, Westreich D, Richardson D, Poole C. Illustrating bias due to conditioning on a collider. Int J Epidemiol. 2010 Apr;39(2):417-20. doi: 10.1093/ije/dyp334. Epub 2009 Nov 19.

  PMID: 19926667 BACKGROUND

• B. R. Kirkwood, J. A. . Sterne, Essential medical statistics (Wiley-Blackwell, 2003).

  BACKGROUND

• Glynn RJ, Schneeweiss S, Sturmer T. Indications for propensity scores and review of their use in pharmacoepidemiology. Basic Clin Pharmacol Toxicol. 2006 Mar;98(3):253-9. doi: 10.1111/j.1742-7843.2006.pto_293.x.

  PMID: 16611199 BACKGROUND

• E. Leuven, B. Sianesi, PSMATCH2: Stata module to perform full Mahalanobis and propensity score matching, common support graphing, and covariate imbalance testing. Stat. Softw. Compon. (2012) (available at http://ideas.repec.org/c/boc/bocode/s432001.html).

  BACKGROUND

• P. R. Rosenbaum, D. B. Rubin, Constructing a Control Group Using Multivariate Matched Sampling Methods That Incorporate the Propensity Score. Am. Stat.. 39, 33 (1985).

  BACKGROUND

• P. R. Rosenbaum, D. B. Rubin, The Central Role of the Propensity Score in Observational Studies for Causal Effects. Biometrika. 70, 41 (1983).

  BACKGROUND

• Davies NM, Gunnell D, Thomas KH, Metcalfe C, Windmeijer F, Martin RM. Physicians' prescribing preferences were a potential instrument for patients' actual prescriptions of antidepressants. J Clin Epidemiol. 2013 Dec;66(12):1386-96. doi: 10.1016/j.jclinepi.2013.06.008. Epub 2013 Sep 24.

  PMID: 24075596 BACKGROUND

• P. S. Clarke, F. Windmeijer, Instrumental Variable Estimators for Binary Outcomes. J. Am. Stat. Assoc.. 107, 1638-1652 (2012).

  BACKGROUND

• L. Hansen, K. Singleton, Generalized instrumental variables estimation of nonlinear rational expectations models. Econometrica. 50, 1269-1286 (1982).

  BACKGROUND

• Clarke PS, Windmeijer F. Identification of causal effects on binary outcomes using structural mean models. Biostatistics. 2010 Oct;11(4):756-70. doi: 10.1093/biostatistics/kxq024. Epub 2010 Jun 3.

  PMID: 20522728 BACKGROUND

• Stata Statistical Software: Release 13. (College Station, TX: StataCorp LP, 2013).

  BACKGROUND

• C. Baum, M. Schaffer, S. Stillman, IVREG2: Stata module for extended instrumental variables/2SLS and GMM estimation. Stat. Softw. Compon. (2002).

  BACKGROUND

• Office of National Statistics, Do smoking rates vary between more and less advantaged areas? (2014), (available at http://www.ons.gov.uk/ons/rel/disability-and-health-measurement/do-smoking-rates-vary-between-more-and-less-advantaged-areas-/2012/sty-smoking-rates.html).

  BACKGROUND

• J. D. Angrist, G. W. Imbens, D. B. Rubin, Identification of causal effects using instrumental variables. J. Am. Stat. Assoc.. 91, 444-455 (1996).

  BACKGROUND

• Davies NM, Taylor AE, Taylor GM, Itani T, Jones T, Martin RM, Munafo MR, Windmeijer F, Thomas KH. Varenicline versus nicotine replacement therapy for long-term smoking cessation: an observational study using the Clinical Practice Research Datalink. Health Technol Assess. 2020 Feb;24(9):1-46. doi: 10.3310/hta24090.

  PMID: 32079557 DERIVED

MeSH Terms

Conditions

Smoking Cessation; Cardiovascular Diseases; Respiration Disorders; Myocardial Infarction; Depression; Anxiety Disorders

Interventions

Varenicline; Nicotine Replacement Therapy

Condition Hierarchy (Ancestors)

Health Behavior; Behavior; Respiratory Tract Diseases; Myocardial Ischemia; Heart Diseases; Vascular Diseases; Infarction; Ischemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Necrosis; Behavioral Symptoms; Mental Disorders

Intervention Hierarchy (Ancestors)

Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Quinoxalines; Drug Therapy; Therapeutics

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr

Study Record Dates

• First Submitted: November 25, 2015
• First Posted: February 12, 2016
• Study Start: September 1, 2006
• Primary Completion: March 31, 2014
• Study Completion: September 30, 2019
• Last Updated: March 5, 2019

Record last verified: 2019-03