title: Cardiovascular and neuropsychiatric safety of varenicline and bupropion compared with nicotine replacement therapy for smoking cessation: study protocol of a retrospective cohort study using the QResearch general practice database.
abstract: BACKGROUND
  Cigarette smoking continues to be the leading cause of preventable death and is the main risk factor of major diseases such as chronic obstructive pulmonary disease (COPD). The best treatment to help smokers quit is a combination of behavioural support with pharmacotherapy. Varenicline is the newest drug on the market and has been shown to be effective in the general smoking population and in smokers with COPD. The safety profile of varenicline was initially established using standard approaches to pharmacovigilance, but postmarketing reports have raised concerns about a possible association between the use of varenicline and cardiovascular and neuropsychiatric events. Although recent studies have not confirmed such an association, further research is needed given the large number of smokers who are being prescribed varenicline, including important subgroups such as smokers with COPD who may be particularly vulnerable to side effects of drugs. The aim of this study is to assess the cardiovascular and neuropsychiatric safety of varenicline using data from the QResearch general practice (GP) database.
  
  
  METHODS
  We will conduct a retrospective cohort study in the QResearch GP database. Patients will be categorised into three exposure groups: prescription of (1) varenicline, (2) bupropion or (3) nicotine replacement therapy (NRT Rx; =reference group). We will separately consider major incident neuropsychiatric and cardiovascular outcomes that occur during 6 months of follow-up using Cox proportional hazards models, adjusted for confounders. Furthermore, propensity score analysis will be used as an analytical approach to account for potential confounding by indication.
  
  
  BACKGROUND
  This work involves analysis of anonymised, routinely collected data. The protocol has been independently peer-reviewed by the QResearch Scientific Board and meets the requirements of the Trent research ethics committee. We plan to disseminate the results from this study via articles in international peer-reviewed journals and presentations at relevant national and international health conferences.
authors.affiliation: Department of Family Medicine, CAPHRI School for Public Health and Primary Care, Maastricht University Medical Centre, Maastricht, The Netherlands Cancer Research UK Health Behaviour Research Centre, University College London, London, UK Allergy and Respiratory Research Group, Centre for Population Health Sciences, The University of Edinburgh, Edinburgh, UK.
authors.forename: Daniel
authors.identifier: http://orcid.org/0000-0002-9454-023X
authors.initials: D
authors.lastname: Kotz
authors.affiliation: Allergy and Respiratory Research Group, Centre for Population Health Sciences, The University of Edinburgh, Edinburgh, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Simpson
authors.affiliation: MHeNS School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Viechtbauer
authors.affiliation: Department of Family Medicine, CAPHRI School for Public Health and Primary Care, Maastricht University Medical Centre, Maastricht, The Netherlands Allergy and Respiratory Research Group, Centre for Population Health Sciences, The University of Edinburgh, Edinburgh, UK.
authors.forename: Onno C P
authors.initials: OC
authors.lastname: van Schayck
authors.affiliation: Cancer Research UK Health Behaviour Research Centre, University College London, London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: West
authors.affiliation: Department of Family Medicine, CAPHRI School for Public Health and Primary Care, Maastricht University Medical Centre, Maastricht, The Netherlands Allergy and Respiratory Research Group, Centre for Population Health Sciences, The University of Edinburgh, Edinburgh, UK Division of General Internal Medicine and Primary Care, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Aziz
authors.initials: A
authors.lastname: Sheikh
mesh_terms: D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage* / Q000009:adverse effects; D001552:Benzazepines / Q000008:administration & dosage* / Q000009:adverse effects; D016642:Bupropion / Q000008:administration & dosage* / Q000009:adverse effects; D015331:Cohort Studies; D058006:General Practice; D006801:Humans; D018722:Nicotinic Agonists / Q000008:administration & dosage* / Q000009:adverse effects; D011810:Quinoxalines / Q000008:administration & dosage* / Q000009:adverse effects; D012189:Retrospective Studies; D012907:Smoking / Q000188:drug therapy / Q000453:epidemiology; D016540:Smoking Cessation / Q000379:methods*; D000074606:Smoking Prevention; D061485:Tobacco Use Cessation Devices; D016896:Treatment Outcome; D006113:United Kingdom / Q000453:epidemiology; D000068580:Varenicline
chemical_list: D018687:Antidepressive Agents, Second-Generation; D001552:Benzazepines; D018722:Nicotinic Agonists; D011810:Quinoxalines; D016642:Bupropion; D000068580:Varenicline
keywords: Epidemiology; Mental Health