{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T07:57:56Z","timestamp":1765612676215,"version":"3.48.0"},"reference-count":55,"publisher":"BMJ","issue":"8","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2014,7,17]]},"published-print":{"date-parts":[[2014,8]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>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\u2005months 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2014-005281","type":"journal-article","created":{"date-parts":[[2014,8,29]],"date-time":"2014-08-29T00:48:00Z","timestamp":1409273280000},"page":"e005281","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"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"],"prefix":"10.1136","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9454-023X","authenticated-orcid":false,"given":"Daniel","family":"Kotz","sequence":"first","affiliation":[{"name":"Department of Family Medicine, CAPHRI School for Public Health and Primary Care, Maastricht University Medical Centre, Maastricht, The Netherlands"},{"name":"Cancer Research UK Health Behaviour Research Centre, University College London, London, UK"},{"name":"Allergy and Respiratory Research Group, Centre for Population Health Sciences, The University of Edinburgh, Edinburgh, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colin","family":"Simpson","sequence":"additional","affiliation":[{"name":"Allergy and Respiratory Research Group, Centre for Population Health Sciences, The University of Edinburgh, Edinburgh, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang","family":"Viechtbauer","sequence":"additional","affiliation":[{"name":"MHeNS School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Onno C P","family":"van Schayck","sequence":"additional","affiliation":[{"name":"Department of Family Medicine, CAPHRI School for Public Health and Primary Care, Maastricht University Medical Centre, Maastricht, The Netherlands"},{"name":"Allergy and Respiratory Research Group, Centre for Population Health Sciences, The University of Edinburgh, Edinburgh, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"West","sequence":"additional","affiliation":[{"name":"Cancer Research UK Health Behaviour Research Centre, University College London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aziz","family":"Sheikh","sequence":"additional","affiliation":[{"name":"Department of Family Medicine, CAPHRI School for Public Health and Primary Care, Maastricht University Medical Centre, Maastricht, The Netherlands"},{"name":"Allergy and Respiratory Research Group, Centre for Population Health Sciences, The University of Edinburgh, Edinburgh, UK"},{"name":"Division of General Internal Medicine and Primary Care, Brigham and Women's Hospital\/Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2014,8,28]]},"reference":[{"key":"2025121223550034000_4.8.e005281.1","unstructured":"World Health Organisation (WHO). WHO report on the global tobacco epidemic. Warning about the dangers of tobacco. Geneva, 2011."},{"key":"2025121223550034000_4.8.e005281.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMsa1211128"},{"key":"2025121223550034000_4.8.e005281.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMsa1211127"},{"key":"2025121223550034000_4.8.e005281.4","unstructured":"World Health Organisation (WHO). Global burden of disease. http:\/\/www.who.int\/mediacentre\/factsheets\/fs310\/en\/index.html (accessed 24 Apr 2012). Secondary Global burden of disease. http:\/\/www.who.int\/mediacentre\/factsheets\/fs310\/en\/index.html (accessed 24 Apr 2012)."},{"key":"2025121223550034000_4.8.e005281.5","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200811-1757ST"},{"key":"2025121223550034000_4.8.e005281.6","unstructured":"Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic pulmonary disease. Revised 2011. http:\/\/www.goldcopd.com (accessed 24 Apr 2012). Secondary Global strategy for the diagnosis, management, and prevention of chronic pulmonary disease. Revised 2011. http:\/\/www.goldcopd.com (accessed 24 Apr 2012)."},{"issue":"(Suppl 2)","key":"2025121223550034000_4.8.e005281.7","first-page":"ii7","article-title":"Smoking cessation: effects on symptoms, spirometry and future trends in COPD","volume":"56","author":"Pride","year":"2001","journal-title":"Thorax"},{"key":"2025121223550034000_4.8.e005281.8","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00060806"},{"key":"2025121223550034000_4.8.e005281.9","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2006.064410"},{"key":"2025121223550034000_4.8.e005281.10","doi-asserted-by":"publisher","DOI":"10.3399\/bjgp10X514729"},{"key":"2025121223550034000_4.8.e005281.11","unstructured":"National Institute for Health and Clinical Excellence (NICE). Smoking cessation services in primary care, pharmacies, local authorities and workplaces, particularly for manual working groups, pregnant women and hard to reach communities. London, 2008."},{"key":"2025121223550034000_4.8.e005281.12","unstructured":"National Institute for Health and Clinical Excellence. NICE technology appraisal guidance 123. Varenicline for smoking cessation. London, 2007."},{"key":"2025121223550034000_4.8.e005281.13","first-page":"CD006103","article-title":"Nicotine receptor partial agonists for smoking cessation","volume":"(4","author":"Cahill","year":"2012","journal-title":"Cochrane Database Syst Rev"},{"key":"2025121223550034000_4.8.e005281.14","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2007.090647"},{"key":"2025121223550034000_4.8.e005281.15","doi-asserted-by":"publisher","DOI":"10.1378\/chest.10-0865"},{"key":"2025121223550034000_4.8.e005281.16","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00014012"},{"key":"2025121223550034000_4.8.e005281.17","doi-asserted-by":"publisher","DOI":"10.1093\/ntr\/ntr075"},{"key":"2025121223550034000_4.8.e005281.18","doi-asserted-by":"publisher","DOI":"10.1503\/cmaj.110218"},{"key":"2025121223550034000_4.8.e005281.19","doi-asserted-by":"publisher","DOI":"10.2165\/11597690-000000000-00000"},{"key":"2025121223550034000_4.8.e005281.20","doi-asserted-by":"publisher","DOI":"10.1192\/bjp.179.5.432"},{"key":"2025121223550034000_4.8.e005281.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2008.06.003"},{"key":"2025121223550034000_4.8.e005281.22","unstructured":"European Medicines Agency. European Medicines Agency concludes new advice to doctors and patients for Champix needed. EMEA press office, 14 December 2007."},{"key":"2025121223550034000_4.8.e005281.23","unstructured":"US Food and Drug Administration. Varenicline (marketed as Chantix) Information. FDA ALERT [2\/1\/2008]. US Food and Drug Administration, 2 January 2008."},{"key":"2025121223550034000_4.8.e005281.24","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.b3805"},{"key":"2025121223550034000_4.8.e005281.25","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.e7176"},{"key":"2025121223550034000_4.8.e005281.26","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.e2856"},{"key":"2025121223550034000_4.8.e005281.27","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1111\/add.12165","article-title":"Use of varenicline versus bupropion and risk of psychiatric adverse events","volume":"108","author":"Pasternak","year":"2013","journal-title":"Addiction"},{"key":"2025121223550034000_4.8.e005281.28","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.f5704"},{"key":"2025121223550034000_4.8.e005281.29","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.e7176"},{"key":"2025121223550034000_4.8.e005281.30","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1007\/s40264-013-0046-6","article-title":"Neuropsychiatric events with varenicline: a modified prescription-event monitoring study in general practice in England","volume":"36","author":"Buggy","year":"2013","journal-title":"Drug Saf"},{"key":"2025121223550034000_4.8.e005281.31","doi-asserted-by":"publisher","DOI":"10.1111\/j.1360-0443.2012.04024.x"},{"key":"2025121223550034000_4.8.e005281.32","doi-asserted-by":"publisher","DOI":"10.1378\/chest.128.4.2099"},{"key":"2025121223550034000_4.8.e005281.33","doi-asserted-by":"publisher","DOI":"10.1586\/14737167.2.4.367"},{"key":"2025121223550034000_4.8.e005281.34","doi-asserted-by":"publisher","DOI":"10.1093\/ntr\/nts002"},{"key":"2025121223550034000_4.8.e005281.35","doi-asserted-by":"publisher","DOI":"10.1136\/tc.2004.009183"},{"key":"2025121223550034000_4.8.e005281.36","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2007.078758"},{"key":"2025121223550034000_4.8.e005281.37","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.316.7146.1714"},{"key":"2025121223550034000_4.8.e005281.38","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.39261.471806.55"},{"key":"2025121223550034000_4.8.e005281.39","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.330.7499.1059"},{"key":"2025121223550034000_4.8.e005281.40","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.330.7504.1366"},{"key":"2025121223550034000_4.8.e005281.41","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.f2573"},{"key":"2025121223550034000_4.8.e005281.42","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2014-004952"},{"key":"2025121223550034000_4.8.e005281.43","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.f114"},{"key":"2025121223550034000_4.8.e005281.44","doi-asserted-by":"crossref","unstructured":"Collins GS Altman DG . An independent and external validation of QRISK2 cardiovascular disease risk score: a prospective open cohort study. BMJ 2010:c2442.","DOI":"10.1136\/bmj.c2442"},{"key":"2025121223550034000_4.8.e005281.45","doi-asserted-by":"publisher","DOI":"10.1136\/thx.54.7.581"},{"key":"2025121223550034000_4.8.e005281.46","unstructured":"Townsend P Phillimore P Beattie A . Health and deprivation: inequality and the North. London: Croom Helm, 1988."},{"key":"2025121223550034000_4.8.e005281.47","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2296-11-1"},{"key":"2025121223550034000_4.8.e005281.48","doi-asserted-by":"publisher","DOI":"10.1002\/sim.4780010204"},{"key":"2025121223550034000_4.8.e005281.49","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.jclinepi.2005.07.004","article-title":"A review of the application of propensity score methods yielded increasing use, advantages in specific settings, but not substantially different estimates compared with conventional multivariable methods","volume":"59","author":"St\u00fcrmer","year":"2006","journal-title":"J Clin Epidemiol"},{"key":"2025121223550034000_4.8.e005281.50","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwq198"},{"key":"2025121223550034000_4.8.e005281.51","doi-asserted-by":"publisher","DOI":"10.1002\/bimj.200810488"},{"key":"2025121223550034000_4.8.e005281.52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v042.i08","article-title":"MatchIt: Nonparametric preprocessing for parametric causal inference","volume":"42","author":"Ho","year":"2011","journal-title":"J Stat Software"},{"key":"2025121223550034000_4.8.e005281.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2008.12.005"},{"key":"2025121223550034000_4.8.e005281.54","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2010.09.006"},{"key":"2025121223550034000_4.8.e005281.55","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2007.11.008"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2014-005281","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T07:55:08Z","timestamp":1765612508000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2014-005281"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,8]]},"references-count":55,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2014,8,28]]},"published-print":{"date-parts":[[2014,8]]}},"alternative-id":["10.1136\/bmjopen-2014-005281"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2014-005281","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"type":"print","value":"2044-6055"},{"type":"electronic","value":"2044-6055"}],"subject":[],"published":{"date-parts":[[2014,8]]}}}