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Given their widespread use, monitoring adverse risks remains important. This study aimed to estimate the neuropsychiatric and cardiovascular risks associated with varenicline and NRT as used in routine UK care.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>Case\u2013cross\u2010over study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Setting<\/jats:title><jats:p>UK\u2010based electronic primary care records in the Clinical Practice Research Datalink from 2006 to 2015 linked to hospital and mortality data sets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Participants<\/jats:title><jats:p>Adult smokers (<jats:italic>n<\/jats:italic>\u00a0=282,429) observed during periods when exposed and not exposed to either varenicline or NRT.<\/jats:p><\/jats:sec><jats:sec><jats:title>Measurements<\/jats:title><jats:p>Main outcomes included suicide, self\u2010harm, myocardial infarction (MI), all\u2010cause death and cause\u2010specific death [MI, chronic obstructive pulmonary disease (COPD)]. In primary analyses, conditional logistic regression was used to compare the chance of varenicline or NRT exposure during the risk period (90\u00a0days prior to the event) with the chance of exposure during an earlier single reference period (91\u2013180\u00a0days prior to the event) or multiple 90\u2010day reference periods to increase statistical power.<\/jats:p><\/jats:sec><jats:sec><jats:title>Findings<\/jats:title><jats:p>In the primary analyses, findings were inconclusive for the associations between varenicline and the main outcomes using a single reference period, while NRT was associated with MI [odds ratio (OR)\u00a0=\u00a01.40, 95% confidence interval (CI)\u00a0=\u00a01.18\u20131.67]. Using multiple reference periods, varenicline was associated with an increased risk of self\u2010harm (OR\u00a0=\u00a01.32, 95% CI\u00a0=\u00a01.12\u20131.56) and suicide (OR\u00a0=\u00a03.56, 95% CI\u00a0=\u00a01.32\u20139.60) but a reduction in all\u2010cause death (OR\u00a0=\u00a00.75, 95% CI\u00a0=\u00a00.61\u20130.93). NRT was associated with MI (OR\u00a0=\u00a01.54, 95% CI\u00a0=\u00a01.36\u20131.74), self\u2010harm (OR\u00a0=\u00a01.30, 95% CI\u00a0=\u00a01.18\u20131.44) and deaths from MI (OR\u00a0=\u00a01.53, 95% CI\u00a0=\u00a01.11\u20132.10), COPD (OR\u00a0=\u00a01.33, 95% CI\u00a0=\u00a01.14\u20131.56) and all causes (OR\u00a0=\u00a01.28, 95% CI\u00a0=\u00a01.18\u20131.40) when using multiple reference periods.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>There appear to be positive associations between (1) nicotine replacement therapy (NRT) and myocardial infarction, death and risk of self\u2010harm and (2) varenicline and increased risk of self\u2010harm and suicide, as well as a negative association between varenicline and all\u2010cause death. The associations may not be causal. They may reflect health changes at the time of smoking cessation (nicotine replacement therapy is prescribed for people with cardiac problems) or be associated with quit attempts (exposure to both medicines was associated with self\u2010harm).<\/jats:p><\/jats:sec>","DOI":"10.1111\/add.15338","type":"journal-article","created":{"date-parts":[[2020,11,16]],"date-time":"2020-11-16T17:12:58Z","timestamp":1605546778000},"page":"1532-1545","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Risk of neuropsychiatric and cardiovascular adverse events following treatment with varenicline and nicotine replacement therapy in the UK Clinical Practice Research Datalink: a case\u2013cross\u2010over study"],"prefix":"10.1111","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5418-4034","authenticated-orcid":false,"given":"Kyla H.","family":"Thomas","sequence":"first","affiliation":[{"name":"Bristol Medical School, Population Health Sciences University of Bristol  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2460-0508","authenticated-orcid":false,"given":"Neil M.","family":"Davies","sequence":"additional","affiliation":[{"name":"Bristol Medical School, Population Health Sciences University of Bristol  Bristol UK"},{"name":"Medical Research Council Integrative Epidemiology Unit University of Bristol  Bristol UK"},{"name":"K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU Norwegian University of Science and Technology  Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1853-0563","authenticated-orcid":false,"given":"Amy E.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Bristol Medical School, Population Health Sciences University of Bristol  Bristol UK"},{"name":"National Institute for Health Research, Bristol Biomedical Research Centre University Hospitals Bristol NHS Foundation Trust and University of Bristol  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2185-0162","authenticated-orcid":false,"given":"Gemma M. J.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Addiction and Mental Health Group (AIM), Department of Psychology University of Bath  Bath UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Gunnell","sequence":"additional","affiliation":[{"name":"Bristol Medical School, Population Health Sciences University of Bristol  Bristol UK"},{"name":"National Institute for Health Research, Bristol Biomedical Research Centre University Hospitals Bristol NHS Foundation Trust and University of Bristol  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard M.","family":"Martin","sequence":"additional","affiliation":[{"name":"Bristol Medical School, Population Health Sciences University of Bristol  Bristol UK"},{"name":"Medical Research Council Integrative Epidemiology Unit University of Bristol  Bristol UK"},{"name":"National Institute for Health Research, Bristol Biomedical Research Centre University Hospitals Bristol NHS Foundation Trust and University of Bristol  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Douglas","sequence":"additional","affiliation":[{"name":"Department of Non\u2010communicable Disease Epidemiology, Faculty of Epidemiology and Population Health LSHTM  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,12,14]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.321.7257.323"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1308383"},{"key":"e_1_2_9_4_1","unstructured":"Health and Social Care Information Centre.Statistics on smoking: England 2016. Leeds UK: Health and Social Care Information Centre;2016."},{"key":"e_1_2_9_5_1","article-title":"Pharmacological interventions for smoking cessation: an overview and network meta\u2010analysis","author":"Cahill K.","year":"2013","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyx109"},{"key":"e_1_2_9_7_1","unstructured":"US Food and Drug Administration.Information for healthcare professionals: Varenicline (marketed as Chantix) and bupropion (marketed as Zyban Wellbutrin and generics). FDA Drug Safety Newsletter [internet]2009; 2. Available at:https:\/\/wayback.archive\u2010it.org\/7993\/20170112005513\/http:\/\/www.fda.gov\/Drugs\/DrugSafety\/PostmarketDrugSafetyInformationforPatientsandProviders\/ucm169988.htm(accessed 18 March 2020)."},{"key":"e_1_2_9_8_1","unstructured":"US Food and Drug Administration.FDA drug safety communication: safety review update of Chantix (varenicline) and risk of cardiovascular adverse events. Drug Safety and Availability [internet]2012. Available at:https:\/\/www.fda.gov\/drugs\/drug-safety-and-availability\/fda-drug-safety-communication\u2010safety\u2010review\u2010update\u2010chantix\u2010varenicline\u2010and\u2010risk\u2010cardiovascular(accessed 18 March 2020)."},{"key":"e_1_2_9_9_1","unstructured":"US Food and Drug Administration.FDA drug safety communication: FDA revises description of mental health side effects of the stop\u2010smoking medicines Chantix (varenicline) and Zyban (bupropion) to reflect clinical trial findings. Drug Safety and Availability [internet]2016. Available at:https:\/\/www.fda.gov\/drugs\/drug-safety-and-availability\/fda-drug-safety-communication-fda\u2010revises\u2010description\u2010mental\u2010health\u2010side\u2010effects\u2010stop\u2010smoking(acessed 18 March 2020)."},{"key":"e_1_2_9_10_1","unstructured":"MacKenzieR.Champix's effectiveness is questionable and safety record is concerning. The Conversation [internet].2017. 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