Antipsychotic drug use and risk of stroke and myocardial infarction: a systematic review and meta-analysis

Zivkovic et al. BMC Psychiatry (2019) 19:189 https://doi.org/10.1186/s12888-019-2177-5 RESEARCH ARTICLE Open Access Antipsychotic drug use and risk of stroke and myocardial infarction: a systematic review and meta-analysis Sanja Zivkovic1, Chan Hee Koh2†, Nandita Kaza2† and Caroline A. Jackson1* Abstract Background: The effect of antipsychotic (AP) drugs on risk of stroke and myocardial infarction (MI) remains unclear due to methodological limitations of, and inconsistencies across, existing studies. We aimed to systematically review studies reporting on the associations between AP drug use and stroke or MI risk, and to investigate whether associations differed among different sub-populations. Methods: We searched Medline, EMBASE, PsychINFO and Cochrane Library (from inception to May 28, 2017) for observational studies reporting on AP drug use and MI or stroke occurrence. We performed random-effects metaanalyses for each outcome, performing sub-groups analyses by study population – specifically general population (i.e. those not restricted to patients with a particular indication for AP drug use), people with dementia only and psychiatric illness only. Where feasible we performed subgroup analyses by AP drug class. Results: From 7008 articles, we included 29 relevant observational studies, 19 on stroke and 10 on MI. Results of cohort studies that included a general population indicated a more than two-fold increased risk of stroke, albeit with substantial heterogeneity (pooled HR 2.31, 95% CI 1.13, 4.74, I2 = 83.2%). However, the risk among patients with dementia was much lower, with no heterogeneity (pooled HR 1.16, 95% CI 1.00, 1.33, I2 = 0%) and there was no clear association among studies of psychiatric populations (pooled HR 1.44, 95% CI 0.90, 2.30; substantial heterogeneity [I2 = 78.8])). Associations generally persisted when stratifying by AP class, but few studies reported on first generation AP drugs. We found no association between AP drug use and MI risk (pooled HR for cohort studies: 1.29, 95% CI 0.88, 1.90 and case-control studies: 1.07, 95% CI 0.94, 1.23), but substantial methodological and statistical heterogeneity among a relatively small number of studies limits firm conclusions. Conclusions: AP drug use may be associated with an increased risk of stroke, but there is no clear evidence that this risk is further elevated in patients with dementia. Further studies are need to clarify the effect of AP drug use on MI and stroke risk in different sub-populations and should control for confounding by indication and stratify by AP drug class. Keywords: Antipsychotics, Myocardial infarction, Stroke, Dementia, Meta-analyses * Correspondence: Chan Hee Koh and Nandita Kaza are joint second authorship 1 Usher Institute of Population Health Sciences & Informatics, University of Edinburgh, Nine Bioquarter, 9 Little France Road, Edinburgh EH16 4UX, Scotland Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zivkovic et al. BMC Psychiatry (2019) 19:189 Background Major mental disorders represent a growing and, until relatively recently, under-recognized global public health burden. Schizophrenia, bipolar disorder, major depression and anxiety feature among the top 20 causes of years lived with disability (YLD) [1] and are associated with marked premature mortality [2–4]. Much of this excess mortality is due to a higher burden of cardiovascular and cerebrovascular disease (largely ischaemic heart disease and stroke) compared to the general population [5–7]. Several factors related to mental illness, including low socioeconomic status, lifestyle, physical comorbidities, genetic predisposition and healthcare access [7–9] could contribute to increased cardio- and cerebrovascular disease incidence in this vulnerable group. Prescription medication, including antipsychotic (AP) drug use, has also been raised as a possible cardiovascular and cerebrovascular disease risk factor, potentially operating through effects on body weight, metabolic factors and thrombosis [10]. Despite their potential to increase risk of circulatory disease, AP drugs are also being increasingly used offlabel, for the treatment of dementia, anxiety, insomnia and post-traumatic stress [11], with little understanding of the long-term side-effects, including risks of major cardiovascular events such as myocardial infarction and stroke. Their increased use in patients with dementia is particularly concerning, with around 20% of patients with dementia in nursing homes in the USA and UK treated with APs [12, 13]. Use of these drugs in this population has been linked to increased risk of stroke as well as other adverse outcomes, including increased mortality [14] and thus regulatory bodies have discouraged the use of AP drug use in people with dementia [15]. However, the evidence for increased stroke risk is based largely on analyses of serious adverse events in randomized controlled trials of AP drugs in patients with dementia [10, 16, 17]. Confirmation of the appropriateness of these attached warnings to AP drug use is important, given that pharmacological alternatives for the treatment of behavioral and psychological symptoms of dementia are quite limited [18]. A number of observational studies have reported on the association between AP use and stroke risk, but until very recently these had not been systematically reviewed. Since commencing the present review, one systematic review and meta-analysis has been published which concluded that first generation, but not second-generation AP drug use was associated with an increased risk of cerebrovascular disease. The authors also reported that among those with dementia in particular, use of any AP was associated with a low risk of cerebrovascular disease [19]. However, this study identified almost half as many studies as in the present review, thus omitting relevant additional studies on this topic. Earlier reviews focused on summarizing the Page 2 of 14 effects of AP drug use specifically in the elderly or those with dementia [10, 20], the most recent of which suggests that AP drug use may be associated with an increased risk of stroke in this population [20]. Existing systematic reviews on the association between AP drug use and risk of myocardial infarction (MI) are conflicting. The first review concluded that the evidence for (...truncated)