Abstract
Introduction
Safety warnings relating to antipsychotic-associated stroke among older persons in the UK and Italy were issued. However, the impact of these safety warnings on stroke risk has not been measured to date.
Objective
The aim of this study was to measure the change in stroke incidence after two safety warnings in both the UK and Italy.
Method
A cohort study was conducted using electronic medical records representative of the UK (The Health Improvement Network) and Italy (Health Search—IQVIA Health LPD), containing data on 11 million and 1 million patients, respectively. After each drug safety warning, elderly antipsychotic new initiators were propensity-score matched 1:1:1 on antipsychotic initiators before any safety warning. Stroke incidence within 6 months of antipsychotic initiation, using an intention-to-treat approach, was the main outcome.
Results
In the UK and Italy, 6342 and 7587 elderly antipsychotic initiators were identified, respectively. A 42% stroke incidence reduction was seen in the UK after the first safety warning [42.3 (95% confidence interval (CI) 35.2–50.8) vs. 24.4 [95% CI 19.0–31.2] events per 1000 person-years (PYs)], while there was a 60% stroke incidence reduction after the second warning (16.9 [95% CI 12.2–23.4] events per 1000 PYs) compared to before the first warning. There was no significant reduction in stroke incidence in Italy.
Conclusion
Antipsychotic safety warnings were followed by a reduction in stroke incidence among older antipsychotic users in the UK, but not Italy.
Similar content being viewed by others
References
Steinberg M, Shao H, Zandi P, Lyketsos CG, Welsh-Bohmer KA, Norton MC, Cache County Investigators, et al. Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache County Study. Int J Geriatr Psychiatry. 2008;23(2):170–7.
Janssen-Cilag Ltd. Risperdal 1 mg film-coated tablets. Summary of product characteristics. Last updated on 06/2015. http://www.medicines.org.uk/emc/medicine/30434. Cited 26 May 2018.
Ballard C, Howard R. Neuroleptic drugs in dementia: benefits and harm. Nat Rev Neurosci. 2006;7(6):492–500.
Medicines and Healthcare Products Regulatory Agency (MHRA). Message to healthcare professionals: atypical antipsychotic drugs and stroke; 2004. http://webarchive.nationalarchives.gov.uk/20141206131857/http://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con019488.pdf. Cited 8 June 2017.
Medicines and Healthcare Products Regulatory Agency (MHRA). Drug safety update; 2009. http://webarchive.nationalarchives.gov.uk/20141206164146/http:/www.mhra.gov.uk/home/groups/pl-p/documents/publication/con041213.pdf. Cited 26 May 2018.
Agenzia Italiana del Farmaco. Il trattamento farmacologico dei disturbi psicotici in pazienti affetti da demenza. http://www.agenziafarmaco.gov.it/content/il-trattamento-farmacologico-dei-disturbi-psicotici-pazienti-affetti-da-demenza. Cited 26 May 2018.
Agenzia Italiana del Farmaco. Il trattamento farmacologico dei disturbi psicotici nei pazienti affetti da demenza—secondo aggiornamento (08/05/2009). http://www.aifa.gov.it/content/il-trattamento-farmacologico-dei-disturbi-psicotici-nei-pazienti-affetti-da-demenza-%E2%80%93-second. Cited 26 May 2018.
Health and Social Care Information Centre. National Dementia and Antipsychotic Prescribing Audit National Summary Report. Published online: 17th July 2012. https://digital.nhs.uk/catalogue/PUB06624. Cited 26 May 2018.
Dementia Action Alliance. Dementia Action Alliance website. https://www.dementiaaction.org.uk/. Cited 26 May 2018.
Gallini A, Andrieu S, Donohue JM, Oumouhou N, Lapeyre-Mestre M, Gardette V. Trends in use of antipsychotics in elderly patients with dementia: impact of national safety warnings. Eur Neuropsychopharmacol. 2014;24(1):95–104.
Schulze J, van den Bussche H, Glaeske G, Kaduszkiewicz H, Wiese B, Hoffmann F. Impact of safety warnings on antipsychotic prescriptions in dementia: nothing has changed but the years and the substances. Eur Neuropsychopharmacol. 2013;23(9):1034–42.
Franchi C, Tettamanti M, Marengoni A, Bonometti F, Pasina L, Cortesi L, et al. Changes in trend of antipsychotics prescription in patients treated with cholinesterase inhibitors after warnings from Italian Medicines Agency. Results from the EPIFARM-Elderly Project. Eur Neuropsychopharmacol. 2012;22(8):569–77.
Guthrie B, Clark SA, Reynish EL, McCowan C, Morales DR. Differential impact of two risk communications on antipsychotic prescribing to people with dementia in Scotland: segmented regression time series analysis 2001–2011. PLoS One. 2013;8(7):e68976.
Sanfélix-Gimeno G, Cervera-Casino P, Peiró S, López-Valcarcel BG, Blázquez A, Barbera T. Effectiveness of safety warnings in atypical antipsychotic drugs: an interrupted time-series analysis in Spain. Drug Saf. 2009;32(11):1075–87.
Sultana J, Fontana A, Giorgianni F, Pasqua A, Cricelli C, Spina E, et al. The effect of safety warnings on antipsychotic drug prescribing in elderly persons with dementia in the United Kingdom and Italy: a population-based study. CNS Drugs. 2016;30(11):1097–109.
Cea Soriano L, Rothenbacher D, Choi HK, García Rodríguez LA. Contemporary epidemiology of gout in the UK general population. Arthritis Res Ther. 2011;13(2):R39.
Schneeweiss S, Setoguchi S, Brookhart A, Dormuth C, Wang PS. Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients. CMAJ. 2007;176(5):627–32.
Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA. 2005;294(15):1934–43.
Kleijer BC, van Marum RJ, Egberts AC, Jansen PA, Knol W, Heerdink ER. Risk of cerebrovascular events in elderly users of antipsychotics. J Psychopharmacol. 2009;23(8):909–14.
Rassen JA, Shelat AA, Franklin JM, Glynn RJ, Solomon DH, Schneeweiss S. Matching by propensity score in cohort studies with three treatment groups. Epidemiology. 2013;24(3):401–9.
Little RJ, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70:41–55.
Shin JY, Choi NK, Lee J, Seong JM, Park MJ, Lee SH, et al. Risk of ischemic stroke associated with the use of antipsychotic drugs in elderly patients: a retrospective cohort study in Korea. PLoS One. 2015;10(3):e0119931.
Goedecke T, Morales DR, Pacurariu A, Kurz X. Measuring the impact of medicines regulatory interventions—systematic review and methodological considerations. Br J Clin Pharmacol. 2017;84(3):419–33.
Douglas IJ, Smeeth L. Exposure to antipsychotics and risk of stroke: self controlled case series study. BMJ. 2008;28(337):a1227.
Lee S, Shafe AC, Cowie MR. UK stroke incidence, mortality and cardiovascular risk management 1999–2008: time-trend analysis from the General Practice Research Database. BMJ Open. 2011;1(2):e000269.
Prieto L, Spooner A, Hidalgo-Simon A, Rubino A, Kurz X, Arlett P. Evaluation of the effectiveness of risk minimization measures. Pharmacoepidemiol Drug Saf. 2012;21(8):896–9.
Trifiró G, Sultana J, Spina E. Are the safety profiles of antipsychotic drugs used in dementia the same? An updated review of observational studies. Drug Saf. 2014;37(7):501–20.
Guthrie B, Clark SA, Reynish EL, McCowan C, Morales DR. Differential impact of two risk communications on antipsychotic prescribing to people with dementia in Scotland: segmented regression time series analysis 2001–2011. PLoS One. 2013;8(7):e68976.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Janet Sultana, Andrea Fontana, Francesco Giorgianni, Silvia Tillati, Claudio Cricelli, Alessandro Pasqua, Elisabetta Patorno, Clive Ballard and Miriam Sturkenboom have no financial relationships with any organisations that might have had an interest in the submitted work over the previous 3 years, or no other relationships or activities that could appear to have influenced the submitted work. Over the last 3 years, Gianluca Trifirò has attended advisory boards on topics not related to this paper, organized by Sandoz, Hospira, Sanofi, Biogen, Ipsen and Shire, and is a consultant for Otsuka. He is principal investigator at the University of Messina of observational studies funded by several pharmaceutical companies (Amgen, AstraZeneca, Daiichi Sankyo, IBSA), as well as scientific coordinator of the Masters program ‘Pharmacovigilance, Pharmacoepidemiology and Pharmacoeconomics: Real-World Data Evaluations’ at the University of Messina, for which he receives unconditional funding from several pharmaceutical companies, including Takeda, Teva, Almirall, Shire, Novartis, Roche, Otsuka and Zambon.
Funding
This work was supported by a grant from the Italian Health Ministry held by Gianluca Trifiro’: [GR-2009-607316—Assessment of the Safety of Antipsychotic Drugs in Elderly with Dementia: An International, Population-Based Study Using Healthcare Databases. The funder played no role in study design, data collection, analysis and interpretation of data, in the writing of the report and in the decision to submit the article for publication.
Ethical approval
The use of THIN database was approved by the Cegidim Scientific Review Committee (SRC 13-085). Use of the Health Search—IQVIA Health LPD database was notified to the Ethics Committee of the University Hospital G. Martino of Messina. In Italy, full ethics approval is not required for retrospective observational studies with anonymised data. The authors declare that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.
Data sharing
The data that support the findings of this study are available from third parties, i.e. the Erasmus Medical Centre for THIN and the Italian Society of General Practitioners/IQVIA for Health Search—IQVIA Health LPD. However, restrictions apply to the availability of these data, which were used under license for the current study and are therefore not publicly available. However, data are available from the authors upon reasonable request and with permission of the Erasmus Medical Centre and the Italian Society of General Practitioners/IQVIA.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Sultana, J., Fontana, A., Giorgianni, F. et al. Measuring the Effectiveness of Safety Warnings on the Risk of Stroke in Older Antipsychotic Users: A Nationwide Cohort Study in Two Large Electronic Medical Records Databases in the United Kingdom and Italy. Drug Saf 42, 1471–1485 (2019). https://doi.org/10.1007/s40264-019-00860-z
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40264-019-00860-z