Drug Safety

, Volume 42, Issue 12, pp 1471–1485 | Cite as

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

  • Janet Sultana
  • Andrea Fontana
  • Francesco Giorgianni
  • Silvia Tillati
  • Claudio Cricelli
  • Alessandro Pasqua
  • Elisabetta Patorno
  • Clive Ballard
  • Miriam Sturkenboom
  • Gianluca TrifiròEmail author
Original Research Article



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.


The aim of this study was to measure the change in stroke incidence after two safety warnings in both the UK and Italy.


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.


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.


Antipsychotic safety warnings were followed by a reduction in stroke incidence among older antipsychotic users in the UK, but not Italy.


Compliance with Ethical Standards

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.


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.

Supplementary material

40264_2019_860_MOESM1_ESM.pdf (378 kb)
Supplementary material 1 (PDF 377 kb)
40264_2019_860_MOESM2_ESM.pdf (324 kb)
Supplementary material 2 (PDF 323 kb)
40264_2019_860_MOESM3_ESM.pdf (583 kb)
Supplementary material 3 (PDF 583 kb)
40264_2019_860_MOESM4_ESM.pdf (354 kb)
Supplementary material 4 (PDF 354 kb)


  1. 1.
    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.CrossRefGoogle Scholar
  2. 2.
    Janssen-Cilag Ltd. Risperdal 1 mg film-coated tablets. Summary of product characteristics. Last updated on 06/2015. Cited 26 May 2018.
  3. 3.
    Ballard C, Howard R. Neuroleptic drugs in dementia: benefits and harm. Nat Rev Neurosci. 2006;7(6):492–500.CrossRefGoogle Scholar
  4. 4.
    Medicines and Healthcare Products Regulatory Agency (MHRA). Message to healthcare professionals: atypical antipsychotic drugs and stroke; 2004. Cited 8 June 2017.
  5. 5.
    Medicines and Healthcare Products Regulatory Agency (MHRA). Drug safety update; 2009. Cited 26 May 2018.
  6. 6.
    Agenzia Italiana del Farmaco. Il trattamento farmacologico dei disturbi psicotici in pazienti affetti da demenza. Cited 26 May 2018.
  7. 7.
    Agenzia Italiana del Farmaco. Il trattamento farmacologico dei disturbi psicotici nei pazienti affetti da demenza—secondo aggiornamento (08/05/2009). Cited 26 May 2018.
  8. 8.
    Health and Social Care Information Centre. National Dementia and Antipsychotic Prescribing Audit National Summary Report. Published online: 17th July 2012. Cited 26 May 2018.
  9. 9.
    Dementia Action Alliance. Dementia Action Alliance website. Cited 26 May 2018.
  10. 10.
    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.CrossRefGoogle Scholar
  11. 11.
    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.CrossRefGoogle Scholar
  12. 12.
    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.CrossRefGoogle Scholar
  13. 13.
    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.CrossRefGoogle Scholar
  14. 14.
    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.CrossRefGoogle Scholar
  15. 15.
    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.CrossRefGoogle Scholar
  16. 16.
    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.CrossRefGoogle Scholar
  17. 17.
    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.CrossRefGoogle Scholar
  18. 18.
    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.CrossRefGoogle Scholar
  19. 19.
    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.CrossRefGoogle Scholar
  20. 20.
    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.CrossRefGoogle Scholar
  21. 21.
    Little RJ, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70:41–55.CrossRefGoogle Scholar
  22. 22.
    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.CrossRefGoogle Scholar
  23. 23.
    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.CrossRefGoogle Scholar
  24. 24.
    Douglas IJ, Smeeth L. Exposure to antipsychotics and risk of stroke: self controlled case series study. BMJ. 2008;28(337):a1227.CrossRefGoogle Scholar
  25. 25.
    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.PubMedPubMedCentralGoogle Scholar
  26. 26.
    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.CrossRefGoogle Scholar
  27. 27.
    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.CrossRefGoogle Scholar
  28. 28.
    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.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Janet Sultana
    • 1
    • 2
  • Andrea Fontana
    • 3
  • Francesco Giorgianni
    • 1
  • Silvia Tillati
    • 1
  • Claudio Cricelli
    • 4
  • Alessandro Pasqua
    • 4
  • Elisabetta Patorno
    • 5
  • Clive Ballard
    • 6
  • Miriam Sturkenboom
    • 7
  • Gianluca Trifirò
    • 1
    • 2
    Email author
  1. 1.Department of Biomedical and Dental Sciences and Morpho-Functional ImagingUniversity of MessinaMessinaItaly
  2. 2.Department of Medical InformaticsErasmus Medical Centre, RotterdamRotterdamThe Netherlands
  3. 3.Fondazione IRCCS Casa Sollievo della Sofferenza, Unit of BiostatisticsSan Giovanni RotondoItaly
  4. 4.Health SearchItalian College of General PractitionersFlorenceItaly
  5. 5.Division of Pharmacoepidemiology and Pharmacoeconomics, Department of MedicineBrigham and Women’s HospitalBostonUSA
  6. 6.University of Exeter Medical SchoolExeterUK
  7. 7.Julius Centre for Global Health, Utrecht University Medical CentreUtrechtThe Netherlands

Personalised recommendations