Skip to main content
SpringerLink
Log in

Antipsychotic Drug Exposure and Risk of Venous Thromboembolism: A Systematic Review and Meta-Analysis of Observational Studies

  • Systematic Review
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Background

Venous thromboembolism (VTE) is a serious disorder that may be complicated by pulmonary embolism (PE). Case reports and observational studies published in the early 1950s suggested that antipsychotic (AP) drugs may represent a risk factor, while observational studies conducted in the last 3 decades have provided conflicting results.

Objective

The aim was to investigate whether AP drugs increase the risk of VTE and PE, and to ascertain the risk associated with first- and second-generation AP drugs and with exposure to individual drugs.

Data Source

Relevant studies were located by searching MEDLINE, PubMed, EMBASE, PsychINFO, CINAHL and Scopus up to March 2013. Reference lists of relevant papers and previous review articles were hand searched for other relevant studies.

Study Selection

Based on the titles and abstracts of 1,386 citations, we identified 30 potentially relevant studies. Of these, 17 studies were eligible for inclusion and were included in the meta-analysis.

Main Outcomes and Measures

The primary outcome measure of this meta-analysis was the occurrence of VTE or PE in individuals exposed to AP drugs in comparison with individuals unexposed or with past exposure to AP drugs.

Results

Antipsychotic exposure was associated with a significant increase in risk of developing VTE [odds ratio (OR) 1.54, 95 % confidence interval (CI) 1.28–1.86, 11 studies]. Exposure to APs did not significantly increase the risk of PE (OR 4.90, 95 % CI 0.77–30.98, three studies), but the overall estimate was highly heterogeneous and the CI included the possibility of substantial harm. Random-effects meta-analysis on the risk of VTE associated with exposure to first- (OR 1.74, 95 % CI 1.28–2.37, six studies) and second-generation (OR 2.07, 95 % CI 1.74–2.52, five studies) APs revealed an increased risk. Only a few studies provided data on individual drugs, and estimates of effect were very uncertain.

Conclusions

Antipsychotic exposure in unselected patient populations may be associated with a 50 % increase in the risk of developing VTE. However, between-study heterogeneity limits the confidence in this estimate. This increased risk similarly applies to first- and second-generation AP drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Kyrle PA, Eichinger S. Deep vein thrombosis. Lancet. 2005;365:1163–74.

    Article  PubMed  Google Scholar 

  2. Zamagni E, Brioli A, Tacchetti P, Zannetti B, Pantani L, Cavo M. Multiple myeloma, venous thromboembolism, and treatment-related risk of thrombosis. Semin Thromb Hemost. 2011;37:209–19.

    Article  PubMed  Google Scholar 

  3. O’Connor DJ, Scher LA, Gargiulo NJ III, Jang J, Suggs WD, Lipsitz EC. Incidence and characteristics of venous thromboembolic disease during pregnancy and the postnatal period: a contemporary series. Ann Vasc Surg. 2011;25:9–14.

    Article  PubMed  Google Scholar 

  4. Baron JA, Gridley G, Weiderpass E, Nyren O, Linet M. Venous thromboembolism and cancer. Lancet. 1998;351:1077–80.

    Article  CAS  PubMed  Google Scholar 

  5. Maurice H. Des complications phlepitiques au cours des traitements par les neuroleptiques. Encephale. 1956;51:797–801.

    Google Scholar 

  6. Grahmann H, Suchenwirth R. Thrombose hazard in chlorpromazine and reserpine therapy of endogenous psychosis. Nervenarzt. 1959;30:224–5.

    CAS  PubMed  Google Scholar 

  7. Mahmodian M. Ursachen der lungenembolie bei psychisch und neurologisch Kranken. Arch Psichiatr Nervenkr. 1963;204:229–44.

    Article  Google Scholar 

  8. Häfner H, Brehm I. Thromboembolic complications in neuroleptic treatment. Compr Psychiatry. 1965;6:25–34.

    Article  Google Scholar 

  9. Lal S, Bleiman M, Brown B. Pulmonary embolism in psychiatric patients. J Am Geriatr Soc. 1966;14:1138–43.

    CAS  PubMed  Google Scholar 

  10. Meier-Ewert K, Baumgart H, Friedenberg P. Thromboembolism complications in neuro- and thymoleptic therapy. Dtsch Med Wochenschr. 1967;92:2174–8.

    Article  CAS  PubMed  Google Scholar 

  11. Scholtz V. Concerning the thromboembolic complications from neuroleptic drugs. Nervenarzt. 1967;38:174–7.

    Google Scholar 

  12. Jonsson AK, Spigset O, Hagg S. Venous thromboembolism in recipients of antipsychotics: incidence, mechanisms and management. CNS Drugs. 2012;26:649–62.

    Article  PubMed  Google Scholar 

  13. Walker AM, Lanza LL, Arellano F, Rothman KJ. Mortality in current and former users of clozapine. Epidemiology. 1997;8:671–7.

    CAS  PubMed  Google Scholar 

  14. Zhang R, Dong L, Shao F, Tan X, Ying K. Antipsychotics and venous thromboembolism risk: a meta-analysis. Pharmacopsychiatry. 2011;44:183–8.

    Article  CAS  PubMed  Google Scholar 

  15. Chapelle C, Quenet S, Delavenne X, Lacut K, Mismetti P, Laporte S, et al. Antipsychotics: a real or confounding risk factor for venous thromboembolism? Pharmacopsychiatry. 2013;46:36–7.

    Article  CAS  PubMed  Google Scholar 

  16. Barbui C, Conti V, Cipriani A. Antipsychotic drug exposure and risk of venous thromboembolism: a systematic review of observational studies. http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42013004435.

  17. Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions Version 5.1.0. The Cochrane Collaboration. 2011. http://www.cochrane-handbook.org.

  18. Wells G, Shea B, Higgins J, Sterne J, Tugwell P, Reeves B. Checklists of methodological issues for review authors to consider when including non-randomized studies in systematic reviews. Res Synth Methods. 2013;4:63–77.

    Article  Google Scholar 

  19. Greenland S. Quantitative methods in the review of epidemiologic literature. Epidemiol Rev. 1987;9:1–30.

    CAS  PubMed  Google Scholar 

  20. Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ. 2008;336:1227–31.

    Article  PubMed  Google Scholar 

  21. Danesh J, Kaptoge S, Mann AG, Sarwar N, Wood A, Angleman SB, et al. Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review. PLoS Med. 2008;5:e78.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.

    Article  PubMed  Google Scholar 

  23. Furukawa TA, Guyatt GH, Griffith LE. Can we individualize the ‘number needed to treat’? An empirical study of summary effect measures in meta-analyses. Int J Epidemiol. 2002;31:72–6.

    Article  PubMed  Google Scholar 

  24. Egger M, Davey SG, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

    Article  CAS  PubMed  Google Scholar 

  25. Guyatt GH, Oxman AD, Schunemann HJ. GRADE guidelines-an introduction to the 10th–13th articles in the series. J Clin Epidemiol. 2013;66:121–3.

    Article  PubMed  Google Scholar 

  26. Barbui C, Dua T, van Ommeren M, Yasamy M, Fleischmann A, Clark N, et al. Challenges in developing evidence-based recommendations using the GRADE approach: the case of mental, neurological, and substance use disorders. Plos Med. 2010;7:e1000322.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Allenet B, Schmidlin S, Genty C, Bosson JL. Antipsychotic drugs and risk of pulmonary embolism. Pharmacoepidemiol Drug Saf. 2012;21:42–8.

    Article  CAS  PubMed  Google Scholar 

  28. Hamanaka S, Kamijo Y, Nagai T, Kurihara K, Tanaka K, Soma K, et al. Massive pulmonary thromboembolism demonstrated at necropsy in Japanese psychiatric patients treated with neuroleptics including atypical antipsychotics. Circ J. 2004;68:850–2.

    Article  PubMed  Google Scholar 

  29. Hippisley-Cox J, Coupland C. Development and validation of risk prediction algorithm (QThrombosis) to estimate future risk of venous thromboembolism: prospective cohort study. BMJ. 2011;343:d4656.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Ishiguro C, Li L, Jick S. Antipsychotic drugs and risk of idiopathic venous thromboembolism: a nested case–control study using the GPRD. Pharmacoepidemiol Drug Saf. 2011;20:130.

    Google Scholar 

  31. Jonsson AK, Brudin L, Ahlner J, Hedenmalm K, Eriksson A, Hagg S. Antipsychotics associated with pulmonary embolism in a Swedish medicolegal autopsy series. Int Clin Psychopharmacol. 2008;23:263–8.

    Article  PubMed  Google Scholar 

  32. Jonsson AK, Horvath-Puho E, Hagg S, Pedersen L, Sorensen HT. Antipsychotics and risk of venous thromboembolism: a population-based case–control study. Clin Epidemiol. 2009;1:19–26.

    Article  PubMed Central  PubMed  Google Scholar 

  33. Kleijer BC, Heerdink ER, Egberts TC, Jansen PA, van Marum RJ. Antipsychotic drug use and the risk of venous thromboembolism in elderly patients. J Clin Psychopharmacol. 2010;30:526–30.

    Article  CAS  PubMed  Google Scholar 

  34. Lacut K, Le GG, Couturaud F, Cornily G, Leroyer C, Mottier D, et al. Association between antipsychotic drugs, antidepressant drugs and venous thromboembolism: results from the EDITH case–control study. Fundam Clin Pharmacol. 2007;21:643–50.

    Article  CAS  PubMed  Google Scholar 

  35. Liperoti R, Pedone C, Lapane KL, Mor V, Bernabei R, Gambassi G. Venous thromboembolism among elderly patients treated with atypical and conventional antipsychotic agents. Arch Intern Med. 2005;165:2677–82.

    Article  PubMed  Google Scholar 

  36. Masopust J, Maly R, Urban A, Hosak L, Ceramkova E. Antipsychotic drugs as a risk factor for venous thromboembolism. Int J Psych Clin Pract. 2007;11:246–9.

    Article  CAS  Google Scholar 

  37. Parker C, Coupland C, Hippisley-Cox J. Antipsychotic drugs and risk of venous thromboembolism: nested case–control study. BMJ. 2010;341:c4245.

    Article  PubMed  Google Scholar 

  38. Parkin L, Skegg DC, Herbison GP, Paul C. Psychotropic drugs and fatal pulmonary embolism. Pharmacoepidemiol Drug Saf. 2003;12:647–52.

    Article  CAS  PubMed  Google Scholar 

  39. Ray JG, Mamdani MM, Yeo EL. Antipsychotic and antidepressant drug use in the elderly and the risk of venous thromboembolism. Thromb Haemost. 2002;88:205–9.

    CAS  PubMed  Google Scholar 

  40. Thomassen R, Vandenbroucke JP, Rosendaal FR. Antipsychotic medication and venous thrombosis. Br J Psychiatry. 2001;179:63–6.

    Article  CAS  PubMed  Google Scholar 

  41. Wolstein J, Grohmann R, Ruther E, Hippius H. Antipsychotic drugs and venous thromboembolism. Lancet. 2000;356:252.

    Article  CAS  PubMed  Google Scholar 

  42. Zornberg GL, Jick H. Antipsychotic drug use and risk of first-time idiopathic venous thromboembolism: a case–control study. Lancet. 2000;356:1219–23.

    Article  CAS  PubMed  Google Scholar 

  43. Hagg S, Jonsson AK, Spigset O. Risk of venous thromboembolism due to antipsychotic drug therapy. Expert Opin Drug Saf. 2009;8:537–47.

    Article  PubMed  Google Scholar 

  44. Hagg S, Spigset O. Antipsychotic-induced venous thromboembolism: a review of the evidence. CNS Drugs. 2002;16:765–76.

    Article  PubMed  Google Scholar 

  45. Ostuzzi G, Bighelli I, Carrara BV, Dusi N, Imperadore G, Lintas C, et al. Making the use of psychotropic drugs more rational through the development of GRADE recommendations in specialist mental healthcare. Int J Ment Health Syst. 2013;7:14.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Conflict of Interest Disclosures

No sources of funding were used to assist in the preparation of this study. Corrado Barbui, Valentino Conti and Andrea Cipriani have no conflicts of interest that are directly relevant to the content of this study.

Author information

Authors and Affiliations

  1. Section of Psychiatry, Department of Public Health and Community Medicine, University of Verona, Policlinico GB Rossi, Piazzale Scuro 10, 37134, Verona, Italy

    Corrado Barbui & Andrea Cipriani

  2. Regional Centre for Pharmacovigilance, Lombardy Region, Milan, Italy

    Valentino Conti

Authors
  1. Corrado Barbui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Valentino Conti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrea Cipriani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Corrado Barbui.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barbui, C., Conti, V. & Cipriani, A. Antipsychotic Drug Exposure and Risk of Venous Thromboembolism: A Systematic Review and Meta-Analysis of Observational Studies. Drug Saf 37, 79–90 (2014). https://doi.org/10.1007/s40264-013-0127-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40264-013-0127-6

Keywords

Search

Navigation