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Personalising drug safety—results from the multi-centre prospective observational study on Adverse Drug Reactions in Emergency Departments (ADRED)

Abstract

Purpose

Adverse drug reactions (ADR) account for 5 to 7% of emergency department (ED) consultations. We aimed to assess medication risk profiles for ADRs leading to ED visits.

Methods

We analysed medication intake and patient demographics in a prospective multi-centre observational study collecting ADR cases in four large EDs in Germany. Odds ratios (OR) were calculated to relate drug classes taken to those suspicious for an ADR after a causality assessment.

Results

A total of 2215 cases of ED visits due to ADRs were collected. The median age of the cohort was 73 years; in median, six co-morbidities and an intake of seven drugs were documented. Antineoplastic/immunomodulating agents had the highest OR for being suspected for an ADR (OR 20.45, 95% CI 14.54–28.77), followed by antithrombotics (OR 2.94, 95% CI 2.49–3.47), antibiotics (OR 2.65, 95% CI 1.78–3.95), systemic glucocorticoids (OR 2.43, 95% CI 1.54–3.82) and drugs affecting the central nervous system (CNS), such as antipsychotics (OR 2.36, 95% CI 1.46–3.81), antidepressants (OR 2.10, 95% CI 1.57–2.83), antiparkinsonian medication (OR 2.11, 95% CI 1.15–3.84), opioids (OR 1.79, 95% CI 1.26–2.54) and non-opioid analgesics (OR 1.32, 95% CI 1.01–1.72).

Conclusions

Patients experiencing ADRs leading to ED visits are commonly old, multi-morbid and multi-medicated. CNS drugs may be more relevant than prior expected. With calculating ORs, we could replicate involvement of antineoplastic agents, antithrombotics, antibiotics, systemic glucocorticoids and non-opioid analgesics as frequently suspected for ADRs in EDs.

Trial registration

DRKS-ID: DRKS00008979.

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Fig. 1

Data availability

The datasets analysed during the current study are available from the corresponding author on reasonable request.

References

  1. 1.

    Tang N, Stein J, Hsia RY, Maselli JH, Gonzales R (2010) Trends and characteristics of US emergency department visits, 1997-2007. JAMA 304(6):664–670

  2. 2.

    Lowthian JA, Curtis AJ, Cameron PA, Stoelwinder JU, Cooke MW, McNeil JJ (2011) Systematic review of trends in emergency department attendances: an Australian perspective. Emerg Med J 28(5):373–377

  3. 3.

    Kellermann AL (2006) Crisis in the emergency department. N Engl J Med 355(13):1300–1303

  4. 4.

    Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, Farrar K, Park BK, Breckenridge AM (2004) Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ 329(7456):15–19. https://doi.org/10.1136/bmj.329.7456.15

  5. 5.

    Schneeweiss S, Hasford J, Gottler M, Hoffmann A, Riethling AK, Avorn J (2002) Admissions caused by adverse drug events to internal medicine and emergency departments in hospitals: a longitudinal population-based study. Eur J Clin Pharmacol 58(4):285–291. https://doi.org/10.1007/s00228-002-0467-0

  6. 6.

    van der Hooft CS, Dieleman JP, Siemes C, Aarnoudse AJ, Verhamme KM, Stricker BH, Sturkenboom MC (2008) Adverse drug reaction-related hospitalisations: a population-based cohort study. Pharmacoepidemiol Drug Saf 17(4):365–371. https://doi.org/10.1002/pds.1565

  7. 7.

    Leendertse AJ, Egberts AC, Stoker LJ, van den Bemt PM (2008) Frequency of and risk factors for preventable medication-related hospital admissions in the Netherlands. Arch Intern Med 168(17):1890–1896. https://doi.org/10.1001/archinternmed.2008.3

  8. 8.

    Lazarou J, Pomeranz BH, Corey PN (1998) Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 279(15):1200–1205

  9. 9.

    Schurig AM, Bohme M, Just KS, Scholl C, Dormann H, Plank-Kiegele B, Seufferlein T, Graff I, Schwab M, Stingl JC (2018) Adverse drug reactions (ADR) and emergencies. Dtsch Arztebl Int 115(15):251–258. https://doi.org/10.3238/arztebl.2018.0251

  10. 10.

    Budnitz DS, Pollock DA, Weidenbach KN, Mendelsohn AB, Schroeder TJ, Annest JL (2006) National surveillance of emergency department visits for outpatient adverse drug events. JAMA 296(15):1858–1866. https://doi.org/10.1001/jama.296.15.1858

  11. 11.

    van Der Hooft CS, Sturkenboom MC, van Grootheest K, Kingma HJ, Stricker BHC (2006) Adverse drug reaction-related hospitalisations. Drug Saf 29(2):161–168

  12. 12.

    Raschetti R, Morgutti M, Menniti-Ippolito F, Belisari A, Rossignoli A, Longhini P, La Guidara C (1999) Suspected adverse drug events requiring emergency department visits or hospital admissions. Eur J Clin Pharmacol 54(12):959–963

  13. 13.

    Angamo MT, Chalmers L, Curtain CM, Bereznicki LR (2016) Adverse-drug-reaction-related hospitalisations in developed and developing countries: a review of prevalence and contributing factors. Drug Saf 39(9):847–857. https://doi.org/10.1007/s40264-016-0444-7

  14. 14.

    Hohl CM, Dankoff J, Colacone A, Afilalo M (2001) Polypharmacy, adverse drug-related events, and potential adverse drug interactions in elderly patients presenting to an emergency department. Ann Emerg Med 38(6):666–671

  15. 15.

    Nguyen JK, Fouts MM, Kotabe SE, Lo E (2006) Polypharmacy as a risk factor for adverse drug reactions in geriatric nursing home residents. Am J Geriatr Pharmacother 4(1):36–41

  16. 16.

    EMA (2017) Guideline on good pharmacovigilance practices (GVP), Annex I - definitions. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/05/WC500143294.pdf. Accessed 6 Dec 2017

  17. 17.

    Meyer UA (2000) Pharmacogenetics and adverse drug reactions. Lancet 356(9242):1667–1671

  18. 18.

    Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W (2001) Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. JAMA 286(18):2270–2279

  19. 19.

    Pedros C, Quintana B, Rebolledo M, Porta N, Vallano A, Arnau JM (2014) Prevalence, risk factors and main features of adverse drug reactions leading to hospital admission. Eur J Clin Pharmacol 70(3):361–367. https://doi.org/10.1007/s00228-013-1630-5

  20. 20.

    Budnitz DS, Lovegrove MC, Shehab N, Richards CL (2011) Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med 365(21):2002–2012

  21. 21.

    Lavan AH, Gallagher P (2016) Predicting risk of adverse drug reactions in older adults. Ther Adv Drug Saf 7(1):11–22

  22. 22.

    Routledge PA, O'mahony M, Woodhouse K (2004) Adverse drug reactions in elderly patients. Br J Clin Pharmacol 57(2):121–126

  23. 23.

    The WHO-UMC System. https://www.who-umc.org/media/2768/standardised-case-causality-assessment.pdf. Accessed 12 June 2017

  24. 24.

    ICH post-approval safety data management: definitions and standards for expedited reporting. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2D/Step4/E2D_Guideline.pdf. Accessed 26 July 2018

  25. 25.

    WHO International Classification of Diseases, Version 10. http://www.who.int/classifications/icd/icd10updates/en/. Accessed 14 Sept 2018

  26. 26.

    WHO Collaborating Centre for Drug Statistics Methodology, Health NIoP ATC/DDD Index 2018. https://www.whocc.no/atc_ddd_index/. Accessed 26 July 2018

  27. 27.

    Menec VH, Chipperfield JG (1997) The interactive effect of perceived control and functional status on health and mortality among young-old and old-old adults. J Gerontol B Psychol Sci Soc Sci 52(3):P118–P126

  28. 28.

    Zizza CA, Ellison KJ, Wernette CM (2009) Total water intakes of community-living middle-old and oldest-old adults. J Gerontol A Biol Sci Med Sci 64(4):481–486

  29. 29.

    Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, Seeman T, Tracy R, Kop WJ, Burke G (2001) Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 56(3):M146–M157

  30. 30.

    Meier F, Maas R, Sonst A, Patapovas A, Muller F, Plank-Kiegele B, Pfistermeister B, Schoffski O, Burkle T, Dormann H (2015) Adverse drug events in patients admitted to an emergency department: an analysis of direct costs. Pharmacoepidemiol Drug Saf 24(2):176–186. https://doi.org/10.1002/pds.3663

  31. 31.

    Liao PJ, Mao CT, Chen TL, Deng ST, Hsu KH (2019) Factors associated with adverse drug reaction occurrence and prognosis, and their economic impacts in older inpatients in Taiwan: a nested case-control study. BMJ Open 9(5):e026771. https://doi.org/10.1136/bmjopen-2018-026771

  32. 32.

    Hanlon JT, Schmader KE, Koronkowski MJ, Weinberger M, Landsman PB, Samsa GP, Lewis IK (1997) Adverse drug events in high risk older outpatients. J Am Geriatr Soc 45(8):945–948

  33. 33.

    Panel AGSBCUE, Fick DM, Semla TP, Beizer J, Brandt N, Dombrowski R, DuBeau CE, Eisenberg W, Epplin JJ, Flanagan N (2015) American Geriatrics Society 2015 updated beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 63(11):2227–2246

  34. 34.

    Patel H, Bell D, Molokhia M, Srishanmuganathan J, Patel M, Car J, Majeed A (2007) Trends in hospital admissions for adverse drug reactions in England: analysis of national hospital episode statistics 1998–2005. BMC Clin Pharmacol 7(1):9

  35. 35.

    Sproule BA, Naranjo CA, Bremner KE, Hassan PC (1997) Selective serotonin reuptake inhibitors and CNS drug interactions. Clin Pharmacokinet 33(6):454–471

  36. 36.

    Perucca E (2006) Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol 61(3):246–255

  37. 37.

    Doucet J, Chassagne P, Trivalle C, Landrin I, Pauty M, Kadri N, Ménard J, Bercoff E (1996) Drug-drug interactions related to hospital admissions in older adults: a prospective study of 1000 patients. J Am Geriatr Soc 44(8):944–948

  38. 38.

    Hosia-Randell HM, Muurinen SM, Pitkälä KH (2008) Exposure to potentially inappropriate drugs and drug-drug interactions in elderly nursing home residents in Helsinki, Finland. Drugs Aging 25(8):683–692

  39. 39.

    Zhou L, Rupa AP (2018) Categorization and association analysis of risk factors for adverse drug events. Eur J Clin Pharmacol 74(4):389–404. https://doi.org/10.1007/s00228-017-2373-5

  40. 40.

    Shehab N, Lovegrove MC, Geller AI, Rose KO, Weidle NJ, Budnitz DS (2016) US emergency department visits for outpatient adverse drug events, 2013-2014. Jama 316(20):2115–2125

  41. 41.

    Scripcaru G, Mateus C, Nunes C (2017) Adverse drug events-analysis of a decade. A Portuguese case-study, from 2004 to 2013 using hospital database. PLoS One 12(6):e0178626. https://doi.org/10.1371/journal.pone.0178626

  42. 42.

    Dormann H, Sonst A, Muller F, Vogler R, Patapovas A, Pfistermeister B, Plank-Kiegele B, Kirchner M, Hartmann N, Burkle T, Maas R (2013) Adverse drug events in older patients admitted as an emergency: the role of potentially inappropriate medication in elderly people (PRISCUS). Dtsch Arztebl Int 110(13):213–219. https://doi.org/10.3238/arztebl.2013.0213

  43. 43.

    Cerreta F, Padrão A, Skibicka-Stepien I, Strampelli A, de Orbe Izquierdo MS (2018) Medicines for older people: assessment and transparency at the European Medicines Agency regarding cardiovascular and antithrombotic medicinal products. Eur Geriatr Med 9(4):415–418

  44. 44.

    Hajjar ER, Cafiero AC, Hanlon JT (2007) Polypharmacy in elderly patients. Am J Geriatr Pharmacother 5(4):345–351. https://doi.org/10.1016/j.amjopharm.2007.12.002

  45. 45.

    Budnitz DS, Shehab N, Kegler SR, Richards CL (2007) Medication use leading to emergency department visits for adverse drug events in older adults. Ann Intern Med 147(11):755–765

  46. 46.

    Qato DM, Alexander GC, Conti RM, Johnson M, Schumm P, Lindau ST (2008) Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States. JAMA 300(24):2867–2878

  47. 47.

    Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA (2002) Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 287(3):337–344

  48. 48.

    Gurwitz JH, Field TS, Harrold LR, Rothschild J, Debellis K, Seger AC, Cadoret C, Fish LS, Garber L, Kelleher M (2003) Incidence and preventability of adverse drug events among older persons in the ambulatory setting. JAMA 289(9):1107–1116

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Acknowledgements

The study trial is registered at the German Clinical Trial Register (DRKS-ID: DRKS00008979).

Funding

The ADRED-study has received financial funding within the framework of the AMTS focus of the German Federal Ministry of Health (BMG), grant number ZMVI5–2514ATA004. M.S. and S.I. are in part supported by the Robert Bosch Foundation, Stuttgart, Germany.

Author information

KJ conducted the analyses and drafted the manuscript. JS designed the ADRED study and supervised all analyses and coordination. MB, MS, SD, MS and KJ conducted the statistical analyses. MS coordinated the study. KS drafted study material. HD, TS, IG and MS supervised the identification of ADR cases at clinical sites. BPK, KE, SI, SS and SJ participated in identification of ADR cases at clinical sites. All authors collaborated in writing and approved the final manuscript.

Correspondence to Julia C. Stingl.

Ethics declarations

Competing interests

The authors declare that they have no competing interests.

Ethical approval

The study was approved by the responsible ethical committee of the University of Bonn (202/15) and reviewed positively by the respective ethical committees of the study centres of the Universities of Erlangen-Nürnberg (43_16Bc), Tübingen (113/16) and Ulm (493/2016BO1).

Informed consent

Informed consent was obtained from individual participants included in the study described in the manuscript.

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Just, K.S., Dormann, H., Böhme, M. et al. Personalising drug safety—results from the multi-centre prospective observational study on Adverse Drug Reactions in Emergency Departments (ADRED). Eur J Clin Pharmacol 76, 439–448 (2020). https://doi.org/10.1007/s00228-019-02797-9

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Keywords

  • Adverse drug reaction
  • Drug safety
  • Emergency department
  • Drug class
  • Medication
  • Older adults