Skip to main content

Advertisement

SpringerLink
Log in

Characterisation of non-warfarin-associated bleeding events reported to the Norwegian spontaneous reporting system

  • Pharmacoepidemiology and Prescription
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

The aim of the study was to analyse non-warfarin-associated bleeding adverse drug events reported to the Norwegian spontaneous reporting system, with characterisation of the bleeding locations, outcome and drug interactions. In addition, concordance in assessments between reporters and evaluators, trend shifts in reporting, and detection of potentially new adverse drug interaction signals were studied.

Methods

Data on bleeding events reported between 1 January 2003 and 31 December 2005 were retrieved from the Norwegian spontaneous reporting system database.

Results

Of 327 case reports of non-warfarin-associated bleeding events, 270 reports (82.6 %) were characterised as serious and 69 (21.1 %) had a fatal outcome. One hundred and eighty-seven bleeds (57.5 %) were gastrointestinal, 57 (17.4 %) were cerebral, and 81 (24.8 %) were from other bleeding sites. The bleeding sites differed with respect to the patient's age, drug use, diagnoses and outcomes. Of drugs associated with bleeding, nonsteroidal anti-inflammatory drugs (NSAIDs)/COX-2 inhibitors (145 reports) and acetylsalicylic acid (128 reports) were most frequently used. Only fibrinolytics were associated with increased mortality. There was a 67.4 % correlation between reporters and evaluators in assessment of drugs associated with bleeding (P < 0.001), with considerable variation in concordance between drug groups.

Conclusion

Non-warfarin-associated bleeding events are associated with substantial mortality. Old age, cerebral bleeds, number of drugs used, and use of fibrinolytics are all independently associated with increased mortality. The recognition of the bleeding risk of commonly used drugs such as acetylsalicylic acid and heparins may be insufficient among prescribers.

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

Similar content being viewed by others

References

  1. Lindquist M (2008) VigiBase, the WHO global ICSR database system: basic facts. Drug Inf J 42:409–419

    Google Scholar 

  2. Strandell J, Caster O, Bate A, Noren N, Edwards IR (2011) Reporting patterns indicative of adverse drug interactions: a systematic evaluation in VigiBase. Drug Saf 34:253–266. doi:10.2165/11586990-000000000-00000

    Article  PubMed  Google Scholar 

  3. Strandell J, Bate A, Lindquist M, Edwards IR (2008) Drug-drug interactions - a preventable patient safety issue? Br J Clin Pharmacol 65:144–146

    Article  PubMed  Google Scholar 

  4. Narum S, Solhaug V, Myhr K, Johansen PW, Brors O, Kringen MK (2011) Warfarin-associated bleeding events and concomitant use of potentially interacting medicines reported to the Norwegian spontaneous reporting system. Br J Clin Pharmacol 71:254–262. doi:10.1111/j.1365-2125.2010.03827.x

    Article  PubMed  Google Scholar 

  5. 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. Br Med J 329:15–19

    Article  Google Scholar 

  6. Wester K, Jonsson A, Spigset O, Hagg S (2007) Spontaneously reported fatal suspected adverse drug reactions: a 10-year survey from Sweden. Pharmacoepidemiol Drug Saf 16:173–180

    Article  PubMed  Google Scholar 

  7. Wysowski DK, Nourjah P, Swartz L (2007) Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med 167:1414–1419

    Article  PubMed  Google Scholar 

  8. Wittkowsky AK, Boccuzzi SJ, Wogen J, Wygant G, Patel P, Hauch O (2004) Frequency of concurrent use of warfarin with potentially interacting drugs. Pharmacotherapy 24:1668–1674

    Article  PubMed  CAS  Google Scholar 

  9. Ronning M (2002) A historical overview of the ATC/DDD methodology. WHO Drug Inf 16:233–234

    Google Scholar 

  10. Castell DO (2010) Medication-induced esophagitis. LaMont JT and Ginsburg CH. UpToDate . 2-3-2010. Ref Type: Electronic Citation

  11. Bate A, Lindquist M, Edwards IR, Olsson S, Orre R, Lansner A, De Freitas RM (1998) A Bayesian neural network method for adverse drug reaction signal generation. Eur J Clin Pharmacol 54:315–321

    Article  PubMed  CAS  Google Scholar 

  12. Wester K, Jonsson AK, Spigset O, Druid H, Hagg S (2008) Incidence of fatal adverse drug reactions: a population based study. Br J Clin Pharmacol 65:573–579

    Article  PubMed  Google Scholar 

  13. Christensen S, Riis A, Norgaard M, Sorensen HT, Thomsen RW (2007) Short-term mortality after perforated or bleeding peptic ulcer among elderly patients: a population-based cohort study. BMC Geriatr 7:8. doi:10.1186/1471-2318-7-8

    Article  PubMed  Google Scholar 

  14. Ahsberg K, Ye W, Lu Y, Zheng Z, von Stael HC (2011) Hospitalisation of and mortality from bleeding peptic ulcer in Sweden: a nationwide time-trend analysis. Aliment Pharmacol Ther 33:578–584. doi:10.1111/j.1365-2036.2010.04562.x

    Article  PubMed  CAS  Google Scholar 

  15. Tanne D, Kasner SE, Demchuk AM, Koren-Morag N, Hanson S, Grond M, Levine SR (2002) Markers of increased risk of intracerebral hemorrhage after intravenous recombinant tissue plasminogen activator therapy for acute ischemic stroke in clinical practice the multicenter rt-PA acute stroke survey. Circulation 105:1679–1685

    Article  PubMed  CAS  Google Scholar 

  16. Sloan MA, Price TR, Petito CK, Randall AMY, Solomon RE, Terrin ML, Gore J, Collen D, Kleiman N, Feit F, Babb J, Herman M, Roberts WC, Sopko G, Bovill E, Forman S, Knatterud GL (1995) Clinical-features and pathogenesis of intracerebral hemorrhage after Rt-Pa and heparin-therapy for acute myocardial-infarction - the thrombolysis in myocardial-infarction (Timi)-Ii pilot and randomized clinical-trial combined experience. Neurology 45:649–658

    Article  PubMed  CAS  Google Scholar 

  17. Rosand J, Eckman MH, Knudsen KA, Singer DE, Greenberg SM (2004) The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med 164:880–884. doi:10.1001/archinte.164.8.880

    Article  PubMed  CAS  Google Scholar 

  18. Liotta EM, Prabhakaran S (2012) Warfarin-associated intracerebral hemorrhage is increasing in prevalence in the United States. J Stroke Cerebrovasc Dis. doi:10.1016/j.jstrokecerebrovasdis.2012.11.015

  19. Leone R, Sottosanti L, Luisa IM, Santuccio C, Conforti A, Sabatini V, Moretti U, Venegoni M (2008) Drug-related deaths: an analysis of the Italian spontaneous reporting database. Drug Saf 31:703–713

    Article  PubMed  Google Scholar 

  20. Chyka PA (2000) How many deaths occur annually from adverse drug reactions in the United States? Am J Med 109:122–130

    Article  PubMed  CAS  Google Scholar 

  21. Liu BA, Knowles SR, Mittmann N, Einarson T, Shear NH (2001) Reporting of fatal adverse drug reactions. Can J Clin Pharmacol 8:84–88

    PubMed  CAS  Google Scholar 

  22. Leone R, Magro L, Moretti U, Cutroneo P, Moschini M, Motola D, Tuccori M, Conforti A (2010) Identifying adverse drug reactions associated with drug-drug interactions: data mining of a spontaneous reporting database in Italy. Drug Saf 33:667–675. doi:10.2165/11534400-000000000-00000

    Article  PubMed  CAS  Google Scholar 

  23. Glintborg B, Andersen SE, Dalhoff K (2005) Drug-drug interactions among recently hospitalised patients - frequent but mostly clinically insignificant. Eur J Clin Pharmacol 61:675–681

    Article  PubMed  Google Scholar 

  24. Magro L, Moretti U, Leone R (2012) Epidemiology and characteristics of adverse drug reactions caused by drug-drug interactions. Expert Opin Drug Saf 11:83–94

    Article  PubMed  CAS  Google Scholar 

  25. Larrue V, von Kummer R, Muller A, Bluhmki E (2001) Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator - A secondary analysis of the European-Australasian Acute Stroke Study (ECASS II). Stroke 32:438–441

    Article  PubMed  CAS  Google Scholar 

  26. Gurwitz JH, Gore JM, Goldberg RJ, Barron HV, Breen T, Rundle AC, Sloan MA, French W, Rogers WJ (1998) Risk for intracranial hemorrhage after tissue plasminogen activator treatment for acute myocardial infarction. Participants in the National Registry of Myocardial Infarction 2. Ann Intern Med 129:597–604

    Article  PubMed  CAS  Google Scholar 

  27. Prisant LM, Herman W (2002) Calcium channel blocker induced gingival overgrowth. J Clin Hypertens (Greenwich) 4:310–311

    Article  Google Scholar 

  28. Klasco RK e. Isotretinoin (Drug Evaluation). Micromedex . 7-12-2011. Ref Type: Electronic Citation

  29. Klasco RK, e. Montelucast (Drug Evaluation). Micromedex . 7-12-2011. Ref Type: Electronic Citation

Download references

Acknowledgments

The authors acknowledge the Norwegian Medicines Agency for providing the data and EXTRA funds from the Norwegian Foundation for Health and Rehabilitation for financing the study. The funding source did not participate in the study design; collection, analysis or interpretation of data; writing the report; or the decision to submit the paper for publication.

Conflicts of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Oslo University Hospital, Oslo, Norway

    Sigrid Narum, Odd Brørs & Marianne Kristiansen Kringen

  2. Regional Medicines Information and Pharmacovigilance Centre (RELIS), Oslo University Hospital, Oslo, Norway

    Vigdis Solhaug & Kirsten Myhr

  3. Center for Psychopharmacology, Diakonhjemmet Hospital, P.O. Box 85, Vinderen, 0319, Oslo, Norway

    Sigrid Narum

  4. Faculty of Medicine, University of Oslo, Oslo, Norway

    Odd Brørs

Authors
  1. Sigrid Narum
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vigdis Solhaug
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kirsten Myhr
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Odd Brørs
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marianne Kristiansen Kringen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sigrid Narum.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Narum, S., Solhaug, V., Myhr, K. et al. Characterisation of non-warfarin-associated bleeding events reported to the Norwegian spontaneous reporting system. Eur J Clin Pharmacol 69, 1445–1452 (2013). https://doi.org/10.1007/s00228-013-1479-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-013-1479-7

Keywords

Search

Navigation