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Prevalence of Drug Combinations Increasing Bleeding Risk Among Warfarin Users With and Without Alzheimer’s Disease

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Abstract

Purpose

The aim of this study was to analyse the prevalence and predictors of drug combinations increasing bleeding risk among warfarin users with and without Alzheimer’s disease (AD).

Methods

This retrospective observational study utilised data from the Finnish MEDALZ-2005 cohort. The MEDALZ-2005 study included all community-dwelling persons with a clinically verified diagnosis of AD at the end of 2005, and one comparison person without AD for each case. Data on drug use was collected from the Prescription Register. We included persons who were warfarin users during the study period 2006–2009. Drug combinations increasing bleeding risk with warfarin included selective serotonin reuptake inhibitors (SSRIs), non-steroidal anti-inflammatory agents (NSAIDs), other antithrombotic drugs and tramadol. Factors associated with combination use were investigated with logistic regression.

Results

During the follow-up, 3385 persons with AD and 4830 persons without AD used warfarin. Drug combinations increasing bleeding risk were more common in warfarin users with AD than without AD [35.9 and 30.5 %, respectively (p < 0.0001)]. The most common combination was SSRIs and warfarin, which was more common among persons with AD (23.8 %) than among persons without AD (10.9 %). NSAIDs and warfarin combination was more common among persons without AD. Combination use was associated with AD, female gender, younger age, diabetes mellitus, rheumatoid arthritis and asthma/chronic obstructive pulmonary disease (COPD).

Conclusions

Use of drug combinations increasing bleeding risk was more common among warfarin users with AD. Special attention should be paid to minimise the duration of concomitant use and to find safer alternatives without increased bleeding risk.

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References

  1. Horton JD, Bushwick BM. Warfarin therapy: evolving strategies in anticoagulation. Am Fam Physician. 1999;59:635–46.

    CAS  PubMed  Google Scholar 

  2. Bauersachs RM. Use of anticoagulants in elderly patients. Thromb Res. 2012;129:107–15.

    Article  CAS  PubMed  Google Scholar 

  3. Sinauridze EI, Panteleev MA, Ataullakhanov FI. Anticoagulant therapy: basic principles, classic approaches and recent developments. Blood Coagul Fibrinolysis. 2012;23:482–93.

    Article  CAS  PubMed  Google Scholar 

  4. Finnish Medical Society Duodecim. Current care: atrial fibrillation. 2014. http://www.kaypahoito.fi/. Accessed 1 Oct 2015.

  5. Wadelius M, Pirmohamed M. Pharmacogenetics of warfarin: current status and future challenges. Pharmacogenomics J. 2007;7:99–111.

    Article  CAS  PubMed  Google Scholar 

  6. Sellers MB, Newby LK. Atrial fibrillation, anticoagulation, fall risk, and outcomes in elderly patients. Am Heart J. 2011;161:241–6.

    Article  PubMed  Google Scholar 

  7. Gasse C, Hollowell J, Meier CR, Haefeli WE. Drug interactions and risk of acute bleeding leading to hospitalisation or death in patients with chronic atrial fibrillation treated with warfarin. Thromb Haemost. 2005;94:537–43.

    CAS  PubMed  Google Scholar 

  8. Donzé J, Clair C, Hug B, Rodondi N, Waeber G, Cornuz J, et al. Risk of falls and major bleeds in patients on oral anticoagulation therapy. Am J Med. 2012;125:773–8.

    Article  PubMed  Google Scholar 

  9. Van Doorn C, Gruber-Baldini AL, Zimmerman S, Hebel RJ, Port CL, Baumgarten M, et al. Dementia as a risk factor for falls and fall injuries among nursing home residents. J Am Geriatr Soc. 2003;51:1213–8.

    Article  PubMed  Google Scholar 

  10. Douglas A, Letts L, Richardson J. A systematic review of accidental injury from fire, wandering and medication self-administration errors for older adults with and without dementia. Arch Gerontol Geriatr. 2011;52:e1–10.

    Article  PubMed  Google Scholar 

  11. Tolppanen A-M, Taipale H, Koponen M, Lavikainen P, Tanskanen A, Tiihonen J, et al. Use of existing data sources in clinical epidemiology: Finnish health care registers in Alzheimer’s disease research—the Medication use among persons with Alzheimer’s disease (MEDALZ-2005) study. Clin Epidemiol. 2013;5:277–85.

    Article  PubMed Central  PubMed  Google Scholar 

  12. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS–ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984;34:939–44.

    Article  CAS  PubMed  Google Scholar 

  13. WHO Collaborating Centre for Drug Statistics Methodology. The anatomical therapeutic chemical classification system. 2014. http://www.whocc.no/atc_ddd_index/. Accessed 1 Oct 2015.

  14. Taipale H, Tanskanen A, Koponen M, Tolppanen A-M, Tiihonen J, Hartikainen S. Antidementia drug use among community-dwelling individuals with Alzheimer’s disease in Finland: a nationwide register-based study. Int Clin Psychopharmacol. 2014;29:216–23.

    Article  PubMed Central  PubMed  Google Scholar 

  15. Taipale H, Koponen M, Tanskanen A, Tolppanen A-M, Tiihonen J, Hartikainen S. Antipsychotic doses among community-dwelling persons with Alzheimer disease in Finland. J Clin Psychopharmacol. 2014;34:435–40.

    Article  CAS  PubMed  Google Scholar 

  16. Taipale H, Koponen M, Tanskanen A, Tolppanen A-M, Tiihonen J, Hartikainen S. Antipsychotic polypharmacy among a nationwide sample of community-dwelling persons with Alzheimer’s disease. J Alzheimers Dis. 2014;41:1223–8.

    CAS  PubMed  Google Scholar 

  17. Torvinen-Kiiskinen S, Taipale H, Tanskanen A, Tiihonen J, Hartikainen S. Concomitant use of acetylcholine esterase inhibitors and urinary antispasmodics among Finnish community-dwelling persons with Alzheimer disease. J Clin Psychopharmacol. 2014;34:1–6.

    Article  Google Scholar 

  18. Böttiger Y, Laine K, Andersson ML, Korhonen T, Molin B, Ovesjö M-L, et al. SFINX-a drug–drug interaction database designed for clinical decision support systems. Eur J Clin Pharmacol. 2009;65:627–33.

    Article  PubMed  Google Scholar 

  19. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373–83.

    Article  CAS  PubMed  Google Scholar 

  20. Howard PA, Ellerbeck EF, Engelman KK, Patternson KL. The nature and frequency of potential warfarin drug interactions that increase the risk of bleeding in patients with atrial fibrillation. Pharmacoepidemiol Drug Saf. 2002;11:569–76.

    Article  CAS  PubMed  Google Scholar 

  21. Hauta-Aho M, Tirkkonen T, Vahlberg T, Laine K. The effect of drug interactions on bleeding risk associated with warfarin therapy in hospitalized patients. Ann Med. 2009;41:619–28.

    Article  CAS  PubMed  Google Scholar 

  22. Kotirum S, Chaiyakunapruk N, Jampachaisri K, Wattanasombat S, Rojnuckarin P. Utilization review of concomitant use of potentially interacting drugs in Thai patients using warfarin therapy. Pharmacoepidemiol Drug Saf. 2007;16:216–22.

    Article  PubMed  Google Scholar 

  23. Wittkowsky AK, Boccuzzi SJ, Wogen J, Wygant G, Patel P, Hauch O. Frequency of concurrent use of warfarin with potentially interacting drugs. Pharmacotherapy. 2004;24:1668–74.

    Article  CAS  PubMed  Google Scholar 

  24. Martinez C, Jones RW, Rietbrock S. Trends in the prevalence of antipsychotic drug use among patients with Alzheimer’s disease and other dementias including those treated with antidementia drugs in the community in the UK: a cohort study. BMJ Open. 2013. doi:10.1136/bmjopen-2012-002080.

  25. Kessing LV, Harhoff M, Andersen PK. Treatment with antidepressants in patients with dementia-a nationwide register-based study. Int Psychogeriatr. 2007;19:902–13.

    Article  PubMed  Google Scholar 

  26. Guthrie B, Clark SA, McCowan C. The burden of psychotropic drug prescribingin people with dementia: a populationdatabase study. Age Ageing. 2010;39:637–42.

    Article  PubMed  Google Scholar 

  27. Finnish Medical Society Duodecim, 2010. Current care: memory disorders. http://www.kaypahoito.fi/. Accessed 1 Oct 2015.

  28. Sink KM, Holden KF, Yaffe K. Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence. JAMA. 2005;293:596–608.

    Article  CAS  PubMed  Google Scholar 

  29. Hallas J, Dall M, Andries A, Andersen BS, Aalykke C, Hansen JM, et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ. 2006;333:726.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Lip G, Windecker S, Huber K, Kirchhof P, Marin F, Ten Berg J, et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group. Eur Heart J. 2014;35:3155–79.

    Article  PubMed  Google Scholar 

  31. Roughead EE, Kalisch LM, Barratt JD, Gilbert AL. Prevalence of potentially hazardous drug interactions amongst Australian veterans. Br J Clin Pharmacol. 2010;70:252–7.

    Article  PubMed Central  PubMed  Google Scholar 

  32. Vitry AI, Roughead EE, Ramsay EN, Preiss AK, Ryan P, Gilbert AL, et al. Major bleeding risk associated with warfarin and co-medications in the elderly population. Pharmacoepidemiol Drug Saf. 2011;20:1057–63.

    Article  PubMed  Google Scholar 

  33. Schalekamp T, Klungel OH, Souverein PC, de Boer A. Effect of oral antiplatelet agents on major bleeding in users of coumarins. Thromb Haemost. 2008;100:1076–83.

    CAS  PubMed  Google Scholar 

  34. Sørensen R, Hansen ML, Abildstrom SZ, Hvelplund A, Andersson C, Jørgensen C, et al. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet. 2009;374:1967–74.

    Article  PubMed  Google Scholar 

  35. Battistella M, Mamdami MM, Juurlink DN, Rabeneck L, Laupacis A. Risk of upper gastrointestinal hemorrhage in warfarin users treated with nonselective NSAIDs or COX-2 inhibitors. Arch Intern Med. 2005;165:189–92.

    Article  CAS  PubMed  Google Scholar 

  36. Penning-van Beest F, Erkens J, Petersen K-U, Koelz HR, Herings R. Main comedications associated with major bleeding during anticoagulant therapy with coumarins. Eur J Clin Pharmacol. 2005;61:439–44.

  37. Pottegård A, Meegaard PM, Holck LHV, dePont Christensen Rd, Madsen H, Hallas J. Concurrent use of tramadol and oral vitamin K antagonists and the risk of excessive anticoagulation: a register-based nested case-control study. Eur J Clin Pharmacol 2013;69:641–6.

  38. Brouquet A, Cudennec T, Benoist S, Moulias S, Beauchet A, Penna C, et al. Impaired mobility, ASA status and administration of tramadol are risk factors for postoperative delirium in patients aged 75 years or more after major abdominal surgery. Ann Surg. 2010;251:759–65.

    Article  PubMed  Google Scholar 

  39. Hughes GJ, Patel PN, Saxena N. Effect of acetaminophen on international normalized ratio in patients receiving warfarin therapy. Pharmacotherapy. 2011;31:591–7.

    Article  CAS  PubMed  Google Scholar 

  40. Agarwal S, Bennett D, Smith DJ. Predictors of warfarin use in atrial fibrillation patients in the inpatient setting. Am J Cardiovasc Drugs. 2010;10:37–48.

    Article  CAS  PubMed  Google Scholar 

  41. Gurwitz JH, Monette J, Rochon PA, Eckler MA, Avorn J. Atrial fibrillation and stroke prevention with warfarin in the long-term care setting. Arch Intern Med. 1997;157:978–84. doi:10.1001/archinte.1997.00440300080006.

    Article  CAS  PubMed  Google Scholar 

  42. Quilliam BJ, Lapane KL, Leibson C. Clinical correlates and drug treatment of residents with stroke in long-term care editorial comment. Stroke. 2001;32:1385–93.

    Article  CAS  PubMed  Google Scholar 

  43. Wilke T, Groth A, Pfannkuche M, Harks O, Fuchs A, Maywald U, et al. Real life anticoagulation treatment of patients with atrial fibrillation in Germany: extent and causes of anticoagulant under-use. J Thromb Thrombolysis. 2015;40(1):97–107.

    Article  CAS  PubMed  Google Scholar 

  44. Beardon PH, McGilchrist MM, McKendrick AD, McDevitt DG, MacDonald TM. Primary non-compliance with prescribed medication in primary care. BMJ Br Med J. 1993;307:846–8.

    Article  CAS  Google Scholar 

  45. Haukka J, Suvisaari J, Tuulio-Henriksson A, Lönnqvist J. High concordance between self-reported medication and official prescription database information. Eur J Clin Pharmacol. 2007;63:1069–74.

    Article  PubMed  Google Scholar 

  46. Rikala M, Hartikainen S, Sulkava R, Korhonen MJ. Validity of the Finnish prescription register for measuring psychotropic drug exposures among elderly Finns: a population-based intervention study. Drugs Aging. 2010;27:337–49.

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors thank the maintainers of Finnish healthcare registers for enabling this research.

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Correspondence to Heidi Taipale.

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None to declare.

Conflicts of interest

JT has served as a consultant to Lundbeck, Organon, Janssen-Cilag, Eli Lilly, AstraZeneca, F. Hoffman-La Roche and Bristol-Myers Squibb. He has received fees for giving expert opinions to Bristol-Myers Squibb and GlaxoSmithKline, lecture fees from Janssen-Cilag, Bristol-Myers Squibb, Eli Lilly, Pfizer, Lundbeck, GlaxoSmithKline, AstraZeneca and Novartis; and a grant from the Stanley Foundation. JT is a member of advisory boards for AstraZeneca, Janssen-Cilag and Otsuka. Other authors declare no conflicts of interest.

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Taipale, H., Vuorikari, H., Tanskanen, A. et al. Prevalence of Drug Combinations Increasing Bleeding Risk Among Warfarin Users With and Without Alzheimer’s Disease. Drugs Aging 32, 937–945 (2015). https://doi.org/10.1007/s40266-015-0316-3

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