Download PDF
Thromb Haemost 2014; 111(05): 912-922
DOI: 10.1160/TH13-09-0723
Platelets and Blood Cells
Schattauer GmbH

Risk of bleeding and antibiotic use in patients receiving continuous phenprocoumon therapy

A case-control study nested in a large insurance- and population-based German cohort
Sascha Abbas
1   PMV Research Group at the Department of Child and Adolescent Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany
,
Peter Ihle
1   PMV Research Group at the Department of Child and Adolescent Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany
,
Sebastian Harder
2   Institute of Clinical Pharmacology, University Hospital Frankfurt am Main, Frankfurt am Main, Germany
,
Ingrid Schubert
1   PMV Research Group at the Department of Child and Adolescent Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany
› Author Affiliations
Further Information

Publication History

Received: 02 September 2013

Accepted after major revision: 28 January 2013

Publication Date:
30 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

There is major concern about coumarins interacting with various drug classes and increasing the risk of overanticoagulation. The aim of the study was to assess bleeding risk in patients with concurrent use of antibiotics and phenprocoumon, the most widely prescribed coumarin in many European countries. We conducted a nested-case-control study within a cohort of 513,338 incident and continuous phenpro-coumon users ≥18 years of age using claims data of the statutory health insurance company AOK, covering 30% of the German population. Bleeding risk associated with current use of antibiotics for systemic use (antibacterials/antimycotics) was calculated using conditional logistic regression in 13,785 cases with a bleeding event and 55,140 risk-set sampling-matched controls. Bleeding risk associated with any antibacterial use in phenprocoumon users was significantly increased [odds ratio (OR) 2.37, 95% confidence interval (CI) 2.20–2.56]. The association was stronger for gastrointestinal than for cerebral bleeding (OR 2.09, 95% CI 1.84–2.38 and OR 1.34, 95% CI 1.03–1.74, respectively) and highest for other/unspecified bleeding (OR 2.92, 95% CI 2.62–3.26). Specific antibiotic classes were strongly associated with bleeding risk, e.g. cotrimoxazole (OR 3.86, 95% CI 3.08–4.84) and fluorquinolones (OR 3.13, 95% CI 2.74–3.59), among those highest for ofloxacin (OR 5.00, 95% CI 3.01–8.32). Combined use of phenprocoumon and antimycotics was not significantly associated with bleeding risk. Risk was not significantly modified by age (pint=0.25) or sex (pint=0.96). The association was stronger the closer the antibiotic exposure was to the bleeding event. Among continuous phenprocoumon users, antibiotics – particularly quinolones and co-trimoxazole – should be prescribed after careful consideration due to an increased bleeding risk. Close monitoring of international normalised ratio levels after prescription is recommended.

Keywords

Epidemiological studies - coagulation inhibitors - risk factors
 

  • References

  • 1 Beinema M, Brouwers JR, Schalekamp T. et al. Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon. Thromb Haemost 2008; 100: 1052-1057.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Hein L. Antithrombotika und Antihämorrhagika. In: Arzneiverordnungsreport 2011. Springer Verlag; 2011: 421-439.
    Google Scholar
  • 3 Ufer M. Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol. Clin Pharmacokinet 2005; 44: 1227-1246.
    CrossrefPubMedGoogle Scholar
  • 4 Rane A, Lindh JD. Pharmacogenetics of anticoagulants. Hum Genomics Proteomics 2010; 2010: 754919.
    PubMedGoogle Scholar
  • 5 Kemkes-Matthes B. Anticoagulation by oral treatment with vitamin K antagonists. Hamostaseologie 2008; 28: 421-427.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Toon S, Heimark LD, Trager WF. et al. Metabolic fate of phenprocoumon in humans. J Pharm Sci 1985; 74: 1037-1040.
    CrossrefPubMedGoogle Scholar
  • 7 Ufer M, Svensson JO, Krausz KW. et al. Identification of cytochromes P450 2C9 and 3A4 as the major catalysts of phenprocoumon hydroxylation in vitro. Eur J Clin Pharmacol 2004; 60: 173-182.
    CrossrefPubMedGoogle Scholar
  • 8 Schmiedl S, Rottenkolber M, Szymanski J. et al. Bleeding complications and liver injuries during phenprocoumon treatment: a multicentre prospective observational study in internal medicine departments. Dtsch Arztebl Int 2013; 110: 244-252.
    PubMedGoogle Scholar
  • 9 Holbrook AM, Pereira JA, Labiris R. et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005; 165: 1095-1106.
    CrossrefPubMedGoogle Scholar
  • 10 Juurlink DN. Drug interactions with warfarin: what clinicians need to know. CMAJ 2007; 177: 369-371.
    CrossrefPubMedGoogle Scholar
  • 11 Schelleman H, Bilker WB, Brensinger CM. et al. Warfarin with fluoroquinolones, sulfonamides, or azole antifungals: interactions and the risk of hospitalization for gastrointestinal bleeding. Clin Pharmacol Ther 2008; 84: 581-588.
    CrossrefPubMedGoogle Scholar
  • 12 Zhang K, Young C, Berger J. Administrative claims analysis of the relationship between warfarin use and risk of hemorrhage including drug-drug and drug-disease interactions. J Manag Care Pharm 2006; 12: 640-648.
    PubMedGoogle Scholar
  • 13 Glasheen JJ, Fugit RV, Prochazka AV. The risk of overanticoagulation with antibiotic use in outpatients on stable warfarin regimens. J Gen Intern Med 2005; 20: 653-656.
    CrossrefPubMedGoogle Scholar
  • 14 Gasse C, Hollowell J, Meier CR. et al. 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: 537-543.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Baillargeon J, Holmes HM, Lin YL. et al. Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults. Am J Med 2012; 125: 183-189.
    CrossrefPubMedGoogle Scholar
  • 16 Ghaswalla PK, Harpe SE, Tassone D. et al. Warfarin-antibiotic interactions in older adults of an outpatient anticoagulation clinic. Am J Geriatr Pharmacother 2012; 10: 352-360.
    CrossrefPubMedGoogle Scholar
  • 17 Vitry AI, Roughead EE, Ramsay EN. et al. Major bleeding risk associated with warfarin and co-medications in the elderly population. Pharmacoepidemiol Drug Saf 2011; 20: 1057-1063.
    CrossrefPubMedGoogle Scholar
  • 18 Fischer HD, Juurlink DN, Mamdani MM. et al. Hemorrhage during warfarin therapy associated with cotrimoxazole and other urinary tract anti-infective agents: a population-based study. Arch Intern Med 2010; 170: 617-621.
    CrossrefPubMedGoogle Scholar
  • 19 Visser LE, Penning-van Bees FJ, Kasbergen AA. et al. Overanticoagulation associated with combined use of antibacterial drugs and acenocoumarol or phenprocoumon anticoagulants. Thromb Haemost 2002; 88: 705-710.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Penning-van Beest FJ, Koerselman J, Herings RM. Risk of major bleeding during concomitant use of antibiotic drugs and coumarin anticoagulants. J Thromb Haemost 2008; 06: 284-290.
    CrossrefPubMedGoogle Scholar
  • 21 Jobski K, Behr S, Garbe E. Drug interactions with phenprocoumon and the risk of serious haemorrhage: a nested case-control study in a large population-based German database. Eur J Clin Pharmacol 2011; 67: 941-951.
    CrossrefPubMedGoogle Scholar
  • 22 German Institute of Medical Documentation and Information. ICD-10. International statistical classification of diseases and related health problems, German Modification. Köln, Deutscher Ärzte-Verlag. 2011
    PubMedGoogle Scholar
  • 23 Heller G, Babitsch B, Gunster C. et al. Mortality following myocardial infarction in women and men: an analysis of insurance claims data from inpatient hospitalizations. Dtsch Arztebl Int 2008; 105: 279-285.
    PubMedGoogle Scholar
  • 24 Abbas S, Ihle P, Hein R. et al. Rehabilitation in Geriatric Patients after Ischemic Stroke - A Comparison of 2 Organisational Systems in Germany Using Claims Data of a Statutory Health Insurance Fund]. Rehabilitation 2013; 52: 375-382.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Jeschke E, Heyde K, Gunster C. The relationship of in-hospital and post-discharge complications and implications for quality measurement in hip replacement surgery - an analysis of AOK administrative data. Gesundheitswesen 2013; 75: 288-295.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Schalekamp T, Brasse BP, Roijers JF. et al. VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement. Clin Pharmacol Ther 2007; 81: 185-193.
    CrossrefPubMedGoogle Scholar
  • 27 Reitsma PH, van der Heijden JF, Groot AP. et al. A C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk. PLoS Med 2005; 02: e312.
    CrossrefPubMedGoogle Scholar
  • 28 Rothman KJ, Greenland S, Lash TL. Case-control studies. In: Modern Epidemiology. 3rd. Lippincott Williams and Wilkins; 2008: 111-127.
    Google Scholar
  • 29 GKV-Arzneimittelindex im Wissenschaftlichen Institut der AOK (WIdO). German Anatomical Therapeutic Chemical Classification with defined daily doses −2011. Köln, Deutsches Institut für medizinische Dokumentation und Information (DIMDI). 2011
    PubMedGoogle Scholar
  • 30 Quan H, Sundararajan V, Halfon P. et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care 2005; 43: 1130-1139.
    CrossrefPubMedGoogle Scholar
  • 31 Charlson ME, Pompei P, Ales KL. et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40: 373-383.
    CrossrefPubMedGoogle Scholar
  • 32 Meda Pharma Marcumar Fachinformationon. 2010 Available at: http://www.pharmatrix.de Accessed July 30, 2013.
    PubMed
  • 33 Rote Liste. Cumarin-(4-Hydroxy)-Derivate. Available at: http://www.rote-liste.de Accessed July 30, 2013.
    PubMed
  • 34 Sanofi Tarivid product information. 2012 Available at: http://mein.sanofi.de Accessed Oct 16, 2013.
    PubMed
  • 35 Bayer HealthCare Ciprobay product information. 2012 Available at: http://www.pharmatrix.de/cms/upload/pdf/fachinfo/fi.UAdeQLcD7U.pdf Accessed Oct 16, 2013.
    PubMed
  • 36 Visser LE, Penning-van Beest FJ, Kasbergen AA. et al. Overanticoagulation associated with combined use of antifungal agents and coumarin anticoagulants. Clin Pharmacol Ther 2002; 71: 496-502.
    CrossrefPubMedGoogle Scholar
  • 37 Flockhardt DA. Drug Interaction: Cytochrome P450 Drug Interaction Table. Indiana Univesrity School of Medicine. 2007 Available at: http://medicine.iupui.edu/clinpharm/ddis Accessed July 30, 2013.
    PubMedGoogle Scholar
  • 38 Bungard TJ, Yakiwchuk E, Foisy M. et al. Drug interactions involving warfarin: practice tool and practical management tips. Can Pharm J 2011; 144: 21-25. e9.
    CrossrefPubMedGoogle Scholar
  • 39 Chen WT, White CM, Phung OJ. et al. Are the risk factors listed in warfarin prescribing information associated with anticoagulation-related bleeding?. A systematic literature review. Int J Clin Pract 2011; 65: 749-763.
    CrossrefPubMedGoogle Scholar
  • 40 Hughes M, Lip GY. Risk factors for anticoagulation-related bleeding complications in patients with atrial fibrillation: a systematic review. QJM 2007; 100: 599-607.
    CrossrefPubMedGoogle Scholar
  • 41 Behr S, Schill W, Pigeot I. Does additional confounder information alter the estimated risk of bleeding associated with phenprocoumon use--results of a two-phase study. Pharmacoepidemiol Drug Saf 2012; 21: 535-545.
    CrossrefPubMedGoogle Scholar
  • 42 Delaney JA, Opatrny L, Brophy JM. et al. Confounding in database pharmacoe-pidemiology studies. Epidemiology 2008; 19: 360-361.
    CrossrefPubMedGoogle Scholar
  • 43 Penning-van Beest FJ, van ME, Rosendaal FR. et al. Characteristics of anticoagulant therapy and comorbidity related to overanticoagulation. Thromb Hae-most 2001; 86: 569-574.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Arnason T, Wells PS, van WC. et al. Accuracy of coding for possible warfarin complications in hospital discharge abstracts. Thromb Res 2006; 118: 253-262.
    CrossrefPubMedGoogle Scholar
  • 45 Harder S, Graff J. Novel oral anticoagulants: clinical pharmacology, indications and practical considerations. Eur J Clin Pharmacol 2013; 69: 1617-1633.
    CrossrefPubMedGoogle Scholar
  • 46 Desai J, Kolb JM, Weitz JI. et al. Gastrointestinal bleeding with the new oral anticoagulants - defining the issues and the management strategies. Thromb Hae-most 2013; 110: 205-212.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Lipsky JJ. Antibiotic-associated hypoprothrombinaemia. J Antimicrob Che-mother 1988; 21: 281-300.
    CrossrefPubMedGoogle Scholar
  • 48 Strom BL, Schinnar R, Gibson GA. et al. Risk of bleeding and hypoprothrombi-naemia associated with NMTT side chain antibiotics: using cefoperazone as a test case. Pharmacoepidemiol Drug Saf 1999; 08: 81-94.
    CrossrefPubMedGoogle Scholar
  • 49 Palareti G, Cosmi B. Bleeding with anticoagulation therapy - who is at risk, and how best to identify such patients. Thromb Haemost 2009; 102: 268-278.
    Article in Thieme ConnectPubMedGoogle Scholar