Risk factors of vitamin K antagonist overcoagulation

Summary

The aims of this case-control study were to identify in vitamin K antagonist (VKA)-treated unselected patients, factors associated with international normalised ratio (INR) values: (i) greater than 6.0.;and (ii) ranging from 4.0 to 6.0 complicated with bleeding. We also assessed VKA-related morbidity in these patients. During a two-month period, 4,188 consecutive and unselected patients were referred to our Emergency Department. At admission, the medical records of each patient and two age- and sex-matched controls were reviewed for: both duration and indication of VKA therapy, previous medical history of VKA-related haemorrhage, underlying co-morbidities, concomitant medications other than VKA, duration of hospitalization and deaths’ causes. Of these 4,188 subjects,50 case-patients (1.19%) were identified; both case-patients and controls did not differ as regards indications and patterns of VKA therapy. Interestingly, two-thirds of case-patients were women, suggesting that female gender may be a risk factor of VKA over-coagulation onset. We identified the following risk factors of VKA over-coagulation: previous medical history of INR levels over therapeutic range, therapy with antibiotics, amiodarone and proton pump inhibitors, as well as fever. A total of 88% of case-patients were hospitalized; mean duration of patients’ hospitalization was seven days [range:1–56 days];no patient died from major bleeding. Our study underscores that it is of utmost importance to consider the strength of indication before starting VKA therapy, as this therapy has been responsible for as high as 1.19% of admissions in unselected subjects referred to an Emergency Department. Our data therefore suggest that internists should be aware of VKA-related high morbidity, particularly in situations at risk of VKA over-coagulation.

Keywords

Vitamin K antagonist - haemorrhage - risk factors - proton pump inhibitors - gender - outcome - morbidity - mortality

• References

• 1 Gitter MJ, Jaeger TM, Pettersson TM. et al. Bleeding and thromboembolism during anticoagulant therapy: a population-based study in Rochester, Minnesota. Mayo Clin Proc 1995; 70: 725-733.
• 2 Landefeld S, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Am J Med 1989; 87: 144-152.
• 3 Launjberg J, Egeblad H, Heaf J. et al. Bleeding complications to oral anticoagulant therapy: multivariate analysis of 1010 treatment years in 551 outpatients. J Intern Med 1991; 229: 351-355.
• 4 Levine MN, Raskog G, Beyth RJ. et al. Hemorrhagic complications of anticoagulant treatment: the seventh ACPP conference on antithrombotic and thrombolytic therapy. Chest 2004; 126: 287S-310S.
• 5 Levine MN, Raskog G, Landefeld S. et al. Hemorrhagic complications of anticoagulant treatment. Chest 2001; 119: 108S-21S.
• 6 McMahan DA, Smith DM, Carey MA, Zhou XH. Risk of major hemorrhage for outpatients treated with warfarin. J Gen Intern Med 1998; 13: 311-316.
• 7 Palareti G, Leali N, Coccheri S. et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet 1996; 348: 423-428.
• 8 Van der Meer FJ, Rosendaal FR, Vandenbroucke JP, Briët E. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Arch Intern Med 1993; 153: 1557-1562.
• 9 Van der Meer FJ, Rosendaal FR, Vandenbroucke JP, Briët E. Assessment of a bleeding risk index in two cohorts of patients treated with oral anticoagulants. Thromb Haemost 1996; 76: 12-16.
• 10 Berwaerts J, Webster J. Analysis of risk factors involved in oral-anticoagulant-related intracranial hemorrhages. Q J Med 2000; 93: 513-521.
• 11 Beyth RJ, Quinn L, Landefeld CS. A multicomponent intervention to prevent major bleeding complications in older patients receiving warfarin. A randomized, controlled trial. Ann Intern Med 2000; 133: 687-695.
• 12 Dahri K, Loewen P. The risk of bleeding with warfarin: a systematic review and performance analysis of clinical prediction rules. Thromb Haemost 2007; 98: 980-987.
• 13 Garcia AA, van der Hoeven NV, Boellard TN. et al. Fibrinogen Alpha 312 and Beta 448 polymorphisms are not related to bleeding during oral vitamin K-antagonist treatment. Thromb Haemost 2007; 97: 676-678.
• 14 Finh SD, Callahan CM, Martin DC. et al. The risk for and severity of bleeding complications in elderly patients treated with warfarin. Ann Intern Med 1996; 124: 970-979.
• 15 Finh SD, McDonell M, Martin D, Henikoff J, Vermes D, Kent D, White RH. Risk factors for complications of chronic anticoagulation: a multicenter study. Ann Intern Med 1993; 118: 511-520.
• 16 Garcia DA, Regan S, Crowther M. et al. Warfarin maintenance dosing patterns in clinical practice: implications for safer anticoagulation in the elderly population. Chest 2005; 127: 2049-2056.
• 17 Garcia DA, Regan S, Crowther M. et al. The risk of hemorrhage among patients with warfarin-associated coagulopathy. J Am Coll Cardiol 2006; 47: 804-808.
• 18 Hylek EM, Evans-Molina C, Shea C. et al. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007; 115: 2689-2696.
• 19 Hylek EM, Heiman H, Skates SJ. et al. Acetaminophen and other risk factors for excessive warfarin anticoagulation. J Am Med Assoc 1998; 279: 657-662.
• 20 Hylek EM, Regan S, Go AS. et al. Clinical predictors of prolonged delay in return of the international normalized ratio to within the therapeutic range after excessive anticoagulation with warfarin. Ann Intern Med 2001; 135: 393-400.
• 21 Kuijer PM, Hutten BA, Prins MH. et al. Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med 1999; 159: 457-460.
• 22 Oldenburg J. Vitamin K intake and atability of oral anticoagulant treatment. Thromb Haemost 2005; 93: 799-800.
• 23 Oldenburg J, Bevans CG, Fregin A. et al. Current pharmacogenetic developments in oral anticoagulation therapy: the influence of variant VKORC1 and CYP2C9 alleles. Thromb Haemost 2007; 98: 570-578.
• 24 Palareti G, Hirsh J, Legnani C. et al. Oral anticoagulation treatment in the elderly. A nested, prospective, case-control study. Arch Intern Med 2000; 160: 470-478.
• 25 Prandoni P, Lensing AW, Piccioli A. et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100: 3484-3488.
• 26 Waldvogel Abramowski S, Boehlen F. et al. Discrepancy between capillary and venous International Normalised Ratio (INR) in a patient on vitamin-K antagonist: potentially serious clinical consequences. Thromb Haemost 2006; 96: 688-689.
• 27 Wehinger C, Stöllberger C, Länger T. et al. Evaluation of risk factors for stroke/embolism and of complications due to anticoagulation therapy in atrial fibrillation. Stroke 2001; 32: 2246-2252.
• 28 White RH, Beyth RJ, Zhou H. et al. Major bleeding after hospitalization for dee-venous thrombosis. Am J Med 1999; 107: 414-424.
• 29 Atrial Fibrillation Investigators Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994; 154: 1449-1457.
• 30 Fang MC, Chang Y, Hylek EM. et al. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med 2004; 141: 745-752.
• 31 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.
• 32 Samuel N. Herbal remedies and anticoagulant therapy. Thromb Haemost 2005; 93: 3-7.
• 33 Schulman S, Beyth RJ. Risk of bleeding with long-term antithrombotic therapy in atrial fibrillation. Eur Heart J 2005; 07 (Suppl C): C 34-40.
• 34 Torn M, Bollen WLEM, van der Meer FJM. et al. Risks of oral anticoagulant therapy with increasing age. Arch Intern Med 2005; 165: 1527-1532.
• 35 Vinker S, Shani M, Baevsky T. et al. Adherence with statins over 8 years in a usual care setting. Am J Manag Care 2008; 14: 388-392.
• 36 Kimmel SE, Chen Z, Price M. et al. The influence of patient adherence on anticoagulation control with warfarin. Results from the International Normalized Ratio adherence and genetics (IN-RANGE) study. Arch Intern Med 2007; 167: 229-235.
• 37 Penning-van Beest FJ, van Meegen E, Rosendaal FR. et al. Characteristics of anticoagulant therapy and comorbidity related to overcoagulation. Thromb Haemost 2001; 86: 569-574.
• 38 Kagansky N, Knobler H, Rimon E, Ozer Z, Levy S. Safety of anticoagulation therpay in well-informed older patients. Arch Intern Med 2004; 164: 2044-2050.
• 39 Visser LE, Penning-van Beest FJ, Kasbergen AA. et al. Overanticoagulation associated with combined use of antibacterial drugs and acenocoumarol of phenprocoumon anticoagulants. Thromb Haemost 2002; 88: 705-710.
• 40 Gage B, Eby C, Johnson J. et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther. 2008 Epub ahead of print.
• 41 Lu Y, Won KA, Nelson BJ. et al. Characteristics of the amiodarone-warfarin interaction during long-term follow-up. Am J Health Syst Pharm 2008; 65: 947-952.
• 42 Whitley HP, Fermo JD, Chumney ECG. et al. Effect of patient-specific factors on weekly warfarin dose. Ther Clin Risk Manag 2007; 03: 499-504.
• 43 Heimark LD, Wienkers L, Kunze K. et al. The mechanism of the intercation between amiodarone and warfarin in humans. Clin Pharmacol Ther 1992; 51: 398-407.
• 44 Hermans JJ, Thijssen HH. Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isoenzyme diversity determines the differences in their pharmacokinetics. Br J Pharmacol 1993; 110: 482-490.
• 45 Holbrook AM, Pereira JA, Labiris R. et al. Dystematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005; 165: 1095-1106.
• 46 Sutfin T, Balmer K, Boström H. et al. Stereoselective interaction of omeprazole with warfarin in healthy men. Ther Drug Monit 1989; 11: 176-184.
• 47 Unge P, Svedberg LE, Nordgren A. et al. A study of the interaction of omeprazole and warfarin in anticoagulated patients. Br J Clin Pharmac 1992; 34: 509-512.
• 48 Zhou Q, Zhou S, Chan E. Effect of omeprazole on the hydroxylation of warfarin enantiomers in human: in-vitro studies with liver microsomes and cDNA-expressed cytochrome P450 isoenzymes. Curr Drug Metab 2005; 06: 399-411.
• 49 Blume H, Donath F, Warnke A. et al. Pharmacokinetic drug profiles of proton pump inhibitors. Drug Saf 2006; 29: 769-784.
• 50 Gullov AL, Koefoed BG, Petersen P. Bleeding during warfarin and aspirin therapy in patients with atrial fibrillation. Arch Intern Med 1999; 159: 1322-1328.
• 51 Fiore LD, Ezekowitz MD, Brophy MT. et al. Combination Hemotherapy and Mortality Prevention (CHAMP) Study Group. Department of Veterans Affairs Cooperative Studies Program Clinical Trial comparing combined warfarin and aspirin with aspirin alone in survivors of acute myocardial infarction: primary results of the CHAMP study. Circulation 2002; 105: 557-563.
• 52 Parra D, Beckley NP, Stevens GR. The effect of acetaminophen on the international ratio in patients stabilized on warfarin therapy. Pharmacotherapy 2007; 27: 675-683.
• 53 Douketis JD, Melo M, Bell CM. et al. Does statin therapy decrease the risk for bleeding in patients who are receiving warfarin?. Am J Med 2007; 120: 369.e9-369.e14.
• 54 Steffensen FH, Kristensen K, Ejlersen E. et al. Major haemorrhagic complications during oral anticoagulant therapy in a Danish population-based cohort. J Intern Med 1997; 242: 497-503.