Bleeding with anticoagulation therapy – Who is at risk, and how best to identify such patients

Summary

Anticoagulation with vitamin K antagonists (VKAs) has been shown to be effective in the prevention and treatment of thrombotic complications in various clinical settings, including atrial fibrillation (AF), venous thromboembolism (VTE), acute coronary syndromes and after invasive cardiac procedures. Bleeding is the most important complication of VKAs and a major concern for both physicians and patients. The occurrence of bleeding during treatment is not only important for the treated subjects, but also for a correct and complete use of this therapy in all the subjects who have a clear clinical indication for anticoagulation. This review analyses the treatment- and person- associated risk factors for bleeding during VKAs and their combination in clinical prediction rules that have been proposed in the attempt to identify those patients at higher risk for bleeding. The clinical prediction rules may help physicians stratify patients into categories of risk and thus to evaluate their individual risk/benefit ratio of starting or prolonging an anticoagulant treatment.

Keywords

Anticoagulation - bleeding - vitamin K antagonists - clinical prediction rules

• References

• 1 Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use – A prevalent adverse effect resulting in regulatory action. Arch Intern Med 2007; 167: 1414-1419.
• 2 Cohen N, Sarafian AD, Alon I. et al. Warfarin for stroke prevention still underused in atrial fibrillation – Patterns of omission. Stroke 2000; 31: 1217-1222.
• 3 Hylek EM, Dantonio J, Evans MC. et al. Translating the results of randomized trials into clinical practice – The challenge of warfarin candidacy among hospitalized elderly patients with atrial fibrillation. Stroke 2006; 37: 1075-1080.
• 4 Singer DE, Albers GW, Dalen JE. et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (Suppl. 06) 546S-592S.
• 5 Garcia DA, Witt DM, Hylek E. et al. Delivery of optimized anticoagulant therapy: consensus statement from the Anticoagulation Forum. Ann Pharmacother 2008; 42: 979-988.
• 6 Phillips KW, Ansell J. Outpatient management of oral vitamin K antagonist therapy: defining and measuring high-quality management. Expert Rev Cardiovasc Ther 2008; 06: 57-70.
• 7 Koudstaal PJ, Dehaene I, Dhooghe M. et al. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993; 342: 1255-1262.
• 8 Chesebro JH, Wiebers DO, Holland AE. et al. Bleeding during antithrombotic therapy in patients with atrial fibrillation. Arch Intern Med 1996; 156: 409-416.
• 9 Palareti G, Leali N, Coccheri S. et al. Bleeding complications of oral anticoagulant treatment: an inception- cohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy. Lancet 1996; 348: 423-428.
• 10 Hylek EM, Evans MC, 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.
• 11 Fang MC, Go AS, Chang YC. et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Amer J Med 2007; 120: 700-705.
• 12 Schulman S, Beyth RJ, Kearon C. et al. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (Suppl. 06) 257S-298S.
• 13 Fanikos J, Correnti GN, Shah R. et al. Major bleeding complications in a specialized anticoagulation service. Am J Cardiol 2005; 96: 595-598.
• 14 Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003; 139: 893-900.
• 15 Choudhry NK, Anderson GM, Laupacis A. et al. Impact of adverse events on prescribing warfarin in patients with atrial fibrillation: matched pair analysis. Br Med J 2006; 332: 141-143.
• 16 Albers GW, Amarenco P, Easton JD. et al. Antithrombotic and thrombolytic therapy for ischemic stroke: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (Suppl. 06) 630S-669S.
• 17 Gladstone DJ, Bui E, Fang J. et al. Potentially preventable strokes in high-risk patients with atrial fibrillation who are not adequately anticoagulated. Stroke 2009; 40: 235-240.
• 18 Go AS, Fang MC, Singer DE. Antithrombotic therapy for stroke prevention in atrial fibrillation. Prog Cardiovasc Dis 2005; 48: 108-124.
• 19 Oden A, Fahlen M. Oral anticoagulation and risk of death: a medical record linkage study. Br Med J 2002; 325: 1073-1075.
• 20 Ansell J, Hirsh J, Hylek E. et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (Suppl. 06) 160S-198S.
• 21 White HD, Gruber M, Feyzi J. et al. Comparison of outcomes among patients randomized to warfarin therapy according to anticoagulant control – Results from SPORTIF III and IV. Arch Intern Med 2007; 167: 239-245.
• 22 Pattacini C, Manotti C, Pini M. et al. A comparative study on the quality of oral anticoagulant therapy (warfarin versus acenocoumarol). Thromb Haemost 1994; 71: 188-191.
• 23 Fihn SD, Gadisseur AA, Pasterkamp E. et al. Comparison of control and stability of oral anticoagulant therapy using acenocoumarol versus phenprocoumon. Thromb Haemost 2003; 90: 260-266.
• 24 Kagansky N, Knobler H, Rimon E. et al. Safety of anticoagulation therapy in well-informed older patients. Arch Intern Med 2004; 164: 2044-2050.
• 25 Palareti G, Legnani C, Guazzaloca G. et al. Risks factors for highly unstable response to oral anticoagulation: a case-control study. Br J Haematol 2005; 129: 72-78.
• 26 Siebenhofer A, Berghold A, Sawicki PT. Systematic review of studies of self-management of oral anticoagulation. Thromb Haemost 2004; 91: 225-232.
• 27 Heneghan C, Coello AP, Garcia Alamino JM. et al. Self-monitoring of oral anticoagulation: a systematic review and meta-analysis. Lancet 2006; 367: 404-411.
• 28 Siebenhofer A, Rakovac I, Kleespies C. et al. Selfmanagement of oral anticoagulation reduces major outcomes in the elderly. A randomized controlled trial. Thromb Haemost 2008; 100: 1089-1098.
• 29 Poller L, Keown M, Ibrahim S. et al. An international multicenter randomized study of computer-assisted oral anticoagulant dosage vs. medical staff dosage. J Thromb Haemost 2008; 06: 935-943.
• 30 Oldenburg J, Bevans CG, Fregin A. et al. Current pharmacogenetic developments in oral anticoagulation therapy: The influence of variant VKORCI and CYP2C9 alleles. Thromb Haemost 2007; 98: 570-578.
• 31 Vecsler M, Loebstein R, Almog S. et al. Combined genetic profiles of components and regulators of the vitamin K-dependent gamma-carboxylation system affect individual sensitivity to warfarin. Thromb Haemost 2006; 95: 205-211.
• 32 Herman D, Peternel P, Stegnar M. et al. The influence of sequence variations in factor VII, gammaglutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement. Thromb Haemost 2006; 95: 782-787.
• 33 Takahashi H, Echizen H. Pharmacogenetics of warfarin elimination and its clinical implications. Clin Pharmacokinet 2001; 40: 587-603.
• 34 Joffe HV, Xu R, Johnson FB. et al. Warfarin dosing and cytochrome P450 2C9 polymorphisms. Thromb Haemost 2004; 91: 1123-1128.
• 35 Beinema M, Brouwers JRBJ, Schalekamp T. et al. Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon. Thromb Haemost 2008; 100: 1052-1057.
• 36 D’Andrea G, D’Ambrosio RL, Di Perna P. et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 2005; 105: 645-649.
• 37 Rieder MJ, Reiner AP, Gage BF. et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005; 352: 2285-2293.
• 38 Bodin L, Horellou MH, Flaujac C. et al. A vitamin K epoxide reductase complex subunit-1 (VKORC1) mutation in a patient with vitamin K antagonist resistance. J Thromb Haemost 2005; 03: 1533-1535.
• 39 Harrington DJ, Underwood S, Morse C. et al. Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit I. Thromb Haemost 2005; 93: 23-26.
• 40 Meckley LM, Wittkowsky AK, Rieder MJ. et al. An analysis of the relative effects of VKORC1 and CYP2C9 variants on anticoagulation related outcomes in warfarin-treated patients. Thromb Haemost 2008; 100: 229-239.
• 41 Schwarz UI, Ritchie MD, Bradford Y. et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med 2008; 358: 999-1008.
• 42 Aithal GP, Day CP, Kesteven PJL. et al. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999; 353: 717-719.
• 43 Sconce EA, Khan TI, Wynne HA. et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 2005; 106: 2329-2333.
• 44 Oldenburg J, Quenzel EM, Harbrecht U. et al. Missense mutations at ALA-10 in the factor IX propeptide: an insignificant variant in normal life but a decisive cause of bleeding during oral anticoagulant therapy. Br J Haematol 1997; 98: 240-244.
• 45 Legnani C, Promenzio M, Guazzaloca G. et al. Assessment of activated partial thromboplastin time and factor IX in subjects attending an anticoagulation clinic. Blood Coagul Fibrinolysis 2000; 11: 537-542.
• 46 Launbjerg J, Egeblad H, Heaf J. et al. Bleeding complications to oral anticoagulant therapy: multivariate analysis of 1,010 treatment years in 551 outpatients. J Intern Med 1991; 229: 351-355.
• 47 Hylek EM, Singer DE. Risk factors far intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120: 897-902.
• 48 Fihn 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.
• 49 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.
• 50 Wickramasinghe LSP, Basu SK, Bansal SK. Longterm oral anticoagulant therapy in elderly patients. Age Ageing 1988; 17: 388-396.
• 51 Redwood M, Taylor C, Bain BJ. et al. The association of age with dosage requirement for warfarin. Age Ageing 1991; 20: 217-220.
• 52 Keeling D. Duration of anticoagulation: decision making based on absolute risk. Blood Rev 2006; 20: 173-178.
• 53 Hart RG, Boop BS, Anderson DC. Oral anticoagulants and intracranial hemorrhage – facts and hypotheses. Stroke 1995; 26: 1471-1477.
• 54 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.
• 55 Fang MC, Chang YC, 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.
• 56 Russmann S, Gohlke-Barwolf C, Jahnchen E. et al. Age-dependent differences in the anticoagulant effect of phenprocoumon in patients after heart valve surgery. Eur J Clin Pharmacol 1997; 52: 31-35.
• 57 Garcia D, 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.
• 58 Shorr RI, Ray WA, Daugherty JR. et al. Concurrent use of nonsteroidal anti-inflammatory drugs and oral anticoagulants places elderly persons at high risk for hemorrhagic peptic ulcer disease. Arch Intern Med 1993; 153: 1665-1670.
• 59 Rosand J, Hylek EM, Odonnell HC. et al. Warfarinassociated hemorrhage and cerebral amyloid angiopathy – A genetic and pathologic study. Neurology 2000; 55: 947-951.
• 60 Smith EE, Rosand J, Knudsen KA. et al. Leukoaraiosis is associated with warfarin-related hemorrhage following ischemic stroke. Neurology 2002; 59: 193-197.
• 61 Gage BF, BirmanDeych E, Kerzner R. et al. Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall. Am J Med 2005; 118: 612-617.
• 62 Longstreth GF. Epidemiology and outcome of patients hospitalized with acute lower gastrointestinal hemorrhage: a population-based study. Am J Gastroenterol 1997; 92: 419-424.
• 63 Arnsten JH, Gelfand JM, Singer DE. Determinants of compliance with anticoagulation: a case-control study. Am J Med 1997; 103: 11-17.
• 64 Palareti G, Poggi M, Guazzaloca G. et al. Assessment of mental ability in elderly anticoagulated patients: its reduction is associated with a less satisfactory quality of treatment. Blood Coagul Fibrinolysis 1997; 08: 411-417.
• 65 Mant J, Hobbs FDR, Fletcher K. et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (The Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 2007; 370: 493-503.
• 66 Sam C, Massaro JM, Dagostino RB. et al. Warfarin and aspirin use and the predictors of major bleeding complications in atrial fibrillation (The Framingham heart study). Am J Cardiol 2004; 94: 947-951.
• 67 Shireman TI, Howard PA, Kresowik TF. et al. Combined anticoagulant-antiplatelet use and major bleeding events in elderly atrial fibrillation patients. Stroke 2004; 35: 2362-2367.
• 68 Pengo V, Legnani C, Noventa F. et al. Oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and risk of bleeding – A multicenter inception cohort study. Thromb Haemost 2001; 85: 418-422.
• 69 Barcellona D, Contu P, Marongiu F. Patient education and oral anticoagulant therapy. Haematologica 2002; 87: 1081-1086.
• 70 Tang EO, Lai CS, Lee KK. et al. Relationship between patients’ warfarin knowledge and anticoagulation control. Ann Pharmacother 2003; 37: 34-39.
• 71 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.
• 72 O’Reilly RA, Rytand DA. “Resistance” to warfarin due to un recognized vitamin K supplemantation. New Engl J Med 1980; 303: 160-161.
• 73 Pedersen FM, Hamberg O, Hess K. et al. The Effect of Dietary Vitamin-K on Warfarin-Induced Anticoagulation. J Intern Med 1991; 229: 517-520.
• 74 Kalra PA, Cooklin M, Wood G. et al. Dietary modification as cause of anticoagulation instability. Lancet 1988; ii: 803.
• 75 Chow WH, Chow TC, Tse TM. et al. Anticoagulation instability with life-threatening complication after dietary modification. Postgrad Med J 1990; 66: 855-857.
• 76 Reese AM, Farnett LE, Lyons RM. et al. Low-dose vitamin K to augment anticoagulation control. Pharmacotherapy Dec 2005; 25: 1746-1751.
• 77 Sconce E, Khan T, Mason J. et al. Patients with unstable control have a poorer dietary intake of vitamin K compared to patients with stable control of anticoagulation. Thromb Haemost 2005; 93: 872-875.
• 78 Sconce E, Avery P, Wynne H. et al. Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Blood 2007; 109: 2419-2423.
• 79 Rombouts EK, Rosendaal FR, FJ VDM. Daily vitamin K supplementation improves anticoagulant stability. J Thromb Haemost 2007; 05: 2043-2048.
• 80 Wittkowsky AK, Bussey HI, Walker MB. et al. Dietary supplement use among anticoagulation clinic patients. J Thromb Haemost 2007; 05: 875-877.
• 81 DiMarco JP, Flaker G, Waldo AL. et al. Factors affecting bleeding risk during anticoagulant therapy in patients with atrial fibrillation: Observations from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Study. Am Heart J 2005; 149: 650-656.
• 82 McMahan DA, Smith DM, Carey MA. et al. Risk of major hemorrhage for outpatients treated with warfarin. J Gen Intern Med 1998; 13: 311-316.
• 83 Hughes M, Lip GYH. Risk factors for anticoagulation-related bleeding complications in patients with atrial fibrillation: a systematic review. QJM 2007; 100: 599-607.
• 84 Abdelhafiz AH, Wheeldon NM. Results of an open-label, prospective study of anticoagulant therapy for atrial fibrillation in an outpatient anticoagulation clinic. Clin Ther 2004; 26: 1470-1478.
• 85 Lip GY, Frison L, Grind M. Effect of hypertension on anticoagulated patients with atrial fibrillation. Eur Heart J 2007; 28: 752-759.
• 86 Hart RG, Tonarelli SB, Pearce LA. Avoiding central nervous system bleeding during antithrombotic therapy recent – Data and ideas. Stroke 2005; 36: 1588-1593.
• 87 Palareti G, Legnani C, Lee A. et al. A comparison of the safety and efficacy of oral antiocoagulation for the treatment of venous thromboembolic disease in patients with or without malignancy. Thromb Haemost 2000; 84: 805-810.
• 88 Gitter MJ, Jaeger TM, Petterson TM. et al. Bleeding and thromboembolism during anticoagulant therapy: a population-based study in rochester, minnesota. Mayo Clin Proc 1995; 70: 725-733.
• 89 Prandoni P, Lensing AWA, 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.
• 90 Bona RD, Sivjee KY, Hickey AD. et al. The efficacy and safety of oral anticoagulation in patients with cancer. Thromb Haemost 1995; 74: 1055-1058.
• 91 Lee AYY, Levine MN, Baker RI. et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349: 146-153.
• 92 Kearon C, Kahn SR, Agnelli G. et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence- Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (Suppl. 06) 454S-545S.
• 93 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.
• 94 Beyth RJ, Landefeld CS. Anticoagulants in older patients: a safety perspective. Drugs Aging 1995; 06: 45-54.
• 95 Battistella M, Mamdami MM, Juurlink DN. et al. Risk of upper gastrointestinal hemorrhage in warfarin users treated with nonselective NSAIDs or COX-2 inhibitors. Arch Intern Med 2005; 165: 189-192.
• 96 Schalekamp T, Klungel OH, Souverein PC. et al. Effect of oral antiplatelet agents on major bleeding in users of coumarins. Thromb Haemost 2008; 100: 1076-1083.
• 97 Dentali F, Douketis JD, Lim W. et al. Combined aspirin-oral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease – A meta-analysis of randomized trials. Arch Intern Med 2007; 167: 117-124.
• 98 Lip GY. Don’t add aspirin for associated stable vascular disease in a patient with atrial fibrillation receiving anticoagulation. Br Med J 2008; 336: 614-615.
• 99 Kucher N, Castellanos LR, Quiroz R. et al. Time trends in warfarin-associated hemorrhage. Am J Cardiol 2004; 94: 403-406.
• 100 Fanikos J, Stapinski C, Koo S. et al. Medication errors associated with anticoagulant therapy in the hospital. Am J Cardiol 2004; 94: 532-535.
• 101 Koo S, Kucher N, Nguyen PL. et al. The effect of excessive anticoagulation on mortality and morbidity in hospitalized patients with anticoagulant-related major hemorrhage. Arch Intern Med 2004; 164: 1557-1560.
• 102 Landefeld CS, 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.
• 103 Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med 1998; 105: 91-99.
• 104 Kuijer PMM, 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.
• 105 Gage BF, Yan Y, Milligan PE. et al. Clinical classification schemes for predicting hemorrhage: Results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J 2006; 151: 713-719.
• 106 Shireman TI, Mahnken JD, Howard PA. et al. Development of a contemporary bleeding risk model for elderly warfarin recipients. Chest 2006; 130: 1390-1396.
• 107 Ruiz-Gimenez N, Suarez C, Gonzalez R. et al. Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost 2008; 100: 26-31.
• 108 Wells PS, Forgie MA, Simms M. et al. The outpatient bleeding risk index: validation of a tool for predicting bleeding rates in patients treated for deep venous thrombosis and pulmonary embolism. Arch Intern Med 2003; 163: 917-920.
• 109 Aspinall SL, DeSanzo BE, Trilli LE. et al. Bleeding Risk Index in an anticoagulation clinic. Assessment by indication and implications for care. J Gen Intern Med 2005; 20: 1008-1013.
• 110 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.
• 111 FDA. FDA approves updated warfarin (Coumadin) prescribing information. August 16. Accessed on 28th April 2009.
• 112 Shurin SB, Nabel EG. Pharmacogenomics--ready for prime time?. N Engl J Med 2008; 358: 1061-1063.
• 113 Canadian Agency for Drugs and Technologies in Health. Pharmacogenomics and warfarin therapy. 2007 Issue # 104.
• 114 Anderson JL, Horne BD, Stevens SM. et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 2007; 116: 2563-2570.
• 115 Lenzini PA, Grice GR, Milligan PE. et al. Laboratory and clinical outcomes of pharmacogenetic vs. clinical protocols for warfarin initiation in orthopedic patients. J Thromb Haemost 2008; 06: 1655-1662.
• 116 Voora D, Eby C, Linder MW. et al. Prospective dosing of warfarin based on cytochrome P-4502C9 genotype. Thromb Haemost 2005; 93: 700-705.
• 117 Wen MS, Lee M, Chen JJ. et al. Prospective study of warfarin dosage requirements based on CYP2C9 and VKORC1 genotypes. Clin Pharmacol Ther 2008; 84: 83-89.
• 118 Lindh JD, Holm L, Andersson ML. et al. Influence of CYP2C9 genotype on warfarin dose requirements--a systematic review and meta-analysis. Eur J Clin Pharmacol 2009; 65: 365-375.
• 119 McClain MR, Palomaki GE, Piper M. et al. A rapid-ACCE review of CYP2C9 and VKORC1 alleles testing to inform warfarin dosing in adults at elevated risk for thrombotic events to avoid serious bleeding. Genet Med 2008; 10: 89-98.
• 120 Kangelaris KN, Bent S, Nussbaum RL. et al. Genetic testing before anticoagulation? A systematic review of pharmacogenetic dosing of warfarin. J Gen Intern Med 2009; 24: 656-664.
• 121 Hillman MA, Wilke RA, Yale SH. et al. A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data. Clin Med Res 2005; 03: 137-145.
• 122 Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin Pharmacol Ther 2008; 83: 460-470.
• 123 Eckman MH, Rosand J, Greenberg SM. et al. Costeffectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation. Ann Intern Med 2009; 150: 73-83.
• 124 Klein TE, Altman RB, Eriksson N. et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 2009; 360: 753-764.