The risk of bleeding with anticoagulant treatments

Summary

Anticoagulant treatments are given to prevent and/or treat thrombotic complications in many clinical conditions, including atrial fibrillation (the most frequent indication for anticoagulant treatment), venous thromboembolism, acute coronary syndromes and after invasive cardiac procedures. Anticoagulation with vitamin K antagonists (VKAs) is currently almost the unique kind of therapy for chronic anticoagulation. It is highly effective in the prevention or treatment of thrombotic events but it is associated with a non negligible risk of bleeding, that is the most important complication of this therapy and a major concern for both physicians and patients. The risk of bleeding and the difficulties for the patients and health care providers associated with the necessary correct management of this treatment are limiting factors for a more widespread prescription of the treatment, leaving without an effective therapy a significant proportion of patients who would have a clear clinical indication for chronic anticoagulation. This review analyses the treatment- and person-associated risk factors for bleeding during VKAs and the tools that have been proposed to assess the individual risk of bleeding. New oral anticoagulant drugs seem to overcome at least some of the limitations of VKAs. Potentially, they can allow a less demanding and more stable anticoagulant treatment, with less side-effects allowing that more patients can receive an appropriate anticoagulant treatment. Based on the so far available phase III clinical studies, it is possible to assume that also these new drugs are associated with a risk of bleeding, that is probably related to the intensity of treatment.

Zusammenfassung

Antikoagulanzien werden verordnet, um thrombotische Komplikationen in vielen klinischen Situationen zu verhindern oder zu be-handeln, wie arterielles Vorhofflimmern (die häufigste Indikation für Antikoagulation), venöse Thromboembolien, akute Koronarsyndrome, sowie nach invasiven kardialen Eingriffen. Antikoagulation mit Vitamin-K-Antagonisten (VKA) ist momentan die einzige The-rapieart für chronische Antikoagulation. Sie ist hocheffektiv in der Prävention oder Be-handlung thrombotischer Ereignisse, ist aber auch negativ assoziiert mit einem nicht zu vernachlässigenden Blutungsrisiko, welches die bedeutendste Komplikation ist und ein großes Problem für Ärzte und Patienten darstellt. Das Blutungsrisiko und die Schwierigkeiten für die Patienten und Ärzte im Zusammenhang mit dem notwendigen korrekten Management dieser Behandlung sind limitierende Faktoren für eine weiter reichende Verordnung, die deshalb einen erheblichen Anteil von Patienten ohne effektive Therapie lässt, welche deutliche klinische Indikationen für eine chronische Antikoagulation haben. Dieses Review analysiert die behandlungs- und personen-assoziierten Risiken für Blutungen bei Gabe von VKAs und die Möglichkeiten, wie individuellen Blutungsrisiken bestimmt werden können. Neue orale Antikoagulanzien scheinen zumindest einige der Begrenzungen der VKAs aufzuheben. Potenziell erlauben sie eine weniger anspruchsvolle und stabilere Antikoagulation mit weniger Nebenwirkungen und somit breiterer Anwendungsmöglichkeit für mehr Pa-tienten. Ausgehend von den momentan verfügbaren Phase-III-Studien sind auch die neu-en Medikamente mit einem Blutungsrisiko as-soziiert, das vermutlich mit der Intensität der Behandlung zusammen hängt.

Keywords

Anticoagulation - bleeding - vitamin K antagonists - new oral anticoagulants

Schlüsselwörter

Antikoagulation - Blutung - Vitamin-K-Antagonisten - neue orale Antikoagulanzien

• References

• 1 Hylek EM, Henault LE, EvansMolina C. et al. The hurdles of warfarin and the hurdles of clinical practice – Response to letter by Testa. et al. Stroke 2006; 37: 2868
• 2 Fanikos J, GrassoCorrenti N, Shah R. et al. Major bleeding complications in a specialized anticoagulation service. Am J Cardiol 2005; 96: 595-598.
• 3 Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a metaanalysis. Ann Intern Med 2003; 139: 893-900.
• 4 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: 257S-298S.
• 5 Atrial Fibrillation I. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Arch Intern Med 1994; 154: 1449-1457.
• 6 Ost D. Continuing anticoagulation following venous thromboembolism – Reply. JAMA Journal of the American Medical Association 2005; 294: 3088-3089.
• 7 Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3: 692-694.
• 8 Levi M, Hovingh GK, Cannegieter SC. et al. Bleeding in patients receiving vitamin K antagonists who would have been excluded from trials on which the indication for anticoagulation was based. Blood 2008; 111: 4471-4476.
• 9 Hylek EM, EvansMolina 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.
• 10 Palareti G, Leali N, Coccheri S. et al. Bleeding complications of oral anticoagulant treatment: an inceptioncohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy. Lancet 1996; 348: 423-428.
• 11 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.
• 12 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.
• 13 Poli D, Antonucci E, Grifoni E. et al. Bleeding risk during oral anticoagulation in atrial fibrillation patients older than 80 years. J Am Coll Cardiol 2009; 54: 999-1002.
• 14 Wickramasinghe LSP, Basu SK, Bansal SK. Longterm oral anticoagulant therapy in elderly patients. Age Ageing 1988; 17: 388-396.
• 15 Redwood M, Taylor C, Bain BJ. et al. The association of age with dosage requirement for warfarin. Age Ageing 1991; 20: 217-220.
• 16 Keeling D. Duration of anticoagulation: decision making based on absolute risk. Blood Rev 2006; 20: 173-178.
• 17 Hylek EM, Singer DE. Risk factors far intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120: 897-902.
• 18 Hart RG, Boop BS, Anderson DC. Oral anticoagulants and intracranial hemorrhage – facts and hypotheses. Stroke 1995; 26: 1471-1477.
• 19 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.
• 20 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.
• 21 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.
• 22 Longstreth GF. Epidemiology and outcome of patients hospitalized with acute lower gastrointestinal hemorrhage: a population-based study. Am J Gastroenterol 1997; 92: 419-424.
• 23 Smith EE, Rosand J, Knudsen KA. et al. Leukoaraiosis is associated with warfarin-related hemorrhage following ischemic stroke. Neurology 2002; 59: 193-197.
• 24 Torn M, Algra A, Rosendaal FR. Oral anticoagulation for cerebral ischemia of arterial origin: high initial bleeding risk. Neurology 2001; 57: 1993-1999.
• 25 Dahl T, Abildgaard U, Sandset PM. Long-term anticoagulant therapy in cerebrovascular disease: does bleeding outweigh the benefit?. J Intern Med 1995; 237: 323-329.
• 26 Petty GW, Brown RD, Whisnant JP. et al. Frequency of major complications of aspirin, warfarin, and intravenous heparin for secondary stroke prevention – A population-based study. Ann Intern Med 1999; 130: 14-22.
• 27 Algra A. Oral anticoagulation in patients after cerebral ischemia of arterial origin and risk of intracranial hemorrhage. Stroke 2003; 34: E45-E46.
• 28 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.
• 29 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.
• 30 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.
• 31 Hutten BA, Prins MH, Gent M. et al. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: A retrospective analysis. J Clin Oncol 2000; 18: 3078-3083.
• 32 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.
• 33 Hart RG, Benavente O, Pearce LA. Increased risk of intracranial hemorrhage when aspirin is combined with warfarin: A meta-analysis and hypothesis. Cerebrovasc Dis 1999; 9: 215-217.
• 34 Rothberg MB, Celestin C, Fiore LD. et al. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: Meta-analysis with estimates of risk and benefit. Ann Intern Med 2005; 143: 241-250.
• 35 Sorensen R, Hansen ML, Abildstrom SZ. 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: 1967-1974.
• 36 Mellemkjaer L, Blot WJ, Sorensen HT. et al. Upper gastrointestinal bleeding among users of NSAIDs: a population-based cohort study in Denmark. Br J Clin Pharmacol 2002; 53: 173-181.
• 37 Landefeld CS, Rosenblatt MW, Goldman L. Bleeding in outpatients treated with warfarin: relation to the prothrombin time and important remediable lesions. Am J Med 1989; 87: 153-159.
• 38 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.
• 39 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.
• 40 Joffe HV, Xu R, Johnson FB. et al. Warfarin dosing and cytochrome P450 2C9 polymorphisms. Thromb Haemost 2004; 91: 1123-1128.
• 41 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.
• 42 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.
• 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 Hylek EM, Go AS, Chang YC. et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003; 349: 1019-1026.
• 47 Rosendaal FR, Cannegieter SC, Vandermeer FJM. et al. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69: 236-237.
• 48 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: 160S-198S.
• 49 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.
• 50 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.
• 51 Chiquette E, Amato MG, Bussey HI. Comparison of an anticoagulation clinic with usual medical care: anticoagulation control, patient outcomes, and health care costs. Arch Intern Med 1998; 158: 1641-1647.
• 52 Heneghan C, AlonsoCoello P, GarciaAlamino JM. et al. Self-monitoring of oral anticoagulation: a systematic review and meta-analysis. Lancet 2006; 367: 404-411.
• 53 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; 6: 935-943.
• 54 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.
• 55 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.
• 56 Shireman TI, Mahnken JD, Howard PA. et al. Development of a contemporary bleeding risk model for elderly warfarin recipients. Chest 2006; 130: 1390-1396.
• 57 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.
• 58 Pisters R, Lane DA, Nieuwlaat R. et al. A novel userfriendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138: 1093-1100.
• 59 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.
• 60 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
• 61 Eikelboom JW, Wallentin L, Connolly SJ. et al. Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation: An Analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial. Circulation 2011; 123: 2363-2372.
• 62 Connolly SJ, Eikelboom J, Joyner C. et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364: 806-817.
• 63 Schulman S, Kearon C, Kakkar AK. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361: 2342-2352.
• 64 Bauersachs R, Berkowitz SD, Brenner B. et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499-2510.
• 65 Steffel J, Braunwald E. Novel oral anticoagulants: focus on stroke prevention and treatment of venous thromboembolism. Eur Heart J. 2011. doi: 10.1093/eurheartj/ehr052