ABC OF ANTITHROMBOTIC THERAPY To Peck Lin, Philomena, and Aloysius To Janet, Edward, Eleanor, and Rosalind ABC OF ANTITHROMBOTIC THERAPY Edited by GREGORY Y H LIP Professor of cardiovascular medicine and director, haemostasis, thrombosis and vascular biology unit, university department of medicine, City Hospital, Birmingham and ANDREW D BLANN Senior lecturer in medicine, haemostasis, thrombosis and vascular biology unit, university department of medicine, City Hospital, Birmingham © BMJ Publishing Group 2003 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording and/or otherwise, without the prior written permission of the publishers. First published in 2003 by BMJ Publishing Group Ltd, BMA House, Tavistock Square, London WC1H 9JR www.bmjbooks.com British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN 0 7279 17714 Typeset by BMJ Electronic Production and Newgen Imaging Systems Printed and bound in Spain by GraphyCems, Navarra Cover image depicts a deep vein thrombosis scan of a leg vein blocked by a thrombus (blood clot, white) in a patient with deep vein thrombosis. With permission from James King-Holmes/Science Photo Library v Contents Contributors vi Preface vii 1 An overview of antithrombotic therapy 1 Andrew D Blann, Martin J Landray, Gregory Y H Lip 2 Bleeding risks of antithrombotic therapy 5 David A Fitzmaurice, Andrew D Blann, Gregory Y H Lip 3 Venous thromboembolism: pathophysiology, clinical features, and prevention 9 Alexander G G Turpie, Bernard S P Chin, Gregory Y H Lip 4 Venous thromboembolism: treatment strategies 13 Alexander G G Turpie, Bernard S P Chin, Gregory Y H Lip 5 Antithrombotic therapy for atrial fibrillation: clinical aspects 16 Gregory Y H Lip, Robert G Hart, Dwayne S G Conway 6 Antithrombotic therapy for atrial fibrillation: pathophysiology, acute atrial fibrillation, and cardioversion 20 Gregory Y H Lip, Robert G Hart, Dwayne S G Conway 7 Antithrombotic therapy in peripheral vascular disease 24 Andrew J Makin, Stanley H Silverman, Gregory Y H Lip 8 Antithrombotic therapy for cerebrovascular disorders 28 Gregory Y H Lip, Sridhar Kamath, Robert G Hart 9 Valvar heart disease and prosthetic heart valves 31 Ira Goldsmith, Alexander G G Turpie, Gregory Y H Lip 10 Antithrombotic therapy in myocardial infarction and stable angina 35 Gregory Y H Lip, Bernard S P Chin, Neeraj Prasad 11 Antithrombotic therapy in acute coronary syndromes 38 Robert D S Watson, Bernard S P Chin, Gregory Y H Lip 12 Antithrombotic strategies in acute coronary syndromes and percutaneous coronary interventions 42 Derek L Connolly, Gregory Y H Lip, Bernard S P Chin 13 Antithrombotic therapy in chronic heart failure in sinus rhythm 46 Gregory Y H Lip, Bernard S P Chin 14 Antithrombotic therapy in special circumstances. I—pregnancy and cancer 51 Bernd Jilma, Sridhar Kamath, Gregory Y H Lip 15 Antithrombotic therapy in special circumstances. II—children, thrombophilia, and miscellaneous conditions 55 Bernd Jilma, Sridhar Kamath, Gregory Y H Lip 16 Anticoagulation in hospitals and general practice 59 Andrew D Blann, David A Fitzmaurice, Gregory Y H Lip Index 63 vi Andrew D Blann Senior lecturer in medicine, haemostasis, thrombosis and vascular biology unit, university department of medicine, City Hospital, Birmingham Bernard S P Chin Research fellow, haemostasis, thrombosis and vascular biology unit, university department of medicine, City Hospital, Birmingham Derek L Connolly Consultant cardiologist, department of cardiology and vascular medicine, Sandwell and West Birmingham Hospitals NHS Trust, Sandwell Hospital, West Bromwich Dwayne S G Conway Research fellow, haemostasis, thrombosis and vascular biology unit, university department of medicine, City Hospital, Birmingham David A Fitzmaurice Reader in primary care and general practice, Medical School, University of Birmingham, Edgbaston, Birmingham Ira Goldsmith Research fellow in cardiothoracic surgery, haemostasis, thrombosis and vascular biology unit, university department of medicine, City Hospital, Birmingham Robert G Hart Professor of neurology, department of medicine (neurology), University of Texas Health Sciences Center, San Antonio, USA Bernd Jilma Associate professor in the department of clinical pharmacology, Vienna University Hospital, Vienna, Austria Sridhar Kamath Research fellow, haemostasis, thrombosis and vascular biology unit, university department of medicine, City Hospital, Birmingham Martin J Landray Lecturer in medicine, haemostasis, thrombosis and vascular biology unit, university department of medicine, City Hospital, Birmingham Gregory Y H Lip Professor of cardiovascular medicine and director, haemostasis, thrombosis and vascular biology unit, university department of medicine, City Hospital, Birmingham Andrew J Makin Research fellow, haemostasis, thrombosis and vascular biology unit, university department of medicine, City Hospital, Birmingham Neeraj Prasad Consultant cardiologist, City Hospital, Birmingham Stanley H Silverman Consultant vascular surgeon, City Hospital, Birmingham Alexander G G Turpie Professor of medicine, McMaster University, Hamilton, Ontario, Canada Robert D S Watson Consultant cardiologist, City Hospital, Birmingham Contributors Preface The seeds for this book were sown with the establishment of the haemostasis, thrombosis and vascular biology unit at the university department of medicine, City Hospital, Birmingham—with the coming together of clinicians and scientists interested in thrombosis and vascular biology, bridging the previous divide in thrombosis between basic science research and the application to clinical practice. Indeed, thrombosis is the underlying pathophysiological process in a wide variety of conditions. A greater understanding of the mechanisms leading to thrombosis, and newer developments in the field of antithrombotic therapy make the field all the more dynamic and exciting. The multidisciplinary team effort and the wide range of research areas studied in our unit forms the core content of the ABC of Antithrombotic Therapy. In major textbooks on thrombosis the scope is comprehensive, background details on physiology and pathophysiology are abundant, and treatment options are listed to exhaustion—the patient may sometimes almost disappear in the wealth of information. Our approach in this book—typical of the ABC series in the British Medical Journal —tries to synthesise and integrate the extensive research and clinical data that are needed to manage a particular situation as masterly as it is possible. We hope we have produced a patient-oriented guide with relevant information from clinical epidemiology, pathophysiology, common sense clinical judgement, and evidence based treatment options, with reference to recently published antithrombotic therapy guidelines from the American College of Chest Physicians, British Society for Haematology, European Society of Cardiology, American College of Cardiology, and American Heart Association. Our expectant readers are physicians, general practitioners, medical or nursing students, nurses, and healthcare scientists who care for patients presenting with thrombosis-related problems, and thus, the scope is necessarily wide, ranging from venous thromboembolism to atrial fibrillation and stroke, and to thrombosis in cancer and thrombophilic states. Chapters on clinical pharmacology and bleeding risk, as well as anticoagulation monitoring are included. Furthermore, this book includes additional chapters which were not included in the 14 issues of this series when it first appeared in the British Medical Journal. We thank our excellent colleagues for their help, encouragement and contributions, as well as Sally Carter at BMJ Books for encouraging us to complete the series and book, nearly to schedule. Gregory Y H Lip Andrew D Blann Birmingham, April 2003 1 An overview of antithrombotic therapy Andrew D Blann, Martin J Landray, Gregory Y H Lip Many of the common problems in clinical practice today relate to thrombosis. The underlying final pathophysiological process in myocardial infarction and stroke is thrombus formation (thrombogenesis). Common cardiovascular disorders such as atrial fibrillation and heart failure are also associated with thrombogenesis. Thrombosis is also a clinical problem in various cancers and after surgery, especially orthopaedic. Pathophysiology Over 150 years ago Virchow recognised three prerequisites for thrombogenesis: abnormal blood flow, vessel wall abnormalities, and blood constituent abnormalities. This concept has been extended by modern knowledge of the endothelial function, flow characteristics, and blood constituents including haemorheological factors, clotting factors, and platelet physiology. As thrombus consists of platelets and fibrin (and often bystanding erythrocytes and white blood cells), optimum antithrombotic prophylactic therapy can and should be directed towards both. Antiplatelet drugs Aspirin and agents acting on the cyclo-oxygenase pathway Aspirin irreversibly inhibits cyclo-oxygenase by acetylation of amino acids that are next to the active site. In platelets, this is the rate limiting step in synthesis of thromboxane A2, and inhibition occurs in the megakaryocyte so that all budding platelets are dysfunctional. Because platelets are unable to regenerate fresh cyclo-oxygenase in response, the effect of aspirin remains as long as the lifespan of the platelet (generally about 10 days). A severe weakness of aspirin is that its specificity for cyclo-oxygenase means it has little effect on other pathways of platelet activation. Thus aspirin fails to prevent aggregation induced by thrombin and only partially inhibits that induced by ADP and high dose collagen. Antithrombotic doses used in clinical trials have varied widely from less than 50 mg to over 1200 mg/day, with no evidence of any difference in clinical efficacy. Absorption is over 80% with extensive presystemic metabolism to salicylic acid. Only the parent acetylsalicylic acid has any significant effect on platelet function. Adverse effects of aspirin include haemorrhage, hypersensitivity and skin rashes, alopecia, and purpura. Sulfinpyrazone also inhibits cyclo-oxygenase (thus producing an aspirin-like state), but is reversible, and also inhibits serotonin uptake by platelets. Iloprost is a prostacyclin analogue that exerts its effects by promoting vasodilatation and inhibiting platelet aggregation induced by ADP, thereby opposing the effects of thromboxane A2. Dipyridamole Dipyridamole inhibits phosphodiesterase, thus preventing the inactivation of cyclic AMP, intraplatelet levels of which are increased, resulting in reduced activation of cytoplasmic second messengers. However, it may also exert its effect in other ways, such as stimulating prostacyclin release and inhibiting thromboxane A2 formation. The influence of this drug on these pathways causes reduced platelet aggregability and adhesion in Contraindications to aspirin Absolute x Active gastrointestinal ulceration x Hypersensitivity x Thrombocytopenia Relative x History of ulceration or dyspepsia x Children under 12 years old x Bleeding disorders x Warfarin treatment Clopidogrel gpIIb/IIa receptor blockers Receptors Arachadonic acid pathway Second messengers Shape change granule release aggregation Soluble coagulation factors Thrombosis Plasma gpIIb/IIa Aspirin Dipyridamole Agonists Collagen Adrenaline ADP Thromboxane Thrombin Exposed sub endothelium Fibrinogen Routes to inhibiting platelet function Cellular components of the blood (eg platelets) Activated platelets Soluble components of the blood (eg fibrinogen) Thrombus Pro-coagulant changes (eg increased VWF, factor V release decreased membrane thrombomodulin) Components of the blood vessel wall Smoking, inflammation Hyperfibrinogenaemia Key components of Virchow’s triad (VWF=von Willebrand factor) Arachadonic acid Endoperoxides Prostacyclin synthetase Thromboxane synthetase Aspirin Cyclo-oxygenase Prostacyclin Thromboxane Platelet metabolism influenced by aspirin 1 vitro with increased platelet survival in vivo. Its effect is relatively short lasting, and repeated dosing or slow release preparations are needed to achieve 24 hour inhibition of platelet function. Clopidogrel and ticlopidine These thienopyridine derivatives inhibit platelet aggregation induced by agonists such as platelet activating factor and collagen, and also dramatically reduce the binding of ADP to a platelet surface purinoreceptor. The mechanism of this inhibitory action seems to be independent of cyclo-oxygenase. There is also impairment of the platelet response to thrombin, collagen, fibrinogen, and von Willebrand factor. The peak action on platelet function occurs after several days of oral dosing. Adverse effects include evidence of bone marrow suppression, in particular leucopenia, especially with ticlopidine. Other receptor blockers Signal transduction generally occurs when specific receptors on the surface are occupied by ligands such as ADP, leading to structural modification of the glycoprotein IIb/IIIa receptor on the surface of the platelet. This is the commonest receptor on the platelet surface and represents the final common pathway for platelet aggregation, resulting in crosslinking of platelets. After intravenous administration of glycoprotein IIb/IIIa receptor inhibitors such as abciximab, platelet aggregation is 90% inhibited within two hours, but function recovers over the course of two days. The major adverse effect is haemorrhage, and concurrent use of oral anticoagulants is contraindicated. Eptifibatide is a cyclic heptapeptide that mimics the part of the structure of fibrinogen that interacts with glycoprotein IIb/IIIa. Thus it is a fraction of the size of abciximab and is targeted at the same structure on the platelet surface. Clinical trials with oral glycoprotein IIb/IIIa receptor inhibitors have been disappointing, with no beneficial effects seen and even some evidence of harm. Anticoagulant drugs Warfarin This 4-hydroxycoumarin compound, the most widely used anticoagulant in Britain and the Western world, inhibits the synthesis of factors dependent on vitamin K (prothrombin; factors VII, IX, and X; protein C; protein S). Factor VII levels fall rapidly (in < 24 hours) but factor II has a longer half life and only falls to 50% of normal after three days. Warfarin is approximately 97% bound to albumin, and free warfarin enters liver parenchymal cells and is degraded in microsomes to an inactive water soluble metabolite that is conjugated and excreted in the bile. Partial reabsorption is followed by renal excretion of conjugated metabolites. There is a considerable variability in warfarin’s effect on patients, its effectiveness being influenced by age, racial background, diet, and co-medications such as antibiotics. Thus it demands frequent laboratory monitoring, the prothrombin time being compared with a standard to produce the international normalised ratio. The degree of anticoagulation required varies with clinical circumstance, but the target international normalised ratio usually ranges from 2 to 4. Phenindione is an alternative oral vitamin K antagonist, but concerns regarding the potential for hepatotoxicity, nephrotoxicity, and blood dyscrasias have reduced its role largely to individuals with documented hypersensitivity to warfarin. Adverse effects of warfarin include haemorrhage, hypersensitivity and skin rashes, alopecia, and purpura. Factors that influence the efficacy of warfarin* Patient factors x Enhanced anticoagulant effect—Weight loss, increased age ( > 80 years), acute illness, impaired liver function, heart failure, renal failure, excess alcohol ingestion x Reduced anticoagulant effect—Weight gain, diarrhoea and vomiting, relative youth (< 40 years), Asian or African-Caribbean background Examples of drug interactions with warfarin x Reduced protein binding—Aspirin, phenylbutazone, sulfinpyrazone, chlorpromazine x Inhibition of metabolism of warfarin—Cimetidine, erythromycin, sodium valproate x Enhanced metabolism of warfarin—Barbiturates, phenytoin, carbamazepine x Reduced synthesis of factors II, VII, IX, X—Phenytoin, salicylates x Reduced absorption of vitamin K—Broad spectrum antibiotics, laxatives x Enhanced risk of peptic ulceration—Aspirin, NSAIDs, corticosteroids x Thrombolytics—Streptokinase, tissue plasminogen activator x Antiplatelet drugs—Aspirin, NSAIDs *This list is intended to be illustrative not exhaustive Warfarin Carboxylase N-terminal glutamyl residue of vitamin K dependent proteins γ-carboxy-glutamyl residue Biological function Vitamin K quinol Vitamin K epoxide Vitamin K metabolism and the effect of warfarin Factors IX, XI, XII Factor II Prothrombin Factor IIa Thrombin Factor XIII Factor XIIIa Insoluble fibrin Soluble fibrin Fibrinogen Factors V, X, calcium phospholipids Factor VII Intrinsic pathway Extrinsic pathway Prothrombinase complex Simplified coagulation cascade ABC of Antithrombotic Therapy 2 Melagatran This oral thrombin inhibitor undergoing phase III trials seems to be well tolerated, with few clinically significant bleeding problems, in patients with venous thromboembolism. Although considerable pharmacokinetic and animal data exist, solid evidence of its effectiveness compared with warfarin and heparin in patients at high or low risk is still awaited. Heparin Heparin is a glycosaminoglycan whose major anticoagulant effect is accounted for by a pentasaccharide with a high affinity for antithrombin III. This binding results in a conformational change in antithrombin III so that inactivation of coagulation enzymes thrombin (IIa), factor IXa, and factor Xa is markedly enhanced. Its short half life means it must be given continuously, and its extensive first pass metabolism means it must be given parenterally, preferably by continuous intravenous infusion, and it is therefore inappropriate for home use. The effect on the intrinsic clotting cascade must be monitored carefully by measuring the activated partial thromboplastin time (APTT), generally aiming for a value 1.5 to 2.5 times that of control. Unfractionated heparin consists of a heterogeneous mixture of polysaccharides with an average molecular weight of 15 000 Da. Low molecular weight heparins (4000-6000 Da) are weaker inhibitors of thrombin but inhibit factor Xa to a similar extent. Different commercial preparations of low molecular weight heparin vary in the ratio of anti-Xa to antithrombin activity, although the clinical relevance of this is uncertain. Better absorption after subcutaneous administration and reduced protein binding result in greatly improved bioavailability. The effective half life after subcutaneous injection is four hours, allowing an injection once daily in most circumstances. These more predictable pharmacokinetics allow the dose to be calculated on the basis of the patient’s weight and reduce the requirement for frequent monitoring. In those rare cases where monitoring is deemed necessary, measurement of plasma levels of anti-Xa activity is needed. Tests of APTT are unhelpful. Major adverse effects of heparin include haemorrhage, osteoporosis, alopecia, thrombocytopenia, and hypersensitivity. At present, the risk of haemorrhage seems to be similar with low molecular weight and unfractionated heparin. However, the risk of heparin induced thrombocytopenia seems to be less with the low molecular weight form. Hirudin and direct thrombin inhibitors Hirudin, a 65 amino acid residue anticoagulant peptide with a relative molecular mass of 7000 Da purified from the leech Hirudo medicinalis, binds thrombin with high specificity and sensitivity. With a true half life of about an hour and a half life effect on the APTT of two to three hours, it may be seen as an alternative to heparin in indications such as unstable angina and in coronary angioplasty. Many derivatives are available, with hirulog and argatroban among the best developed. However, trials of the former have been discouraging: no clear benefit over heparin was shown. Conversely, argatroban may have a role in the anticoagulation of patients unable to tolerate heparin as a result of heparin induced thrombocytopenia. Furthermore, in a clinical trial of patients with heparin induced thrombocytopenia, use of argatroban was associated with a reduction in levels of plasma platelet activation markers. Thrombolytic agents These agents lyse pre-existing thrombus, either by potentiating the body’s own fibrinolytic pathways (such as streptokinase) or Comparison of low molecular weight and unfractionated heparins Unfractionated heparin Low molecular weight heparin Action Anti-XIIa, XIa, IXa, VIIa, antithrombin Mostly anti-Xa Route of administration Subcutaneous Intravenous Subcutaneous Absorption from subcutaneous route Slow Improved Protein binding Proteins in plasma and on endothelium Reduced Bioavailability Subcutaneous—10-30% at low doses, 90% at higher doses Intravenous—100% by definition > 90% Effective half life Subcutaneous—1.5 hours Intravenous—30 min 4 hours Between and within individual variation Extensive Minimal Monitoring APTT Not required (anti-Xa activity) Elimination Liver and kidney Kidney Molecular weight (Da) % of composition 0 5000 10 000 15 000 20 000 0 0.2 0.3 0.4 0.5 0.6 0.7 0.1 Low molecular weight heparin Greater anti-Xa activity Resistant to PF4 Little non-specific binding Greater inhibition of thrombin generation Greater antithrombin activity Less anti-Xa activity Sensitive to PF4 Non-specific binding Less inhibition of thrombin generation Unfractionated heparin Enoxaparin sodium (Lovenox) [3.8:1] Nadroparin calcium (Fraxiparin) [3.6:1] Dalteparin sodium (Fragmin) [2.7:1] The three low molecular weight heparins that have been evaluated in clinical trials of acute coronary syndromes are shown with their respective anti-Xa and antithrombin activity (PF4=platelet factor 4) An overview of antithrombotic therapy 3 by mimicking natural thrombolytic molecules (such as tissue plasminogen activator). The common agents in clinical use are derived from bacterial products (streptokinase) or manufactured using recombinant DNA technology (recombinant tissue plasminogen activator). Newer drugs aim to be less antigenic and more thrombus specific in an attempt to increase efficacy and specificity of various agents; on present evidence, however, the differences between thrombolytic agents are only marginal. Because of the lack of site specificity for these drugs, the major adverse effect is that of haemorrhage (gastrointestinal, intracranial, etc). The other important adverse effect is that of hypersensitivity reaction, especially with streptokinase. This usually manifests as flushing, breathlessness, rash, urticaria, and hypotension. Severe anaphylaxis is rare. Hypersensitivity reactions are avoided by using tissue plasminogen activator or recombinant tissue plasminogen activator, which are not antigenic. Streptokinase Derived from streptococci, this product is an effective thrombolytic agent for the treatment of acute myocardial infarction and pulmonary thromboembolism. Acting by converting plasminogen to plasmin, the main fibrinolytic enzyme, it potentiates fibrinolysis. However, it is not site specific, lysing thrombus anywhere in the body. Being bacteria derived, it is antigenic, and repeated administration results in neutralising antibodies and allergic reactions. For example, a single administration of 1.5 MU for acute myocardial infarction results in neutralising antibodies that have been shown to persist for up to four years and are sufficient to neutralise a repeat administration of a similar dose of the agent in half of cases. Tissue plasminogen activator In clinical use this is produced by recombinant DNA technology and mimics an endogenous molecule that activates the fibrinolytic system. Thus, recombinant tissue plasminogen activator does not elicit an allergic response and is considered more clot specific. Nevertheless, it has a short half life and needs continuous infusion to achieve its greatest efficacy. Accelerated administration of tissue plasminogen activator gives a slight mortality advantage over streptokinase at the cost of a marginal increase in stroke rate. Fibrinolytic drugs Examples Source Mechanism of action Streptokinase Group C � haemolytic streptococci Complexes with and activates plasminogen Urokinase Trypsin-like chemical produced by kidney Direct acting plasminogen activator Reteplase (recombinant tissue plasminogen activator) Recombinant DNA technology Acivates plasminogen, non-immunogenic Contraindications to thrombolysis Absolute x Recent or current haemorrhage, trauma, or surgery x Active peptic ulceration x Coagulation defects x Oesophageal varices x Coma x Recent or disabling cerebrovascular accident x Hypertension x Aortic dissection Relative x Previous peptic ulceration x Warfarin x Liver disease x Previous use of anistreplase or streptokinase within four years (use alternative agent) x Hypersensitivity (anistreplase, streptokinase) x Heavy vaginal bleeding Further reading x Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy, I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308:81-106 x Blann AD, Lip GYH. Virchow’s triad revisited: the importance of soluble coagulation factors, the endothelium, and platelets. Thromb Res 2001;101:321-7 x CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-39 x Catella-Lawson F. Direct thrombin inhibitors in cardiovascular disease. Coron Artery Dis 1997;8:105-11 x Eriksson H, Eriksson UG, Frison L. Pharmacokinetic and pharmacodynamics of melagatran, a novel synthetic LMW thrombin inhibitor, in patients with a DVT. Thromb Haemost 1999;81: 358-63 x International Stroke Trial Collaborative Group. The international stroke trial (IST): a randomised trial of aspirin, subcutaneous heparin, or both, or neither among 19 435 patients with acute ischaemic stroke. Lancet 1997;349:1569-81 x Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001;103:1838-43 x Nurden AT. New thoughts on strategies for modulating platelet function through the inhibition of surface receptors. Haemostasis 1996;20:78-88 x Stirling Y. Warfarin-induced changes in procoagulant and anticoagulant proteins. Blood Coagul Fibrinolysis 1995;6:361-73 The figure showing percentage of composition of unfractionated and low molecular weight heparin in terms of molecular weight is adapted from Levine GN, Ali MN, Schafer AI. Arch Intern Med 2001;161: 937-48. Insoluble fibrin clot Soluble D-dimers tPA uPA Streptokinase Plasminogen Plasmin PAI-I Simplified fibrinolysis (PAI-1=plasminogen activator inhibitor, tPA=tissue plasminogen activator, uPA=urokinase plasminogen activator) ABC of Antithrombotic Therapy 4 2 Bleeding risks of antithrombotic therapy David A Fitzmaurice, Andrew D Blann, Gregory Y H Lip Many of the common cardiovascular disorders (especially in elderly people) are linked to thrombosis—such as ischaemic heart disease, atrial fibrillation, valve disease, hypertension, and atherosclerotic vascular disease—requiring the use of antithrombotic therapy. This raises questions regarding the appropriate use of antithrombotic therapy in older people, especially because strategies such as anticoagulation with warfarin need regular monitoring of the international normalised ratio (INR), a measure of the induced haemorrhagic tendency, and carry a risk of bleeding. The presence of concomitant physical and medical problems increases the interactions and risks associated with warfarin, and anticoagulation in elderly patients often needs an assessment of the overall risk:benefit ratio. Physical frailty in elderly people may reduce access to anticoagulant clinics for INR monitoring. The decline in cognitive function in some elderly patients also may reduce compliance with anticoagulation and the appreciation of bleeding risks and drug interactions. However, in recent studies of anticoagulation in elderly people, no significant associations of anticoagulant control were found with age, sex, social circumstances, mobility, domicillary supervision of medication, or indications for anticoagulation. Warfarin Bleeding is the most serious and common complication of warfarin treatment. For any given patient, the potential benefit from prevention of thromboembolic disease needs to be balanced against the potential harm from induced haemorrhagic side effects. Minor bleeds Most bleeding problems are clinically minor, although patients are unlikely to view such bleeds in these terms. The problems include nose bleeds, bruising, and excessive bleeding after minor injury such as shaving. Patients should be made aware of these common problems and be reassured that these events are expected in patients receiving warfarin treatment. Menorrhagia is surprisingly rare as a major clinical problem, even though it can be severe. More serious problems Patients need access to medical care if they have serious problems. Such problems are generally due to a high INR. Usually, spontaneous bruising, any bleeding that is difficult to arrest, frank haematuria, any evidence of gastrointestinal bleeding, and haemoptysis, need urgent assessment. The definition of minor or major bleeding lacks clarity: in many cases the patient presents with a concern that may need follow up, and a minor bleed can only be defined as such in retrospect. In most cases, evidence of bleeding suggests some underlying pathology but may also be due to drug interactions. For example, a patient with recurrent haemoptysis may be found to have hereditary telangectasia. Further investigation of the cause of bleeding should always be considered, particularly if the bleeding is recurrent. It is also important in these instances to check for concomitant drug use, particularly drugs received over the counter. Patients should be aware that aspirin and Questions to ask when considering oral anticoagulation x Is there a definite indication (such as atrial fibrillation)? x Is there a high risk of bleeding or strong contraindication against anticoagulation? x Will concurrent medication or disease states increase bleeding risk or interfere with anticoagulation control? x Is drug compliance and attendance at anticoagulant clinic for monitoring likely to be a problem? x Will there be regular review of the patient, especially with regard to risks and benefits of anticoagulation? Sudden, unexplained changes to the efficacy of warfarin may be caused by the consumption of over the counter multivitamin tablets or foodstuffs that contain high levels of vitamin K INR=Spatient’s prothrombin timeD ISI mean normal time ISI=international sensitivity ratio. The mean normal prothrombin time is often generated from samples from local healthy subjects or a commercially available standard. The exact value of the ISI depends on the thromboplastin used in the prothrombin time method Purpura, petechiae, and haematoma secondary to over-anticoagulation 5 non-steroidal anti-inflammatory drugs are particularly dangerous in combination with warfarin; however, even supposedly safe drugs such as paracetamol can affect a patient’s bleeding tendency. Incidence of bleeding problems The incidence of severe bleeding problems that may bring patients to an accident and emergency unit has probably been overestimated. The annual incidence of fatality caused by warfarin administration has been estimated to be 1%. However, this is based on old data, and, although difficult to prove, the overall improvement in anticoagulation control in the past 10-15 years means that a more realistic figure is about 0.2%. Methodological problems have hampered the interpretation of previously reported data, particularly with regard to definitions of major and minor bleeding episodes, with some investigators accepting hospital admission for transfusion of up to 4 units of blood as being “minor.” Certainly, the most serious “major” bleed is an intracranial haemorrhage. Reviews of observational and experimental studies showed annual bleeding rates of 0-4.8% for fatal bleeding and 2.4-8.1% for major bleeds. Minor bleeds are reported more often, with about 15% of patients having at least one minor event a year. Risk factors for bleeding Age is the main factor that increases risk of bleeding. One study showed a 32% increase in all bleeding and a 46% increase in major bleeding for every 10 year increase above the age of 40. Early studies suggested an increased risk with increasing target INR, but the data were difficult to interpret because results were reported in both INR and prothrombin time. The actual risk of bleeding should be taken into account as well as the degree of anticoagulation (as measured by the INR). One study which achieved point prevalence of therapeutic INRs of 77% reported no association between bleeding episodes and target INR. Data from an Italian study in 2745 patients with 2011 patient years of follow up reported much lower bleeding rates, with an overall rate of 7.6 per 100 patient years. The reported rates for fatal, major, and minor bleeds were 0.25, 1.1, and 6.2 per 100 patient years respectively. This study confirmed an increased risk with age and found a significantly increased risk during the first 90 days of treatment. Peripheral vascular and cerebrovascular disease carried a higher relative risk of bleeding, and target INR was strongly associated with bleeding with a relative risk of 7.9 (95% confidence interval 5.4 to11.5, P < 0.0001) when the most recent INR recorded was > 4.5. Data from a trial in a UK community showed 39.8 minor, 0.4 major, and no fatal haemorrhagic events per 100 patient years for the total study population, with 3.9 serious thromboembolic events per 100 patient years, of which 0.79 were fatal. Warfarin is therefore a relatively safe drug, particularly if therapeutic monitoring is performed well. Analogies are often made between therapeutic monitoring of warfarin and monitoring of blood glucose for diabetic patients. Given the increase in numbers of patients receiving warfarin, particularly for atrial fibrillation, the scale of the problem is likely to be the same. There is no reason why warfarin monitoring cannot become as routine as glucose monitoring in diabetes: relevant small machines are available for generating an INR (with associated standards and quality control). Overanticoagulation Excessive anticoagulation without bleeding or with only minor bleeding can be remedied by dose reduction or discontinuation. The risk of bleeding is decreased dramatically by lowering the intended INR from 3-4.5 down to 2-3, although this increases Patients at high risk of bleeding with warfarin x Age > 75 years x History of uncontrolled hypertension (defined as systolic blood pressure > 180mm Hg or diastolic blood pressure > 100 mm Hg) x Alcohol excess (acute or chronic), liver disease x Poor drug compliance or clinic attendance x Bleeding lesions (especially gastrointestinal blood loss, such as peptic ulcer disease, or recent cerebral haemorrhage) x Bleeding tendency (including coagulation defects, thrombocytopenia) or concomitant use of non-steroidal anti-inflammatory drugs and antibiotics x Instability of INR control and INR > 3 Risk of bleeding associated with warfarin treatment x Rate of bleeding episodes associated in the general patient population is decreasing (possibly due to better management) x Risk increases with age x Risk of bleeding is directly related to the achieved intensity of INR rather than the target INR (a clear dose-response effect) x Temporal association between measured INR and risk of bleeding x Relative risk of bleeding is increased in patients with cerebrovascular disease and venous thrombosis Computed tomography scan showing intracerebral haemorrhage ABC of Antithrombotic Therapy 6