- Email: [email protected]
Anticoagulation
Practical procedures
Anticoagulation
What’s new?
Muriel S Shannon
• Low molecular weight heparin is the treatment of choice for DVT and PE • Low molecular weight heparin is safe and effective in the prophylaxis and treatment of VTE in pregnancy • Reversal of over-anticoagulation with warfarin resulting in major bleeding can be achieved rapidly using prothrombin complex concentrate
Anticoagulation prevents pathological clot formation (e.g. on heart valves or chambers) and stops propagation and embolization of clots already developed in veins. The type, intensity and duration of anticoagulation depend on the indication. About 1.8% of the UK population require anticoagulation. The two main anticoagulant drugs are heparin and warfarin.
• New antithrombotic agents, including a synthetic pentasaccharide may offer effective anticoagulation with less need for monitoring; trials are promising
Questions to ask Is the patient at risk of bleeding? ask about any history of excessive or abnormal bleeding (e.g. peptic ulceration, haemorrhagic stroke, prolonged bleeding after surgery) and other major haemorrhagic events. The amount and pattern of alcohol use are important; binge-drinking is particularly dangerous. Intravenous drug abusers must be made aware of the risks of injecting while taking anticoagulants. Family history of bleeding should also be determined. Is the patient taking other drugs? all medications must be checked for interactions in the current British national formulary. Many drugs interact with warfarin (e.g. amiodarone), and certain
antibacterials (particularly ciprofloxacin, erythromycin and metronidazole) increase INR. Non-steroidal anti-inflammatory drugs (NSAIDs) and antiplatelet drugs (dipyridamole, aspirin and clopidogrel) increase gastrointestinal tract bleeding. Corticosteroids, thyroxine, allopurinol, cimetidine, omeprazole and certain lipidregulating drugs enhance the action of warfarin. Paracetamol (>28 tablets per week) can increase INR. Anti-epileptics, rifampicin and griseofulvin usually antagonize warfarin. Aspirin in full doses (600 mg) is contraindicated. Low doses (75 mg) may be prescribed in combination with warfarin in patients with arterial thromboembolic disease, but this increases the bleeding risk. The anticoagulant effect of heparin is enhanced by antiplatelet drugs; concomitant use of heparins with parenteral diclofenac or ketorolac increases the risk of haemorrhage. Glyceryl trinitrate reduces heparin’s anticoagulant effect. Is the patient pregnant? warfarin crosses the placenta and can cause adverse effects in the fetus. Exposure to warfarin during organogenesis is associated with chondrodysplasia and severe fetal deformity; avoidance of warfarin during 6–12 weeks’ gestation reduces but does not abolish this risk. Use of oral anticoagulants in later pregnancy is associated with increased fetal wastage and congenital malformation. The risk of fetal damage must be weighed against the problems and risks of converting to heparin in the mother. Heparins do not cross the placenta, but can cause adverse effects in the mother. Low molecular weight heparin (LMWH) is safe and effective in the prophylaxis and treatment of venous thromboembolism (VTE) in pregnancy, but its use in mothers with mechanical heart valves is controversial. The British Committee for Standards in Haematology (BCSH) guidelines discuss therapeutic options;1 management depends on the indication and patient preferences. Heparin is substituted for warfarin at 36 weeks to reduce the risk of fetal intracerebral haemorrhage during delivery. Mothers taking warfarin or heparin can breast-feed.
Muriel S Shannon is Consultant in Haemostasis and Thrombosis at St George’s Hospital, London, UK. She qualified from the University of Glasgow, and trained in haematology at the Royal Free Hospital, London.
Investigations: before starting anticoagulants, perform a clotting screen (prothrombin time ratio or INR, partial thromboplastin time ratio and thrombin time) and platelet count. Dose alterations and close monitoring are required in patients with severe hepatic or renal dysfunction.
Assessing the patient Before starting anticoagulation, the patient must be assessed carefully. Review the indication. Consider contraindications: there are no absolute contraindications to anticoagulant therapy, but if there is active bleeding withhold treatment until it is controlled. Recent major surgery (including neurosurgery) or trauma increase the haemorrhagic risk, and treatment may need to be delayed. Relative contraindications include a history of inherited or acquired coagulation disorders, recent cerebral haemorrhage, active peptic ulceration, uncontrolled hypertension, hepatic or renal dysfunction, alcohol or drug abuse and dementia. In these situations, dose reduction and careful monitoring are required to minimize the risk of bleeding. Heparin should be avoided in patients with thrombocytopenia, because the drug may cause a decrease in platelet count, and should not be given to those with a recent history of heparin hypersensitivity.
THE FOUNDATION YEARS 2:6
261
© 2006 Elsevier Ltd. All rights reserved.
Practical procedures
illness, age and use of aspirin increase the risk. Unfractionated heparin is rapidly reversed by protamine sulphate, 1 mg/100 units, but this agent is less effective against LMWH and repeat administration may be needed. Thrombocytopenia – a decrease in platelet count is occasionally seen after starting unfractionated heparin; this results from platelet aggregation and probably does not occur with LMWH. It has neither haemorrhagic nor thrombotic consequences. Heparin-induced immune thrombocytopenia with thrombosis (HITT) can lead to venous and arterial gangrene with a mortality of 30%. This serious reaction is mediated by an IgG antibody against complexes of heparin and platelet factor 4. It usually develops after 5 or more days’ therapy, but appears sooner in patients previously exposed to heparin (usually unfractionated), and causes platelet activation. LMWH has a lower affinity for platelet factor 4 and the incidence of HITT is lower. Heparin must be stopped immediately and alternative antithrombotic cover instituted (see below). Osteoporosis can develop after several months’ heparin treatment; fractures may result. It is rare with LMWH.
Heparin Pharmacology: unfractionated heparin (a glycosaminoglycan produced by mast cells) is extracted from porcine mucosa. It comprises heterogeneous polysaccharide chains of molecular weight 3–30 kDa. LMWH is produced by depolymerization, yielding chains of 4–6 kDa. Both forms bind and activate antithrombin, accelerating its interaction with activated factor X (Xa) 1000-fold. Differences between unfractionated heparin and LMWH – the antifactor-Xa activity of LMWH is more than 90%, compared with less than 30% for prophylactic unfractionated heparin. After subcutaneous injection, LMWH is better absorbed and has greater bioavailability; its half-life is 3–12 hours, which is 2–4 times that of unfractionated heparin. Excretion of LMWH is reduced by renal impairment. Administration and monitoring: therapeutic unfractionated heparin requires close monitoring, usually by activated partial thromboplastin time ratio (range varies with reagent used). Prophylactic doses are determined by thrombotic risk and do not require laboratory testing. When administering LMWH, monitoring using an antifactor-Xa assay is necessary in patients with renal failure, in children, in pregnancy and in those of very low or very high body weight. The LMWHs commonly used in the UK are dalteparin, enoxaparin and tinzaparin (Table 1).2
Warfarin Pharmacology: warfarin (a coumarin) is the standard oral anticoagulant in the UK. Vitamin K-dependent factors II, VII, IX and X and the coagulation inhibitors proteins C and S require carboxylation to form functional complexes; warfarin inhibits this process. Warfarin is absorbed rapidly; peak plasma levels are achieved in about 1.5 hours and the half-life is 2–3 days. Onset of action depends on the levels of factors II, VII, IX and X (half-life 6–60 hours) and varies from 24 hours to 72 hours.
Problems Bleeding – the risk of major bleeding is low at prophylactic doses, but increases to 2.5% with therapeutic doses of unfractionated heparin compared with 1.5% with LMWH. Concurrent
Heparin regimens Drug
Indication
Dalteparin
• Prophylaxis – moderate risk • Prophylaxis – high risk • Treatment of DVT/PE • Treatment of unstable coronary disease
Recommended regimen Once-daily subcutaneous injection except where stated 2500 units1 5000 units 200 units/kg3 120 units/kg 12-hourly
Enoxaparin
• Prophylaxis – moderate risk • Prophylaxis – high risk • Treatment of DVT/PE • Treatment of unstable coronary disease
20 mg (2000 units) 40 mg (4000 units) 1.5 mg (150 units)/kg3 1 mg (100 units)/kg 12-hourly
Tinzaparin
• Prophylaxis – moderate risk • Prophylaxis – high risk • Treatment of DVT/PE
3500 units 50 units/kg 175 units/kg3
Unfractionated heparin
• Prophylaxis – moderate risk • Prophylaxis – high risk • Treatment of DVT/PE
5000 units 12-hourly 5000 units 8-hourly 5000 units i.v. followed by either 15–25 units/kg/hour i.v. infusion2 or 15,000 units 12-hourly s.c.2
DVT, deep vein thrombosis; PE pulmonary embolism 1 2 3
Dose expressed as units of antifactor Xa activity Daily laboratory monitoring is essential Half dose given 12-hourly in pregnancy
Table 1
THE FOUNDATION YEARS 2:6
262
© 2006 Elsevier Ltd. All rights reserved.
Practical procedures
Administration and monitoring: warfarin is monitored by measuring INR. Recommended target INRs are shown in Table 2.3 The average daily dose is 3–9 mg/day, but it ranges from 0.5 mg to more than 25 mg. Table 3 shows a warfarin initiation protocol for atrial fibrillation that achieves a therapeutic INR with minimal bleeding and predicts a maintenance dose.4 A more intensive induction regimen is used for acute venous thrombosis (Fennerty algorithm).3 High loading doses of warfarin result in rapid reduction of the anticoagulant proteins C and S, and can cause thrombosis of subcutaneous vessels and skin necrosis. To prevent this, heparin is given before starting warfarin in patients with venous thromboembolic disease and is continued until the INR is more than 2 for 2 days. In patients requiring anticoagulation for indications other than thrombosis (e.g. atrial fibrillation), a personal or family history of venous thrombosis should be elicited before starting warfarin, and the starting dose should not exceed 5 mg daily. Factors affecting warfarin requirements include congestive heart failure, liver impairment, variations in alcohol intake, marked variations in diet, vomiting and diarrhoea.
Starting warfarin in patients with atrial fibrillation Days 1–4 • Warfarin, 5 mg daily Day 5 Check INR, adjust dose as follows INR Warfarin • ≤ 1.7 5 mg • 1.8–2.2 4 mg • 2.3–2.7 3 mg • 2.8–3.2 2 mg • 3.3–3.7 1 mg • > 3.7 0 mg Days 6–7 • Dose as for day 5 Day 8 Check INR, adjust dose as follows
Problems Drug interactions are numerous and must be considered when starting new therapy or stopping or changing long-term therapy. The British national formulary should be consulted. Herbal and alternative therapies also interact and should be checked with local drug information services. Patients are advised to avoid all preparations containing aspirin unless specifically prescribed. Paracetamol may be taken for minor aches and pains, but excessive use can increase INR. High INR (without bleeding) – BCSH recommendations are: • INR > target range with no bleeding – omit warfarin for 1–2 days, recommence at lower dose
Target INRs Indication Venous thromboembolism • Deep vein thrombosis/pulmonary embolism prophylaxis (maintain INR > 2.0 if high risk) • Treatment of first episode or recurrence off warfarin • Treatment of recurrence on warfarin • Antiphospholipid syndrome Cardiac indications • Atrial fibrillation (maintain INR > 2.0 for 4 weeks pre- and post-cardioversion) • Dilated cardiomyopathy • Mural thrombus post-myocardial infarction • Rheumatic mitral valve disease • Mechanical heart valves
Day 8 INR • ≤ 1.7 • 1.8–2.4 • 2.5–3.0 • > 3.0
Dose from day 8 6 mg 5 mg 4 mg 3 mg for 4 days
4 mg
• ≤ 1.7 • 1.8–2.4 • 2.5–3.0 • 3.1–3.5 • > 3.5
5 mg 4 mg 3.5 mg 3 mg for 4 days 2.5 mg for 4 days
3 mg
• ≤ 1.7 • 1.8–2.4 • 2.5–3.0 • 3.1–3.5 • > 3.5
4 mg 3.5 mg 3 mg 2.5 mg for 4 days 2 mg for 4 days
2 mg
• ≤ 1.7 • 1.8–2.4 • 2.5–3.0 • 3.1–3.5 • > 3.5
3 mg 2.5 mg 2 mg 1.5 mg for 4 days 1 mg for 4 days
1 mg
• ≤ 1.7 • 1.8–2.4 • 2.5–3.0 • 3.1–3.5 • > 3.5
2 mg 1.5 mg 1 mg 0.5 mg for 4 days Omit for ≥ 2 days
0 mg
• < 2.0 • 2.0–2.9 • 3.0–3.5 • > 3.5
1.5 mg for 4 days 1 mg for 4 days 0.5 mg for 4 days Quit for 2 ≥ days
Target INR
2.0 ± 0.5 2.5 ± 0.5 3.5 ± 0.5 3.5 ± 0.51 2.5 ± 0.5 2.5 ± 0.5 2.5 ± 0.5 2.5 ± 0.5 3.75 ± 0.75
Table 3
1 Varies with clinical condition
• INR > 8.0 with no bleeding – omit warfarin until INR < 5.0 (2–3 days), give vitamin K, 0.5–2.5 mg p.o., if there are risk factors for bleeding. Bleeding – the risk of bleeding increases exponentially with INR more than 5.0, but 80% of serious bleeds occur at the target
Source: British Committee for Standards in Haematology guidelines
Table 2
THE FOUNDATION YEARS 2:6
Previous dose 5 mg
263
© 2006 Elsevier Ltd. All rights reserved.
Practical procedures
VTE Deep vein thrombosis (DVT) and pulmonary embolism (PE) – anticoagulation is given to treat or prevent VTE; it does not lyse thrombi, but prevents propagation and embolization. The incidence of DVT is 1/1000/year; in >10% of cases, embolization to the lungs (PE) occurs. Mortality in PE (30%) is reduced significantly by treatment with heparin followed by warfarin. Proximal lower limb thrombosis requires anticoagulation to prevent embolization. Calf DVT seldom embolizes, but if left untreated may extend above the knee in 10% of patients; repeat imaging is required to detect this. LMWH is as effective as unfractionated heparin in the treatment of DVT, allowing outpatient management of selected patients. Warfarin is given for 6 weeks to 3 months in calf DVT and for 6–12 months in proximal DVT. In PE, LMWH followed by 6 months’ warfarin is effective. Long-term anticoagulation is recommended after two episodes of unprovoked VTE, after life-threatening PE or when ongoing risk factors are present. Inferior vena caval filters require individual assessment. Investigations (including thrombophilia tests) are undertaken in patients with a family history of premature or fatal VTE. Antiphospholipid syndrome – recurrence of VTE is common in patients with persistent antiphospholipid syndrome, and longterm anticoagulation is advised after one episode. Prophylaxis of VTE – LMWH or fondaparinux, in conjunction with mechanical methods (compression stockings), reduces VTE associated with orthopaedic and other high-risk surgery. Moderate risks (e.g. airline flights in at-risk patients, prolonged immobility) require lower doses. Low-intensity warfarin (target INR 1.5) is used in some patients with a long-term indwelling venous catheter.
INR. Treatment depends on the site and severity. For major bleeding, give prothrombin complex concentrate at a dose of up to 50 u/kg depending on INR; if this is unavailable, use fresh frozen plasma, 15 ml/kg. Vitamin K, 1–5 mg, is given by slow intravenous injection and may need to be repeated after 24 hours. Anticoagulation is withheld until bleeding is controlled. Minor bleeding (e.g. epistaxis, haematuria, bruising, subconjunctival haemorrhage) is assessed and local measures used to stop the bleeding. Warfarin is reduced or withheld until bleeding is controlled. Full reversal of anticoagulation with vitamin K may lead to warfarin resistance and should be decided on an individual basis in patients with an artificial heart valve; the degree of reversal depends on the severity of the bleeding. The cause of bleeding should be identified and treated. For dental work, the INR must be <4.0. Surgery – adjustment of anticoagulation is needed for surgical procedures. Patients taking warfarin should not undergo day surgery unless their INR has been adjusted beforehand. For dental work, the INR must be <4.0.
Newer anticoagulant agents Danaparoid sodium is a heparinoid used for thromboprophylaxis in general and orthopaedic surgery. It is useful in HITT, provided there is no cross-reactivity. Fondaparinux is a synthetic pentasaccharide that selectively inhibits factor Xa. It was recently introduced for prophylaxis in orthopaedic surgery. Direct thrombin inhibitors – recombinant hirudin forms an irreversible compound with thrombin and is used in HITT. It has a role in patients with cancer-associated thrombosis resistant to warfarin and heparin. Ximelagatran which binds reversibly to thrombin developed as an alternative oral anticoagulant to warfarin, has been withdrawn due to hepatotoxicity.
Peripheral arterial thrombosis: aspirin is preferred in the treatment of atherosclerosis and peripheral vascular disease. Warfarin with or without aspirin may be required in graft failure.
Indications for anticoagulation Target INRs are listed in Table 2.
Anticoagulant clinics
Cardiac Atrial fibrillation – the most common indication for warfarin is non-valvular atrial fibrillation, in which a 60% reduction in primary and secondary thromboembolic stroke is achieved. The bleeding risk is about 2% in trials, increasing with age. This risk must be assessed in the over-80s; in some, aspirin, 300 mg, is preferred. Patients under 60 years of age with otherwise normal hearts are usually anticoagulated only for elective cardioversion. Other cardiac disease – rheumatic valve disease requires anticoagulation. Other indications are cardiomyopathy, left ventricular aneurysm and mural thrombus. LMWH and aspirin reduce death after myocardial infarction (MI) by 60%, but with an associated risk of bleeding. Post-MI, low-intensity warfarin (INR 1.5) plus aspirin, 75 mg, reduces the incidence of ischaemic events in high-risk men, but increases the risk of cerebral haemorrhage in hypertension. It does not reduce mortality. Heart valve prostheses – patients with bioprosthetic heart valves require only 3 months’ anticoagulation (target INR 2.5) in the absence of other indications. Mechanical valves require longterm anticoagulation. The target INR is determined by valve type and position (range 3–4.5).
THE FOUNDATION YEARS 2:6
Anticoagulation requires expert supervision in a hospital clinic or by the general practitioner, and good patient education. Computerized dosing systems streamline storage and retrieval of laboratory and clinical data, and improve clinic management. Audit of clinical outcomes is essential. ◆
References 1 British Committee for Standards in Haematology. Guidelines on the use and monitoring of heparin. Br J Haematol 2006; 133: 19–34. 2 Collier J. Low molecular weight heparin for venous thromboembolism. Drug Ther Bull 1998; 36: 25–9. 3 British Committee for Standards in Haematology. Guidelines on oral anticoagulation. 3rd ed. Br J Haematol 1998; 101: 374–87. Update in: Br J Haematol 2006; 132: 277–85. 4 Tait R C, Sefcick A. A Warfarin induction regime for outpatient anticoagulation in patients with atrial fibrillation. Br J Haematol 1998; 101: 450–4.
264
© 2006 Elsevier Ltd. All rights reserved.
Practical procedures
heart valves: a meta-analysis. J Am Coll Cardiol 2003; 42: 2042–8. (A study of trials showing benefit with higher-intensity therapy.)
Further reading Royal College of Obstetricians and Gynaecologists. Green-top guidelines: Thromboembolic disease in pregnancy and the Puerperium: Acute Management, April 2001. Available online at: www.rcog.org.uk Hardman S M C, Cowie M R. Anticoagulation in heart disease. BMJ 1999; 318: 238–44. (Review of cardiological indications for anticoagulation.) Fitzmaurice D A, Kesteven P. How to evaluate the performance of oral anticoagulation clinics. Br J Cardiol 2003; 10: 370–2. (Details of service components for regular audit and review.) Vink R, Kraaijenhagen R A, Hutten B A et al. The optimal intensity of vitamin K antagonists in patients with mechanical
THE FOUNDATION YEARS 2:6
Practice points • Assess the risk of bleeding before starting anticoagulation • Check all medications taken by patients on anticoagulants • Ensure that patients understand the medication and its potential complications; provide a record of anticoagulant advice, INR tests and doses • If major bleeding occurs, reverse anticoagulation completely
265
© 2006 Elsevier Ltd. All rights reserved.
Anticoagulation
What’s new?
Muriel S Shannon
• Low molecular weight heparin is the treatment of choice for DVT and PE • Low molecular weight heparin is safe and effective in the prophylaxis and treatment of VTE in pregnancy • Reversal of over-anticoagulation with warfarin resulting in major bleeding can be achieved rapidly using prothrombin complex concentrate
Anticoagulation prevents pathological clot formation (e.g. on heart valves or chambers) and stops propagation and embolization of clots already developed in veins. The type, intensity and duration of anticoagulation depend on the indication. About 1.8% of the UK population require anticoagulation. The two main anticoagulant drugs are heparin and warfarin.
• New antithrombotic agents, including a synthetic pentasaccharide may offer effective anticoagulation with less need for monitoring; trials are promising
Questions to ask Is the patient at risk of bleeding? ask about any history of excessive or abnormal bleeding (e.g. peptic ulceration, haemorrhagic stroke, prolonged bleeding after surgery) and other major haemorrhagic events. The amount and pattern of alcohol use are important; binge-drinking is particularly dangerous. Intravenous drug abusers must be made aware of the risks of injecting while taking anticoagulants. Family history of bleeding should also be determined. Is the patient taking other drugs? all medications must be checked for interactions in the current British national formulary. Many drugs interact with warfarin (e.g. amiodarone), and certain
antibacterials (particularly ciprofloxacin, erythromycin and metronidazole) increase INR. Non-steroidal anti-inflammatory drugs (NSAIDs) and antiplatelet drugs (dipyridamole, aspirin and clopidogrel) increase gastrointestinal tract bleeding. Corticosteroids, thyroxine, allopurinol, cimetidine, omeprazole and certain lipidregulating drugs enhance the action of warfarin. Paracetamol (>28 tablets per week) can increase INR. Anti-epileptics, rifampicin and griseofulvin usually antagonize warfarin. Aspirin in full doses (600 mg) is contraindicated. Low doses (75 mg) may be prescribed in combination with warfarin in patients with arterial thromboembolic disease, but this increases the bleeding risk. The anticoagulant effect of heparin is enhanced by antiplatelet drugs; concomitant use of heparins with parenteral diclofenac or ketorolac increases the risk of haemorrhage. Glyceryl trinitrate reduces heparin’s anticoagulant effect. Is the patient pregnant? warfarin crosses the placenta and can cause adverse effects in the fetus. Exposure to warfarin during organogenesis is associated with chondrodysplasia and severe fetal deformity; avoidance of warfarin during 6–12 weeks’ gestation reduces but does not abolish this risk. Use of oral anticoagulants in later pregnancy is associated with increased fetal wastage and congenital malformation. The risk of fetal damage must be weighed against the problems and risks of converting to heparin in the mother. Heparins do not cross the placenta, but can cause adverse effects in the mother. Low molecular weight heparin (LMWH) is safe and effective in the prophylaxis and treatment of venous thromboembolism (VTE) in pregnancy, but its use in mothers with mechanical heart valves is controversial. The British Committee for Standards in Haematology (BCSH) guidelines discuss therapeutic options;1 management depends on the indication and patient preferences. Heparin is substituted for warfarin at 36 weeks to reduce the risk of fetal intracerebral haemorrhage during delivery. Mothers taking warfarin or heparin can breast-feed.
Muriel S Shannon is Consultant in Haemostasis and Thrombosis at St George’s Hospital, London, UK. She qualified from the University of Glasgow, and trained in haematology at the Royal Free Hospital, London.
Investigations: before starting anticoagulants, perform a clotting screen (prothrombin time ratio or INR, partial thromboplastin time ratio and thrombin time) and platelet count. Dose alterations and close monitoring are required in patients with severe hepatic or renal dysfunction.
Assessing the patient Before starting anticoagulation, the patient must be assessed carefully. Review the indication. Consider contraindications: there are no absolute contraindications to anticoagulant therapy, but if there is active bleeding withhold treatment until it is controlled. Recent major surgery (including neurosurgery) or trauma increase the haemorrhagic risk, and treatment may need to be delayed. Relative contraindications include a history of inherited or acquired coagulation disorders, recent cerebral haemorrhage, active peptic ulceration, uncontrolled hypertension, hepatic or renal dysfunction, alcohol or drug abuse and dementia. In these situations, dose reduction and careful monitoring are required to minimize the risk of bleeding. Heparin should be avoided in patients with thrombocytopenia, because the drug may cause a decrease in platelet count, and should not be given to those with a recent history of heparin hypersensitivity.
THE FOUNDATION YEARS 2:6
261
© 2006 Elsevier Ltd. All rights reserved.
Practical procedures
illness, age and use of aspirin increase the risk. Unfractionated heparin is rapidly reversed by protamine sulphate, 1 mg/100 units, but this agent is less effective against LMWH and repeat administration may be needed. Thrombocytopenia – a decrease in platelet count is occasionally seen after starting unfractionated heparin; this results from platelet aggregation and probably does not occur with LMWH. It has neither haemorrhagic nor thrombotic consequences. Heparin-induced immune thrombocytopenia with thrombosis (HITT) can lead to venous and arterial gangrene with a mortality of 30%. This serious reaction is mediated by an IgG antibody against complexes of heparin and platelet factor 4. It usually develops after 5 or more days’ therapy, but appears sooner in patients previously exposed to heparin (usually unfractionated), and causes platelet activation. LMWH has a lower affinity for platelet factor 4 and the incidence of HITT is lower. Heparin must be stopped immediately and alternative antithrombotic cover instituted (see below). Osteoporosis can develop after several months’ heparin treatment; fractures may result. It is rare with LMWH.
Heparin Pharmacology: unfractionated heparin (a glycosaminoglycan produced by mast cells) is extracted from porcine mucosa. It comprises heterogeneous polysaccharide chains of molecular weight 3–30 kDa. LMWH is produced by depolymerization, yielding chains of 4–6 kDa. Both forms bind and activate antithrombin, accelerating its interaction with activated factor X (Xa) 1000-fold. Differences between unfractionated heparin and LMWH – the antifactor-Xa activity of LMWH is more than 90%, compared with less than 30% for prophylactic unfractionated heparin. After subcutaneous injection, LMWH is better absorbed and has greater bioavailability; its half-life is 3–12 hours, which is 2–4 times that of unfractionated heparin. Excretion of LMWH is reduced by renal impairment. Administration and monitoring: therapeutic unfractionated heparin requires close monitoring, usually by activated partial thromboplastin time ratio (range varies with reagent used). Prophylactic doses are determined by thrombotic risk and do not require laboratory testing. When administering LMWH, monitoring using an antifactor-Xa assay is necessary in patients with renal failure, in children, in pregnancy and in those of very low or very high body weight. The LMWHs commonly used in the UK are dalteparin, enoxaparin and tinzaparin (Table 1).2
Warfarin Pharmacology: warfarin (a coumarin) is the standard oral anticoagulant in the UK. Vitamin K-dependent factors II, VII, IX and X and the coagulation inhibitors proteins C and S require carboxylation to form functional complexes; warfarin inhibits this process. Warfarin is absorbed rapidly; peak plasma levels are achieved in about 1.5 hours and the half-life is 2–3 days. Onset of action depends on the levels of factors II, VII, IX and X (half-life 6–60 hours) and varies from 24 hours to 72 hours.
Problems Bleeding – the risk of major bleeding is low at prophylactic doses, but increases to 2.5% with therapeutic doses of unfractionated heparin compared with 1.5% with LMWH. Concurrent
Heparin regimens Drug
Indication
Dalteparin
• Prophylaxis – moderate risk • Prophylaxis – high risk • Treatment of DVT/PE • Treatment of unstable coronary disease
Recommended regimen Once-daily subcutaneous injection except where stated 2500 units1 5000 units 200 units/kg3 120 units/kg 12-hourly
Enoxaparin
• Prophylaxis – moderate risk • Prophylaxis – high risk • Treatment of DVT/PE • Treatment of unstable coronary disease
20 mg (2000 units) 40 mg (4000 units) 1.5 mg (150 units)/kg3 1 mg (100 units)/kg 12-hourly
Tinzaparin
• Prophylaxis – moderate risk • Prophylaxis – high risk • Treatment of DVT/PE
3500 units 50 units/kg 175 units/kg3
Unfractionated heparin
• Prophylaxis – moderate risk • Prophylaxis – high risk • Treatment of DVT/PE
5000 units 12-hourly 5000 units 8-hourly 5000 units i.v. followed by either 15–25 units/kg/hour i.v. infusion2 or 15,000 units 12-hourly s.c.2
DVT, deep vein thrombosis; PE pulmonary embolism 1 2 3
Dose expressed as units of antifactor Xa activity Daily laboratory monitoring is essential Half dose given 12-hourly in pregnancy
Table 1
THE FOUNDATION YEARS 2:6
262
© 2006 Elsevier Ltd. All rights reserved.
Practical procedures
Administration and monitoring: warfarin is monitored by measuring INR. Recommended target INRs are shown in Table 2.3 The average daily dose is 3–9 mg/day, but it ranges from 0.5 mg to more than 25 mg. Table 3 shows a warfarin initiation protocol for atrial fibrillation that achieves a therapeutic INR with minimal bleeding and predicts a maintenance dose.4 A more intensive induction regimen is used for acute venous thrombosis (Fennerty algorithm).3 High loading doses of warfarin result in rapid reduction of the anticoagulant proteins C and S, and can cause thrombosis of subcutaneous vessels and skin necrosis. To prevent this, heparin is given before starting warfarin in patients with venous thromboembolic disease and is continued until the INR is more than 2 for 2 days. In patients requiring anticoagulation for indications other than thrombosis (e.g. atrial fibrillation), a personal or family history of venous thrombosis should be elicited before starting warfarin, and the starting dose should not exceed 5 mg daily. Factors affecting warfarin requirements include congestive heart failure, liver impairment, variations in alcohol intake, marked variations in diet, vomiting and diarrhoea.
Starting warfarin in patients with atrial fibrillation Days 1–4 • Warfarin, 5 mg daily Day 5 Check INR, adjust dose as follows INR Warfarin • ≤ 1.7 5 mg • 1.8–2.2 4 mg • 2.3–2.7 3 mg • 2.8–3.2 2 mg • 3.3–3.7 1 mg • > 3.7 0 mg Days 6–7 • Dose as for day 5 Day 8 Check INR, adjust dose as follows
Problems Drug interactions are numerous and must be considered when starting new therapy or stopping or changing long-term therapy. The British national formulary should be consulted. Herbal and alternative therapies also interact and should be checked with local drug information services. Patients are advised to avoid all preparations containing aspirin unless specifically prescribed. Paracetamol may be taken for minor aches and pains, but excessive use can increase INR. High INR (without bleeding) – BCSH recommendations are: • INR > target range with no bleeding – omit warfarin for 1–2 days, recommence at lower dose
Target INRs Indication Venous thromboembolism • Deep vein thrombosis/pulmonary embolism prophylaxis (maintain INR > 2.0 if high risk) • Treatment of first episode or recurrence off warfarin • Treatment of recurrence on warfarin • Antiphospholipid syndrome Cardiac indications • Atrial fibrillation (maintain INR > 2.0 for 4 weeks pre- and post-cardioversion) • Dilated cardiomyopathy • Mural thrombus post-myocardial infarction • Rheumatic mitral valve disease • Mechanical heart valves
Day 8 INR • ≤ 1.7 • 1.8–2.4 • 2.5–3.0 • > 3.0
Dose from day 8 6 mg 5 mg 4 mg 3 mg for 4 days
4 mg
• ≤ 1.7 • 1.8–2.4 • 2.5–3.0 • 3.1–3.5 • > 3.5
5 mg 4 mg 3.5 mg 3 mg for 4 days 2.5 mg for 4 days
3 mg
• ≤ 1.7 • 1.8–2.4 • 2.5–3.0 • 3.1–3.5 • > 3.5
4 mg 3.5 mg 3 mg 2.5 mg for 4 days 2 mg for 4 days
2 mg
• ≤ 1.7 • 1.8–2.4 • 2.5–3.0 • 3.1–3.5 • > 3.5
3 mg 2.5 mg 2 mg 1.5 mg for 4 days 1 mg for 4 days
1 mg
• ≤ 1.7 • 1.8–2.4 • 2.5–3.0 • 3.1–3.5 • > 3.5
2 mg 1.5 mg 1 mg 0.5 mg for 4 days Omit for ≥ 2 days
0 mg
• < 2.0 • 2.0–2.9 • 3.0–3.5 • > 3.5
1.5 mg for 4 days 1 mg for 4 days 0.5 mg for 4 days Quit for 2 ≥ days
Target INR
2.0 ± 0.5 2.5 ± 0.5 3.5 ± 0.5 3.5 ± 0.51 2.5 ± 0.5 2.5 ± 0.5 2.5 ± 0.5 2.5 ± 0.5 3.75 ± 0.75
Table 3
1 Varies with clinical condition
• INR > 8.0 with no bleeding – omit warfarin until INR < 5.0 (2–3 days), give vitamin K, 0.5–2.5 mg p.o., if there are risk factors for bleeding. Bleeding – the risk of bleeding increases exponentially with INR more than 5.0, but 80% of serious bleeds occur at the target
Source: British Committee for Standards in Haematology guidelines
Table 2
THE FOUNDATION YEARS 2:6
Previous dose 5 mg
263
© 2006 Elsevier Ltd. All rights reserved.
Practical procedures
VTE Deep vein thrombosis (DVT) and pulmonary embolism (PE) – anticoagulation is given to treat or prevent VTE; it does not lyse thrombi, but prevents propagation and embolization. The incidence of DVT is 1/1000/year; in >10% of cases, embolization to the lungs (PE) occurs. Mortality in PE (30%) is reduced significantly by treatment with heparin followed by warfarin. Proximal lower limb thrombosis requires anticoagulation to prevent embolization. Calf DVT seldom embolizes, but if left untreated may extend above the knee in 10% of patients; repeat imaging is required to detect this. LMWH is as effective as unfractionated heparin in the treatment of DVT, allowing outpatient management of selected patients. Warfarin is given for 6 weeks to 3 months in calf DVT and for 6–12 months in proximal DVT. In PE, LMWH followed by 6 months’ warfarin is effective. Long-term anticoagulation is recommended after two episodes of unprovoked VTE, after life-threatening PE or when ongoing risk factors are present. Inferior vena caval filters require individual assessment. Investigations (including thrombophilia tests) are undertaken in patients with a family history of premature or fatal VTE. Antiphospholipid syndrome – recurrence of VTE is common in patients with persistent antiphospholipid syndrome, and longterm anticoagulation is advised after one episode. Prophylaxis of VTE – LMWH or fondaparinux, in conjunction with mechanical methods (compression stockings), reduces VTE associated with orthopaedic and other high-risk surgery. Moderate risks (e.g. airline flights in at-risk patients, prolonged immobility) require lower doses. Low-intensity warfarin (target INR 1.5) is used in some patients with a long-term indwelling venous catheter.
INR. Treatment depends on the site and severity. For major bleeding, give prothrombin complex concentrate at a dose of up to 50 u/kg depending on INR; if this is unavailable, use fresh frozen plasma, 15 ml/kg. Vitamin K, 1–5 mg, is given by slow intravenous injection and may need to be repeated after 24 hours. Anticoagulation is withheld until bleeding is controlled. Minor bleeding (e.g. epistaxis, haematuria, bruising, subconjunctival haemorrhage) is assessed and local measures used to stop the bleeding. Warfarin is reduced or withheld until bleeding is controlled. Full reversal of anticoagulation with vitamin K may lead to warfarin resistance and should be decided on an individual basis in patients with an artificial heart valve; the degree of reversal depends on the severity of the bleeding. The cause of bleeding should be identified and treated. For dental work, the INR must be <4.0. Surgery – adjustment of anticoagulation is needed for surgical procedures. Patients taking warfarin should not undergo day surgery unless their INR has been adjusted beforehand. For dental work, the INR must be <4.0.
Newer anticoagulant agents Danaparoid sodium is a heparinoid used for thromboprophylaxis in general and orthopaedic surgery. It is useful in HITT, provided there is no cross-reactivity. Fondaparinux is a synthetic pentasaccharide that selectively inhibits factor Xa. It was recently introduced for prophylaxis in orthopaedic surgery. Direct thrombin inhibitors – recombinant hirudin forms an irreversible compound with thrombin and is used in HITT. It has a role in patients with cancer-associated thrombosis resistant to warfarin and heparin. Ximelagatran which binds reversibly to thrombin developed as an alternative oral anticoagulant to warfarin, has been withdrawn due to hepatotoxicity.
Peripheral arterial thrombosis: aspirin is preferred in the treatment of atherosclerosis and peripheral vascular disease. Warfarin with or without aspirin may be required in graft failure.
Indications for anticoagulation Target INRs are listed in Table 2.
Anticoagulant clinics
Cardiac Atrial fibrillation – the most common indication for warfarin is non-valvular atrial fibrillation, in which a 60% reduction in primary and secondary thromboembolic stroke is achieved. The bleeding risk is about 2% in trials, increasing with age. This risk must be assessed in the over-80s; in some, aspirin, 300 mg, is preferred. Patients under 60 years of age with otherwise normal hearts are usually anticoagulated only for elective cardioversion. Other cardiac disease – rheumatic valve disease requires anticoagulation. Other indications are cardiomyopathy, left ventricular aneurysm and mural thrombus. LMWH and aspirin reduce death after myocardial infarction (MI) by 60%, but with an associated risk of bleeding. Post-MI, low-intensity warfarin (INR 1.5) plus aspirin, 75 mg, reduces the incidence of ischaemic events in high-risk men, but increases the risk of cerebral haemorrhage in hypertension. It does not reduce mortality. Heart valve prostheses – patients with bioprosthetic heart valves require only 3 months’ anticoagulation (target INR 2.5) in the absence of other indications. Mechanical valves require longterm anticoagulation. The target INR is determined by valve type and position (range 3–4.5).
THE FOUNDATION YEARS 2:6
Anticoagulation requires expert supervision in a hospital clinic or by the general practitioner, and good patient education. Computerized dosing systems streamline storage and retrieval of laboratory and clinical data, and improve clinic management. Audit of clinical outcomes is essential. ◆
References 1 British Committee for Standards in Haematology. Guidelines on the use and monitoring of heparin. Br J Haematol 2006; 133: 19–34. 2 Collier J. Low molecular weight heparin for venous thromboembolism. Drug Ther Bull 1998; 36: 25–9. 3 British Committee for Standards in Haematology. Guidelines on oral anticoagulation. 3rd ed. Br J Haematol 1998; 101: 374–87. Update in: Br J Haematol 2006; 132: 277–85. 4 Tait R C, Sefcick A. A Warfarin induction regime for outpatient anticoagulation in patients with atrial fibrillation. Br J Haematol 1998; 101: 450–4.
264
© 2006 Elsevier Ltd. All rights reserved.
Practical procedures
heart valves: a meta-analysis. J Am Coll Cardiol 2003; 42: 2042–8. (A study of trials showing benefit with higher-intensity therapy.)
Further reading Royal College of Obstetricians and Gynaecologists. Green-top guidelines: Thromboembolic disease in pregnancy and the Puerperium: Acute Management, April 2001. Available online at: www.rcog.org.uk Hardman S M C, Cowie M R. Anticoagulation in heart disease. BMJ 1999; 318: 238–44. (Review of cardiological indications for anticoagulation.) Fitzmaurice D A, Kesteven P. How to evaluate the performance of oral anticoagulation clinics. Br J Cardiol 2003; 10: 370–2. (Details of service components for regular audit and review.) Vink R, Kraaijenhagen R A, Hutten B A et al. The optimal intensity of vitamin K antagonists in patients with mechanical
THE FOUNDATION YEARS 2:6
Practice points • Assess the risk of bleeding before starting anticoagulation • Check all medications taken by patients on anticoagulants • Ensure that patients understand the medication and its potential complications; provide a record of anticoagulant advice, INR tests and doses • If major bleeding occurs, reverse anticoagulation completely
265
© 2006 Elsevier Ltd. All rights reserved.