The management of established thrombosis has been transformed by low molecular weight heparins. Their pharmacokinetics and dynamics allow them to be given subcutaneously in a dose determined by body weight alone. While this permits treatment of selected patients at home, great care is needed. The correct diagnosis remains essential because the risks of early recurrence and bleeding are little different from those observed with standard heparin. Symptomatic calf vein thrombosis should be treated.
Treatment for established venous thrombosis
Sixty years ago, before heparin came into general use, symptoms of deep leg vein thrombosis progressed from calf to thigh or to the opposite leg in 60% of untreated patients. Embolism occurred in 40% of those with thrombosis and half the patients with pulmonary embolism died.
Today, we expect symptomatic extension or embolism in less than 5% of people treated for extensive deep leg vein thrombosis with standard heparin or a low molecular weight heparin followed by warfarin. Deaths from pulmonary embolism should be below 2%.1
The penalty for inadequate initial therapy is an increased risk of early or late extension, recurrence or embolism - a constant feature of thrombosis treatment trials regardless of whether the fault was too little heparin or (more obviously) leaving out heparin altogether and relying solely on an oral anticoagulant. Why too little heparin at the start should lead to recurrence some weeks or months later while the patient is still taking an oral anticoagulant remains unknown.
Although most venous thrombosis develops in patients who are at risk (surgery, injury, acute medical illness) and can be largely prevented with effective prophylaxis, a sizeable minority of patients with thrombosis and embolism have no apparent predisposition.
All patients with clinically suspected venous thrombosis or pulmonary embolism must have appropriate diagnostic testing to confirm the diagnosis.
Clinical suspicion alone is notoriously treacherous, since symptoms and signs of venous thromboembolism are highly non-specific, and this applies equally to a first presentation and to suspected recurrences. Ultrasound imaging is now the first investigation of choice for proximal (popliteal or femoral) vein thrombosis, although venography retains a key role in cases of suspected calf vein thrombosis (where ultrasound is relatively insensitive) or recurrent disease. A negative ultrasound examination for calf symptoms should be followed by immediate venography or by repeated ultrasound testing during the following week to rule out extension of an undetected calf clot. A normal lung scan rules out suspected pulmonary embolism, while a `high-probability' ventilation-perfusion lung scan is sufficient evidence to treat. Venous ultrasound imaging, spiral CT-scanning or pulmonary angiography may help to guide management in patients with a `non-diagnostic' lung scan.
Calf vein thrombosis: to treat or not to treat
There is ongoing confusion about whether or not patients presenting with symptomatic calf vein thrombosis require treatment.
There is a high clinical recurrence rate during the next 3 months if patients with symptomatic calf vein thrombosis are managed with short-term unfractionated heparin treatment in hospital alone, and are not then given ongoing warfarin therapy. This is quite unlike the natural history of the very small and asymptomatic calf clots that are frequently detected after surgery by the use of routine screening tests during thrombosis prevention trials. These usually resolve without clinical complications. Symptomatic calf vein thrombosis is not a clinically trivial event, and should be treated with heparin followed by warfarin.
Anticoagulant therapy: benefits and risks
Deep leg vein thrombosis is a very strong indication for anticoagulant therapy because of the high risk of early extension and embolism, and of subsequent recurrence. The bleeding risk is highest soon after surgery. It is increased by old age, low body weight, female gender, or malignancy, although none of these is an absolute contraindication. Interruption of the vena cava (see below) is an alternative to anticoagulant therapy within 24-48 hours of major surgery, or when there is active bleeding. There is a need for extra care with laboratory control of standard heparin and warfarin therapy if the bleeding risk is high.
Regimens of administration of heparin vary, but most hospitals have local guidelines which should be consulted. A typical regimen would be an initial intravenous bolus of 2500-5000 IU, followed by a continuous infusion. This starts at about 27 000 IU per 24 hours and is adjusted to prolong the activated partial thromboplastin time (APTT) to 1.5-2 times the control level or about 50-80 seconds (depending on the laboratory reagent used). Twice-daily subcutaneous heparin, starting with 12 500-15 000 IU and adjusted according to the APTT 4 hours after injection, is also effective. This method is not routinely recommended as the dose requirement is too variable and dose adjustment too cumbersome.
Low molecular weight heparins
These drugs are much simpler to use than standard heparins. Given twice-daily by subcutaneous injection, and with the dose adjusted for weight as recommended, there is usually no need for monitoring. The antifactor Xa activity varies little between individuals and the APTT is not useful. Excretion is predominantly renal so there is a case for measuring antifactor Xa activity in renal failure - although this test is poor at predicting bleeding or recurrent thrombosis.
Recent large trials indicate that low molecular weight heparins, given twice daily, and standard heparin produce similar results. It is likely that some low molecular weight heparins can also be given once daily to treat leg vein thrombosis, but the evidence available is not definitive.
Warfarin is started together with heparin or a low molecular weight heparin. The dose required varies so much between individuals that much depends on trial and error, although dose-response algorithms help. One popular regimen is to give a first dose of 10 mg followed by 5 mg on the next day, with subsequent doses adjusted to achieve an international normalised ratio (INR) of 2-3. Starting with 5 mg/day is prudent in the elderly where the maintenance dose is often quite small. Heparin can be stopped after a minimum of 4 days and once the INR has been greater than 2.0 for 2 consecutive days.
Warfarin is continued for 3-6 months. Three months is usually enough for calf vein thrombosis and when patients have a clear-cut predisposing event like surgery. Six months is probably better for extensive thrombosis and in people with 'idiopathic' thrombosis where the risk of recurrence is greater and extends over a longer time. People with `idiopathic' thrombosis may warrant treatment beyond 6 months, but this is unclear. Prolonged treatment is required when there is an ongoing underlying 'hypercoagulable' state.
Failure of anticoagulant therapy
Some of the most difficult management dilemmas result from major bleeding or clinically suspected recurrent thrombosis during anticoagulant therapy.
Major bleeding is best handled by stopping the anticoagulant and reversing its effects. This means vitamin K plus clotting factor replacement for warfarin, and protamine sulphate for standard heparin. Low molecular weight heparins have no complete antidote, although protamine sulphate has some effect. A vena cava filter is considered when the risk of embolism is high and a continuing risk of bleeding forbids a resumption of anticoagulant therapy.
In the case of a clinically suspected recurrence or extension, objective confirmation is essential. Usually, this rules out recurrence as it is quite rare when anticoagulant treatment has been adequate and there is no underlying malignancy. If, however, diagnostic tests confirm or fail to rule out recurrence, then the options include better heparin or warfarin control, a switch from warfarin to heparin or a low molecular weight heparin, or from standard heparin to a low molecular weight heparin, or consideration of caval interruption.
Treatment of leg vein thrombosis at home
Ease of administration means that patients can be taught to self-inject a fixed, but weight-adjusted, dose of low molecular weight heparin at home. Two recently published large randomised trials of home treatment for proximal (femoral or popliteal) deep vein thrombosis have found this gives results similar to those obtained in hospital with intravenous standard heparin (Table 1). Recurrence and bleeding were not significantly different when patients were treated at home. Importantly, the patients managed at home felt, on average, better about their illness.
Economic analysis, to nobody's surprise, overwhelmingly favours home therapy. The higher unit cost of low molecular weight heparins is partly balanced by the costs of giving and monitoring intravenous standard heparin. The cost becomes wholly irrelevant when put against the enormous expense of hospital care. New costs incurred in the community are quite small by comparison.
The understandable enthusiasm for home treatment must be tempered with caution. Patients enrolled in clinical trials were carefully selected because of their willingness to be managed at home and their low bleeding risk. They were looked after by physicians with extensive experience of anticoagulants. Thrombosis and anticoagulants remain dangerous so that plans for home treatment must include contingencies for handling recurrence and bleeding. Starting warfarin remains a tricky business which requires daily blood tests until the maintenance dose is known. Lastly, we must insist on rigorous diagnosis. Clinically suspected thrombosis should not be treated without objective confirmation - just because treatment is now simple and no longer requires admission to hospital.
Treatment of proximal vein thrombosis with twice-daily subcutaneous (sc.) low molecular weight heparins (LMWH) at home compared with continuous intravenous (iv.) infusion of heparin in hospital. Incidence of major bleeding and recurrence, extension or embolism (VTE) during 3 months of follow-up while taking warfarin 2,3
|Drug||sc. LMWH||iv. heparin|
|Enoxaparin (1 mg/kg):||patients = 247||patients = 253|
|– treated entirely at home||120||0|
|– days in hospital for inpatients||2.2 ± 3.8||6.5 ± 3.4|
|– recurrent VTE during 90 days||13 (5.3%)||17 (6.7%)|
|– major bleeding during heparin||5 (2.0%)||3 (1.2%)|
|Nadroparin (weight-based*):||patients = 202||patients = 198|
|– treated entirely at home||72||0|
|– discharged within 48 hours||44||0|
|– recurrent VTE during 90 days||14 (6.9%)||17 (8.6%)|
|– major bleeding during 90 days||1 (0.5%)||4 (2.0%)|
|* dose if <50 kg = 4100 IU; if 50-70 kg = 6150 IU; if >70 kg = 9200 IU|
Thrombosis and embolism in pregnancy
About one third of pregnancy-associated venous thrombosis or pulmonary embolism arises during the pregnancy, rather than soon after delivery. Warfarin crosses the placenta which standard or low molecular weight heparins do not. Warfarin during the first trimester is teratogenic, and at the end of pregnancy causes fetal as well as maternal bleeding. Recommended treatment for confirmed thrombosis during pregnancy is therefore standard heparin, although increasing experience with subcutaneous low molecular weight heparins indicates that they are also effective and relatively safe.
The major concerns about the prolonged use of high-dose standard heparin therapy in pregnancy are osteoporosis and heparin-induced thrombocytopenia. Whether switching to low molecular weight heparins decreases these risks is uncertain, but appears to be increasingly likely.
Thrombolytic therapy or surgery for deep vein thrombosis
The aim of thrombolytic therapy is to achieve clot lysis soon enough to preserve delicate vein valves and so prevent postphlebitic venous insufficiency. Repeat venography done after 3-5 days of streptokinase infusion shows total lysis in about 30% of patients treated within 5 days of the start of symptoms, partial lysis in about 30% and no lysis in the rest. Results with tissue plasminogen activator have been no better. The bleeding risk is high and there has been little clear-cut evidence of long-term benefit in the small clinical follow-up studies done to date. As a result, thrombolytic therapy is considered only in young people with a low bleeding risk seen soon after the onset of extensive thrombosis.
Thrombectomy may have a place in people with impending venous gangrene.
Placing a filter in the inferior vena cava may be appropriate when anticoagulants have failed because of recurrence or bleeding, or when they are contraindicated because of active bleeding or a very high bleeding risk. There is no good evidence that the venographic or ultrasound image of a `floating' thrombus indicates an unusually high risk of embolism, and this appearance alone is not an indication for interrupting the vena cava or for thrombectomy.
(See also Dental implications)
McPherson J, Street A. Tests of haemostasis: detection of the patient at risk of bleeding. Aust Prescr 1995;18:38-41.
|Australian Medicines Handbook: corrections|
1. Chapter 4 - Antidotes and Antivenoms Page 4-3
Dosage - Paracetamol overdose
'IV, maintenance, 50 mg/kg in 500 mL of 5% glucose given over 4 hours; 100 mg/kg in 1 L of 5% glucose given over 4 hours (total dose 300 mg/kg over 21 hours).'
should read -
'IV, maintenance, 50 mg/kg in 500 mL of 5% glucose given over 4 hours; 100 mg/kg in 1 L of 5% glucose given over 16 hours (total dose 300 mg/kg over 21 hours).'
2. Chapter 6 - Cardiovascular Drugs Page 6-61
AMIODARONE Drug interactions
'Digoxin - amiodarone reduces clearance of digoxin; monitor plasma digoxin concentration; increase dose of digoxin as necessary.'
should read -
'Digoxin - amiodarone reduces clearance of digoxin; monitor plasma digoxin concentration; decrease dose of digoxin as necessary.'
- Hyers TM, Hull RD, Weg JG. Antithrombotic therapy for venous thromboembolic disease. Chest 1995;108(4 Suppl):335S-351S.
- Levine M, Gent M, Hirsh J, Leclerc J, Anderson D, Weitz J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996;334:677-81.
- Koopman MM, Prandoni P, Piovella F, Ockelford PA, Brandjes DP, van der Meer J, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group. N Engl J Med 1996;334:682-7.