1. Warfarin and heparin
Anticoagulation therapy is commonly used for primary and secondary prevention of venous thromboembolism, prevention of systemic embolism in patients with AF or mechanical heart valves, and for treatment of acute coronary syndromes.
Anticoagulation may also be used in primary prevention of MI in high-risk patients, congestive cardiac failure, mitral stenosis in the absence of AF and acute cerebral ischaemic syndromes, although evidence in these areas is less convincing.
Warfarin
Warfarin has a high bioavailability and reaches maximal blood concentrations in 90 minutes. Enzyme inducers, such as barbiturates, rifampicin and carbamazepine can increase metabolism.
Measurement of the prothrombin time is one way to monitor warfarin treatment. Owing to variations in responsiveness, an International Sensitivity Index is now used for reporting by converting PT ratio to INR.
Point-of-care and patient self-testing offer the potential to simplify oral anticoagulation testing by allowing greater independence and freedom.
Side-effects with warfarin are bleeding and skin necrosis. The risk of bleeding is related to intensity of anticoagulation. Contributing factors include age over 65, concomitant drug use, renal insufficiency and anaemia.
Skin necrosis with warfarin occurs on the third to eighth day of therapy. It is sensible to use warfarin in low doses and gradually increase once every few weeks while concomitant administration with heparin is continued. Other complications include gastrointestinal disturbances, headache and fever.
Heparin
Heparin is a sulphated mucopolysaccharide; the unfractionated drug has a high first-pass metabolism. The dose–response relationship is not linear and the anticoagulant effect increases disproportionately as doses are increased, so heparin therapy requires intensive monitoring.
Low molecular weight heparin (LMWH) has better absorption after subcutaneous administration, and reduced protein binding results in improved bioavailability. The effective half-life is four to six hours, allowing once-daily administration.
LMWH possesses greater activity against activated factor X than prothrombin and has a more predictable anticoagulant effect. The activated partial thromboplastin time (APTT) has been used to monitor therapeutic doses of unfractionated heparin. A target ratio versus midpoint of normal range of 1.5–2.5 is employed. The APTT is insensitive to LMWH and cannot be used for dosage monitoring. When it is being used for prophylaxis or treatment, routine monitoring is not required with LMWH.
Bleeding is the most common side-effect of heparin. Other factors increasing risk include concurrent illness, renal failure and liver disease.
Treatment strategies are to withhold heparin and to administer protamine sulphate for severe bleeds.
Heparin-induced thrombocytopenia is an immune mediated reaction, which may be secondary to heparin and causing platelet aggregation. The more severe form recurs rapidly on rechallenge and may necessitate stopping further doses.
Other complications of heparin include hypersensitivity reactions, alopecia, osteoporosis, priapism and hepatic dysfunction.
High INR values
Patients with or without bleeding
- Temporary omission of warfarin.
- Vitamin K administration.
- Transfusion of fresh frozen plasma concentrates of coagulation factors and/or prothrombin complex concentrate depending on the urgency.
2. Practical aspects
In patients at high risk of acute thrombosis, once the indication has been confirmed, the traditional method of initiating therapy is administration of warfarin, with or without concurrent administration of heparin.
Where possible, routine measurements of the patient’s coagulation status and liver function should be performed. In acute situations, concurrent administration of heparin and daily monitoring of INR for the first few days are recommended. Once therapeutic INR is achieved, checks can be limited to weekly, then fortnightly and, when stable, four- to 12-weekly.
For patients who do not require rapid anticoagulation, a slow loading regimen of 3mg daily with an initial INR measurement at one week is safe. Alternatively, a 2mg dose daily can be used with a two-week initial INR check.
Therapeutic anticoagulation is achieved in the majority of patients within a few weeks. This avoids over-anticoagulation and bleeding risks associated with rapid loading.
For patients requiring more rapid initiation of anticoagulation, regimens starting with 5mg doses, or a single 10mg dose followed by 5mg doses, are often used.
Point-of-care monitors use capillary blood to measure a thromboplastin mediated clotting time that is converted to a plasma PT / INR.
3. Special conditions
Anticoagulation in pregnancy
Pregnancy predisposes to venous thromboembolism. Generally, antithrombotic therapy started pre-pregnancy will need to be continued during pregnancy and puerperium.
However, warfarin predisposes to foetal and maternal bleeding and causes typical first trimester embryopathy and fetal CNS abnormalities.
Heparin does not cross the placenta, but the use of unfractionated heparin can cause bleeding, thrombocytopenia and osteoporosis in the mother. LMWH seems to be relatively safe. Where possible, warfarin should be completely avoided during the entirety of pregnancy.
Prophylaxis of venous thromboembolism can be by either unfractionated heparin or LMWH. Similarly, either can be used in the treatment of venous thromboembolism, with appropriate monitoring and cessation of therapy during labour.
In patients with antiphospholipid syndrome, heparin (alone or in combination with aspirin) may be used.
Pregnant patients with prosthetic heart valves pose a real dilemma. Given the uncertain efficacy of LMWH in this situation and the potential risks and medico-legal implications of warfarin, treatment strategy must be fully discussed with the patient, who should be allowed to make an informed choice.
Recommended options include using adjusted dose of unfractionated heparin or LMWH throughout pregnancy or warfarin throughout pregnancy, except in the first trimester and the latter half of the third trimester, when it should be replaced with unfractionated heparin or LMWH.
Anticoagulation in cancer
Venous thromboembolism is a frequent complication in patients with cancer. In general, primary and secondary prevention should be similar to that of non-cancer patients. For practical purposes, recommended therapeutic levels remain the same. Sometimes, a low-dose warfarin regimen is used for certain chemotherapy patients and those with indwelling venous catheters.
Anticoagulation in surgery
The management of warfarin-treated patients requiring surgery can be problematic. For those considered to be at high risk of thromboembolism, warfarin can be replaced by treatment doses of unfractionated heparin or LMWH up to 24 hours before surgery, with the expectation that their effect may last until 12 hours before surgery.
For those undergoing dental procedures, tranexamic acid or aminocaproic acid mouthwash can be used without interrupting therapy.
Previous bleeding
Management of patients requiring thromboprophylaxis, but who have had bleeding complications in the past, is challenging. Studies have shown that lowering the target INR range from 3.0–4.5 to 2.0–3.0 significantly reduces bleeding risk.
Therefore, a reduction in target INR in certain very high-risk groups may be warranted. In certain subgroups, aspirin may be an alternative.
The future
Direct thrombin inhibitors include lepirudin, bivalirudin and argatroban.
Lepirudin is derived from hirudin, an anticoagulant found in the common leech, Hirudo medicinalis, and is approved in patients with HIT to prevent thromboembolic complications. Bivalirudin is thought to have a lower risk of bleeding and recent trials results look promising.
Fondaparinux is a synthetic polysaccharide which enhances antithrombin activity towards factor Xa. This promising class of drugs can be administered orally and requires minimal monitoring. Fondaparinux has been shown to be at least as effective as unfractionated heparin in treating pulmonary embolism and as LMWH in treating DVT and in thromboembolic prophylaxis after orthopaedic surgery. Recent trials have shown promise for this agent in the management of acute coronary syndrome.
Websites on anticoagulation therapy, page 29
