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Published on 1 March 2002

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Various approaches to anticoagulant treatment

Frederick F Fenech
MD FRCP FRCPE FRCPG FACP
Professor of Medicine
University of Malta
Malta
Director
International Institute for Ageing
United Nations
Malta

Anticoagulants interfere with the activities of the various coagulation factors at various stages of the coagulation cascade. They are used to induce acute coagulation and are increasingly used for chronic anticoagulation. Both these clinical conditions are more prevalent in the ever-increasing elderly population. However, it is in this age group that the decision to initiate anticoagulation is the most difficult. The difficulty stems from concern about the adverse effects of bleeding complications, particularly intracranial haemorrhage. Though there is no reluctance on the part of physicians to anticoagulate patients with deep vein thrombosis (DVT), it is well recognised that chronic anticoagulation is underused for stroke prevention in patients with atrial fibrillation. Heparins and the coumarins are the anti-coagulants most frequently used in clinical practice.

Heparins
Unfractionated heparin (UFH) has been the drug of choice in conditions where acute anticoagulation is required. Indeed, UFH has enjoyed the sole anticoagulant status for about half a century. It is a naturally occurring mucopolysaccharide polymer with a tetrasaccharide sequence. Commercial heparin preparations are heterogeneous with only 20% of the product biologically active. Heparin acts by binding to and inactivating antithrombin III and has equivalent activity against thrombin and factor Xa. It dramatically reduces thrombin generation and fibrin formation. UFH is usually administered by continuous IV infusion at a rate sufficient to raise the activated partial thromboplastin time (APTT) to 1.5–2 times the patient’s preheparin APTT.

Other modes of administration are IV injections or subcutaneous injections given at four-hourly or six-hourly intervals. As the pharmacological action of UFH is unpredictable, its administration requires close monitoring and therefore hospitalisation. Hospitalisation to initiate treatment with heparin followed by long-term anticoagulation with warfarin has been the traditional approach to treating DVT, which practically always precedes the potentially fatal pulmonary embolism (PE). Usually heparin and warfarin are given together for the first 5–7 days, then heparin is stopped and anticoagulation continued with warfarin. Table 1 records the dose and mode of administration of UFH in various clinical settings.

[[HPE03_table1_50]]

On occasions, long-term heparin administration with a portable external or an implantable pump is needed for patients with recurrent thromboembolism that is refractory to oral anticoagulants, for pregnant women with thromboembolism and for patients with disseminated intravascular coagulation (DIC). Lower doses of heparin (5,000 units, 12 hourly) have also been used to prevent DVT in high-risk medical and surgical patients.

The major complication is bleeding, although thrombocytopenia and osteoporosis are other adverse effects

A distinct advance in heparin use has been the development of low molecular weight heparins (LMWHs). These drugs are fragments of UFH produced by chemical or enzymatic polymerisation. They have a distinct pharmacological profile that is largely determined by their composition. They produce their major effect by combining with antithrombin and exerting antithrombin and anti-factor Xa effects. The effects of the different LMWHs differ and each product has a distinct profile so that the preparations are not interchangeable.

The major difference between UFH and LMWH is that, while UFH has equal activity against thrombin and factor Xa, LMWHs have greater activity against factor Xa. In their relative inhibitory activity against thrombin and factor Xa this means that, although APTT is useful to monitor the anticoagulant activity of UFH, it is of no use when LMWHs are used. The appropriate test in such a situation would be the plasma antifactor Xa assay. Table 2 lists the advantages of LMWH over UFH.

[[HPE03_table2_51]]

LMWHs were  initially developed for the prophylaxis of postsurgical DVT. They are now used not only for prophylaxis but also for the treatment of thrombotic disorders of both the venous and arterial type. Despite being more expensive, the LMWHs are replacing UFH in most subcutaneous indications.

The use of these refined heparins has made it possible to treat thrombotic disorders in an outpatient setting. Many studies have shown that the treatment of venous thromboembolism with LMWH is safe and as effective as that with standard UFH when both are used in appropriate doses. Three large randomised studies have shown that LMWHs can be safely administered subcutaneously to outpatients in comparison with UFH intravenous injections to hospitalised patients with proximal DVT (Table 3).(1–3) The introduction of LMWH, however, represents a major advance in the clinical application of heparin. Home treatment of thromboembolic disease is now a reasonable practice, but patients receiving the treatment should have relatively few complicating factors, be ­cooperative and have ready access to hospital.

[[HPE03_table3_51]]

Research at the moment is being carried on into the development of an oral formulation of UFH and LMWH. If successful, this will have a major impact on the use of UFH and LMWHs.

The increased awareness of heparin-induced ­thrombocytopenia stimulated a search for alternative drugs. Despite the development of alternative anticoagulants that are direct thrombin inhibitors (eg, hirudin, lepirudin, desirudin and argatroban), they have failed to provide similar clinical outcomes to the heparins. However, these antithrombin drugs are useful in the anticoagulant management of heparin-compromised patients. None of the currently available antiplatelet drugs exhibit any degree of antithrombin action.(4,5)

The coumarins
The coumarin anticoagulants include warfarin and dicumarol. Warfarin is the oral anticoagulant most commonly used for the prevention and treatment of thromboembolism. Warfarin acts by depressing the synthesis of vitamin K coagulation factors – factors II, VII, IX and X – resulting in synthesis of biologically inactive forms of these coagulation proteins. It also inhibits the vitamin K-dependent gamma-carboxylation of proteins C and S. Activated protein C in the presence of protein S inhibits activated factor VIII and activated factor V activity.

Its therapeutic effect is only apparent by 24 hours and the peak effect may not be achieved for 2–5 days. Its effect may last five days. There is a direct relationship between dose of warfarin and anticoagulant response. During the first few days, prolongation of the prothrombin time (PT) mainly reflects the depression of factor VII, which has a half-life of 5–7 hours. Equilibrium levels of factors of II, IX and X take one week; this is the reason why heparin and warfarin should overlap by 4–5 days. It is important to remember that it has no effect on existing clots.

The simplest way to induce anticoagulation is to administer a single dose of 5–10mg warfarin daily given at the same time (usually between 5pm and 7pm) and to monitor until the PT is 1.5–2 times the control value. Effective anticoagulation requires at least a week of warfarin administration.

As commercial thromboplastin preparations had different potencies, markedly affecting the PT results, a more precise method was needed to assess the intensity of coagulation with warfarin. The international normalised ratio (INR) has been adopted by hospitals and clinicians, using a standardised human brain thromboplastin known as Manchester Comparative Reagent. The INR should be checked daily or on alternate days after commencing therapy, then weekly for 4–6 weeks and thereafter every 4–8 weeks if control or compliance are satisfactory. The maintenance dose of warfarin is usually between 3mg and 9mg daily and is regulated by the INR results.

Changes in the patient’s medical condition or drugs may alter anticoagulation control and necessitate more frequent monitoring. Various clinical conditions require different degrees of anticoagulation. Table 4 lists the various INR ranges required for different clinical conditions. Since undercoagulation is ineffective and overanticoagulation may lead to bleeding, patient monitoring in specialised anticoagulant clinics is essential for anticoagulation to be safe and effective; therefore the treatment has to be individualised.

[[HPE03_table4_52]]

As patients requiring anticoagulation are often on other medications, it is important to know how warfarin interacts with other drugs. Table 5 lists the drugs which increase and decrease warfarin’s anticoagulant effect.

[[HPE03_table5_52]]

There are a number of conditions where warfarin is contraindicated. These include pregnancy, nonthrombotic embolic stroke, severe hepatic and renal disease and hypersensitivity to warfarin. Like all drugs, warfarin has a number of adverse reactions (Table 6). Bleeding is by far the most important complication of both the heparins and warfarin. On the whole, bleeding from heparin can easily be controlled by stopping the administration of the drug or by administering the antidote protamine sulphate, which acts very fast; on the other hand, the antidote to warfarin, vitamin K1, takes several hours to work, and large doses may reduce the response to renewed therapy with warfarin for one week or more.

[[HPE03_table6_53]]

The clinical indications for anticoagulation include  DVT, PE, atrial fibrillation, complications of rheumatic heart disease, prosthetic heart valves, transient ischaemic attack and carotid artery disease (Table 7). The duration of anticoagulation varies depending on whether the risk factors are temporary or permanent. Long-term anticoagulation with warfarin for nonrheumatic atrial fibrillation is highly indicated in order to prevent ischaemic stroke.

[[HPE03_table7_53]]

Anticoagulant therapy demands certain responsibilities from the pharmacist. A pharmaceutical care plan, which includes the patient’s medical and drug history as well as current medication, is set up in order to ensure that the patient is protected from potential risks of such treatment. Patient education is very important to ensure that the patient is aware of the risks associated with drug interaction and poor compliance. Before discharge, the patients are given an anticoagulant booklet and are counselled about the importance of informing their doctor, pharmacist and dentist that they happen to be receiving anticoagulant drugs. It is the pharmacist’s responsibility to alert the patient should a change in the brand of warfarin occur, since this would necessitate the checking of the INR until stability is achieved again. This might also be required if the doses are missed.

References

  1. Levine M, Gent M, Hirsh 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.
  2. Koopman M, Prandoni P, Piovella F, 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. N Engl J Med 1996;334:682-7.
  3. The COLUMBUS Investigators. Low-molecular weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997;377:657-62.
  4. Schwarz T, Schmidt B, Hohlein U, Beyer J, Schroder HE, Schellong SM. Eligibility for home treatment of deep vein thrombosis prospective study. BMJ2001;322: 1212-3.
  5. Greinacher A, Volpel H, Janssen U, et al. Recombinant hirudin (lepirudin) provides safe and effective ­anticoagulation in patients with heparin-induced thrombocytopenia. Circulation 1999;99:73-80.


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