13.1 Introduction

Warfarin is the oral anticoagulant of choice. Nicoumalone and phenindione are licensed in the UK but are potentially more toxic than warfarin and are seldom used. All currently-available oral anticoagulants act by antagonising the effect of vitamin K, resulting in reduced hepatic production of active coagulation factors II, VII, IX and X, and hence in prolongation of the prothrombin time and INR. This usually takes 48-72 hours to develop fully. Hence in acute thromboembolism anticoagulation should be commenced with heparin, which should be continued until the INR has been within the desired range of the target for at least two consecutive days. Heparin is not required when oral anticoagulants are started electively for prophylaxis of thromboembolism, except in certain thrombophilias.^{19, 73}

Indications for oral anticoagulants are summarised in Table 3, together with a summary of the target INR¹³⁴ and its optimal range as defined in observational studies or randomised trials. It should be noted that audits have indicated that only about 30% of INRs are within the target range at any one time.¹³⁴

The average daily dose of warfarin to achieve an INR within the desired range of the target (usually 2.0-3.0) is 5 mg, but with wide variation (range 1-15 mg). Warfarin sensitivity varies widely between individuals, and within the same person, due to variables such as age, diet, diseases and drugs.¹⁹

A well-stabilised patient may need an INR check only every 4-8 weeks; however, any change in clinical state or in medication should prompt more frequent checks. The doctor monitoring anticoagulant treatment should be aware of the indication for treatment, target therapeutic range, and the planned duration of therapy.

13.2 Initiation, dosage and monitoring of oral anticoagulants

After clinical assessment has demonstrated an indication for oral anticoagulant treatment (see Table 3), the patient's medical history, drug history, and compliance should be assessed for cautions and contraindications (see Table 8). Many drugs interfere with both the pharmacology and bleeding risks of oral anticoagulants, most by enhancing, but some by suppressing the anticoagulant effect (see Table 9). The drug regimen should be simplified if possible. Potentially interacting drugs should be exchanged for non-interacting ones (e.g. cimetidine should be replaced by an alternative H2 receptor antagonist such as ranitidine); and aspirin stopped unless combination therapy is indicated (see section 4). In patients with peptic ulcer, H. pylori eradication therapy should be considered (see the SIGN guideline on H.pylori eradication in dyspeptic disease156).

The indication for oral anticoagulants, the appropriate target therapeutic range of the INR, and the proposed duration of treatment should be recorded in the case records, and notified in writing to the anticoagulant clinic if monitoring is to be performed there. Details of other medications and relevant medical conditions should also be notified in writing to the anticoagulant clinic.

Table 8

Checklist of drug interactions with Warfarin

Note: This list is not exhaustive: if in doubt consult British National Formulary

Table 9

One schedule for inpatient dosage and monitoring of full-dose Warfarin therapy in patients with active thrombosis⁵³

APTT ratio should be within or below therapeutic range (1.5-2.5). If APTT ratio is above this range the heparin effect on INR should be neutralised by adding protamine (0.4 mg/ml plasma) to the sample in the haematology laboratory.

A baseline blood sample for blood count (including platelet count), coagulation screen, urea, and liver function tests should be obtained prior to starting oral anticoagulants. This may show contra-indications or risk factors for bleeding, such as anaemia, thrombocytopenia, renal failure, or a prolonged prothrombin time due to "auto-anticoagulation", e.g. due to severe liver disease. In venous thromboembolism, a baseline thrombophilia screen may help in diagnosis of protein C or S deficiency prior to reduction of plasma levels of these proteins by oral anticoagulant therapy.

On starting oral anticoagulants, the INR should be charted in the case records along with daily dosage. An oral anticoagulant booklet (issued by the Scottish Office Department of Health, Room 64, St Andrew's House, Edinburgh EH1 3DH) should be fully completed, and patients (or relatives/carers) taken systematically through the educational "dos and don'ts" in this booklet prior to anticoagulant therapy, and periodically thereafter.

The daily dose of warfarin should be taken at a fixed time.

In hospitalised patients with active thromboembolism, the generally accepted starting regimen for treatment of acute thromboembolism is 5-10 mg/day warfarin on days one and two; thereafter dosing is determined according to the daily INR ⁵³ (see Table 9). The initial dosing regimen should be lower (5 mg) when there is increased sensitivity to warfarin (e.g. age over 65 years, low body weight, parenteral feeding, drug therapy which increases warfarin sensitivity e.g. some antibiotics, heart failure, liver failure, prolonged baseline prothrombin time). In patients taking both heparin and warfarin at the start of treatment, the INR can be used for dosing warfarin without stopping heparin, provided that the APTT ratio is within or below the therapeutic range for heparin (see Table 9).

Hospitalised patients with acute thromboembolism should not be discharged from hospital INR monitoring until stability within the appropriate target therapeutic range is achieved. Prior to hospital discharge, the hospital should communicate with the general practitioner (or other medical practitioner assuming patient care) to advise the recommended INR target range and the duration of therapy; and agree and ensure arrangements for continued patient and INR monitoring. Prior to discharge, patients should be given written information on the date and place of the next monitoring visit.

In outpatients without acute thromboembolism who are started on long term prophylactic oral anticoagulants (e.g. for atrial fibrillation) a less intensive starting regimen is appropriate.^{149, 157, 158}

Long term monitoring of oral anticoagulant therapy may be performed either by hospital departments (e.g. anticoagulant clinics managed by haematology departments) or by the patient's general practitioner; local arrangements vary. In either case: monitoring should be performed or supervised by knowledgeable and experienced staff; and quality control of clinical performance monitored cumulative records of INR and warfarin dose should be maintained a reliable patient recall and review system should be kept.

A review of comparative trials of anticoagulant clinic care versus routine medical care reported a trend for lower rates of major bleeding and thromboembolic events with anticoagulant clinic care;¹⁵⁹ however, further comparative studies are required.

Computer programs for management of oral anticoagulant dose may be superior to management by experienced medical staff.^{160, 161}

Patient self-management of oral anticoagulation also requires further study.¹⁶²

While "near patient" testing of the INR by several devices is commercially available, their accuracy and quality control should be professionally validated prior to use, and ongoing quality control arranged with a local haematology laboratory. Professional guidelines state that INR measurement be performed (or quality controlled) by a haematology department.163 Such a department should be accredited by Clinical Pathology Accreditation Ltd; and should make appropriate arrangements for the transfer of patients' blood samples to the laboratory for prompt processing.

Written reports should be sent to the requesting clinician through the hospital internal delivery systems, or by first class post to other hospitals or general practitioners. All INR results outwith the range 2.0-4.5 should be communicated to the requesting clinician on the same day, as should any other requests marked as "urgent". Such a department should also provide a 24-hour consultative medical service to respond to clinical queries about anticoagulation.

Each clinical unit (e.g. ward, outpatient clinic, GP surgery) must have formal arrangements for processing reports to ensure the result reaches the requesting doctor timeously, and to ensure that the result is entered on the patient's clinical record (and in the outpatient's anticoagulant booklet). There should be a reliable system for promptly informing patients of the results of their INRs and any change in oral anticoagulant dose.

13.3 Reversal of oral anticoagulant therapy in patients with bleeding or high INR

The most common cause of fatal or disabling bleeding in patients receiving anticoagulant therapy is intracranial or intraspinal bleeding.164, 165, 166, 167, 168 Any such patients who have head injury, headache (recent or severe), confusion, impaired consciousness, or focal neurological symptoms and signs should have urgent CT scanning to detect such bleeding, followed by appropriate referral.

The necessity for therapeutic intervention and the urgency for reversal of oral anticoagulant therapy will depend upon the reason why the patient is anticoagulated, the desired therapeutic range of the INR, the presence of either known local pathology (e.g. peptic ulcer) or systemic disorders (e.g. renal failure), and the severity and site of haemorrhage. The risk of haemorrhage rises with increasing INR, and the risk of thrombosis rises with decreasing INR.^{164, 165, 166, 167, 168} If the patient has become over anticoagulated it is important to ascertain the reason for this. Recent guidelines have been published.^{134, 154, 169}

In the patient with active bleeding, as well as measuring the INR, it is important to perform a full coagulation screen (APTT, fibrinogen and platelet count) and a full blood count to ensure that the patient does not have any other abnormality predisposing to bleeding, e.g. thrombocytopenia. Blood urea and liver function tests should be checked to assess the hepatic and renal status.

Immediate management should be directed towards arresting bleeding, even although in doing so it may temporarily increase the risk of thrombosis in individuals with continuing long term risk, e.g. in the presence of a prosthetic heart valve.

Reversal of anticoagulation can be achieved by stopping warfarin, administering vitamin K1, or giving blood products containing the vitamin K dependent clotting factors, i.e. factor IX complex concentrate (containing factors II, IX and X) and factor VII concentrate, or fresh frozen plasma. The advantages and disadvantages of each of these options are set out in Table 10.

A suggested scheme for treating patients is set out in Table 11. After corrective therapy has been initiated the INR should be monitored at appropriate time intervals: for those given vitamin K1 after 4-6 hours; and after factor IX complex concentrate immediately, again after 4-6 hours, and then daily.^{170, 171}

In patients with a high INR but no bleeding, stopping anticoagulant therapy alone will only result in a gradual reduction over several days in the INR. In the presence of a very high INR (over 8.0) or other risk factors for bleeding, a small dose of vitamin K1 (0.5 mg intravenously or 5 mg orally) can be given.^{170, 172, 173} Such a dose will restore the INR to the usual therapeutic range and not make the patient resistant to further anticoagulation with oral anticoagulants. Evidence level III

In patients with a high INR (>8.0) or other risk factors for bleeding, vitamin K1 (0.5 mg intravenously or 5 mg orally) should be considered.

In patients with non-severe bleeding and a high INR, warfarin should be stopped for 1-2 days and vitamin K1 (0.5-2 mg intravenously or 5-10 mg orally) should be considered.

For individuals with more severe haemorrhage a larger dose of vitamin K₁ can be used, but this may render the patient relatively resistant to re-anticoagulation. Vitamin K₁ should be infused slowly, because large doses given rapidly may result in facial flushing, chest tightness, cyanosis and hypotension. It should not be given intramuscularly because of the risk of haematoma formation. The bioavailability of vitamin K₁ after oral administration is very variable; if permanent reversal of anticoagulation is required a dose of 10 mg is appropriate.¹³⁴ Vitamin K₁ has a short plasma half of 1-2 hours and a biological effect that only lasts for a few hours and therefore repeated infusions are desirable.¹⁷⁴ Major haemorrhage associated with a high INR, in patients who need continued long term anticoagulation, can be managed by intravenous vitamin K₁ along with an infusion of factor IX complex concentrate.^{171, 175} Factor IX complex concentrate also contains factors II and X (but not factor VII). It is therefore effective therapy for rapid reversal of the anticoagulant effect of warfarin but carries a risk of thrombosis.^{171, 175} It should only be used when there is severe haemorrhage and not merely to correct a high INR which can be more appropriately accomplished by a small dose of vitamin K₁. Factor VII concentrate should also be given if available. Evidence level III

Table 10

Options for reversal of oral anticoagulant therapy

Method	Advantage	Disadvantage
Stop warfarin	Simple	May take several days for INR to normalise particularly with liver disease
Vitamin K1 Dosage: - 0.5-5 mg IV - 5-10 mg orally (depending on urgency)	Safe if given slowly	- 2-6 hours to take effect - 12-24 hours to take effect
Factor IX complex concentrate (Factor II, IX, X) Dosage: 50 IU/kg body weight	Acts immediately Small volume Can be given quickly	Exposes patient to pooled blood product which rarely may transmit hepatitis B (but safe from hepatitis C and HIV). Effect is temporary (8-24 hours) and should be combined with Vitamin K1. Risk of thromboembolism
Factor VII concentrate Dosage: 50 IU/kg body weight	Should be given with factor IX complex	As for factor IX complex concentrate
Fresh frozen plasma Dosage: 1 litre for adult	Acts immediately	Large intravenous volume load. Allergic reactions. Not as efficacious as factor IX complex concentrate. Difficult to give repeat infusions because of large volume. Virally inactivated plasma is preferred.

Table 11

Strategies for reversal of oral anticoagulant therapy

In patients with life threatening haemorrhage, factor IX complex concentrate should be given at a dose of 50 IU/kg body weight: such therapy is more efficacious than fresh frozen plasma.175,176 If factor VII concentrate is available it should be given at a similar dose.134 In addition, intravenous vitamin K1 should be given (5 mg, repeated as necessary).

The potential of coagulation factor concentrates (or fresh frozen plasma) to transmit most clinically important viral infections should be considered; this is reduced by a viral inactivation step during manufacture.

Consideration should also always be given to ascertain whether there may be an underlying structural lesion predisposing to bleeding, particularly if bleeding is present when the INR is within the therapeutic range.

For all individuals who become over anticoagulated it is essential (if the clinical decision is to continue oral anticoagulants) that they are well tutored in their use. In particular, they should be re-educated as to know what medicines to avoid (especially aspirin), what to do if they bleed, and when and where to get their INR checked; and be taken through their Department of Health Anticoagulant Booklet which they should carry with them. It is particularly important that the patients are well educated when initially starting on warfarin because the most common time for bleeding is during the first month of therapy.

13.4 Management of oral anticoagulant therapy before and after surgery and invasive procedures

When patients receiving oral anticoagulant drugs require surgery (including dental extractions), or other invasive procedures, their increased risk of excessive bleeding during and after surgery should be considered.

Possible measures to reduce this risk include: urgent reversal of oral anticoagulant therapy elective discontinuation of the oral anticoagulant, or dose reduction, to achieve a lower INR substitution of heparin

Urgent reversal of oral anticoagulant therapy (see section 13.3) may be required in the event of need for urgent surgery with high risk of bleeding (e.g. neurosurgery, ocular surgery) or need for urgent invasive procedures (e.g. liver or renal biopsy, transhepatic percutaneous shunting, lumbar puncture, myelograpy, epidural or spinal anaesthesia). The latter procedures carry an increased risk of spinal haemorrhage and paraplegia, and should not be performed until anticoagulation has been reversed. The need for lumbar puncture or myelography should be discussed with a neurologist or neurosurgeon before anticoagulant therapy is reversed, because reversal carries a risk of thromboembolism and because alternative investigations (e.g. MRI scanning) may be preferable.

Elective discontinuation of the oral anticoagulant, or dose reduction, to achieve a lower INR under which elective surgery can be performed, with an acceptable risk of bleeding. The individual's risk of bleeding will vary both with the type of surgery, and with the presence of other risk factors for bleeding. With the exceptions of neurosurgery, ocular surgery, and surgery performed under epidural or spinal anaesthesia (which require total reversal of the INR to <1.3), most surgery can be safely performed when the INR falls to 1.5.^{177, 178} For the majority of patients with an initial INR within the usual target therapeutic range (2.0-3.0), it takes 4-5 days after discontinuation of warfarin therapy for the INR to fall to 1.5 or less; elderly patients and those with INR greater than 3.0 may require a longer discontinuation time.^{177, 178} If total reversal of warfarin (INR under 1.3) is required, 6-7 days of discontinuation may be required. After warfarin therapy is restarted, it takes about 3 days on average for the INR to increase above 2.0.¹⁷⁸

Substitution of heparin (which can be rapidly reversed in the event of bleeding) during the period of lower INR, to reduce the risk of thromboembolism. Surgery increases the risk of venous thromboembolism: both heparin and oral anticoagulants are effective in prophylaxis.5 While a perioperative INR between 1.5 and 2.0 may have some prophylactic effect,¹⁷⁸ patients at increased risk of venous thromboembolism should be considered for additional antithrombotic prophylaxis while the perioperative INR is less than 2.0.¹⁷⁸ Options include intravenous unfractionated heparin (monitored by the APTT); low molecular weight heparin; mechanical methods (graduated elastic compression stockings or intermittent pneumatic compression); or insertion of an inferior vena caval filter in very high risk patients (e.g. surgery within two weeks of proximal DVT or PE).¹⁷⁸

There is also an increased risk of arterial and cardiac thromboembolism during the period of lower INR when oral anticoagulants are discontinued or reduced to reduce the risk of perioperative bleeding.^{177, 178} Options include intravenous unfractionated heparin (monitored by the APTT) in high risk patients (e.g. surgery within four weeks of arterial or cardiac thromboembolism); or subcutaneous low-dose unfractionated heparin or low molecular weight heparin.¹⁷⁸

It is recommended that surgeons, dentists and physicians intending to perform surgery or invasive procedures in patients receiving anticoagulant therapy seek advice concerning management of such therapy from a haematologist, prior to performing such procedures. Management will vary according to the perceived relative risks of bleeding and thromboembolism in the individual patient.

13.5 Drug interactions

Oral anticoagulants have many interactions with commonly prescribed drugs. A checklist is given in table 8.

13.6 The role of the pharmacist or nurse specialist in anticoagulation clinics

Pharmacists can play an important role in improving anticoagulant control (both in hospital and in primary care) by drug history taking, titration of dosage according to INR, patient counselling and dispensing of continuing supplies, and in making arrangements for future clinical appointments.^{179, 180} Advantages from pharmacist-run anticoagulant clinics include continuity of care, maintenance of accurate patient records, reduced workload for doctors, identification of drug interactions, and identification and minimisation of adverse effects.^{181, 182} Guidance on how to establish such a clinic has been published.^{179, 180, 181, 182} There is also increasing involvement of nurse specialists in anticoagulation clinics.