1.1 Background

Arterial, cardiac and venous thromboembolism are major causes of death and disability in developed countries, particularly Scotland. Each year, over 50,000 people in Scotland suffer coronary thrombosis (presenting as sudden cardiac death, acute myocardial infarction, or acute unstable angina) which frequently results in death or in disabling heart failure.² A further 17,000 people are hospitalised each year for stroke, which again is often fatal or disabling: about 85% of strokes are due to thromboembolism (from the heart, aorta, neck arteries or, rarely, leg veins) and about 15% are due to intracranial bleeding (including that associated with anticoagulant therapy).³ About 500 amputations and 2,000 other operations are performed in Scotland annually for lower limb ischaemia, which is often due to thromboembolism from the heart, aorta or arteries to the lower limbs.⁴ Finally, about 10,000 people in Scotland develop deep vein thrombosis of the lower limb (DVT) or its sequel, pulmonary embolism (PE) each year: PE occurs in about 1% of hospital admissions and is the most common preventable cause of death in hospitalised patients and pregnant or puerperal women.⁵ DVT may also be followed by the post-thrombotic leg syndrome which includes chronic venous ulceration: another major consumer of health service costs.

1.2 Causes of thrombosis

Thrombosis usually occurs at sites of vessel or heart wall damage (e.g. rupture of an atherosclerotic plaque; diseased or replacement heart valves; mural thrombus following endocardial injury after myocardial infarction) and/or blood flow disturbance (e.g. atrial fibrillation, leg veins in immobile patients). The contributions of platelet-fibrin thrombi to arterial and venous occlusion and to clinical events have been established by morphological studies (pathological, angiographic and angioscopic); epidemiological studies of haemostatic variables (related to platelets, coagulation and fibrinolysis); and especially by large randomised controlled trials of antiplatelet, anticoagulant or thrombolytic therapies.⁶

1.3 Antithrombotic therapy

Recent overviews of such controlled trials have suggested that antithrombotic prophylaxis in appropriate people at increased risk of thrombosis, and antithrombotic treatment in appropriate patients with acute thrombosis, not only reduces disability and mortality, but is also cost-effective.⁶ Routine antithrombotic therapy in selected, high-risk patients therefore appears to offer a major, cost-effective health gain in Scotland.

1.4 Antiplatelet therapy

Antiplatelet therapy, usually with aspirin, is clearly effective (and also cost-effective) in reducing death in acute myocardial infarction or acute ischaemic stroke and in the prevention of serious vascular events when given as secondary prophylaxis to patients with clinical evidence of arterial disease (see table 1).^{6, 7, 8, 9} It is also effective in prevention of stroke in selected patients with heart valve disease, atrial fibrillation,^{6, 10, 11, 12} and in primary prevention of myocardial infarction in men with multiple risk factors.^{13, 14} Such patients are readily identified by general practitioners and by hospital doctors.

Table 1

Antiplatelet therapy: effects on secondary prophylaxis of myocardial infarction, stroke or vascular death.^{7, 9}

*NNT = number needed to treat over the duration indicated to prevent one vascular event

Despite this clear evidence of efficacy, recent audit studies have shown that many such patients do not receive aspirin from their general practitioners or hospital doctors.^{15, 16}

1.5 Anticoagulant therapy

Anticoagulant therapy, usually with heparin injections short term and/or oral anticoagulants (usually warfarin) long term, is also clearly effective in prevention of serious vascular events when given as prophylaxis to high-risk patients, or as treatment of acute arterial or venous thrombosis.^{5, 6, 10, 11, 12, 14, 17, 18, 19, 20, 21, 22} (See tables 2 and 3.) However, full-dose anticoagulation is also a common cause of major internal bleeding, including intracranial, gastrointestinal or retroperitoneal haemorrhage, which can be fatal. Recent audit studies have shown that many high-risk patients do not receive anticoagulant prophylaxis or treatment; that there is wide variation in the doses of heparin and warfarin prescribed, the target effect and range, and in both inpatient and outpatient laboratory monitoring and patient monitoring; and that communication between clinicians, laboratories and patients can be improved.^{16, 23, 24, 25, 26}

It is therefore important to select patients most likely to benefit from anticoagulant therapy (i.e. those in whom the risk of major thromboembolic events exceeds the risk of major bleeding); and to minimise both thromboembolic and haemorrhagic morbidity and mortality during anticoagulant therapy. Approaches to the latter include: use (and clinical audit) of optimal target effect and range for unfractionated heparin and warfarin; patient and laboratory monitoring; patient education; and effective communication between patients, general practitioners, hospital doctors, anticoagulant clinics, haematology laboratories, and other relevant health care professionals (e.g. pharmacists, dentists). With the increasing use of heparin in hospitals, and the increasing use of long-term warfarin in outpatients (e.g. for primary or secondary prophylaxis in patients with atrial fibrillation), many people in Scotland are now 'iatrogenic haemophiliacs', for whom it is important that general practitioners, hospital services and health boards ensure that the considerable potential of anticoagulant prophylaxis to reduce thromboembolic mortality is not only assured by clinical audit of use and monitoring, but is also not outweighed by increased morbidity and mortality due to drug-induced bleeding.

1.6 Thrombolytic therapy

As distinct from antithrombotic therapy with aspirin, heparin or warfarin, which prevents or reduces formation of platelet-fibrin thrombi, thrombolytic (fibrinolytic) agents lyse fibrin thrombi by activating endogenous plasminogen to plasmin, which dissolves fibrin. Short term thrombolytic therapy with streptokinase, anistreplase, or tissue plasminogen activator (alteplase) has been shown in a recent overview of large randomised controlled trials to significantly reduce mortality and morbidity (including stroke and heart failure) when given to selected patients with evolving acute myocardial infarction (MI).²⁷ A Scottish consensus statement on thrombolytic therapy in the early treatment of acute MI has been issued.² International guidelines and consensus statements on thrombolytic therapy, not only for acute myocardial infarction, but also for peripheral arterial and venous thromboembolism, have also been published.^{28, 29} The benefits and risks of thrombolysis in acute ischaemic stroke are being evaluated in large, randomised controlled trials: at present the balance is unclear. The use of thrombolytic therapy will not be addressed in detail in the pilot edition of this guideline.

Table 2

Indications for parenteral anticoagulation with heparins

* For full discussion of the supporting evidence and grades of recommendations for these indications, see the section noted.

1.7 Prophylaxis of venous thromboembolism

A Scottish national guideline has been issued for identification of risk of venous thromboembolism and prophylaxis in patients at increased risk during hospitalisation, pregnancy or the puerperium⁵ and is being revised in 1999. This use of anticoagulant therapy will therefore not be addressed in the present guideline.

1.8 Aim of the guideline

The aim of this national guideline is to assist individual health boards, general practitioners, hospital departments and hospitals to produce local guidelines for:

1. identification of patients at increased risk for arterial thromboembolism, or who have acute thromboembolism
2. routine administration and monitoring of appropriate, effective antithrombotic prophylaxis and treatment in such patients
3. prevention and management of anticoagulant overdosage or bleeding during anticoagulant therapy.

1.9 Contraindications and other exceptions to the recommendations

To avoid constant repetition, the words "unless contraindicated" have not been included in every recommendation on the use of drug therapy in this guideline, but all recommendations should be interpreted as carrying this caveat. The balance of risks (bleeding) and benefits of antithrombotic therapies should be carefully assessed in the individual patient.

Table 3

Indications for oral anticoagulation (usually with warfarin)

* For full discussion of the supporting evidence and grades of recommendations for these indications, see the section noted.