Uses Of Antiplatelet Drugs

Antiplatelet therapy protects 'at risk' patients against stroke, myocardial infarction or death. A meta-analysis of 145 clinical trials of prolonged

• Myocardial infarction. Aspirin should be given indefinitely to patients who have survived myocardial infarction.There is as yet no case for using aspirin to prevent myocardial infarction in those without important risk factors for the disease.

• Transient ischaemic attacks (TIAs) or minor ischaemic stroke.There is grave risk ol progression to completed stroke and patients should receive aspirin indefinitely. Before starting treatment it Is important to exclude intracerebral haemorrhage (by computed tomography) and other conditions that mtmicTIAs. e.g. cardiac arrhythmia, migraine, focal epilepsy and hypoglycaemia.

• Unstable angma.The chance of myocardial infarction is high and aspirin should be used with other drugs, i.e. a |i-adrenoccptor antagonist,a nitrate.a calcium channel blocker and possibly heparin i.v. as is judged appropriate.

• Arterial grafts, peripheral vascular disease. Aspirin (possibly combined with dipyridamole for grafts) should be given to prevent occlusion.These drugs may also be used to protect against thrombotic occlusion following percutaneous transluminal coronary angioplasty.

• Inhibitors of ADP-dependent platelet aggregation, e.g. ticlopidine.clopidorgrel, and glycoprotein I lb-Ilia antagonists, e.g. abcixlmab. can be expected to form part of regimens for cardiovascular disease.as evidence accumulates antiplatelet therapy versus control and 29 trials between antiplatelet regimens found that the chance of nonfatal myocardial infarction and nonfatal stroke were reduced by one-third, and that there was a one-sixth reduction in the risk of death from any vascular cause.22 Expressed in another way, in the first month after an acute myocardial infarction (a vulnerable period) aspirin prevents death, stroke or a further heart attack in about 4 patients for every 100 treated. Aspirin is by far the most commonly used antiplatelet agent. The optimum dose is not certain but one not exceeding aspirin 325 mg is acceptable, and 75-100 mg/d may be as effective and preferred where there is gastric intolerance. Aspirin alone (mainly) or aspirin plus dipyridamole greatly reduced the risk of occlusion where vascular grafts or arterial patency was studied systematically23

Many patients who take aspirin for vascular disease may also require an NSAID for, e.g. joint disease, and it may be argued that the NSAID renders aspirin unnecessary as both act by inhibition of prostaglandin G/H synthase. As inhibition by aspirin is irreversible and that by NSAIDs may not be, continued use of aspirin in such circumstances seems prudent, especially if NSAID use is intermittent.

Haemostatics

Etamsylate (Dicynene) is given systemically to reduce capillary bleeding, e.g. in menorrhagia.

Adrenaline (epinephrine) may be useful for epistaxis, stopping haemorrhage by local vasoconstriction when applied by packing the nostril with ribbon gauze soaked in adrenaline solution.

Fibrin glue consists of fibrinogen and thrombin contained in two syringes, the tips of which form a common port. The two components are thus delivered in equal volumes to a bleeding point where fibrinogen is converted to fibrin at a rate determined by the concentration of thrombin. Fibrin glue can be used to secure surgical haemostasis, e.g. on a large raw surface, and to prevent external oozing of blood in patients with haemophilia (see also below).

22 Antiplatelet Trialists' Collaboration 1994 British Medical Journal 308: 81.

23 Antiplatelet Trialists' Collaboration 1994 British Medical Journal 308:159.

Sclerosing agents. Chemicals may be used to cause inflammation and thrombosis in veins so as to induce permanent obliteration, e.g. ethanolamine oleate injection, sodium tetradecyl sulphate (given i.v. for varicose veins) and oily phenol injection (given submucously for haemorrhoids). Local reactions, tissue necrosis and embolus can occur.

Haemophilia

Management of the haemophilia A and haemophilia B (genetic deficiencies of factor VIII or IX) is a matter for those with special expertise but the following points are of general interest.

• Haemorrhage can sometimes be stopped by pressure; edges of superficial wounds should be strapped, not stitched.

• Minor bleeding can be stopped with plasma factor levels of 25-30% but severe bleeding requires a level of at least 50% and surgical procedures or life-threatening haemorrhage require targets of 75-100%. In haemophilia A antihaemophilic globulin (factor VIII) concentrate (tV2 8-12 h) should be used for bleeding that is more than minor. Administration of each unit of factor VIII per kg body weight raises the plasma level by 2%. Repeat dosing 2-3 times daily is necessary to maintain levels.

Factor VIII is available as ultrapure recombinant product, ultrapure plasma-derived product, high purity plasma-derived product and intermediate purity plasma-derived product. Factor IX (t1/, 18-24 h) should be used for bleeding that is more than minor in haemophilia B (Christmas disease). Administration of each unit of factor IX per kg body weight raises the plasma level by 1%. Maintenance doses are required every 18-24 h.

Factor IX is available as ultrapure recombinant product, high purity plasma derived product and low purity plasma-derived product. Duration of therapy is determined by speed of recovery of the affected joint or resolution of a haematoma. After surgery at least 10-14 days of replacement therapy is required to ensure adequate wound healing and scar formation. Recombinant factor VIII or IX concentrates are recommended for all previously untreated patients, those who have been previously treated but remain hepatitis C virus or HIV seronegative, and for mild to moderate severity disease when desmopressin is not sufficient. Primary prophylaxis with factor VIII three times weekly or factor IX concentrate twice weekly at doses to keep the factor level above 1-2% beginning in toddlers (through an indwelling venous cannula) results in a significant reduction in spontaneous bleeds and arthropathy. Tranexamic acid helps stabilise thrombi in both diseases.

For patients with high titre factor VIII inhibitors, standard factor IX complex products are first-line therapy but activated factor IX complex concentrates may be necessary for continued, more frequent or more severe bleeding. Porcine factor VIII or recombinant human factor Vila may be necessary for major bleeds or elective surgery.

The cloning of the factor VIII gene and development of retroviral-vector delivery systems have raised the possibility that the defect in haemophilia A may be corrected by gene therapy. In a sense this is already a reality; patients with haemophilia A who underwent liver transplantation for progressive hepatic disease were found to be producing haemostatic concentrations of factor VIII.

Von Willebrand's disease

Patients with type 2B or severe type 3 von Willebrand's disease, those with severe haemorrhage or patients who require major surgery, need replacement therapy with intermediate purity plasma-derived factor VIII concentrate known to have high molecular weight von Willebrand factor (vWF) multimers.24 The larger multimers are required for normal biological function. In type 2A and 2B von Willebrand's disease large multimers are absent in plasma, in type 3 von Willebrand's disease all multimers are absent. This is preferred to cryoprecipitate which is rich in vWF but has not undergone any viral inactivation process.

Desmopressin (DDAVP) (see p. 712) 0.3-0.4 micrograms/kg body weight i.v. (also available in a concentrated intranasal form) increases factor VIII and von Willebrand factor levels by 3-5 times baseline in mild to moderate haemophilia A; its use may render transfusion unnecessary after minor procedures such as dental extraction. It is also effective in mild to moderate type 1 von Willebrand's disease for which DDAVP offers nontransfusional treatment. Tachyphylaxis occurs with repeated dosage but stores are repleted after an interval of 2-4 days. Patients with severe deficiency of either factor and patients with any form of haemophilia B do not respond to DDAVP. Adverse effects include flushing, headache, tachycardia, mild hypertension and hyponatraemia.

Homocysteine and vascular disease

High plasma concentrations of homocysteine are associated with increased risk of thrombotic vascular

24 von Willebrands factor is a glycoprotein molecule of 2050 residues which is assembled into multimers (polymers).

events. The association is now known to be causal, strong and directly related. Severe hyperhomo-cysteinaemia accompanies inherited deficiency of enzymes that metabolise homocysteine, e.g. classical homocystinuria, but lesser degrees have other causes, including nutritional B vitamin deficiency. The normal plasma homocysteine it taken to be 5-15 micromol/1 and higher values are associated with thrombotic risk. The high plasma homocysteine of patients with classical homocystinuria responds to treatment with folic acid, vitamin B12 and vitamin B6 (pyridoxine). Clinical trials now in progress will establish whether multivitamin therapy will become a treatment option for patients with mild or moderate hyperhomocysteinaemia, and thrombotic vascular disease.

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