Antiplatelet Drugs: Clinical Pharmacology and Therapeutic Use

Because platelets are so important in thrombus formation, drugs which inhibit platelet function (the ‘antiplatelet drugs’) have considerable potential as antithrombotic agents. Among the antiplatelet drugs, only aspirin, sulphinpyrazone, dipyridamole, hydroxychloroquine, and clofibrate have had wide clinical trial. Their effects on platelet metabolism differ. Aspirin prevents platelet prostaglandin synthesis by acetylating and irreversibly inactivating platelet prostaglandin synthetase, while sulphinpyrazone is a reversible inhibitor of the same enzyme. Both aspirin and sulphinpyrazone impair the platelet release reaction and reduce platelet aggregation, but neither prevents platelet adhesion to the subendothelium or to foreign surfaces. On the other hand, dipyridamole reduces platelet adhesion as well as aggregation, probably by inhibiting phosphodiesterase and so raising platelet cyclic AMP levels. The effects of hydroxy-chloroquine and clofibrate have been less well defined. As the antiplatelet drugs form a diverse group of substances with differing effects on platelet function, it is hardly surprising that every potential clinical application of each antiplatelet drug or drug combination has had to be tested separately, and that these drugs have not proved to be equally effective. One or more antiplatelet drugs have now been evaluated in each of the following situations Prosthetic heart valves, other foreign surfaces, and artery surgery: Systemic embolism remains a major hazard after prosthetic heart valve replacement, justifying long term oral anticoagulant treatment. There is now good evidence that adding aspirin or dipyridamole to the oral anticoagulant further reduces the risk of embolism, but that aspirin and dipyridamole alone or together are relatively ineffective when used without an oral anticoagulant in these patients. In haemodialysis patients with silastic arteriovenous shunts sulphinpyrazone significantly reduces the shunt thrombosis rate, while some antiplatelet drugs may also reduce thrombus formation on the membranes of dialyzers and blood oxygenators. Preliminary studies suggest that aspirin may improve the outcome after reconstructive surgery for chronic obstructive artery disease, especially when there is a poor postoperative haemodynamic result, but long term sulphinpyrazone treatment has no such benefit. Aspirin may also increase the early patency rate of arteriovenous fistulas, but has not reduced the likelihood of pulse loss after arteriotomy for cardiac catheterisation. Elderly patients at high risk of developing myocardial infarction or stroke: There is evidence that long term sulphinpyrazone treatment may reduce cardiovascular mortality in elderly men with clinical evidence of atherosclerosis, and especially a history of stroke. However, no such effect was seen in elderly patients treated with aspirin. Myocardial ischaemia and infarction: Although this has been proposed on theoretical grounds, long term antiplatelet drug treatment cannot be recommended for primary prevention of myocardial infarction on present evidence. The results of some retrospective surveys suggest that regular aspirin intake by people without clinical evidence of ischaemic heart disease may prevent myocardial infarction, but other surveys have not confirmed this. Prospective studies have shown that long term clofibrate treatment has no effect on cardiovascular mortality, although it can apparently prevent non-fatal infarction at the cost of some undesirable side effects. On the other hand, there is evidence that antiplatelet drug treatment may be of value after myocardial infarction. The preliminary results of one prospective multicentre study suggest that sulphinpyrazone dramatically reduces the likelihood of sudden death in the first year after infarction, while aspirin treatment was associated with a consistent, but statistically insignificant, trend towards reduced post-infarct mortality in three other studies. Results with clofibrate have varied; two clofibrate trials found that long term treatment reduced mortality after myocardial infarction only when infarction was associated with angina pectoris, while a third found clofibrate had no effect on mortality, regardless of the presence or absence of angina. Hopefully, the presently confusing data on the value of antiplatelet drugs in patients with myocardial ischaemia will be clarified by large scale trials which are still in progress. Cerebral ischaemia: There is increasing evidence that aspirin can prevent further attacks in many patients with transient cerebral ischaemia. More importantly, one large multicentre study found that long term aspirin treatment reduced the incidence of stroke by 50 % in men with transient cerebral ischaemic attacks, although the drug had no apparent effect in women. An early trial also suggested that sulphinpyrazone can arrest transient cerebral ischaemic episodes, but this was not confirmed by later experience. Present information therefore suggests that aspirin is now the drug of first choice in men with transient cerebral ischaemia, while oral anticoagulants should be preferred in women with this disorder. Venous thrombosis: Several studies suggest that aspirin prevents venous thrombosis and pulmonary embolism after hip surgery, though again the effect may be restricted to men. This is an important observation, as other safe prophylactic methods are relatively ineffective in orthopaedic patients. There is also evidence that hydroxychloroquine and the combination of aspirin with dipyridamole may prevent thrombosis after general surgery. However, in these patients, low dose heparin treatment is very effective and safe, has been much better evaluated, and remains the prophylactic method of choice. Microvascular disorders and organ transplantation: Although it has been proposed that antiplatelet drugs may modify the course of many microvascular disorders with a presumably important thrombotic component and that of organ transplant rejection, the evidence has generally been unconvincing. However, aspirin is dramatically effective in a rare syndrome sometimes seen in patients with thrombocytosis; the painful microvascular occlusions of the fingers and toes in this disorder resolve completely for 2 to 3 days after a single dose. Dosages and side effects: Presently used daily doses of the antiplatelet drugs are: aspirin 300 to 1500mg; sulphinpyrazone 600 to 800mg; dipyridamole 400mg when used alone or 100mg when used with aspirin; clofibrate 1.5 to 2.0g; and hydroxychloroquine 800mg. Like all drugs, the antiplatelet agents have their side effects. Aspirin has the greatest effect on the bleeding time; it can cause spontaneous bleeding in patients with a pre-existing haemostatic defect, and probably increases postoperative bleeding. However, this has not been a problem with the other antiplatelet drugs. The long term combination of oral anticoagulants with dipyridamole appears to be safe, but their combination with aspirin is contraindicated by the unacceptable risk of gastrointestinal bleeding. Non-bleeding side effects include gastrointestinal intolerance with aspirin and sulphinpyrazone, dose-related headache with dipyridamole, and gallstone formation with long term clofibrate treatment.