Piatelets and Vascular Occlusion

There is evidence that aspirin is partially effective in the prophylaxis of various vasoocclusive disorders. This article reviews pharmacologic opportunities for improvement over and above the therapeutic effect of aspirin. It is concluded that several rational possibilities merit consideration, in particular, the use of combinations of drugs that affect the thrombotic process at different points. Such strategies will ultimately require validation by clinical trial. Circulation 73, No. 2, 240-243, 1986. VASCULAR OCCLUSIONS, especially in the arterial circulation, are the principal source of mortality and morbidity in Western society. Occasionally the cause is a generalized disease process that affects blood flow (e.g., hyperviscosity states such as macroglobulinemia or polycythemia) or blood vessel walls (e.g., giant cell arteritis or syphilitic vasculitis). Such diseases offer specific points of therapeutic attack. Recently the pathophysiology of hypercoagulable states associated with protein C deficiency, antithrombin III deficiency, and the lupus anticoagulant have been elucidated. 1-' Such insights provide new therapeutic approaches to these disorders and no doubt further instances of such specific entities will be discovered in the future. However, overwhelmingly the most common pathology in the arterial circulation is the atheromatous plaque and related thrombosis. Atheromatous plaques are very common, but they are usually clinically undetectable. Risk factors for their development, such as cigarette smoking, raised blood pressure, or abnormal blood lipids can be determined by screening an asymptomatic population. Drug treatment aimed at these etiologically significant conditions in high-risk groups may reduce the risk of overt vascular disease (see Dollery and Bulpitt' and Oliver7 for reviews). However, some studies have recorded negative results, for example the multiple risk factor intervention trial,6 and at present treatment is of proven benefit only in very high-risk groups. The majority of vascular catastrophes occur in individuals who do not fall into such groups.7 It may be possible to improve this situation if new risk factors are identified. In particular, components of the coagulation pathway (facFrom the Department of Clinical Pharmacology, Royal Postgraduate Medical School, London. Address for correspondence: Dr. J. M. Ritter, Department of Clinical Pharmacology, Royal Postgraduate Medical School, Ducane Road, London W12 OHS, England. 240 tors VJIc, VIIc, and fibrinogen) may prove to be powerful predictors of cardiovascular death.8 However, it is likely that effective primary prevention will depend either on treating everyone or on developing detection techniques that are sufficiently noninvasive and cheap to be used in screening large asymptomatic populations. Such techniques could in principle be either structural or biochemical. However, structural techniques such as Doppler ultrasound are likely to be too time-consuming and expensive for mass screening. The recent finding of raised levels of the urinary metabolite of prostacyclin in patients with severe atheromatous disease9 suggests that a biochemical approach to detecting the extent of atheroma is not impossible, although other markers of arterial damage may prove to be more sensitive. Whether some such method would be worthwhile as a screening technique will depend on its ability to identify a subgroup at particular risk and to follow changes in response to a therapeutic measure. Some interventions (such as stopping smoking) are so clearly advantageous that there is no need to restrict them to a population at particular risk. Some dietary measures (such as avoidance of gross excesses of fats and cholesterol) probably fall into the same category, whereas others (e.g., increased consumption of food rich in eicosapentaenoic acid) are more contentious, and certainly require further study. This is also true of most drugs that might be used in the primary prevention of atheromatous disease. This article concentrates on possibilities for drug therapy, and particularly on drugs acting on the eicosanoid cascade that may modify platelet/vessel wall interactions. The platelet is an attractive target for pharmacologic attack, first because of its role in thrombosis. The probable efficacy of aspirin in the secondary prevention of myocardial infarction'0 and of CIRCULATION by gest on A ril 7, 2017 http://ciajournals.org/ D ow nladed from PLATELETS AND VASCULAR OCCLUSION stroke and death in patients experiencing transient ischemic attacks'1 is encouraging in this context. Second, platelets are also implicated, albeit indirectly, in the development of the atheromatous plaques themselves. Thus, experimental intimal proliferative lesions in rabbits do not occur in thrombocytopenic animals.12 Pigs with von Willebrand's disease in which platelets fail to adhere to the subendothelium develop fewer atheromatous lesions than do control pigs both on normal and high-cholesterol diets.'3 It has been suggested that platelet-derived growth factor may be the stimulus to the smooth muscle cell proliferation that is central to the development of atheroma,14 although the evidence for this is limited to observations on cultured cells. Whether or not platelet-derived growth factor proves to be an important link between platelets and atheromatous plaques, antiplatelet drugs can influence atheroma formation, at least experimentally: proliferative arterial lesions caused by homocystine infusions in baboons were prevented by dipyridamole. 1' New therapeutic avenues may arise from the application of new drugs or from more rational use of existing ones. Antiplatelet drugs offer opportunities of both kinds. Their value in secondary prevention must be judged against existing therapies (aspirin, anticoagulants, /3-blockers), in terms of efficacy, adverse reactions, and cost. In the case of primary prevention, controlled studies will be needed, such as the study of aspirin in British doctors in progress under the direction of Sir Richard Doll. Antiplatelet drugs include the following categories: (1) cyclooxygenase inhibitors, (2) thromboxane synthase inhibitors, (3) thromboxane receptor antagonists, (4) antiaggregatory prostaglandin (PG) agonists, and (5) platelet phosphodiesterase inhibitors. What prospects do these drugs offer for a greater effect on valvular disease than that on aspirin? Cyclooxygenase inhibitors. Can the value of aspirin therapy be improved by the use of low doses (20 to 40 mg/day)? Conventional doses of aspirin may inhibit both platelet (proaggregatory) and vascular (antiaggregatory) prostanoids, posing an "aspirin dilemma."16 17 Low doses are more selective,18' 19 at least in healthy subjects. The use of such doses should have advantages in reducing adverse effects. Whether it will also increase efficacy has been challenged.20 21 We agree with Patrono22 that this question can only be answered by clinical investigation rather than by philosophical discourse, while acknowledging that the size (and cost) of clinical trials large enough to achieve adequate statistical power to detect effects of realistic magnitude will be considerable. It is unlikely that other cyclooxygenase inhibitors will have greater efficacy than aspirin, but it is possible that some may be of value in specific circumstances such as renal impairment or gastric intolerance. In this context the selectivity of sulindac in sparing renal cyclooxygenase in vivo23 is noteworthy. This selectivity has recently been questioned.24 However, in patients with mild renal impairment ibuprofen caused a fall in glomerular filtration, whereas sulindac, in a dose that caused substantial inhibition of platelet thromboxane synthesis, had no effect on renal function or prostaglandin production.25 The combined lipoxygenase/cyclooxygenase inhibitor BW 755C does not inhibit gastric prostacyclin synthesis and is not ulcerogenic in rats at doses that do inhibit the formation of PGs in inflammatory exudate,26 raising the possibility of cyclooxygenase inhibitors that specifically spare the stomach. Thromboxane synthase inhibitors. It was hoped that this class of drug, exemplified by dazoxiben, would be an improvement over cyclooxygenase inhibitors for two reasons. First, it would circumvent the "aspirin dilemma" referred to above, since vascular PGI2 synthesis would be unimpaired. Since low-dose aspirin therapy achieves selective inhibition of platelets at low cost, this rationale is not so attractive as at first appeared. A second reason these drugs could be superior to cyclooxygenase inhibitors is that by diverting endoperoxide precursor from platelets to vessel wall, they might augment prostacyclin synthesis.16 The occurrence of such "steal" has been repeatedly demonstrated in appropriate conditions in vitro27 30 and has even been demonstrated in vivo.31 If, as appears likely,32 3 prostacyclin functions locally at sites of endothelial disruption where platelets are in direct apposition to subendothelium, this mechanism is of great potential importance and may well be underestimated in studies of healthy subjects. Thus, recent evidence34 shows that PGI2 synthase is present in high amounts in aortic smooth muscle as well as endothelium but with much lower amounts of PGH synthase in smooth muscle. A supply of platelet PGH2 to smooth muscle cells will therefore circumvent the rate-limiting step in PGI2 synthesis in this tissue. However, a problem with the use of thromboxane synthase inhibitors is that the endoperoxide intermediates themselves are agonists on thromboxane receptors and are therefore proaggregatory in their own right.35 This problem may not be insuperable, however, as discussed below. Thromboxane receptor antagonists. Several drugs fall in this group, including EP 045, which does not affect thromboxane synthesis and does not contract smooth muscle while inhibiting platelet aggregation.36 Used 241 Vol. 73, No. 2, February 1986 by gest on A ril 7, 2017 http://ciajournals.org/ D ow nladed from