Prevention Of Atherothrombosis Research Articles

Basic Principles of Platelet Biology and Clinical Implications

Platelet activation and subsequent accumulation at sites of vascular injury are the first steps in hemostasis. Excessive platelet activation after atherosclerotic plaque rupture or endothelial cell erosion may also lead to the formation of occlusive thrombi, which are responsible for acute ischemic events. Multiple pathways are involved in platelet activation, including those activated by adenosine diphosphate (ADP), thromboxane A(2) (TXA(2)), serotonin, collagen, and thrombin. Antiplatelet agents used for prevention of atherothrombosis have focused on blocking the formation of TXA(2) (eg, aspirin) and interfering with ADP stimulation mediated by the P2Y(12) receptor (eg, clopidogrel). These agents, used alone or in combination, significantly decrease the risk for atherothrombotic events, but a significant residual risk for recurrent ischemic events remains. This has been, in part, attributed to persistence of elevated platelet reactivity despite the use of these agents. Several novel antiplatelet agents are currently under clinical development, with the goal of achieving more efficacious platelet inhibition. These include agents that more efficiently block TXA(2)-mediated effects, as well as more potent P2Y(12) receptor antagonists. In addition, inhibition of the protease-activated receptor-1 platelet activation pathway stimulated by thrombin has emerged as a rational target for clinical development. An overview of the basic principles of platelet biology is given and currently available antiplatelet agents, as well as those under clinical development, are reviewed.

Platelet Interactions as Therapeutic Targets for Prevention of Atherothrombosis

Physiologically, platelets perform important tasks to maintain the homeostasis of the vascular wall and the surrounding environment. In pathologic conditions, however, platelets contribute to the formation of atherosclerotic plaques as well as to atherothrombotic events (i.e., acute myocardial infarction). This review aims to elucidate the role of platelets in atherogenesis and atherothrombosis and to provide an insight into current and future strategies for platelet inhibition.

The Prevalence of Intolerance for Low-Dose Acetylsalicylacid in the Secondary Prevention of Atherothrombosis

The Prevalence of Intolerance for Low-Dose Acetylsalicylacid in the Secondary Prevention of Atherothrombosis

Prostacyclin receptor/thromboxane receptor interactions and cellular responses in human atherothrombotic disease

Twenty-five years have passed since Vane and colleagues proposed a prostacyclin and thromboxane balance as critical to cardiovascular homeostasis. Prostacyclin prevents platelet aggregation and promotes vasodilatation, opposing the effects of thromboxane. Possible compensation by redundant functions, such as nitric oxide, long prevented appreciation of this balance. Effective use of low-dose aspirin in the secondary prevention of atherothrombosis suggested a clinical importance for the balance. However, it was not until the cyclooxygenase-2 inhibitor rofecoxib was withdrawn because of increased cardiovascular events that this critical balance was confirmed in humans. Moreover, clinical observations are supported by elegant animal receptor knockout experiments and subsequent human genetic variant studies. Combined, these findings provide valuable insight into the roles of these prostanoids in the development of atherothrombosis, emphasizing the need to reevaluate the use of selective prostacyclin- and thromboxane-based therapies in cardiovascular disease.

The Prevalence of Intolerance for Low-Dose Acetylsalicylacid in the Secondary Prevention of Atherothrombosis

Daily low-dose acetylsalicylacid (ASA) is prescribed to patients with atherothrombosis frequently to prevent vascular complications. In reports on complications and side effects of low-dose ASA use in the literature there is a range of definitions. We explored the incidence, characteristics and consequences of symptoms suggestive of ASA intolerance in patients on low-dose ASA. General practitioners and specialists in 105 centres were asked to review their patient files for the last 10 consecutive patients who were prescribed ASA. Participating patients completed a questionnaire about their current ASA use (doctors completed the questionnaire together with the patients), use of co-medication and symptoms suggestive of ASA intolerance. A total of 947 patients were included in this study. Sixty patients (6.6%) had ceased ASA treatment, predominantly because of the occurrence of side effects suspected to be caused by ASA use. A quarter of the patients concomitantly used an anti-acid agent. Of the 947 patients, 271 (30.6%) indicated symptoms during ASA intake. The most common symptoms were related to the gastrointestinal tract (25.1%). In patients prescribed a low-dose of ASA monotherapy, side effects suggestive of intolerance are common. More awareness should be created to detect and treat these symptoms, because the occurrence of side effects is the most important reason for patients to discontinue ASA treatment.

Effect of acarbose on platelet-derived microparticles, soluble selectins, and adiponectin in diabetic patients

Platelet-derived microparticles (PDMP), selectins, and adiponectin play an important role in the development of atherosclerosis in diabetes. Acarbose has been shown to have a beneficial effect on postprandial hyperglycemia in diabetic patients. However, its influence on PDMP, selectins, and adiponectin in these patients is poorly understood. We investigated the effect of acarbose on circulating levels of PDMP, selectins, and adiponectin in patients with type 2 diabetes. Acarbose (300 mg/day) was administered for 3 months. Levels of PDMP, sP-selectin, sL-selectin, and adiponectin were measured by ELISA at baseline and after 1 and 3 months of treatment. The levels of PDMP, sP-selectin, and sL-selectin were higher in diabetic patients than in hypertensive patients (PDMP; 35.1 +/- 34.2 vs. 53.3 +/- 56.7 U/ml, P < 0.05: sP-selectin; 134 +/- 52 vs. 235 +/- 70 ng/dl, P < 0.01: sL-selectin; 569 +/- 183 vs. 805 +/- 146 ng/ml, P < 0.05), while there were no significant differences between hypertensive and hyperlipidemic patients. Before acarbose treatment, the adiponectin level of diabetic patients was lower than that of hypertensive patients. Acarbose therapy significantly decreased the plasma PDMP level relative to baseline. Acarbose also caused a significant decrease of sP-selectin and sL-selectin. On the other hand, acarbose therapy led to a significant increase of adiponectin after 3 months of administration compared with baseline (adiponectin: diabetes versus hypertension, 3.61 +/- 1.23 vs. 5.87 +/- 1.92 microg/ml, P < 0.05; diabetes versus controls, 2.81 +/- 0.95 vs. 6.13 +/- 1.24 microg/ml, P < 0.01). Twelve of the 30 diabetic patients had a history of thrombotic complications. Furthermore, the reduction of PDMP and selectins during acarbose therapy was significantly greater in the thrombotic group (12 of 30) than in the nonthrombotic group (18 of 30) of diabetic patients. Acarbose may be beneficial for primary prevention of atherothrombosis in patients with type 2 diabetes. However, it requires a large clinical trial to test this hypothesis.

4. Clinical Perspectives of New Antiplatelet Drugs

Previous studies clearly demonstrated the efficacy of antiplatelet drugs for secondary prevention of atherothrombosis in patients with atherosclerotic diseases. However, clinical events still occur in some patients despite receiving conventional antiplatelet therapy. Recently several new drugs have been developed to further improve the efficacy of antiplatelet agents. Prasugrel, ticagrelor and cangrelor are new P2Y12 receptor antagonists that possess better metabolic profiles than clopidogrel, and show more potent and consistent efficacy for the inhibition of platelet aggregation. In patients with acute coronary syndrome (ACS), prasugrel and ticagrelor were superior to clopidogrel in reducing cardiovascular events, although intravenous cangrelor did not show superiority over clopidogrel. The thrombin receptor antagonist SCH-530348 showed a trend to reduce ischemic events without significantly increasing major bleeding in patients with ACS receiving both aspirin and clopidogrel in a phase 2 study. Results of ongoing clinical trials will provide further insight on the clinical benefits of these new antiplatelet drugs for the treatment of atheroembolic diseases.

Platelet Activation and Atherothrombosis

This review of the role of platelets in atherothrombosis illuminates the surprisingly numerous activities of these tiny, anucleate cells and stresses their participation in the inflammatory component of atherothrombosis. The information is presented in the context of the prevention of atherothrombosis by antiplatelet agents now in clinical use.

Annexin A5 as a Novel Player in Prevention of Atherothrombosis in SLE and in the General Population

During recent years it has become evident that atherosclerosis is an inflammatory disease. Furthermore, immune reactions and especially autoimmunity, were demonstrated to modulate atherosclerosis in animal experiments. An interesting example of how autoimmune reactions can influence atherosclerosis and consequences thereafter, is systemic lupus erythematosus (SLE)-associated cardiovascular disease (CVD). Antithrombotic effect exerted by Annexin A5 (ANXA5) is thought to be mediated mainly by forming a mechanical shield over phospholipids (PLs) reducing availability of PLs for coagulation reactions. However, more specific properties of ANXA5 might be of importance for its antithrombotic function. Such examples include downregulation of surface-expressed tissue factor (TF), as well as upregulation of urokinase-type plasminogen activator (uPA) by ANXA5. Also, interaction of ANXA5 with ligands involved in hemostasis, such as sulfatide and heparin, has been demonstrated. We have recently described a novel mechanism potentially contributing to atherothrombosis in SLE, with ANXA5 binding to endothelium decreased in SLE, an effect caused by antiphospholipid antibodies (aPL). It may be hypothesized that ANXA5 can be effective as a treatment to prevent plaque rupture and atherothrombosis not only in SLE, but also in the general population prone to CVD. Antiatherothrombotic potential of ANXA5 deserves further attention and careful studies as the mechanism behind the majority of clinically significant cardiovascular ischemic disease is atherothrombosis, formed on an underlying vulnerable atherosclerotic lesion. It may be hypothesized that ANXA5 can be effective as a treatment to prevent plaque rupture and atherothrombosis not only in SLE, but also in a general population prone to CVD.

Vascular wall–produced prostaglandin E2 exacerbates arterial thrombosis and atherothrombosis through platelet EP3 receptors

Prostanoids, bioactive lipids derived from arachidonic acid (AA), are important for vascular homeostasis. Among them, prostaglandin E2 (PGE2) enhances aggregation of platelets submaximally stimulated in vitro. This results from activation of EP3, one of the four PGE2 receptors, which decreases the threshold at which agonists activate platelets to aggregate. Although PGE2 altered venous thrombosis induced by administration of AA, its role in pathophysiopathological conditions has remained speculative. We report that arterial walls subjected to inflammatory stimuli produce PGE2. In several models, we show that PGE2 produced by the arterial wall facilitates arterial thrombosis. Next, we detected PGE2 in mouse atherosclerotic plaques. We demonstrate that this plaque-produced PGE2 is not altered and is still able to activate EP3. In addition, we present evidence that PGE2 can leave the plaque and activate EP3 on blood platelets. Consistent with these findings, we observed that atherothrombosis induced in vivo by mechanical rupture of the plaque was drastically decreased when platelets lacked EP3. In conclusion, PGE2 facilitates the initiation of arterial thrombosis and, hence, contributes to atherothrombosis. Inhibition of the platelet EP3 receptor should improve prevention of atherothrombosis.

Mechanisms of Action and Targets for Actual and Future Antiplatelet Drugs

Platelets are key players in arterial thrombosis and have become important targets in the primary and secondary prevention of atherothrombosis. Antiplatelet drugs are primarily directed against platelets and inhibit platelet activation by a number of different mechanisms. They are used for the prevention and treatment of thrombotic processes, especially in the arterial vascular system. Antiplatelet drugs in clinical use and experimental drugs are discussed.

Platelet microparticles and platelet adhesion: Therapeutic implications for the prevention and treatment of stroke

Platelets are believed to play a part in all stages of the pathogenesis of ischemic stroke, from the initial formation of the atherosclerotic plaque, through plaque destabilization to the development of neuronal cell death. A process common to all of these pathogenic changes is the ability of the activated platelet to adhere to the site of disease. In addition, the release of the membrane vesicles from platelets enhances many of these processes. Therefore, an understanding of platelet adhesion and platelet microparticle release can aid the development toward the treatment and prevention of stroke. There has been much research into interventions that can reduce platelet activation in atherosclerosis and stroke. The benefits of nonpharmacologic interventions in stroke, such as diet and lifestyle modification, may in part be mediated by their effects on platelet activation. In addition, the antiplatelet drug aspirin has been shown to be useful in both the treatment of acute stroke and the secondary prevention of atherothrombosis. Other antiplatelet agents, such as the glycoprotein IIb/IIIa inhibitors and triflusal, are currently being evaluated for the treatment of acute atherothrombotic stroke.

Low-Dose Aspirin for the Prevention of Atherothrombosis

This review considers the role of low-dose aspirin for the prevention of atherothrombosis, discussing the molecular mechanism of action of aspirin as well as clinical and epidemiologic studies of aspirin as an antiplatelet agent, with special emphasis on the benefits and risks in different patient populations.

Approach to "aspirin allergy" in cardiovascular patients.

Aspirin (ASA), by irreversibly inhibiting platelet cyclooxygenase-1 enzyme (COX-1), prevents platelet aggregation and is the mainstay of pharmacotherapy of patients with coronary artery disease (CAD). Long-term ASA therapy reduces mortality in CAD patients after an initial coronary event. Periprocedural ASA therapy significantly reduces major adverse cardiovascular events (MACE) after percutaneous coronary interventions.1,2 Despite a plethora of clinical data showing marked efficacy of ASA therapy in cardiovascular patients, ASA use continues to be less than optimal in real-world registries.3,4 A history of adverse reactions to ASA may prevent long-term use in a cardiovascular patient, thereby reducing optimal event protection. Most adverse reactions to ASA, such as gastrointestinal intolerance, are predictable and are dose and host related.5 However, ASA can also cause a hypersensitivity reaction, of which there are 3 types: respiratory sensitivity (asthma and/or rhinitis), cutaneous sensitivity (urticaria and/or angioedema), and systemic sensitivity (anaphylactoid reaction).6 Various terms have been used to describe the hypersensitivity reactions to ASA, including ASA intolerance, ASA idiosyncrasy, pseudoallergic reactions, and ASA sensitivity.7 The prevalence of ASA sensitivity in cardiovascular patients is not well known. Besides substitution with an alternative class of antiplatelet agents such as thienopyridines, ASA desensitization is an option for ASA-allergic patients who require long-term therapy for cardiovascular diseases.7 In this article, we review various hypersensitivity reactions to ASA and discuss desensitization protocols to allow ASA therapy in ASA-sensitive cardiovascular patients. ### ASA-Exacerbated Respiratory Disease ASA-exacerbated respiratory disease (AERD) is a triad of asthma, ASA sensitivity, and rhinitis/nasal polyps. Patients with AERD have aggressive mucosal inflammation and suffer from precipitation of asthma and rhinitis after ingestion of ASA and nonsteroidal antiinflammatory drugs (NSAIDs).8 AERD is also commonly referred to as ASA-sensitive, ASA-induced, or ASA-intolerant asthma. AERD is the cause of 10% to 15% of all cases of asthma,8 is usually …

Understanding the mechanism and prevention of arterial occlusive thrombus formation by anti-platelet agents.

For many years, platelet aggregation, which is mediated exclusively by the binding of fibrinogen to activated glycoprotein (GP) IIb/IIIa, has been used for the screening of antiplatelet agents. However, clinical experience with anti-GP IIb/IIIa agents, which can completely inhibit platelet aggregation, has shown that these drugs are not the most ideal agents for the prevention of atherothrombosis. Recently, many investigators have reported that platelets play a major role in thrombus formation at sites exposed to blood flow, and also that there is a crucial difference between the mechanism of platelet thrombus formation under blood flow conditions in vivo and that of platelet aggregation occurring in conventional aggregometry. Indeed, multiple receptor-ligand interactions, including von Willebrand factor (VWF) binding with platelet GP Ibalpha and GP IIb/IIIa, collagen binding with collagen receptors, as well as stimulation of platelet receptors, such as adenosine 5'-diphosphate (ADP) receptors, appear to be involved in the process of in vivo arterial thrombus formation. Moreover, not only platelets, but also the coagulation cascade activated by the procoagulant activity expressed on the surface of activated platelets, are believed to play a crucial role in the formation of occlusive thrombi. These findings suggest that drugs which block events upstream of the final common pathway for platelet aggregation might be better antiplatelet agents than those that merely inhibit platelet aggregation. We may then expect new antiplatelet agents on the horizon that exert their actions against both thrombus formation under blood flow conditions and against the procoagulant activity appearing on the surface of activated platelets.

Clopidogrel

Clopidogrel is an ADP receptor antagonist that is indicated for the reduction of atherosclerotic events including myocardial infarction, ischaemic stroke and vascular death in patients with atherosclerosis manifested by recent stroke, myocardial infarction or established peripheral vascular disease. In the 19 185 patients enrolled in the multicentre, randomised double-blind CAPRIE study, the annual risk of the combined end-point of ischaemic stroke, myocardial infarction and death from vascular disease (vascular death) was significantly lower during treatment with clopidogrel 75 mg/day than aspirin 325 mg/day [5.3 vs 5.8%/year, respectively; relative risk reduction (RRR) 8.7%, p = 0.043] after a mean follow-up of 1.9 years. Clopidogrel provided even greater reductions in the risk of recurrent ischaemic events than aspirin in patients with a history of coronary artery bypass surgery, diabetes mellitus and in those receiving concomitant lipid-lowering therapy. Moreover there was a significant reduction in the incidence of hospitalisation in patients treated with clopidogrel. In a patient population (Saskatchewan, Canada) with a greater risk of ischaemic events than the CAPRIE study population, the number of patients needed to be treated with clopidogrel to prevent 1 ischaemic event was estimated to be 70 (vs 200 in the CAPRIE study). In randomised trials and registry surveys, clopidogrel 75 mg/day plus aspirin had similar efficacy (as measured by adverse cardiac outcomes) to ticlopidine 250mg twice daily plus aspirin during the 30 days after placement of intracoronary stents. Tolerability of clopidogrel was significantly better than ticlopidine in the randomised, double-blind CLASSICS study. Among patients treated with clopidogrel or aspirin in the CAPRIE study, the overall gastrointestinal tolerability of clopidogrel was generally better than that of aspirin; the frequency of gastrointestinal haemorrhage was significantly lower among patients treated with clopidogrel than aspirin. Diarrhoea, rash and pruritus were significantly more common with clopidogrel than aspirin. Clopidogrel was significantly more effective than aspirin in the prevention of vascular events (ischaemic stroke, myocardial infarction or vascular death) [corrected] in patients with atherothrombotic disease manifested by recent myocardial infarction, recent ischaemic stroke or symptomatic peripheral arterial occlusive disease [corrected] in the CAPRIE study. The overall tolerability profile of the drug was similar to that of aspirin, although gastrointestinal haemorrhage occurred significantly less often in clopidogrel recipients. The drug is widely used in combination with aspirin for the prevention of atherothrombosis after placement of intravascular stents, and available data suggest that this combination is as effective as ticlopidine plus aspirin for this indication.

Synthetic inhibitors of platelet glycoprotein IIb/IIIa in clinical development.

Activation of the platelet glycoprotein (GP IIb/IIIa) receptor on the platelet surface is the final pathway of platelet aggregation, regardless of the initiating stimulus. Inhibitors of GP IIb/IIIa receptors include monoclonal antibodies (abciximab) against this receptor and peptidic and nonpeptidic synthetic specific receptor blockers. Abciximab exchanges between and binds to platelets for as long as 2 weeks, whereas synthetic GP IIb/IIIa inhibitors inhibit ex vivo platelet aggregation for only a few hours after the end of infusion, but some have the advantage of also being orally active. In the secondary prevention of atherothrombosis, large-scale trials were successfully conducted with aspirin, dipyridamole, ticlopidine, and clopidogrel. In the first large-scale trials with GP IIb/IIIa inhibitors, abciximab was investigated. In aggregate, synthetic GP IIb/IIIa inhibitors, combined with aspirin and heparin, were shown to reduce ischemic events in patients with high- and low-risk coronary intervention, stents, unstable angina, and non-Q-wave infarction. With short-term use of synthetic GP IIb/IIIa inhibitors, there is no suppression of clinical evident restenosis 6 months after the end of treatment. With the doses currently used, bleeding occurs more often with the synthetic GP IIb/IIIa inhibitors (used for 3 days) than with abciximab (used for 12 hours), but there are no direct comparisons between these drugs.

Regulation of Fibrinolysis in the Development of Atherothrombosis: Role of Adipose Tissue

IntroductionAmong the list of coronary risk factors, it has recently been proposed that fibrinolytic system impairment, due to increased plasminogen activator inhibitor-1 (PAI-1) levels in plasma, could predict complications of atherosclerosis. The fibrinolytic system1 is regulated by a balance between activators and inhibitors. PAI-1, which inhibits t-PA and u-PA, is the main inhibitor of plasminogen activation. An increased PAI-1 concentration induces a reduction in plasmin formation and leads to fibrin accumulation.2-5 PAI-1 also induces changes in vessel wall remodeling through the activation of metalloproteinases and growth factors and the degradation of the extracellular matrix.4 In addition to its antiprotease activity, PAI-1 also participates in the cellular adhesion and migration processes. Because it binds to vitronectin in the same part of the molecule as vitronectin receptor or u-PA receptor, it mediates the release of cells from their substrate.6,7 All of these properties indicate that PAI-1 can be involved in tissue remodeling and thrombotic processes and, therefore, participates in the development of atherothrombosis.In plasma, an elevated PAI-1 concentration is presently considered a risk factor for coronary vascular events. It appears that PAI-1 is an inducible target controlled for in insulin resistance and obesity, which are situations that favor the development of atherothrombosis. It has been postulated that PAI-1 could contribute to an increased susceptibility to atherothrombosis in insulin-resistant patients. The production of PAI-1 by adipose tissue has recently been demonstrated. The elucidation of the regulation of PAI-1 synthesis and the identification of factors responsible for increased plasma PAI-1 concentration in the insulin-resistant state might lead to therapeutic concepts for the prevention of atherothrombosis.

Platelet-Active Drugs: The Relationships Among Dose, Effectiveness, and Side Effects

Since our last report on antithrombotic therapy in 1995, 1 Hirsh J Dalen JE Fuster V et al. Aspirin and other platelet-active drugs: the relationship among dose, effectiveness and side effects. Chest. 1995; 108: 247S-257S Abstract Full Text Full Text PDF PubMed Google Scholar new information has been published on the role of aspirin and other platelet-active drugs in the treatment and prevention of atherothrombosis. These new data can be summarized as follows: (1) two large randomized studies have tested the efficacy and safety of aspirin in patients with acute ischemic stroke; 2 International Stroke Trial Collaborative GroupThe International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischemic stroke. Lancet. 1997; 349: 1569-1581 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar ,3 CAST (Chinese Acute Stroke Trial) Collaborative GroupCAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischemic stroke. Lancet. 1997; 349: 1641-1649 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar (2) two recent studies have shown that low-dose aspirin therapy is effective and safe in the primary prevention of ischemic heart disease in men at high risk 4 The Medical Research Council's General Practice Research FrameworkThrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischemic heart disease in men at increased risk. Lancet. 1998; 351: 233-241 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar as well as in men and women with hypertension; 4a Hansson L Zanchetti A Carruthers SG et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998; 351: 1755-1762 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar (3) the clinical efficacy of dipyridamole has to be reassessed in the light of the European Stroke Prevention Study-2 (ESPS-2); 5 Diener HC Cunha L Forbes C et al. European Stroke Prevention Study: II. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996; 143: 1-13 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar (4) a novel thienopyridine derivative, clopidogrel, has been shown to be at least as effective as aspirin in one very large phase III trial 6 CAPRIE Steering CommitteeA randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet. 1996; 348: 1329-1339 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and may be a safer alternative to aspirin than ticlopidine; (5) besides abciximab, now on the market in many countries, several platelet glycoprotein (GP) IIb/IIIa (integrin αIlbβ3) antagonists are in various stages of clinical development and have shown improved efficacy over conventional antithrombotic treatment in high-risk acute coronary settings; 7 Anderson KM Weisman HF Coller BS. Platelet glycoprotein IIb/IIIa receptor inhibitors. in: Hennekens CH Buring JE Manson JE Clinical trials in cardiovascular disease. WB Saunders, Philadelphia1999 Google Scholar and (6) the additive effect of ticlopidine and aspirin in the prevention of coronary stent thrombosis has been demonstrated, 8 STARSN Engl J Med. 1998; (in press) Google Scholar while controversial results have been reported for the combination of low-dose aspirin with low-intensity oral anticoagulation with warfarin. 4 The Medical Research Council's General Practice Research FrameworkThrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischemic heart disease in men at increased risk. Lancet. 1998; 351: 233-241 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar ,9 Coumadin Aspirin Reinfarction Study (CARS) InvestigatorsRandomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction. Lancet. 1997; 350: 389-396 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar