Role of Antiplatelet Therapies in Preventing Atherothrombosis
Journal of Hematology & Thromboembolic Diseases

Journal of Hematology & Thromboembolic Diseases
Open Access

ISSN: 2329-8790

+44 7868 792050

Review Article - (2013) Volume 1, Issue 2

Role of Antiplatelet Therapies in Preventing Atherothrombosis

Mohamed Z Khalil*
Consultant Cardiologist, Saudi British Hospital, Riyadh, Saudi Arabia
*Corresponding Author: Mohamed Z Khalil, Consultant Cardiologist, Saudi British Hospital, P. O. Box 285627, Riyadh, 11323, Saudi Arabia, Tel: 966 550055587, Fax: 966 12693760 Email:


Platelets exhibit a major role in development and progression of atherothrombosis. The normal function of platelets is to secure hemostasis at sites of vascular injuries. Abnormal endovascular structure may result in excessive platelet function with consequence of progressive or acute reduction in vascular lumen and cessation of blood flow. Despite succeeding in averting bleeding, total occlusion of a vessel leads to inevitable ischemia with eventual cell death upon lack of blood supply clinically manifesting as myocardial infarction in coronary vessels, cerebral infarction (stroke) in cerebral vessels, or peripheral gangrene in peripheral arterial disease. Antiplatelets long have been used to halt the process of atherothrombosis preventing further tissue damage at the expense of bleeding as well as other side effects. In this review, the role of antiplatelets in primary and secondary prevention of thrombotic events is explored in light of evidence based clinical practice.

Keywords: Antiplatelets; Atherothrombosis; Myocardial infarction; Stroke; Acute coronary syndrome


Acute coronary syndromes (ACS) are increasing in incidence throughout the world with clear heavy burden on humanity. The progressive and pervasive nature of ACS affecting younger and more commonly older men as well as women, sparing only young children has activated scientific research for proper understanding the magnitude of the problem.

In contrast to ACS, stroke in the young is unusual and most probably a manifestation of structural abnormality, nonetheless, older individuals with transient ischemic attack (TIA) and stroke show evidence of pathophysiology similar to ACS with common denominator being atherothrombosis in the vast majority of cases.

Generally, atherothrombotic manifestation of ischemia relies on the presence or absence of collateral circulation. Lack of such collaterals, at the cellular level, means only one outcome and that is death of cells fed by the occluded vessel. Documentation of reversing pre-infarction tissue is evident in coronary vessels and to a lesser extent in cerebral as well as peripheral circulations [1-4]. It is imperative to understand the nature of atherothrombotic development in order to initiate timely treatments.

Atherothrombosis is a simple term refers to thrombus formation on top of atherosclerotic plaque disruption of diseased arterial lumen. Fascinatingly, platelets are activated in response to disrupted atheromatous plaque in an attempt of mending the vessel wall, however, in the presence of atherosclerosis; thrombus formation narrows the lumen resulting in ischemia that may extend to total vessel occlusion. Moreover, studies have demonstrated that softer atherosclerotic plaques are more vulnerable to atherothrombosis, irrespective to the luminal diameter prior to platelet activation [5-9]. Vulnerable plaque is characterized by similar cholesterol deposition and inflammatory cellular infiltrates but thinner cap that is more likely to disrupt compared to non-vulnerable plaque [10-20]. Additionally, vulnerable plaques are asymptomatic as the luminal effects of these lesions are less likely to cause ischemia, hence interventional stabilization is not recommended.

The role of antiplatelet therapies, shown in clinical trials, is well established in the management of atherothrombosis [21-28]. Reduction of atherothrombotic events is clearly gained at the expense of bleeding from administration of antiplatelets, particularly in patients with platelet dysfunction such as patients with chronic kidney disease [29]. The balance between platelet inhibition and evading bleeding remains to be a difficult task to physicians administering antiplatelet therapies. Furthermore, combination of antiplatelet therapies is another concern increasing the risk for bleeding while achieving modest platelet inhibition as well as modest reduction of thrombotic events [30-35].

Platelets are discoid un-nucleated cells (thrombocytes), produced from the bone marrow to circulate in the blood stream for a lifespan of 10 days. Obviously, decrease in platelet count is accompanied by reduction in platelet function that manifests clinically at low critical count. It is important to emphasize that platelet dysfunction may be present despite normal platelet count. Moreover, the concept of selective inhibition of certain platelet function whereas other functions of platelets are intact has ignited an era of scientific research targeting development of antiplatelet agents that are selective in performance.

Thrombocytopenia is a term used to describe reduction in the number of platelets, nonetheless, platelet function may remain intact in the presence of thrombocytopenia till reaching critical alarming number beyond which bleeding is inevitable. The reserve function of platelets is what maintains platelet function despite reduction in platelet count. That is why we don’t have universal cutoff number for platelets count that work correctly for all patients suffering from thrombocytopenia.

It has been shown that platelets are not that simple in their response towards endovascular injuries harboring many receptors upon activation thrombus formation ensue [36-39]. The function of platelets may be altered either by reduction in platelet count or decreased function in the setting of normal platelet count in several disorders including renal disease, hepatic disease, hematological malignancies, infectious diseases, disseminated intravascular coagulopathy, pancreatitis, immune-mediated thrombocytopenia, and certain medications.

Platelet Function

Understanding of platelet function is mandatory prior to discussing antiplatelet therapies, hence; the term “antiplatelet” needs to be refined in the near future, either to describe platelet receptor antagonists, or more specifically to represent inhibition of platelet function; namely: activation, degranulation (release), adhesion, or aggregation.

Activation of platelets in the blood flow is provoked by exposure of adhesive molecules, including collagen and von Willebrand Factor (vWF), at the site of vascular lumen injury. This step is integral in securing hemostasis by circulating platelets adjacent to luminal wall at the periphery of blood flow, and enforced by high sheer rates. Activation of platelet occurs through surface receptors for collagen, thromboxane A2, thrombin, and adenosine diphosphate (ADP). The exact size of platelet plug required to patch up the area of vascular injury in an attempt to prevent bleeding is governed by the release of natural platelet inhibitors namely prostaglandin I2 and nitric oxide from activated endothelial cells at the perimeter of vessel injury. Further control of later thrombus formation is mediated by activation of protein C; a natural anticoagulant inhibits thrombin formation by carving activated factors V and VIII, as well as the natural fibrinolysis.

Platelets contain several different types of storage granules to be released upon activation, a process often referred to as degranulation. Dense granules contain small non-protein molecules such as; ADP, adenosine triphosphate (ATP), serotonin and calcium, which are released to recruit other platelets. Alpha granules are more abundant and contain large adhesive polypeptides for instance vWF, protease inhibitors, platelet derived growth factors, and fibrinogen that provide essential aid to healing at the site of injury. The third type of platelet storage granules are lysosomes whose enzymes are released to act on platelets as well as vascular endothelial cells to eliminate the circulating platelet aggregate and to form stable covalent cross-links between proteins.

Adhesion is a crucial function of platelets at the site of vascular injury, which is activated in response to exposure to subendothelial matrix triggering interactions between glycoprotein (GP) Ib and vWF. Furthermore, exposed collagen type I, III, and VI are vessel wall components prompting platelet adhesion to impede bleeding. Other adhesive molecules corroborating in the process of platelet adhesion are integrin α2β1, GP VI, fibronectin, thrombospondin, and laminin.

Thrombus propagation is dependent on the formation of platelet aggregation. Platelets bind soluble adhesive proteins and form a reactive surface for continuing platelet aggregation. Recruitment of additional platelets for aggregation is mediated by platelet agonists such as thromboxane A2 (TA2), platelet activating factor (PAF), ADP and serotonin, which bind recruited platelets to the adhered platelets. Additionally, platelet agonists signal morphological changes in the shape of platelets resulting in long membrane projections, which allow the platelets to interact with one another to form aggregates. GPIIb/IIIa is an integrin receptor present at high density on platelets and is considered the main adhesion molecule involved in platelet aggregation. The final common pathway of platelet aggregation is induced by fibrinogen acting as a bridge between two GPIIb/IIIa molecules on the membranes of adjacent platelets under lower shear rates, while aggregation induced by high shear conditions is induced by vWF substituting for fibrinogen. Moreover, activated platelets not only recruit additional platelets to the growing plug formed at the site of vascular injury, but also play a principal role in secondary hemostasis by providing a valuable catalytic surface for activation of the coagulation cascade.

Site of Action of Antiplatelet Therapies

Aspirin: Aspirin (acetylsalicylic acid) irreversibly inhibits cyclooxygenase-1 (COX-1) enzyme and blocks the production of TA2 from arachidonic acid of platelets. The detailed mechanism of action is summarized to acetylation of the platelet COX-1 at the functionally important amino acid serine529 preventing access of arachidonic acid to the catalytic site of the enzyme at tyrosine385 and results in an irreversible inhibition of platelet-dependent TA2 formation.

There are several limitations of the antiplatelet efficacy of Aspirin; first: platelet activation caused by other factors, such as shear stress and ADP, remains unchanged and might result in aspirin resistance. Secondly: inhibition of COX-1 by aspirin will also reduce the amount of precursors for vascular prostacyclin synthesis. Third: in the presence of aspirin that blocks COX-1, platelets utilize COX-2 pathway to synthesize TA2.

The beneficial efficacy of aspirin for primary prevention of vascular thrombosis is counterbalanced by hazards of excess bleeding, which has resulted in critically selecting subjects at increased risk of thrombosis for prevention after considerable evaluation for the existing risk of bleeding [40,41]. Conversely, the benefits of aspirin for secondary prevention clearly outweigh the risks of bleeding, thus aspirin continues to be fundamental of antithrombotic therapy as secondary prevention in coronary, cerebral as well as peripheral vascular thrombotic events. Moreover, it has been shown that aspirin therapy for secondary prevention reduces both fatal and nonfatal coronary events, while only nonfatal thrombotic events were prevented by aspirin in the primary prevention of ischemic heart disease [42].

Thienopyridines: The action of thienopyridines is mediated through prevention of ADP-induced platelet activation and aggregation by irreversibly inhibiting the platelet ADP receptor P2Y12. Indirectly acting thienopyridines (ticlopidine, clopidogrel, and prasugrel) are prodrugs that need to be converted by hepatic cytochrome P-450 (CYP) to active metabolites, which covalently and irreversibly bind to the P2Y12 receptor. The antiplatelet activities of the indirectly acting thienopyridines are delayed as a consequence of the need for metabolism of the prodrug. Furthermore, there are considerable interindividual discrepancies in the degree of metabolism of the prodrug leading to unpredictability in platelet inhibition.

Direct P2Y12 inhibitors: The recent additions of antiplatelet therapies are direct and reversible P2Y12 antagonists (cangrelor, ticagrelor, and elinogrel), which have rapid onset and offset of platelet inhibition in contrast to thienopyridines. Blocking the P2Y12 receptor causes inhibition of stimulated adenylyl cyclase, ADP, TA2, and the proteinase-activated receptor-1 (PAR1) selective peptide agonist [43-47]. Furthermore, blockade of the P2Y12 receptor has been shown to decrease platelet aggregation under shear conditions as well as subsequent thrombus formation [48-50].

Glycoprotein (GP) IIb/IIIa inhibitors: The final common pathway of platelet aggregation is operational through Platelet membrane GPIIb/ IIIa receptors that allow binding of fibrinogen and vWF at multiple sites present on each platelet, resulting in aggregation. Gp IIb/IIIa receptor antagonists (abciximab, tirofiban, eptifibatide) inhibit fibrinogen from effectively cross-linking platelets preventing aggregation and thrombus probagation. The benefit of this mechanism of action is that inhibition of platelet aggregation occurs independently of the specific platelet activating agonist without inhibition of initial platelet adherence to injured vascular surface. Moreover, GP IIb/IIIa blockade has the ability to induce dethrombosis via dissolution of platelet-rich clot by disrupting fibrinogen-platelet interaction [51-61].

PAR-1/thrombin receptor antagonists (TRAs): The ideal antiplatelet therapy is one that is easily administered, available in oral format, promotes platelet activation contributing to thrombosis but not essential for hemostasis. Currently, novel oral antiplatelet agents targeting the PAR-1 pathway may provide more comprehensive platelet inhibition without increased bleeding risk. Inhibition of PAR-1 represents a reasonable advance to development of novel antiplatelet agents [62-71]. Two oral PAR-1 inhibitors are currently in clinical research with promising efficacy but noticeable bleeding risk indicative of further requirement for patients’ selection; vorapaxar is undergoing evaluation in large phase 3 trials, whereas Atopaxar is currently being evaluated in phase 2 trials [72-75].

Antiplatelet therapies in clinical practice: Atherosclerosis is a continuum of multiple risk factors affecting the structure and function of blood vessels throughout the body over long duration. The clinical manifestations of atherothrombosis is obviously evident by either chronic narrowing of the vascular lumen giving rise to reduced blood supply to certain tissues, or mare dramatically abrupt and acute occlusion of a feeding vessel with consequent catastrophic cellular death if left untreated. Coronary artery disease (CAD), cerebro-vascular disease, and peripheral artery disease (PAD) are of major importance due to the ability of reversing a devastating clinical event upon timely intervention. Therefore, the role of antiplatelet therapies is to halt the natural thrombotic function of platelets at sites of atherothrombotic pathological events.

Coronary atherothrombosis: Non ST segment elevation myocardial infarction (NSTEMI), as well as unstable angina (UA), is the outcome of incomplete occlusion of a particular coronary artery, with evident chance for intervention to reverse the pathology. Patients with NSTEMI are identified on vectorcardiography (ECG) by the absence of ST segment elevation and further ECG evaluation do not show Q waves, in contrast to patients with ST elevation and eventually develop Q waves on ECG, while patients without elevated biomarker values are designated with a diagnosis of unstable angina [76]. Early studies on antiplatelet therapy, were conducted mainly to study the efficacy of aspirin in short-term as well as long-term treatment for patients with CAD, have shown it to be effective in both primary i.e. in patients without previous coronary events but are at increased risk for developing CAD, as well as secondary prevention, and therefore rendered as standard of care in clinical practice [77-94]. Nonetheless, another antiplatelet has to be added to aspirin in the treatment of patients with NSTEMI/UA, from the thienopyridines or more recently from the P2Y12 inhibitors, for initial and maintenance treatment as well as GPIIa/IIIb for the acute phase therapy [95-104].

The concept of dual antiplatelet therapy has been the standard of care to patients with acute coronary events, particularly for those who underwent percutanous coronary intervention (PCI) and following coronary stenting [105-109]. Dual antiplatelet therapy (DAPT) is a term used to describe additional antiplatelet therapy to aspirin. The pathophysiologic motivation for DAPT is prompted by the presence of two different pharmacodynamic mechanisms. The duration of DAPT remains to be determined according to patient’s requirements, nonetheless, recent analysis revealed no clinical benefit of prolonged dual antiplatelet therapy for duration of 2 years compared to 6 months, in patients with CAD and treated with PCI, irrespective of the type of stent used, and resulted in increased risk of bleeding [110]. Moreover, it has been demonstrated that preoperative use of dual antiplatelet therapy is associated with an increased risk of infection, blood transfusion, and mortality after coronary artery bypass grafting (CABG) surgery [111].

The use of P2Y12 receptor inhibitors in the setting of ACS as well as PCI is associated with faster onset of action, greater potency and reversibility of platelet inhibition compared to clopidogrel [112]. Clinical studies have shown evident reduction of rates of vascular death and myocardial infarction (MI) comparing ticagrelor to clopidogrel in patients with ACS at the expense of increased bleeding [113-123]. Additionally, shorter period of drug discontinuation before CABG surgery was required in ticagrelor-treated patients compared to clopidogrel-treated patients to limit the severity of post-surgical bleeding [124-126]. Furthermore, prasugrel was significantly more effective than clopidogrel in reducing ischemic events and stent thrombosis of different types [127-128]. Current guidelines reflect the superiority of newer P2Y12 inhibitors (ticagrelor, prasugrel) as both agents are recommended in STEMI patients replacing clopidogrel [129-131]. The administration of ticagrelor is recommended in patients with NSTEMI/UA, regardless of invasive or non-invasive treatment strategy is opted [132,133].

In patients with ACS, the use of GP IIb/IIIa inhibitors is associated with beneficial reduction of death and MI, and this benefit has been demonstrated among patients with STEMI as well as high risk patients with NSTEMI/UA. The beneficial use of these agents as part of tripleantiplatelet therapy may not outweigh the risk, particularly, in patients with a concern for increased risk of bleeding. An early invasive strategy using GP IIb/IIIa inhibitor significantly reduced the incidence of major cardiac events in patients with unstable angina who demonstrated elevated levels of cardiac markers as well as patients with NSTEMI [134]. Antiplatelet therapy with the GP IIb/IIIa inhibitor abciximab in patients with STEMI treated with PCI, improved outcome and reduced major adverse coronary events (MACE). The INFUSE-AMI trial demonstrated reduction in infarct size of intracoronary administration of abciximab compared to thrombectomy in patients treated with PCI for large anterior STEMI [135]. Efficacy of small-molecule GP IIb/IIIa inhibitors (tirofiban, eptifibatide) has been demonstrated in high-risk patients with NSTEMI/UA treated with early invasive strategy, while safety concerns, particularly, increased bleeding as well as transfusions rates, lashed out their use in low risk NSTEMI/UA patients [136].

Cerebral atherothrombosis: Secondary prevention of recurrent cerebral Atherothrombosis (TIA, Stroke) using aspirin as initial antiplatelet therapy remains the cornerstone of treatment in patients without indication for anticoagulation [137,138]. Overall, prevention for non cardio-embolic cerebral Atherothrombosis is attained by administration of single antiplatelet agent and mostly, this is done using aspirin, unless in patients who are intolerant to aspirin, alternative use of clopidogrel, or to lesser extent, ticlopidine has been used [139,140]. It is important to emphasize that primary prevention of cerebral atherothrombosis using aspirin is recommended only in selected patients after establishing a clear cause for treatment that outweigh the risk of bleeding [141].

Aspirin has been shown to result in approximately a quarter risk reduction for recurrent nonfatal stroke compared to placebo [142]. The dose of aspirin has been debated in clinical trials for long time, ultimately, evidence has documented lower doses, between 50 and 325 mg for prevention of recurrent non-cardioembolic TIA or stroke, as efficacious as higher doses but with less bleeding risk, predominantly gastrointestinal bleeding [143,144].

Primary as well as secondary prevention of cerebral atherothrombosis research clinical trials were largely unsuccessful in confirming superiority of clopidogrel over aspirin, nonetheless, for patients intolerant to aspirin use, clopidogrel may be used as a reasonable alternative [145]. Moreover, combination of clopidogrel with aspirin for stroke prevention, have been shown to result in more bleeding without marked benefit to balance the risk, over using either aspirin or clopidogrel antiplatelet monotherapy [146].

For secondary prevention of non-cardioembolic stroke, aspirin in combination with extended-release dipyridamole antiplatelet therapy has been shown to be more effective than aspirin alone [147]. Fascinatingly, the combination of aspirin and extended-release dipyridamole was twice as effective for stroke prevention as either drug alone, with rates of bleeding of not exceeding those of aspirin monotherapy [148-152]. Triflusal is a derivative of salicylic acid that inhibits platelet-dependent TA2 formation by blocking COX while preserving vascular prostacyclin, which provides safety of less bleeding compared to aspirin particularly in secondary prevention [153]. Moreover, for secondary prevention of stroke, cilostazol; another antiplatelet agent has been shown to provide similar efficacy to aspirin with potentially less bleeding events [154].

Appropriate choices for therapy in patients with non-cardioembolic stroke or TIA may consist of either aspirin as monotherapy, the combination of aspirin and extended-release dipyridamole, or clopidogrel alone. Furthermore, the combination of clopidogrel with aspirin for stroke secondary prevention is inappropriate compared to monotherapy due to increased bleeding risk without significant benefit.

Peripheral atherothrombosis: Peripheral artery disease (PAD) is a clinical manifestation of reduced arterial blood supply to the extremities (upper and lower limbs) secondary to pathological mechanisms similar to CAD as well as cerebral atherothrombosis. Patients with PAD present a spectrum of disease severity that may be asymptomatic or symptomatic with intermittent claudication and peripheral gangrene comparable to NSTEMI and STEMI or TIA and stroke in CAD or cerebro-vascular disease respectively. It has been found that combination antithrombotic therapy with an antiplatelet agent and an oral anticoagulant was not more effective than antiplatelet therapy alone in preventing major cardiovascular complications [155]. Antiplatelet monotherapy primarily by aspirin or by clopidogrel in aspirin intolerant patients is beneficial for patients with asymptomatic PAD, while combination therapy of aspirin and clopidogrel is reserved for patients with symptomatic PAD.


The effect of aging on vascular patency is magnified by adopting unhealthy lifestyle resulting in atherothrombosis presenting as ACS, MI, TIA, or stroke either alone or in combination. Platelets play pivotal role in the pathology of progressing atherothrombosis, hence, antiplatelet therapy is recommended. The choice of antiplatelet therapy for treatment decisions is largely related to patient’s clinical variables. Bleeding is a major side effect of antiplatelet treatment that often can be prevented by appropriate therapeutics initiation as well as patient’s monitoring. The faultless antiplatelet agent is still to be developed hopefully in the near future guided by more biochemical dissection of platelet functions and pharmaceutical progress.


  1. Mehta RH, Roe MT, Chen AY, Lytle BL, Pollack CV Jr, et al. (2006) Recent trends in the care of patients with non-ST-segment elevation acute coronary syndromes: insights from the CRUSADE initiative. Arch Intern Med 166: 2027-2034.
  2. Pantoni L (2010) Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 9: 689-701.
  3. Okroglic S, Widmann CN, Urbach H, Scheltens P, Heneka MT (2013) Clinical symptoms and risk factors in cerebral microangiopathy patients. PLoS One 8: e53455.
  4. European Stroke Organisation, Tendera M, Aboyans V, Bartelink ML, Baumgartner I, Clément D, et al. (2011) ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). Eur Heart J. 32: 2851-2906.
  5. Baldewsing RA, Schaar JA, Mastik F, van der Steen AF (2007) Local elasticity imaging of vulnerable atherosclerotic coronary plaques. Adv Cardiol 44: 35-61.
  6. Schaar JA, de Korte CL, Mastik F, Baldewsing R, Regar E, et al. (2003) Intravascular palpography for high-risk vulnerable plaque assessment. Herz 28: 488-495.
  7. Maurice RL, Fromageau J, Cardinal MH, Doyley M, de Muinck E, et al. (2008) Characterization of atherosclerotic plaques and mural thrombi with intravascular ultrasound elastography: a potential method evaluated in an aortic rabbit model and a human coronary artery. IEEE Trans Inf Technol Biomed. 12: 290-298.
  8. Baldewsing RA, Schaar JA, Mastik F, Oomens CW, van der Steen AF (2005) Assessment of vulnerable plaque composition by matching the deformation of a parametric plaque model to measured plaque deformation. IEEE Trans Med Imaging 24: 514-528.
  9. Schaar JA, De Korte CL, Mastik F, Strijder C, Pasterkamp G, et al. (2003) Characterizing vulnerable plaque features with intravascular elastography. Circulation 108: 2636-2641.
  10. Kolodgie FD, Virmani R, Burke AP, Farb A, Weber DK, et al. (2004) Pathologic assessment of the vulnerable human coronary plaque. Heart 90: 1385-1391.
  11. Mauriello A, Sangiorgi G, Fratoni S, Palmieri G, Bonanno E, et al. (2005) Diffuse and active inflammation occurs in both vulnerable and stable plaques of the entire coronary tree: a histopathologic study of patients dying of acute myocardial infarction. J Am Coll Cardiol 45: 1585-1593.
  12. Virmani R, Burke AP, Farb A, Kolodgie FD (2002) Pathology of the unstable plaque. Prog Cardiovasc Dis 44: 349-356.
  13. Madjid M, Vela D, Khalili-Tabrizi H, Casscells SW, Litovsky S (2007) Systemic infections cause exaggerated local inflammation in atherosclerotic coronary arteries: clues to the triggering effect of acute infections on acute coronary syndromes. Tex Heart Inst J. 34: 11-18.
  14. Shah PK (2002) Pathophysiology of coronary thrombosis: role of plaque rupture and plaque erosion. Prog Cardiovasc Dis 44: 357-368.
  15. Alfonso F, Virmani R (2011) New morphological insights on coronary plaque rupture: bridging the gap from anatomy to clinical presentation? JACC Cardiovasc Interv 4: 83-86.
  16. Virmani R, Burke AP, Kolodgie FD, Farb A (2003) Pathology of the thin-cap fibroatheroma: a type of vulnerable plaque. J Interv Cardiol 16: 267-272.
  17. van der Wal AC, Becker AE (1999) Atherosclerotic plaque rupture--pathologic basis of plaque stability and instability. Cardiovasc Res 41: 334-344.
  18. Lafont A (2003) Basic aspects of plaque vulnerability. Heart 89: 1262-1267.
  19. Cheruvu PK, Finn AV, Gardner C, Caplan J, Goldstein J, et al. (2007) Frequency and distribution of thin-cap fibroatheroma and ruptured plaques in human coronary arteries: a pathologic study. J Am Coll Cardiol 50: 940-949.
  20. Braganza DM, Bennett MR (2001) New insights into atherosclerotic plaque rupture. Postgrad Med J 77: 94-98.
  21. Kikano GE, Brown MT (2007) Antiplatelet therapy for atherothrombotic disease: an update for the primary care physician. Mayo Clin Proc 82: 583-593.
  22. Ellahham S (2008) Role of antiplatelet agents in the primary and secondary prevention of atherothrombotic events in high risk-patients. South Med J 101: 273-283.
  23. Tran H, Anand SS (2004) Oral antiplatelet therapy in cerebrovascular disease, coronary artery disease, and peripheral arterial disease. JAMA 292: 1867-1874.
  24. Alexandrov AV, Alagona P (2008) Stroke and atherothrombosis: an update on the role of antiplatelet therapy. Int J Stroke 3: 175-181.
  25. Munger MA, Hawkins DW (2004) Atherothrombosis: epidemiology, pathophysiology, and prevention. J Am Pharm Assoc (2003) 44: S5-12.
  26. Faxon DP, Nesto RW (2006) Antiplatelet therapy in populations at high risk of atherothrombosis. J Natl Med Assoc 98: 711-721.
  27. Ling G, Ovbiagele B (2009) Oral antiplatelet therapy in the secondary prevention of atherothrombotic events. Am J Cardiovasc Drugs 9: 197-209.
  28. Antithrombotic Trialists' Collaboration (2002) Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324: 71-86.
  29. Cohen M (2009) Expanding the recognition and assessment of bleeding events associated with antiplatelet therapy in primary care. Mayo Clin Proc 84: 149-160.
  30. Sørensen R, Hansen ML, Abildstrom SZ, Hvelplund A, Andersson C, et al. (2009) Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet 374: 1967-1974.
  31. Buresly K, Eisenberg MJ, Zhang X, Pilote L (2005) Bleeding complications associated with combinations of aspirin, thienopyridines derivatives, and warfarin in elderly patients following acute myocardial infarction. Arch Intern Med. 165: 784-789.
  32. Lamberts M, Olesen JB, Ruwald MH, Hansen CM, Karasoy D, et al. (2012) Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study 126: 1185-1193.
  33. DeEugenio D, Kolman L, DeCaro M, Andrel J, Chervoneva I, et al. (2007) Risk of major bleeding with concomitant dual antiplatelet therapy after percutaneous coronary intervention in patients receiving long-term warfarin therapy. Pharmacotherapy 27: 691-696.
  34. Aronow HD, Steinhubl SR, Brennan DM, Berger PB, Topol EJ; CREDO Investigators (2009) Bleeding risk associated with 1 year of dual antiplatelet therapy after percutaneous coronary intervention: Insights from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Am Heart J 157: 369-374.
  35. Berger PB, Bhatt DL, Fuster V, Steg PG, Fox KA, et al. (2010) Bleeding complications with dual antiplatelet therapy among patients with stable vascular disease or risk factors for vascular disease: results from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. Circulation 121: 2575-2583.
  36. Stegner D, Nieswandt B (1998) Platelet receptor signaling in thrombus formation. J Mol Med 89: 109-121.
  37. Rivera J, Lozano ML, Navarro-Núñez L, Vicente V (2009) Platelet receptors and signaling in the dynamics of thrombus formation. Haematologica 94: 700-711.
  38. Nurden AT, Caen JP (1975) Specific roles for platelet surface glycoproteins in platelet function. Nature 255: 720-722.
  39. Mosher DF, Vaheri A, Choate JJ, Gahmberg CG (1979) Action of thrombin on surface glycoproteins of human platelets. Blood 53: 437-445.
  40. De Caterina R, Renda G (2012) Clinical use of aspirin in ischemic heart disease: past, present and future. Curr Pharm Des 18: 5215-5223.
  41. Becker RC, Meade TW, Berger PB, Ezekowitz M, O'Connor CM, et al. (2008) The primary and secondary prevention of coronary artery disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133: 776S-814S.
  42. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council's General Practice Research Framework. (1998) Lancet 351: 233-241.
  43. Badr Eslam R, Lang IM, Kaider A, Panzer S (2013) Human platelet protease-activated receptor-1 responsiveness to thrombin related to P2Y12 inhibition. Transl Res .
  44. Angiolillo DJ, Capodanno D, Goto S (2010) Platelet thrombin receptor antagonism and atherothrombosis. Eur Heart J 31: 17-28.
  45. Mukherjee D (2012) Cardiovascular and Hematological Medicine in 2013 - Advances and Insights. Cardiovasc Hematol Agents Med Chem .
  46. Moheimani F, Jackson DE (2012) P2Y12 receptor: platelet thrombus formation and medical interventions. Int J Hematol 96: 572-587.
  47. Held C (2012) Lessons from platelet inhibition and patient outcomes. Curr Opin Cardiol 27: 355-360.
  48. Gachet C (2005) The platelet P2 receptors as molecular targets for old and new antiplatelet drugs. Pharmacol Ther 108: 180-192.
  49. Conley PB, Delaney SM (2003) Scientific and therapeutic insights into the role of the platelet P2Y12 receptor in thrombosis. Curr Opin Hematol 10: 333-338.
  50. Turner NA, Moake JL, McIntire LV (2001) Blockade of adenosine diphosphate receptors P2Y(12) and P2Y(1) is required to inhibit platelet aggregation in whole blood under flow. Blood 98: 3340-3345.
  51. Stephens G, He M, Wong C, Jurek M, Luedemann HC, et al. (2012) Development of a perfusion chamber assay to study in real time the kinetics of thrombosis and the antithrombotic characteristics of antiplatelet drugs. Thromb J 10: 11.
  52. Colombo A, Lavarra F, Danna P, Viecca M (2004) Angiographic demonstration of coronary dethrombosis with eptifibatide. J Invasive Cardiol 16: 343-344.
  53. Leclerc JR (2002) Platelet glycoprotein IIb/IIIa antagonists: lessons learned from clinical trials and future directions. Crit Care Med 30: S332-340.
  54. Tcheng JE (1996) Glycoprotein IIb/IIIa receptor inhibitors: putting the EPIC, IMPACT II, RESTORE, and EPILOG trials into perspective. Am J Cardiol 78: 35-40.
  55. Lincoff AM (1998) Trials of platelet glycoprotein IIb/IIIa receptor antagonists during percutaneous coronary revascularization. Am J Cardiol 82: 36P-42P.
  56. Dobesh PP, Latham KA (1998) Advancing the battle against acute ischemic syndromes: a focus on the GP IIb-IIIa inhibitors. Pharmacotherapy 18: 663-685.
  57. Berkowitz SD (2000) Current knowledge of the platelet glycoprotein IIb/IIIa receptor antagonists for the treatment of coronary artery disease. Haemostasis 30 Suppl 3: 27-43.
  58. Chong PH (1998) Glycoprotein IIb/IIIa receptor antagonists in the management of cardiovascular diseases. Am J Health Syst Pharm 55: 2363-2386.
  59. Gowda RM, Khan IA, Vasavada BC, Sacchi TJ (2004) Therapeutics of platelet glycoprotein IIb/IIIa receptor antagonism. Am J Ther 11: 302-307.
  60. Mandava P, Thiagarajan P, Kent TA (2008) Glycoprotein IIb/IIIa antagonists in acute ischaemic stroke: current status and future directions. Drugs 68: 1019-1028.
  61. Cheng JW (2002) Efficacy of glycoprotein IIb/IIIa-receptor inhibitors during percutaneous coronary intervention. Am J Health Syst Pharm 59: S5-14.
  62. Lee M, Saver JL, Hong KS, Wu HC, Ovbiagele B (2012) Risk of intracranial hemorrhage with protease-activated receptor-1 antagonists. Stroke 43: 3189-3195.
  63. Leonardi S, Becker RC (2012) PAR-1 inhibitors: a novel class of antiplatelet agents for the treatment of patients with atherothrombosis. Handb Exp Pharmacol : 239-260.
  64. Leonardi S, Tricoci P, Becker RC (2012) Protease-activated receptor-1 inhibitors: a novel class of antiplatelet agents for the treatment of patients with acute coronary syndrome. Adv Cardiol 47: 87-99.
  65. Wiisanen ME, Moliterno DJ (2012) Platelet protease-activated receptor antagonism in cardiovascular medicine. Coron Artery Dis 23: 375-379.
  66. Chatterjee S, Sharma A, Mukherjee D (2013) PAR-1 antagonists: current state of evidence. J Thromb Thrombolysis 35: 1-9.
  67. Packard KA, Campbell JA, Knezevich JT, Davis EM (2012) Emerging antiplatelet therapy for coronary artery disease and acute coronary syndrome. Pharmacotherapy 32: 244-273.
  68. Tello-Montoliu A, Jover E, Rivera J, Valdés M, Angiolillo DJ, et al. (2012) New perspectives in antiplatelet therapy. Curr Med Chem 19: 406-427.
  69. Ji X, Hou M (2011) Novel agents for anti-platelet therapy. J Hematol Oncol 4: 44.
  70. Gurbel PA, Jeong YH, Tantry US (2011) Vorapaxar: a novel protease-activated receptor-1 inhibitor. Expert Opin Investig Drugs 20: 1445-1453.
  71. Tomasello SD, Angiolillo DJ, Goto S (2010) Inhibiting PAR-1 in the prevention and treatment of atherothrombotic events. Expert Opin Investig Drugs 19: 1557-1567.
  72. Morrow DA, Scirica BM, Fox KA, Berman G, Strony J, et al. (2009) Evaluation of a novel antiplatelet agent for secondary prevention in patients with a history of atherosclerotic disease: design and rationale for the Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2 degrees P)-TIMI 50 trial. Am Heart J. Sep 158: 335-341.e3.
  73. Tricoci P, Huang Z, Held C, Moliterno DJ, Armstrong PW, et al. (2012) Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med 366: 20-33.
  74. Goto S, Ogawa H, Takeuchi M, Flather MD, Bhatt DL, et al. (2010) Double-blind, placebo-controlled Phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease. Eur Heart J 31: 2601-2613.
  75. O'Donoghue ML, Bhatt DL, Flather MD, Goto S, Angiolillo DJ, et al. (2012) Atopaxar and its effects on markers of platelet activation and inflammation: results from the LANCELOT CAD program. J Thromb Thrombolysis 34: 36-43.
  76. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, et al. (2012) Third universal definition of myocardial infarction. Eur Heart J 33: 2551-2567.
  77. Baigent C, Collins R, Appleby P, Parish S, Sleight P, et al. (1998) ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither. The ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. BMJ 316: 1337-1343.
  78. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988 Aug 13;2:349-60.
  79. (1992) ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 casesof suspected acute myocardial infarction. Lancet 339: 753-770.
  80. (1988) Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. J Am Coll Cardiol 12: 3A-13A.
  81. Brouwer MA, van den Bergh PJ, Aengevaeren WR, Veen G, Luijten HE, et al. (2002) Aspirin plus coumarin versus aspirin alone in the prevention of reocclusion after fibrinolysis for acute myocardial infarction: results of the Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis (APRICOT)-2 Trial. Circulation 106: 659-665.
  82. Berger JS, Stebbins A, Granger CB, Ohman EM, Armstrong PW, et al. (2008) Initial aspirin dose and outcome among ST-elevation myocardial infarction patients treated with fibrinolytic therapy. Circulation 117: 192-199.
  83. Fuchs I, Spiel AO, Frossard M, Derhaschnig U, Riedmüller E, et al. (2010) Platelet hyperfunction is decreased by additional aspirin loading in patients presenting with myocardial infarction on daily aspirin therapy. Crit Care Med 38: 1423-1429.
  84. Herlitz J, Holm J, Peterson M, Karlson BW, Haglid Evander M, et al. (2004) Effect of fixed low-dose warfarin added to aspirin in the long term after acute myocardial infarction; the LoWASA Study. Eur Heart J 25: 232-239.
  85. Latini R, Santoro E, Masson S, Tavazzi L, Maggioni AP, et al. (2000) Aspirin does not interact with ACE inhibitors when both are given early after acute myocardial infarction: results of the GISSI-3 Trial. Heart Dis 2: 185-190.
  86. Vetrano A, Milani M, Corsini G (1999) Effects of aspirin or picotamide, an antithromboxane agent, in combination with low-intensity oral anticoagulation in patients with acute myocardial infarction: a controlled randomized pilot trial. G Ital Cardiol 29: 524-528.
  87. Zeymer U, Jünger C, Zahn R, Bauer T, Bestehorn K, et al. (2011) Effects of a secondary prevention combination therapy with an aspirin, an ACE inhibitor and a statin on 1-year mortality of patients with acute myocardial infarction treated with a beta-blocker. Support for a polypill approach. Curr Med Res Opin 27: 1563-1570.
  88. Glasziou P (1989) Aspirin after myocardial infarction. Med J Aust 150: 50, 52.
  89. Harrington RA, Becker RC, Cannon CP, Gutterman D, Lincoff AM, et al. (2008) Antithrombotic therapy for non-ST-segment elevation acute coronary syndromes: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133: 670S-707S.
  90. Harrington RA, Becker RC, Ezekowitz M, Meade TW, O'Connor CM, et al. (2004) Antithrombotic therapy for coronary artery disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126: 513S-548S.
  91. Becker RC, Meade TW, Berger PB, Ezekowitz M, O'Connor CM, et al. (2008) The primary and secondary prevention of coronary artery disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133: 776S-814S.
  92. Goodman SG, Menon V, Cannon CP, Steg G, Ohman EM, et al. (2008) Acute ST-segment elevation myocardial infarction: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133: 708S-775S.
  93. Khalil MZ, Abba AA (2003) Management of acute myocardial infarction. Do we follow guidelines applied in practice? Saudi Med J 24: 1234-1237.
  94. Timm Bauer, Helge Möllmann, Franz Weidinger, Uwe Zeymer, Ricardo Seabra-Gomes, et al. (2010) Use of platelet glycoprotein IIb/IIIa inhibitors in diabetics undergoing PCI for non-ST-segment elevation acute coronary syndromes: impact of clinical status and procedural characteristics. Clin Res Cardiol 99: 375-383.
  95. Damman P, Woudstra P, Kuijt WJ, de Winter RJ, James SK (2012) P2Y12 platelet inhibition in clinical practice. J Thromb Thrombolysis 33: 143-153.
  96. Floyd CN, Passacquale G, Ferro A (2012) Comparative pharmacokinetics and pharmacodynamics of platelet adenosine diphosphate receptor antagonists and their clinical implications. Clin Pharmacokinet 51: 429-442.
  97. Capranzano P, Mehran R, Tamburino C, Stone GW, Dangas G (2010) Clinical impact of enhanced inhibition of P2Y12-mediated platelet aggregation in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention. Hosp Pract (Minneap) 38: 38-43.
  98. Cattaneo M, Podda GM (2010) State of the art of new P2Y12 antagonists. Intern Emerg Med 5: 385-391.
  99. Bernlochner I, Sibbing D (2012) Thienopyridines and other ADP-receptor antagonists. Handb Exp Pharmacol : 165-198.
  100. Storey RF (2011) Pharmacology and clinical trials of reversibly-binding P2Y12 inhibitors. Thromb Haemost 105 Suppl 1: S75-81.
  101. Oh EY, Abraham T, Saad N, Rapp JH, Vastey FL, et al. (2012) A comprehensive comparative review of adenosine diphosphate receptor antagonists. Expert Opin Pharmacother 13: 175-191.
  102. Trenk D, Stone GW, Gawaz M, Kastrati A, Angiolillo DJ, et al. (2012) A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol 59: 2159-2164.
  103. Collet JP, O'Connor S (2012) Clinical effects and outcomes with new P2Y12 inhibitors in ACS. Fundam Clin Pharmacol 26: 16-18.
  104. Rogacka R, Chieffo A, Michev I, Airoldi F, Latib A, et al. (2008) Dual antiplatelet therapy after percutaneous coronary intervention with stent implantation in patients taking chronic oral anticoagulation. JACC Cardiovasc Interv 1: 56-61.
  105. Baber U, Akhter M, Kothari S, Sharma SK, Kini A (2010) Efficacy of modified dual antiplatelet therapy combined with warfarin following percutaneous coronary intervention with drug-eluting stents. J Invasive Cardiol 22: 80-83.
  106. Lee SW, Chun KJ, Park SW, Kim HS, Kim YH, et al. (2010) Comparison of Triple antiplatelet therapy and dual antiplatelet therapy in patients at high risk of restenosis after drug-eluting stent implantation (from the DECLARE-DIABETES and -LONG Trials). Am J Cardiol 105: 168-173.
  107. Lee SW, Park SW, Yun SC, Kim YH, Park DW, et al. (2010) Triple antiplatelet therapy reduces ischemic events after drug-eluting stent implantation: Drug-Eluting stenting followed by Cilostazol treatment Reduces Adverse Serious cardiac Events (DECREASE registry). Am Heart J 159: 284-291.e1.
  108. Faxon DP, Lawler E, Young M, Gaziano M, Kinlay S (2012) Prolonged clopidogrel use after bare metal and drug-eluting stent placement: the Veterans Administration drug-eluting stent study. Circ Cardiovasc Interv 5: 372-380.
  109. Valgimigli M, Campo G, Percoco G, Monti M, Ferrari F, et al. (2010) Randomized comparison of 6- versus 24-month clopidogrel therapy after balancing anti-intimal hyperplasia stent potency in all-comer patients undergoing percutaneous coronary intervention Design and rationale for the PROlonging Dual-antiplatelet treatment after Grading stent-induced Intimal hyperplasia study (PRODIGY). Am Heart J 160: 804-811.
  110. Blasco-Colmenares E, Perl TM, Guallar E, Baumgartner WA, Conte JV, et al. (2009) Aspirin plus clopidogrel and risk of infection after coronary artery bypass surgery. Arch Intern Med 169: 788-796.
  111. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, et al. (2009) Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361: 1045-1057.
  112. James S, Budaj A, Aylward P, Buck KK, Cannon CP, et al. (2010) Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 122: 1056-1067.
  113. Cannon CP, Harrington RA, James S, Ardissino D, Becker RC, et al. (2010) Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet 375: 283-293.
  114. Held C, Asenblad N, Bassand JP, Becker RC, Cannon CP, et al. (2011) Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial. J Am Coll Cardiol 57: 672-684.
  115. Kowalczyk M, Banach M, Mikhailidis DP, Hannam S, Rysz J (2009) Ticagrelor--a new platelet aggregation inhibitor in patients with acute coronary syndromes. An improvement of other inhibitors? Med Sci Monit 15: MS24-30.
  116. James S, Akerblom A, Cannon CP, Emanuelsson H, Husted S, et al. (2009) Comparison of ticagrelor, the first reversible oral P2Y(12) receptor antagonist, with clopidogrel in patients with acute coronary syndromes: Rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J. 157: 599-605.
  117. Husted S, James S, Becker RC, Horrow J, Katus H, et al. (2012) Ticagrelor versus clopidogrel in elderly patients with acute coronary syndromes: a substudy from the prospective randomized PLATelet inhibition and patient Outcomes (PLATO) trial. Circ Cardiovasc Qual Outcomes 5: 680-688.
  118. Anderson SD, Shah NK, Yim J, Epstein BJ (2010) Efficacy and safety of ticagrelor: a reversible P2Y12 receptor antagonist. Ann Pharmacother 44: 524-537.
  119. Varenhorst C, Alström U, Scirica BM, Hogue CW, Åsenblad N, et al. (2012) Factors contributing to the lower mortality with ticagrelor compared with clopidogrel in patients undergoing coronary artery bypass surgery. J Am Coll Cardiol 60: 1623-1630.
  120. Husted S (2011) Evaluating the risk-benefit profile of the direct-acting P2Y(12) inhibitor ticagrelor in acute coronary syndromes. Postgrad Med 123: 79-90.
  121. Abergel E, Nikolsky E (2010) Ticagrelor: an investigational oral antiplatelet treatment for reduction of major adverse cardiac events in patients with acute coronary syndrome. Vasc Health Risk Manag 6: 963-977.
  122. Becker RC, Bassand JP, Budaj A, Wojdyla DM, James SK, et al. (2011) Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J 32: 2933-2944.
  123. Husted S, Harrington RA, Cannon CP, Storey RF, Mitchell P, et al. (2009) Bleeding risk with AZD6140, a reversible P2Y12 receptor antagonist, vs. clopidogrel in patients undergoing coronary artery bypass grafting in the DISPERSE2 trial. Int J Clin Pract 63: 667-670.
  124. Cannon CP, Husted S, Harrington RA, Scirica BM, Emanuelsson H, et al. (2007) Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol 50: 1844-1851.
  125. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, et al. (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357: 2001-2015.
  126. Montalescot G, Wiviott SD, Braunwald E, Murphy SA, Gibson CM, et al. (2009) Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 373: 723-731.
  127. Wenger NK (2012) What's new in antiplatelet and anticoagulant therapy recommendations for unstable angina/non-ST-elevation myocardial infarction: 2012 focused update from the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. Clin Cardiol. 35: 669-672.
  128. Thomas D, Giugliano RP (2012) Management of non-ST-segment elevation acute coronary syndrome: comparison of the updated guidelines from North America and Europe. Crit Pathw Cardiol 11: 62-73.
  129. Vandvik PO, Lincoff AM, Gore JM, Gutterman DD, Sonnenberg FA, et al. (2012) American College of Chest Physicians. Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141: e637S-68S.
  130. Jneid H (2012) The 2012 ACCF/AHA Focused Update of the Unstable Angina/Non-ST-Elevation Myocardial Infarction (UA/NSTEMI) Guideline: a critical appraisal. Methodist Debakey Cardiovasc J 8: 26-30.
  131. 2012 Writing Committee Members, Jneid H, Anderson JL, Wright RS, Adams CD, et al. (2012) 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/Non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 126: 875-910.
  132. Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE Jr, et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2012 Aug 14;60: 645-81.
  133. Cannon CP, Weintraub WS, Demopoulos LA, Vicari R, Frey MJ, et al. (2001) Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 344: 1879-1887.
  134. Stone GW, Maehara A, Witzenbichler B, Godlewski J, Parise H, et al. (2012) Intracoronary abciximab and aspiration thrombectomy in patients with large anterior myocardial infarction: the INFUSE-AMI randomized trial. JAMA 307: 1817-1826.
  135. Cannon CP (2003) Small molecule glycoprotein IIb/IIIa receptor inhibitors as upstream therapy in acute coronary syndromes: insights from the TACTICS TIMI-18 trial. J Am Coll Cardiol 41: 43S-48S.
  136. (1997) The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet 349: 1569-1581.
  137. Chen ZM, Sandercock P, Pan HC, Counsell C, Collins R, et al. (2000) Indications for early aspirin use in acute ischemic stroke : A combined analysis of 40 000 randomized patients from the chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups. Stroke 31: 1240-1249.
  138. Hass WK, Easton JD, Adams HP Jr, Pryse-Phillips W, Molony BA, et al. (1989) A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. Ticlopidine Aspirin Stroke Study Group. N Engl J Med 321: 501-507.
  139. CAPRIE Steering Committee (1996) A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 348: 1329-1339.
  140. Goldstein LB, Bushnell CD, Adams RJ, Appel LJ, Braun LT, et al. (2011) Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42: 517-584.
  141. Warlow C (2002) Aspirin should be first-line antiplatelet therapy in the secondary prevention of stroke. Stroke 33: 2137-2138.
  142. Antithrombotic Trialists' Collaboration (2002) Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324: 71-86.
  143. Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P, et al. (2008) Antithrombotic and thrombolytic therapy for ischemic stroke: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133: 630S-669S.
  144. Rezkalla SH, Benz M (2003) Antiplatelet therapy from clinical trials to clinical practice. Clin Med Res 1: 101-104.
  145. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, et al. (2004) Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 364: 331-337.
  146. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, et al. (1996) European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 143: 1-13.
  147. Halkes PH, Gray LJ, Bath PM, Diener HC, Guiraud-Chaumeil B, et al. (2008) Dipyridamole plus aspirin versus aspirin alone in secondary prevention after TIA or stroke: a meta-analysis by risk. J Neurol Neurosurg Psychiatry 79: 1218-1223.
  148. Chaturvedi S (2008) Acetylsalicylic acid + extended-release dipyridamole combination therapy for secondary stroke prevention. Clin Ther 30: 1196-1205.
  149. Lenz TL, Hilleman DE (2000) Aggrenox: a fixed-dose combination of aspirin and dipyridamole. Ann Pharmacother 34: 1283-1290.
  150. Shah H, Gondek K (2000) Aspirin plus extended-release dipyridamole or clopidogrel compared with aspirin monotherapy for the prevention of recurrent ischemic stroke: a cost-effectiveness analysis. Clin Ther 22: 362-370.
  151. Verro P, Gorelick PB, Nguyen D (2008) Aspirin plus dipyridamole versus aspirin for prevention of vascular events after stroke or TIA: a meta-analysis. Stroke 39: 1358-1363.
  152. Culebras A, Rotta-Escalante R, Vila J, Domínguez R, Abiusi G, et al. (2004) Triflusal vs aspirin for prevention of cerebral infarction: a randomized stroke study. Neurology 62: 1073-1080.
  153. Shinohara Y, Katayama Y, Uchiyama S, Yamaguchi T, Handa S, et al. (2010) Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. Lancet Neurol 9: 959-968.
  154. Warfarin Antiplatelet Vascular Evaluation Trial Investigators, Anand S, Yusuf S, Xie C, Pogue J, et al. (2007) Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med 357: 217-227.
Citation: Khalil MZ (2013) Role of Antiplatelet Therapies in Preventing Atherothrombosis. J Hematol Thromb Dis 1:108.

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