ISSN: 1734-1922
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Acute management of ACS
Use of oral antiplatelet agents in acute coronary syndromes

Dharam J. Kumbhani
Deepak L. Bhatt

Arch Med Sci 2010; 6, 1A: S 48–S 54
Online publish date: 2010/01/26
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Acute coronary syndromes (ACS) include unstable angina, non-ST elevation myocardial infarction (NSTEMI) and ST elevation myocardial infarction (STEMI), and are a major source of mortality and morbidity in the general population, accounting for more than 1.4 million hospitalizations annually in the United States alone [1]. Platelet activation and aggregation plays a pivotal role in the pathophysiology of ACS, and antiplatelet agents are one of the cornerstones in the management of these patients. Indeed, the Antithrombotic Trialists’ collaborative meta-analysis of 19,288 patients with acute coronary syndromes from 15 clinical trials demonstrated that one month of antiplatelet therapy resulted in 38 fewer serious vascular events per 1,000 treated patients, including 13 fewer non-fatal myocardial infarctions (p < 0.0001), 23 fewer vascular deaths (p < 0.0001), and 2 fewer strokes (p = 0.02) per 1,000 treated patients [2].

The primary mechanism for the development of acute coronary syndromes appears to be fissuring or rupturing of an atherosclerotic plaque, with subsequent thrombus formation, with resultant reduction or complete obliteration of epicardial coronary blood flow. Following the initial arterial injury, there is near-instantaneous deposition of platelets, with adherence of platelets to the subendothelial collagen. This is mediated primarily by the von Willebrand factor (vWF) [3, 4]. The platelet glycoprotein (GP) Ib/IX receptor binds vWF and is the initial protein involved in the initial contact between platelets and the vessel wall [5]. Following adhesion, platelet activation occurs, with release of platelet contents including serotonin, adenosine diphosphate (ADP), and thromboxane A2, which are capable of activating further platelets. Further platelet recruitment and aggregation depends on the expression of a second platelet receptor, the GP IIb/IIIa receptor complex. The GP IIb/IIIa receptor has to be first converted from an “inactive” conformation to an “active” conformation, which is influenced by several agonists, including ADP, thrombin, vWF, fibrinogen, and a host of other adhesive proteins in the extracellular matrix including collagen [3, 6]. ADP in particular exerts its influence on platelets by at least three separate receptors, including P2Y12 (inhibits adenylylcyclase and induced platelet aggregation), P2Y1 (mediates mobilization of calcium from intracellular stores and change in platelet shape), and a third ligand-gated ion channel (permits rapid calcium influx into platelets) [7]. The activated GP IIb/IIIa receptor complex then avidly binds multivalent ligands including vWF and soluble fibrinogen, and cross-links nearby activated platelets [8]. In addition, conversion of fibrinogen to insoluble fibrin by generated thrombin consolidates and stabilizes the platelet-rich thrombus.

Antiplatelet agents
Currently available antiplatelet agents include aspirin, thienopyridines, GP IIb/IIIa inhibitors, and others such as cilostazol and dipyridamole. Several newer agents are also currently being investigated (Table I). While a number of oral GP IIb/IIIa inhibitors have been investigated in ACS, only intravenous preparations are approved for use in the United States as of today, owing to a lack of demonstrable efficacy and a higher risk of bleeding with oral agents [9]. For the purpose of this article, we will restrict our discussion to oral antiplatelet agents only in acute coronary syndromes.

Aspirin, or acetyl salicylic acid (ASA), is the most widely used and cost-effective drug in the prevention of platelet aggregation. It exerts its antiplatelet action mainly by irreversibly acetylating a serine residue of platelet cyclo-oxygenase (COX)-1 [10], thus inhibiting the formation of thromboxane A2, which is a potent stimulator of platelets. Data regarding the utility of aspirin in STEMI was first outlined by the Second International Study of Infarct Survival (ISIS-2) trial, in which aspirin 160 mg daily was associated with a 23% significant reduction in mortality five weeks after MI, compared with placebo [11]. Similarly, aspirin 324 mg daily was associated with a significant 51% reduction in mortality compared with placebo in patients presenting with NSTEMI in the VA Cooperative study [12].
Current ACC/AHA recommendations
In order to ensure rapid and complete inhibition of thromboxane mediated platelet aggregation, a loading dose of 162 mg (class I, level of evidence: A) to 325 mg (class I, level of evidence: C) of aspirin is currently recommended in all patients presenting with ACS [2, 13-15]. Current guidelines also recommend the use of 75 to 162 mg of aspirin daily lifelong thereafter for long-term prevention of serious vascular events in these patients (class I, level of evidence: A). This dose achieves an efficacy that is comparable to higher doses, but without a significant increase in bleeding or gastro-intestinal toxicity [2, 14, 15].

Thienopyridines exert their antiplatelet effects by irreversibly blocking the P2Y12 receptor, thereby inhibiting platelet activation through ADP, and thus limit ADP-mediated conversion of glycoprotein IIb/IIIa to its active form [3, 6, 7]. Although some studies have demonstrated an incremental benefit of thienopyridine monotherapy over aspirin alone, dual therapy with aspirin and a thienopyridine is highly efficacious in ACS, especially in reducing the incidence of stent thrombosis, and is one of the mainstays in the management of these patients. Currently, clopidogrel is the most widely used thienopyridine.

Clopidogrel is a prodrug, and is converted to its active metabolite, a carboxylic acid derivative, SR 26334, in the liver [16]. The benefit of clopidogrel in non-ST-elevation acute coronary syndromes was demonstrated in the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, in which 300 mg of clopidogrel as a loading dose, followed by 75 mg daily in addition to aspirin 75-325 mg daily was associated with a significant 20% reduction in the incidence of nonfatal myocardial infarction (MI), stroke or cardiovascular death, and a 23% reduction in the incidence of MI, compared with placebo, over a mean duration of follow-up of 9 months. Clopidogrel was however associated with a 38% higher risk of major bleeding [17]. Similarly, the benefit of clopidogrel in patients presenting within 12 h of STEMI was demonstrated in the Clopidogrel as Adjunctive Reperfusion Therapy – Thrombolysis in Myocardial Infarction (CLARITY-TIMI) 28 trial, in which 300 mg of clopidogrel as a loading dose, followed by 75 mg daily in addition to aspirin 75-162 mg daily was associated with a significant 36% reduction in the incidence of death, recurrent MI or TIMI flow grade of 0 or 1 on angiography, compared with placebo. The largest benefit was noted in the rate of an occluded infarct-related artery (41% reduction), and there was also a trend towards a reduction in the incidence of recurrent MI (p = 0.08). While both major and minor bleeding seemed higher with clopidogrel, this difference was not statistically significant [18]. Subsequent studies have confirmed the utility of clopidogrel in acute coronary syndromes [19].
Some uncertainty exists about the optimum dosing of clopidogrel. Randomized trials establishing its efficacy and providing data on bleeding risks used a loading dose of 300 mg orally followed by a daily oral maintenance dose of 75 mg [17-19]. Platelet inhibition studies indicate that the incidence of clopidogrel hypo- or non-responsiveness may be as high as 27-30% with this dose, and higher oral loading doses such as 600 or 900 mg of clopidogrel which inhibit platelet aggregation more rapidly and achieve a higher absolute level of inhibition of platelet aggregation may be beneficial in clopidogrel patients [20-22]. Moreover, recent data seems to indicate that even in patients with acute coronary syndromes who are already on clopidogrel, reloading with 900 mg of clopidogrel achieves significantly higher platelet inhibition than 300 mg or 600 mg [22]. However, the additive clinical efficacy and the safety of higher oral loading doses have not been rigorously established but is being studied in a large ongoing ACS trial which is comparing the 600 mg and 300 mg loading doses.
Current ACC/AHA recommendations
ST-elevation myocardial infarction
In patients presenting with STEMI who have undergone diagnostic cardiac catheterization and for whom PCI is planned, current guidelines recommend the initiation and continuation of clopidogrel for at least 1 month after bare metal stent implantation, for several months after drug-eluting stent implantation (3 months for sirolimus, 6 months for paclitaxel), and for up to 12 months in patients who are not at high risk for bleeding (class I, level of evidence: B) [14]. Given an increased risk of late stent thrombosis with drug-eluting stents [23], future guidelines will likely mirror current practice, where clopidogrel is continued for at least 1 year following drug-eluting stent implantation. Current STEMI guidelines also recommend the addition of clopidogrel 75 mg daily to aspirin in patients with STEMI even if they do not undergo primary PCI (class I, level of evidence: A), for a period of at least 14 days (class I, level of evidence: B) or up to 1 year (class IIa, level of evidence: C). In addition, patients who are intolerant to aspirin should receive a thienopyridine, preferably clopidogrel 300 mg as a bolus followed by 75 mg daily indefinitely (class I, level of evidence: C) [14].
Non-ST-elevation acute coronary syndromes
For UA/NSTEMI patients in whom an initial invasive strategy is selected, antiplatelet therapy in addition to aspirin should be initiated before diagnostic angiography (“upstream” use) with either clopidogrel (loading dose followed by daily maintenance dose) or an intravenous GP IIb/IIIa inhibitor (class I, level of evidence: A). In patients undergoing PCI, the preferred loading dose of clopidogrel is 600 mg. Guidelines regarding the optimal duration of clopidogrel therapy post-PCI are same as for STEMI. For UA/NSTEMI patients in whom an initial conservative strategy is selected, clopidogrel loading dose followed by daily maintenance dose should be added to ASA and anticoagulant therapy as soon as possible after admission and administered for at least 1 month (class I, level of evidence: A) and ideally up to 1 year (class I, level of evidence: B) [15].

Despite the remarkable benefit noted with clopidogrel in patients with acute coronary syndromes, considerable individual variability of response exists, and suboptimal platelet inhibition may occur in as many as 30% of patients, which has been associated with stent thrombosis and adverse cardiovascular events [24, 25]. Prasugrel is a newer generation thienopyridine that, like clopidogrel, is a prodrug that gets converted to an active metabolite in vivo. However, it results in more complete platelet inhibition than clopidogrel, with significantly less variation in individual response [24]. In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 trial, prasugrel 60 mg loading dose followed by 10 mg daily was associated with a 24% reduction in nonfatal MI, a 34% reduction in urgent target-vessel revascularization (TVR), and a 52% reduction in stent thrombosis, compared with 300 mg loading dose followed by 75 mg daily of clopidogrel in patients presenting with acute coronary syndromes. Life-threatening bleeding was 52% more likely with prasugrel compared with clopidogrel, and the bleeding risk increased in elderly patients, patients with history of cerebrovascular disease, and body weight < 60 kg [26].

Current ACC/AHA recommendations
Prasugrel is currently undergoing FDA review, and is likely to figure prominently in future acute coronary syndrome management guidelines.

Ticlopidine is also converted to an active metabolite in vivo. Data from as early as 1990 demonstrated that ticlopidine 250 mg twice daily was associated with a 46% reduction in nonfatal MI, and a 47% reduction in vascular mortality in patients with unstable angina, compared with conventional therapy [27]. However, the association of ticlopidine with neutropenia, often severe (reported rate of occurrence is 2.4% for neutrophils < 1.2 × 109/l and 0.8% for neutrophils < 0.45 × 109/l), and its comparative expense, have led to a virtual abandonment of this therapy as an alternative to aspirin in most situations. Moreover, ticlopidine has also been associated with a variety of other hematological dyscrasias, such as thrombocytopenia, aplastic anemia, and thrombotic thrombocytopenic purpura [28].
Current ACC/AHA recommendations
Given its significant toxicities, ticlopidine is current recommended only in patients who are allergic to clopidogrel or aspirin (in the absence of contraindications) [14, 15].

Cilostazol exerts its antiplatelet action by selective antagonism of the phosphodiesterase (PDE) 3A enzyme. In addition, it also inhibits the uptake of adenosine, and has been shown to inhibit platelet aggregation. Most, if not all, of its actions are mediated by cyclic adenosine monophosphate (cAMP) [29]. Although its efficacy has been demonstrated in preventing restenosis following PCI in some small studies [30], similar studies in ACS are lacking at this point, and cilostazol is not currently approved for use in this situation.

Dipyridamole has a number of different actions on platelets, and has been primarily used in patients with ischemic strokes in combination with aspirin [31]. Its most important action is probably to inhibit the cyclic guanosine monophosphate (cGMP) PDE V enzyme, thereby enhancing the antiplatelet effects of the NO/cyclic GMP signaling pathway [32]. It is also known to inhibit adenosine uptake, and has the ability to increase the release of prostanoids from the endothelium [33]. Its efficacy in secondary prevention in post-MI patients is doubtful [34, 35], and it is currently not approved for use in ACS.

Antiplatelet drug resistance
Antiplatelet drug resistance refers to the development of a thrombotic event while on antiplatelet agents due to ineffective or incomplete platelet inhibition. Low levels of platelet inhibition have also been associated with an elevated risk of ischemic events [36]. Although probably best characterized for aspirin, “resistance” or “hypo-responsiveness” has been described for clopidogrel and GP IIb/IIIa inhibitors [37].
While “resistance” may in fact result from patient non-compliance, a number of mechanisms for true antiplatelet resistance have been elucidated. Patients with diabetes and obesity may be more likely to develop clopidogrel resistance, possibly due to elevated plasma fibrinogen [38, 39]. Other well-described mechanisms include incomplete suppression of thromboxane A2 generation with aspirin, accelerated turnover with introduction of newly formed, drug-unaffected platelets into the bloodstream, increased platelet sensitivity to collagen and ADP, and stress-induced COX-2 generation in platelets. Interference from other medications such as atorvastatin causing a decrease in bioavailability, or poor absorption of enteric-coated aspirin in certain patients can also contribute to antiplatelet resistance. In addition, single nucleotide polymorphisms conferring resistance to antiplatelet agents have also been described. For example, the P2Y12 H2 haplotype has been shown to be associated with thienopyridine resistance [37, 40].
Although not currently recommended for routine use, a number of platelet function tests are being evaluated [37, 39], and some assays have demonstrated exciting clinical results. In a recent randomized clinical trial, Bonello et al. demonstrated the utility of using vasodilator-stimulated phosphoprotein (VASP) phosphorylation analysis in patients undergoing PCI. Almost 50% of eligible patients receiving 600 mg of clopidogrel as a loading dose had clopidogrel hyporesponsivess, as defined by a VASP index of > 50%. Patients in the VASP-guided group received additional loading doses of clopidogrel (as high as 2,400 mg of clopidogrel) to reduce the VASP index below 50%, with a significantly lower incidence of major adverse cardiac events (MACE) at 30 days, compared with the conventional therapy group. Major and minor bleeding was similar [41]. Further large scale randomized studies of this and other assays will help clarify their role in routine medical practice.

Newer oral antiplatelet agents
A number of novel antiplatelet agents with different mechanisms of action are being investigated, and are in various stages of development. Several agents have already shown promising results in initial studies, and the future of antiplatelet agents seems to be bright as our understanding of platelet biology and interactions evolves.
Ticagrelor (AZD6140)
AZD6140 is the first of a new class of orally active non-thienopyridines, the cyclopentyltriazolopyrimidines [42]. It binds to the platelet ADP (P2Y12) receptor in a reversible manner. In the Dose confirmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in non-ST-segment Elevation myocardial infarction-2 (DISPERSE-2), AZD6140 270 mg loading dose followed by 90 mg twice daily, and 180 mg twice daily achieved significantly better inhibition of platelet activity (IPA) than clopidogrel 300 mg followed by 75 mg daily (79 vs. 95 vs. 64%). There was a reduction in MI with the higher dose compared with clopidogrel at 4 weeks, and a trend towards a benefit at 12 weeks. Minor bleeding was more common with the higher dose, major and life-threatening bleeding were similar [43, 44]. Further phase III clinical trial evaluation is ongoing.
Yet another reversible, direct P2Y12 receptor inhibitor, PRT060128 is has been developed in both oral and intravenous formulations. Its intravenous preparation has been shown to achieve dose-dependent complete inhibition of ADP-induced platelet aggregation [45]. Phase II clinical trials are currently underway.
SCH 530348
SCH 530348 belongs to a novel class of antiplatelet agents, called thrombin receptor antagonists (TRAs). Thrombin plays a major role in platelet activation, and does so through a cell surface Gp/Gi-coupled protease-activated receptor (PAR)-1, also known as the thrombin receptor [42, 46]. SCH 530348 is a PAR-1 receptor blocker that inhibits the activation and aggregation of platelets. Phase III clinical trials in patients with acute coronary syndromes as well as with stable coronary disease are ongoing.
This is a novel TRA, and has shown promising efficacy in vitro [47]. Phase II clinical trials are currently underway.
NCX-4016 is a nitric oxide (NO) releasing preparation of aspirin. It thus combines the beneficial effects of aspirin (thromboxane A2 inhibition) with NO (vasodilatative, antiatherogenic, antithrombotic, gastroprotective) [33].
Unlike aspirin which indirectly inhibits thromboxane A2 formation, S18886 acts directly on the thromboxane receptor [33]. It thus also inhibits other eicosanoids not affected by aspirin, such as hydroxyeicosatetraenoic acids (HETEs) and isoprostanes.
CTRP (C1qTNF-related protein)-1
This is a collagen inhibitor, and acts by blocking the ability of vWF to bind to bind to collagen, thus inhibition platelet adhesion [48].
Thus, several new antiplatelet drugs are under evaluation. Depending on their particular effects on ischemic and bleeding events, these agents may have a substantial impact in the field of acute coronary syndromes.

Dr Bhatt has received honoraria for consulting on scientific advisory boards from Astra Zeneca, Bristol Myers Squibb, Centocor, Daiichi Sankyo, Eisai, Eli Lilly, Glaxo Smith Kline, Millennium, Otsuka, Paringenix, PDL, Sanofi Aventis, Schering Plough, The Medicines Company; having received honoraria for lectures from Bristol Myers Squibb, Sanofi Aventis, and The Medicines Company; and having provided expert testimony regarding clopidogrel (the compensation was donated to a non-profit organization).

No funding was received for this manuscript.

1. Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics – 2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2008; 117: e25-146.
2. Antithrombotic Trialist’s Collaboration. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71-86.
3. Lincoff AM. Platelet glycoprotein IIb/IIIa inhibitors in cardiovascular disease. 2nd ed. Totowa, NJ. Humana Press 2003; 13-50.
4. Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein IIB-IIIA receptors in cardiovascular medicine. N Engl J Med 1995; 332: 1553-9.
5. Phillips DR, Charo IF, Parise LV, Fitzgerald LA. The platelet membrane glycoprotein IIB-IIIA complex. Blood 1988; 71: 831-43.
6. Shattil SJ, Ginsberg MH, Brugge JS. Adhesive signaling in platelets. Curr Opin Cell Biol 1994; 6: 695-704.
7. Hollopeter G, Jantzen HM, Vincent D, et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 2001; 409: 202-7.
8. Jennings LK, Saucedo JF. Antiplatelet and anticoagulant agents: key differences in mechanisms of action, clinical application, and therapeutic benefit in patients with non-ST-segment-elevation acute coronary syndromes. Curr Opin Cardiol 2008; 23: 302-8.
9. The SYMPHONY investigators. Comparison of sibrafiban with aspirin for prevention of cardiovascular events after acute coronary syndromes: a randomised trial. Lancet 2000; 355: 337-45.
10. Roth GJ, Stanford N, Majerus PW. Acetylation of prostaglandin synthase by aspirin. Proc Natl Acad Sci USA 1975; 72: 3073-6.
11. ISIS-2. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction. Lancet 1988; 2: 349-60.
12. Lewis HD Jr, Davis JW, Archibald DG, et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med 1983; 309: 396-403.
13. Reilly IAG, Fitzgerald GA. Inhibition of thromboxane formation in vivo and ex vivo: implications for therapy with platelet inhibitory drugs. Blood 1987; 69: 180-6.
14. Canadian Cardiovascular Society, American Academy of Family Physicians, American College of Cardiology, American Heart Association, Antman EM, Hand M, Armstrong PW, et al. 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2008; 51: 210-47.
15. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol 2007; 50: e1-157.
16. Herbert, J, Frehel, D, Vallee, E, et al. Clopidogrel, a novel antiplatelet and antithrombotic agent. Cardiovasc Drug Rev 1993; 11: 180-98.
17. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.
18. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005; 352: 1179-89.
19. Helton TJ, Bavry AA, Kumbhani DJ, et al. Incremental effect of clopidogrel on important outcomes in patients with cardiovascular disease: A meta-analysis of randomized trials. Am J Cardiovasc Drugs 2007; 7: 289-97.
20. Kastrati, A, Mehilli, J, Schuhlen, H, et al A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004; 350: 232-8.
21. Wiviott SD, Trenk D, Frelinger AL, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: The prasugrel in comparison to clopidogrel for inhibition of platelet activation and aggregation-thrombolysis in myocardial infarction 44 (PRINCIPLE-TIMI 44) trial. Circulation 2007; 116: 2923-32.
22. Collett JP, Silvain J, Landivier A, et al. Dose effect of clopidogrel reloading in patients already on 75-mg maintenance dose. The RELOAD study. Circulation 2008; 118: 1225-33.
23. Bavry AA, Kumbhani DJ, Helton TJ, et al. Late stent thrombosis of drug-eluting stents: A meta-analysis of randomized clinical trials. Am J Med 2006; 119: 1056-61.
24. Brandt JT, Payne CD, Wiviott SD, et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 2007; 153: 66.e9-16.
25. Price MJ. Newer antiplatelet therapies in development. Am J Health-Sys Pharm 2008; 65 (Suppl5): S11-5.
26. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopiodgrel in patients with acute coronary syndromes. N Eng J Med 2007; 357: 2001-15.
27. Balsano F, Rizzon P, Violi F, et al. Antiplatelet treatment with ticlopidine in unstable angina. A controlled multicenter clinical trial. The Studio della Ticlopidina nell’Angina Instabile Group. Circulation 1990; 82: 17-26.
28. Patrono C, Baigent C, Hirsh J, et al. Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th ed. Chest 2008; 133 (6 Suppl): 199S-233S.
29. Schror K. The pharmacology of cilostazol. Diabetes Obes Metab 2002; 4 Suppl 2: S14-9.
30. Douglas JS Jr, Holmes DR Jr, Kereiakes DJ, et al. Coronary stent restenosis in patients treated with cilostazol. Circulation 2005; 112: 2826-32.
31. ESPRIT Study Group, Halkes PH, van Gijn J, Kappelle LJ, et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006; 367: 1665-73.
32. Aktas B, Utz A, Hoenig-Liedl P, Walter U, Geiger J. Dipyridamole enhances NO/cGMP-mediated vasodilator-stimulated phosphoprotein phosphorylation and signaling in human platelets: in vitro and in vivo/ex vivo studies. Stroke 2003; 34: 764-9.
33. Meadows TA, Bhatt DL. Clinical aspects of platelet inhibitors and thrombus formation. Circ Res 2007; 100: 1261-75.
34. The Persantine-Aspirin Reinfarction Study Research Group. Persantine and aspirin in coronary heart disease. Circulation 1980; 62: 449-61.34.
35. Klimt CR, Knatterud GL, Stamler J, Meier P. Persantine-Aspirin Reinfarction Study. Part II. Secondary coronary prevention with persantine and aspirin. J Am Coll Cardiol 1986; 7: 251.
36. Price MJ, Endemann S, Gollapudi RR, et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008; 29: 992-1000.
37. Michelson AD. Platelet function testing in cardiovascular diseases. Circulation 2004; 110: e489-3.
38. Ang L, Palakodeti V, Khalid A, et al. Elevated plasma fibrinogen and diabetes mellitus are asscoiated with lower platelet inhibition of platelet reactivity with clopidogrel. J Am Coll Cardiol 2008; 52: 1052-9.
39. Bhatt DL. What makes platelets angry: Diabetes, fibrinogen, obesity, and impaired response to antiplatelet therapy? J Am Coll Cardiol 2008; 52: 1060-1.
40. Fontana P, Gaussem P, Aiach M, et al, P2Y12 H2 haplotype is associated with peripheral arterial disease: a case-control study. Circulation 2003; 108: 2971-3.
41. Bonello L, Camoin-Jau L, Arques S, et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. J Am Coll Cardiol 2008; 51: 1404-11.
42. Angiolillo DJ, Capranzano P. Pharmacology of emerging novel platelet inhibitors. Am Heart J 2008; 156 (2 Suppl): S10-5.
43. Cannon CP, Husted S, Harrington RA, et al. 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 2007; 50: 1844-51.
44. Storey RF, Husted S, Harrington RA, et al. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol 2007; 50: 1852-6.
45. Gretler DD, Conley PB, Andre P, et al. “First in human” experience with PRT060128, a new direct-acting, reversible, P2Y12 inhibitor for IV and oral use. J Am Coll Cardiol 2007; 49(Suppl): 326A [abstract].
46. Derian CK, Maryanoff BE, Zhang HC, et al. Therapeutic potential of protease-activated receptor-1 antagonists. Expert Opin Investig Drugs 2003; 12: 209-21.
47. Kogushi M, Yokohama H, Kitamura S, et al. Effects of E5555, a protease-activated receptor-1 antagonist, on the inflammatory markers in vitro. J Thromb Haemost 2007; 5 (Suppl 1): P-M-059 [abstract].
48. Lasser G, Guchhait P, Ellsworth JL, et al. C1qTNF-related protein-1 (CTRP-1): a vascular wall protein that inhibits collagen-induced platelet aggregation by blocking VWF binding to collagen. Blood 2006; 107: 423-30.
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