Antiplatelet drugs are important components in the management of atherothrombotic vascular disease. However, several limitations restrict the safety and efficacy of current antiplatelet therapy in clinical practice. Interpatient variability and resistance to aspirin and/or clopidogrel has spurred efforts for the development of novel agents. Indeed, several antiplatelet drugs are at various stages of evaluation; those at advanced stage of development are the focus of this review.
Mehta SR, Yusuf S., Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001;358(9281):527-533.
2.
Steinhubl SR , Berger PB, Mann JT 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002; 288(19):2411-2420.
3.
Coons JC, Battistone S.2007Guideline update for unstable angina/non-ST-segment elevation myocardial infarction: focus on antiplatelet and anticoagulant therapies . Ann Pharmacother.2008;42(7):989-1001.
4.
Jagroop IA, Kakafika AI, Mikhailidis DPPlatelets and vascular risk: an option for treatment. Curr Pharm Des. 2007;13(16): 1669-1683.
5.
Sapoznikov B. , Vilkin A., Hershkovici M., Fishman M., Eliakim R., Niv Y.Minidose aspirin and gastrointestinal bleeding-a retrospective, case-control study in hospitalized patients. Dig Dis Sci. 2005;50(9):1621-1624.
6.
Tournoij E., Peters RJ, Langenberg M., Kanhai KJ, Moll FLThe prevalence of intolerance for low-dose acetylsalicylacid in the secondary prevention of atherothrombosis. Eur J Vasc Endovasc Surg.2009;37(5):597-603.
Brandt JT, Close SL, Iturria SJ, et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost. 2007;5(12):2429-2436.
9.
Guha S., Sardar P., Guha P., et al. Dual antiplatelet drug resistance in patients with acute coronary syndrome. Indian Heart J.2009; 61(1):68-73.
10.
Papathanasiou A., Goudevenos J., Tselepis ADAspirin resistance in cardiovascular disease: pathogenesis, diagnosis and clinical impact. Curr Pharmaceut Des.2009;15(10):1085-1094.
11.
Pinto Slottow TL, Bonello L., Gavini R., et al. Prevalence of aspirin and clopidogrel resistance among patients with and without drug-eluting stent thrombosis. Am J Cardiol. 2009;104(4):525-530.
12.
Shuldiner AR , O’Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009 ;302(8):849-857.
13.
Diener HC, Bogousslavsky J., Brass LM, et al. 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. 2004;364(9431):331-337.
14.
Bhatt DL, Fox KA, Hacke W., et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354(16):1706-1717.
15.
Davi G., Patrono C.Platelet activation and atherothrombosis. N Engl J Med.2007;357(24):2482-2494.
16.
Jagroop IA, Burnstock G., Mikhailidis DPBoth the ADP receptors P2Y1 and P2Y12, play a role in controlling shape change in human platelets. Platelets. 2003;14(1):15-20.
17.
Soulet C., Sauzeau V., Plantavid M., et al. Gi-dependent and -independent mechanisms downstream of the P2Y12 ADP-receptor. J Thromb Haemost. 2004;2(1):135-146.
18.
Mazoyer E., Ripoll L., Boisseau MR, et al. How does ticlopidine treatment lower plasma fibrinogen? Thromb Res. 1994;75(3): 361-370.
19.
Hayakawa M. , Kuzuya F.Effects of ticlopidine on erythrocyte aggregation in thrombotic disorders. Angiology. 1991;42(9): 747-753.
20.
Hermann A., Rauch BH, Braun M., Schrör K., Weber AAPlatelet C.D40 ligand (CD40L)-subcellular localization, regulation of expression, and inhibition by clopidogrel. Platelets. 2001 ;12(2): 74-82.
21.
Klinkhardt U., Bauersachs R., Adams J., Graff J., Lindhoff-Last E., Harder S.Clopidogrel but not aspirin reduces P-selectin expression and formation of platelet-leukocyte aggregates in patients with atherosclerotic vascular disease. Clin Pharmacol Ther. 2003;73(3):232-241.
22.
Klinkhardt U., Graff J., Harder S.Clopidogrel, but not abciximab, reduces platelet leukocyte conjugates and P-selectin expression in a human ex vivo in vitro model. Clin Pharmacol Ther. 2002; 71(3):176-185.
23.
de Lorgeril M., Bordet JC, Salen P., et al. Ticlopidine increases nitric oxide generation in heart-transplant recipients: a possible novel property of ticlopidine . J Cardiovasc Pharmacol. 1998; 32(2):225-230.
24.
Arrebola MM , De la Cruz JP, Villalobos MA, Pinacho A., Guerrero A., Sánchez de la Cuesta F. In vitro effects of clopidogrel on the platelet-subendothelium interaction, platelet thromboxane and endothelial prostacyclin production, and nitric oxide synthesis . J Cardiovasc Pharmacol. 2004;43(1):74-82.
25.
Ha-Duong NT , Dijols S., Macherey AC, Goldstein JA, Dansette PM, Mansuy D.Ticlopidine as a selective mechanism-based inhibitor of human cytochrome P450 2C19. Biochemistry. 2001;40(40):12112-12122.
26.
Richter T., Murdter TE, Heinkele G., et al. Potent mechanism-based inhibition of human CYP2B6 by clopidogrel and ticlopidine. J Pharmacol Exp Ther. 2004 ;308(1):189-197.
27.
http://www.drugs.com/pro/ticlopidine.html. Accessed September 29, 2010).
28.
Bertrand ME , Rupprecht HJ, Urban P., et al. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS) . Circulation. 2000; 102(6):624-9.
29.
Kim KA, Park PW, Hong SJ, Park JYThe effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance. Clin Pharmacol Ther. 2008;84(2):236-42.
30.
Wallentin L. , Varenhorst C., James S., et al. Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J. 2008;29(1):21-30.
31.
PLAVIX. http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20(General%20Monographs-%20P)/PLAVIX.html . Accessed June 2, 2010.
32.
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 trial. Circulation. 2007;116(25):2923-2932.
33.
Lau WC, Gurbel PA, Watkins PB, et al. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation. 2004;109(2):166-71.
34.
Matsagas M. , Jagroop IA, Geroulakos G., Mikhailidis DPThe effect of a loading dose (300 mg) of clopidogrel on platelet function in patients with peripheral arterial disease . Clin Appl Thromb Hemost. 2003;9(2):115-120.
35.
Hashemzadeh M., Goldsberry S., Furukawa M., Khoynezhad A., Movahed MRADP receptor-blocker thienopyridines: chemical structures, mode of action and clinical use. A review . J Invasive Cardiol.2009;21(8):406-412.
36.
Niitsu Y., Jakubowski JA, Sugidachi A., Asai F.Pharmacology of CS-747 (prasugrel, LY640315), a novel, potent antiplatelet agent with in vivo P2Y12 receptor antagonist activity. Semin Thromb Hemost. 2005;31(2):184-194.
37.
McCaslin J. , Smout J., Kesteven P., Stansby G.Oral antiplatelet agents and bleeding risk in relation to major cardiovascular surgery. Curr Drug Saf . 2006;1(3):281-287.
Chen L., Bracey AW, Radovancevic R., et al. Clopidogrel and bleeding in patients undergoing elective coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2004;128(3): 425-31.
40.
Hongo RH, Ley J., Dick SE, Yee RRThe effect of clopidogrel in combination with aspirin when given before coronary artery bypass grafting. J Am Coll Cardiol. 2002;40(2):231-237.
41.
Yende S., Wunderink RGEffect of clopidogrel on bleeding after coronary artery bypass surgery . Crit Care Med. 2001;29(12): 2271-2275.
42.
Boxed Warning Added to Clopidogrel Label, Testing Suggested . http://www.medpagetoday.com/InfectiousDisease/PublicHealth/18982?utm_content=GroupCL&utm_medium=email&impressionId=1268468432171&utm_campaign=DailyHeadlines&utm_source=mSpoke&userid=220693 >. Accessed June 2, 2010.
43.
Mega JL, Simon T., Anderson JL, et al. CYP2C19 genetic variants and clinical outcomes with clopidogrel: a collaborative meta-analysis. Circulation.2009;120:S598-S599.
44.
Gurbel PA, Tantry US, Shuldiner AR, Kereiakes DJGenotyping one piece of the puzzle to personalize antiplatelet therapy . J Am Coll Cardiol.2010;56(2):112-116.
45.
Juurlink DN , Gomes T., Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel . CMAJ.2009;180(7):713-718.
46.
Ho PM, Maddox TM, Wang L., et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA.2009; 301(9):937-944.
47.
Gilard M., Arnaud B., Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol. 2008;51(3):256-260.
48.
Chow CK, Moayyedi P., Devereaux PJIs it safe to use a proton pump inhibitor with clopidogrel?Pol Arch Med Wewn. 2009; 119(9):564-568.
49.
Barragan P. , Bouvier JL, Roquebert PO, et al. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv . 2003;59(3):295-302.
50.
COGENT: No adverse CV interaction with clopidogrel, PPIs. http://www.cardiologytoday.com/view.aspx?rid=44123. Accessed June 2, 2010.
51.
Cogent trial shows lack of adverse interaction between clopidogrel and stomach medicine. http://www.eurekalert.org/pub_releases/2009-09/crf-cts092409.php. Accessed June 2, 2010.
52.
Stockl KM, Le L., Zakharyan A., et al. Risk of rehospitalization for patients using clopidogrel with a proton pump inhibitor. Arch Intern Med. 2010;170(8):704-710.
53.
Early Communication about an Ongoing Safety Review of clopidogrel bisulfate (marketed as Plavix). http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm079520.htm. Accessed June 2, 2010.
54.
New Details on Potential Adverse Coumarin-Clopidogrel Interaction . http://www.mednewscenter.com/new-details-on-potential-adverse-coumarin-clopidogrel-interaction.htm . Accessed June 2, 2010.
55.
Sibbing D., von Beckerath N., Morath T., et al. Oral anticoagulation with coumarin derivatives and antiplatelet effects of clopidogrel. Eur Heart J.2010;31(10):1205-1211.
56.
Inauen W., Bombeli T., Baumgartner HR, Haeberli A., Straub PWEffects of the oral anticoagulant phenprocoumon on blood coagulation and thrombogenesis induced by rabbit aorta subendothelium exposed to flowing human blood: role of dose and shear rate. J Lab Clin Med. 1991 ;118(3):280-288.
Do Point-of-Care Platelet Function Assays Predict Clinical Outcomes in Clopidogrel Pretreated Patients Undergoing Elective PCI (POPULAR Study)?http://www.cardiosource.com/rapidnewssummaries/summary.asp?SumID=481 . Accessed June 2, 2010.
59.
Un-POPULAR? Utility of platelet-function tests ‘‘modest.’’http://www.theheart.org/article/1049535.do. Accessed June 2, 2010.
60.
GRAVITAS: Gauging Responsiveness With A VerifyNow Assay-Impact On Thrombosis And Safety. http://www.clinicaltrials.gov/ct2/show/NCT00645918?term=GRAVITAS&rank=1. Accessed June 2, 2010.
61.
Petersen KURelevance of metabolic activation pathways: the example of clopidogrel and prasugrel. Arzneimittelforschung.2009;59(5):213-227.
62.
Herbert JM, Savi P.P2Y12, a new platelet ADP receptor, target of clopidogrel. Semin Vasc Med. 2003;3(2):113-122.
63.
Helft G., Osende JI, Worthley SG, et al. Acute antithrombotic effect of a front-loaded regimen of clopidogrel in patients with atherosclerosis on aspirin. Arterioscler Thromb Vasc Biol. 2000; 20(10):2316-2321.
64.
Weerakkody GJ , Jakubowski JA, Brandt JT, et al. Comparison of speed of onset of platelet inhibition after loading doses of clopidogrel versus prasugrel in healthy volunteers and correlation with responder status . Am J Cardiol . 2007;100(2):331-336.
65.
Small DS, Farid NA, Payne CD, et al. Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. J Clin Pharmacol. 2008; 48(4):475-484.
66.
Jernberg T. , Payne CD, Winters KJ, et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J. 2006; 27(10):1166-1173.
67.
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(1):66e9-66e16.
68.
Jakubowski JA, Payne CD, Li YG, et al. The use of the Verify-Now P2Y12 point-of-care device to monitor platelet function across a range of P2Y12 inhibition levels following prasugrel and clopidogrel administration . Thromb Haemost. 2008;99(2): 409-415.
69.
Jakubowski JA, Payne CD, Li YG, et al. A comparison of the antiplatelet effects of prasugrel and high-dose clopidogrel as assessed by VASP-phosphorylation and light transmission aggregometry. Thromb Haemost. 2008;99(1):215-222.
70.
Porto I., Giubilato S., De Maria GL, Biasucci LM, Crea F.Platelet P2Y12 receptor inhibition by thienopyridines: status and future. Expert Opin Investig Drugs.2009 ;18(9):1317-1332.
71.
Third Optimizing Anti-Platelet Therapy in Diabetes MellitUS (OPTIMUS-3). http://clinicaltrials.gov/ct2/show/results/NCT00642174?sect=X430125#othr. Accessed June 2, 2010.
72.
Montalescot G., Wiviott SD, Braunwald E., et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet.2009;373(9665):723-731.
73.
Wiviott SD, Braunwald E., McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001-2015.
74.
Murphy SA, Antman EM, Wiviott SD, et al. Reduction in recurrent cardiovascular events with prasugrel compared with clopidogrel in patients with acute coronary syndromes from the TRITON-TIMI 38 trial. Eur Heart J. 2008;29(20):2473-2479.
75.
Wiviott SD, Braunwald E., McCabe CH, et al. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet. 2008;371(9621):1353-1363.
76.
Prasugrel: Different mortality trends in STEMI and non-STEMI patients in TRITON . http://www.theheart.org/article/1063881.do. Accessed June 2, 2010.
77.
Floyd JS, Serebruany VLPrasugrel as a potential cancer promoter: review of the unpublished data. Arch Intern Med. 2010;170(12):1078-1080.
78.
Food and Drug Administration.Briefing document , February 3, 2009Meeting of FDA Cardiovascular and Renal Drugs Advisory. http://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4412b1-01-FDA.pdf . Accessed 13 July, 2010.
79.
Honn KV, Tang DG, Crissman JDPlatelets and cancer metastasis: a causal relationship? Cancer Metastasis Rev. 1992;11(3-4):325-351.
80.
Struyf S., Burdick MD, Peeters E., et al. Platelet factor-4 variant chemokine CXCL4L1 inhibits melanoma and lung carcinoma growth and metastasis by preventing angiogenesis. Cancer Res. 2007;67(12):5940-5948.
81.
Mahoney EM, Wang K., Arnold SV, et al. Cost-effectiveness of prasugrel versus clopidogrel in patients with acute coronary syndromes and planned percutaneous coronary intervention: results from the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with Prasugrel-Thrombolysis in Myocardial Infarction TRITON-TIMI 38. Circulation.2010; 121(1):71-79.
Prasugrel compared with high-dose Clopidogrel in acute coronary syndrome. The randomized, double-blind ACAPULCO study. http://crtonline.org/pdf/ACAPULCO.pdf. Accessed June 2, 2010.
84.
EMEA European Medicine Agency EFFIENT.http://www.emea.europa.eu/humandocs/Humans/EPAR/efient/efient.htm . Accessed June 2, 2010.
FDA approves effient to reduce the risk of heart attack in angioplasty patients. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm171497.htm. Accessed June 2, 2010.
87.
EFFIENT risk evaluation and mitigation strategy, FDA. http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM187493.pdf . Accessed June 2, 2010.
88.
A comparison of prasugrel and clopidogrel in acute coronary syndrome subjects (TRILOGY ACS). http://www.clinicaltrials.gov/ct2/show/NCT00699998?term=prasugrel&rank=8. Accessed June 2, 2010.
89.
CYPRESS-CYPheR for evaluating sustained safety. http://www.clinicaltrials.gov/ct2/show/NCT00954707?term=prasugrel&rank=16. Accessed June 2, 2010.
90.
Efficacy study of combined prasugrel and bivalirudin versus clopidogrel and heparin in myocardial infarction (BRAVE-4). http://www.clinicaltrials.gov/ct2/show/NCT00976092?term=prasugrel&rank=11. Accessed June 2, 2010.
91.
The dual antiplatelet therapy study (DAPT Study). http://www.clinicaltrials.gov/ct2/show/NCT00977938?term=prasugrel&rank=15. Accessed June 2, 2010.
92.
TAXUS libertē post approval study. http://www.clinicaltrials.gov/ct2/show/NCT00997503?term=prasugrel&rank=14 . Accessed June 2, 2010.
93.
A Comparison of Prasugrel at PCI or Time of Diagnosis of Non-ST Elevation Myocardial Infarction (ACCOAST). http://www.clinicaltrials.gov/ct2/show/NCT01015287?term=prasugrel&rank=9. Accessed June 2, 2010.
94.
Testing platelet reactivity in patients undergoing elective stent placement on clopidogrel to guide alternative therapy with prasugrel (TRIGGER-PCI) . http://www.clinicaltrials.gov/ct2/show/NCT00910299?term=TRIGGER+PCI&rank=1 . Accessed June 2, 2010.
95.
Gurbel PA, Bliden KP, Antonino MJ, et al. The effect of elinogrel on high platelet reactivity during dual antiplatelet therapy and the relation to cyp 2c19*2 genotype: first experience in patients. J Thromb Haemost. 2010;8:43-53.
96.
Berger JS, Roe MT, Gibson CM, et al. Safety and feasibility of adjunctive antiplatelet therapy with intravenous elinogrel, a direct-acting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial infarction: the Early Rapid ReversAl of platelet thromboSis with intravenous Elinogrel before PCI to optimize reperfusion in acute Myocardial Infarction (ERASE MI) pilot trial. Am Heart J.2009;158(6):998.e1-1004.e1.
97.
A Phase 2 Safety and Efficacy Study of PRT060128, a Novel Intravenous and Oral P2Y12 Inhibitor, in Non-Urgent PCI (INNO-VATE-PCI) . http://www.clinicaltrials.gov/ct2/show/NCT00751231?term=PRT060128&rank=1. Accessed June 2, 2010.
98.
van Giezen JJ, Humphries RGPreclinical and clinical studies with selective reversible direct P2Y12 antagonists. Semin Thromb Hemost. 2005;31(2):195-204.
99.
Kowalczyk M. , Banach M., Mikhailidis DP, Hannam S., Rysz J.Ticagrelor-a new platelet aggregation inhibitor in patients with acute coronary syndromes. An improvement of other inhibitors?Med Sci Monit. 2009;15(12):MS24-MS30.
100.
Husted S., Emanuelsson H., Heptinstall S., Sandset PM, Wickens M., Peters G.Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J. 2006;27(9): 1038-1047.
101.
Gurbel PA, Bliden KP, Butler K., et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation.2009;120(25):2577-2585.
102.
Serebruany VLDyspnoea after AZD6140: safety first? Eur Heart J. 2006;27(12):1505-1506.
103.
Serebruany VL, Stebbing J., Atar D.Dyspnoea after antiplatelet agents: the AZD6140 controversy. Int J Clin Pract. 2007;61(3): 529-533.
104.
Wallentin L., Becker RC, Budaj A., et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057.
105.
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(19):1844-1851.
106.
Bjorkman JA , Kirk I., van Giezen JJAZD6140 inhibits adenosine uptake into erythrocytes and enhances coronary blood flow after local ischemia or intracoronary adenosine infusion. Circulation . 2007;116:; II_28..
107.
Is there too much excitement for ticagrelor?http://www.theheart.org/article/1049933.do. Accessed June 2, 2010.
108.
James S., Akerblom A., Cannon CP, et al. 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.2009; 157(4):599-605.
109.
Cannon CP, Harrington RA, James S., et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet.2010;375(9711):283-293.
110.
Van Giezen JJ, Nilsson L., Berntsson P., et al. Ticagrelor binds to human P2Y(12) independently from ADP but antagonizes ADPinduced receptor signaling and platelet aggregation. J Thromb Haemost.2009;7(9):1556-1565.
111.
Husted S., van Giezen JJTicagrelor: the first reversibly binding oral P2Y12 receptor antagonist . Cardiovasc Ther.2009;27(4): 259-274.
112.
Ticagrelor versus clopidogrel in patients with acute coronary syndomes undergoing coronary artery bypass surgery: results from the PLATO trial. http://www.cardio.se/fileArchive/Kongresser/ACC-2010/PLATO-CABG.pdf . Accessed June 2, 2010.
113.
Gurbel PA, Bliden KP, Butler K., et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND Study. Circulation.2010;121(10): 1188-1199.
114.
Greenbaum AB, Grines CL, Bittl JA, et al. Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: results from a 2-part, phase II, multicenter, randomized, placebo- and active-controlled trial. Am Heart J.2006 ;151(3):689.e1-689.e10.
115.
Akers WS, Oh JJ, Oestreich JH, Ferraris S., Wethington M., Steinhubl SRPharmacokinetics and pharmacodynamics of a bolus and infusion of cangrelor: a direct, parenteral P2Y12 receptor antagonist. J Clin Pharmacol.2010;50(1):27-35.
116.
Bouman HJ, van Werkum JW, Hackeng CM, Clappers N., Ten Berg JMCangrelor increases the magnitude of platelet inhibition and reduces interindividual variability in clopidogrel-pretreated subjects. Neth Heart J.2009;17(5):195-198.
117.
Harrington RA, Stone GW, McNulty S., et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med.2009; 361(24):2318-2329.
118.
Bhatt DL, Lincoff AM, Gibson CM, et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med.2009; 361(24):2330-2341.
119.
Kastrati A. , Ndrepepa G.Cangrelor- a champion lost in translation?N Engl J Med. 2009;361(24):2382-2384.
120.
Greenbaum AB , Ohman EM, Gibson CM, et al. Preliminary experience with intravenous P2Y12 platelet receptor inhibition as an adjunct to reduced-dose alteplase during acute myocardial infarction: results of the Safety, Tolerability and Effect on Patency in Acute Myocardial Infarction (STEP-AMI) angiographic trial . Am Heart J. 2007;154(4):702-709.
121.
Coughlin SRProtease-activated receptors in hemostasis, thrombosis and vascular biology . J Thromb Haemost. 2005;3(8): 1800-1814.
122.
Leger AJ, Jacques SL, Badar J., et al. Blocking the protease-activated receptor 1-4 heterodimer in platelet-mediated thrombosis. Circulation. 2006;113(9):1244-1254.
123.
Derian CK, Damiano BP, Addo MF, et al. Blockade of the thrombin receptor protease-activated receptor-1 with a small-molecule antagonist prevents thrombus formation and vascular occlusion in nonhuman primates. J Pharmacol Exp Ther. 2003;304(2):855-861.
124.
Kato Y., Kita Y., Hirasawa-Taniyama Y., et al. Inhibition of arterial thrombosis by a protease-activated receptor 1 antagonist, FR171113, in the guinea pig. Eur J Pharmacol . 2003; 473(2-3):163-169.
125.
Vandendries ER, Hamilton JR, Coughlin SR, Furie B., Furie BCPar4 is required for platelet thrombus propagation but not fibrin generation in a mouse model of thrombosis. Proc Natl Acad Sci U S A. 2007;104(1):288-292.
126.
Maurice P. , Legrand C., Fauvel-Lafeve F.Platelet adhesion and signaling induced by the octapeptide primary binding sequence (KOGEOGPK) from type III collagen . FASEB J. 2004;18(12): 1339-1347.
127.
Oestreich J.SCH-530348, a thrombin receptor (PAR-1) antagonist for the prevention and treatment of atherothrombosis. Curr Opin Investig Drugs. 2009;10(9):988-996.
128.
Bhatt DL, Topol EJScientific and therapeutic advances in antiplatelet therapy. Nat Rev Drug Discov. 2003;2(1):15-28.
129.
Becker RC, Moliterno DJ, Jennings LK, et al. Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study. Lancet.2009;373(9667): 919-928.
130.
Trial to assess the effects of SCH 530348 in preventing heart attack and stroke in patients with atherosclerosis (TRA 2 P- TIMI 50) (Study P04737AM2). http://www.clinicaltrials.gov/ct2/show/NCT00526474?term=SCH530348&rank=4 . Accessed June 2, 2010.
131.
Trial to assess the effects of SCH 530348 in preventing heart attack and stroke in patients with acute coronary syndrome (TRA•CER) (Study P04736AM2). http://www.clinicaltrials.gov/ct2/show/NCT00527943?term=SCH+530348&rank=2 . Accessed June 2, 2010.
132.
Kai Y. , Hirano K., Maeda Y., Nishimura J., Sasaki T., Kanaide H.Prevention of the hypercontractile response to thrombin by proteinase-activated receptor-1 antagonist in subarachnoid hemorrhage. Stroke. 2007;38(12):3259-3265.
133.
Serebruany VL, Kogushi M., Dastros-Pitei D., Flather M., Bhatt DLThe in-vitro effects of E5555, a protease-activated receptor (PAR)-1 antagonist, on platelet biomarkers in healthy volunteers and patients with coronary artery disease. Thromb Haemost . 2009;102(1):111-119.
134.
A Double-Blind Study of E5555 in Japanese patients with acute coronary syndrome. http://www.clinicaltrials.gov/ct2/show/NCT00619164?term=E5555&rank=1. Accessed June 2, 2010.
135.
A double-blind study of E5555 in Japanese subjects with coronary artery disease. http://www.clinicaltrials.gov/ct2/show/NCT00540670?term=E5555&rank=2. Accessed June 2, 2010.
136.
Safety and tolerability of E5555 and its effects on markers of intravascular inflammation in subjects with coronary artery disease. http://www.clinicaltrials.gov/ct2/show/NCT00312052?term=E5555&rank=3 . Accessed June 2, 2010.
137.
McAdam BF, Catella-Lawson F., Mardini IA, Kapoor S., Lawson JA, FitzGerald GASystemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A. 1999; 96(1):272-277.
Morrow JD, Hill KE, Burk RF, et al. A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism. Proc Natl Acad Sci U S A.1990;87(23):9383-9387.
140.
Viles-Gonzalez JF, Fuster V., Corti R., et al. Atherosclerosis regression and TP receptor inhibition: effect of S18886 on plaque size and composition-a magnetic resonance imaging study. Eur Heart J. 2005 ;26(15):1557-1561.
141.
Belhassen L., Pelle G., Dubois-Rande JL, Adnot S.Improved endothelial function by the thromboxane A2 receptor antagonist S 18886 in patients with coronary artery disease treated with aspirin. J Am Coll Cardiol . 2003;41(7):1198-1204.
142.
Vilahur G. , Casani L., Badimon L.A thromboxane A2/prostaglandin H2 receptor antagonist (S18886) shows high antithrombotic efficacy in an experimental model of stent-induced thrombosis. Thromb Haemost. 2007;98(3):662-669.
143.
van der Hoorn JW, Jukema JW, Bekkers ME, et al. Negative effects of rofecoxib treatment on cardiac function after ischemia-reperfusion injury in APOE3Leiden mice are prevented by combined treatment with thromboxane prostanoidreceptor antagonist S18886 (terutroban). Crit Care Med. 2008; 36(9):2576-2582.
144.
Grover GJ, Sleph PG, Weiss HREffect of thromboxane receptor blockade on oxygen supply/consumption variables during reperfusion in the anesthetized dog. J Pharmacol Exp Ther. 1990; 253(3):1097-1102.
145.
Ge ZD, Auchampach JA, Piper GM, Gross GJComparison of cardioprotective efficacy of two thromboxane A2 receptor antagonists . J Cardiovasc Pharmacol. 2003 ;41(3):481-488.
146.
Bal Dit Sollier C., Crassard I., Simoneau G., Bergmann JF, Bousser MG, Drouet L.Effect of the thromboxane prostaglandin receptor antagonist terutroban on arterial thrombogenesis after repeated administration in patients treated for the prevention of ischemic stroke. Cerebrovasc Dis. 2009;28(5):505-513.
147.
Hennerici MGRationale and design of the Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin with Terutroban in Patients with a History of Ischemic Stroke or Transient Ischemic Attack (PERFORM) Study. Cerebrovasc Dis.2009;27(suppl 3):28-32.
148.
Bousser MG, Amarenco P., Chamorro A., et al. The Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack (PERFORM) study: baseline characteristics of the population. Cerebrovasc Dis.2009;27(6):608-613.
Radomski MW , Palmer RM, Moncada S.The role of nitric oxide and cGMP in platelet adhesion to vascular endothelium . Biochem Biophys Res Commun . 1987;148(3):1482-1489.
151.
Radomski MW , Palmer RM, Moncada S.Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium . Lancet. 1987;2(8567):1057-1058.
152.
Radomski MW , Palmer RM, Moncada S.The anti-aggregating properties of vascular endothelium: interactions between prostacyclin and nitric oxide. Br J Pharmacol. 1987;92(3):639-646.
153.
Sogo N., Magid KS, Shaw CA, Webb DJ, Megson ILInhibition of human platelet aggregation by nitric oxide donor drugs: relative contribution of cGMP-independent mechanisms. Biochem Biophys Res Commun. 2000;279(2):412-419.
154.
Shaul PWEndothelial nitric oxide synthase, caveolae and the development of atherosclerosis . J Physiol. 2003;547(pt1):21-33.
155.
Minuz P., Degan M., Gaino S., et al. NCX4016 (NO-Aspirin) has multiple inhibitory effects in LPS-stimulated human monocytes. Br J Pharmacol. 2001;134(4):905-911.
156.
Khuseyinova N., Koenig W.Biomarkers of outcome from cardiovascular disease. Curr Opin Crit Care. 2006;12(5):412-419.
157.
Tuttolomondo A., Pinto A., Corrao S., et al. Immuno-inflammatory and thrombotic/fibrinolytic variables associated with acute ischemic stroke diagnosis. Atherosclerosis.2009;203(2):503-508.
158.
Palmer RM, Ferrige AG, Moncada S.Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327(6122):524-526.
159.
Zhao CX, Xu X., Cui Y., et al. Increased endothelial nitric-oxide synthase expression reduces hypertension and hyperinsulinemia in fructose-treated rats. J Pharmacol Exp Ther.2009;328(2): 610-620.
160.
Kwiecien SS , Pawlik MW, Brzozowski T., et al. Nitric oxide (NO)-releasing aspirin and (NO) donors in protection of gastric mucosa against stress. J Physiol Pharmacol. 2008;59(suppl 2): 103-115.
161.
Napoli C., Aldini G., Wallace JL, et al. Efficacy and age-related effects of nitric oxide-releasing aspirin on experimental restenosis. Proc Natl Acad Sci U S A. 2002;99(3):1689-1694.
162.
Wan S. , Shukla N., Angelini GD, Yim AP, Johnson JL, Jeremy JYNitric oxide-donating aspirin (NCX 4016) inhibits neointimal thickening in a pig model of saphenous vein-carotid artery interposition grafting: a comparison with aspirin and morpholinosydnonimine (SIN-1). J Thorac Cardiovasc Surg . 2007;134(4):1033-1039.
163.
Fiorucci S. , Santucci L., Wallace JL, et al. Interaction of a selective cyclooxygenase-2 inhibitor with aspirin and NO-releasing aspirin in the human gastric mucosa . Proc Natl Acad Sci U S A. 2003;100(19):10937-10941.
164.
Wallace JL , Miller MJNitric oxide in mucosal defense: a little goes a long way. Gastroenterology. 2000;119(2):512-520.
165.
Ma L., Wallace JLEndothelial nitric oxide synthase modulates gastric ulcer healing in rats . Am J Physiol Gastrointest Liver Physiol. 2000;279(2):G341-G346.
166.
Brown JF, Keates AC, Hanson PJ, Whittle BJNitric oxide generators and cGMP stimulate mucus secretion by rat gastric mucosal cells. Am J Physiol. 1993;265(3pt1):G418-G422.