1932

Abstract

Ischemic heart disease and stroke are major causes of death and morbidity worldwide. Coronary and cerebrovascular events are a consequence of thrombus formation caused by atherosclerotic plaque rupture or embolism, both of which result from platelet activation and aggregation and thrombin-mediated fibrin generation via the coagulation cascade. Current and emerging antiplatelet and anticoagulant agents are evolving rapidly. The use of aspirin for primary prevention continues to be controversial, as are the doses appropriate for secondary prevention. Development of new oral and intravenous adenosine diphosphate P2Y inhibitors and novel antiplatelet agents continues to transform the landscape of antiplatelet therapy. Oral anticoagulation has advanced with the use of direct thrombin and factor Xa inhibitors that do not require therapeutic monitoring. In this review, we discuss the pharmacology and growing clinical evidence for traditional and new antiplatelet and anticoagulant therapies.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-010814-124438
2015-01-06
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/55/1/annurev-pharmtox-010814-124438.html?itemId=/content/journals/10.1146/annurev-pharmtox-010814-124438&mimeType=html&fmt=ahah

Literature Cited

  1. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K. 1.  et al. 2012. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380:2095–128 [Google Scholar]
  2. Angiolillo DJ, Ferreiro JL. 2.  2013. Antiplatelet and anticoagulant therapy for atherothrombotic disease: the role of current and emerging agents. Am. J. Cardiovasc. Drugs 13:233–50 [Google Scholar]
  3. Ruggeri ZM, Mendolicchio GL. 3.  2007. Adhesion mechanisms in platelet function. Circ. Res. 100:1673–85 [Google Scholar]
  4. Depta JP, Bhatt DL. 4.  2013. Current uses of aspirin in cardiovascular disease. Hot Topics Cardiol. 8:7–21 [Google Scholar]
  5. 5. Steer. Comm. Physicians' Health Study Res. Group 1989. Final report on the aspirin component of the ongoing Physicians' Health Study. N. Engl. J. Med. 321:129–35 [Google Scholar]
  6. Baigent C, Blackwell L, Collins R, Emberson J, Godwin J. 6.  et al. 2009. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 373:1849–60 [Google Scholar]
  7. Vandvik PO, Lincoff AM, Gore JM, Gutterman DD, Sonnenberg FA. 7.  et al. 2012. 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 [Google Scholar]
  8. Pearson TA, Blair SN, Daniels SR, Eckel RH, Fair JM. 8.  et al. 2002. AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 update: consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases. Circulation 106:388–91 [Google Scholar]
  9. Bell AD, Roussin A, Cartier R, Chan WS, Douketis JD. 9.  et al. 2011. The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society guidelines. Can. J. Cardiol. 27:Suppl. AS1–59 [Google Scholar]
  10. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z. 10.  et al. 2012. European guidelines on cardiovascular disease prevention in clinical practice (version 2012). Eur. Heart J. 33:1635–701 [Google Scholar]
  11. 11. U.S. Prev. Serv. Task Force. 2009. Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann. Intern. Med. 150:396–404 [Google Scholar]
  12. 12. Antithrombotic Trialists' Collab 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 [Google Scholar]
  13. Steinhubl SR, Bhatt DL, Brennan DM, Montalescot G, Hankey GJ. 13.  et al. 2009. Aspirin to prevent cardiovascular disease: the association of aspirin dose and clopidogrel with thrombosis and bleeding. Ann. Intern. Med. 150:379–86 [Google Scholar]
  14. Peters RJ, Mehta SR, Fox KA, Zhao F, Lewis BS. 14.  et al. 2003. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation 108:1682–87 [Google Scholar]
  15. Mehta SR, Bassand JP, Chrolavicius S, Diaz R, Eikelboom JW. 15.  et al. 2010. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N. Engl. J. Med. 363:930–42 [Google Scholar]
  16. Murdoch D, Plosker GL. 16.  2006. Triflusal: a review of its use in cerebral infarction and myocardial infarction, and as thromboprophylaxis in atrial fibrillation. Drugs 66:671–92 [Google Scholar]
  17. Costa J, Ferro JM, Matías-Guiu J, Alvarez-Sabin J, Torres F. 17.  2005. Triflusal for preventing serious vascular events in people at high risk. Stroke 37:2193–95 [Google Scholar]
  18. Tello-Montoliu A, Jover E, Rivera J, Valdes M, Angiolillo DJ, Marin F. 18.  2012. New perspectives in antiplatelet therapy. Curr. Med. Chem. 19:406–27 [Google Scholar]
  19. Bousser MG, Amarenco P, Chamorro A, Fisher M, Ford I. 19.  et al. 2011. Terutroban versus aspirin in patients with cerebral ischaemic events (PERFORM): a randomised, double-blind, parallel-group trial. Lancet 377:2013–22 [Google Scholar]
  20. Neri Serneri GG, Coccheri S, Marubini E, Violi F. 20.  Comm. Investig. Drug Eval. Atheroscler. Vasc. Dis. Diabet. Study Group 2004. Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease: the DAVID study. Eur. Heart J. 25:1845–52 [Google Scholar]
  21. Depta JP, Bhatt DL. 21.  2012. Antiplatelet therapy and proton pump inhibition: cause for concern?. Curr. Opin. Cardiol. 27:642–50 [Google Scholar]
  22. Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA. 22.  et al. 2010. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab. Dispos. 38:92–99 [Google Scholar]
  23. 23. CAPRIE Steer. Comm 1996. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 348:1329–39 [Google Scholar]
  24. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G. 24.  et al. 2001. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N. Engl. J. Med. 345:494–502 [Google Scholar]
  25. Sabatine MS, Cannon CP, Gibson CM, López-Sendón JL, Montalescot G. 25.  et al. 2005. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N. Engl. J. Med. 352:1179–89 [Google Scholar]
  26. Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC. 26.  et al. 2005. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 366:1607–21 [Google Scholar]
  27. Steinhubl SR, Berger PB, Mann JT III, Fry ET, DeLago A. 27.  et al. 2002. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 288:2411–20 [Google Scholar]
  28. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR. 28.  et al. 2006. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N. Engl. J. Med. 354:1706–17 [Google Scholar]
  29. Mehta SR, Tanguay JF, Eikelboom JW, Jolly SS, Joyner CD. 29.  et al. 2010. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 376:1233–43 [Google Scholar]
  30. Gurbel PA, Tantry US. 30.  2006. Drug insight: clopidogrel nonresponsiveness. Nat. Clin. Pract. Cardiovasc. Med. 3:387–95 [Google Scholar]
  31. Tantry US, Bonello L, Aradi D, Price MJ, Jeong YH. 31.  et al. 2013. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J. Am. Coll. Cardiol. 62:2261–73 [Google Scholar]
  32. Taubert D, von Beckerath N, Grimberg G, Lazar A, Jung N. 32.  et al. 2006. Impact of P-glycoprotein on clopidogrel absorption. Clin. Pharmacol. Ther. 80:486–501 [Google Scholar]
  33. Depta JP, Bhatt DL. 33.  2008. Aspirin and platelet adenosine diphosphate receptor antagonists in acute coronary syndromes and percutaneous coronary intervention: role in therapy and strategies to overcome resistance. Am. J. Cardiovasc. Drugs 8:91–112 [Google Scholar]
  34. Bhatt DL. 34.  2007. Intensifying platelet inhibition—navigating between Scylla and Charybdis. N. Engl. J. Med. 357:2078–81 [Google Scholar]
  35. Stone GW, Witzenbichler B, Weisz G, Rinaldi MJ, Neumann FJ. 35.  et al. 2013. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet 382:614–23 [Google Scholar]
  36. Gurbel PA, Erlinge D, Ohman EM, Neely B, Neely M. 36.  et al. 2012. Platelet function during extended prasugrel and clopidogrel therapy for patients with ACS treated without revascularization: the TRILOGY ACS platelet function substudy. JAMA 308:1785–94 [Google Scholar]
  37. Price MJ, Berger PB, Teirstein PS, Tanguay JF, Angiolillo DJ. 37.  et al. 2011. Standard- versus high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 305:1097–105 [Google Scholar]
  38. Collet JP, Cuisset T, Range G, Cayla G, Elhadad S. 38.  et al. 2012. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N. Engl. J. Med. 367:2100–9 [Google Scholar]
  39. Trenk D, Stone GW, Gawaz M, Kastrati A, Angiolillo DJ. 39.  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. 59:2159–64 [Google Scholar]
  40. Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA. 40.  et al. 2011. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J. Am. Coll. Cardiol. 58:e44–122 [Google Scholar]
  41. Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR. 41.  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. J. Am. Coll. Cardiol. 60:645–81 [Google Scholar]
  42. Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E. 42.  et al. 2011. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur. Heart J. 32:2999–3054 [Google Scholar]
  43. Depta JP, Bhatt DL. 43.  2010. Omeprazole and clopidogrel: Should clinicians be worried?. Clevel. Clin. J. Med. 77:113–16 [Google Scholar]
  44. Shi S, Klotz U. 44.  2008. Proton pump inhibitors: an update of their clinical use and pharmacokinetics. Eur. J. Clin. Pharmacol. 64:935–51 [Google Scholar]
  45. Frelinger AL III, Lee RD, Mulford DJ, Wu J, Nudurupati S. 45.  et al. 2012. A randomized, 2-period, crossover design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers. J. Am. Coll. Cardiol. 59:1304–11 [Google Scholar]
  46. Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A. 46.  et al. 2010. Clopidogrel with or without omeprazole in coronary artery disease. N. Engl. J. Med. 363:1909–17 [Google Scholar]
  47. Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FK. 47.  et al. 2008. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J. Am. Coll. Cardiol. 52:1502–17 [Google Scholar]
  48. Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ. 48.  et al. 2010. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. Circulation 122:2619–33 [Google Scholar]
  49. Galper BZ, Mauri L. 49.  2013. Antiplatelet therapy after coronary stenting. Curr. Treat. Options Cardiovasc. Med. 15:1–10 [Google Scholar]
  50. O'Gara PT, Kushner FG, Ascheim DD, Casey DE, Chung MK. 50.  et al. 2013. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 61:e78–140 [Google Scholar]
  51. Wijns W, Kolh P, Danchin N, Di Mario C, Falk V. 51.  et al. 2010. Guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery. Eur. Heart J. 31:2501–55 [Google Scholar]
  52. Steg PG, James SK, Atar D, Badano LP, Lundqvist CB. 52.  et al. 2012. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force on the management of ST-segment acute myocardial infarction of the European Society of Cardiology (ESC). Eur. Heart J. 33:2569–619 [Google Scholar]
  53. Park SJ, Park DW, Kim YH, Kang SJ, Lee SW. 53.  et al. 2010. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. N. Engl. J. Med. 362:1374–82 [Google Scholar]
  54. Gwon HC, Hahn JY, Park KW, Song YB, Chae IH. 54.  et al. 2012. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: ‘EXCELLENT’ randomized, multicenter study. Circulation 125:505–13 [Google Scholar]
  55. Valgimigli M, Campo G, Monti M, Vranckx P, Percoco G. 55.  et al. 2012. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation 125:2015–26 [Google Scholar]
  56. Feres F, Costa RA, Abizaid A, Leon MB, Marin-Neto JA. 56.  et al. 2013. Three versus twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA 310:2510–22 [Google Scholar]
  57. Mauri L, Kereiakes DJ, Normand SL, Wiviott SD, Cohen DJ. 57.  et al. 2010. Rationale and design of the dual antiplatelet therapy study, a prospective, multicenter, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months of dual antiplatelet therapy in subjects undergoing percutaneous coronary intervention with either drug-eluting stent or bare metal stent placement for the treatment of coronary artery lesions. Am. Heart J. 160:1035–41 [Google Scholar]
  58. Farid NA, Kurihara A, Wrighton SA. 58.  2010. Metabolism and disposition of the thienopyridine antiplatelet drugs ticlopidine, clopidogrel, and prasugrel in humans. J. Clin. Pharmacol. 50:126–42 [Google Scholar]
  59. Jakubowski JA, Winters KJ, Naganuma H, Wallentin L. 59.  2007. Prasugrel: a novel thienopyridine antiplatelet agent: a review of preclinical and clinical studies and the mechanistic basis for its distinct antiplatelet profile. Cardiovasc. Drug Rev. 25:357–74 [Google Scholar]
  60. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W. 60.  et al. 2007. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 357:2001–15 [Google Scholar]
  61. Montalescot G, Wiviott SD, Braunwald E, Murphy SA, Gibson CM. 61.  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 373:723–31 [Google Scholar]
  62. Erlinge D, ten Berg J, Foley D, Angiolillo DJ, Wagner H. 62.  et al. 2012. Reduction in platelet reactivity with prasugrel 5 mg in low-body-weight patients is noninferior to prasugrel 10 mg in higher-body-weight patients: results from the FEATHER trial. J. Am. Coll. Cardiol. 60:2032–40 [Google Scholar]
  63. Erlinge D, Gurbel PA, James S, Lindahl TL, Svensson P. 63.  et al. 2013. Prasugrel 5 mg in the very elderly attenuates platelet inhibition but maintains noninferiority to prasugrel 10 mg in nonelderly patients: the GENERATIONS trial, a pharmacodynamic and pharmacokinetic study in stable coronary artery disease patients. J. Am. Coll. Cardiol. 62:577–83 [Google Scholar]
  64. Montalescot G, Bolognese L, Dudek D, Goldstein P, Hamm C. 64.  et al. 2013. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N. Engl. J. Med. 369:999–1010 [Google Scholar]
  65. Roe MT, Armstrong PW, Fox KA, White HD, Prabhakaran D. 65.  et al. 2012. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N. Engl. J. Med. 367:1297–309 [Google Scholar]
  66. Roe MT, Goodman SG, Ohman EM, Stevens SR, Hochman JS. 66.  et al. 2013. Elderly patients with acute coronary syndromes managed without revascularization: insights into the safety of long-term dual antiplatelet therapy with reduced-dose prasugrel versus standard-dose clopidogrel. Circulation 128:823–33 [Google Scholar]
  67. Wiviott SD, White HD, Ohman EM, Fox KA, Armstrong PW. 67.  et al. 2013. Prasugrel versus clopidogrel for patients with unstable angina or non-ST-segment elevation myocardial infarction with or without angiography: a secondary, prespecified analysis of the TRILOGY ACS trial. Lancet 382:605–13 [Google Scholar]
  68. Capodanno D, Dharmashankar K, Angiolillo DJ. 68.  2010. Mechanism of action and clinical development of ticagrelor, a novel platelet ADP P2Y12 receptor antagonist. Expert Rev. Cardiovasc. Ther. 8:151–58 [Google Scholar]
  69. Gurbel PA, Bliden KP, Butler K, Tantry US, Gesheff T. 69.  et al. 2009. 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 120:2577–85 [Google Scholar]
  70. Capodanno D, Ferreiro JL, Angiolillo DJ. 70.  2013. Antiplatelet therapy: new pharmacological agents and changing paradigms. J. Thromb. Haemost. 11:Suppl. 1316–29 [Google Scholar]
  71. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H. 71.  et al. 2009. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 361:1045–57 [Google Scholar]
  72. Mahaffey KW, Wojdyla DM, Carroll K, Becker RC, Storey RF. 72.  et al. 2011. Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 124:544–54 [Google Scholar]
  73. 73. US Food Drug Admin 2011. FDA approves blood-thinning drug Brilinta to treat acute coronary syndromes: boxed warning says daily aspirin doses above 100 milligrams decrease effectiveness Washington, DC: US Food Drug Admin http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm263964.htm
  74. Kohli P, Udell JA, Murphy SA, Cannon CP, Antman EM. 74.  et al. 2014. Discharge aspirin dose and clinical outcomes in patients with acute coronary syndromes treated with prasugrel versus clopidogrel: an analysis from the TRITON-TIMI 38 Study (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis In Myocardial Infarction 38). J. Am. Coll. Cardiol. 63:225–32 [Google Scholar]
  75. Montalescot G, Lassen JF, Hamm CW, Lapostolle F, Silvain J. 75.  et al. 2013. Ambulance or in-catheterization laboratory administration of ticagrelor for primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: rationale and design of the randomized, double-blind Administration of Ticagrelor in the cath Lab or in the Ambulance for New ST elevation myocardial Infarction to open the Coronary artery (ATLANTIC) study. Am. Heart J. 165:515–22 [Google Scholar]
  76. Ueno M, Rao SV, Angiolillo DJ. 76.  2010. Elinogrel: pharmacological principles, preclinical and early phase clinical testing. Future Cardiol. 6:445–53 [Google Scholar]
  77. Angiolillo DJ, Welsh RC, Trenk D, Neumann FJ, Conley PB. 77.  et al. 2012. Pharmacokinetic and pharmacodynamic effects of elinogrel: results of the platelet function substudy from the intravenous and oral administration of elinogrel to evaluate tolerability and efficacy in nonurgent percutaneous coronary intervention patients (INNOVATE-PCI) trial. Circ. Cardiovasc. Interv. 5:347–56 [Google Scholar]
  78. Welsh RC, Rao SV, Zeymer U, Thompson VP, Huber K. 78.  et al. 2012. A randomized, double-blind, active-controlled phase 2 trial to evaluate a novel selective and reversible intravenous and oral P2Y12 inhibitor elinogrel versus clopidogrel in patients undergoing nonurgent percutaneous coronary intervention: the INNOVATE-PCI trial. Circ. Cardiovasc. Interv. 5:336–46 [Google Scholar]
  79. Ferreiro JL, Ueno M, Angiolillo DJ. 79.  2009. Cangrelor: a review on its mechanism of action and clinical development. Expert Rev. Cardiovasc. Ther. 7:1195–201 [Google Scholar]
  80. Harrington RA, Stone GW, McNulty S, White HD, Lincoff AM. 80.  et al. 2009. Platelet inhibition with cangrelor in patients undergoing PCI. N. Engl. J. Med. 361:2318–29 [Google Scholar]
  81. Bhatt DL, Lincoff AM, Gibson CM, Stone GW, McNulty S. 81.  et al. 2009. Intravenous platelet blockade with cangrelor during PCI. N. Engl. J. Med. 361:2330–41 [Google Scholar]
  82. White HD, Chew DP, Dauerman HL, Mahaffey KW, Gibson CM. 82.  et al. 2012. Reduced immediate ischemic events with cangrelor in PCI: a pooled analysis of the CHAMPION trials using the universal definition of myocardial infarction. Am. Heart J. 163:182–90.e4 [Google Scholar]
  83. Bhatt DL, Stone GW, Mahaffey KW, Gibson CM, Steg PG. 83.  et al. 2013. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N. Engl. J. Med. 368:1303–13 [Google Scholar]
  84. Généreux P, Stone GW, Harrington RA, Gibson CM, Steg PG. 84.  et al. 2013. Impact of intra-procedural stent thrombosis during percutaneous coronary intervention: insights from the CHAMPION PHOENIX trial (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention). J. Am. Coll. Cardiol. 63:619–29 [Google Scholar]
  85. Angiolillo DJ, Firstenberg MS, Price MJ, Tummala PE, Hutyra M. 85.  et al. 2012. Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial. JAMA 307:265–74 [Google Scholar]
  86. Meadows TA, Bhatt DL. 86.  2007. Clinical aspects of platelet inhibitors and thrombus formation. Circ. Res. 100:1261–75 [Google Scholar]
  87. Angiolillo DJ, Capodanno D, Goto S. 87.  2010. Platelet thrombin receptor antagonism and atherothrombosis. Eur. Heart J. 31:17–28 [Google Scholar]
  88. Becker RC, Moliterno DJ, Jennings LK, Pieper KS, Pei J. 88.  et al. 2009. Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study. Lancet 373:919–28 [Google Scholar]
  89. Goto S, Yamaguchi T, Ikeda Y, Kato K, Yamaguchi H, Jensen P. 89.  2010. Safety and exploratory efficacy of the novel thrombin receptor (PAR-1) antagonist SCH530348 for non-ST–segment elevation acute coronary syndrome. J. Atheroscler. Thromb. 17:156–64 [Google Scholar]
  90. Tricoci P, Huang Z, Held C, Moliterno DJ, Armstrong PW. 90.  et al. 2012. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N. Engl. J. Med. 366:20–33 [Google Scholar]
  91. Morrow DA, Braunwald E, Bonaca MP, Ameriso SF, Dalby AJ. 91.  et al. 2012. Vorapaxar in the secondary prevention of atherothrombotic events. N. Engl. J. Med. 366:1404–13 [Google Scholar]
  92. Goto S, Ogawa H, Takeuchi M, Flather MD, Bhatt DL. 92.  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. 31:2601–13 [Google Scholar]
  93. O'Donoghue ML, Bhatt DL, Wiviott SD, Goodman SG, Fitzgerald DJ. 93.  et al. 2011. Safety and tolerability of atopaxar in the treatment of patients with acute coronary syndromes: the lessons from antagonizing the cellular effects of Thrombin–Acute Coronary Syndromes Trial. Circulation 123:1843–53 [Google Scholar]
  94. Wiviott SD, Flather MD, O'Donoghue ML, Goto S, Fitzgerald DJ. 94.  et al. 2011. Randomized trial of atopaxar in the treatment of patients with coronary artery disease: the Lessons from Antagonizing the Cellular Effect of Thrombin–Coronary Artery Disease Trial. Circulation 123:1854–63 [Google Scholar]
  95. Gresele P, Momi S, Falcinelli E. 95.  2011. Anti-platelet therapy: phosphodiesterase inhibitors. Br. J. Clin. Pharmacol. 72:634–46 [Google Scholar]
  96. Dinicolantonio JJ, Lavie CJ, Fares H, Menezes AR, O'Keefe JH. 96.  et al. 2013. Meta-analysis of cilostazol versus aspirin for the secondary prevention of stroke. Am. J. Cardiol. 112:1230–34 [Google Scholar]
  97. ESPRIT Study Group, Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A. 97.  2006. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 367:1665–73 [Google Scholar]
  98. Diener HC, Sacco RL, Yusuf S, Cotton D, Ôunpuu S. 98.  et al. 2008. Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study. Lancet Neurol. 7:875–84 [Google Scholar]
  99. ESPS Group. 99.  1987. The European Stroke Prevention Study (ESPS): principal end-points. Lancet 330:1351–54 [Google Scholar]
  100. Sacco RL, Diener HC, Yusuf S, Cotton D, Ôunpuu S. 100.  et al. 2008. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N. Engl. J. Med. 359:1238–51 [Google Scholar]
  101. Bhatt DL. 101.  2011. Glycoprotein IIb/IIIa inhibitors: Do they still have a role?. J. Am. Coll. Cardiol. 57:1200–1 [Google Scholar]
  102. Hanna EB, Rao SV, Manoukian SV, Saucedo JF. 102.  2010. The evolving role of glycoprotein IIb/IIIa inhibitors in the setting of percutaneous coronary intervention strategies to minimize bleeding risk and optimize outcomes. JACC Cardiovasc. Interv. 3:1209–19 [Google Scholar]
  103. Depta JP, Bhatt DL. 103.  2010. Atherothrombosis and atrial fibrillation: important and often overlapping clinical syndromes. Thromb. Haemost. 104:657–63 [Google Scholar]
  104. Depta JP, Cannon CP, Fonarow GC, Zhao X, Peacock WF. 104.  et al. 2009. Patient characteristics associated with the choice of triple antithrombotic therapy in acute coronary syndromes. Am. J. Cardiol. 104:1171–78 [Google Scholar]
  105. Lip GYH, Huber K, Andreotti F, Arnesen H, Airaksinen KJ. 105.  et al. 2010. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/stenting. Thromb. Haemost. 103:13–28 [Google Scholar]
  106. Dewilde WJM, Oirbans T, Verheugt FWA, Kelder JC, De Smet BJGL. 106.  et al. 2013. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 381:1107–15 [Google Scholar]
  107. Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR. 107.  et al. 2008. Bivalirudin during primary PCI in acute myocardial infarction. N. Engl. J. Med. 358:2218–30 [Google Scholar]
  108. Mehran R, Lansky AJ, Witzenbichler B, Guagliumi G, Peruga JZ. 108.  et al. 2009. Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year results of a randomised controlled trial. Lancet 374:1149–59 [Google Scholar]
  109. Schulz S, Kastrati A, Ferenc M, Massberg S, Birkmeier KA. 109.  et al. 2013. One-year outcomes with abciximab and unfractionated heparin versus bivalirudin during percutaneous coronary interventions in patients with non-ST-segment elevation myocardial infarction: updated results from the ISAR-REACT 4 trial. Eurointervention 9:430–36 [Google Scholar]
  110. Steg PG, van ‘t Hof A, Hamm CW, Clemmensen P, Lapostolle F. 110.  et al. 2013. Bivalirudin started during emergency transport for primary PCI. N. Engl. J. Med. 369:2207–17 [Google Scholar]
  111. Kirtane AJ, Sandhu P, Mehran R, McEntegart M, Cristea E. 111.  et al. 2014. Association between intraprocedural thrombotic events and adverse outcomes after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction (a Harmonizing Outcomes With RevasculariZatiON and Stents in Acute Myocardial Infarction [HORIZONS-AMI] Substudy). Am. J. Cardiol. 113:36–43 [Google Scholar]
  112. Shahzad A, Kemp I, Mars C, Wilson K, Roome C. 112.  et al. 2014. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet 3841849–58
  113. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J. 113.  et al. 2009. Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 361:1139–51 [Google Scholar]
  114. Lip GYH, Clemens A, Noack H, Ferreira J, Connolly SJ, Yusuf S. 114.  2013. Patient outcomes using the European label for dabigatran: a post-hoc analysis from the RE-LY database. Thromb. Haemost. 111:933–42 [Google Scholar]
  115. Connolly SJ, Wallentin L, Ezekowitz MD, Eikelboom J, Oldgren J. 115.  et al. 2013. The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) study. Circulation 128:237–43 [Google Scholar]
  116. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE. 116.  et al. 2011. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N. Engl. J. Med. 365:883–91 [Google Scholar]
  117. Bauersachs R, Berkowitz SD, Brenner B, Büller HR, Decousus H. 117.  et al. 2010. Oral rivaroxaban for symptomatic venous thromboembolism. N. Engl. J. Med. 363:2499–510 [Google Scholar]
  118. Büller HR, Prins MH, Lensin AWA, Decousus H, Jacobson BF. 118.  et al. 2012. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N. Engl. J. Med. 366:1287–97 [Google Scholar]
  119. Mega JL, Braunwald E, Mohanavelu S, Burton P, Poulter R. 119.  et al. 2009. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 374:29–38 [Google Scholar]
  120. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL. 120.  et al. 2012. Rivaroxaban in patients with a recent acute coronary syndrome. N. Engl. J. Med. 366:9–19 [Google Scholar]
  121. Gibson CM, Chakrabarti AK, Mega J, Bode C, Bassand JP. 121.  et al. 2013. Reduction of stent thrombosis in patients with acute coronary syndromes treated with rivaroxaban in ATLAS-ACS 2 TIMI 51. J. Am. Coll. Cardiol. 62:286–90 [Google Scholar]
  122. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS. 122.  et al. 2013. Oral apixaban for the treatment of acute venous thromboembolism. N. Engl. J. Med. 369:799–808 [Google Scholar]
  123. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM. 123.  et al. 2011. Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 365:981–92 [Google Scholar]
  124. Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R. 124.  et al. 2011. Apixaban in patients with atrial fibrillation. N. Engl. J. Med. 364:806–17 [Google Scholar]
  125. Alexander JH, Lopes RD, James S, Kilaru R, He Y. 125.  et al. 2011. Apixaban with antiplatelet therapy after acute coronary syndrome. N. Engl. J. Med. 365:699–708 [Google Scholar]
  126. Cohen M, Bhatt DL, Alexander JH, Montalescot G, Bode C. 126.  et al. 2007. Randomized, double-blind, dose-ranging study of otamixaban, a novel, parenteral, short-acting direct factor Xa inhibitor, in percutaneous coronary intervention: the SEPIA-PCI trial. Circulation 115:2642–51 [Google Scholar]
  127. Sabatine MS, Antman EM, Widimsky P, Ebrahim IO, Kiss RG. 127.  et al. 2009. Otamixaban for the treatment of patients with non-ST-elevation acute coronary syndromes (SEPIA-ACS1 TIMI 42): a randomised, double-blind, active-controlled, phase 2 trial. Lancet 374:787–95 [Google Scholar]
  128. Steg PG, Mehta SR, Pollack CV Jr, Bode C, Cohen M. 128.  et al. 2013. Anticoagulation with otamixaban and ischemic events in non-ST-segment elevation acute coronary syndromes: the TAO randomized clinical trial. JAMA 310:1145–55 [Google Scholar]
  129. Dyke CK, Steinhubl SR, Kleiman NS, Cannon RO, Aberle LG. 129.  et al. 2006. First-in-human experience of an antidote-controlled anticoagulant using RNA aptamer technology: a phase 1a pharmacodynamic evaluation of a drug-antidote pair for the controlled regulation of factor IXa activity. Circulation 114:2490–97 [Google Scholar]
  130. Povsic TJ, Vavalle JP, Aberle LH, Kasprzak JD, Cohen MG. 130.  et al. 2013. A Phase 2, randomized, partially blinded, active-controlled study assessing the efficacy and safety of variable anticoagulation reversal using the REG1 system in patients with acute coronary syndromes: results of the RADAR trial. Eur. Heart J. 34:2481–89 [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-010814-124438
Loading
/content/journals/10.1146/annurev-pharmtox-010814-124438
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error