Antithrombotic therapy for acute coronary syndrome: Past, present and future

Summary

Plaque erosions and ruptures are the histopathological hallmarks of arterial thrombus formation in the coronary arteries. The clinical condition associated with this process is usually referred to as acute coronary syndrome (ACS). Importantly, both blood platelets and the coagulation cascade are key players for initiation, amplification and perpetuation of ACS. There has been great progress in ACS treatment in recent decades, both at the technical level of (percutaneous) revascularisation and at the level of antithrombotic treatment. Numerous trials have led to significant advancements in the development of effective anticoagulant and antiplatelet drugs. The large number of randomised controlled clinical trials (RCTs) and the huge number of patients enrolled in these RCTs, with mega trials including >10,000 patients, is unique in the history of medical research and also reflects the exceptional efforts associated with these huge research activities. The crucial issue, however, with respect to optimising treatment, relates to finding the delicate balance between the reduction of thrombotic events by effective drug treatment and the induction of bleeding that is linked to the use of potent or multiple antithrombotic agents. Interestingly, there is a gap in modern days between current guideline recommendations favouring potent platelet inhibition in ACS and the utilization of the respective drugs in clinical practice. In this review, we will summarise and discuss the past, present and future antithrombotic treatment for ACS patients with a focus on the development of optimised antiplatelet treatment strategies and their utilisation in the real world.

Keywords

Acute coronary syndrome - platelets - antiplatelet drugs - coagulation cascade

• References

• 1 Fuster V. et al. The pathogenesis of coronary artery disease and the acute coronary syndromes (2). N Engl J Med 1992; 326: 310-318.
• 2 Roffi M. et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016; 37: 267-315.
• 3 Amsterdam EA. et al. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 64: e139-e228.
• 4 De Caterina R. et al. General mechanisms of coagulation and targets of anticoagulants (Section I). Position Paper of the ESC Working Group on Thrombosis--Task Force on Anticoagulants in Heart Disease. Thromb Haemost 2013; 109: 569-579.
• 5 Nabel EG, Braunwald E. A tale of coronary artery disease and myocardial infarction. N Engl J Med 2012; 366: 54-63.
• 6 Valgimigli M. et al. Bivalirudin or Unfractionated Heparin in Acute Coronary Syndromes. N Engl J Med 2015; 373: 997-1009.
• 7 Shahzad A. et al. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet 2014; 384: 1849-1858.
• 8 Han Y. et al. Bivalirudin vs heparin with or without tirofiban during primary percutaneous coronary intervention in acute myocardial infarction: the BRIGHT randomized clinical trial. J Am Med Assoc 2015; 313: 1336-1346.
• 9 Stone GW. et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006; 355: 2203-2216.
• 10 Stone GW. et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358: 2218-2230.
• 11 Lincoff AM. et al. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularisation: REPLACE-2 randomized trial. J Am Med Assoc 2004; 292: 696-703.
• 12 Kastrati A. et al. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. J Am Med Assoc 2006; 295: 1531-1538.
• 13 Kastrati A. et al. Abciximab and heparin versus bivalirudin for non-ST-elevation myocardial infarction. N Engl J Med 2011; 365: 1980-1989.
• 14 Mega JL. et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366: 9-19.
• 15 Group FO-T. et al. Low-dose vs standard-dose unfractionated heparin for percutaneous coronary intervention in acute coronary syndromes treated with fondaparinux: the FUTURA/OASIS-8 randomized trial. J Am Med Assoc 2010; 304: 1339-1349.
• 16 Schomig A. et al. Mechanical reperfusion in patients with acute myocardial infarction presenting more than 12 hours from symptom onset: a randomized controlled trial. J Am Med Assoc 2005; 293: 2865-2872.
• 17 Steinhubl SR. et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. J Am Med Assoc 2002; 288: 2411-2420.
• 18 Yusuf S. 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.
• 19 Chen ZM. et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005; 366: 1607-1621.
• 20 Sabatine MS. et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005; 352: 1179-1189.
• 21 Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet 1988; 2: 349-360.
• 22 ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. Lancet 1992; 339: 753-770.
• 23 Angiolillo DJ. The evolution of antiplatelet therapy in the treatment of acute coronary syndromes: from aspirin to the present day. Drugs 2012; 72: 2087-2116.
• 24 Ndrepepa G. et al. Periprocedural bleeding and 1-year outcome after percutaneous coronary interventions: appropriateness of including bleeding as a component of a quadruple end point. J Am Coll Cardiol 2008; 51: 690-697.
• 25 Schomig A. et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996; 334: 1084-1089.
• 26 Leon MB. et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998; 339: 1665-1671.
• 27 Bertrand ME. et al. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (fantastic) study. Circulation 1998; 98: 1597-1603.
• 28 Urban P. et al. Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: the multicenter aspirin and ticlopidine trial after intracoronary stenting (MATTIS). Circulation 1998; 98: 2126-2132.
• 29 Mehta SR. 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: 527-533.
• 30 Muller I. et al. Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement. Heart 2001; 85: 92-93.
• 31 Serebruany VL. et al. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005; 45: 246-251.
• 32 Angiolillo DJ. et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 2007; 49: 1505-1516.
• 33 Tantry US. et al. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol 2013; 62: 2261-2273.
• 34 Aradi D. et al. Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention. Eur Heart J 2015; 36: 1762-1771.
• 35 Sibbing D. et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 2009; 53: 849-856.
• 36 Franchi F, Angiolillo DJ. Novel antiplatelet agents in acute coronary syndrome. Nat Rev Cardiol 2015; 12: 30-47.
• 37 Sugidachi A. et al. The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties. Br J Pharmacol 2000; 129: 1439-1446.
• 38 Brandt JT. 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-e16.
• 39 Wiviott SD. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
• 40 Saito S. et al. Efficacy and safety of adjusted-dose prasugrel compared with clopidogrel in Japanese patients with acute coronary syndrome: the PRASFIT-ACS study. Circ J 2014; 78: 1684-1692.
• 41 Zeymer U. et al. Use, efficacy and safety of prasugrel in patients with ST segment elevation myocardial infarction scheduled for primary percutaneous coronary intervention in clinical practice. Results of the prospective ATACS-registry. Int J Cardiol 2015; 184: 122-127.
• 42 Beigel R. et al. Real-World Use of Novel P2Y12 Inhibitors in Patients with Acute Myocardial Infarction: A Treatment Paradox. Cardiology 2017; 136: 21-28.
• 43 Zeymer U. et al. P2Y12 receptor inhibitors in patients with non-ST-elevation acute coronary syndrome in the real world: use, patient selection, and outcomes from contemporary European registries. Eur Heart J Cardiovasc Pharmacother 2016; 2: 229-243.
• 44 Alexopoulos D. et al. Contemporary antiplatelet treatment in acute coronary syndrome patients undergoing percutaneous coronary intervention: 1-year outcomes from the GReek AntiPlatElet (GRAPE) Registry. J Thromb Haemost 2016; 14: 1146-1154.
• 45 Roe MT. et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularisation. N Engl J Med 2012; 367: 1297-1309.
• 46 Husted S. et al. 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: 1038-1047.
• 47 Bonaca MP. et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372: 1791-1800.
• 48 Lindholm D. et al. Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularisation: results from the PLATO trial. Eur Heart J 2014; 35: 2083-2093.
• 49 Wallentin L. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045-1057.
• 50 Serebruany VL. Viewpoint: paradoxical excess mortality in the PLATO trial should be independently verified. Thromb Haemost 2011; 105: 752-759.
• 51 Serebruany VL, Fortmann SD. Viewpoint: “underutilisation of novel antiplatelet agents--myths, generics, and economics„. Thromb Haemost 2014; 112: 4-9.
• 52 Goto S. et al. Ticagrelor vs. clopidogrel in Japanese, Korean and Taiwanese patients with acute coronary syndrome -- randomized, double-blind, phase III PHILO study. Circ J 2015; 79: 2452-2460.
• 53 Sahlen A. et al. Outcomes in patients treated with ticagrelor or clopidogrel after acute myocardial infarction: experiences from SWEDEHEART registry. Eur Heart J 2016; 37: 3335-3342.
• 54 Levine GN. et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016; 68: 1082-1115.
• 55 Steg PG. et al. 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 elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur Heart J 2012; 33: 2569-2619.
• 56 O’Gara PT. et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013; 127: 529-555.
• 57 Authors/Task Force m. et al. 2014 ESC/EACTS Guidelines on myocardial revascularisation: The Task Force on Myocardial Revascularisation of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014; 35: 2541-2619.
• 58 Investigators C-O. et al. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med 2010; 363: 930-942.
• 59 Sarafoff N. et al. Triple therapy with aspirin, prasugrel, and vitamin K antagonists in patients with drug-eluting stent implantation and an indication for oral anticoagulation. J Am Coll Cardiol 2013; 61: 2060-2066.
• 60 Sibbing D, Massberg S. There’s life in the old dog yet: clopidogrel competing with prasugrel and ticagrelor for treatment of ACS patients. Thromb Haemost 2014; 112: 10-11.
• 61 Karve AM. et al. Contemporary Use of Ticagrelor in Interventional Practice (from Blue Cross Blue Shield of Michigan Cardiovascular Consortium). Am J Cardiol 2015; 115: 1502-1506.
• 62 Serebruany VL, DiNicolantonio JJ. Viewpoint: mismatch between the European and American guidelines on oral antiplatelet P2Y12 inhibitors after acute coronary syndromes. Thromb Haemost 2013; 110: 5-10.
• 63 Mauri L. et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014; 371: 2155-2166.
• 64 Sibbing D. et al. Pre-treatment with P2Y12 inhibitors in ACS patients: who, when, why, and which agent?. Eur Heart J 2016; 37: 1284-1295.
• 65 Capodanno D, Angiolillo DJ. Pretreatment with antiplatelet drugs in invasively managed patients with coronary artery disease in the contemporary era: review of the evidence and practice guidelines. Circ Cardiovasc Interv 2015; 8: e002301.
• 66 Montalescot G. et al. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med 2013; 369: 999-1010.
• 67 Montalescot G. et al. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med 2014; 371: 1016-1027.
• 68 Steg PG. et al. Effect of cangrelor on periprocedural outcomes in percutaneous coronary interventions: a pooled analysis of patient-level data. Lancet 2013; 382: 1981-1992.
• 69 Bhatt DL. et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009; 361: 2330-2341.
• 70 Bhatt DL. et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med 2013; 368: 1303-1313.
• 71 Harrington RA. et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 2009; 361: 2318-2329.
• 72 Westman PC. et al. A comparison of cangrelor, prasugrel, ticagrelor, and clopidogrel in patients undergoing percutaneous coronary intervention: A network meta-analysis. Cardiovasc Revasc Med 2016 ; Epub ahead of print.
• 73 Tricoci P. et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med 2012; 366: 20-33.
• 74 Morrow DA. et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 2012; 366: 1404-1413.
• 75 Ndrepepa G. et al. Bivalirudin versus heparin plus a glycoprotein IIb/IIIa inhibitor in patients with non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention after clopidogrel pretreatment: pooled analysis from the ACUITY and ISAR-REACT 4 trials. Circ Cardiovasc Interv 2012; 5: 705-712.
• 76 Stone GW. et al. Bivalirudin versus heparin with or without glycoprotein IIb/IIIa inhibitors in patients with STEMI undergoing primary percutaneous coronary intervention: pooled patient-level analysis from the HORIZONS-AMI and EUROMAX trials. J Am Coll Cardiol 2015; 65: 27-38.
• 77 Cavender MA, Sabatine MS. Bivalirudin versus heparin in patients planned for percutaneous coronary intervention: a meta-analysis of randomised controlled trials. Lancet 2014; 384: 599-606.
• 78 Adamo M. et al. Assessing the cardiology community position on transradial intervention and the use of bivalirudin in patients with acute coronary syndrome undergoing invasive management: results of an EAPCI survey. EuroIntervention 2016; 12: 1154-1163.
• 79 Motovska Z. et al. Prasugrel versus Ticagrelor in Patients with Acute Myocardial Infarction Treated with Primary Percutaneous Coronary Intervention: Multicenter Randomized PRAGUE-18 Study. Circulation 2016 ; Epub ahead of print.
• 80 Bonaca MP, Wiviott SD. Prasugrel Versus Ticagrelor: Uncertainty Remains. Circulation 2016; 134: 1613-1616.
• 81 Schulz S. et al. Randomized comparison of ticagrelor versus prasugrel in patients with acute coronary syndrome and planned invasive strategy--design and rationale of the iNtracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 5 trial. Journal of cardiovascular translational research 2014; 7: 91-100.
• 82 Vranckx P. et al. Long-term ticagrelor monotherapy versus standard dual antiplatelet therapy followed by aspirin monotherapy in patients undergoing biolimus-eluting stent implantation: rationale and design of the GLOBAL LEADERS trial. EuroIntervention 2015; 11.
• 83 Baber U. et al. Ticagrelor with aspirin or alone in high-risk patients after coronary intervention: Rationale and design of the TWILIGHT study. Am Heart J 2016; 182: 125-134.
• 84 Bergmeijer TO. et al. CYP2C19 genotype-guided antiplatelet therapy in ST-segment elevation myocardial infarction patients-Rationale and design of the Patient Outcome after primary PCI (POPular) Genetics study. Am Heart J 2014; 168: 16-22 e1.
• 85 Sibbing D. et al. A randomised trial on platelet function-guided de-escalation of antiplatelet treatment in ACS patients undergoing PCI. Rationale and design of the Testing Responsiveness to Platelet Inhibition on chronic Antiplatelet Treatment for Acute Coronary Syndromes (TROPICAL-ACS) Trial. Thromb Haemost 2017; 117: 188-195.
• 86 Angiolillo DJ. et al. Antithrombotic Therapy in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention: A North American Perspective-2016 Update. Circ Cardiovasc Interv 2016 ; Epub ahead of print.
• 87 Dewilde WJ. et al. 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 2013; 381: 1107-1115.
• 88 Gibson CM. et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med 2016; 375: 2423-2434.
• 89 Urban P. et al. Polymer-free Drug-Coated Coronary Stents in Patients at High Bleeding Risk. N Engl J Med 2015; 373: 2038-2047.