GEMINI-ACS-1: toward unearthing the antithrombotic therapy cornerstone for acute coronary syndromes
2017; Elsevier BV; Volume: 389; Issue: 10081 Linguagem: Inglês
10.1016/s0140-6736(17)30760-2
ISSN1474-547X
AutoresPaul A. Gurbel, Udaya S. Tantry,
Tópico(s)Atrial Fibrillation Management and Outcomes
ResumoThe cornerstone of acute coronary syndrome therapy was firmly laid when ISIS-2 showed a 23% reduction in vascular death with aspirin versus placebo. 1 ISIS-2 ISIS-2 (Second International Study of Infarct Survival) Collaborative GroupRandomised 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 PubMed Google Scholar The antithombotic effect of aspirin is largely explained by inhibition of COX 1, a central enzyme mediating platelet activation. This and pleotropic cardioprotective properties should be considered before forsaking or replacing aspirin, particularly early in the highly prothrombotic state of a new acute coronary syndrome (panel). 2 Tantry US Mahla E Gurbel PA Aspirin resistance. Prog Cardiovasc Dis. 2009; 52: 141-152 Summary Full Text Full Text PDF PubMed Scopus (74) Google Scholar , 3 Undas A Brummel-Ziedins KE Mann KG Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions. Blood. 2007; 109: 2285-2292 Crossref PubMed Scopus (187) Google Scholar The enhanced antithrombotic effect of combining aspirin with clopidogrel, an inhibitor of the P2Y12 receptor, another key pathway of platelet activation, revolutionised treatment of acute coronary syndromes. 10 Cadroy Y Bossavy JP Thalamas C et al. Early potent antithrombotic effect with combined aspirin and a loading dose of clopidogrel on experimental arterial thrombogenesis in humans. Circulation. 2000; 101: 2823-2828 Crossref PubMed Scopus (234) Google Scholar Dual antiplatelet therapy (DAPT) then became the standard of care for patients with high risk coronary artery disease and efficacy was increased with more potent P2Y12 inhibition by prasugrel and ticagrelor. 4 Gurbel PA Tantry US Combination antithrombotic therapies. Circulation. 2010; 121: 569-583 Crossref PubMed Scopus (100) Google Scholar , 11 Wiviott SD Braunwald E McCabe CH et al. for the TRITON-TIMI 38 InvestigatorsPrasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007; 357: 2001-2015 Crossref PubMed Scopus (5539) Google Scholar , 12 Wallentin L Becker RC Budaj A et al. PLATO InvestigatorsTicagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009; 361: 1045-1057 Crossref PubMed Scopus (5517) Google Scholar The major downside of aspirin is bleeding, notably gastrointestinal, that is increased by concomitant P2Y12 blockade. Furthermore, 1 year recurrent ischaemic event rates of about 10% in patients given prasugrel and ticagrelor suggest a ceiling of benefit from high levels of P2Y12 blockade. 4 Gurbel PA Tantry US Combination antithrombotic therapies. Circulation. 2010; 121: 569-583 Crossref PubMed Scopus (100) Google Scholar , 11 Wiviott SD Braunwald E McCabe CH et al. for the TRITON-TIMI 38 InvestigatorsPrasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007; 357: 2001-2015 Crossref PubMed Scopus (5539) Google Scholar , 12 Wallentin L Becker RC Budaj A et al. PLATO InvestigatorsTicagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009; 361: 1045-1057 Crossref PubMed Scopus (5517) Google Scholar Unlike aspirin, which inhibits only the thromboxane (Tx)A2-dependent pathway of platelet activation, ticagrelor and prasugrel inhibit both the P2Y12-dependent and TxA2-dependent pathways. These data suggest that aspirin only provides limited additional antiplatelet effects when P2Y12 is potently blocked. 5 Kirkby NS Leadbeater PD Chan MV et al. Antiplatelet effects of aspirin vary with level of P2Y12 receptor blockade supplied by either ticagrelor or prasugrel. J Thromb Haemost. 2011; 9: 2103-2105 Crossref PubMed Scopus (57) Google Scholar Studies are now exploring aspirin abandonment or replacement with factor Xa inhibitors that inhibit the so-called thrombin pathway. 13 Vranckx P Valgimigli M Windecker S 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. 2016; 12: 1239-1245 Crossref PubMed Scopus (92) Google Scholar , 14 Baber U Dangas G Cohen DJ 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 Summary Full Text Full Text PDF PubMed Scopus (90) Google Scholar In addition to amplifying thrombin generation, factor Xa elicited a proinflammatory response by directly activating PAR-1 and PAR-2 receptors and its inhibition improved left ventricular function after ischaemia reperfusion suggesting pleiotropic effects (panel). 6 Esmon CT Targeting factor Xa and thrombin: impact on coagulation and beyond. Thromb Haemost. 2014; 111: 625-723 Crossref PubMed Scopus (94) Google Scholar , 7 Goto M Miura S Suematsu Y et al. Rivaroxaban, a factor Xa inhibitor, induces the secondary prevention of cardiovascular events after myocardial ischemia reperfusion injury in mice. Int J Cardiol. 2016; 220: 602-607 Summary Full Text Full Text PDF PubMed Scopus (21) Google Scholar In the landmark ATLAS ACS-2 trial, low dose rivaroxaban (2·5 mg twice a day), a factor Xa inhibitor, added to aspirin and clopidogrel, reduced major cardiovascular adverse events in patients with recent acute coronary syndromes, but with more than two-fold increased major bleeding. 8 Mega JL Braunwald E Wiviott SD et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012; 366: 9-19 Crossref PubMed Scopus (1582) Google Scholar PanelBenefits and limitations of aspirin and rivaroxabanAspirin therapy Benefits •Predictable inhibition of important platelet activation pathway, COX 1 •Attenuates amplification of platelet activation in response to other agonists •Pleotropic cardioprotective effects: •Dose-dependent inhibition of ADP and collagen-induced aggregation •Inhibition of thrombin generation. •Increased fibrin clot permeability and lysis •Inhibition of proinflammatory signalling 2 Tantry US Mahla E Gurbel PA Aspirin resistance. Prog Cardiovasc Dis. 2009; 52: 141-152 Summary Full Text Full Text PDF PubMed Scopus (74) Google Scholar , 3 Undas A Brummel-Ziedins KE Mann KG Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions. Blood. 2007; 109: 2285-2292 Crossref PubMed Scopus (187) Google Scholar •Cost far less than rivaroxiban Limitations •Gastrointestinal bleeding 4 Gurbel PA Tantry US Combination antithrombotic therapies. Circulation. 2010; 121: 569-583 Crossref PubMed Scopus (100) Google Scholar •Increased bleeding with P2Y12 receptor inhibitor or other antithrombotic agent 4 Gurbel PA Tantry US Combination antithrombotic therapies. Circulation. 2010; 121: 569-583 Crossref PubMed Scopus (100) Google Scholar •Minimal additional antiplatelet effect in presence of potent P2Y12 receptor inhibitor 5 Kirkby NS Leadbeater PD Chan MV et al. Antiplatelet effects of aspirin vary with level of P2Y12 receptor blockade supplied by either ticagrelor or prasugrel. J Thromb Haemost. 2011; 9: 2103-2105 Crossref PubMed Scopus (57) Google Scholar Rivaroxaban Benefits •Attenuation of thrombin generation 6 Esmon CT Targeting factor Xa and thrombin: impact on coagulation and beyond. Thromb Haemost. 2014; 111: 625-723 Crossref PubMed Scopus (94) Google Scholar •Anti-inflammatory effects: •Inhibition of PAR-1 and PAR-2 mediated signalling 6 Esmon CT Targeting factor Xa and thrombin: impact on coagulation and beyond. Thromb Haemost. 2014; 111: 625-723 Crossref PubMed Scopus (94) Google Scholar •Pleotropic effects: •Attenuation inflammation and left ventricular damage after ischaemia reperfusion injury 7 Goto M Miura S Suematsu Y et al. Rivaroxaban, a factor Xa inhibitor, induces the secondary prevention of cardiovascular events after myocardial ischemia reperfusion injury in mice. Int J Cardiol. 2016; 220: 602-607 Summary Full Text Full Text PDF PubMed Scopus (21) Google Scholar •Increased efficacy when added to DAPT 8 Mega JL Braunwald E Wiviott SD et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012; 366: 9-19 Crossref PubMed Scopus (1582) Google Scholar Limitations •Unknown role of low dose in attenuating platelet function/thrombotic risk in highly thrombotic state such as ACS when added to P2Y12 inhibitor alone 9 Ohman EM Roe MT Steg PG et al. Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial. Lancet. 2017; (published online March 18.)http://dx.doi.org/10.1016/S0140-6736(17)30751-1 Summary Full Text Full Text PDF PubMed Scopus (160) Google Scholar •Increased bleeding when added to DAPT 8 Mega JL Braunwald E Wiviott SD et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012; 366: 9-19 Crossref PubMed Scopus (1582) Google Scholar •Possible increased bleeding risk when added to P2Y12 inhibitor alone 9 Ohman EM Roe MT Steg PG et al. Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial. Lancet. 2017; (published online March 18.)http://dx.doi.org/10.1016/S0140-6736(17)30751-1 Summary Full Text Full Text PDF PubMed Scopus (160) Google Scholar •Cost far more than than asprin ACS=acute coronary syndromes. ADP=adenosine diphosphate. COX 1=cyclooxygenase 1. DAPT=dual antiplatelet therapy. PAR=protease activated receptor. Aspirin therapy Benefits •Predictable inhibition of important platelet activation pathway, COX 1 •Attenuates amplification of platelet activation in response to other agonists •Pleotropic cardioprotective effects: •Dose-dependent inhibition of ADP and collagen-induced aggregation •Inhibition of thrombin generation. •Increased fibrin clot permeability and lysis •Inhibition of proinflammatory signalling 2 Tantry US Mahla E Gurbel PA Aspirin resistance. Prog Cardiovasc Dis. 2009; 52: 141-152 Summary Full Text Full Text PDF PubMed Scopus (74) Google Scholar , 3 Undas A Brummel-Ziedins KE Mann KG Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions. Blood. 2007; 109: 2285-2292 Crossref PubMed Scopus (187) Google Scholar •Cost far less than rivaroxiban Limitations •Gastrointestinal bleeding 4 Gurbel PA Tantry US Combination antithrombotic therapies. Circulation. 2010; 121: 569-583 Crossref PubMed Scopus (100) Google Scholar •Increased bleeding with P2Y12 receptor inhibitor or other antithrombotic agent 4 Gurbel PA Tantry US Combination antithrombotic therapies. Circulation. 2010; 121: 569-583 Crossref PubMed Scopus (100) Google Scholar •Minimal additional antiplatelet effect in presence of potent P2Y12 receptor inhibitor 5 Kirkby NS Leadbeater PD Chan MV et al. Antiplatelet effects of aspirin vary with level of P2Y12 receptor blockade supplied by either ticagrelor or prasugrel. J Thromb Haemost. 2011; 9: 2103-2105 Crossref PubMed Scopus (57) Google Scholar Rivaroxaban Benefits •Attenuation of thrombin generation 6 Esmon CT Targeting factor Xa and thrombin: impact on coagulation and beyond. Thromb Haemost. 2014; 111: 625-723 Crossref PubMed Scopus (94) Google Scholar •Anti-inflammatory effects: •Inhibition of PAR-1 and PAR-2 mediated signalling 6 Esmon CT Targeting factor Xa and thrombin: impact on coagulation and beyond. Thromb Haemost. 2014; 111: 625-723 Crossref PubMed Scopus (94) Google Scholar •Pleotropic effects: •Attenuation inflammation and left ventricular damage after ischaemia reperfusion injury 7 Goto M Miura S Suematsu Y et al. Rivaroxaban, a factor Xa inhibitor, induces the secondary prevention of cardiovascular events after myocardial ischemia reperfusion injury in mice. Int J Cardiol. 2016; 220: 602-607 Summary Full Text Full Text PDF PubMed Scopus (21) Google Scholar •Increased efficacy when added to DAPT 8 Mega JL Braunwald E Wiviott SD et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012; 366: 9-19 Crossref PubMed Scopus (1582) Google Scholar Limitations •Unknown role of low dose in attenuating platelet function/thrombotic risk in highly thrombotic state such as ACS when added to P2Y12 inhibitor alone 9 Ohman EM Roe MT Steg PG et al. Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial. Lancet. 2017; (published online March 18.)http://dx.doi.org/10.1016/S0140-6736(17)30751-1 Summary Full Text Full Text PDF PubMed Scopus (160) Google Scholar •Increased bleeding when added to DAPT 8 Mega JL Braunwald E Wiviott SD et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012; 366: 9-19 Crossref PubMed Scopus (1582) Google Scholar •Possible increased bleeding risk when added to P2Y12 inhibitor alone 9 Ohman EM Roe MT Steg PG et al. Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial. Lancet. 2017; (published online March 18.)http://dx.doi.org/10.1016/S0140-6736(17)30751-1 Summary Full Text Full Text PDF PubMed Scopus (160) Google Scholar •Cost far more than than asprin ACS=acute coronary syndromes. ADP=adenosine diphosphate. COX 1=cyclooxygenase 1. DAPT=dual antiplatelet therapy. PAR=protease activated receptor. Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trialA dual pathway antithrombotic therapy approach combining low-dose rivaroxaban with a P2Y12 inhibitor for the treatment of patients with acute coronary syndromes had similar risk of clinically significant bleeding as aspirin and a P2Y12 inhibitor. A larger, adequately powered trial would be required to definitively assess the efficacy and safety of this approach. Full-Text PDF
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