- Email: [email protected]
GEMINI-ACS-1: toward unearthing the antithrombotic therapy cornerstone for acute coronary syndromes
Comment
GEMINI-ACS-1: toward unearthing the antithrombotic therapy cornerstone for acute coronary syndromes The cornerstone of acute coronary syndrome therapy was firmly laid when ISIS-2 showed a 23% reduction in vascular death with aspirin versus placebo.1 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).2,3 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 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.4,11,12 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.4,11,12 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 Studies are now exploring aspirin abandonment or replacement with factor Xa inhibitors that inhibit the so-called thrombin pathway.13,14 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).6,7 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 Building on ATLAS-ACS 2 and the above evidence supporting aspirin abandonment, E Magnus Ohman and colleagues9 report in The Lancet results from the randomised GEMINI-ACS-1 trial, the first large attempt (n=3037 patients from 371 sites in 21 countries) to replace the acute coronary syndrome therapy
Published Online March 18, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)30760-2 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(17)30751-1
Panel: Benefits and limitations of aspirin and rivaroxaban 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 signalling2,3 • Cost far less than rivaroxiban Limitations • Gastrointestinal bleeding4 • Increased bleeding with P2Y12 receptor inhibitor or other antithrombotic agent4 • Minimal additional antiplatelet effect in presence of potent P2Y12 receptor inhibitor5
Rivaroxaban Benefits • Attenuation of thrombin generation6 • Anti-inflammatory effects: • Inhibition of PAR-1 and PAR-2 mediated signalling6 • Pleotropic effects: • Attenuation inflammation and left ventricular damage after ischaemia reperfusion injury7 • Increased efficacy when added to DAPT8 Limitations • Unknown role of low dose in attenuating platelet function/thrombotic risk in highly thrombotic state such as ACS when added to P2Y12 inhibitor alone9 • Increased bleeding when added to DAPT8 • Possible increased bleeding risk when added to P2Y12 inhibitor alone9 • 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.
www.thelancet.com Published online March 18, 2017 http://dx.doi.org/10.1016/S0140-6736(17)30760-2
1
Comment
cornerstone. The investigators and sponsor should be congratulated for conducting thoughtful and exciting research. Their primary aim was to examine the safety of ATLAS ACS-2 low dose rivaroxaban (2·5 mg twice daily)—a quarter of the daily dose for atrial fibrillation—compared with 100 mg daily aspirin on top of clopidogrel or ticagrelor. 1518 patients were randomly assigned to receive aspirin and 1519 to receive rivaroxaban within 10 days after admission for the index acute coronary syndromes and received a minimum of 180 days of treatment. The primary endpoint was thrombolysis in myocardial infarction (TIMI) clinically significant bleeding not related to coronary artery bypass grafting (major, minor, or requiring medical attention). GEMINI-ACS-1 enrolled patients representing a very high risk white population (2824 [93%]); 2707 (89%) had myocardial infarction and 2581 (85%) were stented. Importantly, patients were on stable DAPT (>48 h) by the time of randomisation. Randomised therapy was started a median of 5·5 days after the index event and continued for a median of 291 days. To derive the sample size, an observed hazard ratio (HR) of 1·0 between rivaroxaban and aspirin would have an upper bound of the 95% CI of 1·4 with 170 bleeding events; 154 events occurred. Genetic testing for clopidogrel poor metaboliser status was done and the results are not yet reported. The primary endpoint was similar between groups and occurred in 80 (5%) patients in the rivaroxaban group and 74 (5%) patients in the aspirin group (HR 1·09 [95% CI 0·80–1·50]; p=0·58) with no interaction between randomised treatment and P2Y12 inhibitor type. But, almost all bleeding metrics were non-significantly lower with aspirin and a 50% increased bleed rate with rivaroxaban cannot be excluded. The primary endpoint was non-significantly higher with ticagrelor versus clopidogrel, irrespective of aspirin or rivaroxaban therapy. Although clearly undersized for ischaemic events, the composite exploratory ischaemic endpoint (cardiovascular death, myocardial infarction, stroke, or definite stent thrombosis) was similar in both groups (76 patients [5%] in the rivaroxaban group vs 72 [5%] patients in the aspirin group; HR 1·06 [95% CI 0·77–1·46]; p=0·73). However, in a post-hoc analysis, rivaroxaban was associated with non-significantly higher occurrence of the ischaemic composite endpoint in the first 30 days (HR 1·48 [95% CI 0·80–2·73); 2
p=0·216). This finding is notable and might be explained by the strong effect of platelet function on thrombosis in this time period. Numerically, the lowest composite ischaemic endpoint rate was noted with aspirin plus ticagrelor therapy (ticagrelor plus aspirin=3·9%; ticagrelor plus rivaroxaban=4·7%; clopidogrel plus rivaroxaban=5·4%; and clopidogrel plus aspirin=5·9%).9 Thus, it might be premature to believe that a low dose Xa inhibitor on top of a P2Y12 inhibitor can be effective and safe therapy for most stabilised patients with acute coronary syndromes. The totality of the evidence of GEMINI-ACS-1 favours aspirin. We agree with the investigators that current adverse event rates in patients with acute coronary syndromes are unacceptable and mandate investigations of novel treatment strategies. However, a clearer mechanistic understanding of how so-called thrombin pathway inhibition compares with TxA2-dependent pathway inhibition on top of P2Y12 inhibition seems necessary before undertaking larger attempts to replace the cornerstone. In-depth phenotyping of haemostasis pathways to identify the optimal candidate for Xa and platelet inhibition, instead of a largely one-size-fits-all approach, could advance this field. Until we have more convincing evidence, aspirin remains the cornerstone on which P2Y12 blockade is added to treat the highly prothrombotic state of acute coronary syndromes. *Paul A Gurbel, Udaya S Tantry Inova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, Falls Church, VA 22042, USA (PAG, UST); Johns Hopkins University School of Medicine, Baltimore, MD, USA (PAG); and Duke University School of Medicine, Durham, NC, USA (PAG) [email protected] PAG has received consulting honoraria from AstraZeneca, Boehringer, Merck, Janssen, and Bayer for advice on the design of pharmacodynamic and clinical trials and from Haemonetics on the design of clinical trials; has received research grants from Haemonetics to evaluate point-of-care determination of thrombogenicity, DCRI to study the effect of therapy to raise HDL, Merck to study the effects of vorapaxar, National Institutes of Health to study the effects of a novel parenteral PAR-1 blocker, Bayer to study the interaction of naproxen sodium and aspirin, Medimmune to study the effect of recombinant LCAT, and Coramed to study a point-of-care device that assesses thrombogenicity; and has patents on platelet function testing (patent numbers: 8058023, 8070678, 9188597, 9110062, 8440420). UST declares no competing interests. 1
2
ISIS-2 ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. 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: 349–60. Tantry US, Mahla E, Gurbel PA. Aspirin resistance. Prog Cardiovasc Dis 2009; 52: 141–52.
www.thelancet.com Published online March 18, 2017 http://dx.doi.org/10.1016/S0140-6736(17)30760-2
Comment
3 4 5 6 7
8 9
Undas A, Brummel-Ziedins KE, Mann KG. Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions. Blood 2007; 109: 2285–92. Gurbel PA, Tantry US. Combination antithrombotic therapies. Circulation 2010; 121: 569–83. 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: 2103–05. Esmon CT. Targeting factor Xa and thrombin: impact on coagulation and beyond. Thromb Haemost 2014; 111: 625–23. 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: 602–07. 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. 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.
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: 2823–28. 11 Wiviott SD, Braunwald E, McCabe CH, et al, for the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001–15. 12 Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045–57. 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: 1239–45. 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: 125–34
www.thelancet.com Published online March 18, 2017 http://dx.doi.org/10.1016/S0140-6736(17)30760-2
3
GEMINI-ACS-1: toward unearthing the antithrombotic therapy cornerstone for acute coronary syndromes The cornerstone of acute coronary syndrome therapy was firmly laid when ISIS-2 showed a 23% reduction in vascular death with aspirin versus placebo.1 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).2,3 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 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.4,11,12 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.4,11,12 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 Studies are now exploring aspirin abandonment or replacement with factor Xa inhibitors that inhibit the so-called thrombin pathway.13,14 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).6,7 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 Building on ATLAS-ACS 2 and the above evidence supporting aspirin abandonment, E Magnus Ohman and colleagues9 report in The Lancet results from the randomised GEMINI-ACS-1 trial, the first large attempt (n=3037 patients from 371 sites in 21 countries) to replace the acute coronary syndrome therapy
Published Online March 18, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)30760-2 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(17)30751-1
Panel: Benefits and limitations of aspirin and rivaroxaban 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 signalling2,3 • Cost far less than rivaroxiban Limitations • Gastrointestinal bleeding4 • Increased bleeding with P2Y12 receptor inhibitor or other antithrombotic agent4 • Minimal additional antiplatelet effect in presence of potent P2Y12 receptor inhibitor5
Rivaroxaban Benefits • Attenuation of thrombin generation6 • Anti-inflammatory effects: • Inhibition of PAR-1 and PAR-2 mediated signalling6 • Pleotropic effects: • Attenuation inflammation and left ventricular damage after ischaemia reperfusion injury7 • Increased efficacy when added to DAPT8 Limitations • Unknown role of low dose in attenuating platelet function/thrombotic risk in highly thrombotic state such as ACS when added to P2Y12 inhibitor alone9 • Increased bleeding when added to DAPT8 • Possible increased bleeding risk when added to P2Y12 inhibitor alone9 • 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.
www.thelancet.com Published online March 18, 2017 http://dx.doi.org/10.1016/S0140-6736(17)30760-2
1
Comment
cornerstone. The investigators and sponsor should be congratulated for conducting thoughtful and exciting research. Their primary aim was to examine the safety of ATLAS ACS-2 low dose rivaroxaban (2·5 mg twice daily)—a quarter of the daily dose for atrial fibrillation—compared with 100 mg daily aspirin on top of clopidogrel or ticagrelor. 1518 patients were randomly assigned to receive aspirin and 1519 to receive rivaroxaban within 10 days after admission for the index acute coronary syndromes and received a minimum of 180 days of treatment. The primary endpoint was thrombolysis in myocardial infarction (TIMI) clinically significant bleeding not related to coronary artery bypass grafting (major, minor, or requiring medical attention). GEMINI-ACS-1 enrolled patients representing a very high risk white population (2824 [93%]); 2707 (89%) had myocardial infarction and 2581 (85%) were stented. Importantly, patients were on stable DAPT (>48 h) by the time of randomisation. Randomised therapy was started a median of 5·5 days after the index event and continued for a median of 291 days. To derive the sample size, an observed hazard ratio (HR) of 1·0 between rivaroxaban and aspirin would have an upper bound of the 95% CI of 1·4 with 170 bleeding events; 154 events occurred. Genetic testing for clopidogrel poor metaboliser status was done and the results are not yet reported. The primary endpoint was similar between groups and occurred in 80 (5%) patients in the rivaroxaban group and 74 (5%) patients in the aspirin group (HR 1·09 [95% CI 0·80–1·50]; p=0·58) with no interaction between randomised treatment and P2Y12 inhibitor type. But, almost all bleeding metrics were non-significantly lower with aspirin and a 50% increased bleed rate with rivaroxaban cannot be excluded. The primary endpoint was non-significantly higher with ticagrelor versus clopidogrel, irrespective of aspirin or rivaroxaban therapy. Although clearly undersized for ischaemic events, the composite exploratory ischaemic endpoint (cardiovascular death, myocardial infarction, stroke, or definite stent thrombosis) was similar in both groups (76 patients [5%] in the rivaroxaban group vs 72 [5%] patients in the aspirin group; HR 1·06 [95% CI 0·77–1·46]; p=0·73). However, in a post-hoc analysis, rivaroxaban was associated with non-significantly higher occurrence of the ischaemic composite endpoint in the first 30 days (HR 1·48 [95% CI 0·80–2·73); 2
p=0·216). This finding is notable and might be explained by the strong effect of platelet function on thrombosis in this time period. Numerically, the lowest composite ischaemic endpoint rate was noted with aspirin plus ticagrelor therapy (ticagrelor plus aspirin=3·9%; ticagrelor plus rivaroxaban=4·7%; clopidogrel plus rivaroxaban=5·4%; and clopidogrel plus aspirin=5·9%).9 Thus, it might be premature to believe that a low dose Xa inhibitor on top of a P2Y12 inhibitor can be effective and safe therapy for most stabilised patients with acute coronary syndromes. The totality of the evidence of GEMINI-ACS-1 favours aspirin. We agree with the investigators that current adverse event rates in patients with acute coronary syndromes are unacceptable and mandate investigations of novel treatment strategies. However, a clearer mechanistic understanding of how so-called thrombin pathway inhibition compares with TxA2-dependent pathway inhibition on top of P2Y12 inhibition seems necessary before undertaking larger attempts to replace the cornerstone. In-depth phenotyping of haemostasis pathways to identify the optimal candidate for Xa and platelet inhibition, instead of a largely one-size-fits-all approach, could advance this field. Until we have more convincing evidence, aspirin remains the cornerstone on which P2Y12 blockade is added to treat the highly prothrombotic state of acute coronary syndromes. *Paul A Gurbel, Udaya S Tantry Inova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, Falls Church, VA 22042, USA (PAG, UST); Johns Hopkins University School of Medicine, Baltimore, MD, USA (PAG); and Duke University School of Medicine, Durham, NC, USA (PAG) [email protected] PAG has received consulting honoraria from AstraZeneca, Boehringer, Merck, Janssen, and Bayer for advice on the design of pharmacodynamic and clinical trials and from Haemonetics on the design of clinical trials; has received research grants from Haemonetics to evaluate point-of-care determination of thrombogenicity, DCRI to study the effect of therapy to raise HDL, Merck to study the effects of vorapaxar, National Institutes of Health to study the effects of a novel parenteral PAR-1 blocker, Bayer to study the interaction of naproxen sodium and aspirin, Medimmune to study the effect of recombinant LCAT, and Coramed to study a point-of-care device that assesses thrombogenicity; and has patents on platelet function testing (patent numbers: 8058023, 8070678, 9188597, 9110062, 8440420). UST declares no competing interests. 1
2
ISIS-2 ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. 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: 349–60. Tantry US, Mahla E, Gurbel PA. Aspirin resistance. Prog Cardiovasc Dis 2009; 52: 141–52.
www.thelancet.com Published online March 18, 2017 http://dx.doi.org/10.1016/S0140-6736(17)30760-2
Comment
3 4 5 6 7
8 9
Undas A, Brummel-Ziedins KE, Mann KG. Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions. Blood 2007; 109: 2285–92. Gurbel PA, Tantry US. Combination antithrombotic therapies. Circulation 2010; 121: 569–83. 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: 2103–05. Esmon CT. Targeting factor Xa and thrombin: impact on coagulation and beyond. Thromb Haemost 2014; 111: 625–23. 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: 602–07. 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. 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.
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: 2823–28. 11 Wiviott SD, Braunwald E, McCabe CH, et al, for the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001–15. 12 Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045–57. 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: 1239–45. 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: 125–34
www.thelancet.com Published online March 18, 2017 http://dx.doi.org/10.1016/S0140-6736(17)30760-2
3