Direct Oral Anticoagulants in Acute Coronary Syndrome Ingo Ahrens and Christoph Bode Patients with acute coronary syndromes (ACS) require a specific antithrombotic therapy in the immediate and the post ACS phase. The current antithrombotic therapy in the acute phase of an ACS combines antiplatelet and anticoagulant drugs in order to reduce ischemic cardiovascular events. In the post ACS phase, dual antiplatelet therapy (DAPT; aspirin and a P2Y12 receptor antagonist) is the current mainstay of antithrombotic treatment and is recommended in the guidelines of the major North American and European clinical cardiology associations (AHA, ACC, and ESC). Recently, the addition of rivaroxaban, a low dose oral direct factor Xa inhibitor (2.5 mg twice daily), to DAPT (aspirin plus second-generation P2Y12 inhibitor) showed a significant reduction of cardiovascular and overall mortality in the major phase III clinical trial ATLAS ACS 2 TIMI 51. This led to the approval of low-dose rivaroxaban in addition to aspirin and clopidogrel by the European Medicines Agency (EMA) in 2013. Other direct oral anticoagulants (apixaban, dabigatran etexilate) have also been assessed in phase II (dabigatran etexilate) and phase III (apixaban) post ACS clinical trials. In the studied dosing regimens, these drugs failed to show a net clinical benefit in addition to dual antiplatelet therapy. The major clinical phase II and III post ACS studies of direct oral anticoagulants are summarized and discussed in this article along with the concept of long-term anticoagulation for the secondary prevention of ischemic events after ACS and implications for the future of antithrombotic therapy in the current era of third-generation P2Y12 receptor inhibitors (Prasugrel and Ticagrelor). Semin Hematol 51:147–151. C 2014 Elsevier Inc. All rights reserved.
T
he acute coronary syndrome (ACS) is characterized by a platelet-mediated activation of the coagulation system (in which platelets do play a central role), which is sustained for a significant period of time following the ACS and may persist for months if not longer in highrisk patients.1 Antithrombotic therapy is the key therapeutic strategy to reduce ischemic cardiovascular adverse events in patients with ACS and represents the umbrella-term for antiplatelet and anticoagulant therapy. Until recently, the recommendations for long-term antithrombotic treatment of patients after an ACS were restricted to antiplatelet therapy. Current clinical guidelines of major cardiology associations (American Heart Association [AHA], American College of Cardiology [ACC], European Society of Cardiology [ESC]) still include the strongest recommendations for a dual antiplatelet therapy (DAPT) consisting of low-dose aspirin
Heart Center, University of Freiburg, Department for Cardiology and Angiology I, Freiburg, Germany Conflicts of interest: IA received speaker’s honoraria from Bayer Healthcare, Lilly, Sanofi Aventis, and Daiichi Sankyo. CB received speaker's honoraria from Bayer Healthcare, Merck, Astra-Zeneca, Daiichi Sankyo, and Sanofi Aventis. Address correspondence to Ingo Ahrens, MD, Heart Center, University of Freiburg, Department for Cardiology and Angiology I, Hugstetter Street 55, 79106 Freiburg, Germany. E-mail: ingo. [email protected] 0037-1963/$ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminhematol.2014.03.004
Seminars in Hematology, Vol 51, No 2, April 2014, pp 147–151
and a P2Y12 receptor inhibitor for 9–12 months. Regarding the P2Y12 receptor inhibitor, current ESC guidelines have a level IB recommendation for the third-generation P2Y12 receptor antagonists (prasugrel and ticagrelor) and should therefore be preferred over the second-generation P2Y12 receptor inhibitor clopidogrel, which has a level IC recommendation.2,3
ANTIPLATELET AND VITAMIN K-ANTAGONIST THERAPY IN THE POST ACS PHASE The hypothesis that long-term oral anticoagulation could be superior to single antiplatelet therapy (aspirin) for the secondary prevention of ischemic events in the post ACS phase has already been assessed in the pre-clopidogrel era. The WARIS II study (The Warfarin, Aspirin, Reinfarction Study) randomized 3630 patients admitted for acute myocardial infarction to Norwegian hospitals after surviving the acute phase to long-term treatment with either aspirin alone (160 mg/d), international normalized ratio (INR)-guided warfarin therapy (INR 2.8–4.2), or aspirin (75 mg/d) plus INR-guided warfarin (INR 2.0–2.5).4 The primary outcome of the study was the composite of death, nonfatal reinfarction, or thromboembolic stroke and was significantly reduced in patients on warfarin alone compared to aspirin alone (16.7% v 20% for warfarin v aspirin, 147
148 respectively, P ¼ .03). In addition, also the combination of warfarin and aspirin did significantly reduce the primary endpoint compared to aspirin alone (15% v 20% for warfarin v aspirin respectively, P ¼ .001).4 However, only 19% (684) of all randomized patients were treated by percutaneous coronary intervention (PCI), which does not allow to transfer the results of this study to non-conservatively treated patients with ACS. Furthermore the benefit that was seen with warfarin treatment was accompanied by a significant increase in major, nonfatal bleeding (0.62% v 0.17% for both warfarin v the aspirin group, respectively, P o.001).4 In a similar clinical trial (ASPECT-2 study) with a lower total patient number (n ¼ 999) conducted in the Netherlands, patients after ACS were randomized to lowdose aspirin, high-intensity oral anticoagulation with a vitamin K antagonist (VKA), or low-dose aspirin plus moderate-intensity oral anticoagulation with a VKA. The primary composite endpoint of myocardial infarction, stroke, or death was reached in 9% of the low-dose aspirin-treated patients. In the high-intensity oral anticoagulant-treated patients and in the combined low-dose aspirin plus moderate-intensity oral anticoagulant–treated patients, there was a significant reduction of the primary endpoint compared to low-dose aspirin (both 5%, P ¼ .048 and P ¼ .03, respectively).5 Both studies (WARIS II and ASPECT-2) have been conducted before the widespread clinical establishment of DAPT and PCI with routine coronary artery stent implantation and have therefore be interpreted with caution. However, these trials did demonstrate that the concept of the combined antiplatelet and anticoagulant therapy in the post ACS phase could be favorable if not outweighed by the incidence of major bleeding events.
DOACs in addition to antiplatelet therapy in the post ACS phase The addition of direct oral anticoagulants (DOACs) to antiplatelet therapy (excluding third- generation P2Y12 receptor antagonists) for the secondary prevention of ischemic events in patients with a recent coronary syndrome has been studied in three clinical phase II (dabigatran etexilate, rivaroxaban, apixaban) and two clinical phase III studies (apixaban and rivaroxaban). The studies and their results are summarized graded by the respective DOAC that has been examined in this indication below.
Dabigatran Etexilate The oral direct thrombin inhibitor dabigatran etexilate (Pradaxa, Boehringer Ingelheim, Ingelheim am Rhein, Germany) has been studied in addition to antiplatelet therapy in the RE-DEEM study, a randomized, doubleblind, placebo-controlled, dose-escalation phase II clinical trial in patients after (r14 days) a ST-segment elevation myocardial infarction (STEMI), or after a non-STsegment elevation myocardial infarction (NSTEMI). A total of 1,861 patients were randomized and almost all
I. Ahrens and C. Bode
patients (99.2%) were receiving dual antiplatelet therapy with aspirin (r100 mg/d) and clopidogrel (75 mg/d). On top of dual antiplatelet therapy, patients were either treated for a period of 6 months with dabigatran 50, 75, 110, or 150 mg twice daily, or placebo, respectively. The primary outcome was the composite of major (definition of the International Society on Thrombosis and Haemostasis, ISTH) or clinically relevant non-major bleeding. The secondary endpoints were reduction in D-dimer levels and cardiovascular ischemic events.6 From all randomized patients, 60% had a recent STEMI and 40% had a recent NSTEMI. The primary endpoint of major or clinically relevant non-major bleeding occurred in a dose-dependent manner in the dabigatran in addition to DAPT-treated patients (3.5%, 4.3%, 7.9%, and 7.8% for the 50, 75, 110, and 150 mg twice-daily dabigatran treatments, respectively), while the bleeding rate in the placebo in addition to DAPT-treated patients was lower (2.2%, Po.001 for a linear trend).6 However, major (according to Thrombolysis in Myocardial Infarction, TIMI criteria) or severe bleeding was low in all dabigatran treatment groups with an absolute increase compared to placebo o1%.6 The secondary efficacy endpoint of D-dimer concentrations was measured after 1 and 4 weeks. D-dimer levels were significantly reduced in all dabigatran treatment groups compared to placebo at 1 and 4 weeks (P o.001). The secondary efficacy endpoint of cardiovascular ischemic events (including cardiovascular death, nonfatal myocardial infarction, or non-haemorrhagic stroke) occurred at a rate of 3.8% in the placebo in addition to DAPT-treated patients and in 4.6%, 4.9%, 3.0%, and 3.5% of the dabigatran in addition to DAPT-treated patients, respectively.6 The authors of the RE-DEEM study concluded that a dabigatran dose of 110–150 mg twice daily (which showed the potential to reduce cardiac ischemic events while increasing major bleeding modestly in the RE-DEEM study) could be chosen if the concept of dabigatran treatment on top of DAPT in patients with a recent ACS is carried forward in a phase III clinical trial.6 Dabigatran in addition to antiplatelet therapy in patients with a recent ACS is currently not under further clinical investigation.
Apixaban The addition of the oral direct factor Xa inhibitor apixaban (Eliquis, Bristol-Myers Squibb & Pfizer, New York, NY) to standard antiplatelet therapy consisting of aspirin (r 165 mg/d) with or without the secondgeneration P2Y12 inhibitor clopidogrel (left to the discretion of the treating physician) in patients with a recent (within 7 days) NSTEMI, STEMI, or non-STsegment elevation acute coronary syndrome (NSTE-ACS) was assessed in the randomized phase II, double-blind, placebo-controlled, dose-ranging study APPRAISE (Apixaban for the Prevention of Acute Ischemic and Safety Events). Patients were randomized to placebo or four
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different blinded doses of apixaban (2.5 mg twice daily, 10 mg daily, 10 mg twice daily, or 20 mg daily) for 26 weeks (6 months).7 The primary endpoint was major or clinically relevant non-major bleeding, whereas major bleeding was defined by the ISTH definition. The secondary endpoint was the composite of cardiovascular death, myocardial infarction, severe recurrent ischemia, or ischemic stroke. A total of 1,715 patients were enrolled in the study (63% after a recent STEMI, 30% after a recent NSTEMI, and 8% after unstable angina). Dual antiplatelet therapy (aspirin þ clopidogrel) was administered to 76% of all patients. The two higher dosing arms of apixaban (10mg BID and 20mg QD) were discontinued during the study due to excess total bleeding events. There was a dose dependent increase in the primary endpoint of major or clinically relevant non-major bleeding with increasing doses of apixaban compared to placebo. In the two lower doses of apixaban, major or clinically relevant non-major bleeding occurred at a rate of 5.7% (2.5 mg twice daily) and 7.9% (10 mg daily) compared to 3.0% with placebo.7 The secondary efficacy endpoint of cardiovascular death, myocardial infarction, sever recurrent ischemia, or ischemic stroke occurred at a numerically, but not statistically significant, lower rate of 7.6% and 6.0% for the 2.5-mg twice-daily and 10-mg daily apixaban treatment arms compared to 8.7% in the placebo-treated patients.7 The authors of the APPRAISE study concluded from their data that a 10.mg daily dose of apixaban in addition to antiplatelet therapy showed the most favorable risk/benefit profile and should therefore be chosen for further clinical evaluation in patients at a high risk of ischemic events.7 Apixaban at a dose of 5 mg twice daily added to “standard” antiplatelet therapy was subsequently assessed in the large randomized, double-blind, placebo-controlled phase III clinical trial, APPRAISE-2, in patients with a recent (within 7 days) ACS and at least two additional risk factors for recurrent ischemic events. The primary efficacy outcome was the composite of cardiovascular death, myocardial infarction, or ischemic stroke and the primary safety outcome was defined as major bleeding according to the TIMI definition.8 The trial planned to enroll 10,800 patients but was prematurely stopped after recruitment of 7,392 patients due to an increase in major bleeding events with the addition of apixaban that was not counterbalanced by a reduction of ischemic events. The median follow-up time was 241 days. Forty percent of all patients had a recent STEMI as the index event, 42% had a recent NSTEMI, and 18% had unstable angina. The majority of patients (81%) were on DAPT (aspirin and clopidogrel). The primary efficacy endpoint of cardiovascular death, myocardial infarction, or ischemic stroke occurred at a rate of 13.2% (per 100 patient-years) with apixaban associated in addition to antiplatelet therapy and at a rate of 14% (per 100 patient-years) with placebo associated in addition to antiplatelet therapy (P ¼ .51).8 At the same time, the primary safety endpoint of TIMI major bleeding occurred significantly more frequent in patients treated with
apixaban in addition to antiplatelet therapy at a rate of 2.4 events (per 100 patient-years) compared to placebo in addition to antiplatelet therapy treated patients in whom only 0.9 events (per 100 patient-years) were registered (P ¼ .001).8 There was also a significant increase in the rate of intracranial bleeding with apixaban and in addition antiplatelet therapy (0.6 events per 100 patient-years) compared to antiplatelet therapy plus placebo (0.2 events per 100 patient-years, P ¼ .03).8 Apixaban in addition to antiplatelet therapy in patients with a recent ACS is currently not under further clinical investigation.
Rivaroxaban The oral direct factor Xa inhibitor rivaroxaban (Xarelto, Bayer Healthcare, Leverkusen, Germany) has been studied in the randomized, double-blind, dose-escalation clinical phase II study, ATLAS ACS-TIMI 46, in 3,491 patients with a recent (r7 days) ACS. A stratification, based on the local investigators intent to administer a P2Y12 receptor inhibitor or not, was included in the design of the trial. Stratum 1 was for aspirin use only and stratum 2 for aspirin and a P2Y12 inhibitor (predominately clopidogrel). A total of 761 patients were included in stratum 1 and 2,730 in stratum 2. This resulted in 80.8% of patients being on DAPT (aspirin þ P2Y12 inhibitor). In stratum 1 (single antiplatelet therapy with aspirin), patients were randomized to antiplatelet therapy plus either placebo, antiplatelet therapy plus rivaroxaban (5, 10, or 20mg) QD or rivaroxaban (2.5, 5, 10 mg) twice daily. In stratum 2 (DAPT), there was an additional dose group in the rivaroxaban treatment arms (15 mg rivaroxaban daily or 7.5 mg rivaroxaban twice daily, respectively). Of all randomized patients, 52.15% had a STEMI as the index event, 30.55% had an NSTEMI, and 17,85% had unstable angina as the index event.9 The primary safety endpoint was defined as clinically significant bleeding (a composite of TIMI major, TIMI minor, and bleeding requiring medical attention). The primary efficacy endpoint was the composite of death, myocardial infarction, stroke, or severe recurrent ischemia requiring revascularization. Patients were treated with placebo or rivaroxaban in addition to aspirin (stratum 1) or aspirin þ P2Y12 inhibitor (stratum 2) for 6 months. The primary safety endpoint of clinically significant bleeding was increased in rivaroxaban in addition to antiplatelet therapy in a dosedependent manner compared to placebo in addition to antiplatelet therapy. In stratum 1, the bleeding rates were 1.7% in the placebo-treated group versus 2.9% and 1.4% (5 mg daily and 2.5 mg twice daily), 7.6% and 5.5% (10 mg daily and 5 mg twice daily), 10.6% and 10.7% (20 mg daily and 10 mg twice daily), for the rivaroxaban-treated patients, respectively. In stratum 2, the bleeding rates were 3.8% in the placebo-treated patients compared to 11.7% and 8.2% (5 mg daily and 2.5 mg twice daily), 11.6% and 12.2% (10 mg daily and 5 mg twice daily), 13.1% and 12.3% (15 mg daily
150
and 7.5 mg twice daily), 17.8% and 16% (20 mg daily and 10 mg twice daily) in the rivaroxaban-treated patients, respectively.9 In the analysis of all patients randomized, the primary efficacy endpoint occurred in 5.6% of patients treated with rivaroxaban compared to 7% of the placebotreated patients (P ¼ .1).9 The secondary efficacy endpoint of death, myocardial infarction, or stroke was significantly reduced in rivaroxaban-treated patients (3.9%) compared to placebo-treated patients (5.5%, P ¼ .027).9 Based on the data from this trial, the authors suggested to use the 2.5-mg and 5-mg twice-daily rivaroxaban dosing regimens for further evaluation of the concept of low-dose rivaroxaban in addition to antiplatelet therapy in patients with a recent ACS in a large clinical phase III study. The subsequent phase III clinical study ATLAS ACS 2 TIMI 51 was conducted as a randomized double-blind, placebo-controlled trial in 15,526 patients with a recent (r7 days) ACS. In addition to DAPT (aspirin 75–100 mg/d and clopidogrel 75 mg/d), patients received either 2.5-mg or 5-mg twice-daily rivaroxaban or placebo. A total of 92.8% of all randomized patients did finally receive DAPT.10 The study was event driven and by the time of completion, patients were on treatment with rivaroxaban or placebo in addition to DAPT for a mean of 13 months and a maximum of up to 31 months. The primary efficacy endpoint was a composite of death from cardiovascular causes, myocardial infarction, or stroke. The primary safety endpoint was TIMI major bleeding not related to coronary artery bypass grafting. The primary efficacy endpoint was significantly reduced with both rivaroxaban treatment doses compared to placebo (8.9% v 10.7% for the rivaroxaban- and placebo-treated patients, respectively, P ¼ .008). At the same time, the primary safety bleeding endpoint occurred at a significantly higher rate with rivaroxaban treatment (2.1% v 0.6% for the rivaroxaban and placebo respectively, P o.001).10 The rate of fatal bleedings was not significantly different (0.3% v 0.2% for the rivaroxaban- and placebo-treated patients respectively, P ¼ .66). With the lower of the two studied rivaroxaban doses (the twice-daily 2.5-mg dose), there was a survival benefit that was not observed with the 5-mg twice-daily dose. In the 2.5-mg twice-daily dose the rate of death from cardiovascular causes was 2.7% versus 4.1% in the placebo group (P ¼ .002) and the rate of death from any cause was 2.9% versus 4.5% in the placebo group (P ¼ .002).10 In comparison to the 5-mg twice-daily dose, the lower 2.5-mg twice-daily dose was associated with significantly fewer fatal bleedings (0.1% v 0.4% for the 2.5-mg and 5-mg twicedaily dosing groups, respectively, P ¼ .04).10 There was a consistent reduction of the primary efficacy endpoint with rivaroxaban treatment across the patient subgroups except patients with a previous stroke or transient ischemic attack.10 Based on the results of this trial, rivaroxaban at a twice-daily dose of 2.5 mg in combination with antiplatelet therapy (aspirin and clopidogrel) has been approved in patients after an ACS in adult patients with elevated biomarkers in May 2013 by the European Commission.
I. Ahrens and C. Bode
LESSONS FROM THE ATLAS ACS 2 TIMI 51 TRIAL The ATLAS ACS 2 TIMI 51 study reintroduced the concept of prolonged oral anticoagulation in post ACS patients for the prevention of ischemic events, which has been assessed in the pre-clopidogrel era with VKAs as oral anticoagulants.4,5 Furthermore, with the results of ATLAS ACS 2 TIMI 51 a new concept of low-dose oral anticoagulation (“dampening” of the activated coagulation system) in addition to DAPT was inaugurated. With the widespread uptake of PCI with stent implantation almost two decades ago, the acute or late stent thrombosis emerged as one of the major clinical threats to the patients in the post ACS phase.11 Although the 2-year rate of stent thrombosis with current stent technologies and in the current setting of low-dose aspirin combined with a P2Y12 receptor antagonist is relatively low (0.5%– 1.9%),12,13 it still poses a life-threatening risk to the patient. In a subgroup analysis of all patients that underwent PCI and had at least one stent implanted (n ¼ 9,631, 63% of all randomized patients in ATLAS ACS 2 TIMI 51), the addition of twice-daily rivaroxaban 2.5 mg to low-dose aspirin plus clopidigrel significantly reduced the incidence of stent thrombosis (1.9% v 1.5%, for the rivaroxaban- v placebo-treated patients, respectively, P ¼ .023).14 In addition, rivaroxaban twice daily 2.5 mg in combination with low-dose aspirin and clopidogrel was associated with a significant reduction in cardiovascular death among patients treated with stents (2.27% v 1.35%, for the rivaroxaban- v placebo-treated patients respectively, P ¼ .014).14 The overall net clinical benefit of low-dose rivaroxaban in addition to standard DAPT was also evident in the subgroup analysis of all STEMI patients enrolled in ATLAS ACS 2 TIMI 51 (7,817, 50% of all patients randomized). In addition to a significant reduction of the composite primary endpoint of cardiovascular death, myocardial infarction, or stroke (8.4% v 10.6% for rivaroxaban-treated patients v placebo-treated patients, respectively, P ¼ .019) with both doses of rivaroxaban (2.5 mg and 5 mg twice daily), the lower 2.5-mg twicedaily dose led also to a significant reduction of cardiovascular death in STEMI patients (2.5% v 4.2% for rivaroxaban- v placebo-treated patients, respectively, P ¼ .006).15 The clinical benefit of rivaroxaban in STEMI patients was associated with an increase of non-coronary bypass grafting TIMI major bleeding (2.2% v 0.6% for rivaroxaban v placebo, respectively, P o.001) and an increase in intracranial hemorrhage (0.6% v 0.1% for rivaroxaban v placebo, P ¼ .01%) but was not associated with significant increase in fatal bleeding compared to placebo-treated patients with STEMI (0.2% v 0.1%, P ¼ .51).15
UNRESOLVED ISSUES AND FUTURE PERSPECTIVE Low-dose twice-daily rivaroxaban in addition to aspirin and clopidogrel is superior to DAPT alone for secondary
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prevention of ischemic events in post ACS patients. Furthermore, this novel combined low-dose oral anticoagulant plus DAPT was associated with a significant reduction in cardiovascular and overall mortality. The last time that this has been achieved with a novel antithrombotic therapy in patients with ACS was in the major clinical phase III PLATO trial. In this trial, in patients with ACS treated with low-dose aspirin the addition of the third-generation P2Y12 inhibitor ticagrelor did significantly reduce cardiovascular and all-cause death compared to the second-generation P2Y12 inhibitor clopidogrel.16 However, due to the new therapeutic option of low-dose rivaroxaban added to low-dose aspirin plus clopidogrel we are currently in the situation that the best possible antithrombotic therapy in the post ACS phase has to be redefined. While certainly low-dose rivaroxaban added to low-dose aspirin plus clopidogrel is a superior therapeutic option for the secondary treatment in patients with ACS, it is not yet known whether the net clinical benefit seen with low-dose rivaroxaban in the ATLAS ACS 2 TIMI 52 trial would also remain or even increase if low-dose rivaroxaban is combined with low-dose aspirin and a third-generation P2Y12 inhibitor (Ticagrelor or Prasugrel). Another open question is whether low-dose rivaroxaban added to low-dose aspirin and clopidogrel could even be superior to the current guideline recommended DAPT with low-dose aspirin plus ticagrelor or prasugrel. This question may not be answered by a comparison of the event rates in the PLATO trial with the event rates in the ATLAS ACS 2 TIMI 51 trial and needs to be assessed along with other possible combinations of antithrombotic therapy (eg, low-dose rivaroxaban added to third-generation P2Y12 antagonist without aspirin) in randomized controlled clinical trials.
REFERENCES 1. Merlini PA, Bauer KA, Oltrona L, et al. Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation. 1994;90:61-8. 2. Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33: 2569-619. 3. Hamm CW, Bassand JP, Agewall S, et al. 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
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ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2011;32:2999-3054. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002;347:969-74. van Es RF, Jonker JJ, Verheugt FW, et al. Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial. Lancet. 2002;360: 109-13. Oldgren J, Budaj A, Granger CB, et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J. 2011;32:2781-9. Committee AS, Investigators, Alexander JH, et al. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation. 2009;119: 2877-85. Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med.. 2011;365:699-708. Mega JL, Braunwald E, Mohanavelu S, et al. Rivaroxaban v placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet. 2009;374:29-38. 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. Baim DS, Carrozza JP Jr. Stent thrombosis. Closing in on the best preventive treatment. Circulation. 1997;95:1098-100. Palmerini T, Biondi-Zoccai G, et al. Stent thrombosis with drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis. Lancet. 2012;379:1393-402. Palmerini T, Kirtane AJ, Serruys PW, et al. Stent thrombosis with everolimus-eluting stents: meta-analysis of comparative randomized controlled trials. Circ Cardiovasc Interv. 2012; 5:357-64. Gibson CM, Chakrabarti AK, Mega J, et al. Reduction of stent thrombosis in patients with acute coronary syndromes treated with rivaroxaban in ATLAS-ACS 2 TIMI 51. J Am Coll Cardiol. 2013;62:286-90. Mega JL, Braunwald E, Murphy SA, et al. Rivaroxaban in patients stabilized after a ST-segment elevation myocardial infarction: results from the ATLAS ACS-2-TIMI-51 trial (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction-51). J Am Coll Cardiol. 2013;61:1853-9. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor v clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045-57.
T
he acute coronary syndrome (ACS) is characterized by a platelet-mediated activation of the coagulation system (in which platelets do play a central role), which is sustained for a significant period of time following the ACS and may persist for months if not longer in highrisk patients.1 Antithrombotic therapy is the key therapeutic strategy to reduce ischemic cardiovascular adverse events in patients with ACS and represents the umbrella-term for antiplatelet and anticoagulant therapy. Until recently, the recommendations for long-term antithrombotic treatment of patients after an ACS were restricted to antiplatelet therapy. Current clinical guidelines of major cardiology associations (American Heart Association [AHA], American College of Cardiology [ACC], European Society of Cardiology [ESC]) still include the strongest recommendations for a dual antiplatelet therapy (DAPT) consisting of low-dose aspirin
Heart Center, University of Freiburg, Department for Cardiology and Angiology I, Freiburg, Germany Conflicts of interest: IA received speaker’s honoraria from Bayer Healthcare, Lilly, Sanofi Aventis, and Daiichi Sankyo. CB received speaker's honoraria from Bayer Healthcare, Merck, Astra-Zeneca, Daiichi Sankyo, and Sanofi Aventis. Address correspondence to Ingo Ahrens, MD, Heart Center, University of Freiburg, Department for Cardiology and Angiology I, Hugstetter Street 55, 79106 Freiburg, Germany. E-mail: ingo. [email protected] 0037-1963/$ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminhematol.2014.03.004
Seminars in Hematology, Vol 51, No 2, April 2014, pp 147–151
and a P2Y12 receptor inhibitor for 9–12 months. Regarding the P2Y12 receptor inhibitor, current ESC guidelines have a level IB recommendation for the third-generation P2Y12 receptor antagonists (prasugrel and ticagrelor) and should therefore be preferred over the second-generation P2Y12 receptor inhibitor clopidogrel, which has a level IC recommendation.2,3
ANTIPLATELET AND VITAMIN K-ANTAGONIST THERAPY IN THE POST ACS PHASE The hypothesis that long-term oral anticoagulation could be superior to single antiplatelet therapy (aspirin) for the secondary prevention of ischemic events in the post ACS phase has already been assessed in the pre-clopidogrel era. The WARIS II study (The Warfarin, Aspirin, Reinfarction Study) randomized 3630 patients admitted for acute myocardial infarction to Norwegian hospitals after surviving the acute phase to long-term treatment with either aspirin alone (160 mg/d), international normalized ratio (INR)-guided warfarin therapy (INR 2.8–4.2), or aspirin (75 mg/d) plus INR-guided warfarin (INR 2.0–2.5).4 The primary outcome of the study was the composite of death, nonfatal reinfarction, or thromboembolic stroke and was significantly reduced in patients on warfarin alone compared to aspirin alone (16.7% v 20% for warfarin v aspirin, 147
148 respectively, P ¼ .03). In addition, also the combination of warfarin and aspirin did significantly reduce the primary endpoint compared to aspirin alone (15% v 20% for warfarin v aspirin respectively, P ¼ .001).4 However, only 19% (684) of all randomized patients were treated by percutaneous coronary intervention (PCI), which does not allow to transfer the results of this study to non-conservatively treated patients with ACS. Furthermore the benefit that was seen with warfarin treatment was accompanied by a significant increase in major, nonfatal bleeding (0.62% v 0.17% for both warfarin v the aspirin group, respectively, P o.001).4 In a similar clinical trial (ASPECT-2 study) with a lower total patient number (n ¼ 999) conducted in the Netherlands, patients after ACS were randomized to lowdose aspirin, high-intensity oral anticoagulation with a vitamin K antagonist (VKA), or low-dose aspirin plus moderate-intensity oral anticoagulation with a VKA. The primary composite endpoint of myocardial infarction, stroke, or death was reached in 9% of the low-dose aspirin-treated patients. In the high-intensity oral anticoagulant-treated patients and in the combined low-dose aspirin plus moderate-intensity oral anticoagulant–treated patients, there was a significant reduction of the primary endpoint compared to low-dose aspirin (both 5%, P ¼ .048 and P ¼ .03, respectively).5 Both studies (WARIS II and ASPECT-2) have been conducted before the widespread clinical establishment of DAPT and PCI with routine coronary artery stent implantation and have therefore be interpreted with caution. However, these trials did demonstrate that the concept of the combined antiplatelet and anticoagulant therapy in the post ACS phase could be favorable if not outweighed by the incidence of major bleeding events.
DOACs in addition to antiplatelet therapy in the post ACS phase The addition of direct oral anticoagulants (DOACs) to antiplatelet therapy (excluding third- generation P2Y12 receptor antagonists) for the secondary prevention of ischemic events in patients with a recent coronary syndrome has been studied in three clinical phase II (dabigatran etexilate, rivaroxaban, apixaban) and two clinical phase III studies (apixaban and rivaroxaban). The studies and their results are summarized graded by the respective DOAC that has been examined in this indication below.
Dabigatran Etexilate The oral direct thrombin inhibitor dabigatran etexilate (Pradaxa, Boehringer Ingelheim, Ingelheim am Rhein, Germany) has been studied in addition to antiplatelet therapy in the RE-DEEM study, a randomized, doubleblind, placebo-controlled, dose-escalation phase II clinical trial in patients after (r14 days) a ST-segment elevation myocardial infarction (STEMI), or after a non-STsegment elevation myocardial infarction (NSTEMI). A total of 1,861 patients were randomized and almost all
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patients (99.2%) were receiving dual antiplatelet therapy with aspirin (r100 mg/d) and clopidogrel (75 mg/d). On top of dual antiplatelet therapy, patients were either treated for a period of 6 months with dabigatran 50, 75, 110, or 150 mg twice daily, or placebo, respectively. The primary outcome was the composite of major (definition of the International Society on Thrombosis and Haemostasis, ISTH) or clinically relevant non-major bleeding. The secondary endpoints were reduction in D-dimer levels and cardiovascular ischemic events.6 From all randomized patients, 60% had a recent STEMI and 40% had a recent NSTEMI. The primary endpoint of major or clinically relevant non-major bleeding occurred in a dose-dependent manner in the dabigatran in addition to DAPT-treated patients (3.5%, 4.3%, 7.9%, and 7.8% for the 50, 75, 110, and 150 mg twice-daily dabigatran treatments, respectively), while the bleeding rate in the placebo in addition to DAPT-treated patients was lower (2.2%, Po.001 for a linear trend).6 However, major (according to Thrombolysis in Myocardial Infarction, TIMI criteria) or severe bleeding was low in all dabigatran treatment groups with an absolute increase compared to placebo o1%.6 The secondary efficacy endpoint of D-dimer concentrations was measured after 1 and 4 weeks. D-dimer levels were significantly reduced in all dabigatran treatment groups compared to placebo at 1 and 4 weeks (P o.001). The secondary efficacy endpoint of cardiovascular ischemic events (including cardiovascular death, nonfatal myocardial infarction, or non-haemorrhagic stroke) occurred at a rate of 3.8% in the placebo in addition to DAPT-treated patients and in 4.6%, 4.9%, 3.0%, and 3.5% of the dabigatran in addition to DAPT-treated patients, respectively.6 The authors of the RE-DEEM study concluded that a dabigatran dose of 110–150 mg twice daily (which showed the potential to reduce cardiac ischemic events while increasing major bleeding modestly in the RE-DEEM study) could be chosen if the concept of dabigatran treatment on top of DAPT in patients with a recent ACS is carried forward in a phase III clinical trial.6 Dabigatran in addition to antiplatelet therapy in patients with a recent ACS is currently not under further clinical investigation.
Apixaban The addition of the oral direct factor Xa inhibitor apixaban (Eliquis, Bristol-Myers Squibb & Pfizer, New York, NY) to standard antiplatelet therapy consisting of aspirin (r 165 mg/d) with or without the secondgeneration P2Y12 inhibitor clopidogrel (left to the discretion of the treating physician) in patients with a recent (within 7 days) NSTEMI, STEMI, or non-STsegment elevation acute coronary syndrome (NSTE-ACS) was assessed in the randomized phase II, double-blind, placebo-controlled, dose-ranging study APPRAISE (Apixaban for the Prevention of Acute Ischemic and Safety Events). Patients were randomized to placebo or four
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different blinded doses of apixaban (2.5 mg twice daily, 10 mg daily, 10 mg twice daily, or 20 mg daily) for 26 weeks (6 months).7 The primary endpoint was major or clinically relevant non-major bleeding, whereas major bleeding was defined by the ISTH definition. The secondary endpoint was the composite of cardiovascular death, myocardial infarction, severe recurrent ischemia, or ischemic stroke. A total of 1,715 patients were enrolled in the study (63% after a recent STEMI, 30% after a recent NSTEMI, and 8% after unstable angina). Dual antiplatelet therapy (aspirin þ clopidogrel) was administered to 76% of all patients. The two higher dosing arms of apixaban (10mg BID and 20mg QD) were discontinued during the study due to excess total bleeding events. There was a dose dependent increase in the primary endpoint of major or clinically relevant non-major bleeding with increasing doses of apixaban compared to placebo. In the two lower doses of apixaban, major or clinically relevant non-major bleeding occurred at a rate of 5.7% (2.5 mg twice daily) and 7.9% (10 mg daily) compared to 3.0% with placebo.7 The secondary efficacy endpoint of cardiovascular death, myocardial infarction, sever recurrent ischemia, or ischemic stroke occurred at a numerically, but not statistically significant, lower rate of 7.6% and 6.0% for the 2.5-mg twice-daily and 10-mg daily apixaban treatment arms compared to 8.7% in the placebo-treated patients.7 The authors of the APPRAISE study concluded from their data that a 10.mg daily dose of apixaban in addition to antiplatelet therapy showed the most favorable risk/benefit profile and should therefore be chosen for further clinical evaluation in patients at a high risk of ischemic events.7 Apixaban at a dose of 5 mg twice daily added to “standard” antiplatelet therapy was subsequently assessed in the large randomized, double-blind, placebo-controlled phase III clinical trial, APPRAISE-2, in patients with a recent (within 7 days) ACS and at least two additional risk factors for recurrent ischemic events. The primary efficacy outcome was the composite of cardiovascular death, myocardial infarction, or ischemic stroke and the primary safety outcome was defined as major bleeding according to the TIMI definition.8 The trial planned to enroll 10,800 patients but was prematurely stopped after recruitment of 7,392 patients due to an increase in major bleeding events with the addition of apixaban that was not counterbalanced by a reduction of ischemic events. The median follow-up time was 241 days. Forty percent of all patients had a recent STEMI as the index event, 42% had a recent NSTEMI, and 18% had unstable angina. The majority of patients (81%) were on DAPT (aspirin and clopidogrel). The primary efficacy endpoint of cardiovascular death, myocardial infarction, or ischemic stroke occurred at a rate of 13.2% (per 100 patient-years) with apixaban associated in addition to antiplatelet therapy and at a rate of 14% (per 100 patient-years) with placebo associated in addition to antiplatelet therapy (P ¼ .51).8 At the same time, the primary safety endpoint of TIMI major bleeding occurred significantly more frequent in patients treated with
apixaban in addition to antiplatelet therapy at a rate of 2.4 events (per 100 patient-years) compared to placebo in addition to antiplatelet therapy treated patients in whom only 0.9 events (per 100 patient-years) were registered (P ¼ .001).8 There was also a significant increase in the rate of intracranial bleeding with apixaban and in addition antiplatelet therapy (0.6 events per 100 patient-years) compared to antiplatelet therapy plus placebo (0.2 events per 100 patient-years, P ¼ .03).8 Apixaban in addition to antiplatelet therapy in patients with a recent ACS is currently not under further clinical investigation.
Rivaroxaban The oral direct factor Xa inhibitor rivaroxaban (Xarelto, Bayer Healthcare, Leverkusen, Germany) has been studied in the randomized, double-blind, dose-escalation clinical phase II study, ATLAS ACS-TIMI 46, in 3,491 patients with a recent (r7 days) ACS. A stratification, based on the local investigators intent to administer a P2Y12 receptor inhibitor or not, was included in the design of the trial. Stratum 1 was for aspirin use only and stratum 2 for aspirin and a P2Y12 inhibitor (predominately clopidogrel). A total of 761 patients were included in stratum 1 and 2,730 in stratum 2. This resulted in 80.8% of patients being on DAPT (aspirin þ P2Y12 inhibitor). In stratum 1 (single antiplatelet therapy with aspirin), patients were randomized to antiplatelet therapy plus either placebo, antiplatelet therapy plus rivaroxaban (5, 10, or 20mg) QD or rivaroxaban (2.5, 5, 10 mg) twice daily. In stratum 2 (DAPT), there was an additional dose group in the rivaroxaban treatment arms (15 mg rivaroxaban daily or 7.5 mg rivaroxaban twice daily, respectively). Of all randomized patients, 52.15% had a STEMI as the index event, 30.55% had an NSTEMI, and 17,85% had unstable angina as the index event.9 The primary safety endpoint was defined as clinically significant bleeding (a composite of TIMI major, TIMI minor, and bleeding requiring medical attention). The primary efficacy endpoint was the composite of death, myocardial infarction, stroke, or severe recurrent ischemia requiring revascularization. Patients were treated with placebo or rivaroxaban in addition to aspirin (stratum 1) or aspirin þ P2Y12 inhibitor (stratum 2) for 6 months. The primary safety endpoint of clinically significant bleeding was increased in rivaroxaban in addition to antiplatelet therapy in a dosedependent manner compared to placebo in addition to antiplatelet therapy. In stratum 1, the bleeding rates were 1.7% in the placebo-treated group versus 2.9% and 1.4% (5 mg daily and 2.5 mg twice daily), 7.6% and 5.5% (10 mg daily and 5 mg twice daily), 10.6% and 10.7% (20 mg daily and 10 mg twice daily), for the rivaroxaban-treated patients, respectively. In stratum 2, the bleeding rates were 3.8% in the placebo-treated patients compared to 11.7% and 8.2% (5 mg daily and 2.5 mg twice daily), 11.6% and 12.2% (10 mg daily and 5 mg twice daily), 13.1% and 12.3% (15 mg daily
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and 7.5 mg twice daily), 17.8% and 16% (20 mg daily and 10 mg twice daily) in the rivaroxaban-treated patients, respectively.9 In the analysis of all patients randomized, the primary efficacy endpoint occurred in 5.6% of patients treated with rivaroxaban compared to 7% of the placebotreated patients (P ¼ .1).9 The secondary efficacy endpoint of death, myocardial infarction, or stroke was significantly reduced in rivaroxaban-treated patients (3.9%) compared to placebo-treated patients (5.5%, P ¼ .027).9 Based on the data from this trial, the authors suggested to use the 2.5-mg and 5-mg twice-daily rivaroxaban dosing regimens for further evaluation of the concept of low-dose rivaroxaban in addition to antiplatelet therapy in patients with a recent ACS in a large clinical phase III study. The subsequent phase III clinical study ATLAS ACS 2 TIMI 51 was conducted as a randomized double-blind, placebo-controlled trial in 15,526 patients with a recent (r7 days) ACS. In addition to DAPT (aspirin 75–100 mg/d and clopidogrel 75 mg/d), patients received either 2.5-mg or 5-mg twice-daily rivaroxaban or placebo. A total of 92.8% of all randomized patients did finally receive DAPT.10 The study was event driven and by the time of completion, patients were on treatment with rivaroxaban or placebo in addition to DAPT for a mean of 13 months and a maximum of up to 31 months. The primary efficacy endpoint was a composite of death from cardiovascular causes, myocardial infarction, or stroke. The primary safety endpoint was TIMI major bleeding not related to coronary artery bypass grafting. The primary efficacy endpoint was significantly reduced with both rivaroxaban treatment doses compared to placebo (8.9% v 10.7% for the rivaroxaban- and placebo-treated patients, respectively, P ¼ .008). At the same time, the primary safety bleeding endpoint occurred at a significantly higher rate with rivaroxaban treatment (2.1% v 0.6% for the rivaroxaban and placebo respectively, P o.001).10 The rate of fatal bleedings was not significantly different (0.3% v 0.2% for the rivaroxaban- and placebo-treated patients respectively, P ¼ .66). With the lower of the two studied rivaroxaban doses (the twice-daily 2.5-mg dose), there was a survival benefit that was not observed with the 5-mg twice-daily dose. In the 2.5-mg twice-daily dose the rate of death from cardiovascular causes was 2.7% versus 4.1% in the placebo group (P ¼ .002) and the rate of death from any cause was 2.9% versus 4.5% in the placebo group (P ¼ .002).10 In comparison to the 5-mg twice-daily dose, the lower 2.5-mg twice-daily dose was associated with significantly fewer fatal bleedings (0.1% v 0.4% for the 2.5-mg and 5-mg twicedaily dosing groups, respectively, P ¼ .04).10 There was a consistent reduction of the primary efficacy endpoint with rivaroxaban treatment across the patient subgroups except patients with a previous stroke or transient ischemic attack.10 Based on the results of this trial, rivaroxaban at a twice-daily dose of 2.5 mg in combination with antiplatelet therapy (aspirin and clopidogrel) has been approved in patients after an ACS in adult patients with elevated biomarkers in May 2013 by the European Commission.
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LESSONS FROM THE ATLAS ACS 2 TIMI 51 TRIAL The ATLAS ACS 2 TIMI 51 study reintroduced the concept of prolonged oral anticoagulation in post ACS patients for the prevention of ischemic events, which has been assessed in the pre-clopidogrel era with VKAs as oral anticoagulants.4,5 Furthermore, with the results of ATLAS ACS 2 TIMI 51 a new concept of low-dose oral anticoagulation (“dampening” of the activated coagulation system) in addition to DAPT was inaugurated. With the widespread uptake of PCI with stent implantation almost two decades ago, the acute or late stent thrombosis emerged as one of the major clinical threats to the patients in the post ACS phase.11 Although the 2-year rate of stent thrombosis with current stent technologies and in the current setting of low-dose aspirin combined with a P2Y12 receptor antagonist is relatively low (0.5%– 1.9%),12,13 it still poses a life-threatening risk to the patient. In a subgroup analysis of all patients that underwent PCI and had at least one stent implanted (n ¼ 9,631, 63% of all randomized patients in ATLAS ACS 2 TIMI 51), the addition of twice-daily rivaroxaban 2.5 mg to low-dose aspirin plus clopidigrel significantly reduced the incidence of stent thrombosis (1.9% v 1.5%, for the rivaroxaban- v placebo-treated patients, respectively, P ¼ .023).14 In addition, rivaroxaban twice daily 2.5 mg in combination with low-dose aspirin and clopidogrel was associated with a significant reduction in cardiovascular death among patients treated with stents (2.27% v 1.35%, for the rivaroxaban- v placebo-treated patients respectively, P ¼ .014).14 The overall net clinical benefit of low-dose rivaroxaban in addition to standard DAPT was also evident in the subgroup analysis of all STEMI patients enrolled in ATLAS ACS 2 TIMI 51 (7,817, 50% of all patients randomized). In addition to a significant reduction of the composite primary endpoint of cardiovascular death, myocardial infarction, or stroke (8.4% v 10.6% for rivaroxaban-treated patients v placebo-treated patients, respectively, P ¼ .019) with both doses of rivaroxaban (2.5 mg and 5 mg twice daily), the lower 2.5-mg twicedaily dose led also to a significant reduction of cardiovascular death in STEMI patients (2.5% v 4.2% for rivaroxaban- v placebo-treated patients, respectively, P ¼ .006).15 The clinical benefit of rivaroxaban in STEMI patients was associated with an increase of non-coronary bypass grafting TIMI major bleeding (2.2% v 0.6% for rivaroxaban v placebo, respectively, P o.001) and an increase in intracranial hemorrhage (0.6% v 0.1% for rivaroxaban v placebo, P ¼ .01%) but was not associated with significant increase in fatal bleeding compared to placebo-treated patients with STEMI (0.2% v 0.1%, P ¼ .51).15
UNRESOLVED ISSUES AND FUTURE PERSPECTIVE Low-dose twice-daily rivaroxaban in addition to aspirin and clopidogrel is superior to DAPT alone for secondary
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prevention of ischemic events in post ACS patients. Furthermore, this novel combined low-dose oral anticoagulant plus DAPT was associated with a significant reduction in cardiovascular and overall mortality. The last time that this has been achieved with a novel antithrombotic therapy in patients with ACS was in the major clinical phase III PLATO trial. In this trial, in patients with ACS treated with low-dose aspirin the addition of the third-generation P2Y12 inhibitor ticagrelor did significantly reduce cardiovascular and all-cause death compared to the second-generation P2Y12 inhibitor clopidogrel.16 However, due to the new therapeutic option of low-dose rivaroxaban added to low-dose aspirin plus clopidogrel we are currently in the situation that the best possible antithrombotic therapy in the post ACS phase has to be redefined. While certainly low-dose rivaroxaban added to low-dose aspirin plus clopidogrel is a superior therapeutic option for the secondary treatment in patients with ACS, it is not yet known whether the net clinical benefit seen with low-dose rivaroxaban in the ATLAS ACS 2 TIMI 52 trial would also remain or even increase if low-dose rivaroxaban is combined with low-dose aspirin and a third-generation P2Y12 inhibitor (Ticagrelor or Prasugrel). Another open question is whether low-dose rivaroxaban added to low-dose aspirin and clopidogrel could even be superior to the current guideline recommended DAPT with low-dose aspirin plus ticagrelor or prasugrel. This question may not be answered by a comparison of the event rates in the PLATO trial with the event rates in the ATLAS ACS 2 TIMI 51 trial and needs to be assessed along with other possible combinations of antithrombotic therapy (eg, low-dose rivaroxaban added to third-generation P2Y12 antagonist without aspirin) in randomized controlled clinical trials.
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