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Prof. Steen Dalby Kristensen,
Prof. Philippe Gabriel Steg,
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Philippe Gabriel Steg (France)
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Steen Dalby Kristensen (Denmark)
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Parenteral anticoagulants such as unfractionated heparin, low-molecular weight heparins, fondaparinux or bivalirudin are recommended in the first hours to days of an acute coronary syndrome (ACS). In the era prior to acute percutaneous coronary intervention (PCI), long-term oral anticoagulation with vitamin K antagonists (VKA) was proven beneficial in patients with myocardial infarction (MI) (1). However, the introduction of early PCI with stenting and the results of the CURE study (2) boosted the use of dual antiplatelet therapy in ACS. As triple therapy with aspirin, clopidogrel and VKA is associated with an increased risk of bleeding (3), the use of VKA has never become routine therapy following ACS. The new oral anticoagulants (direct thrombin and factor Xa inhibitors) pose several advantages over VKA (4). The use of VKA is complicated by a narrow therapeutic window, a slow onset and offset, and several food and drug interactions. Moreover, it requires careful monitoring, which is not necessary with the new oral anticoagulants targeting thrombin or factor Xa. These drugs have been evaluated in the prevention and treatment of venous thromboembolism and in patients with atrial fibrillation. So far, results are very promising. Their potential benefit in the treatment of ACS is currently being investigated (4). The RUBY-1 trial reported by PG Steg et al. is a well-conducted double-blind, randomised trial evaluating the safety, tolerability and efficacy of a new oral factor Xa inhibitor, darexaban, after ACS. Six different dosing regimens of darexaban were tested against placebo for 26 weeks in patients with ACS. The primary endpoint was the occurrence of major bleeding, but other safety measures such as liver toxicity were also investigated. As a secondary endpoint ischaemic events were recorded. The 1,279 ACS patients were randomized as soon as possible after discontinuation of parenteral antithrombotic therapy (median randomization at day four). More than 70% were ST-elevation MI patients and around 75% of all patients underwent PCI prior to inclusion. Median age was 56 years and only about 20% were women. More than 96% of the patients were on dual antiplatelet therapy with aspirin and clopidogrel. Patients with active bleeding during the first days were excluded, as were patients with recent stroke/transitoric ischaemic attack (less than 12 months prior to index event) or with renal creatinine clearance of <60 mL/min. Major and non-major clinically relevant bleeding was recorded and adjudicated by an independent committee during the 26-week study participation. In the placebo group the bleeding rate was 3.1% of which almost all occurred within the first 90 days. Bleeding rates were higher in all darexaban groups and revealed a clear dose-response relationship (6.2, 6.5 and 9.3% for 10, 30 and 60 mg daily, respectively). In the darexaban groups, bleeding events continued to accumulate after 90 days. There was no significant difference in bleeding events for patients receiving darexaban once or twice daily. No cases of fatal bleeding or intracranial haemorrhage were reported in any study group. Adverse events leading to discontinuation of the study drug were more frequent in the groups receiving the high-dose regimens of darexaban. No decrease in ischaemic event rates was shown with darexaban versus placebo, but the study was underpowered to evaluate efficacy. Darexaban showed good tolerability with no major adverse effects and with no signs of liver toxicity. In accordance with previous phase II trials, this study confirms that oral factor Xa inhibitors confer an excess bleeding rate when administered on top of aspirin and aspirin plus clopidogrel. In the phase II APPRAISE trial, apixaban was associated with an excess bleeding rate, particularly in patients on dual antiplatelet therapy (6), and the larger phase III study APPRAISE-2 has recently been terminated prematurely after recruitment of 7392 patients because of a significant increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events (7). Also, in the ATLAS trial, a phase II trial in which the addition of the factor Xa inhibitor rivaroxaban was tested against placebo, bleeding rates were decisive. Among ACS patients receiving either aspirin monotherapy or dual antiplatelet therapy a dose-dependent increase in bleeding events was reported (8). However, compared with placebo, rivaroxaban was associated with a significant reduction in the secondary end point: the composite of death, myocardial infarction and stroke (8). In ACS patients treated with dual antiplatelet therapy, careful dosing of factor Xa inhibitors is crucial in order to successfully balance on the cutting edge of thrombosis and bleeding. This dilemma will be emphasized in the years to come, as the more potent platelet P2Y12 inhibitors such as prasugrel and ticagrelor are entering the scene. These drugs are more efficacious than clopidogrel, but are also more prone to cause bleeding. The RUBY-1 trial investigators wisely tested several dosing regimens of darexaban and the results support that the lower dose should be used in future studies on ACS patients. The number of ischaemic events is highest in the first weeks to months after ACS (2) and as the excess bleeding rate with darexaban in RUBY-1 was less pronounced during the first 3 months of therapy, it might be worthwhile to consider shorter treatment duration of darexaban in future ACS studies. A large phase III trial, the ATLAS-ACS 2 TIMI 51 with the 2 lowest doses of rivaroxiban found in ATLAS to be associated with a trend toward improved efficacy is currently ongoing. More than 15,000 patients will be included to evaluate if factor Xa-inhibition on top of single or dual antiplatelet therapy is safe and may improve ischaemic outcome (9). Clearly, the concern is that a reduction in ischaemic events with the addition of oral factor Xa inhibition to dual antiplatelet therapy might be outbalanced by an increase in bleeding. Hopefully, future studies will enable the identification of the right combinations of drugs for the right patients in order to further improve clinical outcomes in the setting of ACS. References: 1. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med 2002; 347:969–974. 2. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation N Engl J Med 2001 Aug 16;345(7):494-502. 3. Sørensen R, Hansen ML, Abildstrom SZ, Hvelplund A, Andersson C, Jørgensen C, Madsen JK, Hansen PR, Køber L, Torp-Pedersen C, Gislason GH. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet 2009;374:1967–1974. 4. Steffel J, Braunwald E. Novel oral anticoagulants: focus on stroke prevention and treatment of venous thromboembolism. Eur Heart J 2011 doi: 10.1093/eur heart j/ehr052. 5. Steg PG, Mehta S, Jukema JV, Lip GYH, Gibson CM, Kovar F, Kala P, Garcia-Hernandez A, Renfurm RW, Granger CB. RUBY-1: A randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome. Eur Heart J 2011; 6. APPRAISE Steering Committee and Investigators, Alexander JH, Becker RC, Bhatt DL, Cools F, Crea F, Dellborg M, Fox KA, Goodman SG, Harrington RA, Huber K, Husted S, Lewis BS, Lopez-Sendon J, Mohan P, Montalescot G, Ruda M, Ruzyllo W, Verheugt F, Wallentin. 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;119:2877–2885. 7. Alexander, JH, Lopes RD, James S, Kilaru R, He Y, Mohan P, Bhatt DL, Goodman S, Verheugt FW, Flather M, Huber K, Liaw D, Husted SE, Lopez-Sendon J, De Caterina, R, Jansky P, Darius H, Vinereanu D, Cornel JH, Cools F, Atar D, Leiva-Pons JL, Keltai M, Ogawa H, Pais P, Parkhomenko A, Ruzyllo W, Diaz R, White H, Ruda M, Geraldes M, Lawrence J, Harrington, RH, Wallentin L, for the APPRAISE-2 Investigators. Apixaban with Antiplatelet Therapy after Acute Coronary Syndrome, NEJM July 24, 2011; 10.1056/nejmoa1105819 nejm.org. 8. Mega JL, Braunwald E, Mohanavelu S, Burton P, Poulter R, Misselwitz F, Hricak V, Barnathan ES, Bordes P, Witkowski A, Markov V, Oppenheimer L, Gibson CM; ATLAS ACS-TIMI 46 study group. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 2009;374:29–38. 9. Gibson CM, Mega JL, Burton P, Goto S, Verheugt F, Bode C, Plotnikov A, Sun X, Cook-Bruns N, Braunwald E. Rationale and design of the Anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndrome-thrombolysis in myocardial infarction 51 (ATLAS-ACS 2 TIMI 51) trial: a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of rivaroxaban in subjects with acute coronary syndrome. Am Heart J 2011;161:815–821.
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