Apixaban

Summary

Apixaban is a potent reversible inhibitor of the activated human coagulation factor X. This new oral anticoagulant has favourable pharmacokinetic and pharmocodynamic properties which include a concentration-dependent anticoagulant effect, good oral bioavailability, balanced elimination and excretion, infrequent drug or food interactions, and the lack of liver toxicity. Apixaban has already completed a large part of its phase 3 clinical trial programme. In the ARISTOTLE study, which focused on stroke prevention in atrial fibrillation, apixaban showed a balanced efficacy and safety profile, being superior to warfarin both in the prevention of strokes and in the risk of causing major bleeding. A further trial related to this indication, AVERROES, demonstrated the clear superiority of apixaban compared to aspirin treatment. In the primary prophylaxis of venous thromboembolism after orthopaedic surgery, apixaban successfully completed the ADVANCE study programme and was approved in Europe for patients undergoing elective hip or knee replacement. The results of the AMPLIFY and AMPLIFY- EXT studies will soon show whether the inhibitor is also effective in the treatment and secondary prophylaxis after acute deep vein thrombosis and pulmonary embolism. On the other hand, the use of apixaban in the primary prophylaxis of venous thrombosis in hospitalised medical patients, and its administration on top of antiplatelet therapy to patients who have suffered an acute coronary syndrome, have not received support by the results of ADOPT and APPRAISE-II, respectively. In conclusion, on the basis of the available evidence, apixaban appears to be a valuable therapeutic option for the prevention of venous thrombosis and embolic stroke.

Zusammenfassung

Apixaban ist ein hoch potenter, reversibler Inhibitor des humanen Gerinnungsfaktors Xa (FXa). Es verfügt über günstige pharmakokinetische und pharmakodynamische Eigenschaften einschließlich einer konzentrationsabhängigen Antikoagulationswirkung, einer guten oralen Bioverfügbarkeit, einer ausgewogenen Elimination, eines niedrigen Potenzials von Interaktionen mit anderen Medikamenten und Nahrung und eines günstigen Sicherheitsprofils ohne Lebertoxizität. Apixaban hat bereits einen Großteil seines Phase-III-Studienprogramms abgeschlossen. In der Schlaganfallprophylaxe bei Vorhofflimmern wies Apixaban in der ARISTOTLE-Studie ein sehr ausgewogenes Wirksamkeits- und Sicherheitsprofil auf und senkte signifikant – verglichen mit Warfarin – die Inzidenz rezidivierender (insbesondere hämorrhagischer) Schlaganfälle und peripherer Embolien bei gleichzeitiger Reduktion signifikanter Blutungen. In dieser Indikation bestätigte auch der Vergleich von Apixaban mit Azetylsalizylsäure in der AVERROES- Studie die klare Überlegenheit des Faktor- Xa-Inhibitors. Apixaban absolvierte ebenfalls erfolgreich das ADVANCE-Studienprogramm in der Primärprophylaxe venöser Thromboembolien nach elektivem Hüft- oder Kniegelenkersatz und hat bereits in Europa die Zulassung für diese Indikationen erhalten. Erwartet werden in den kommenden Monaten die Ergebnisse der AMPLIFY- und AMPLIFY- EXT-Studie zur Therapie und Sekundär - prävention der venösen Thromboembolie. Der Einsatz von Apixaban nach einem akuten Koronarsyndrom oder zur Prophylaxe venöser Thromboembolien bei akut erkrankten internistischen Patienten erhielt dagegen von der APPRAISE-II- und ADOPT-Studie keine Unterstützung. Auf der Basis der aktuellen Daten - lage verspricht Apixaban eine wertvolle Option für die Prophylaxe von Schlaganfällen und Venen thrombosen zu werden.

Keywords

Apixaban - thrombosis - oral anticoagulants - atrial fibrillation - stroke - venous thromboembolism - acute coronary syndrome

Schlüsselwörter

Apixaban - Thrombose - orale Antikoagulanzien - Schlaganfall - venöse Thromboembolie - akutes Koronarsyndrom

• Literatur

• 1 Borissoff JI, Spronk HM, ten Cate H. The hemostatic system as a modulator of atherosclerosis. N Engl J Med 2011; 364: 1746-1760.
• 2 Wong PC, Pinto DJ, Zhang D. Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor. J Thromb Thrombolysis 2011; 31: 478-492.
• 3 Wong PC, Crain EJ, Xin B. et al. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost 2008; 06: 820-829.
• 4 Wong PC, Jiang X. Apixaban, a direct factor Xa inhibitor, inhibits tissue-factor induced human platelet aggregation in vitro: comparison with direct inhibitors of factor VIIa, XIa and thrombin. Thromb Haemost 2010; 104: 302-310.
• 5 Camm AJ, Kirchhof P, Lip GY. et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31: 2369-2429.
• 6 Granger CB, Armaganijan LV. Newer oral anticoagulants should be used as first-line agents to prevent thromboembolism in patients with atrial fibrillation and risk factors for stroke or thromboembolism. Circulation 2012; 125: 159-164.
• 7 Ogilvie IM, Newton N, Welner SA. et al. Underuse of oral anticoagulants in atrial fibrillation: a systematic review. Am J Med 2010; 123: 638-645.
• 8 Nieuwlaat R, Capucci A, Lip GY. et al. Antithrombotic treatment in real-life atrial fibrillation patients: a report from the Euro Heart Survey on Atrial Fibrillation. Eur Heart J 2006; 27: 3018-3026.
• 9 Waldo AL, Becker RC, Tapson VF, Colgan KJ. Hospitalized patients with atrial fibrillation and a high risk of stroke are not being provided with adequate anticoagulation. J Am Coll Cardiol 2005; 46: 1729-1736.
• 10 Go AS, Hylek EM, Borowsky LH. et al. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Ann Intern Med 1999; 131: 927-934.
• 11 Hylek EM, Evans-Molina C, Shea C. et al. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007; 115: 2689-2696.
• 12 Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med 2011; 365: 2002-2012.
• 13 Connolly SJ, Eikelboom J, Joyner C. et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364: 806-817.
• 14 Granger CB, Alexander JH, McMurray JJ. et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992.
• 15 Lassen MR, Raskob GE, Gallus A. et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 2009; 361: 594-604.
• 16 Lassen MR, Raskob GE, Gallus A. et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010; 375: 807-815.
• 17 Lassen MR, Gallus A, Raskob GE. et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010; 363: 2487-2498.
• 18 Kearon C, Akl EA, Comerota AJ. et al. Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl. 02) e419S-e494S.
• 19 Hull RD, Schellong SM, Tapson VF. et al. Extendedduration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med 2010; 153: 8-18.
• 20 Goldhaber SZ, Leizorovicz A, Kakkar AK. et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med 2011; 365: 2167-2177.
• 21 Bauersachs R, Berkowitz SD, Brenner B. et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499-2510.
• 22 Alexander JH, Lopes RD, James S. et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011; 365: 699-708.
• 23 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.
• 24 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
• 25 Patel MR, Mahaffey KW, Garg J. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-891.
• 26 Gage BF, Waterman AD, Shannon W. et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285: 2864-2870.
• 27 Oldgren J, Budaj A, Granger CB. et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, doubleblind, phase II trial. Eur Heart J 2011; 32: 2781-2789.
• 28 Steg PG, Mehta SR, Jukema JW. et al. 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; 32: 2541-2554.
• 29 Tricoci P, Huang Z, Held C. et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med 2012; 366: 20-33.