Der lange Weg zu den NOAK

Zusammenfassung

Vor 100 Jahren war der Ablauf der Blutgerinnung nur in groben Zügen bekannt und über den Wirkmechanismus des damals entdeckten gerinnungshemmenden Wirkstoffs Heparin gab es nur vage Vorstellungen. Infolge des raschen pragmatischen Einsatzes haben Heparin, so wie auch das in den 20er- Jahren entwickelte Warfarin, einen jahrzehntelangen Siegeszug angetreten. Erst gegen Ende des letzten Jahrhunderts gelang die Synthese von Antikoagulanzien mit gezieltem Wirkmechanismus, wie z. B. dem Faktor-Xa-Hemmer Fondaparinux oder die rekombinante Herstellung des direkten Thrombinhemmers Hirudin, dicht gefolgt von der Synthese der Nicht-Vitamin-K-antagonistischen oralen Antikoagulanzien (NOAK). Letztere wurden seit Anfang des 21. Jahrhunderts klinisch entwickelt und sind mittlerweile für verschiedene Indikationen verfügbar. NOAK zeichnen sich durch reproduzierbare orale Bioverfügbarkeit, kurze Halbwertszeit im Vergleich zu Vitamin- K-Antagonisten, geringe Interaktionen mit anderen Arzneimitteln, fixe Dosierung ohne Laborkontrolle sowie ein günstigeres Nutzen-/ Risikoprofil als die konventionellen Gerinnungshemmer aus. Beim Einsatz dieser Präparate ist zu beachten, dass es Unterschiede in der Metabolisierung, der renalen Eliminierung und den Dosierungsregeln gibt.

Schlüsselwörter

Heparin - niedermolekulares Heparin - Vitamin-K-Antagonisten - orale Antikoagulanzien - NOAK

• References

• 1 Haas S, Gruber-Gerardy KF. Gerinnungsforschung – Hundert Jahre vom Naturstoff zum direkten Xa- Inhibitor. Mainz: Medbrain Verlag; 2011
• 2 McLean J. The discovery of heparin. Circulation 1959; 19: 75-78.
• 3 Haas G. Über Blutwaschung. Klinische Wochenschrift 1928; 07: 1356-62.
• 4 Wardrop D, Keeling D. The story of the discovery of heparin and warfarin. Br J Haematol 2008; 141: 757-763.
• 5 Best CH. Preparation of Heparin and Its Use in the First Clinical Cases. Circulation 1959; 19: 79-86.
• 6 Murray DWG, Jacques LB, Perrett TS. et al. Heparin and thrombosis of veins following injury. Surgery 1937; 02: 163-187.
• 7 Duxberry BM, Poller L. The oral anticoagulant saga: past, present, and future. Clin Appl Thromb Hemost 2001; 07: 269-275.
• 8 Bell RG, Sadowski JA, Matschiner JT. Mechanism of action of warfarin. Warfarin and metabolism of vitamin K 1. Biochemistry 1972; 11: 1959-1961.
• 9 Vinazzer H, Stemberger A, Haas S. et al. Influence of heparin; of different heparin fractions and of a low molecular weight heparin-like substance on the mechanism of fibrinolysis. Thromb Res 1982; 27: 341-352.
• 10 Haas S, Blümel G. Prophylaxis of thromboembolism with various low-molecular-weight heparins. Haemostasis 1988; 18 (Suppl. 03) 82-87.
• 11 Haas S, Stemberger A, Fritsche HM. et al. Prophylaxis of deep vein thrombosis in high risk patients undergoing total hip replacement with low molecular weight heparin plus dihydroergotamine. Arzneimittelforschung 1987; 37: 839-843.
• 12 Haas S, Blümel G. An objective evaluation of the clinical potential of low molecular weight heparins in the prevention of thromboembolism. Semin Thromb Hemost 1989; 15: 424-434.
• 13 Leyvraz P, Bachmann F, Bohnet J. et al. Thromboembolic prophylaxis in total hip replacement: a comparison between the low molecular weight heparinoid Lomoparan and heparin-dihydroergotamine. Br J Surg 1992; 79: 911-4.
• 14 Wolf H, Encke A, Haas S. et al. Comparison of the efficacy and safety of Sandoz low molecular weight heparin and unfractionated heparin: interim analysis of a multicenter trial. Semin Thromb Hemost 1991; 17: 343-346.
• 15 Freick H, Haas S. Prevention of deep vein thrombosis by low-molecular-weight heparin and dihydroergotamine in patients undergoing total hip replacement. Thromb Res 1991; 63: 133-143.
• 16 Haas S, Stemberger AW, Fritsche HM. et al. Study of a dose-dependent effect of the glycosaminoglycan polysulfate on various parameters of blood coagulation. Semin Thromb Hemost 1991; 17 (Suppl. 02) 214-218.
• 17 Haas S, Flosbach CW. Antithromboembolic efficacy and safety of enoxaparin in general surgery. German multicentre trial Eur J Surg Suppl 1994; 571: 37-43.
• 18 Nurmohamed MT, Verhaeghe R, Haas S. et al. A comparative trial of a low molecular weight heparin (enoxaparin) versus standard heparin for the prophylaxis of postoperative deep vein thrombosis in general surgery. Am J Surg 1995; 169: 567-571.
• 19 Kakkar VV, Boeckl O, Boneu B. et al. Efficacy and safety of a low-molecular-weight heparin and standard unfractionated heparin for prophylaxis of postoperative venous thromboembolism: European multicenter trial. World J Surg 1997; 21: 2-8.
• 20 Adolf J, Fritsche HM, Haas S. et al. Comparison of 3,000 IU aXa of the low molecular weight heparin certoparin with 5,000 IU aXa in prevention of deep vein thrombosis after total hip replacement. German Thrombosis Study Group Int Angiol 1999; 18: 122-126.
• 21 Haas S, Walenga JM, Jeske WP. et al. Heparin-induced thrombocytopenia: the role of platelet activation and therapeutic implications. Semin Thromb Hemost 1999; 25 (Suppl. 01) 67-75.
• 22 Eichler P, Budde U, Haas S. et al. First workshop for detection of heparin-induced antibodies: validation of the heparin-induced platelet-activation test (HIPA) in comparison with a PF4/heparin ELISA. Thromb Haemost 1999; 81: 625-629.
• 23 Klinkhardt U, Breddin HK, Esslinger HU. et al. Interaction between the LMWH reviparin and aspirin in healthy volunteers. Br J Clin Pharmacol 2000; 49: 337-341.
• 24 Haas S, Walenga JM, Jeske WP. et al. Heparin-induced thrombocytopenia: clinical considerations of alternative anticoagulation with various glycosaminoglycans and thrombin inhibitors. Clin Appl Thromb Hemost 1999; 05: 52-59.
• 25 Haas S. Low molecular weight heparins in the prevention of venous thromboembolism in nonsurgical patients. Semin Thromb Hemost 1999; 25 (Suppl. 03) 101-105.
• 26 Haas S, Wolf H, Kakkar AK, Fareed J, Encke A. Prevention of fatal pulmonary embolism and mortality in surgical patients: a randomized doubleblind comparison of LMWH with unfractionated heparin. Thromb Haemost 2005; 94 (04) 814-819.
• 27 Kirchmaier CM, Wolf H, Schäfer H. et al. Efficacy of a low molecular weight heparin administered intravenously or subcutaneously in comparison with intravenous unfractionated heparin in the treatment of deep venous thrombosis. Certoparin- Study Group. International Angiology 1998; 17: 135-145.
• 28 Choay J, Petitou M, Lormeau JC. et al. Structureactivity relationship in heparin: a synthetic pentasaccharide with high affinity for antithrombin III and eliciting high anti-factor Xa activity. Biochem Biophys Res Commun 1983; 116: 492-499.
• 29 Eriksson BI, Borris L, Dahl OE. et al. Oral, direct Factor Xa inhibition with BAY 59–7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2006; 04: 121-8.
• 30 Eriksson BI, Borris LC, Dahl OE. et al. A oncedaily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59–7939), for thromboprophylaxis after total hip replacement. Circulation 2006; 114: 2374-2381.
• 31 Turpie AG, Lassen MR, Eriksson BI. et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost 2011; 105: 444-453.
• 32 Turpie AG, Haas S, Kreutz R. et al. A non-interventional comparison of rivaroxaban with standard of care for thromboprophylaxis after major orthopaedic surgery in 17,701 patients with propensity score adjustment. Thromb Haemost 2014; 111: 94-102.
• 33 Agnelli G, Gallus A, Goldhaber SZ. et al. Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59–7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59–7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) study. Circulation 2007; 116: 180-187.
• 34 Prins MH, Lensing AWA, Bauersachs R. et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J 2013; 11: 21.
• 35 Ageno W, Mantovani LG, Haas S. et al. Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. Lancet Haematol 2016; 03: e12-21.
• 36 EINSTEIN Investigators. Bauersachs R, Berkowitz SD. et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499-2510.
• 37 Bauersachs R, Haas S, Kreutz R. et al. Sicherheit und Wirksamkeit von Rivaroxaban im Vergleich zur Standard-Antikoagulation bei tiefen Venenthrombosen im klinischen Alltag – Subgruppenanalyse XALIA-DE für Deutschland. Phlebologie 2016; 45: 187-193.
• 38 Ruff CT, Giugliano RP, Braunwald E. et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383: 955-962.
• 39 Camm AJ, Amarenco P, Haas S. et al. XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation. Eur Heart J 2016; 37: 1145-1153.
• 40 Connolly SJ, Wallentin L, Ezekowitz MD. et al. The Long-Term Multicenter Observational Study of Dabigatran Treatment in Patients With Atrial Fibrillation (RELY-ABLE) Study. Circulation 16; 128: 237-243.