Author's Accepted Manuscript
Direct oral anticoagulants (DOAC) versus “new” oral anticoagulants (NOAC)? Lars M. Asmis MD
www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S0037-1963(14)00012-2 http://dx.doi.org/10.1053/j.seminhematol.2014.03.003 YSHEM50768
To appear in: Semin Hematol
Cite this article as: Lars M. Asmis MD, Direct oral anticoagulants (DOAC) versus “new” oral anticoagulants (NOAC)?, Semin Hematol , http://dx.doi.org/10.1053/j.seminhematol.2014.03.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Direct oral anticoagulants (DOAC) versus “new” oral anticoagulants (NOAC)? Direct oral anticoagulants (DOAC) represent a class of drugs that was developed more than 10 years ago. Direct in this context implies that these anticoagulants inhibit a target molecule by themselves and do not require the presence of other proteins for their action such as plasma antithrombin for heparins or hepatic γ‐carboxylase for vitamin K antagonists. Today two main subclasses of DOAC are in clinical use, agents directed against activated factor II (anti‐FIIa) and agents directed against activated factor X (anti‐FXa) as depicted in Figure 1. Ximelagatran, was the first direct anti‐FIIa to obtain European and American health agency approval in 2003 and 2005, respectively. Rivaroxaban was the first direct anti‐FXa to achieve health agency approval in 2008. As time since the original discovery progresses, the designation “new” oral anticoagulants or NOAC is progressively becoming inappropriate. Based on the mechanism of action the designation DOAC has come into use over the past years. The authors of this theme issue of Seminars in Hematology were asked to vote on the preferred designation and chose for the more recent of the two. Direct anticoagulants are possibly the anticoagulants that were first isolated for medical use. This hypothesis is based on the guest editor’s amateur queries into historic publications. Long before McLean & Howell discovered heparin in canine liver (1916+1918) and Karl Link investigated the active principle of vitamin K antagonists (1933) the effects of hirudin (Haycraft 1884) were known. Hirudo medicinalis, the medicinal leach produces this peptide anticoagulant and secretes it in saliva to permit digestion of blood sucked up by the parasite (1,2). It took more than 150 years to evolve from the direct thrombin inhibitor hirudin that could only be applied parenterally and had a narrow therapeutic window to modern oral direct anticoagulants. Ximelagatran, as mentioned above, was the first such molecule to obtain FDA approval. After successful clinical testing it had to be taken off the market after rare but lethal hepatic complications in 2006. The fear of anticoagulant‐induced hepatitis and other side effects has since then persisted.
The good news for patients and clinicians has been that the follow‐up products including the thrombin inhibitor dabigatran etexilate and the FXa inhibitors, rivaroxaban, apixaban and edoxaban, have not showed such toxicity. The less good news is, that doctors in general underreport adverse drug effects. According to Etminan the average MD reports one adverse drug effect less than every 300 years (3). Rigorous post marketing surveillance thus is one of the lessons that has to be taken from the above described events. The driving force behind the clinical development of DOAC was based on the inadequacies of older direct and indirect anticoagulants including need of parenteral administration, the necessity for monitoring, narrowness of the therapeutic window, associated bleeding risk, to name only some (4). The wait for the advent of these novel molecules was long. The prerequisite for their development was knowledge of the exact three dimensional structures of the target molecules’ active sites. X‐ray crystallographic models of thrombin and FXa were used to aid design and maximize effects of DOAC. This issue of Seminars In Hematology brings together a group of renowned experts who review topics including DOAC’s mechanisms of action, their pharmacology, the associated bleeding risks, their perioperative management as well as major trials in VTE prevention and treatment, atrial fibrillation, acute coronary syndrome and special indications including cancer. I wish to thank the contributing authors for their tremendous efforts to provide us and our readers with the most updated information and the chief editors together with their editorial staff for outstanding support. Lars M. Asmis M.D. Guest editor Lars M. Asmis, MD
Unilabs Coagulation Laboratory & Center for Perioperative Thrombosis and Hemostasis, Zurich, Switzerland; [email protected] References 1.) Link KP. The discovery of dicumarol and its sequels. Circulation 1959; 19:97‐107. 2.) Mannucci PM & Poller L. Venous thrombosis and anticoagulant therapy. British Journal of Haematology 2001; 114:258‐70 3.) Etminan M, Carleton B, Rochon PA. Quantifying adverse drug events: are systematic reviews the answer? Drug Safety 2004; 27:757‐61. 4.) Ansell J. Warfarin versus new agents: interpreting the data. Hematology Am Soc Hematol Educ Program. 2010:221‐8. 5.) Hoffman M, Monroe DM 3rd. The action of high‐dose factor VIIa (FVIIa) in a cell‐based model of hemostasis. Semin Hematol 2001; 38(4Suppl 12):6‐9.
Figure 1: DOAC – Sites of action
Legend to figure 1 Fig. 1: DOAC – sites of action. Based on the cellular model of hemostasis this figure depicts DOAC sites’ of action. Tissue factor bearing cells (TF+ cells) are key to initiating coagulation according the model originally described by Hoffman & Monroe (5). The complex of TF and activated factor VII (FVIIa) leads to the generation of activated factor X (FXa). In the subsequent amplification phase first traces of activated factor II (FIIa = thrombin) are generated, which in turn leads to activation of multiple targets. In the propagation phase the surface of activated platelets then serves as a platform for the FXa‐based generation of the thrombin burst necessary for the last phase resulting in fibrin stabilization (insoluble fibrin: fibrini). Sites of direct inhibtors of FXa (anti factor Xa) and thrombin (anti FIIa) are depicted in red and in blue.
Direct oral anticoagulants (DOAC) versus “new” oral anticoagulants (NOAC)? Lars M. Asmis MD
www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S0037-1963(14)00012-2 http://dx.doi.org/10.1053/j.seminhematol.2014.03.003 YSHEM50768
To appear in: Semin Hematol
Cite this article as: Lars M. Asmis MD, Direct oral anticoagulants (DOAC) versus “new” oral anticoagulants (NOAC)?, Semin Hematol , http://dx.doi.org/10.1053/j.seminhematol.2014.03.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Direct oral anticoagulants (DOAC) versus “new” oral anticoagulants (NOAC)? Direct oral anticoagulants (DOAC) represent a class of drugs that was developed more than 10 years ago. Direct in this context implies that these anticoagulants inhibit a target molecule by themselves and do not require the presence of other proteins for their action such as plasma antithrombin for heparins or hepatic γ‐carboxylase for vitamin K antagonists. Today two main subclasses of DOAC are in clinical use, agents directed against activated factor II (anti‐FIIa) and agents directed against activated factor X (anti‐FXa) as depicted in Figure 1. Ximelagatran, was the first direct anti‐FIIa to obtain European and American health agency approval in 2003 and 2005, respectively. Rivaroxaban was the first direct anti‐FXa to achieve health agency approval in 2008. As time since the original discovery progresses, the designation “new” oral anticoagulants or NOAC is progressively becoming inappropriate. Based on the mechanism of action the designation DOAC has come into use over the past years. The authors of this theme issue of Seminars in Hematology were asked to vote on the preferred designation and chose for the more recent of the two. Direct anticoagulants are possibly the anticoagulants that were first isolated for medical use. This hypothesis is based on the guest editor’s amateur queries into historic publications. Long before McLean & Howell discovered heparin in canine liver (1916+1918) and Karl Link investigated the active principle of vitamin K antagonists (1933) the effects of hirudin (Haycraft 1884) were known. Hirudo medicinalis, the medicinal leach produces this peptide anticoagulant and secretes it in saliva to permit digestion of blood sucked up by the parasite (1,2). It took more than 150 years to evolve from the direct thrombin inhibitor hirudin that could only be applied parenterally and had a narrow therapeutic window to modern oral direct anticoagulants. Ximelagatran, as mentioned above, was the first such molecule to obtain FDA approval. After successful clinical testing it had to be taken off the market after rare but lethal hepatic complications in 2006. The fear of anticoagulant‐induced hepatitis and other side effects has since then persisted.
The good news for patients and clinicians has been that the follow‐up products including the thrombin inhibitor dabigatran etexilate and the FXa inhibitors, rivaroxaban, apixaban and edoxaban, have not showed such toxicity. The less good news is, that doctors in general underreport adverse drug effects. According to Etminan the average MD reports one adverse drug effect less than every 300 years (3). Rigorous post marketing surveillance thus is one of the lessons that has to be taken from the above described events. The driving force behind the clinical development of DOAC was based on the inadequacies of older direct and indirect anticoagulants including need of parenteral administration, the necessity for monitoring, narrowness of the therapeutic window, associated bleeding risk, to name only some (4). The wait for the advent of these novel molecules was long. The prerequisite for their development was knowledge of the exact three dimensional structures of the target molecules’ active sites. X‐ray crystallographic models of thrombin and FXa were used to aid design and maximize effects of DOAC. This issue of Seminars In Hematology brings together a group of renowned experts who review topics including DOAC’s mechanisms of action, their pharmacology, the associated bleeding risks, their perioperative management as well as major trials in VTE prevention and treatment, atrial fibrillation, acute coronary syndrome and special indications including cancer. I wish to thank the contributing authors for their tremendous efforts to provide us and our readers with the most updated information and the chief editors together with their editorial staff for outstanding support. Lars M. Asmis M.D. Guest editor Lars M. Asmis, MD
Unilabs Coagulation Laboratory & Center for Perioperative Thrombosis and Hemostasis, Zurich, Switzerland; [email protected] References 1.) Link KP. The discovery of dicumarol and its sequels. Circulation 1959; 19:97‐107. 2.) Mannucci PM & Poller L. Venous thrombosis and anticoagulant therapy. British Journal of Haematology 2001; 114:258‐70 3.) Etminan M, Carleton B, Rochon PA. Quantifying adverse drug events: are systematic reviews the answer? Drug Safety 2004; 27:757‐61. 4.) Ansell J. Warfarin versus new agents: interpreting the data. Hematology Am Soc Hematol Educ Program. 2010:221‐8. 5.) Hoffman M, Monroe DM 3rd. The action of high‐dose factor VIIa (FVIIa) in a cell‐based model of hemostasis. Semin Hematol 2001; 38(4Suppl 12):6‐9.
Figure 1: DOAC – Sites of action
Legend to figure 1 Fig. 1: DOAC – sites of action. Based on the cellular model of hemostasis this figure depicts DOAC sites’ of action. Tissue factor bearing cells (TF+ cells) are key to initiating coagulation according the model originally described by Hoffman & Monroe (5). The complex of TF and activated factor VII (FVIIa) leads to the generation of activated factor X (FXa). In the subsequent amplification phase first traces of activated factor II (FIIa = thrombin) are generated, which in turn leads to activation of multiple targets. In the propagation phase the surface of activated platelets then serves as a platform for the FXa‐based generation of the thrombin burst necessary for the last phase resulting in fibrin stabilization (insoluble fibrin: fibrini). Sites of direct inhibtors of FXa (anti factor Xa) and thrombin (anti FIIa) are depicted in red and in blue.
![[New direct oral oral anticoagulants (DOACs) - indications of DOACs].](/assets/img/hold.png)
