New Anticoagulant Drugs
Sunday, February 25, 2007
The traditional anticoagulant drugs warfarin, unfractionated heparin (UFH) and low molecular weight heparin (LMWH) have a number of limitations, including issues regarding laboratory monitoring, food and drug interactions (warfarin), and a narrow therapeutic window. Ideal characteristics of new anticoagulant drugs include the following features: good bioavailability, no food or drug interaction, rapid onset of action, a wide therapeutic window, a predictable anticoagulant response making laboratory monitoring unnecessary, availability of an antidote, and effectiveness and safety at least equivalent to the currently available drugs. Whereas the older anticoagulant drugs have an effect on multiple factors in the coagulation pathway, the new drugs selectively inhibit a single coagulation factor, most notably thrombin (factor IIa) and factor Xa.
These new drugs may be classified according to their target coagulation factor, and whether they are orally or parenterally administered (see below). Here follows a brief overview of these agents, and a more detailed discussion of the parenteral factor Xa inhibitor fondaparinux.
Classification of new anticoagulant drugs
(asterisk indicates FDA-approval)
Thrombin inhibitors
· Parenteral -
o Hirudin (Lepirudin)*
o Argatroban*
o Bivalirudin*
· Oral -
o Ximelagatran (withdrawn from market)
o Dabigatran
Factor Xa inhibitors
· Parenteral
o Fondaparinux*
o Idraparinux
· Oral
o Rivaroxaban
o Apixaban
o Others
The parenteral direct thrombin inhibitors lepirudin and argatroban are approved for the treatment of heparin-induced thrombocytopenia (HIT). They are both administered intravenously and monitored by the APTT (target range 1.5-2 x baseline for lepirudin, 1.5-3 x baseline for argatroban). Lepirudin is excreted by the kidneys, while argatroban is metabolized by the liver. Bivalirudin is approved for percutaneous coronary interventions. All of these drugs have short half-lives (25-60 min).
The promising oral direct thrombin inhibitor ximelagatran, which required no laboratory monitoring, was recently withdrawn from the market due to hepatotoxicity. Dabigatran is another agent in this class, currently undergoing evaluation.
Parenteral factor Xa inhibitors act as indirect inhibitors since their effect is mediated through antithrombin (formerly known as antithrombin III). Fondaparinux is a pentasaccharide obtained by chemical synthesis. It binds to antithrombin resulting in a conformational change in the antithrombin molecule, thereby greatly potentiating its inhibition of factor Xa. It is administered once daily by subcutaneous injection in a fixed dose, and no laboratory monitoring is required. This drug shows no cross-reactivity with HIT antibodies, and has not been associated with any instance of HIT. The drug is excreted by the kidneys, and has a half-life of 17 hours. No antidote is available.
Fondaparinux has been shown to be effective in the prevention of venous thromboembolism (VTE) following orthopedic surgery. A meta-analysis of four large trials (Arch Int Med. 2002;162:1833-40) showed that fondaparinux was significantly more effective than LMWH in reducing the incidence of VTE after hip replacement, hip fracture surgery and major knee surgery, with an overall 55% decrease in risk reduction compared with LMWH. Fondaparinux was shown in other trials to be at least as effective and safe as LMWH/UFH in the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), in the prevention of VTE after abdominal surgery, and in the treatment of acute coronary syndrome. Fondaparinux is the first selective factor Xa inhibitor to be FDA approved as an anticoagulant. It is currently approved for prevention of VTE following hip fracture surgery, total hip and total knee replacement, and major abdominal surgery. It is also approved for the initial treatment of DVT and PE. The drug in both prophylactic and therapeutic doses prolongs the PT by approximately 1 second, and the APTT by approximately 4-5 seconds, however laboratory monitoring is not indicated.
Oral factor Xa inhibitors (rivaroxaban, apixaban and others) act as direct inhibitors; their effect is not mediated by antithrombin. These drugs also require no laboratory monitoring. They are currently undergoing extensive phase II and phase III studies on prevention and treatment of VTE, and initial reports look promising.
In conclusion, selective inhibitors of specific coagulation factors (thrombin and factor Xa) represent a new class of anticoagulants. They have the potential to be at least as effective and safe as conventional anticoagulants without the need for laboratory monitoring.
posted by Fred Plapp @ 3:30 PM,
