Anticoagulants

VTE prevention: shortcomings of current anticoagulants lead to underuse

While warfarin and the heparins have been the mainstay of antithrombotic therapy for decades, many clinicians find these older, multi-targeted medications challenging to use.¹⁷ These challenges, combined with under-appreciation of the degree of venous thromboembolic (VTE) risk in certain patients, have led to considerable underuse of preventive antithrombotic therapy in some countries. Observational studies reveal that fewer than half of the patients at high risk of VTE receive thromboprophylactic treatment.^{57, 90, 91}

The ideal anticoagulant

New anticoagulants that more closely meet the criteria for an ideal anticoagulant could improve the quality of care. Such an advance also might help overcome gaps between evidence-based treatment recommendations and clinical practice. Researchers are exploring single targets in the coagulation cascade in an effort to develop medications with the following properties:^{89, 92}:

Administered orally, one tablet once daily
Highly effective in reducing venous thromboembolism
Predictable dose response and kinetics
Low rate of bleeding events
No routine coagulation monitoring required
Wide therapeutic window
No dose adjustment required
Little interaction with food or other drugs
Low, nonspecific plasma protein binding
Inhibition of both free and clot-bound coagulation factors

Traditional anticoagulants: VKAs and heparin

The most widely used medications for treating thrombosis are heparins and vitamin K antagonists (VKAs). These medications have proven efficacy, but lack many properties of an ideal anticoagulant.

Heparins require parenteral administration with its attendant drawbacks — inconvenience and discomfort
VKAs can be administered orally, but have a narrow therapeutic window and a slow onset of action, along with unpredictable pharmacology. In addition, many foods and drugs interact with VKAs. As a result, periodic blood tests and frequent dose adjustments are necessary to maintain the optimal degree of anticoagulation
Currently, long-term use of single coagulation factor inhibitors are limited by the requirement for parenteral administration^{17, 88}

Recently approved anticoagulants

Rivaroxaban and dabigatran etexilate are the first new oral anticoagulants to be approved since the introduction of the first VKA, warfarin, in the 1950s.¹⁹⁴ These novel agents have the potential to advance the standard of care for patients with a wide range of thrombotic conditions. Both medications have recently been approved in the European Union, Canada and many other countries worldwide for the prevention of VTE in adult patients undergoing elective hip or knee replacement surgery. ^{251, 267, 269} Each medication offers key properties of an ideal anticoagulant, without the well-recognised limitations of heparins and VKAs.^{89, 201}

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Article references

17 - Turpie AG. Oral, direct factor Xa inhibitors in development for the prevention and treatment of thromboembolic diseases. Arterioscler Thromb Vasc Biol. 2007;27(6):1238-1247.
57 - Cohen AT, Tapson VF, Bergmann JF, et al; ENDORSE Investigators. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet. 2008;371(9610):387-394.
90 - Spencer FA, Emery C, Lessard D, et al. The Worcester Venous Thromboembolism study: a population-based study of the clinical epidemiology of venous thromboembolism. J Gen Intern Med. 2006;21(7):722-727.
91 - Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest. 2001;119(1)(suppl):132S-175S.
89 - Haas S. New oral Xa and IIa inhibitors: updates on clinical trial results. J Thromb Thrombolysis. 2008;25(1):52-60.
92 - Hirsh J, O'Donnell M, Weitz JI. New anticoagulants. Blood. 2005;105(2):453-463.
88 - Spyropoulos AC. Investigational treatments of venous thromboembolism. Expert Opin Investig Drugs. 2007;16(4):431-440.
194 - Friedman RJ. New oral anticoagulants for thromboprophylaxis after elective total hip and knee arthroplasty. Thrombosis. 2010:1-9. Article ID 280731.
251 - Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 2010.
267 - Summary of product characteristics for Pradaxa. London, England: European Medicines Agency; 2008.
269 - Summary of product characteristics for Xarelto. London, England: European Medicine Agency; 2008.
201 - Haas S. New anticoagulants - towards the development of an "ideal" anticoagulant. Vasa. 2009;38(1):13-29.

Warfarin: A vitamin K antagonist. Most commonly used oral anticoagulant in chronic prevention or treatment of VTE.
Venous thromboembolism: A condition in which a blood clot (thrombus) forms in a vein, which in some cases then breaks free and enters the circulation as an embolus, finally lodging in and completely obstructing a blood vessel, e.g., in lungs causing a PE. The term encompasses both DVT and PE.
Coagulation cascade: Series of reactions by which a small stimulus is amplified to produce rapid coagulation.
Coagulation factors: Group of plasma protein substances (Factor I to XIII) contained in the plasma, which act together to bring about blood coagulation.
Coagulation monitoring: Coagulation monitoring is practice of checking a specific coagulation parameter in order to adjust the dose. A precise adjustment of the drug intake allows the patient to stay within a defined therapeutic range, which is measured by prothrombin time or International Normalized Ratio (INR).
Parenteral: Not through the alimentary canal but rather by injection through another route.
Vitamin K antagonists: Vitamin K antagonists block the regeneration of the reduced form of vitamin K.
Dabigatran: The active form of the prodrug dabigatran etexilate, an oral direct thrombin inhibitor.
Rivaroxaban: Oral, direct Factor Xa inhibitor.