Thrombosis — localized blood clot formation — is a leading cause of morbidity and mortality associated with arterial diseases, such as myocardial infarction and stroke, and venous thromboembolic (VTE) disorders, including deep vein thrombosis and pulmonary embolism1. VTE is the third leading cause of cardiovascular-related death, after myocardial infarction and stroke, and is one of the leading causes of death in patients with cancer.
Antithrombotic drugs, including anticoagulants, antiplatelet agents and direct thrombolytics, are used for both the prevention and the acute treatment of thrombosis1 (Table 1). Anticoagulants target elements of the coagulation cascade (Fig. 1) and are typically used for short- and long-term management of thrombotic disorders of both the arterial and venous systems. The most common use of anticoagulation is for stroke prevention in patients with atrial fibrillation (Table 1).
Current anticoagulants
Vitamin K antagonists and heparins have dominated the anticoagulant market for over half a century. Warfarin inhibits the vitamin K-dependent activation of several clotting factors (Fig. 1) and is the most commonly prescribed anticoagulant. Until recently, it was the only orally bioavailable agent of this kind and it remains the only approved drug for long-term anticoagulation therapy. Use of warfarin in patients with atrial fibrillation reduces the incidence of stroke by 64%. Despite proven efficacy, warfarin carries the risk of serious or fatal bleeding, has an unpredictable pharmacokinetic profile, is subject to drug–drug interactions and is affected by an individual's genetic make-up and diet, making it hard to dose. Various generic vitamin K antagonists overall generated global sales of over US$700 million in 2008 (Ref. 2).
Heparins interact with various factors of the coagulation cascade (Fig. 1) and are used for short-term prophylaxis of thrombosis. Heparins are injectable, which limits their use to an in-patient setting or for short-term (not more than 2 weeks) VTE prophylaxis. In the case of unfractionated heparins, additional complications include monitoring and dose adjustment requirements and the risk of heparin-induced thrombocytopoenia (HIT), which develops in 3% of patients. HIT leads to thrombosis and increased mortality. The incidence of HIT is substantially reduced with low molecular weight heparins (LMWHs). The most widely prescribed LMWH, enoxaparin (Lovenox; Sanofi–Aventis), is the leading drug for the prophylaxis of VTE and is also used in acute coronary syndromes. It is the best-selling anticoagulant on the market, with global sales of approximately $4 billion in 2008. However, over the next 5 years, the market share of enoxaparin is expected to decline owing to generic competition and the introduction of new oral anticoagulants.
The large market opportunity and knowledge of the shortcomings of current anticoagulants resulted in increased interest in new agents that would be at least as effective as those currently available, but with an improved safety profile (specifically, reduced risk of bleeding) and greater ease of use (oral agents, especially in a chronic setting).
Direct thrombin inhibitors
Thrombin, or factor IIa, catalyses the production of fibrin (Fig. 1) and is involved in other coagulation-related reactions, making it an attractive therapeutic target.
Parenteral direct thrombin inhibitors (DTIs) currently on the market are primarily used in patients undergoing percutaneous coronary intervention (PCI) and in patients with or at risk for HIT. In the United States, bivalirudin (Angiomax; Medicines Company) has become a dominant anticoagulant used in PCI. Improved patient outcomes drive its widespread use. Patients treated with bivalirudin show a reduction in severe bleeding of up to 59% and a reduction in 1 year mortality of up to 47% compared with those treated with a combination of heparin and a platelet glycoprotein IIb and IIIa inhibitor3. Bivalirudin goes off-patent in 2010 (unless a patent extension is granted), after which its market share is expected to be eroded by generic competition.
The first approved oral DTI, ximelagatran (Exanta; AstraZeneca), was withdrawn from the market in 2006 owing to its link to liver toxicity. Last year, a second oral DTI, dabigatran (Pradaxa; Boehringer Ingelheim) gained approval in the European Union and Canada for prevention of VTE following joint-replacement surgery2; a filing for US approval is expected in 2009. However, the biggest market opportunity for dabigatran (or indeed for any oral anticoagulant) lies in stroke prevention in patients with atrial fibrillation. Phase III trial results in atrial fibrillation are expected in 2009. Given its large lead in development (about 3 years ahead of competition), dabigatran could become a dominant player in this setting, ending the era of warfarin and rapidly achieving a blockbuster status.
Factor Xa inhibitors
Factor Xa is a coagulation factor that is essential for the formation of thrombin (Fig. 1). Several oral factor Xa inhibitors are in late stages of development: rivaroxaban (Xarelto; Bayer/Johnson&Johnson), apixaban (Bristol–Myers Squibb/Pfizer) and edoxaban (Daiichi Sankyo). Market indicators
Rivaroxaban was approved for the prevention of VTE post joint-replacement surgery in the European Union and Canada last year. In Phase III studies, rivaroxaban demonstrated a reduced rate of deep vein thrombosis, pulmonary embolism and all-cause mortality versus enoxaparin (9.6% versus 18.9%) without an increased risk of bleeding4. A new drug application (NDA) for this indication is under review by the US Food and Drug Administration. Phase III trials in stroke prevention due to atrial fibrillation are ongoing.
An NDA for apixaban for VTE prophylaxis after orthopaedic surgery was originally planned for 2009. However, apixaban missed a primary end point of non-inferiority to enoxaparin in the Phase III ADVANCE-1 trial. Despite this setback, development of apixaban for this indication continues in ADVANCE-2 and -3 trials. In addition to VTE prophylaxis, apixaban is in Phase III trials for stroke prevention due to atrial fibrillation and in Phase II studies in acute coronary syndromes.
Daiichi Sankyo's strategy for edoxaban is to seek approval in the largest market segment — atrial fibrillation — right from the start. A pivotal Phase III programme was initiated at the end of 2008. However, the company also plans to pursue indications such as VTE and acute coronary syndromes at a later stage.
Market outlook
The anticoagulant market is projected to grow from around $6 billion in 2008 to over $9 billion in 2014 (Fig. 2). The growth will be driven by demographics of the ageing population and increased incidence of cardiovascular disease, but mainly by the approval of new agents that will offer substantial improvements over the current standards of care. The availability of oral anticoagulants is poised to have the greatest effect on the atrial fibrillation-related stroke prevention segment of the market, in which the use of warfarin is expected to become obsolete (Fig. 2).
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