The Future of Anticoagulant Therapy

Major advances in the development of oral anticoagulants have resulted in considerable progress towards the goal of safe and effective oral anticoagulants that do not require frequent monitoring or dose adjustment, and have minimal food/drug interactions as highlighted recently in several reports [1-7] and summarized in recent reviews in Cardiovascular Therapeutics and other journals [1-4]. Indirect inhibitors of factor Xa and factor IIa such as low-molecular weight heparin (LMWH) and the pentasaccharide fondaparinux represent improvements over traditional drugs, such as unfractionated heparin, for acute treatment of VTE, constituting a more targeted anticoagulant approach, with predictable pharmacokinetic profiles, and no requirement for monitoring [6, 7]. Vitamin K antagonist, with its inherent limitations in terms of multiple food and drug interactions and frequent need for monitoring, remains the only oral anticoagulant approved for long-term secondary Thromboprophylaxis in VTE. The oral direct thrombin inhibitor ximelagatran was withdrawn from the world market due to safety concerns. Newer anticoagulant drugs such as oral direct thrombin inhibitors (dabigatran), oral direct factor Xa inhibitors (rivaroxaban, apixaban, and several others) are being introduced into the European and Canadian markets and have the potential to greatly expand oral antithrombotics for both acute and long-term treatment of VTE, and for the prevention of stroke in atrial fibrillation patients [1-9]. See Figure 1 for historical progression in anticoagulation and Figure 2 for the structure of the first oral direct anti-Xa and the first direct anti-IIa. Historical progression in the advances in anticoagulation. Structure of the first oral direct anti-Xa (Rivaroxaban) (A) and the first oral direct anti-IIa (Dabigatran) (B). The current anti-thrombotic (anti-coagulant) strategies are expected to change the landscape of thrombosis management dramatically. A number of these new oral anticoagulant therapies are set to enter the market, raising a number of questions: How will it evolve? What are the future scenarios? Will it be cost effective? With so many drugs in development, will it turn into another ‘me-too’ market? Or, will one drug dominate? Can heparin, LMWHs warfarin be replaced? In a comprehensive RECORD clinical trial program involving over 12,500 patients, rivaroxaban, a direct factor Xa inhibitor, taken as a once-daily tablet, demonstrated improved efficacy of up to 50% over the existing standard of care: the injectable, LMWH enoxaparin [8, 9]. Rivaroxaban (Figure 2) is the only oral anticoagulant to have demonstrated superior efficacy over enoxaparin, the mainstay of current Thromboprophylaxis [8, 9]. Results of the RECORD 1 and 3 trials, which compared rivaroxaban with enoxaparin, demonstrated that prophylactic treatment with rivaroxaban was associated with a 70% relative risk reduction (RRR) in the development of venous blood clots in hip replacement patients (2.6% absolute risk reduction) and 49% RRR in knee replacement patients (9.2% absolute risk reduction), whilst demonstrating comparable bleeding and side effect profiles [2, 3]. With its efficacy advantages and convenient oral administration, which requires no coagulation monitoring, rivaroxaban has the potential to have a significant impact on clinical practice [3-7]. In March 2009, the FDA Advisory panel recommended the approval of rivaroxaban (Xarelto, Johnson & Johnson, New Brunswick, NJ, USA), which would be the first new oral anticoagulant since the approval of warfarin in 1954 for the prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing hip and knee replacement surgery. The recommendation is based on data from the four phase 3 RECORD trials, which together compared the factor Xa inhibitor rivaroxaban at 10 mg per day, with the subcutaneously administered LMWH enoxaparin for prevention of venous thromboembolism after hip or knee surgery in more than 12,500 patients [6-9]. In October 2010, the FDA approved the first new oral direct anti-IIa anticoagulant in 55 years, dabigatran (marketed by Boehringer Ingelheim Pharmaceuticals, Ingelheim, Germany, under the trade name Pradaxa) for stroke prevention in patients with nonvalvular atrial fibrillation. As demonstrated in the 18,113 patients RE-LY trial, Pradaxa 150 mg taken twice daily significantly reduced stroke and systemic embolism by 35% beyond the reduction achieved with warfarin, the current standard of care for patients with nonvalvular atrial fibrillation. Pradaxa 150 mg twice daily significantly reduced both ischemic and hemorrhagic strokes compared with warfarin. Treatment with Pradaxa does not require blood monitoring or related dose adjustments and has no recommended dietary restrictions. The FDA also approved Pradaxa 75 mg twice daily for the small sub-set of patients who have severe renal impairment. The stroke prevention trials with the new oral anti-IIa and anti-Xa in AF patients might have potential in replacing the most hated (must be monitored and the need for life style adjustment) and the most loved dominant oral anticoagulant (cheap) warfarin. The future of the new anticoagulants will depend on the combined safety, efficacy, convenience, and health cost saving profiles as compared to the current conventional antithrombotics. Even with equivalent efficacy and safety to that of standard antithrombotics, the lack of drug, food interactions, and the elimination of the need to monitor would favor the new oral agents even at relatively higher cost. However, certain indications such as VTE during pregnancy would not be replaced by these upcoming novel oral small molecule anticoagulants. In addition, the expanded utility of heparin derivatives and their associated polypharmacological actions will not be replaced with the single mechanism based small molecule anticoagulants. The future of all new oral factor Xa or IIa inhibitors will depend on the relative efficacy, safety, and cost.

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