The future of anticoagulant therapy.

Major advances in the development of oral anticoagulants haveresulted in considerable progress towards the goal of safe and ef-fective oral anticoagulants that do not require frequent monitor-ing or dose adjustment, and have minimal food/drug interactionsas highlighted recently in several reports [1–7] and summarized inrecent 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 fon-daparinux represent improvements over traditional drugs, such asunfractionated heparin, for acute treatment of VTE, constituting amore targeted anticoagulant approach, with predictable pharma-cokinetic proﬁles, and no requirement for monitoring [6,7]. Vita-min K antagonist, with its inherent limitations in terms of multi-ple food and drug interactions and frequent need for monitoring,remains the only oral anticoagulant approved for long-term sec-ondary Thromboprophylaxis in VTE. The oral direct thrombin in-hibitor ximelagatran was withdrawn from the world market dueto safety concerns. Newer anticoagulant drugs such as oral directthrombin inhibitors (dabigatran), oral direct factor Xa inhibitors(rivaroxaban, apixaban, and several others) are being introducedinto the European and Canadian markets and have the potentialto greatly expand oral antithrombotics for both acute and long-term treatment of VTE, and for the prevention of stroke in atrialﬁbrillation patients [1–9]. See Figure 1 for historical progressionin anticoagulation and Figure 2 for the structure of the ﬁrst oraldirect anti-Xa and the ﬁrst direct anti-IIa.The current anti-thrombotic (anti-coagulant) strategies are ex-pected to change the landscape of thrombosis management dra-matically. A number of these new oral anticoagulant therapies areset to enter the market, raising a number of questions: How willit 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, LMWHswarfarin be replaced?In a comprehensive RECORD clinical trial program involvingover 12,500 patients, rivaroxaban, a direct factor Xa inhibitor,taken as a once-daily tablet, demonstrated improved efﬁcacy of upto 50% over the existing standard of care: the injectable, LMWHenoxaparin [8,9]. Rivaroxaban (Figure 2) is the only oral antico-agulant to have demonstrated superior efﬁcacy over enoxaparin,the mainstay of current Thromboprophylaxis [8,9].Results of the RECORD 1 and 3 trials, which compared ri- The futureof all neworal factorXa or IIainhibitorswill dependon therelativeefﬁcacy,safety, andcost.varoxaban with enoxaparin, demonstrated that prophylactic treat-ment with rivaroxaban was associated with a 70% relative riskreduction (RRR) in the development of venous blood clots inhip 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 administra-tion, which requires no coagulation monitoring, rivaroxaban hasthe potential to have a signiﬁcant impact on clinical practice [3–7].In March 2009, the FDA Advisory panel recommended theapproval of rivaroxaban (Xarelto, Johnson & Johnson, NewBrunswick, NJ, USA), which would be the ﬁrst new oral antico-agulant since the approval of warfarin in 1954 for the prophylaxisof deep vein thrombosis (DVT) and pulmonary embolism (PE) inpatients undergoing hip and knee replacement surgery. The rec-ommendation is based on data from the four phase 3 RECORD tri-als, which together compared the factor Xa inhibitor rivaroxabanat 10 mg per day, with the subcutaneously administered LMWHenoxaparin for prevention of venous thromboembolism after hipor knee surgery in more than 12,500 patients [6–9].In October 2010, the FDA approved the ﬁrst new oral di-rect anti-IIa anticoagulant in 55 years, dabigatran (marketedby Boehringer Ingelheim Pharmaceuticals, Ingelheim, Germany,under the trade name Pradaxa) for stroke prevention in pa-tients with nonvalvular atrial ﬁbrillation. As demonstrated inthe 18,113 patients RE-LY trial, Pradaxa 150 mg taken twicedaily signiﬁcantly reduced stroke and systemic embolism by35% beyond the reduction achieved with warfarin, the cur-rent standard of care for patients with nonvalvular atrial ﬁb-rillation. Pradaxa 150 mg twice daily signiﬁcantly reducedboth ischemic and hemorrhagic strokes compared with war-farin. Treatment with Pradaxa does not require blood monitor-ing or related dose adjustments and has no recommended di-etary restrictions. The FDA also approved Pradaxa 75 mg twicedaily for the small sub-set of patients who have severe renalimpairment.