title: Prophylaxis of venous thromboembolism: low molecular weight heparin compared to the selective anticoagulants rivaroxaban, dabigatran and fondaparinux.
abstract: Newer therapeutic options available in the prevention of postoperative thromboembolism, currently focused on fondaparinux, rivaroxaban and dabigatran warrant an overall therapeutic assessment. The constitutive comparisons with enoxaparin are based on a combined outcome measure solely driven by the incidence of "asymptomatic deep vein thrombosis". Its validity as a clinically relevant endpoint is missing if antithrombotics of different classes are compared. This is because they target different phases of thrombogenesis i. e. ahead and beyond the asymptomatic stage of thrombosis. Additional concerns refer to the dosing-regimens and their practical administration: Fondaparinux, rivaroxaban and dabigatran are dosed to achieve maximum effects very close to their limits of tolerance whereas wide dosing spectra for the low molecular weight herparin (LMWH)'s indicate the potential for dose adaptation and increase. The other disadvantage to the control-heparin originates in the timing for the 1st administration which doesn't fit in with the "just-in-time" principle. So the enoxaparin-regimen is lacking in benchmark-quality - with the consequence that the meaning of the Phase III-trials does'nt go beyond a mere technical demarcation from the marketed variant of the product as defined by the stipulations in the package insert. As to tolerance the selective anticoagulants exhibit an increased risk of major and other clinically relevant bleeding, exceeding that of enoxaparin by 30% (P<0.001). The outcome of the meta-analyses on fondaparinux, rivaroxaban and dabigatran is supported by product-specific calculations and assessments of the European Medicine Equivalence Agency (EMEA). Rivaroxaban and dabigatran show significant age-dependent renal accumulation. Because the dose-finding studies were restricted to patients over 60 year old the regimens definitely established are not applicable to younger patients. The reason for the limited therapeutic index of the selective anticoagulants originates in their monovalent activity as such not adequately matching the complexity of thrombogenesis and early thrombus extension. Their class-specific limitations are compensated through more intensive dosage-regimens which result in accentuated bleeding complications. Connotatively the hypothesis emerged that antiXa- and IIa-effects interact synergistically which translates into enhanced efficacy and tolerance. Experimental studies on hirudin with pentasaccharide and hirudin with "lower low molecular weight heparin" (3KDA) support such rationale.
authors: Department of Pharmacology, Institute of Pharmacy, University of Regensburg, Regensburg, Germany. welzel@iabg.de
authors: D
authors: D
authors: Welzel
authors: R
authors: R
authors: Hull
authors: J
authors: J
authors: Fareed