Acta Angiol Vol. 25, No. 3, pp. 157–161 Doi: 10.5603/AA.2019.0014 REVIEW Copyright © 2019 Via Medica ISSN 1234–950X www.journals.viamedica.pl/acta_angiologica Effectiveness and safety of sulodexide in the treatment of venous diseases Witold Tomkowski, Małgorzata Dybowska National Institute of Tuberculosis and Respiratory Disease, Warsaw, Poland Abstract This article presents a review of the literature assessing the effectiveness and safety of sulodexide in the proph- ylaxis of deep vein thrombosis and treatment of chronic venous disease. It was demonstrated that sulodexide is effective and safe in the prophylaxis of deep vein thrombosis and treatment of chronic venous insufficiency with ulcers. Sulodexide is characterized by low frequency of bleeding complications. Key words: sulodexide, venous thromboembolic disease, chronic venous disease Acta Angiol 2019; 25, 3: 157–161 Sulodexide is a naturally occurring glycosaminoglycan Sulodexide contains 80% of fast moving heparin obtained from pig intestine. Clinical uses of sulodexide (FMH) and 20% of dermatan sulfate (free fraction) [3]. include prevention of venous thromboembolic disease Structure of FMH resembles that of unfractionated (VTD) recurrence, treatment of chronic venous disease heparin. Its biological and pharmacological effects on (CVD) and moderate chronic arterial occlusive disease the coagulation cascade are also similar to heparin [3]. of the lower limbs. In this publication, we analyze the Dermatan sulfate contains fewer sulfate residues, scientific evidence regarding effectiveness and safety of thus exhibiting weaker anticoagulant effect. Mean sulodexide in the treatment of VTD and CVD. molecular weight of dermatan sulfate (free fraction) In order to understand the pharmacological func- is several times greater than FMH. The anticoagulant tions of sulodexide, it is necessary to know the structure effect of dermatan sulfate involves inhibition of active of vascular endothelium. The surface of tunica intima coagulation factor II (thrombin) through affinity to of those vessels is lined by glycocalyx, which is com- heparin cofactor II, which is a natural inhibitor of this posed of proteoglycans, hyaluronic acid, glycoproteins, factor [4]. and white cells absorbed on its surface. Glycocalyx Sulodexide is packaged in a parenteral form (am- plays a number of important roles: regulates vascular poules), which can be administered intravenously and permeability, controls their tone, determines inter- intramuscularly, as well as in the form of capsules for action of vascular wall with leukocytes and thrombo- oral administration. cytes, and regulates response to vascular stress. The Bioavailability of oral preparation of sulodexide above-mentioned mechanisms are decisive for proper reaches 40% and maximal concentration is reached blood flow, which is directly related to anticoagulant after four hours from capsule ingestion. Sulodexide and pro-fibrinolytic action of glycocalyx [1, 2]. Serum exhibits significant affinity to endothelium and glycoc- antithrombin (AT), which binds to heparin sulfate con- alyx — higher than to the circulating proteins (which tained in proteoglycans of the glycocalyx, is the key to is why it affects global coagulation parameters only to its anticoagulant effect. Such a combination changes a minimal extent). When administered orally, it does spatial structure of AT. Conformational changes of an- not affect the activated partial thromboplastin time tithrombin are responsible for its anticoagulant action: (aPTT) [5]. they potentiate anticoagulant effect and inhibition of Sulodexide is metabolized in the liver and excreted several active coagulation factors [2]. through the kidneys [5]. Address for correspondence: Małgorzata Dybowska, National Institute of Tuberculosis and Respiratory Disease, Plocka 26, 02–138 Warsaw, Poland, e-mail: [email protected] www.journals.viamedica.pl/acta_angiologica 157 Acta Angiol, 2019, Vol. 25, No. 3 The effect of sulodexide on the coagulation system In this group of patients, the risk of recurrence is only is less than unfractionated heparin or low molecular reduced when chronic prophylaxis (therapy) of DVT weight heparins because its pharmacological action is recurrence with anticoagulants is continued. The risk of contained mainly to the glycocalyx. DVT recurrence increases when anticoagulation stops It should be emphasized that sulodexide accelerates and the probability of DVT recurrence is independent spontaneous fibrinolysis of intravascular thrombi by of the length of anticoagulation therapy [12]. increasing the concentration of plasminogen activator Two elements play a fundamental role in chronic (tPA) and inhibiting tissue plasminogen inhibitor (PAI) [6]. prophylaxis (therapy) of DVT recurrence: effective- Sulodexide also reduces platelet aggregation [7]. ness of anticoagulant agents measured as reduction in The anti-inflammatory action of sulodexide con- relative risk of DVT recurrence and safety of therapy, stitutes an important biological effect directly related which is measured by the incidence of hemorrhagic to its clinical effects [7]. It is related directly to the complications, the most important of which are major inhibition of thrombin activity and thrombogenesis bleedings requiring hospitalization — some of them be- and indirectly to the inhibition of leukocyte activity and ing life-threatening. Sulodexide is characterized by great their adhesion to endothelium, reduction of cytokine safety in the prophylaxis of DVT recurrence [11–13]. release and platelet aggregation [7]. Sulodexide exhibits To a physician involved in the treatment of DVT, an inhibitory effect on the macrophage, heparanase and episodes of DVT recurrence, as well as, hemorrhagic metalloproteinase activity ]8]. complications constitute the most undesirable and However, the most important and central effect critical elements of therapy. Therefore, the incidence of sulodexide involves the protection and repair of of recurrences and the frequency of bleeding compli- endothelium and glycocalyx by supplying glycosamino- cations should be assessed simultaneously as a clinical glycans to its structures [8]. net benefit when comparing different anticoagulation It should be mentioned that sulodexide also affects agents [13]. Unilateral comparison of the effectiveness lipid metabolism. It reduces triglyceride levels and in- or safety alone is flawed and may pose a threat to the creases HDL concentrations. Sulodexide also reduces patient’s outcome. Somewhat lower effectiveness of blood viscosity [8]. sulodexide in the prevention of DVT recurrence is The half-life of sulodexide is significantly longer than compensated by an excellent safety profile [13]. in unfractionated heparin. In contrast to heparins, oral Very high effectiveness and excellent safety profile administration is feasible [5]. of sulodexide in the prevention of DVT recurrence was The most important are the biological effects of demonstrated in the SURVET trial [11]. It was a mul- sulodexide, which translate into clinical effects [1–5]. ti-center, randomized, double-blind study comparing These effects include anticoagulant action within arter- the effectiveness and safety of sulodexide versus pla- ies and veins, profibrinolytic action, anti-inflammatory cebo. The study included 615 patients who completed effect, protection of the endothelium and glycocalyx, 3–12 months of chronic anticoagulation therapy after and regulation of the vascular tone [8]. an episode of DVT or pulmonary embolism (PE). Deep vein thrombosis was diagnosed in 92% and PE in 8% Effectiveness and safety of sulodexide of patients included in the study. in the prevention of venous Sulodexide 2 × 2 capsules (2 × 500 LSU) or placebo thromboembolic disease (VTD) were administered over a 2-year period together with compression therapy. Scientific evidence regarding the effectiveness and ex- The effectiveness of sulodexide, basing on the frequency cellent safety profile of sulodexide in the prophylaxis of DVT recurrence and safety, was assessed as the frequen- (therapy) of deep vein thrombosis (DVT) recurrence is cy of hemorrhagic complications — major bleeding and solid and translated into recommendations contained clinically relevant bleeding complications other than major. in the Polish guidelines [9–12]. DVT recurrence took place in 4.9% of patients in The treatment of DVT consists of three phases: the sulodexide group and in 9.7% of patients in the acute treatment phase, usually lasting 5–7 days (in placebo group (HR 0.49; 95%CI 0.27–0.92; P = 0.02; patients treated with rivaroxaban this phase lasted after applying statistical methods of unification of popu- 21 days), long-term anticoagulation therapy lasting 3 lation HR = 0.45) within a 24-month follow-up period. months, and chronic prophylaxis (therapy) of DVT There were no major bleeding complications in the recurrence, which lasts from several months to years, group of patients receiving sulodexide as well as in the and may be indefinite in some patients [12]. placebo group. Only two clinically significant bleeding Long-term, chronic anticoagulation prophylaxis complications other than major bleeding were observed (therapy) is indicated i.a. in patients with idiopathic DVT. in each group. 158 www.journals.viamedica.pl/acta_angiologica Witold Tomkowski, Małgorzata Dybowska, Effectiveness and safety of sulodexide in the treatment of venous diseases The SURVET trial corroborated an acceptable crocirculation. Increase in venous pressures is accom- effectiveness