Description of the condition
Leg ulcers are usually defined as a loss of skin on the lower limb that takes more than six weeks to heal (Nelson 2008). Leg ulceration is a common chronic disease and the prevalence ranges from 0.62 to five per 1000 people, varying from country to country, for example, the prevalence of leg ulcers is 0.62/1000 in Australia (Baker 1991), 1/1000 in China (Fu 1998), 1.6/1000 in Sweden (Nelzen 1994), 1.5 to 3/1000 in the United Kingdom (NHS CRD 1997), and 5/1000 for the proportion of the population in the United States that is over 20 years of age (Coon 1973). Moreover, leg ulcer prevalence increases with age, rising to a peak prevalence between 60 and 80 years old, with women suffering from ulcers about 1.6 times more frequently than men (Valencia 2001). In addition, high risk factors for leg ulcers include prolonged standing (McCulloch 2001), obesity, a sedentary lifestyle and family history (Beebe-Dimmer 2005).
Approximately, 80% to 85% of all leg ulcers occur as a result of venous diseases (Simon 2004). Venous leg ulcers, also known as varicose ulcers or stasis ulcers, are a chronic and recurrent disease. The estimated recurrence rate for healed ulcers ranges from 26% to 69% in the first year (Mayer 1994; Franks 1995), rising to 75% after two years (Mayer 1994). Leg ulcers have become a big financial burden to both patients and health services (Hareendran 2005). The annual expenditure on leg ulceration is GBP 230 to 400 million (1991 prices) according to the National Health Service in the United Kingdom (Bosanquet 1992), and the cost is estimated to be as high as USD 1.9 to 2.5 billion per year in the United States (Valencia 2001). Moreover, leg ulcers can have a serious impact on patients' quality of life (González-Consuegra 2011; Herberger 2011).
Venous leg ulcers are strongly associated with chronic venous insufficiency (CVI) (White 2005). The venous blood flow system in the lower extremity consists of the deep veins, superficial veins and perforator veins, all of which are equipped with one-way open valves to prevent reflux (flow in the opposite direction). Deep veins are distributed within the calf muscle, and possess high blood pressure due to contraction of the calf muscle. By contrast, blood pressure within the superficial veins is lower. Perforator veins communicate between the deep and superficial veins. Normally, the valves of the perforator veins close when the calf muscle contracts in order to separate the superficial veins from the high pressure of the deep veins. The valves open while the calf muscle relaxes to let blood from the superficial veins flow through the perforator veins into the deep veins. Abnormally, CVI occurs when the normal venous system is disturbed by diseases of the venous system (incompetent vein valves, loss of vein wall elasticity, lesions obstructing the venous tract, etc.) or failure of the calf muscle pumping system (Valencia 2001; White 2005), which lead to an increase in venous pressure, which is termed 'venous hypertension'. Venous hypertension is responsible for most venous disease symptoms of the leg, such as oedema (swelling due to fluid retention), lipodermatosclerosis (painful inflammation and discolouration of skin), varicose veins and ulceration. (Andreozzi 2012).
Despite the above, the pathogenic steps between venous hypertension and leg ulcers are not fully understood. One theory, called the pericapillary fibrin cuffs and fibrinolytic abnormalities hypothesis (Valencia 2001), proposes that sustained venous hypertension increases capillary permeability, leading to the leakage of fibrinogen out of the capillaries. Leaked fibrinogen polymerises to form a barrier to the diffusion of oxygen and nutrients, i.e. the 'pericapillary fibrin cuff'. The lack of oxygen and nutrients leads to local tissue cell death and the formation of ulcers (Browse 1982). Another theory, the white cell trapping hypothesis (Valencia 2001), proposes that venous hypertension decreases the pressure gradient between the arterial and venous systems of the lower extremity, leading to a reduction in the flow rate of capillary blood that results in white blood cells (leukocytes) becoming trapped. These white blood cells can form a direct physical barrier, and also release certain mediators (such as collagenase, elastase, cytokines, free radicals and chemotactic factors, etc.), resulting in an increase in capillary permeability, leakage of fibrinogen, and the inflammatory reaction that leads to ulceration (Pascarella 2005).
As there is no gold standard for the diagnosis of venous leg ulcers, it is difficult to apply a standard definition. Nonetheless, it is important to distinguish the origin of a leg ulcer i.e. whether it is due to venous, arterial or neuropathic disease, or any other causes (Velasco 2011). Arterial leg ulcers can be excluded through measuring the ankle-brachial pressure index (ABPI) by doppler ultrasonography. An ABPI less than or equal to 0.5 indicates that leg ulcers are caused by arterial disease. Neuropathic ulcers are more common in patients suffering from diabetes mellitus (Valencia 2001).
Description of the intervention
The goals of interventions for venous leg ulcers include promoting ulcer healing, reducing recurrence of ulcers, improving quality of life and reducing adverse effects (De Araujo 2003; Nelson 2008). Among the variety of types of therapy, compression therapy has emerged as the standard treatment for venous leg ulcers (NHS CRD 1997; Nelson 2008; O'Meara 2009), however, it usually takes a long time for ulcer healing (Erickson 1995), and compression is not suitable for patients with arterial disease (NHS CRD 1997; Nelson 2008). Adjuvant (additional) drug therapies have also been studied (e.g. pentoxifylline (Jull 2011), flavonoids (Scallon 2013), and aspirin (Magolbo 2011)). Sulodexide has also been suggested as a potential candidate for adjuvant treatment of venous leg ulcers (Nelson 2008).
Sulodexide is a highly purified glycosaminoglycan (GAG) consisting of 80% fast-moving heparin (FMH) and 20% dermatan sulphate (DS). The FMH (7000 Da) is composed of unfractionated heparin and a fraction with a lower electrophoretic mobility. The DS (25,000 Da) is a polydisperse polysaccharide (Cosmi 2003). Compared with heparin, sulodexide shows a longer half-life and lower risk of haemorrhage (Lasierra-Cirujeda 2010).
Sulodexide is primarily used in patients with thrombotic risk diseases, and is administrated either orally or parenterally (e.g. via infusion). Scondotto et al first studied sulodexide clinically for the treatment of venous leg ulcers (Scondotto 1999), followed by Coccheri et al (Coccheri 2002), and Kucharzewski et al (Kucharzewski 2003).
How the intervention might work
Sulodexide has good antithrombotic and profibrinolytic activities, and also an anti-inflammatory effect (Andreozzi 2012).
Sulodexide has an antithrombotic effect by inhibiting thrombin activity and thrombin formation (Cosmi 2003). Thrombin is an essential part of the coagulation (blood clotting) system as it helps to convert fibrinogen to fibrin. Sulodexide has a positive effect on various blood components that inhibit thrombin activity and also has a negative effect on blood components that promote the conversion of prothrombin into thrombin.
Sulodexide exerts fibrinolytic activity by promoting the conversion of plasminogen to plasmin, which results in fibrinolysis (the breaking up of fibrin).
Moreover, recent studies demonstrate sulodexide has anti-inflammatory activity (Andreozzi 2012). Karoń 2007 demonstrated that systemic (whole body) administration of sulodexide reduced intraperitoneal and vascular inflammation in rats. (Ciszewicz 2009) demonstrated that sulodexide exerts an anti-inflammatory effect in human endothelial cells by suppressing the generation of oxygen-derived free radicals, and the release of monocyte chemotactic protein-1 (MCP-1) and interleukin-6 (IL-6).
Why it is important to do this review
Venous leg ulcers are a common, chronic, recurrent disease. Although the activity of sulodexide has been investigated in clinical trials treating venous leg ulcers, its role has not been conclusively defined, and it would be helpful to do so.