Notas de prensa
Venous thromboembolism: causes, consequences and treatment
Venous thromboembolism (VTE) is a common, potentially fatal condition. It is estimated to be the third most common cardiovascular disorder after coronary heart disease and stroke.
The clinical manifestations of VTE are deep vein thrombosis (DVT) and pulmonary embolism (PE), a consequence of DVT. The annual incidence of VTE among Caucasians of European origin is 1?2 per 1,000 up to the age of 40; after this age, the incidence doubles each decade.1 The incidence is higher among those of African origin and lower among Asian and Native Americans.1 Mortality associated with VTE is relatively high, especially in cases of PE ? the 7-day mortality rate is 40.9% in patients with PE and 3.7% in those with DVT.2 Although a number of therapeutic options are available for the treatment and prevention of VTE, they are associated with a number of drawbacks that significantly limit their use.
Pathophysiologic basis of VTE
The fluidity of blood within the vasculature is maintained through a fine balance between circulating proteins that cause coagulation and those that prevent it. Under normal circumstances, proteins that promote coagulation are inactive, but are activated in response to injury of the blood vessel. The subsequent formation of a thrombus (or clot) serves a protective function by preventing blood loss. However, not all thrombi are formed in response to vessel injury. Three main factors have long been recognised as responsible for the pathogenesis of thrombosis:
? Alterations in blood flow ? more specifically, pooling of blood after prolonged immobility
? Alterations in vessel walls due to certain disease conditions, inflammation or trauma
? Alterations in the composition of blood such that there is an increase in blood coagulability, for example in certain genetic blood disorders
Thrombosis can occur in any part of vasculature; in veins, arteries or within the heart itself ? the clinical manifestation will depend on the vessel affected. DVT arises following the formation of a thrombus in one of the veins, predominantly the deep veins of the leg. Some thrombi can become dislodged from the vessel wall and are transported via blood to the lungs, where they block the vessels. This process is known as PE. Up to 5% of deep vein thrombi result in fatal PE.3 While PE is the most significant short-term complication of DVT, the major long-term complication is post-thrombotic syndrome, which can lead to swelling, pain, ulceration and in some cases gangrene. An additional complication of DVT is the high risk of recurrence. The incidence of recurrence has been estimated to be 5% after 3 months, 8.6% after 6 months and 17.5% after 2 years of follow-up.4 Consequently, VTE is considered a chronic disease, necessitating long-term therapy in many cases.
Numerous risk factors are associated with VTE, the most important of which are increasing age, immobility and surgery. Others include cancer and its treatment, the use of oral contraceptives, indwelling venous catheters, and several acute (e.g. myocardial infarction, infections) and chronic (e.g. stroke, hypertension, obesity) medical conditions.
Prevention and treatment of DVT
VTE is a complication of many conditions. The efficacy of primary prevention in patients undergoing orthopaedic surgery (OS) is well established ? Without preventive treatment, as many as 80 percent of orthopaedic surgery patients would develop DVT (including asymptomatic thrombi), and risk developing PE.5 Frequently used prophylactic agents for OS include low molecular weight heparin (LMWH) and warfarin. The treatment of acute VTE consists predominantly of unfractionated heparin (UFH) or LMWH for 5?10 days followed by warfarin alone for several months. A long duration of therapy is necessary as a secondary preventive measure in the event of VTE recurrence. According to the guidelines developed by the American College of Chest Physicians, patients with a first episode of DVT secondary to a transient (reversible) risk factor should receive treatment with a VKA for 3 months.6 For patients with a first episode of DVT (unknown risk factor), treatment with a VKA should last for at least 6?12 months.6
Limitations of current therapy
For the past 50 years, the heparins and warfarin have been the cornerstone of anticoagulant therapy. The heparins, and the more recently developed fondaparinux, are administered as subcutaneous injections. Warfarin and other vitamin K antagonists (VKAs) are given orally; however, their use is associated with numerous limitations. Notably, they have a narrow therapeutic window, which means that there is little difference in the dose that provides optimal protection against thrombosis and the dose that leads to excessive bleeding. Therefore, patients must regularly undergo monitoring to ensure the dose of warfarin is within the therapeutic range. VKAs also interact with many drugs; this is of great significance in an increasingly aging population that requires polytherapy. Other important limitations are drug-food interactions and slow onset and offset of action.
Given the limitations of currently available agents, many patients do not receive satisfactory anticoagulant therapy. For those who do receive therapy, it is often inconvenient and inadequate. It is clear that there is a significant need for a fixed dose oral anticoagulant that is as effective as VKAs, with minimal risk of bleeding, rapid onset, minimal drug?drug and food interactions and predictable effects without the need for coagulation monitoring.
Dabigatran etexilate, a novel oral anticoagulant in clinical development, is expected to meet all the above criteria and therefore has the potential to successfully address a significant unmet clinical need. The ongoing extensive clinical trial programme of dabigatran etexilate, RE-VOLUTIONTM, is currently evaluating its efficacy and safety in the primary prevention, treatment and secondary prevention of VTE. The efficacy and safety of dabigatran etexilate is also being evaluated for stroke prevention in patients with atrial fibrillation.
1. Heit JA. J Thromb Thrombolysis 2006; 21: 23?9.
2. Heit,JA, et al. Arch Intern Med 2000; 160: 761?8.
3. Turpie AG, et al. BMJ 2002; 325: 887?90.
4. Prandoni P, et al. Ann Intern Med 1996; 125: 1?7.
5. American Academy of Orthopedic Surgeons information webpage http://orthoinfo.aaos.org/fact/printer_page.cfm?topcategory=Knee&Thread_ID=264.
6. Buller HR, et al. Chest 2004; 126:401S? 428S.