Description of the condition
Venous thromboembolism (VTE), a disease comprised of deep vein thrombosis (DVT), pulmonary embolism (PE) or both, is a common (1 to 2 per 1000 person-years) (Oger 2000; Spencer 2006), preventable and treatable condition. However, it is a potentially fatal disease with a short-term mortality rate of approximately 25% (Kyrle 2005; Murin 2002; NÆSS 2007). The risk of recurrence during the first few weeks after the acute phase of VTE is high and remains about 10% per year for non-provoked VTE with a case-fatality rate of 3.6% to 12% (Carrier 2010; Douketis 2007; Kyrle 2010). The implications of recurrent VTE are not just mortality but also considerable morbidity with post-thrombotic syndrome (Leizorovicz 1998). The likelihood of recurrence varies among patients and is influenced by a number of factors including the presence or absence of trigger risk factors, characteristics of the index event (proximal DVT or PE compared to distal DVT) and patients' clinical features (male sex, post-thrombotic syndrome, overweight, age). While risk factors for recurrence have been identified, and indeed predictive rules determining duration of anticoagulation have been developed (Vienna Score, Men Do and Her 2 Do from Canada and Italy), these are not universally adopted in clinical practice (Eichinger 2010; Rodger 2008; Tosetto 2012).
VTE can be either provoked by triggers, such as a cast, surgery, immobilization, recent trauma, or unprovoked with no apparent trigger. Patients with VTE are treated initially with therapeutic parenteral anticoagulants (usually subcutaneous low molecular weight heparin (LWMH)) and with a vitamin K antagonist (VKA) (that is, warfarin). Parenteral therapy is continued until the international normalised ratio (INR) is ≥ 2 for at least 24 hours, after which parenteral therapy is stopped. All patients are treated with anticoagulants for at least three months; after this time it is recommended to extend treatment for unprovoked VTE if the bleeding risk is low to moderate (Kearon 2012).
Recently, new oral anticoagulants (NOACs) such as direct factor Xa inhibitors (apixaban, rivaroxaban and edoxaban) and direct thrombin inhibitors (dabigatran) have emerged as a treatment option in the acute phase of VTE, with similar (or better) efficacy as the VKAs but with potentially lower bleeding rates and easier administration (Agnelli 2013; Bauersachs 2010; Hokusai-VTE 2013; Schulman 2009).
Description of the intervention
Provoked VTE has a low annual risk of recurrence, therefore oral anticoagulation can be safely discontinued after three months of therapy (Baglin 2003; Heit 2000; Prandoni 1996; Research Committee British Thoracic Society 1992; Segal 2007). Treatment with anticoagulants can significantly reduce the recurrence of unprovoked VTE but the risk of bleeding is increased during such treatment. The optimal duration of extended treatment for unprovoked VTE is unknown because of limited data in the literature. Physicians have to decide upon extended treatment based on the benefit (that is, prevention of VTE recurrence) and risk (that is, of bleeding) due to anticoagulation treatment (Carrier 2010). The recurrence risk increases once anticoagulation is stopped, whether a short or prolonged period of treatment has been recommended to the patient (Boutitie 2011).
For many decades, and according to the American College of Chest Physicians guidelines (Kearon 2012), VKA (that is, warfarin) has been the drug of choice for long-term treatment of VTE. Warfarin is not an ideal drug since it has a narrow therapeutic window and multiple food and drug interactions. It therefore requires close monitoring and dose adjustment in order to avoid the risk of VTE recurrence or bleeding, or both (Weitz 2005).
Antiplatelet therapy (that is, acetylsalicylic acid (aspirin)) may have a role in long-term prevention of recurrent VTE after initial VKA therapy of VTE. Two studies that were published recently demonstrated a reduction of VTE recurrence and major vascular events by a third (two to three fold less than anticoagulants), with a low annual risk of bleeding (0.3%) (Becattini 2012; Brighton 2012).
NOACs such as dabigatran, rivaroxaban and apixaban have been studied for extended treatment of VTE after the initial anticoagulation period, and randomized controlled trials have been published in recent years (Agnelli 2013; Bauersachs 2010; Schulman 2013). When compared to placebo or warfarin, all NOACs demonstrated efficacy in the reduction of VTE recurrence, some with lower bleeding rates compared to warfarin (Agnelli 2013; Bauersachs 2010; Schulman 2013). When compared to placebo, increased bleeding rates were found with dabigatran and rivaroxaban but apixaban demonstrated no increase in the rate of major bleeding (Agnelli 2013; Bauersachs 2010; Schulman 2013).
Risk factors for the recurrence of VTE have been identified, and predictive scores determining the duration of anticoagulation have been developed (Eichinger 2010; Rodger 2008; Tosetto 2012). Overall, none of these models has been incorporated into clinical use because management studies and external prospective validation are still needed.
Why it is important to do this review
Prolonged treatment with anticoagulation prevents VTE recurrence. However, the current standard treatment with a VKA is associated with bleeding complications. Thus, the question regarding the duration of therapy for secondary prevention of VTE recurrence, and which is the best anticoagulant to achieve this goal, remain open. NOACs or antiplatelet agents may offer a simple and relatively safe alternative to VKAs to prevent secondary VTE in patients with unprovoked VTE. No Cochrane review has compared the available oral therapeutic options (aspirin, warfarin and NOACs). To date, there is a lack of best evidence to guide decision making for either the optimal duration of extended prophylaxis or the type of oral anticoagulant for preventing secondary unprovoked VTE. In order to assess which is the best oral anticoagulant currently available for the secondary prevention of VTE, we will perform a systematic review and meta-analysis of all randomized controlled trials that are available in the literature. We intend to reach this decision based on both the efficacy of the oral anticoagulants in preventing VTE recurrence and their safety as regards bleeding complications.