Description of the condition
Deep vein thrombosis (DVT) occurs when a blood clot or thrombus forms in the deep venous system. This is most commonly observed in the veins in the leg or pelvis. It is a relatively common condition affecting approximately 1 in 1000 people (SIGN 2010). If left untreated, the thrombus can dislodge and travel in the blood to the pulmonary arteries blocking the supply of blood to the lungs. This is termed a pulmonary embolism (PE) and is a life-threatening condition. The incidence of PE is approximately 3 to 4 per 10,000 people but this is likely to be underestimated as it is based on clinical data. DVT is present in approximately 70% to 80% of people with a PE, yet only 15% of PE cases have symptoms of DVT (Huerta 2007). Another complication of DVT is post-thrombotic syndrome (PTS). PTS is long-term condition caused by the reduction in the return of venous blood to the heart and symptoms include chronic pain, skin discolouration, oedema and, in severe cases, varicose veins and venous ulceration (Kahn 2002). Several prospective and retrospective cohort studies have measured the incidence of PTS after a symptomatic DVT (Ginsberg 2001; Johnson 1995; Mohr 2000; Monreal 1993; Prandoni 1996; Saarinen 2000). Estimates range from a 20% to 50% incidence within one to two years of a DVT, with 5% to 10% of cases classified as severe.
According to guidelines by the American College of Chest Physicians, risk factors for DVT are classified as provoked or unprovoked (Kearon 2012). Provoked DVT occurs following surgery or by a non-surgical transient risk factor such as history of venous thromboembolism (VTE), venous insufficiency, chronic heart failure, thrombophilia, obesity, immobility (such as prolonged travel, acute medical illness or hospitalisation), cancer, oestrogens (pregnancy, use of oral contraceptives or hormone replacement therapy) and trauma (SIGN 2010).
Diagnosis of DVT is made by general assessment of the patient's medical history and physical examination. The UK National Institute for Health and Care Excellence recommend that patients presenting with a suspected DVT should be assessed for pre-test probability of DVT using a two-level Wells score (NICE 2012a; Wells 2003). Points are awarded to clinical features present including active cancer, recent immobilisation or surgery, tenderness or swelling, and history of DVT in order to estimate the clinical probability of a DVT. The American College of Chest Physicians recommend that patients with a low pre-test probability of a first lower extremity DVT should undergo initial testing with D-dimer or ultrasound of the proximal veins (Bates 2012). Patients with moderate pre-test probability should undergo D-dimer, proximal compression or whole-leg ultrasound, while patients with a high pre-test probability should undergo proximal compression or whole-leg ultrasound (Bates 2012).
A D-dimer test is based on the principle that the formation of a thrombus is followed by an immediate fibrinolytic response including the release of fibrin degradation products, predominantly D-dimer, into the circulation. Therefore, a negative D-dimer suggests that thrombosis is not occurring and thus is a useful tool in excluding DVT along with clinical scores and imaging. It is important to consider that while a positive result can indicate DVT, there are other potential reasons for a positive D-dimer including liver disease, inflammation, malignancy, pregnancy, trauma and recent surgery (NICE 2012a). Furthermore D-dimer assays vary in sensitivity and the choice of assay used by an institution is based on cost and availability.
Ultrasound is a diagnostic imaging technique in which high-frequency sound waves are transmitted into the body and the speed at which it is reflected back to the transducer forms an image. Compression ultrasound involves using the probe to try to compress the vascular lumen. If the lumen is fully compressible it indicates that a thrombus has not occurred. Duplex ultrasound is similar but it involves the use of the Doppler signal to determine blood flow properties. In addition, colour imaging can be used to augment the images. Ultrasound is non-invasive and has a high sensitivity and specificity for detecting proximal DVT (NICE 2012a). Guidelines recommend completing either proximal or whole leg ultrasound determined by local practice, access to testing and cost (Bates 2012).
Description of the intervention
Until recently, standard treatment of a DVT was with an indirect thrombin inhibitor, namely unfractionated heparin (UFH), low molecular weight heparin (LMWH) or vitamin K antagonists (VKA). These drugs block the action of thrombin either by "activating naturally occurring thrombin inhibitors or by inhibiting specific factors in the coagulation system that subsequently impact on thrombin generation or
activity" (Weitz 2003). Present guidelines recommend initial therapy for DVT with a parenteral anticoagulant (UFH or LMWH or fondaparinux) and initial VKA initiation (Kearon 2012). Recommendations include the use of LMWH or fondaparinux over UFH for initial therapy of DVT. Although heparin or VKAs are effective anticoagulants, there are limitations associated with each. Heparin-induced thrombocytopenia (HIT) is a severe immune-mediated condition in which the effect of heparin is reversed (Koster 2007). Approximately 50% of patients with isolated HIT develop a further thrombosis (Warkentin 1996). HIT is managed by discontinuing heparin but alternative anticoagulation must be administered to treat the thrombosis and prevent a recurrence (Lewis 2001). Meanwhile, VKAs have a narrow therapeutic window, require frequent monitoring and dosage adjustments, and can have multiple interactions with other drugs (Ageno 2012).
Two further classes of oral anticoagulants have been developed: direct thrombin inhibitors (DTI) and factor Xa inhibitors. Oral DTIs and factor Xa inhibitors have characteristics that may be favourable over heparin and VKA, including oral administration, a predictable effect, lack of frequent monitoring or re-dosing and few known drug interactions (Fox 2012).
How the intervention might work
Oral direct thrombin inhibitors
Oral DTIs work by binding directly to the enzyme thrombin without the need for a co-factor such as antithrombin. Unlike heparins and VKAs, DTIs can inhibit both soluble thrombin and fibrin-bound thrombin (Kam 2005). Other advantages include a more predictable anticoagulant effect because of their lack of binding to other proteins, an antiplatelet effect and the absence of HIT (Lee 2011). There are several types of oral DTIs.
Dabigatran etexilate is a reversible oral DTI that is metabolised to its active ingredient, dabigatran, in the gastrointestinal tract (Ageno 2012). It does not require anticoagulation monitoring, is excreted by the kidneys and has a half-life of 12 to 17 hours. As well as a treatment for venous thrombosis, this drug has been involved in many large randomised studies of atrial fibrillation (Connolly 2009), acute coronary syndromes (Oldgren 2011), and prevention of thrombosis following orthopaedic surgery (Eriksson 2007), and in patients with mechanical heart valves (Van de Werf 2012). In common with the other novel oral anticoagulants, dabigatran was associated with a lower incidence of intracranial haemorrhage (compared with VKA). However, again compared with VKA, dabigatran showed a higher incidence of indigestion and heartburn and a higher incidence of gastrointestinal bleeding. Dabigatran, in the atrial fibrillation studies, showed a tendency (although ultimately not statistically significant) to increased incidence of myocardial infarction (Baetz 2008).
Ximelagatran is a prodrug that is metabolised to melagatran as it is better absorbed from the gastrointestinal tract (Kam 2005). It has a plasma half-life of three hours, has a predictable response after oral administration and does not require coagulation monitoring. Ximelgatran was found to be effective in the treatment of VTE but caused unacceptable liver toxicity (Boudes 2006), and was, therefore, never licensed.
Oral factor Xa inhibitors
Factor Xa inhibitors bind directly to the active site of factor Xa, thus blocking the activity of the clotting factor. Unlike indirect factor Xa inhibitors such as fondaparinux, direct factor Xa inhibitors "inactivate free FXa and FXa incorporated with the prothrombinase complex equally well" and do not require interaction with the inhibitor antithrombin (Eriksson 2009). They have been shown to be non-inferior to VKA but without the need for regular blood test monitoring. They appear to have fewer drug interactions (compared with VKA) and no food or alcohol interactions.
Rivaroxaban is a reversible oral direct factor Xa inhibitor. For the initial treatment of acute DVT, the recommended dosage of rivaroxaban is 15 mg twice daily for the first 21 days followed by 20 mg once daily for continued treatment and prevention of recurrence (NICE 2012b).
Apxaban is an oral, small molecule, reversible inhibitor of factor Xa with a plasma half-life of 8 to 15 hours (Eriksson 2009).
Betrixaban is an orally administered direct factor Xa inhibitor. It has a half-life of 15 hours, offers the convenience of once daily dosing and may exhibit fewer drug interactions than warfarin (Palladino 2013).
Edoxaban is an oral direct inhibitor of activated factor X that is rapidly absorbed with a half-life of 9 to 11 hours. Edoxaban has a dual mechanism of elimination with one-third eliminated via the kidneys and the remainder excreted in the faeces. It also offers the convenience of once-daily dosing (Eikelboom 2010), and is used in conjunction with LMWH for five days.
Why it is important to do this review
The effectiveness of oral DTIs and factor Xa inhibitors for the treatment of VTE has been studied in several randomised controlled trials (EINSTEIN-DVT study (EINSTEIN Investigators), ODIXa-DVT study (Agnelli 2007), Botticelli study (Botticelli Investigators), AMPLIFY study (Agnelli 2013), RE-COVER II study (Schulman 2011), THRIVE studies (Eriksson 2003)). One non-Cochrane systematic review has examined the effectiveness of DTIs and factor Xa inhibitors versus VKAs in the treatment of acute VTE (Fox 2012). The primary outcome was VTE and results were not presented for DVT and PE separately. To date, no systematic review has been conducted examining the effectiveness of oral inhibitors in the treatment of DVT alone. Given the relatively high incidence of DVT and the emergence of these new anticoagulants, it is important to establish the safety and effectiveness of these new treatments.
We are currently conducting another Cochrane systematic review to determine the effectiveness of oral DTIs and oral factor Xa inhibitors for the treatment of PE (Robertson 2014).