Description of the condition
Pulmonary embolism (PE) is a potentially life-threatening condition in which a blood clot blocks the supply to the lungs. PE is often a consequence of a thrombus in the deep veins of the legs (deep vein thrombosis (DVT)) that dislodges and travels in the blood to the pulmonary arteries. The prevalence of PE has been estimated as 3 to 4 per 10,000 people, although the true prevalence is hard to measure due to underestimation by diagnostic imaging and overestimation by postmortem 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). One complication of PE is chronic thromboembolic pulmonary hypertension (CTPH). CTPH occurs when the clot obstructs the pulmonary arteries causing excessive pressure in the pulmonary artery and stress to the right ventricle. CTPH is less common but it can result in heart failure (NICE 2012a).
Risk factors for PE are similar to those for DVT and are classified as provoked or unprovoked (Kearon 2012). Provoked PE occurs following surgery or pregnancy, 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 PE is made by general assessment of the patient's medical history, physical examination and clinical pre-test probability. However, it can be particularly challenging as the symptoms (dyspnoea, pleuritic chest pain, retrosternal chest pain, cough and haemoptysis) are not specific (NICE 2012a). In severe cases, the right ventricle fails leading to dizziness, syncope, tachypnoea, tachycardia, hypoxia, elevated jugular venous pressure, systemic hypotension and cardiogenic shock (NICE 2012a). The UK National Institute for Health and Care Excellence recommend that people presenting with a suspected PE should be assessed using a two-level PE Wells score (NICE 2012a; Wells 2000). Points are awarded for clinical features present including clinical signs of DVT, heart rate greater than 100 beats per minute, recent immobilisation or surgery, previous DVT, haemoptysis and malignancy (Wells 2000). For patients with a low pre-test probability, the use of a D-dimer assay combined with a clinical prediction rule has a high negative predictive value and avoids the need for unnecessary imaging (Qaseem 2007). However, for patients who have intermediate or high pre-test probability of PE, imaging is essential. Patients with a score of greater than 4 are judged to be likely to have had a PE and should undergo immediate diagnostic imaging. If this cannot be performed immediately, patients should be given immediate interim parenteral anticoagulant therapy until the imaging test is done. Patients with a negative diagnosis in whom a DVT is likely should be given a proximal leg vein ultrasound scan (NICE 2012a).
There are two types imaging techniques used to diagnose PE: computed tomography pulmonary angiogram (CTPA) and ventilation perfusion (V/Q) scan.
1. Computed tomography pulmonary angiogram
CTPA involves injecting a contrast agent intravenously and performing a computed tomography (CT) scan of the chest to visualise the pulmonary arteries and detect any thrombi in the pulmonary arteries down to the subsegmental branches. The procedure has over 90% specificity and sensitivity in diagnosing PE in the main, lobar and segmental pulmonary arteries (Riedel 2004). However, the radiation dose administered to the patient is much larger than that of a V/Q scan, and thus patients who have a CTPA are at increased life-time risk of cancer (Anderson 2009). CTPA is contraindicated in patients who have an allergy to contrast media, renal impairment or in whom the risk of radiation is too high. In these patients, a V/Q scan is performed instead (NICE 2013).
2. Ventilation perfusion scan
A V/Q scan comprises of two parts: the ventilation part where the patient breathes in a radioisotope (in the form of a gas or an aerosol) and the perfusion part where the patient is given an intravenous injection of the isotope. A gamma camera is used to detect where the isotopes are in the lungs and the images show which areas of the lungs are ventilated but not perfused (NICE 2012a). Another version of this test, the V/Q single photon emission computed tomography (V/Q SPECT) has been developed. The camera is rotated around the patient thus generating three-dimensional images and leading to a more accurate diagnosis (Laurence 2012).
Description of the intervention
Until recently, standard treatment of a PE was with an indirect thrombin inhibitor, namely unfractionated heparin (UFH), low molecular weight heparin (LMWH) or vitamin K antagonists (VKAs). 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 PE 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 PE. Although heparin and VKAs are effective anticoagulants, there are limitations associated with each. LMWH must be administered parenterally and may be associated with an increased risk of bleeding and haemodynamic instability (Kearon 2012). 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. DTIs and factor Xa inhibitors have characteristics that may be favourable over heparin and VKAs, including ease of oral administration, a predictable effect, lack of frequent monitoring or re-dosing and fewer known drug interactions (compared with the VKA) (Fox 2012).
How the intervention might work
Oral direct thrombin inhibitors
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, lack of an antiplatelet effect and no suspected concern of heparin-induced thrombocytopenia (HIT) (Lee 2011). There are several types of 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 is 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. Ximelagatran 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 direct factor Xa inhibitor. For the initial treatment of acute PE, 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). The plasma half-life, if renal function is normal, is 12 hours.
Apixaban is an oral, small molecule, reversible inhibitor of factor Xa with a plasma half-life of 8 to 15 hours, taken twice daily (Eriksson 2009).
Betrixaban is an orally administered direct factor Xa inhibitor. It also 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 oral 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 PE alone.
We are currently conducting another Cochrane systematic review measuring the effectiveness of oral DTIs and oral factor Xa inhibitors for the treatment of DVT (Robertson 2014).