Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of pulmonary embolism

  • Protocol
  • Intervention



This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effectiveness of oral DTIs and oral factor Xa inhibitors for the treatment of PE.


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.

1. Dabigatran

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).

2. Ximelagatran

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

1. Rivaroxaban

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.

2. Apixaban

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).

3. Betrixaban

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).

4. Edoxaban

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).


To assess the effectiveness of oral DTIs and oral factor Xa inhibitors for the treatment of PE.


Criteria for considering studies for this review

Types of studies

Randomised controlled trials in which patients with a confirmed PE were allocated to receive an oral DTI or an oral factor Xa inhibitor for the treatment of PE. We will include published studies and studies in progress if preliminary results are available. We will place no restrictions on publication status and non-English studies will be eligible for inclusion in the review. We will exclude DTIs and factor Xa inhibitors that are not given by the oral route.

Types of participants

Patients with a PE, confirmed by standard imaging techniques (CTPA, V/Q scan).

Types of interventions

  • Oral DTIs (e.g. dabigatran, ximelagatran) (although ximelagatran was withdrawn from the market in 2006 due to safety issues, we will include it in the review to make the results as comprehensive as possible).

  • Oral factor Xa inhibitors (e.g. rivaroxaban, apixaban, betrixaban, edoxaban),

  • Other anticoagulants (e.g. LMWH, UFH, VKAs),

Comparisons will include:

  1. One oral DTI versus another oral DTI.

  2. One oral factor Xa inhibitor versus another oral factor Xa inhibitor.

  3. Oral DTI versus oral factor Xa inhibitor.

  4. Oral DTI or oral factor Xa inhibitor versus another anticoagulant.

Types of outcome measures

Primary outcomes
  • Recurrent PE, confirmed by standard imaging techniques (CTPA, V/Q scan).

  • Recurrent VTE (clinically overt DVT, confirmed by standard imaging techniques including proximal leg vein ultrasound scan or D-dimer test, or both; or clinically overt PE, confirmed by CTPA or V/Q scan, or both).

  • Clinically overt DVT confirmed by standard imaging techniques (proximal leg vein ultrasound scan, venography) or D-dimer test, or both.

Secondary outcomes
  • All-cause mortality.

  • Adverse effects of treatment including major bleeding (as defined by the International Society on Thrombosis and Haemostasis (ISTH); Schulman 2005).

    1. Fatal bleeding;

    2. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome;

    3. Bleeding causing a fall in haemoglobin level of 20 g/L (1.24 mmol/L) or more, or leading to transfusion of two or more units of whole blood or red cells;

    4. Any combination of points 1 to 3.

  • Health-related quality of life, as reported in included studies.

Search methods for identification of studies

Electronic searches

The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) will search the Specialised Register and the Cochrane Central Register of Controlled Trials (CENTRAL) (www.thecochranelibrary.com). See Appendix 1 for details of the search strategy used to search CENTRAL. The Specialised Register is maintained by the TSC and is constructed from weekly electronic searches of MEDLINE, EMBASE, CINAHL and AMED, and through handsearching of relevant journals. The full list of the databases, journals and conference proceedings which have been searched, as well as the search strategies used, are described in the Specialised Register section of the Cochrane Peripheral Vascular Diseases Group module in The Cochrane Library (www.thecochranelibrary.com).

The TSC will search the following trial databases for details of ongoing and unpublished studies:

Searching other resources

We will search the reference lists of relevant articles retrieved by electronic searches for additional citations.

Data collection and analysis

Selection of studies

One review author (LR) will use the selection criteria to identify trials for inclusion and the second review author (PK) will independently confirm this selection. We will resolve any disagreements by discussion.

Data extraction and management

Two review authors (LR, PK) will independently extract the data from the included studies. We will record information about the trial design, diagnosis of PE, baseline characteristics of participants and type of prophylaxis. We will record recurrent PE (fatal and non-fatal) and DVT data as the primary outcome measures. We will collect data on all-cause mortality and adverse effects of treatment including clinically relevant bleeding and health-related quality of life in accordance with the secondary outcome measures. We will contact authors of included studies if further information or clarification is required. We will resolve any disagreements in data extraction and management by discussion and seek the opinion of an expert, if required.

Assessment of risk of bias in included studies

Two review authors (LR, PK) will independently use The Cochrane Collaboration's 'Risk of bias' tool for assessing risk of bias for each of the included studies (Higgins 2011). The tool provides a protocol for judgements on sequence generation, allocation methods, blinding, incomplete outcome data, selective outcome reporting and any other relevant biases. We will judge each of these domains as either high, low or unclear risk of bias according to Higgins 2011, and provide support for each judgement. We will present the conclusions in a 'Risk of bias' table. We will resolve any disagreements by discussion.

Measures of treatment effect

We will base the analysis on intention-to-treat data from the individual clinical trials. As the primary and secondary outcomes are all binary measures, we will compute odds ratios (ORs) using a fixed-effect model and calculate the 95% confidence intervals (CI) of the effect sizes.

Unit of analysis issues

The unit of analysis in this review will be the individual patient.

Dealing with missing data

We will seek information about drop-outs, withdrawals and other missing data and, if not reported, we will contact study authors for this information.

Assessment of heterogeneity

We will assess heterogeneity between the trials by visual examination of the forest plot to check for overlapping CIs, the Chi2 test for homogeneity with a 10% level of significance and we will use the I2 statistic to measure the degree of inconsistency between the studies. An I2 result of greater than 50% may represent moderate to substantial heterogeneity (Deeks 2011).

Assessment of reporting biases

For each analysis, we will assess publication bias by funnel plots if a sufficient number of studies (10 or more) are available in the meta-analyses. There are many reasons for funnel plot asymmetry, and we will consult the Cochrane Handbook for Systematic Reviews of Interventions to aid the interpretation of the results (Sterne 2011).

Data synthesis

The review authors will independently extract the data. One review author (LR) will input the data into Review Manager 5 (RevMan 2012), and the second review author (PK) will cross-check data entry. We will resolve any discrepancies by consulting the source publication.

We will use a fixed-effect model to meta-analyse the data. If the I2 statistic indicates heterogeneity greater than 50%, we will perform a random-effects model analysis instead of a fixed-effect model analysis.

Subgroup analysis and investigation of heterogeneity

  1. History of VTE.

  2. Age.

  3. Active cancer (treatment within last six months or palliative).

  4. Pregnancy.

  5. Major surgery requiring general or regional anaesthesia in the previous 12 weeks.

  6. Recent period of immobility (bedridden three or more days in the previous 12 weeks).

  7. Thrombophilia (genetic or acquired).

Sensitivity analysis

We will perform sensitivity analyses by excluding studies that we judge to be at high risk of bias. We will also perform sensitivity analyses with and without ximelagatran a priori given that this drug is no longer available.


Appendix 1. CENTRAL search strategy

#1MeSH descriptor: [Antithrombins] explode all trees
#2MeSH descriptor: [Hirudin Therapy] explode all trees
#3thrombin near/3 inhib*:ti,ab,kw (Word variations have been searched)
#4hirudin*:ti,ab,kw (Word variations have been searched)
#5*hirudin*:ti,ab,kw (Word variations have been searched)
#6dabigatran or Pradaxa or Rendix:ti,ab,kw (Word variations have been searched)
#7BIBR-953* or BIBR953* or BIBR-1048 or BIBR1048:ti,ab,kw (Word variations have been searched)
#8ximelagatran or Exanta or Exarta or melagatran:ti,ab,kw (Word variations have been searched)
#9AZD0837 or AZD-0837:ti,ab,kw (Word variations have been searched)
#10S35972 or S-35972
#11#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10
#12MeSH descriptor: [Factor Xa] explode all trees and with qualifiers: [Antagonists & inhibitors - AI]
#13Factor X* near/4 (antag* or inhib* or block*):ti,ab,kw (Word variations have been searched)
#14FX* near/4 (antag* or inhib* or block*):ti,ab,kw (Word variations have been searched)
#1510* near/4 (antag* or inhib* or block*)
#16#12 or #13 or #14 or #15
#17rivaroxaban or Xarelto:ti,ab,kw (Word variations have been searched)
#18Bay-597939 or Bay597939:ti,ab,kw (Word variations have been searched)
#19betrixaban or PRT054021:ti,ab,kw (Word variations have been searched)
#20apixaban:ti,ab,kw (Word variations have been searched)
#21BMS-562247 or BMS-562247 or ELIQUIS:ti,ab,kw (Word variations have been searched)
#22*x?ban:ti,ab,kw (Word variations have been searched)
#23DU-176b or DU176b:ti,ab,kw (Word variations have been searched)
#24PRT-054021 or PRT-054021:ti,ab,kw (Word variations have been searched)
#25YM150 or YM-150 or LY517717 or LY-517717 or DU-176b or DU176*:ti,ab,kw (Word variations have been searched)
#26GW813893 or "Tak 442" or TAK442 or PD0348292 or GSK-813893 or GSK813893:ti,ab,kw (Word variations have been searched)
#27#17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26
#28#11 or #16 or #27
#29MeSH descriptor: [Thrombosis] this term only
#30MeSH descriptor: [Thromboembolism] this term only
#31MeSH descriptor: [Venous Thromboembolism] explode all trees
#32MeSH descriptor: [Venous Thrombosis] explode all trees
#33(thrombo* or thrombus* or embol*):ti,ab,kw (Word variations have been searched)
#34MeSH descriptor: [Pulmonary Embolism] explode all trees
#35PE or DVT or VTE:ti,ab,kw (Word variations have been searched)
#36((vein* or ven*) near thromb*):ti,ab,kw (Word variations have been searched)
#37blood clot:ti,ab,kw (Word variations have been searched)
#38#29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37
#39#28 and #38 in Trials

Contributions of authors

LR: drafted the protocol; will select studies for inclusion, extract data, assess the quality of studies, perform data analysis and write the review.
PK: commented on the protocol; will select studies for inclusion, extract data, assess the quality of the studies and comment on the review.

Declarations of interest

LR: none known.
PK has received consultancy fees for attendance at advisory boards of Boehringer-Ingelheim, Bayer, and Daiitchi-Sankyo and payment from Bayer for lectures at the 2013 anticoagulation masterclass. PK's institution was paid travel/accommodation/meeting expenses by Boehringer-Ingelheim for his attendance at the 2013 ISTH meeting and staff and NHS costs by Boehringer-Ingelheim and Daiitchi-Sankyo for involvement in phase III trials of novel anticoagulants in venous thrombosis.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK.

    The PVD Group editorial base is supported by the Chief Scientist Office.