Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis

  • Protocol
  • Intervention

Authors


Abstract

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 DVT.

Background

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.

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 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).

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. 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.

1. Rivaroxaban

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).

2. Apixaban

Apxaban is an oral, small molecule, reversible inhibitor of factor Xa with a plasma half-life of 8 to 15 hours (Eriksson 2009).

3. Betrixaban

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).

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 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).

Objectives

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

Methods

Criteria for considering studies for this review

Types of studies

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

Types of participants

Patients with a DVT, confirmed by standard imaging techniques (venography, impedance plethysmography, whole leg compression ultrasound, proximal compression ultrasound).

Types of interventions

  • Oral DTIs (e.g. dabigatran, ximelagatran) (although ximelagatran was withdrawn from the market in 2006 due to safety issues, we will included it in the review to make the results as comprehensive as possible).

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

  • Other anticoagulants (e.g. LMWH, UFH or 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 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 computed tomography pulmonary angiography (CTPA) or ventilation/perfusion (V/Q) scan, or both).

  • PE (fatal/non-fatal), confirmed by CTPA or V/Q scan.

Secondary outcomes
  • All-cause mortality.

  • PTS.

  • 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 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 hand searching 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 DVT, baseline characteristics of participants and type of prophylaxis. We will record recurrent DVT and PE (fatal and non-fatal) data as the primary outcome measures. We will collect data on all-cause mortality, PTS, 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 are judged 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.

Appendices

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

  • National Institute for Health Research (NIHR), UK.

    The review authors are supported by a programme grant from the NIHR.

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

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

  • National Institute for Health Research (NIHR), UK.

    The PVD Group editorial base is supported by a programme grant from the NIHR.

Ancillary