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Cochrane Database of Systematic Reviews Review - Intervention

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

Authors' declarations of interest

Version published: 14 April 2023 Version history

https://doi.org/10.1002/14651858.CD010956.pub3
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Background

Deep vein thrombosis (DVT) is a condition in which a clot forms in the deep veins, most commonly of the leg. It occurs in approximately one in 1000 people. If left untreated, the clot can travel up to the lungs and cause a potentially life‐threatening pulmonary embolism (PE). Previously, a DVT was treated with the anticoagulants heparin and vitamin K antagonists. However, two forms of direct oral anticoagulants (DOACs) have been developed: oral direct thrombin inhibitors (DTIs) and oral factor Xa inhibitors, which have characteristics that may be favourable compared to conventional treatment, including oral administration, a predictable effect, lack of frequent monitoring or dose adjustment and few known drug interactions. DOACs are now commonly being used for treating DVT: recent guidelines recommended DOACs over conventional anticoagulants for both DVT and PE treatment. This Cochrane Review was first published in 2015. It was the first systematic review to measure the effectiveness and safety of these drugs in the treatment of DVT. This is an update of the 2015 review. 

Objectives

To assess the effectiveness and safety of oral DTIs and oral factor Xa inhibitors versus conventional anticoagulants for the long‐term treatment of DVT.

Search methods

The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 1 March 2022.

Selection criteria

We included randomised controlled trials (RCTs) in which people with a DVT, confirmed by standard imaging techniques, were allocated to receive an oral DTI or an oral factor Xa inhibitor compared with conventional anticoagulation or compared with each other for the treatment of DVT. 

Data collection and analysis

We used standard Cochrane methods. Our primary outcomes were recurrent venous thromboembolism (VTE), recurrent DVT and PE. Secondary outcomes included all‐cause mortality, major bleeding, post‐thrombotic syndrome (PTS) and quality of life (QoL). We used GRADE to assess the certainty of evidence for each outcome.

Main results

We identified 10 new studies with 2950 participants for this update. In total, we included 21 RCTs involving 30,895 participants. Three studies investigated oral DTIs (two dabigatran and one ximelagatran), 17 investigated oral factor Xa inhibitors (eight rivaroxaban, five apixaban and four edoxaban) and one three‐arm trial investigated both a DTI (dabigatran) and factor Xa inhibitor (rivaroxaban). Overall, the studies were of good methodological quality.

Meta‐analysis comparing DTIs to conventional anticoagulation showed no clear difference in the rate of recurrent VTE (odds ratio (OR) 1.17, 95% confidence interval (CI) 0.83 to 1.65; 3 studies, 5994 participants; moderate‐certainty evidence), recurrent DVT (OR 1.11, 95% CI 0.74 to 1.66; 3 studies, 5994 participants; moderate‐certainty evidence), fatal PE (OR 1.32, 95% CI 0.29 to 6.02; 3 studies, 5994 participants; moderate‐certainty evidence), non‐fatal PE (OR 1.29, 95% CI 0.64 to 2.59; 3 studies, 5994 participants; moderate‐certainty evidence) or all‐cause mortality (OR 0.66, 95% CI 0.41 to 1.08; 1 study, 2489 participants; moderate‐certainty evidence). DTIs reduced the rate of major bleeding (OR 0.58, 95% CI 0.38 to 0.89; 3 studies, 5994 participants; high‐certainty evidence).  

For oral factor Xa inhibitors compared with conventional anticoagulation, meta‐analysis demonstrated no clear difference in recurrent VTE (OR 0.85, 95% CI 0.71 to 1.01; 13 studies, 17,505 participants; moderate‐certainty evidence), recurrent DVT (OR 0.70, 95% CI 0.49 to 1.01; 9 studies, 16,439 participants; moderate‐certainty evidence), fatal PE (OR 1.18, 95% CI 0.69 to 2.02; 6 studies, 15,082 participants; moderate‐certainty evidence), non‐fatal PE (OR 0.93, 95% CI 0.68 to 1.27; 7 studies, 15,166 participants; moderate‐certainty evidence) or all‐cause mortality (OR 0.87, 95% CI 0.67 to 1.14; 9 studies, 10,770 participants; moderate‐certainty evidence). Meta‐analysis showed a reduced rate of major bleeding with oral factor Xa inhibitors compared with conventional anticoagulation (OR 0.63, 95% CI 0.45 to 0.89; 17 studies, 18,066 participants; high‐certainty evidence). 

Authors' conclusions

The current review suggests that DOACs may be superior to conventional therapy in terms of safety (major bleeding), and are probably equivalent in terms of efficacy. There is probably little or no difference between DOACs and conventional anticoagulation in the prevention of recurrent VTE, recurrent DVT, pulmonary embolism and all‐cause mortality. DOACs reduced the rate of major bleeding compared to conventional anticoagulation. The certainty of evidence was moderate or high.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Are direct oral anticoagulants (a type of 'blood thinner') better than conventional anticoagulation for treating people with a blood clot in a deep vein? 

What is deep vein thrombosis?

Deep vein thrombosis (DVT) is when a blood clot forms, usually in a deep vein of the leg or pelvis. Approximately 1 in 1000 people will develop a DVT. If it is not treated, the clot can travel in the blood and block the blood vessels in the lungs. This life‐threatening condition is called a pulmonary embolism. It occurs in approximately 3 to 4 people per 10,000 people. The chances of getting a DVT are increased if you have certain risk factors. These include previous clots, prolonged periods of immobility (such as travelling on aeroplanes or taking bed rest), cancer, exposure to oestrogens (pregnancy, oral contraceptives or hormone replacement therapy), trauma and blood disorders such as thrombophilia (abnormal blood clotting). A DVT is diagnosed by determining the risk factors and performing an ultrasound of the leg veins. 

How is deep vein thrombosis treated? 

If a DVT is confirmed, people are treated with an anticoagulant: a medicine that either treats or prevents blood clots, often called a 'blood thinner'. Previously, the medicines of choice were heparin, fondaparinux and vitamin K antagonists, known as 'conventional anticoagulants'. However, these medicines can cause side effects and have limitations.

Two types of anticoagulant have been developed: direct thrombin inhibitors (DTI) and factor Xa inhibitors. These anticoagulants are given orally (that is, by mouth, in the form of a pill), have a predictable effect, do not require frequent monitoring or re‐dosing (taking multiple doses), and have few known interactions with other medicines. For these reasons, direct oral anticoagulants have become the medicines of choice for treating DVT. 

What did we want to find out?

We wanted to find out if direct oral anticoagulants are useful and safe for treating people with DVT compared with conventional treatments. 

What did we do?

We searched for studies in which people with a confirmed DVT were randomly allocated to one of two treatment groups. These types of studies give the most reliable evidence about treatment effects. People in the experimental groups received an oral direct thrombin inhibitor or an oral factor Xa inhibitor, and their results were compared to the results of people given conventional anticoagulation. All participants were given long‐term treatment of DVT (minimum duration of 3 months). 

What did we find?

After searching for relevant studies, we found 21 studies with 30,895 participants. We combined the data from the studies and found that there was no clear difference in the incidence of:

‐ recurrent venous thromboembolism (DVT, pulmonary embolism, or both);
‐ recurrent DVT;
‐ pulmonary embolism (blood clot in the lungs); or
‐ death
between people treated with oral direct thrombin inhibitors or oral factor Xa inhibitor compared to those given conventional anticoagulants.

Compared to conventional treatment, both direct thrombin inhibitors and factor Xa inhibitors reduced the major bleeding which happened during the treatment of DVT.

What are the limitations of the evidence?

Our confidence in the evidence is generally moderate because few people overall experienced the outcomes. The evidence answered the question we addressed directly and the results of the studies were consistent. However, further studies are needed to explore how one direct oral anticoagulant compares with another. Future well‐designed studies may also provide important evidence for post‐thrombotic syndrome (a condition that can happen to people who have had a DVT of the leg, causing chronic pain, swelling and other symptoms in the leg) and quality of life.

How up to date is this evidence?

This review updates a previous Cochrane Review. The evidence is up to date to 1 March 2022.

Key messages

When treating people with a DVT, current evidence shows there is probably a similar effect between direct oral anticoagulants and conventional anticoagulants for preventing recurrent venous thromboembolism, recurrent DVT, pulmonary embolism and death. Direct oral anticoagulants reduced major bleeding compared to conventional anticoagulation.

Authors' conclusions

Implications for practice

The current review suggests that direct oral anticoagulants (DOACs) may be superior to conventional therapy in terms of safety (major bleeding), and are probably equivalent in terms of efficacy (recurrent venous thromboembolism (VTE), recurrent deep vein thrombosis (DVT), fatal and non‐fatal pulmonary embolism (PE) and mortality). The clear practical benefit of DOACs is the ease of use. This may provide clinical and economic benefits in the avoidance of the warfarin‐loading phase of treatment (as shown in some of the studies), with its concomitant use of parenteral anticoagulants and frequent international normalised ratio (INR) testing. However, precautions are required with the use of DOACs. They are all, to some extent, renally excreted, and there is evidence of wide inter‐individual variation in anticoagulant response. 

Implications for research

There is evidence of wide inter‐individual variation in anticoagulant effect from the fixed doses of DOACs currently prescribed. This may be of clinical importance, and further research is needed to investigate dosage adjustment for various subgroups, including people with: malignancy, DVT in unusual sites (e.g. upper limbs), travel‐associated DVT, thrombophilic abnormality (e.g. anti‐phospholipid syndrome), obesity or renal impairment. Further research is also needed to investigate any impact on the decision to use extended phase anticoagulation and interruption of procedures with DOAC use. Furthermore, future studies should directly compare one DOAC to another to determine which is most effective and safe, especially given that research from observational studies has shown that apixaban decreased risk of major bleeding events compared with rivaroxaban in people with VTE. For outcomes, studies rarely analysed quality of life and post‐thrombotic syndrome (PTS). Future studies should consider recording and reporting these important outcomes. Finally, as we noted above, all‐cause mortality has yet to be estimated for DVT treated with dabigatran, so more research is needed in this area.

Summary of findings

Open in table viewer
Summary of findings 1. Oral DTIs versus conventional anticoagulation for participants with diagnosed DVT

Oral DTIs versus conventional anticoagulation for participants with diagnosed DVT

Patient or population: participants with diagnosed DVT 
Setting: hospital 
Intervention: oral DTIs 
Comparison: conventional anticoagulation

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with conventional anticoagulation

Risk with oral DTIs

Recurrent VTE

 

(7 months)

Study population

OR 1.17
(0.83 to 1.65)

5994
(3 RCTsa)

⊕⊕⊕⊝
Moderateb

 

21 per 1000

25 per 1000
(18 to 35)

Recurrent DVT

 

(7 months)

Study population

OR 1.11
(0.74 to 1.66)

5994
(3 RCTsa)

⊕⊕⊕⊝
Moderateb

 

15 per 1000

17 per 1000
(11 to 25)

Fatal PE

 

(7 months)

Study population

OR 1.32
(0.29 to 6.02)

5994
(3 RCTsa)

⊕⊕⊕⊝
Moderateb

 

1 per 1000

1 per 1000
(0 to 6)

Non‐fatal PE

 

(7 months)

Study population

OR 1.29
(0.64 to 2.59)

5994
(3 RCTsa)

⊕⊕⊕⊝
Moderateb

 

5 per 1000

6 per 1000
(3 to 12)

All‐cause mortality

 

(7 months)

Study population

OR 0.66
(0.41 to 1.08)

2489
(1 RCT)

⊕⊕⊕⊝
Moderateb

 

34 per 1000

22 per 1000
(14 to 36)

Major bleeding

 

(7 months)

Study population

OR 0.58
(0.38 to 0.89)

5994
(3 RCTsa)

⊕⊕⊕⊕
High

 

19 per 1000

11 per 1000
(7 to 17)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). 
CI: confidence interval; DTIs: direct thrombin inhibitors; DVT: deep vein thrombosis; OR: odds ratio; PE: pulmonary embolism; RCT: randomised controlled trial; VTE: venous thromboembolism

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

aThe data from RE‐COVER 2009 and RE‐COVER II 2014 were taken from one pooled analysis and are therefore shown as one study in our analyses
bWe downgraded one level for imprecision due to the low number of events and a small sample size; the possibility of publication bias is not excluded but we did not consider it sufficient to downgrade the certainty of evidence.

Open in table viewer
Summary of findings 2. Oral factor Xa inhibitors compared to conventional anticoagulation for participants with diagnosed DVT

Oral factor Xa inhibitors versus conventional anticoagulation for participants with diagnosed DVT

Patient or population: participants with diagnosed DVT 
Setting: hospital
Intervention: oral factor Xa inhibitors
Comparison: conventional anticoagulation

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with conventional anticoagulation

Risk with oral factor Xa

Recurrent VTE

 

(3 to 12 months)

Study population

OR 0.85
(0.71 to 1.01)

17,505
(13 RCTs)

⊕⊕⊕⊝
Moderatea

One of the 13 studies reported no events

34 per 1000

29 per 1000
(24 to 34)

Recurrent DVT

 

(3 to 12 months)

Study population

OR 0.70
(0.49 to 1.01)

16,439
(9 RCTs)

⊕⊕⊕⊝
Moderatea

 

16 per 1000

12 per 1000
(8 to 17)

Fatal PE

 

(3 to 12 months)

Study population

OR 1.18
(0.69 to 2.02)

15,082
(6 RCTs)

⊕⊕⊕⊝
Moderatea

 

3 per 1000

4 per 1000
(2 to 6)

Non‐fatal PE

 

(3 to 12 months)

Study population

OR 0.93
(0.68 to 1.27)

15,166
(7 RCTs)

⊕⊕⊕⊝
Moderatea

 

11 per 1000

10 per 1000
(8 to 14)

All‐cause mortality

 

(3 to 6 months)

Study population

OR 0.87
(0.67 to 1.14)

10,770
(9 RCTs)

 

⊕⊕⊕⊝
Moderatea

Three of the nine studies reported no events

23 per 1000

20 per 1000
(16 to 27)

Major bleeding

 

(3 to 12 months)

Study population

OR 0.63
(0.45 to 0.89)

18,066
(17 RCTs)

 

⊕⊕⊕⊕
High

Five of 17 studies reported no events

17 per 1000

11 per 1000
(8 to 15)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). 

CI: confidence interval; DVT: deep vein thrombosis; OR: odds ratio; PE: pulmonary embolism; RCT: randomised controlled trial; VTE: venous thromboembolism

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

aWe downgraded one level for imprecision due to the low number of events and a small sample size; the possibility of publication bias is not excluded but we did not consider it sufficient to downgrade the quality of evidence.

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. DVT and pulmonary embolism (PE) occur with an incidence of approximately one per 1000 annually in adults (Cushman 2007; White 2003); the incidence of DVT in the general population is around five per 10,000 per annum (Fowkes 2003). 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 four to 12 per 10,000 people, but this is likely to be underestimated and the incidence has been increasing steadily (Barco 2021; Bĕlohlávek 2013; Keller 2020; Konstantinides 2020; Wendelboe 2016). The two interrelated conditions, DVT and PE, are different clinical manifestations of venous thromboembolism (VTE). Among VTE, about two‐thirds of cases manifest as DVT only and one‐third as PE with or without DVT (Stone 2017). Another complication of DVT is post‐thrombotic syndrome (PTS). PTS is a long‐term condition caused by the reduction in the return of venous blood to the heart. Symptoms include chronic pain, skin discolouration, oedema and, in severe cases, varicose veins and venous ulceration (Kahn 2002). The incidence of PTS after a symptomatic DVT is estimated to be between 12% and 60%; PTS added an additional 75% to the cost of treating DVT (Ashrani 2009; Kahn 2014).

There are many risk factors for DVT. When a risk factor is transient (such as major surgery), DVT is termed "provoked". DVT occurring in the absence of transient risk factors is termed "unprovoked" (Kearon 2012). Provoked DVT occurs following surgery or by a non‐surgical transient risk factor, such as the history of 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 an individual's medical history and physical examination. The UK National Institute for Health and Care Excellence (NICE) recommends that people presenting with a suspected DVT should be assessed for pre‐test probability of DVT using the 2‐level DVT Wells score (NICE 2020; 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 (ACCP) recommends that people 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; Wells 2003). People with moderate pre‐test probability should undergo D‐dimer, proximal compression or whole‐leg ultrasound, while people with a high pre‐test probability should undergo proximal compression or whole‐leg ultrasound (Bates 2012; Wells 2003).

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 or a raised D‐dimer level, including cancer, disseminated intravascular coagulation, pregnancy, inflammation and infection (NICE 2020). 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 non‐invasive diagnostic imaging technique that uses sound waves to produce images of structures within the body. 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 high sensitivity and specificity for detecting proximal DVT (NICE 2020). Guidelines recommend completing either proximal or whole‐leg ultrasound, determined by local practice, access to testing and cost (Bates 2012).

Description of the intervention

Anticoagulation is an essential component of therapy for DVT, which can prevent the progression of DVT to PE and the recurrence of thrombosis. The 30‐day mortality rate exceeds 3% in people with DVT who are not anticoagulated; this mortality risk is as high as 31% in people with PE (Sogaard 2014). The conventional treatment of DVT is with an indirect thrombin inhibitor, namely unfractionated heparin (UFH), or low molecular weight heparin (LMWH), followed by 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). Although heparin and VKAs are effective anticoagulants, there are limitations associated with each. Heparin‐induced thrombocytopenia (HIT) is a rare, potentially life‐threatening, reaction to heparin (Ortel 2022). Approximately 50% of people with isolated HIT develop further thrombosis (Warkentin 1996). Meanwhile, VKAs have a narrow therapeutic window, require frequent monitoring and dosage adjustments, and have multiple interactions with other drugs (Ageno 2012).

Two further classes of direct oral anticoagulants (DOACs) have been developed: direct thrombin inhibitors (DTIs) and factor Xa inhibitors. Oral DTIs and factor Xa inhibitors have characteristics that may be favourable over heparin and VKAs, including oral administration, a predictable effect, lack of frequent monitoring or dose adjustment, and few known drug interactions (Almutairi 2017; Fox 2012). 

Anticoagulant therapy for VTE (DVT and PE) can be divided into three stages: initiation phase (five to 21 days) with initial provision of anticoagulants after diagnosis; treatment phase (three months), the period that completes treatment for the acute VTE following initiation; and the extended phase (three months to no planned stop date) for secondary prevention, with anticoagulant use at full or reduced dose (Stevens 2021). Previous ACCP guidelines recommend initial therapy for DVT with a parenteral anticoagulant (UFH or LMWH or fondaparinux) and initial VKA initiation; recommendations include the use of LMWH or fondaparinux over UFH for initial therapy of DVT (Kearon 2012). The latest updates of ACCP guidelines recommended apixaban, dabigatran, edoxaban or rivaroxaban over VKA as treatment‐phase (first three months) anticoagulant therapy for people with VTE (DVT of the leg or PE), and recommended an oral Xa inhibitor (apixaban, edoxaban, rivaroxaban) over LMWH for the initiation and treatment phases of therapy for acute VTE associated with cancer (Kearon 2016; Stevens 2021). Similarly, the 2019 European Society of Cardiology (ESC) guidelines recommended DOACs in preference to VKAs in eligible individuals ready for an oral anticoagulant (Konstantinides 2020). The NICE 2020 guidelines recommended offering either apixaban or rivaroxaban as initial choices, and suggested other regimens only for people suitable for neither: consider a DOAC for people with active cancer and confirmed proximal DVT or PE, and consider other strategies when DOAC is unsuitable.

According to research by Lutsey and colleagues, the use of DOACs (especially rivaroxaban and apixaban) to treat VTE has increased dramatically in the USA since the US Food and Drug Administration (FDA) approved them for this application (Lutsey 2019). Drawing on individual health insurance data for 2012 to 2017, they found that DOACs accounted for less than 2% of the prescriptions for VTE treatment at the beginning of 2012 and increased to more than 80% by the fourth quarter of 2017 (Lutsey 2019). 

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, but only one available for clinical use.

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 stroke prevention in atrial fibrillation (Calkins 2017; Cannon 2017; Connolly 2009), acute coronary syndromes (Oldgren 2011), prevention of thrombosis following orthopaedic surgery (Eriksson 2007; Van der Veen 2021), and in people with mechanical heart valves (Eikelboom 2013; Van de Werf 2012). In common with the other DOACs, dabigatran was associated with a lower incidence of intracranial haemorrhage (compared with VKAs). However, again compared with VKAs, dabigatran showed a higher incidence of indigestion, heartburn and gastrointestinal bleeding (Schulman 2014). 

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), especially with prolonged use (Testa 2007), and was never licensed.

Oral factor Xa inhibitors

Factor Xa inhibitors bind directly to the active site of factor Xa, thus blocking the activity of this 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 VKAs but without the need for regular blood test monitoring. They appear to have fewer drug interactions (compared with VKAs) and no food or alcohol interactions.

Rivaroxaban

Rivaroxaban is a reversible oral direct factor Xa inhibitor with a half‐life estimated to be eight to 10 hours (Spyropoulos 2012). 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; the dose can be reduced to 10 mg once daily beyond six months (Skelley 2018). The absorption of rivaroxaban (the 15 mg and 20 mg dosage) is predicated on giving it with food; therefore, rivaroxaban is recommended to be taken with food (Skelley 2018; Stampfuss 2013).

Apixaban

Apixaban is an oral, small molecule, reversible inhibitor of factor Xa with a plasma half‐life of eight to 15 hours (Eriksson 2009). The recommended dosage for apixaban is 10 mg twice daily for one week, then 5 mg twice daily. For people with severe renal impairment (creatinine clearance (CrCL) of 15 mL/min to 29 mL/min), apixaban should be used with caution (Leung 2022).

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). Betrixaban is only labelled for VTE prophylaxis, not treatment (Skelley 2018). For the prophylaxis of VTE, the recommended dose of betrixaban is an initial single dose of 160 mg starting on day 1, followed by 80 mg once daily taken for 35 to 42 days at the same time each day with food. For people with severe renal impairment (CrCL 15 mL/min to 29 mL/min computed by Cockcroft‐Gault using actual body weight), the recommended dose of betrixaban is an initial single dose of 80 mg followed by 40 mg once daily (FDA 2017).

Edoxaban

Edoxaban is an oral direct inhibitor of activated factor X that is rapidly absorbed with a half‐life of nine 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). The recommended dose is 60 mg once daily after parenteral anticoagulation for five to 10 days (Leung 2022).

Why it is important to do this review

Given the relatively high incidence and serious consequence of DVT, and the emergence and adoption of these DOACs, it is important to establish the safety and effectiveness of these treatments. Multiple non‐Cochrane systematic reviews have examined the effectiveness of DTIs and factor Xa inhibitors versus VKAs in the treatment of VTE (Almutairi 2017; Fox 2012; Mulder 2020). However, their primary outcome was VTE and they did not present results for DVT and PE separately. 

This review was originally conducted in 2015 and included 11 randomised controlled trials of 27,945 participants. It examined the effectiveness of oral DTIs and oral factor Xa inhibitors in the treatment of DVT alone, and showed that they are potentially effective and safe alternatives to conventional anticoagulation treatment for acute DVT (Robertson 2015). However, none of the included studies in the previous version focused on and measured important outcomes, such as PTS or health‐related quality of life, and all‐cause mortality has yet to be estimated for DVT treated with dabigatran (the only FDA‐approved DTI). In addition, data were limited for important subgroups (e.g. people with cancer). Further, no study compared one DOAC with another, a fact highlighted in both NICE and ACCP guidelines (NICE 2020; Stevens 2021).

Since 2015, many new randomised controlled trials on this topic have been published (AMPLIFY‐J 2015; Farhan 2019; Ohmori 2019; PRAIS 2019; Raskob 2018), with some reporting on quality of life (Sukovatykh 2017) and PTS (de Athayde 2019), and more studies focused on cancer‐associated DVT (Caravaggio 2020; Hokusai VTE Cancer 2018; Mokadem 2021). Further, the previous version included data published only in a conference abstract for the eTRIS 2016 study. As DOACs are now ubiquitous in the context of primary treatment for VTE, there is a continued need to assess their comparative effectiveness, and to explore and understand how to optimise their management in high‐risk situations. It is important to update the evidence presented in this Cochrane Review to include any newly available data, providing trustworthy evidence synthesis for more informed decision‐making.

Objectives

To assess the effectiveness and safety of oral DTIs and oral factor Xa inhibitors versus conventional anticoagulants for the long‐term treatment of DVT.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials in which people with a confirmed DVT were allocated to receive an oral DTI or an oral factor Xa inhibitor for the treatment of DVT. We included published studies and studies in progress if preliminary results were available. We also included non‐English studies in the review. There was no restriction on publication status. We excluded DTIs and factor Xa inhibitors that were not given by the oral route. We also excluded studies where treatment lasted less than three months, as a meta‐analysis of DVT treatment strategies has demonstrated an increased rate of recurrence after less than three months of anticoagulation but no significant difference with various longer periods of treatment (Boutitie 2011).

Types of participants

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

Types of interventions

We included the following interventions:

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

  • oral factor Xa inhibitors (e.g. rivaroxaban, apixaban, edoxaban);

  • other anticoagulants (e.g. LMWH, UFH or VKAs).

We included the following comparisons:

  • oral DTI or oral factor Xa inhibitor versus another anticoagulant;

  • one oral DTI versus another oral DTI;

  • one oral factor Xa inhibitor versus another oral factor Xa inhibitor;

  • oral DTI versus oral factor Xa inhibitor.

Treatment had to be for a minimum duration of three months as this is conventional anticoagulation practice for a DVT.

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)

  • Recurrent DVT, confirmed by standard imaging techniques, including proximal leg vein ultrasound scan or D‐dimer test

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

Secondary outcomes

  • All‐cause mortality

  • Major bleeding (an adverse event; as defined by the International Society on Thrombosis and Haemostasis (ISTH); Schulman 2005):

    • fatal bleeding;

    • symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra‐articular or pericardial, or intramuscular with compartment syndrome;

    • 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;

    • any combination of the above.

  • PTS as defined by Kahn 2016

  • Health‐related quality of life (as reported in studies)

Search methods for identification of studies

Electronic searches

The Cochrane Vascular Information Specialist conducted systematic searches of the following databases, from inception to 1 March 2022, for randomised controlled trials and controlled clinical trials without language, publication year or publication status restrictions:

  • the Cochrane Vascular Specialised Register via the Cochrane Register of Studies (CRS‐Web);

  • the Cochrane Central Register of Controlled Trials (CENTRAL; 2022) via the Cochrane Register of Studies Online (CRSO);

  • MEDLINE (Ovid MEDLINE Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE); 

  • Embase Ovid;

  • CINAHL (Cumulative Index to Nursing and Allied Health Literature) EBSCO. 

We developed search strategies for other databases from the search strategy designed for MEDLINE. Where appropriate, they were combined with adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomised controlled trials and controlled clinical trials, as described in the Cochrane Handbook for Systematic Reviews of Interventions Chapter 4 (Lefebvre 2021). Search strategies for major databases are provided in Appendix 1.

We searched the following trials registries:

The most recent searches were carried out on 1 March 2022.

Searching other resources

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

Data collection and analysis

Selection of studies

Pairs of reviewers (XW, YM, ML, JL, XH, QW, LY), independently and in duplicate, used the selection criteria to identify trials for inclusion.  We resolved any disagreements by discussion.

Data extraction and management

Two pairs of review authors (ML, YM, JL, XH) independently extracted the data from the included studies. We recorded information about the trial design; exclusions post‐randomisation; losses to follow‐up; duration of study; unit of randomisation; country and setting; number of participants; age and sex of participants; participant inclusion and exclusion criteria; intervention and control group sample sizes, type, dose and duration of intervention; diagnosis of DVT; baseline characteristics of participants; funding source and declarations of interest declared by study authors. We recorded recurrent VTE, recurrent DVT and PE (fatal and non‐fatal) data as the primary outcome measures. We also collected data on all‐cause mortality, major bleeding, PTS and health‐related quality of life in accordance with the secondary outcome measures. We contacted authors of included studies where further information or clarification was required. We resolved any disagreements in data extraction and management by discussions with a third review author (XW) if required.

Assessment of risk of bias in included studies

Two pairs of review authors (ML, YM, JL, XH) independently used Cochrane's risk of bias tool to assess risk of bias for each of the included studies (Higgins 2017). 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 judged each of these domains as high, low or unclear risk of bias according to Higgins 2017, and provided support for each judgement. We presented the conclusions in a risk of bias table. We resolved any disagreements by discussion with a third review author (XW) if required.

Measures of treatment effect

We based the analysis on intention‐to‐treat data from the individual clinical trials.  

For dichotomous outcomes, we used odds ratios (ORs) as the effect measure, with 95% confidence intervals (CIs). For continuous data, we calculated mean differences (MDs) with 95% CIs. If similar outcomes were measured using different scales, we planned to calculate the standardised mean difference (SMD).

Unit of analysis issues

The unit of analysis in this review was the individual participant.

Dealing with missing data

We sought information about dropouts, withdrawals and other missing data and, if not reported, we contacted study authors for this information.

Assessment of heterogeneity

We assessed heterogeneity between the trials by: visually examining forest plots to check for overlap among CIs; using the Chi2 test for homogeneity with a 10% level of significance; and using 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 2022).

Assessment of reporting biases

We investigated publication bias by funnel plots where a sufficient number of studies (10 or more) were available in the meta‐analyses. There are many reasons for funnel plot asymmetry, and we referred to the Cochrane Handbook for Systematic Reviews of Interventions to aid the interpretation of the results (Sterne 2011).

Data synthesis

One review author (XW) entered the data into RevMan Web (RevMan Web 2019), and a second review author (XH) cross‐checked data entry. We resolved any discrepancies by consulting the source publication.

We used a random‐effects model to synthesise the data, even when low heterogeneity was indicated by small I² values. This was because we expected that clinical heterogeneity across studies may exist, such as different oral factor Xa inhibitors (e.g. apixaban, rivaroxaban, edoxaban), different indirect thrombin inhibitors in the control group (e.g. warfarin, dalteparin), and different treatment durations (e.g. three, six and 12 months).

Subgroup analysis and investigation of heterogeneity

We planned to conduct subgroup analysis only when each subgroup was reported by at least two studies. Due to the limited number of included studies in each subgroup, we were not able to perform the following subgroup analyses: 

  • history of VTE;

  • age;

  • pregnancy;

  • major surgery requiring general or regional anaesthesia in the previous 12 weeks;

  • recent period of immobility (bedridden for three or more days in the previous 12 weeks);

  • thrombophilia (genetic or acquired).

We performed subgroup analysis by duration of treatment to identify treatment effects of three months of treatment and more than three months of treatment. We also conducted subgroup analysis by different oral Xa factor inhibitors since individual drugs may have potential differences in effectiveness and safety. For treatment effects by populations with active cancer versus no cancer, we carried out subgroup analysis when sufficient data were available.

Sensitivity analysis

We performed sensitivity analyses by excluding studies that we judged to be at high risk of bias in any domain. We also performed sensitivity analyses by excluding the study that gave participants ximelagatran, as this drug is no longer available.

Summary of findings and assessment of the certainty of the evidence

We developed summary of finding tables using GRADEpro GDT software (GRADEpro GDT). We created one table for the comparisons 'Oral DTIs versus conventional anticoagulation for participants with diagnosed DVT' and 'Oral factor Xa inhibitors compared to conventional anticoagulation for participants with diagnosed DVT'. We assessed the certainty of the body of evidence for each outcome as high, moderate, low or very low by considering the risk of bias, inconsistency, indirectness, imprecision and publication bias, according to the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2022). We assessed the certainty of evidence for the following outcomes: recurrent VTE, recurrent DVT, fatal PE, non‐fatal PE, all‐cause mortality and major bleeding. We included footnotes to justify decisions to downgrade the certainty of the evidence.

Results

Description of studies

Results of the search

See Figure 1.

Figure 1
Study flow diagram

Study flow diagram

For this update, the searches identified 11,673 records, leaving 8962 records after deduplication. We assessed 8786 records as not relevant based on the title and abstract screening. We assessed 176 potentially relevant records by screening full‐text publications. We identified 10 new studies (35 reports) eligible for inclusion in the review, and 47 additional reports for already included studies. The previous version of the review included 11 studies (44 reports); therefore, we ultimately included a total of 21 studies (126 reports) in this review update. See Characteristics of included studies. Five references reported on more than one study and are listed more than once, making the total count of reports of included studies 131. We excluded 16 studies (51 reports) with reasons; we identified 11 ongoing studies (11 reports); and we assessed one study (one report) as awaiting classification. We assessed the remaining thirty‐one records as not relevant.

Included studies

The Characteristics of included studies table presents details of the included studies.

Twenty‐one studies (30,895 participants) met the criteria and were included in the review (AMPLIFY 2013; AMPLIFY‐J 2015; Botticelli DVT 2008; Caravaggio 2020; de Athayde 2019; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; EINSTEIN‐PE 2012; eTRIS 2016; Farhan 2019; Hokusai‐VTE 2013;  Hokusai VTE Cancer 2018; J‐EINSTEIN DVT and PE 2015; Mokadem 2021; ODIXa‐DVT 2007; Ohmori 2019; PRAIS 2019; RE‐COVER 2009; RE‐COVER II 2014; Sukovatykh 2017; THRIVE 2005). All studies were two‐arm trials with the exception of one, the Sukovatykh 2017 study, which was a three‐arm trial, comparing both a DTI (dabigatran) and factor Xa inhibitor (rivaroxaban) to conventional anticoagulation.

Four studies (7691 participants) compared oral DTIs with conventional anticoagulation (RE‐COVER 2009; RE‐COVER II 2014; Sukovatykh 2017; THRIVE 2005). One study tested ximelagatran (THRIVE 2005). The THRIVE 2005 study was a phase III, double‐blind, double‐dummy, dose‐guiding study in which 2489 people with a VTE were given ximelagatran 24 mg, 36 mg, 48 mg or 60 mg twice daily for six months. The control treatment was LMWH (enoxaparin or dalteparin) followed by warfarin. Three studies tested dabigatran (RE‐COVER 2009; RE‐COVER II 2014; Sukovatykh 2017). RE‐COVER 2009 was a phase III, non‐inferiority, double‐blind, double‐dummy trial in which 2539 people with a VTE were given dabigatran 150 mg twice daily or warfarin. Treatment was for six months and included sham monitoring of international normalised ratio (INR) and sham titration of warfarin in the control group. To gain regulatory approval, the study was repeated with an identical design (RE‐COVER II 2014). Sukovatykh 2017 was a clinical trial in which 95 participants were randomly divided into the dabigatran (150 mg twice daily for six months), rivaroxaban (15 mg twice daily for three weeks, then 20 mg once daily until end of the six‐month course) or warfarin group. All studies measured recurrent VTE; three studies measured recurrent DVT, PE (fatal and non‐fatal), all‐cause mortality and major clinically relevant bleeding (RE‐COVER 2009; RE‐COVER II 2014; THRIVE 2005); one reported quality of life measured by the 36‐item Short Form Health Survey (SF‐36) (Sukovatykh 2017).

Eighteen studies (30,895 participants) tested oral factor Xa inhibitors (AMPLIFY 2013; AMPLIFY‐J 2015; Botticelli DVT 2008; Caravaggio 2020; de Athayde 2019; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; EINSTEIN‐PE 2012; eTRIS 2016; Farhan 2019; Hokusai VTE Cancer 2018; Hokusai‐VTE 2013; J‐EINSTEIN DVT and PE 2015; Mokadem 2021; ODIXa‐DVT 2007; Ohmori 2019; PRAIS 2019; Sukovatykh 2017). Of these studies, nine investigated rivaroxaban (de Athayde 2019; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; EINSTEIN‐PE 2012; Farhan 2019; J‐EINSTEIN DVT and PE 2015; ODIXa‐DVT 2007; PRAIS 2019; Sukovatykh 2017), five investigated apixaban (AMPLIFY 2013; AMPLIFY‐J 2015; Botticelli DVT 2008; Caravaggio 2020; Mokadem 2021), and four investigated edoxaban (eTRIS 2016; Hokusai VTE Cancer 2018; Hokusai‐VTE 2013; Ohmori 2019). Four studies were dose‐ranging (Botticelli DVT 2008; EINSTEIN‐DVT dose 2008; J‐EINSTEIN DVT and PE 2015; ODIXa‐DVT 2007), while the remaining 14 studies were fixed dose (AMPLIFY 2013; AMPLIFY‐J 2015; Botticelli DVT 2008; Caravaggio 2020; de Athayde 2019; EINSTEIN‐DVT 2010; eTRIS 2016; Farhan 2019; Hokusai VTE Cancer 2018; Hokusai‐VTE 2013; Mokadem 2021; Ohmori 2019; PRAIS 2019; Sukovatykh 2017). The control treatment was heparin combined with VKA in 12 studies (AMPLIFY 2013; AMPLIFY‐J 2015; Botticelli DVT 2008; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; EINSTEIN‐PE 2012; eTRIS 2016; Farhan 2019; Hokusai‐VTE 2013; J‐EINSTEIN DVT and PE 2015; ODIXa‐DVT 2007; PRAIS 2019), LMWH in three studies (Caravaggio 2020; Hokusai VTE Cancer 2018; Mokadem 2021), and VKA in three studies (de Athayde 2019; Ohmori 2019; Sukovatykh 2017). Sukovatykh 2017 was a three‐arm trial comparing dabigatran, rivaroxaban and warfarin. Duration of treatment was 12 weeks in five studies (Botticelli DVT 2008; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; eTRIS 2016; ODIXa‐DVT 2007), 5.5 to 6.5 months in 12 studies (AMPLIFY 2013; AMPLIFY‐J 2015; Caravaggio 2020; de Athayde 2019; EINSTEIN‐PE 2012; Farhan 2019; Hokusai‐VTE 2013; J‐EINSTEIN DVT and PE 2015; Mokadem 2021; Ohmori 2019; PRAIS 2019; Sukovatykh 2017), 12 months in one study (Ohmori 2019), and six to 12 months in one study (Hokusai VTE Cancer 2018).

Thirteen oral factor Xa inhibitor studies measured recurrent VTE (AMPLIFY 2013; AMPLIFY‐J 2015; Botticelli DVT 2008; Caravaggio 2020; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; EINSTEIN‐PE 2012; eTRIS 2016; Hokusai VTE Cancer 2018; Hokusai‐VTE 2013; J‐EINSTEIN DVT and PE 2015; Mokadem 2021; ODIXa‐DVT 2007), nine measured recurrent DVT (AMPLIFY 2013; Botticelli DVT 2008; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; EINSTEIN‐PE 2012; Hokusai‐VTE 2013; Mokadem 2021; ODIXa‐DVT 2007; PRAIS 2019), six measured fatal PE (AMPLIFY 2013; Botticelli DVT 2008; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; Hokusai‐VTE 2013; ODIXa‐DVT 2007), seven measured non‐fatal PE (AMPLIFY 2013; Botticelli DVT 2008; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; eTRIS 2016; Hokusai‐VTE 2013; ODIXa‐DVT 2007), nine measured all‐cause mortality (AMPLIFY 2013; AMPLIFY‐J 2015; Botticelli DVT 2008; de Athayde 2019; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; Mokadem 2021; ODIXa‐DVT 2007; PRAIS 2019), and 17 measured major bleeding (AMPLIFY 2013; AMPLIFY‐J 2015; Botticelli DVT 2008; Caravaggio 2020; de Athayde 2019; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; EINSTEIN‐PE 2012; eTRIS 2016; Farhan 2019; Hokusai VTE Cancer 2018; Hokusai‐VTE 2013; J‐EINSTEIN DVT and PE 2015; Mokadem 2021; ODIXa‐DVT 2007; Ohmori 2019; PRAIS 2019). The Sukovatykh 2017 study reported quality of life and de Athayde 2019 reported PTS.

We included the EINSTEIN‐PE 2012 study, as 25% of participants had concurrent symptomatic DVT. We contacted the authors of this study, who provided us with the data for the subgroup of people with DVT; however, it was not possible to obtain data on fatal PE, non‐fatal PE and all‐cause mortality from the study authors. We included four studies in participants with either DVT, PE or both (AMPLIFY‐J 2015; Caravaggio 2020; Hokusai VTE Cancer 2018; Hokusai‐VTE 2013). For these studies, we collected reported data from the subgroup of people with an index DVT (44 participants in AMPLIFY‐J 2015, 517 in Caravaggio 2020, 4921 in Hokusai‐VTE 2013, and 389 in Hokusai VTE Cancer 2018). We were unable to obtain outcome data on all‐cause mortality from the authors of the Hokusai‐VTE 2013 study.

Excluded studies

See Characteristics of excluded studies.

We excluded 16 studies from this review (ADAM VTE trial 2020; AMPLIFY Extended Study 2013; Borsi 2021; CASTA DIVA Trial 2022; COBRRA 2017; CONKO‐011 study 2015; DIVERSITY 2021; EINSTEIN‐CHOICE 2017; EINSTEIN‐Jr 2020; Peacock 2018; PRIORITY 2022; REMEDY 2013; RE‐SONATE 2013; SELECT‐D 2018; THRIVE I 2003; THRIVE III 2003). 

Participants in the AMPLIFY Extended Study 2013 had already taken part in the included AMPLIFY 2013 study. Similarly, REMEDY 2013 and RE‐SONATE 2013 were extended treatment studies and participants had already taken part in the RE‐COVER 2009 and RE‐COVER II 2014 studies. We excluded the THRIVE I 2003 study as treatment was only for four weeks. We excluded THRIVE III 2003 as the control group was administered a placebo, which did not fit as an intervention in this review. We excluded nine studies as, although all participants had venous thromboembolism, specific data on the subgroup with a DVT were not published (ADAM VTE trial 2020; Borsi 2021; CASTA DIVA Trial 2022; COBRRA 2017; CONKO‐011 study 2015; DIVERSITY 2021; EINSTEIN‐Jr 2020; PRIORITY 2022; SELECT‐D 2018). We made attempts to contact the authors for these data but were unsuccessful. We excluded EINSTEIN‐CHOICE 2017 as the comparator was aspirin. We excluded Peacock 2018 as participants had PE only.

Studies awaiting classification

We assessed one trial as 'awaiting classification'; there are currently insufficient details to assess its eligibility for inclusion (NCT01780987).

Ongoing studies

Eleven trials are ongoing and there are currently no suitable data available for review (EudraCT 2014‐002606‐20; NCT01516840; NCT02464969; NCT02664155; NCT02744092; NCT02798471; NCT02829957; NCT03129555; NCT03266783; NCT04066764; NCT05171049). See Characteristics of ongoing studies.

Risk of bias in included studies

See Figure 2 and Figure 3.

Figure 2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

Figure 3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

Allocation

Nineteen studies were at low risk of bias for sequence generation as they used a computerised system to generate the randomisation sequence (AMPLIFY 2013; AMPLIFY‐J 2015; Botticelli DVT 2008; Caravaggio 2020; de Athayde 2019; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; EINSTEIN‐PE 2012; eTRIS 2016; Farhan 2019; Hokusai VTE Cancer 2018; Hokusai‐VTE 2013; J‐EINSTEIN DVT and PE 2015; Mokadem 2021; ODIXa‐DVT 2007; PRAIS 2019; RE‐COVER 2009; RE‐COVER II 2014; THRIVE 2005). Two studies were at unclear risk of bias: Ohmori 2019 used block randomisation (1:1) but did not describe the process in detail, and Sukovatykh 2017 did not report information about randomisation.

Similarly, 19 studies adequately concealed the treatment allocation with the use of a computerised system and we judged them to be at low risk of selection bias for allocation concealment (AMPLIFY 2013; AMPLIFY‐J 2015; Botticelli DVT 2008; Caravaggio 2020; de Athayde 2019; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; EINSTEIN‐PE 2012; eTRIS 2016; Farhan 2019; Hokusai VTE Cancer 2018; Hokusai‐VTE 2013; J‐EINSTEIN DVT and PE 2015; Mokadem 2021; ODIXa‐DVT 2007; PRAIS 2019; RE‐COVER 2009; RE‐COVER II 2014; THRIVE 2005). Two studies were at an unclear risk because of insufficient information (Ohmori 2019; Sukovatykh 2017). The eTRIS 2016 study was reported as an abstract in the previous version of the review and we have now included the full‐text report. This did not provide clear information regarding allocation concealment. However, personal communication with the study author revealed that treatment allocation was concealed with the use of a computerised system and, therefore, we judged this study to be at low risk of bias. 

Blinding

We assessed 14 studies to be at low risk of bias for blinding (AMPLIFY‐J 2015; Botticelli DVT 2008; Caravaggio 2020; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; EINSTEIN‐PE 2012; eTRIS 2016; Farhan 2019; Hokusai VTE Cancer 2018; J‐EINSTEIN DVT and PE 2015; Mokadem 2021; ODIXa‐DVT 2007; Ohmori 2019; PRAIS 2019). They either did not blind participants and personnel to the control treatment or did not report blinding, but we judged that the lack of blinding in the control group was unlikely to have affected the outcomes of this review. A further five studies were double‐blinded and used placebo tablets or injection so were at low risk of bias (AMPLIFY 2013; Hokusai‐VTE 2013; RE‐COVER 2009; RE‐COVER II 2014; THRIVE 2005). Therefore, we judged 19 studies to be at low risk of performance bias. The de Athayde 2019 study reported PTS but provided no information about blinding for participants. The PTS score included participants' self‐reported domains (such as pain, cramps, heaviness, pruritus and paraesthesia), so we judged the risk of blinding for participants and personnel as high, as knowing what treatment group they were in may have affected the outcome. The Sukovatykh 2017 study measured quality of life using SF‐36, which is a participant self‐reported instrument. We judged the risk of blinding for both participants and personnel as unclear as no information was provided, and knowing what treatment group participants were in may have affected the outcome.

Fourteen studies blinded outcome assessors to treatment, and we judged them to be at low risk of detection bias (AMPLIFY 2013; AMPLIFY‐J 2015; Botticelli DVT 2008; Caravaggio 2020; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; EINSTEIN‐PE 2012; Hokusai VTE Cancer 2018; Hokusai‐VTE 2013; J‐EINSTEIN DVT and PE 2015; ODIXa‐DVT 2007; RE‐COVER 2009; RE‐COVER II 2014; THRIVE 2005). We rated a further five studies that either did not blind outcome assessors or reported insufficient information on this to be at low risk of detection bias, as a lack of blinding was unlikely to have affected the objective outcome (eTRIS 2016; Farhan 2019; PRAIS 2019; Mokadem 2021; Ohmori 2019). The de Athayde 2019 study blinded the physician responsible for data assessment; however, the PTS score included participants' self‐reported domains, so we judged this study to have an unclear risk of detection bias. The Sukovatykh 2017 study did not provide enough information for an assessment of detection bias to be made so we also judged it to be at an unclear risk of detection bias.

Incomplete outcome data

Seventeen studies sufficiently reported missing outcome data and were balanced across treatment groups. Therefore, we judged these studies to be at low risk of attrition bias (AMPLIFY‐J 2015; Botticelli DVT 2008; Caravaggio 2020; de Athayde 2019; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; EINSTEIN‐PE 2012; Hokusai VTE Cancer 2018; Hokusai‐VTE 2013; J‐EINSTEIN DVT and PE 2015; Mokadem 2021; ODIXa‐DVT 2007; PRAIS 2019; RE‐COVER 2009; RE‐COVER II 2014; Sukovatykh 2017; THRIVE 2005). The AMPLIFY 2013 inappropriately excluded a number of randomised participants from the intention‐to‐treat analysis. Furthermore, a large number of participants within each treatment group were classified as discontinuing the study for "other reasons" with no explanation given. We therefore deemed this study to be at high risk of attrition bias. We also judged the risk of attrition bias as high for the eTRIS 2016, Farhan 2019 and Ohmori 2019 studies, as they all lost more than 20% of participants and did not clarify if the loss was balanced across groups.

Selective reporting

Sixteen studies clearly stated and reported their pre‐specified outcomes and, therefore, we judged these to be at low risk of reporting bias (AMPLIFY‐J 2015; Botticelli DVT 2008; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; EINSTEIN‐PE 2012; Farhan 2019; Hokusai VTE Cancer 2018; Hokusai‐VTE 2013; J‐EINSTEIN DVT and PE 2015; Mokadem 2021; ODIXa‐DVT 2007; PRAIS 2019; RE‐COVER 2009; RE‐COVER II 2014; Sukovatykh 2017; THRIVE 2005). We judged five studies to be at high risk of reporting bias (AMPLIFY 2013; Caravaggio 2020; de Athayde 2019; eTRIS 2016; Ohmori 2019). The AMPLIFY 2013 study pre‐defined minor bleeding as a secondary outcome but data were not reported in the paper. In addition, this study analysed non‐inferiority using an ITT analysis. When compared with the per‐protocol analysis, ITT favoured the finding of non‐inferior results. This may have skewed the result in favour of increased efficacy of apixaban. The Caravaggio 2020 study defined quality of life as a secondary outcome in its protocol but no information was reported in the full text. This study also stated that a "significant interaction was noted between age subgroups and treatment for recurrent venous thromboembolism", but no result was found in the paper and appendix. Both the de Athayde 2019 and Ohmori 2019 studies failed to report the pre‐defined secondary outcome complications in their full report. The eTRIS 2016 study planned to report the number of participants with major adverse cardiovascular events (MACE) when registered; however, this outcome was not provided in the full text. Protocols were available for eight studies (AMPLIFY 2013; Caravaggio 2020; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; EINSTEIN‐PE 2012; Hokusai VTE Cancer 2018; Hokusai‐VTE 2013; Ohmori 2019). 

Other potential sources of bias

We judged the other risk of bias for all included studies as low as no potential risks were detected.

Effects of interventions

See: Summary of findings 1 Oral DTIs versus conventional anticoagulation for participants with diagnosed DVT; Summary of findings 2 Oral factor Xa inhibitors compared to conventional anticoagulation for participants with diagnosed DVT

Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation

In the meta‐analysis of oral DTIs versus conventional anticoagulation, we used data from Goldhaber 2016, as it reported the separate deep vein thrombosis (DVT) data for RE‐COVER 2009 and RE‐COVER II 2014. It combined these studies, which is reflected in the data analysis tables and summary of findings Table 1 by showing only one study for this comparison.

Recurrent venous thromboembolism (VTE)

Meta‐analysis of three studies (5994 participants) showed no clear difference in the rate of recurrent VTE between the groups treated with a DTI and conventional anticoagulation with heparin and a VKA (RE‐COVER 2009; RE‐COVER II 2014; THRIVE 2005). The incidence was 2.37% (71 events/2998 participants) in the DTI group and 2.04% (61 events/2996 participants) in the conventional anticoagulation group, leading to an odds ratio (OR) of 1.17 (95% confidence interval (CI) 0.83 to 1.65; 3 studies, 5994 participants; I2 = 0%; moderate‐certainty evidence; Analysis 1.1). 

Recurrent deep vein thrombosis

Three studies reported recurrent DVT (RE‐COVER 2009; RE‐COVER II 2014; THRIVE 2005). The incidence was 1.70% (51 events/2998 participants) in the DTI group and 1.54% (46 events/2996 participants) in the conventional anticoagulation group, leading to an OR of 1.11 (95% CI 0.74 to 1.66; 3 studies, 5994 participants; I2 = 0%; moderate‐certainty evidence; Analysis 1.2). 

Fatal pulmonary embolism

The same three studies reported fatal PE. The incidence of fatal PE was 0.13% (4 events/2998 participants) in the DTI group compared with 0.10% (3 events/2996 participants) in the conventional anticoagulation group (OR 1.32, 95% CI 0.29 to 6.02; 3 studies, 5994 participants; I2 = 0%; moderate‐certainty evidence; Analysis 1.3).

Non‐fatal pulmonary embolism

The same three studies reported non‐fatal PE, which occurred in 0.60% (18 events/2998 participants) of DTI participants and 0.47% (14 events/2996 participants) of conventional anticoagulation participants (OR 1.29, 95% CI 0.64 to 2.59; 3 studies, 5994 participants; I2 = 0%; moderate‐certainty evidence; Analysis 1.4). 

All‐cause mortality

We could not obtain the all‐cause mortality data from RE‐COVER 2009 and RE‐COVER II 2014 from any report or by contacting authors. There was no difference in the rate of all‐cause mortality between the two treatment groups based on data from THRIVE 2005. The incidence was 2.26% (28 events/1240 participants) in the DTI (ximelagatran) group and 3.36% (42 events/1249 participants) in the conventional anticoagulation group, with an OR of 0.66 (95% CI 0.41 to 1.08; 1 study, 2489 participants; moderate‐certainty evidence; Analysis 1.5). 

Major bleeding

Meta‐analysis showed that DTIs were associated with fewer major bleeding episodes than conventional anticoagulation therapy. Of the DTI participants, 1.13% (34 events/2998 participants) had a major clinically relevant bleeding episode compared with 1.94% (58 events/2996 participants) of conventional anticoagulation participants, resulting in an OR of 0.58 (95% CI 0.38 to 0.89; 3 studies, 5994 participants; I2 = 0%; high‐certainty evidence; Analysis 1.6). 

Post‐thrombotic syndrome

None of the included studies measured PTS as an outcome.

Health‐related quality of life

Sukovatykh 2017 used SF‐36 scales to measure the quality of life (0 to 100 mm scales where a higher score indicates better health). The study authors did not report the overall score and baseline data, so we collected data as physical component of health and psychological component of health at 12 months as these were reported. Both indices appeared to be higher in the dabigatran group compared to the warfarin group: physical component: mean difference (MD) 6.75 (95% CI 2.37 to 11.13; 1 study, 75 participants; Analysis 1.7) and psychological component: MD 6.45 (95% CI 3.24 to 9.66; 1 study, 75 participants; Analysis 1.8).

Sensitivity analyses

As part of the planned sensitivity analysis, we removed the THRIVE 2005 study testing ximelagatran from the meta‐analyses since the drug is no longer available (Analysis 2.1; Analysis 2.2; Analysis 2.3; Analysis 2.4; Analysis 2.5). Excluding these results had little effect on the outcomes. The rate of recurrent VTE (OR 1.21, 95% CI 0.78 to 1.89), recurrent DVT (OR 1.24, 95% CI 0.76 to 2.03), fatal PE (OR 0.66, 95% CI 0.11 to 3.97) and non‐fatal PE (OR 1.12, 95% CI 0.43 to 2.91) remained similar between participants treated with dabigatran and participants treated with a VKA. However, excluding the ximelagatran study resulted in a similar point estimate for major bleeding but was no longer statistically significant (OR 0.62, 95% CI 0.35 to 1.08) due to insufficient statistical power.

We deemed no studies to be at high risk of bias, therefore, we did not perform a sensitivity analysis excluding studies judged to be of high risk of bias.

Oral factor Xa inhibitors versus conventional anticoagulation

Recurrent venous thromboembolism

Meta‐analysis of 13 studies (17,505 participants) demonstrated that there was no clear difference in the rate of recurrent VTE in participants treated with an oral factor Xa inhibitor compared with conventional anticoagulation (AMPLIFY 2013; AMPLIFY‐J 2015; Botticelli DVT 2008; Caravaggio 2020; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; EINSTEIN‐PE 2012; eTRIS 2016; Hokusai VTE Cancer 2018; Hokusai‐VTE 2013; J‐EINSTEIN DVT and PE 2015; Mokadem 2021; ODIXa‐DVT 2007). The AMPLIFY‐J 2015 study had no events in either group and so did not contribute to the analysis (not estimable). The incidence was 2.90% (267 events/9207 participants) in the factor Xa inhibitor group and 3.42% (283 events/8298 participants) in the conventional anticoagulation group, leading to an OR of 0.85 (95% CI 0.71 to 1.01; 13 studies, 17,505 participants; I2 = 0%; moderate‐certainty evidence; Analysis 3.1). When analysed according to duration of treatment, the incidence of recurrent VTE was slightly lower in participants treated with factor Xa inhibitors for three months compared with participants treated with conventional anticoagulation (OR 0.68, 95% CI 0.47 to 0.99; 5 studies, 5001 participants). There was no clear difference in the incidence between the two groups when duration of treatment was for longer than three months (OR 0.90, 95% CI 0.74 to 1.10; 8 studies, 12,460 participants) (test for subgroup differences: P = 0.20). Further, subgroup analysis of people experiencing DVT with cancer (OR 0.69, 95% CI 0.51 to 0.94; 4 studies, 4248 participants) versus without cancer (OR 0.82, 95% CI 0.59 to 1.15; 4 studies, 5579 participants) suggested no subgroup difference (test for subgroup differences: P = 0.45, Analysis 4.1). We produced a funnel plot and found no indication of publication bias (Figure 4). No subgroup effect was indicated when analysed by the three oral factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) (test for subgroup differences: P = 0.48, Analysis 5.1).

Figure 4
Funnel plot of oral factor Xa inhibitors versus conventional anticoagulants for recurrent VTE 

Funnel plot of oral factor Xa inhibitors versus conventional anticoagulants for recurrent VTE 

Recurrent deep vein thrombosis

Data on recurrent DVT was available in nine studies (16,439 participants) (AMPLIFY 2013; Botticelli DVT 2008; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; EINSTEIN‐PE 2012; Hokusai‐VTE 2013; Mokadem 2021; ODIXa‐DVT 2007; PRAIS 2019). The authors of Hokusai‐VTE 2013 kindly provided us with separate data on recurrent DVT and fatal and non‐fatal PE. There was no clear difference in rate of recurrent DVT between oral factor Xa inhibitors (1.26%, 109 events/8633 participants) and conventional anticoagulation (1.64%, 128 events/7806 participants), leading to an OR of 0.70 (95% CI 0.49 to 1.01; 9 studies, 16,439 participants; I2 = 30%; moderate‐certainty evidence; Analysis 3.2). When analysed according to treatment duration, there were no clear differences in the incidence of recurrent DVT between participants treated with factor Xa inhibitors and participants treated with conventional anticoagulation for either three months (OR 0.50, 95% CI 0.22 to 1.15; 4 studies, 4917 participants) or more than three months (OR 0.86, 95% CI 0.63 to 1.17; 5 studies, 11,522 participants). No subgroup differences were indicated (test for subgroup differences: P = 0.23). As a limited number of studies reporting on this outcome provided separate data for participants with or without cancer, we were not able to undertake subgroup analysis on this characteristic. No subgroup effect was indicated when analysed by the three oral factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) (test for subgroup differences: P = 0.20, Analysis 5.2).

Fatal pulmonary embolism

Six studies (15,082 participants) reported fatal PE (AMPLIFY 2013; Botticelli DVT 2008; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; Hokusai‐VTE 2013; ODIXa‐DVT 2007). There was no clear difference in the rate of fatal PE between the two treatment groups. Meta‐analysis showed that fatal PE occurred in 0.42% (33 events/7945 participants) in the factor Xa inhibitor group versus 0.32% (23 events/7137 participants) in the conventional anticoagulation group (OR 1.18, 95% CI 0.69 to 2.02; 6 studies, 15,082 participants; I2 = 0%; moderate‐certainty evidence; Analysis 3.3). We found no clear difference in the incidence of fatal PE between participants treated with factor Xa inhibitors and conventional anticoagulation when treatment was for three months (OR 1.68, 95% CI 0.36 to 7.94; 4 studies, 4917 participants) and for more than three months (OR 1.15, 95% CI 0.54 to 2.44; 2 studies, 10,165 participants). No subgroup differences were indicated (test for subgroup differences: P = 0.67). As a limited number of studies reporting on this outcome provided separate data for participants with or without cancer, we were not able to undertake subgroup analysis on this characteristic. No subgroup effect was indicated when analysed by the three oral factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) (test for subgroup differences: P = 0.36, Analysis 5.3).

Non‐fatal pulmonary embolism

Seven studies (15,166 participants) reported non‐fatal PE (AMPLIFY 2013; Botticelli DVT 2008; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; eTRIS 2016; Hokusai‐VTE 2013; ODIXa‐DVT 2007). The incidence was 1.00% (80 events/8001 participants) in the factor Xa inhibitor group versus 1.11% (80 events/7165 participants) in the conventional anticoagulation group (OR 0.93, 95% CI 0.68 to 1.27; 7 studies, 15,166 participants; I2 = 0%; moderate‐certainty evidence; Analysis 3.4). There was no clear difference in incidence of non‐fatal PE between factor Xa inhibitors and conventional anticoagulation when treatment was for three months (OR 0.87, 95% CI 0.51 to 1.48; 5 studies, 5001 participants) and for more than three months (OR 0.96, 95% CI 0.65 to 1.43; 2 studies, 10,165 participants). No subgroup differences were indicated (test for subgroup differences: P = 0.77). As a limited number of studies reporting on this outcome provided separate data for participants with or without cancer, we were not able to undertake subgroup analysis on this characteristic. No subgroup effect was indicated when analysed by the three oral factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) (test for subgroup differences: P = 0.84, Analysis 5.4).

All‐cause mortality

Nine studies (10,770 participants) reported all‐cause mortality (AMPLIFY 2013; AMPLIFY‐J 2015; Botticelli DVT 2008; de Athayde 2019; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; Mokadem 2021; ODIXa‐DVT 2007; PRAIS 2019). We did not include the EINSTEIN‐PE 2012 as it was not possible to obtain the specific all‐cause mortality data on participants with an index DVT. The AMPLIFY‐J 2015, de Athayde 2019 and PRAIS 2019 studies had no events in either group and contributed no estimate in the forest plot. Meta‐analysis showed no clear difference in the rate of all‐cause mortality between the two treatment groups (OR 0.87, 95% CI 0.67 to 1.14; 9 studies, 10,770 participants; I2 = 0%; moderate‐certainty evidence; Analysis 3.5). The incidence was 2.12% (126 events/5834 participants) in the factor Xa inhibitor group and 2.35% (118 events/4936 participants) in the conventional anticoagulation group. Furthermore, there was no difference in the incidence of all‐cause mortality between participants treated with factor Xa inhibitors and conventional anticoagulation when treatment was three months (OR 0.85, 95% CI 0.58 to 1.25; 4 studies, 5072 participants) or more than three months (OR 0.95, 95% CI 0.55 to 1.67; 5 studies, 5698 participants). No subgroup differences were indicated (test for subgroup differences: P = 0.75). As a limited number of studies reporting on this outcome provided separate data for participants with or without cancer, we were not able to undertake subgroup analysis on this characteristic. No subgroup effect was indicated when analysed by different oral factor Xa inhibitors (apixaban and rivaroxaban) (test for subgroup differences: P = 0.61, Analysis 5.5).

Major bleeding

We included 17 studies (18,066 participants) in the meta‐analysis of major bleeding (AMPLIFY 2013; AMPLIFY‐J 2015; Botticelli DVT 2008; Caravaggio 2020; de Athayde 2019; EINSTEIN‐DVT dose 2008; EINSTEIN‐DVT 2010; EINSTEIN‐PE 2012; eTRIS 2016; Farhan 2019; Hokusai VTE Cancer 2018; Hokusai‐VTE 2013; J‐EINSTEIN DVT and PE 2015; Mokadem 2021; ODIXa‐DVT 2007; Ohmori 2019; PRAIS 2019). Five studies reported zero events in both experimental and control groups and contributed no estimate to the pooled result (AMPLIFY‐J 2015; de Athayde 2019; eTRIS 2016; J‐EINSTEIN DVT and PE 2015; Ohmori 2019). The incidence was 1.04% (101 events/9536 participants) in the factor Xa inhibitor group and 1.68% (145 events/8530 participants) in the conventional anticoagulation group. This led to an OR of 0.63 (95% CI 0.45 to 0.89; 17 studies, 18,066 participants; I2 = 18%; high‐certainty evidence; Analysis 3.6), indicating that factor Xa inhibitors reduced the risk of major bleeding compared with conventional anticoagulation. We produced a funnel plot and found no indication of publication bias (Figure 5).

Figure 5
Funnel plot of oral factor Xa inhibitors versus conventional anticoagulants for major bleeding

Funnel plot of oral factor Xa inhibitors versus conventional anticoagulants for major bleeding

When analysed according to treatment duration, no subgroup differences were indicated (test for subgroup differences: P = 0.48) between treatment for three months (OR 0.78, 95% CI 0.42 to 1.43; 5 studies, 5170 participants) or for more than three months (OR 0.60, 95% CI 0.39 to 0.91; 12 studies, 12,986 participants).  

Additional analysis indicated a possible subgroup difference between people with cancer (OR 0.93, 95% CI 0.49 to 1.76; 3 studies, 1006 participants) and people without cancer (OR 0.30, 95% CI 0.17 to 0.52; 6 studies, 5795 participants) (test for subgroup differences: P = 0.009, Analysis 4.2). No subgroup effect was indicated when analysed by the three oral factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) (test for subgroup differences: P = 0.65, Analysis 5.6).

Post‐thrombotic syndrome

The de Athayde 2019 study reported PTS as an outcome, and the results indicated that oral factor Xa inhibitor (rivaroxaban) had a lower rate of PTS events compared with warfarin. The incidence for rivaroxaban was 8.70% (4 events/46 participants) for both six months and 12 months; for warfarin, the incidence was 36.84% (14 events /38 participants) at six months, and 28.95% (11 events/38 participants) at 12 months. This led to an OR of 0.16 (95% CI 0.05 to 0.55; 1 study, 84 participants) and 0.23 (95% CI 0.08 to 0.46; 1 study, 84 participants; Analysis 3.7) at six months and 12 months, respectively. 

Health‐related quality of life

Sukovatykh 2017 used SF‐36 scales (described above) to measure the quality of life of 65 participants. The factor Xa inhibitors group had a better score on the physical component of health (MD 5.55, 95% CI 1.18 to 9.92) and a similar score on the psychological component (MD 1.41, 95% CI ‐2.61 to 5.43) when compared with the warfarin group (Analysis 3.8; Analysis 3.9).

Sensitivity analyses

As planned, we excluded studies with a high risk of bias in sensitivity analysis (Analysis 6.1; Analysis 6.2; Analysis 6.3; Analysis 6.4; Analysis 6.5; Analysis 6.6). The rate of recurrent VTE (OR 0.89, 95% CI 0.70 to 1.13), recurrent DVT (OR 0.72, 95% CI 0.45 to 1.13), fatal PE (OR 1.73, 95% CI 0.81 to 3.69), non‐fatal PE (OR 0.84, 95% CI 0.57 to 1.23) and all‐cause mortality (OR 0.94, 95%CI 0.66 to 1.35) remained similar when excluding high risk studies. However, excluding these studies did alter the result for major bleeding to no difference between oral factor Xa inhibitors versus conventional anticoagulation (OR 0.76, 95% CI 0.55 to 1.05).  

Oral direct thrombin inhibitor versus oral factor Xa inhibitor

Sukovatykh 2017 was the only study to compare an oral DTI with an oral factor Xa inhibitor, and the only outcome of interest reported was quality of life. Sukovatykh 2017 compared oral dabigatran to oral rivaroxaban for quality of life using SF‐36 scales. The DTI group had a similar score on the physical component of health (MD 1.20, 95% CI ‐2.89 to 5.29; 1 study, 60 participants) and a higher score on the psychological component (MD 5.04, 95% CI 1.24 to 8.84; 1 study, 60 participants) compared to the factor Xa inhibitor group (Analysis 7.1; Analysis 7.2).

Discussion

Summary of main results

We included an additional ten studies for this update, bringing the total to 21 included studies involving 30,895 participants. Compared with conventional anticoagulation, three studies investigated oral direct thrombin inhibitors (DTIs) (two dabigatran and one ximelagatran), 17 studies investigated oral factor Xa inhibitors (eight rivaroxaban, five apixaban and four edoxaban) and one study with three arms investigated both a DTI (dabigatran) and a factor Xa inhibitor (rivaroxaban).

Recurrent venous thromboembolism

Meta‐analyses showed no clear difference between direct oral anticoagulants (DOACs) and conventional anticoagulation in the prevention of recurrent VTE during treatment. This is unsurprising as the incidence of recurrent events during treatment with vitamin K antagonists (VKAs) is low and often only occurs in people with an aggressive thrombotic tendency, such as people with metastatic malignancy.

The duration of treatment in the included studies varied, from three months (Botticelli DVT 2008; EINSTEIN‐DVT dose 2008; eTRIS 2016; ODIXa‐DVT 2007), four months (EINSTEIN‐DVT 2010), six months (AMPLIFY 2013; AMPLIFY‐J 2015; Caravaggio 2020; de Athayde 2019; Farhan 2019; J‐EINSTEIN DVT and PE 2015; Mokadem 2021; PRAIS 2019; RE‐COVER 2009; RE‐COVER II 2014; Sukovatykh 2017; THRIVE 2005), six to 12 months (Hokusai VTE Cancer 2018), and 12 months (EINSTEIN‐PE 2012; Hokusai‐VTE 2013; Ohmori 2019). Our analyses showed little or no statistical heterogeneity amongst the included studies. We performed subgroup analyses by grouping studies where treatment was for three months only and for longer than three months. No differences were observed for oral factor Xa versus conventional anticoagulation. This is consistent with findings from previous studies, which have also indicated that there is little difference in outcomes between three, six and 12 months' treatment, although recurrence rates after treatment rose if anticoagulated for less than three months (Boutitie 2011). 

We did not detect any subgroup differences between DVT associated with cancer versus without cancer. A review by Kahale 2018 found that compared to low molecular weight heparin (LMWH), DOACs may reduce VTE but may increase risk of major bleeding in people with cancer. However, the Mulder 2020 review did not find a difference in these outcomes in cancer‐associated venous thromboembolism (Mulder 2020). 

Recurrent deep vein thrombosis

There is no clear difference between DOACs and conventional anticoagulation in the prevention of recurrent DVT. 

Fatal pulmonary embolism

Meta‐analyses showed no clear difference in the rate of fatal pulmonary embolism (PE) between DOACs and conventional anticoagulation, indicating that neither was more or less effective. This association was unaffected by the length of treatment. However, it is important to note that the confidence intervals (CIs) were wide for both DTIs and factor Xa inhibitors due to the small number of events overall.

Non‐fatal pulmonary embolism

Meta‐analyses also showed no clear difference in the rate of non‐fatal PE between DOACs and conventional anticoagulation regardless of treatment duration, indicating that neither was more or less effective. However, it is important to note that the CIs were wide due to the small number of non‐fatal PE events overall.

All‐cause mortality

There is no clear difference in preventing all‐cause mortality between the DOACs tested in this review (apixaban, rivaroxaban and ximelagatran) and conventional anticoagulants; no clear difference was observed between treatment durations of three months and longer. This result is unsurprising as current treatment with heparin and VKAs is associated with very low mortality.

Major bleeding

Results of our meta‐analysis indicated that DOACs were associated with a reduction in major bleeding compared with conventional anticoagulation. This appears to be a class effect and may be due to the different mechanisms of action. The included studies all used the strict definition of major bleeding provided by the International Society on Thrombosis and Haemostasis (ISTH) (Schulman 2005), except for the de Athayde 2019 study, which did not report the definition. For factor Xa inhibitors compared with conventional anticoagulation, no subgroup difference was indicated by treatment duration, but there may be a difference between participants with cancer and those without. We cannot draw conclusions from these subgroup analyses as both were heavily dependent on one trial with a high risk of bias in selective reporting and missing data. In addition, research from observational studies showed that apixaban decreased risk of major and minor bleeding events compared with rivaroxaban in VTE patients (Aryal 2019; Ballestri 2023; Liu 2022), while the subgroup analysis based on randomised controlled trials (RCTs) included in this review did not show a difference. 

Post‐thrombotic syndrome

Only one small study comparing oral factor Xa inhibitor (rivaroxaban) with conventional anticoagulation measured post‐thrombotic syndrome (PTS). The incidence was lower in the oral factor Xa inhibitor group versus the warfarin group; however, the PTS score was partially self‐reported by participants, who were not blinded in this study. This prevents us from drawing any strong conclusions on this outcome.

Health‐related quality of life

Only one small study measured participants' quality of life. It did not report baseline data so we could not conclude whether DOACs improved quality of life versus conventional anticoagulation. This was also the only study we found that compared a DTI (dabigatran) with a factor Xa inhibitor (rivaroxaban).

Overall completeness and applicability of evidence

This review assessed whether DOACs, such as DTIs and factor Xa inhibitors, reduced the rate of recurrent VTE, recurrent DVT, fatal PE, non‐fatal PE, all‐cause mortality, major bleeding and PTS, and whether DOACs improved quality of life in people with a DVT. Three studies explored DTIs, 17 studies explored factor Xa inhibitors, and one explored both. All studies included similar study populations, with three focused on cancer‐associated DVT. The trials analysed and reported all of the addressed outcomes, with PTS and health‐related quality of life reported in only one study with a small sample size. Statistical heterogeneity was low for all outcomes. This was expected as each individual study had strict inclusion criteria, which resulted in the overall participant population of this review having almost identical conditions. Furthermore, for each particular drug, the concentrations used across studies were similar.

We could not perform subgroup analyses according to history of VTE, age, pregnancy, major surgery requiring general or regional anaesthesia in the previous 12 weeks, recent period of immobility, and thrombophilia because of the lack of participant‐level data. Additionally, the treatment effect may differ between DVT in unusual sites (e.g. upper limbs) and lower limbs, considering different clinical symptoms and risk (Ageno 2019; Cote 2017); however, almost all the participants from included studies had been diagnosed with DVT in lower limbs. Thus, we could not address this issue in this review. These analyses might be important to guide the clinical management of people with different risk factors for DVT.  

In the subgroup analysis based on participants with cancer versus without cancer, most included trials for DOACs included only small numbers of participants with cancer, and likely included those with only lower‐risk malignancies. Dedicated cancer‐associated DVT trials have not been performed for DTIs, and results in this review relating to their use in cancer‐associated thrombosis should therefore be interpreted with caution.

Although many researchers consider DVT and PE to be manifestations of the same disorder, we elected to study these two conditions separately as there is evidence of clinically significant differences between them. The majority of recurrent events occur at the same site as the original thrombosis (in other words, in a person presenting with a PE, a recurrent event after treatment is much more likely to be another PE); both oral contraceptive use and Factor V Leiden mutation are more likely to be associated with DVT than PE; and, for example, lung disease is much more likely to be associated with PE. An update of the review on the effectiveness of oral DTIs and factor Xa inhibitors for the treatment of PE is ongoing (Li 2023). 

We found no studies comparing:

  • one oral DTI versus another oral DTI;

  • one oral factor Xa inhibitor versus another oral factor Xa inhibitor.

While DOACs are more expensive than VKAs, these costs are offset by reduced bleeding and laboratory monitoring costs (Chen 2020). The UK's National Institute for Health and Care Excellence (NICE) conducted a recent cost‐effectiveness analysis of DOACs versus conventional anticoagulation for the treatment of DVT and PE (NICE 2020). Within the DOACs, apixaban appeared to be the most cost‐effective, both in people with a DVT and people with a PE. Rivaroxaban had the next most favourable effect on major bleeding and generated the second highest total quality‐adjusted life years (QALYs). The cost of the two drugs was similar and the difference in total costs was mainly led by differences in the number of bleeding events. 

Certainty of the evidence

We created summary of findings tables for both our main comparisons and reported recurrent VTE, recurrent DVT, fatal PE, non‐fatal PE, all‐cause mortality and major bleeding. We assessed the certainty of the evidence using GRADE criteria (Schünemann 2022).

summary of findings Table 1 presented the result of oral DTIs versus conventional anticoagulation used for the treatment of DVT. We found moderate‐certainty evidence suggesting that DTIs were not inferior to conventional anticoagulation for reducing recurrent VTE, recurrent DVT, fatal PE, non‐fatal PE, and all‐cause mortality when used for treating DVT. We downgraded the certainty by one level for all of these outcomes because of imprecision due to the low number of events. High‐certainty evidence indicated that DTIs had a lower rate of major bleeding. This difference became unclear when we excluded the study on ximelagatran in sensitivity analysis. Ximelagatran was not approved and not used in practice.

summary of findings Table 2 presented the result of oral factor Xa inhibitors versus conventional anticoagulation used for the treatment of DVT. We found moderate‐certainty evidence indicating no clear difference between oral factor Xa inhibitors and conventional anticoagulation in preventing recurrent VTE, recurrent DVT, fatal PE, non‐fatal PE and all‐cause mortality. We downgraded the certainty by one level for all of these outcomes because of imprecision due to small sample size or the low number of events. High‐certainty evidence indicated that oral factor Xa inhibitors had a lower rate of major bleeding.

Potential biases in the review process

The search was as comprehensive as possible and we are confident that we have included all relevant studies. However, the possibility remains that some relevant trials, particularly in the 'grey' literature (e.g. conference proceedings), have been missed. Pairs of review authors independently performed study selection and data extraction in duplicate in order to minimise bias in the review process. The inclusion and exclusion criteria set out in the protocol were strictly adhered to in order to limit subjectivity (Robertson 2014). We performed data collection according to the process suggested by Cochrane. We also followed Cochrane processes as described by Higgins 2017 for assessing the risk of bias. Furthermore, we used the GRADE approach, which enabled us to rate the certainty of evidence systematically and interpret the data appropriately. For two of the included studies, RE‐COVER 2009 and RE‐COVER II 2014, we could only obtain data for DVT participants from a pooled analysis from Goldhaber 2016. We were able to obtain all outcomes, except all‐cause mortality, from both trials. Evidence regarding all‐cause mortality of DTIs versus control is therefore supported by only one study.

Agreements and disagreements with other studies or reviews

To our knowledge, this is the first systematic review of RCTs, now updated, to measure the efficacy and safety of oral anticoagulants in people with a DVT. We found 12 other systematic reviews that assessed the same oral anticoagulants but in people with a VTE (Antoniazzi 2014; Castellucci 2013; Di Minno 2015; Fox 2012; Gomez‐Outes 2014; Hirschl 2014; Kakkos 2014; Kang 2014; Loffredo 2015; Sardar 2013; Senoo 2017; Van der Huille 2014). Five reviews found similar results to this review: that DOACs are associated with less bleeding than conventional treatment (Antoniazzi 2014; Fox 2012; Gomez‐Outes 2014; Hirschl 2014; Kakkos 2014; Loffredo 2015; Senoo 2017; Van der Huille 2014).

The review by Fox 2012 included eight of the 11 studies that we included in the 2015 version of this review. The Fox 2012 review did not include the remaining studies (AMPLIFY 2013; Hokusai‐VTE 2013), but did not state the reasons for this in the review. Meta‐analysis was done by brand rather than class of drug. Fox 2012 found no difference in recurrent VTE between the two treatment groups. Rivaroxaban was the only drug found to be significantly associated with fewer major bleeding episodes (OR 0.57, 95% CI 0.39 to 0.84). All‐cause mortality did not differ between the two treatment groups.

The review by Van der Huille 2014 excluded four studies that were included in our review. They excluded three as they were phase II trials (Botticelli DVT 2008; ODIXa‐DVT 2007; THRIVE 2005), and one as it had not been published in a peer‐reviewed journal at the time of the review (RE‐COVER II 2014). Therefore, only five studies were included in the review (AMPLIFY 2013; EINSTEIN‐DVT 2010; EINSTEIN‐PE 2012; Hokusai‐VTE 2013; RE‐COVER 2009). Meta‐analysis showed no difference between the two treatment groups in terms of recurrent VTE, fatal PE and all‐cause mortality. However, the DOACs were associated with a reduced risk of major bleeding (risk ratio (RR) 0.60, 95% CI 0.41 to 0.88) and fatal bleeding (RR 0.36, 95% CI 0.15 to 0.87).

Hirschl 2014 included six studies and found no differences between DOACs and conventional treatment regarding recurrent VTE and mortality (AMPLIFY 2013; EINSTEIN‐DVT 2010; EINSTEIN‐PE 2012; Hokusai‐VTE 2013; RE‐COVER 2009; RE‐COVER II 2014). However, they reported bleeding was reduced by rivaroxaban (RR 0.55, 95% CI 0.38 to 0.81), apixaban (RR 0.31, 95% CI 0.17 to 0.55) and edoxaban (RR 0.81, 95% CI 0.71 to 0.93). The reviews by Gomez‐Outes 2014 and Kang 2014 included the same six studies as Hirschl 2014. Gomez‐Outes 2014 found no difference in the risk of recurrent VTE between the two treatment groups (RR 0.91, 95% CI 0.79 to 1.06) and DOACs were associated with reduced major bleeding (absolute risk difference ‐0.6%, 95% CI ‐1.0% to ‐0.3%). Kang 2014 reported that DOACs did not differ in the risk of mortality or recurrent VTE. However, an indirect comparison suggested that dabigatran was associated with increased major bleeding compared to apixaban (RR 2.69, 95% CI 1.19 to 6.07) and edoxaban also had a higher bleeding rate compared with apixaban (RR 2.74, 95% CI 1.40 to 5.39). The review from Kakkos 2014 also included these six studies on treatment for VTE and reached similar conclusions.

Di Minno 2015 focused on the treatment of unprovoked or provoked VTE and included five studies (EINSTEIN‐DVT 2010; EINSTEIN‐PE 2012; Hokusai‐VTE 2013; RE‐COVER 2009; RE‐COVER II 2014). This review found that DOACs and VKAs had equal efficacy in treating VTE.

The Loffredo 2015 review included seven studies (AMPLIFY 2013; EINSTEIN‐DVT 2010; EINSTEIN‐PE 2012; Hokusai‐VTE 2013; RE‐COVER 2009; RE‐COVER II 2014; THRIVE 2005). The results suggested that DOACs for participants with acute VTE are not inferior to conventional therapy for recurrent VTE and all‐cause mortality, and reduced major bleeding (RR 0.63, 95% CI 0.47 to 0.83). However, there might be an increased incidence of myocardial infarction.

Senoo 2017 focused on Japanese participants only and included three studies (AMPLIFY‐J 2015; Hokusai‐VTE 2013; J‐EINSTEIN DVT and PE 2015). This review found that DOACs had a decreased risk for all bleeding (RR 0.69, 95% CI 0.50 to 0.95), without any significant differences in recurrent VTE (RR 0.84, 95% CI 0.29 to 2.43).

The review by Antoniazzi 2014 included people with VTE and atrial fibrillation. The review was only available as an abstract report and included eight studies. Its results showed that the risk of major bleeding was lower in people treated with dabigatran (RR 0.83, 95% CI 0.78 to 0.97).

The reviews by Castellucci 2013 and Sardar 2013 compared oral anticoagulants with antiplatelet drugs but the focus was on the secondary prevention of VTE rather than treatment.

Several systematic reviews focused on cancer‐associated VTE have been published in recent years, but these made no separate results for DVT available (Desai 2020; Kahale 2018; Li 2019; Mulder 2020; Yang 2019). The results differed slightly among these reviews, but all suggested a similar trend: that DOACs likely reduce recurrent VTE but may increase the risk of major bleeding in participants with cancer‐associated VTE.

Study flow diagram

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Figure 1

Study flow diagram

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Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

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Risk of bias summary: review authors' judgements about each risk of bias item for each included study

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

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Funnel plot of oral factor Xa inhibitors versus conventional anticoagulants for recurrent VTE 

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Figure 4

Funnel plot of oral factor Xa inhibitors versus conventional anticoagulants for recurrent VTE 

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Funnel plot of oral factor Xa inhibitors versus conventional anticoagulants for major bleeding

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Figure 5

Funnel plot of oral factor Xa inhibitors versus conventional anticoagulants for major bleeding

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Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 1: Recurrent venous thromboembolism

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Analysis 1.1

Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 1: Recurrent venous thromboembolism

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Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 2: Recurrent deep vein thrombosis

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Analysis 1.2

Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 2: Recurrent deep vein thrombosis

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Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 3: Fatal pulmonary embolism

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Analysis 1.3

Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 3: Fatal pulmonary embolism

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Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 4: Non‐fatal pulmonary embolism

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Analysis 1.4

Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 4: Non‐fatal pulmonary embolism

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Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 5: All‐cause mortality

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Analysis 1.5

Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 5: All‐cause mortality

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Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 6: Major bleeding

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Analysis 1.6

Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 6: Major bleeding

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Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 7: Health‐related quality of life: SF‐36 physical component

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Analysis 1.7

Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 7: Health‐related quality of life: SF‐36 physical component

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Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 8: Health‐related quality of life: SF‐36 psychological component

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Analysis 1.8

Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 8: Health‐related quality of life: SF‐36 psychological component

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Comparison 2: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation (sensitivity analysis excluding ximelagatran), Outcome 1: Recurrent venous thromboembolism

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Analysis 2.1

Comparison 2: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation (sensitivity analysis excluding ximelagatran), Outcome 1: Recurrent venous thromboembolism

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Comparison 2: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation (sensitivity analysis excluding ximelagatran), Outcome 2: Recurrent deep vein thrombosis

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Analysis 2.2

Comparison 2: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation (sensitivity analysis excluding ximelagatran), Outcome 2: Recurrent deep vein thrombosis

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Comparison 2: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation (sensitivity analysis excluding ximelagatran), Outcome 3: Fatal pulmonary embolism

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Analysis 2.3

Comparison 2: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation (sensitivity analysis excluding ximelagatran), Outcome 3: Fatal pulmonary embolism

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Comparison 2: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation (sensitivity analysis excluding ximelagatran), Outcome 4: Non‐fatal pulmonary embolism

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Analysis 2.4

Comparison 2: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation (sensitivity analysis excluding ximelagatran), Outcome 4: Non‐fatal pulmonary embolism

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Comparison 2: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation (sensitivity analysis excluding ximelagatran), Outcome 5: Major bleeding

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Analysis 2.5

Comparison 2: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation (sensitivity analysis excluding ximelagatran), Outcome 5: Major bleeding

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Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 1: Recurrent venous thromboembolism

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Analysis 3.1

Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 1: Recurrent venous thromboembolism

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Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 2: Recurrent deep vein thrombosis

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Analysis 3.2

Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 2: Recurrent deep vein thrombosis

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Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 3: Fatal pulmonary embolism

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Analysis 3.3

Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 3: Fatal pulmonary embolism

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Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 4: Non‐fatal pulmonary embolism

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Analysis 3.4

Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 4: Non‐fatal pulmonary embolism

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Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 5: All‐cause mortality

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Analysis 3.5

Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 5: All‐cause mortality

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Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 6: Major bleeding

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Analysis 3.6

Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 6: Major bleeding

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Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 7: Post‐thrombotic syndrome

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Analysis 3.7

Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 7: Post‐thrombotic syndrome

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Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 8: Health‐related quality of life: SF‐36 physical component

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Analysis 3.8

Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 8: Health‐related quality of life: SF‐36 physical component

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Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 9: Health‐related quality of life: SF‐36 psychological component

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Analysis 3.9

Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 9: Health‐related quality of life: SF‐36 psychological component

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Comparison 4: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis of participants with versus without active cancer, Outcome 1: Recurrent VTE

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Analysis 4.1

Comparison 4: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis of participants with versus without active cancer, Outcome 1: Recurrent VTE

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Comparison 4: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis of participants with versus without active cancer, Outcome 2: Major bleeding

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Analysis 4.2

Comparison 4: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis of participants with versus without active cancer, Outcome 2: Major bleeding

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Comparison 5: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis by different oral factor Xa inhibitors, Outcome 1: Recurrent venous thromboembolism

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Analysis 5.1

Comparison 5: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis by different oral factor Xa inhibitors, Outcome 1: Recurrent venous thromboembolism

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Comparison 5: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis by different oral factor Xa inhibitors, Outcome 2: Recurrent deep vein thrombosis

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Analysis 5.2

Comparison 5: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis by different oral factor Xa inhibitors, Outcome 2: Recurrent deep vein thrombosis

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Comparison 5: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis by different oral factor Xa inhibitors, Outcome 3: Fatal pulmonary embolism

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Analysis 5.3

Comparison 5: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis by different oral factor Xa inhibitors, Outcome 3: Fatal pulmonary embolism

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Comparison 5: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis by different oral factor Xa inhibitors, Outcome 4: Non‐fatal pulmonary embolism

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Analysis 5.4

Comparison 5: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis by different oral factor Xa inhibitors, Outcome 4: Non‐fatal pulmonary embolism

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Comparison 5: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis by different oral factor Xa inhibitors, Outcome 5: All‐cause mortality

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Analysis 5.5

Comparison 5: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis by different oral factor Xa inhibitors, Outcome 5: All‐cause mortality

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Comparison 5: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis by different oral factor Xa inhibitors, Outcome 6: Major bleeding

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Analysis 5.6

Comparison 5: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis by different oral factor Xa inhibitors, Outcome 6: Major bleeding

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Comparison 6: Oral factor Xa inhibitors versus conventional anticoagulation (sensitivity analysis excluding high risk of bias studies), Outcome 1: Recurrent venous thromboembolism

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Analysis 6.1

Comparison 6: Oral factor Xa inhibitors versus conventional anticoagulation (sensitivity analysis excluding high risk of bias studies), Outcome 1: Recurrent venous thromboembolism

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Comparison 6: Oral factor Xa inhibitors versus conventional anticoagulation (sensitivity analysis excluding high risk of bias studies), Outcome 2: Recurrent deep vein thrombosis

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Analysis 6.2

Comparison 6: Oral factor Xa inhibitors versus conventional anticoagulation (sensitivity analysis excluding high risk of bias studies), Outcome 2: Recurrent deep vein thrombosis

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Comparison 6: Oral factor Xa inhibitors versus conventional anticoagulation (sensitivity analysis excluding high risk of bias studies), Outcome 3: Fatal pulmonary embolism

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Analysis 6.3

Comparison 6: Oral factor Xa inhibitors versus conventional anticoagulation (sensitivity analysis excluding high risk of bias studies), Outcome 3: Fatal pulmonary embolism

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Comparison 6: Oral factor Xa inhibitors versus conventional anticoagulation (sensitivity analysis excluding high risk of bias studies), Outcome 4: Non‐fatal pulmonary embolism

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Analysis 6.4

Comparison 6: Oral factor Xa inhibitors versus conventional anticoagulation (sensitivity analysis excluding high risk of bias studies), Outcome 4: Non‐fatal pulmonary embolism

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Comparison 6: Oral factor Xa inhibitors versus conventional anticoagulation (sensitivity analysis excluding high risk of bias studies), Outcome 5: All‐cause mortality

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Analysis 6.5

Comparison 6: Oral factor Xa inhibitors versus conventional anticoagulation (sensitivity analysis excluding high risk of bias studies), Outcome 5: All‐cause mortality

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Comparison 6: Oral factor Xa inhibitors versus conventional anticoagulation (sensitivity analysis excluding high risk of bias studies), Outcome 6: Major bleeding

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Analysis 6.6

Comparison 6: Oral factor Xa inhibitors versus conventional anticoagulation (sensitivity analysis excluding high risk of bias studies), Outcome 6: Major bleeding

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Comparison 7: Oral direct thrombin inhibitor (DTI) versus oral factor Xa inhibitor, Outcome 1: Health‐related quality of life: SF‐36 physical component

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Analysis 7.1

Comparison 7: Oral direct thrombin inhibitor (DTI) versus oral factor Xa inhibitor, Outcome 1: Health‐related quality of life: SF‐36 physical component

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Comparison 7: Oral direct thrombin inhibitor (DTI) versus oral factor Xa inhibitor, Outcome 2: Health‐related quality of life: SF‐36 psychological component

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Analysis 7.2

Comparison 7: Oral direct thrombin inhibitor (DTI) versus oral factor Xa inhibitor, Outcome 2: Health‐related quality of life: SF‐36 psychological component

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Summary of findings 1. Oral DTIs versus conventional anticoagulation for participants with diagnosed DVT

Oral DTIs versus conventional anticoagulation for participants with diagnosed DVT

Patient or population: participants with diagnosed DVT 
Setting: hospital 
Intervention: oral DTIs 
Comparison: conventional anticoagulation

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with conventional anticoagulation

Risk with oral DTIs

Recurrent VTE

 

(7 months)

Study population

OR 1.17
(0.83 to 1.65)

5994
(3 RCTsa)

⊕⊕⊕⊝
Moderateb

 

21 per 1000

25 per 1000
(18 to 35)

Recurrent DVT

 

(7 months)

Study population

OR 1.11
(0.74 to 1.66)

5994
(3 RCTsa)

⊕⊕⊕⊝
Moderateb

 

15 per 1000

17 per 1000
(11 to 25)

Fatal PE

 

(7 months)

Study population

OR 1.32
(0.29 to 6.02)

5994
(3 RCTsa)

⊕⊕⊕⊝
Moderateb

 

1 per 1000

1 per 1000
(0 to 6)

Non‐fatal PE

 

(7 months)

Study population

OR 1.29
(0.64 to 2.59)

5994
(3 RCTsa)

⊕⊕⊕⊝
Moderateb

 

5 per 1000

6 per 1000
(3 to 12)

All‐cause mortality

 

(7 months)

Study population

OR 0.66
(0.41 to 1.08)

2489
(1 RCT)

⊕⊕⊕⊝
Moderateb

 

34 per 1000

22 per 1000
(14 to 36)

Major bleeding

 

(7 months)

Study population

OR 0.58
(0.38 to 0.89)

5994
(3 RCTsa)

⊕⊕⊕⊕
High

 

19 per 1000

11 per 1000
(7 to 17)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). 
CI: confidence interval; DTIs: direct thrombin inhibitors; DVT: deep vein thrombosis; OR: odds ratio; PE: pulmonary embolism; RCT: randomised controlled trial; VTE: venous thromboembolism

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

aThe data from RE‐COVER 2009 and RE‐COVER II 2014 were taken from one pooled analysis and are therefore shown as one study in our analyses
bWe downgraded one level for imprecision due to the low number of events and a small sample size; the possibility of publication bias is not excluded but we did not consider it sufficient to downgrade the certainty of evidence.

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Summary of findings 1. Oral DTIs versus conventional anticoagulation for participants with diagnosed DVT
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Summary of findings 2. Oral factor Xa inhibitors compared to conventional anticoagulation for participants with diagnosed DVT

Oral factor Xa inhibitors versus conventional anticoagulation for participants with diagnosed DVT

Patient or population: participants with diagnosed DVT 
Setting: hospital
Intervention: oral factor Xa inhibitors
Comparison: conventional anticoagulation

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with conventional anticoagulation

Risk with oral factor Xa

Recurrent VTE

 

(3 to 12 months)

Study population

OR 0.85
(0.71 to 1.01)

17,505
(13 RCTs)

⊕⊕⊕⊝
Moderatea

One of the 13 studies reported no events

34 per 1000

29 per 1000
(24 to 34)

Recurrent DVT

 

(3 to 12 months)

Study population

OR 0.70
(0.49 to 1.01)

16,439
(9 RCTs)

⊕⊕⊕⊝
Moderatea

 

16 per 1000

12 per 1000
(8 to 17)

Fatal PE

 

(3 to 12 months)

Study population

OR 1.18
(0.69 to 2.02)

15,082
(6 RCTs)

⊕⊕⊕⊝
Moderatea

 

3 per 1000

4 per 1000
(2 to 6)

Non‐fatal PE

 

(3 to 12 months)

Study population

OR 0.93
(0.68 to 1.27)

15,166
(7 RCTs)

⊕⊕⊕⊝
Moderatea

 

11 per 1000

10 per 1000
(8 to 14)

All‐cause mortality

 

(3 to 6 months)

Study population

OR 0.87
(0.67 to 1.14)

10,770
(9 RCTs)

 

⊕⊕⊕⊝
Moderatea

Three of the nine studies reported no events

23 per 1000

20 per 1000
(16 to 27)

Major bleeding

 

(3 to 12 months)

Study population

OR 0.63
(0.45 to 0.89)

18,066
(17 RCTs)

 

⊕⊕⊕⊕
High

Five of 17 studies reported no events

17 per 1000

11 per 1000
(8 to 15)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). 

CI: confidence interval; DVT: deep vein thrombosis; OR: odds ratio; PE: pulmonary embolism; RCT: randomised controlled trial; VTE: venous thromboembolism

GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

aWe downgraded one level for imprecision due to the low number of events and a small sample size; the possibility of publication bias is not excluded but we did not consider it sufficient to downgrade the quality of evidence.

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Summary of findings 2. Oral factor Xa inhibitors compared to conventional anticoagulation for participants with diagnosed DVT
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Comparison 1. Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1.1 Recurrent venous thromboembolism Show forest plot

2

5994

Odds Ratio (M‐H, Random, 95% CI)

1.17 [0.83, 1.65]

1.2 Recurrent deep vein thrombosis Show forest plot

2

5994

Odds Ratio (M‐H, Random, 95% CI)

1.11 [0.74, 1.66]

1.3 Fatal pulmonary embolism Show forest plot

2

5994

Odds Ratio (M‐H, Random, 95% CI)

1.32 [0.29, 6.02]

1.4 Non‐fatal pulmonary embolism Show forest plot

2

5994

Odds Ratio (M‐H, Random, 95% CI)

1.29 [0.64, 2.59]

1.5 All‐cause mortality Show forest plot

1

2489

Odds Ratio (M‐H, Random, 95% CI)

0.66 [0.41, 1.08]

1.6 Major bleeding Show forest plot

2

5994

Odds Ratio (M‐H, Random, 95% CI)

0.58 [0.38, 0.89]

1.7 Health‐related quality of life: SF‐36 physical component Show forest plot

1

65

Mean Difference (IV, Random, 95% CI)

6.75 [2.37, 11.13]

1.8 Health‐related quality of life: SF‐36 psychological component Show forest plot

1

65

Mean Difference (IV, Random, 95% CI)

6.45 [3.24, 9.66]
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Comparison 1. Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation
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Comparison 2. Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation (sensitivity analysis excluding ximelagatran)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

2.1 Recurrent venous thromboembolism Show forest plot

1

3505

Odds Ratio (M‐H, Random, 95% CI)

1.21 [0.78, 1.89]

2.2 Recurrent deep vein thrombosis Show forest plot

1

3505

Odds Ratio (M‐H, Fixed, 95% CI)

1.24 [0.76, 2.03]

2.3 Fatal pulmonary embolism Show forest plot

1

3505

Odds Ratio (M‐H, Fixed, 95% CI)

0.66 [0.11, 3.97]

2.4 Non‐fatal pulmonary embolism Show forest plot

1

3505

Odds Ratio (M‐H, Random, 95% CI)

1.12 [0.43, 2.91]

2.5 Major bleeding Show forest plot

1

3505

Odds Ratio (M‐H, Fixed, 95% CI)

0.62 [0.35, 1.08]
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Comparison 2. Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation (sensitivity analysis excluding ximelagatran)
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Comparison 3. Oral factor Xa inhibitors versus conventional anticoagulation

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

3.1 Recurrent venous thromboembolism Show forest plot

13

17461

Odds Ratio (M‐H, Random, 95% CI)

0.85 [0.71, 1.01]

3.1.1 Treatment duration 3 months

5

5001

Odds Ratio (M‐H, Random, 95% CI)

0.68 [0.47, 0.99]

3.1.2 Treatment duration > 3 months

8

12460

Odds Ratio (M‐H, Random, 95% CI)

0.90 [0.74, 1.10]

3.2 Recurrent deep vein thrombosis Show forest plot

9

16439

Odds Ratio (M‐H, Random, 95% CI)

0.70 [0.49, 1.01]

3.2.1 Treatment duration 3 months

4

4917

Odds Ratio (M‐H, Random, 95% CI)

0.50 [0.22, 1.15]

3.2.2 Treatment duration > 3 months

5

11522

Odds Ratio (M‐H, Random, 95% CI)

0.86 [0.63, 1.17]

3.3 Fatal pulmonary embolism Show forest plot

6

15082

Odds Ratio (M‐H, Random, 95% CI)

1.18 [0.69, 2.02]

3.3.1 Treatment duration 3 months

4

4917

Odds Ratio (M‐H, Random, 95% CI)

1.68 [0.36, 7.94]

3.3.2 Treatment duration > 3 months

2

10165

Odds Ratio (M‐H, Random, 95% CI)

1.15 [0.54, 2.44]

3.4 Non‐fatal pulmonary embolism Show forest plot

7

15166

Odds Ratio (M‐H, Random, 95% CI)

0.93 [0.68, 1.27]

3.4.1 Treatment duration 3 months

5

5001

Odds Ratio (M‐H, Random, 95% CI)

0.87 [0.51, 1.48]

3.4.2 Treatment duration > 3 months

2

10165

Odds Ratio (M‐H, Random, 95% CI)

0.96 [0.65, 1.43]

3.5 All‐cause mortality Show forest plot

9

10770

Odds Ratio (M‐H, Random, 95% CI)

0.87 [0.67, 1.14]

3.5.1 Treatment duration 3 months

4

5072

Odds Ratio (M‐H, Random, 95% CI)

0.85 [0.58, 1.25]

3.5.2 Treatment duration > 3 months

5

5698

Odds Ratio (M‐H, Random, 95% CI)

0.95 [0.55, 1.67]

3.6 Major bleeding Show forest plot

17

18066

Odds Ratio (M‐H, Random, 95% CI)

0.63 [0.45, 0.89]

3.6.1 Treatment duration 3 months

5

5170

Odds Ratio (M‐H, Random, 95% CI)

0.78 [0.42, 1.43]

3.6.2 Treatment duration > 3 months

12

12896

Odds Ratio (M‐H, Random, 95% CI)

0.60 [0.39, 0.91]

3.7 Post‐thrombotic syndrome Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

3.7.1 6 months

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

3.7.2 12 months

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

3.8 Health‐related quality of life: SF‐36 physical component Show forest plot

1

65

Mean Difference (IV, Fixed, 95% CI)

5.55 [1.18, 9.92]

3.9 Health‐related quality of life: SF‐36 psychological component Show forest plot

1

65

Mean Difference (IV, Fixed, 95% CI)

1.41 [‐2.61, 5.43]
Figures and Tables -
Comparison 3. Oral factor Xa inhibitors versus conventional anticoagulation
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Comparison 4. Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis of participants with versus without active cancer

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

4.1 Recurrent VTE Show forest plot

7

9827

Odds Ratio (M‐H, Random, 95% CI)

0.75 [0.59, 0.94]

4.1.1 Participants without cancer

4

5579

Odds Ratio (M‐H, Random, 95% CI)

0.82 [0.59, 1.15]

4.1.2 Participant with Cancer

4

4248

Odds Ratio (M‐H, Random, 95% CI)

0.69 [0.51, 0.94]

4.2 Major bleeding Show forest plot

9

6801

Odds Ratio (M‐H, Random, 95% CI)

0.54 [0.27, 1.08]

4.2.1 Participants without cancer

6

5795

Odds Ratio (M‐H, Random, 95% CI)

0.30 [0.17, 0.52]

4.2.2 Participant with Cancer

3

1006

Odds Ratio (M‐H, Random, 95% CI)

0.93 [0.49, 1.76]
Figures and Tables -
Comparison 4. Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis of participants with versus without active cancer
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Comparison 5. Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis by different oral factor Xa inhibitors

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

5.1 Recurrent venous thromboembolism Show forest plot

13

17461

Odds Ratio (M‐H, Random, 95% CI)

0.85 [0.71, 1.01]

5.1.1 Apixaban

5

6381

Odds Ratio (M‐H, Random, 95% CI)

0.76 [0.57, 1.02]

5.1.2 Edoxaban

3

5394

Odds Ratio (M‐H, Random, 95% CI)

0.98 [0.74, 1.29]

5.1.3 Rivaroxaban

5

5686

Odds Ratio (M‐H, Random, 95% CI)

0.85 [0.45, 1.61]

5.2 Recurrent deep vein thrombosis Show forest plot

9

16439

Odds Ratio (M‐H, Random, 95% CI)

0.70 [0.49, 1.01]

5.2.1 Apixaban

3

5820

Odds Ratio (M‐H, Random, 95% CI)

0.65 [0.40, 1.07]

5.2.2 Edoxaban

1

4921

Odds Ratio (M‐H, Random, 95% CI)

1.04 [0.68, 1.59]

5.2.3 Rivaroxaban 

5

5698

Odds Ratio (M‐H, Random, 95% CI)

0.56 [0.29, 1.09]

5.3 Fatal pulmonary embolism Show forest plot

6

15082

Odds Ratio (M‐H, Random, 95% CI)

1.18 [0.69, 2.02]

5.3.1 Apixaban

2

5720

Odds Ratio (M‐H, Random, 95% CI)

0.82 [0.39, 1.71]

5.3.2 Edoxaban

1

4921

Odds Ratio (M‐H, Random, 95% CI)

1.74 [0.73, 4.16]

5.3.3 Rivaroxaban

3

4441

Odds Ratio (M‐H, Random, 95% CI)

1.98 [0.34, 11.62]

5.4 Non‐fatal pulmonary embolism Show forest plot

7

15166

Odds Ratio (M‐H, Random, 95% CI)

0.93 [0.68, 1.27]

5.4.1 Apixaban

2

5720

Odds Ratio (M‐H, Random, 95% CI)

0.62 [0.08, 4.98]

5.4.2 Edoxaban

2

5005

Odds Ratio (M‐H, Random, 95% CI)

0.78 [0.46, 1.32]

5.4.3 Rivaroxaban

3

4441

Odds Ratio (M‐H, Random, 95% CI)

0.95 [0.55, 1.64]

5.5 All‐cause mortality Show forest plot

9

10770

Odds Ratio (M‐H, Random, 95% CI)

0.87 [0.67, 1.14]

5.5.1 Apixaban

4

6058

Odds Ratio (M‐H, Random, 95% CI)

0.98 [0.59, 1.65]

5.5.2 Rivaroxaban

5

4712

Odds Ratio (M‐H, Random, 95% CI)

0.83 [0.56, 1.23]

5.6 Major bleeding Show forest plot

17

18066

Odds Ratio (M‐H, Random, 95% CI)

0.63 [0.45, 0.89]

5.6.1 Apixaban

6

7141

Odds Ratio (M‐H, Random, 95% CI)

0.61 [0.27, 1.42]

5.6.2 Edoxaban

4

5405

Odds Ratio (M‐H, Random, 95% CI)

0.88 [0.48, 1.64]

5.6.3 Rivaroxaban

7

5520

Odds Ratio (M‐H, Random, 95% CI)

0.61 [0.36, 1.05]
Figures and Tables -
Comparison 5. Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis by different oral factor Xa inhibitors
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Comparison 6. Oral factor Xa inhibitors versus conventional anticoagulation (sensitivity analysis excluding high risk of bias studies)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

6.1 Recurrent venous thromboembolism Show forest plot

10

11616

Odds Ratio (M‐H, Random, 95% CI)

0.89 [0.70, 1.13]

6.2 Recurrent deep vein thrombosis Show forest plot

8

11195

Odds Ratio (M‐H, Random, 95% CI)

0.72 [0.45, 1.13]

6.3 Fatal pulmonary embolism Show forest plot

5

9838

Odds Ratio (M‐H, Random, 95% CI)

1.73 [0.81, 3.69]

6.4 Non‐fatal pulmonary embolism Show forest plot

5

9838

Odds Ratio (M‐H, Random, 95% CI)

0.84 [0.57, 1.23]

6.5 All‐cause mortality Show forest plot

7

5321

Odds Ratio (M‐H, Random, 95% CI)

0.94 [0.66, 1.35]

6.6 Major bleeding Show forest plot

11

11855

Odds Ratio (M‐H, Random, 95% CI)

0.76 [0.55, 1.05]
Figures and Tables -
Comparison 6. Oral factor Xa inhibitors versus conventional anticoagulation (sensitivity analysis excluding high risk of bias studies)
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Comparison 7. Oral direct thrombin inhibitor (DTI) versus oral factor Xa inhibitor

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

7.1 Health‐related quality of life: SF‐36 physical component Show forest plot

1

60

Mean Difference (IV, Random, 95% CI)

1.20 [‐2.89, 5.29]

7.2 Health‐related quality of life: SF‐36 psychological component Show forest plot

1

60

Mean Difference (IV, Random, 95% CI)

5.04 [1.24, 8.84]
Figures and Tables -
Comparison 7. Oral direct thrombin inhibitor (DTI) versus oral factor Xa inhibitor
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