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

Appendices

Appendix 1. Sources searched and search strategies

Source

Search strategy

Hits retrieved

1. Medline (Ovid MEDLINE® Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE® Daily and Ovid MEDLINE®) 1946 to present

(Date of most recent search: 2 March 2022)

1 exp Pulmonary Embolism/

2 exp THROMBOEMBOLISM/

3 (emboli* adj4 pulmonary).ti,ab.

4 thromboemboli*.ti,ab.

5 (PE or VTE).ti,ab.

6 (Pulmonary adj4 clot).ti,ab.

7 (lung adj4 clot).ti,ab.

8 or/1‐7

9 exp ANTITHROMBINS/

10 Hirudin Therapy/

11 (thrombin adj3 inhib*).ti,ab.

12 hirudin*.ti,ab.

13 (dabigatran or Pradaxa or Rendix).ti,ab.

14 (BIBR‐953* or BIBR953* or BIBR‐1048 or BIBR1048).ti,ab.

15 (ximelagatran or Exanta or Exarta or melagatran).ti,ab.

16 (AZD0837 or AZD‐0837).ti,ab.

17 (S35972 or S‐35972).ti,ab.

18 Factor Xa Inhibitors/

19 (Factor X* adj4 (antag* or inhib* or block*)).ti,ab.

20 (FX* adj4 (antag* or inhib* or block*)).ti,ab.

21 (FX* adj4 (antag* or inhib* or block*)).ti,ab.

22 (10* adj4 (antag* or inhib* or block*)).ti,ab.

23 (rivaroxaban or Xarelto).ti,ab.

24 (Bay‐597939 or Bay597939).ti,ab.

25 (betrixaban or PRT054021).ti,ab.

26 apixaban.ti,ab.

27 (BMS‐562247 or BMS‐562247 or ELIQUIS).ti,ab.

28 (DU‐176b or DU176b).ti,ab.

29 (PRT‐054021 or PRT054021).ti,ab.

30 (YM150 or YM‐150 or LY517717 or LY‐517717 or DU‐176b or DU176*).ti,ab.

31 (GW813893 or "Tak 442" or TAK442 or PD0348292 or GSK‐813893 or GSK813893).ti,ab.

32 (edoxaban or lixiana).ti,ab.

33 or/9‐32

34 8 and 33

35 randomized controlled trial.pt.

36 controlled clinical trial.pt.

37 randomized.ab.

38 placebo.ab.

39 drug therapy.fs.

40 randomly.ab.

41 trial.ab.

42 groups.ab.

43 or/35‐42

44 exp animals/ not humans.sh.

45 43 not 44

46 34 and 45

March 2022: 2641

2. EMBASE via Ovid

(Date of most recent search: 2 March 2022)

1 exp lung embolism/

2 exp thromboembolism/

3 (emboli* adj4 pulmonary).ti,ab.

4 thromboemboli*.ti,ab.

5 (PE or VTE).ti,ab.

6 (Pulmonary adj4 clot).ti,ab.

7 (lung adj4 clot).ti,ab.

8 or/1‐7

9 exp antithrombin/

10 anticoagulant therapy/

11 (thrombin adj3 inhib*).ti,ab.

12 hirudin*.ti,ab.

13 (dabigatran or Pradaxa or Rendix).ti,ab.

14 (BIBR‐953* or BIBR953* or BIBR‐1048 or BIBR1048).ti,ab.

15 (ximelagatran or Exanta or Exarta or melagatran).ti,ab.

16 (AZD0837 or AZD‐0837).ti,ab.

17 (S35972 or S‐35972).ti,ab.

18 blood clotting factor 10a inhibitor/

19 (Factor X* adj4 (antag* or inhib* or block*)).ti,ab.

20 (FX* adj4 (antag* or inhib* or block*)).ti,ab.

21 (10* adj4 (antag* or inhib* or block*)).ti,ab.

22 (rivaroxaban or Xarelto).ti,ab.

23 (Bay‐597939 or Bay597939).ti,ab.

24 (betrixaban or PRT054021).ti,ab.

25 apixaban.ti,ab.

26 (BMS‐562247 or BMS‐562247 or ELIQUIS).ti,ab.

27 (DU‐176b or DU176b).ti,ab.

28 (PRT‐054021 or PRT054021).ti,ab.

29 (YM150 or YM‐150 or LY517717 or LY‐517717 or DU‐176b or DU176*).ti,ab.

30 (GW813893 or "Tak 442" or TAK442 or PD0348292 or GSK‐813893 or GSK813893).ti,ab.

31 (edoxaban or lixiana).ti,ab.

32 or/9‐31

33 8 and 32

34 randomized controlled trial/

35 controlled clinical trial/

36 random$.ti,ab.

37 randomization/

38 intermethod comparison/

39 placebo.ti,ab.

40 (compare or compared or comparison).ti.

41 ((evaluated or evaluate or evaluating or assessed or assess) and (compare or compared or comparing or comparison)).ab.

42 (open adj label).ti,ab.

43 ((double or single or doubly or singly) adj (blind or blinded or blindly)).ti,ab.

44 double blind procedure/

45 parallel group$1.ti,ab.

46 (crossover or cross over).ti,ab.

47 ((assign$ or match or matched or allocation) adj5 (alternate or group$1 or intervention$1 or patient$1 or subject$1 or participant$1)).ti,ab.

48 (assigned or allocated).ti,ab.

49 (controlled adj7 (study or design or trial)).ti,ab.

50 (volunteer or volunteers).ti,ab.

51 trial.ti.

52 or/34‐51

53 33 and 52

March 2022: 7892

3. CINAHL via Ebsco

(Date of most recent search: 2 March 2022)

S47 S31 AND S46

S46 S32 OR S33 OR S34 OR S35 OR S36 OR S37 OR S38 OR S39 OR S40 OR S41 OR S42 OR S43 OR S44 OR S45

S45 MH "Random Assignment"

S44 MH "Triple‐Blind Studies"

S43 MH "Double‐Blind Studies"

S42 MH "Single‐Blind Studies"

S41 MH "Crossover Design"

S40 MH "Factorial Design"

S39 MH "Placebos"

S38 MH "Clinical Trials"

S37 TX "multi‐centre study" OR "multi‐center study" OR "multicentre study" OR "multicenter study" OR "multi‐site study"

S36 TX crossover OR "cross‐over"

S35 AB placebo*

S34 TX random*

S33 TX trial*

S32 TX "latin square"

S31 S8 AND S30

S30 S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25 OR S26 OR S27 OR S28 OR S29

S29 TX apixaban

S28 TX edoxaban or lixiana

S27 TX GW813893 or "Tak 442" or TAK442 or PD0348292 or GSK‐813893 or GSK813893

S26 TX YM150 or YM‐150 or LY517717 or LY‐517717 or DU‐176b or DU176*

S25 TX PRT‐054021 or PRT054021

S24 TX DU‐176b or DU176b

S23 TX BMS‐562247 or BMS‐562247 or ELIQUIS

S22 TX betrixaban or PRT054021

S21 TX Bay‐597939 or Bay597939

S20 TX rivaroxaban or Xarelto

S19 TX (10* n4 (antag* or inhib* or block*) )

S18 TX (FX* n4 (antag* or inhib* or block*))

S17 TX (Factor X* n4 (antag* or inhib* or block*))

S16 TX S35972 or S‐35972

S15 TX AZD0837 or AZD‐0837

S14 TX ximelagatran or Exanta or Exarta or melagatran

S13 TX BIBR‐953* or BIBR953* or BIBR‐1048 or BIBR1048

S12 TX Antithrombins

S11 TX dabigatran or Pradaxa or Rendix

S10 TX hirudin*

S9 TX thrombin n3 inhib*

S8 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7

S7 TX PE or VTE

S6 TX lung N4 clot

S5 TX Pulmonary N4 clot

S4 TX thromboemboli*

S3 TX emboli* N4 pulmonary

S2 (MH "Thromboembolism+")

S1 (MH "Pulmonary Embolism")

March 2022: 473

4. VASCULAR REGISTER IN CRSW

(Date of most recent search: 2 March 2022)

rivaroxaban OR apixaban OR dabigatran OR ximelagatran OR betrixaban OR edoxaban

March 2022: 1568

5. CENTRAL via CRSO

(Date of most recent search: 2 March 2022)

#1 MESH DESCRIPTOR Pulmonary Embolism EXPLODE ALL TREES 1057

#2 MESH DESCRIPTOR THROMBOEMBOLISM EXPLODE ALL TREES 2166

#3 (emboli* adj4 pulmonary):TI,AB,KY 345

#4 thromboemboli*:TI,AB,KY 10025

#5 (PE or VTE):TI,AB,KY 7326

#6 (Pulmonary adj4 clot):TI,AB,KY 14

#7 (lung adj4 clot):TI,AB,KY 1

#8 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 15873

#9 MESH DESCRIPTOR ANTITHROMBINS EXPLODE ALL TREES 2289

#10 MESH DESCRIPTOR Hirudin Therapy EXPLODE ALL TREES 75

#11 (thrombin adj3 inhib*):TI,AB,KY 698

#12 hirudin*:TI,AB,KY 483

#13 (dabigatran or Pradaxa or Rendix):TI,AB,KY 1068

#14 (BIBR‐953* or BIBR953* or BIBR‐1048 or BIBR1048):TI,AB,KY 48

#15 (ximelagatran or Exanta or Exarta or melagatran):TI,AB,KY 182

#16 (AZD0837 or AZD‐0837):TI,AB,KY 22

#17 (S35972 or S‐35972):TI,AB,KY 0

#18 MESH DESCRIPTOR Factor Xa Inhibitors EXPLODE ALL TREES 1091

#19 (Factor X* adj4 (antag* or inhib* or block*)):TI,AB,KY 1113

#20 (FX* adj4 (antag* or inhib* or block*)):TI,AB,KY 107

#21 (FX* adj4 (antag* or inhib* or block*)):TI,AB,KY 107

#22 (10* adj4 (antag* or inhib* or block*)):TI,AB,KY 1677

#23 (rivaroxaban or Xarelto):TI,AB,KY 1898

#24 (Bay‐597939 or Bay597939):TI,AB,KY 0

#25 (betrixaban or PRT054021):TI,AB,KY 93

#26 apixaban:TI,AB,KY 1030

#27 (BMS‐562247 or BMS‐562247 or ELIQUIS):TI,AB,KY 48

#28 (DU‐176b or DU176b):TI,AB,KY 53

#29 (PRT‐054021 or PRT054021):TI,AB,KY 3

#30 (YM150 or YM‐150 or LY517717 or LY‐517717 or DU‐176b or DU176*):TI,AB,KY 108

#31 (GW813893 or "Tak 442" or TAK442 or PD0348292 or GSK‐813893 or GSK813893):TI,AB,KY 7

#32 (edoxaban or lixiana):TI,AB,KY 620

#33 #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 7475

#34 #8 AND #33 2079

March 2022: 533

6. Clinicaltrials.gov

(Date of most recent search: 2 March 2022)

Pulmonary Embolism OR thromboembolism | rivaroxaban OR apixaban OR dabigatran OR ximelagatran OR betrixaban OR edoxaban

March 2022: 146

7. ICTRP Search Portal

(Date of most recent search: 2 March 2022)

Pulmonary Embolism OR thromboembolism | rivaroxaban OR apixaban OR dabigatran OR ximelagatran OR betrixaban OR edoxaban

March 2022: 159

TOTAL before de‐duplication

March 2022: 13412

TOTAL after de‐duplication

March 2022: 10797

Appendix 2. CRS search strategy 2015

Search run on Wednesday 28 January 2015

 

 

 

 

#1

MESH DESCRIPTOR Antithrombins EXPLODE ALL TREES

790

#2

MESH DESCRIPTOR Hirudin Therapy

75

#3

(thrombin near3 inhib*):TI,AB,KY

444

#4

hirudin*:TI,AB,KY

327

#5

(dabigatran or Pradaxa or Rendix):TI,AB,KY

199

#6

(BIBR‐953* or BIBR953* or BIBR‐1048 or BIBR1048):TI,AB,KY

9

#7

(ximelagatran or Exanta or Exarta or melagatran):TI,AB,KY

147

#8

(AZD0837 or AZD‐0837):TI,AB,KY

12

#9

(S35972 or S‐35972):TI,AB,KY

0

#10

#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9

1387

#11

MESH DESCRIPTOR Factor Xa Inhibitors

1

#12

(Factor X* near4 (antag* or inhib* or block*)):TI,AB,KY

415

#13

(FX* near4 (antag* or inhib* or block*)):TI,AB,KY

33

#14

(10* near4 (antag* or inhib* or block*) ):TI,AB,KY

842

#15

#11 OR #12 OR #13 OR #14

1237

#16

(rivaroxaban or Xarelto):TI,AB,KY

251

#17

(Bay‐597939 or Bay597939):TI,AB,KY

0

#18

(betrixaban or PRT054021):TI,AB,KY

14

#19

apixaban:TI,AB,KY

134

#20

(BMS‐562247 or BMS‐562247 or ELIQUIS):TI,AB,KY

0

#21

(DU‐176b or DU176b):TI,AB,KY

11

#22

(PRT‐054021 or PRT054021):TI,AB,KY

1

#23

(YM150 or YM‐150 or LY517717 or LY‐517717 or DU‐176b or DU176*):TI,AB,KY

38

#24

(GW813893 or "Tak 442" or TAK442 or PD0348292 or GSK‐813893 or GSK813893):TI,AB,KY

3

#25

edoxaban or lixiana

51

#26

#16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25

456

#27

#10 OR #15 OR #26

2793

#28

MESH DESCRIPTOR Thrombosis

1133

#29

MESH DESCRIPTOR Thromboembolism

841

#30

MESH DESCRIPTOR Venous Thromboembolism

159

#31

MESH DESCRIPTOR Venous Thrombosis EXPLODE ALL TREES

1857

#32

(thrombus* or thrombotic* or thrombolic* or thromboemboli* or thrombos* or embol*):TI,AB,KY

13382

#33

MESH DESCRIPTOR Pulmonary Embolism EXPLODE ALL TREES

676

#34

(PE or DVT or VTE):TI,AB,KY

3057

#35

((vein* or ven*) near thromb*):TI,AB,KY

5003

#36

(blood near3 clot*):TI,AB,KY

1305

#37

(pulmonary near3 clot*):TI,AB,KY

5

#38

(lung near3 clot*):TI,AB,KY

3

#39

#28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38

16505

#40

#27 AND #39

1026

Study flow diagram

Figures and Tables -
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

Figures and Tables -
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

Figures and Tables -
Figure 3

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

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Comparison 1: Oral DTIs versus conventional anticoagulation, Outcome 1: Recurrent pulmonary embolism

Figures and Tables -
Analysis 1.1

Comparison 1: Oral DTIs versus conventional anticoagulation, Outcome 1: Recurrent pulmonary embolism

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Comparison 1: Oral DTIs versus conventional anticoagulation, Outcome 2: Recurrent venous thromboembolism

Figures and Tables -
Analysis 1.2

Comparison 1: Oral DTIs versus conventional anticoagulation, Outcome 2: Recurrent venous thromboembolism

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Comparison 1: Oral DTIs versus conventional anticoagulation, Outcome 3: Deep vein thrombosis

Figures and Tables -
Analysis 1.3

Comparison 1: Oral DTIs versus conventional anticoagulation, Outcome 3: Deep vein thrombosis

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Comparison 1: Oral DTIs versus conventional anticoagulation, Outcome 4: Major bleeding

Figures and Tables -
Analysis 1.4

Comparison 1: Oral DTIs versus conventional anticoagulation, Outcome 4: Major bleeding

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Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 1: Recurrent pulmonary embolism

Figures and Tables -
Analysis 2.1

Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 1: Recurrent pulmonary embolism

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Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 2: Recurrent venous thromboembolism

Figures and Tables -
Analysis 2.2

Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 2: Recurrent venous thromboembolism

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

Figures and Tables -
Analysis 2.3

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

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Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 4: All‐cause mortality

Figures and Tables -
Analysis 2.4

Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 4: All‐cause mortality

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Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 5: Major bleeding

Figures and Tables -
Analysis 2.5

Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 5: Major bleeding

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Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 6: Recurrent venous thromboembolism (subgroup analysis based on different types of factor Xa inhibitors)

Figures and Tables -
Analysis 2.6

Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 6: Recurrent venous thromboembolism (subgroup analysis based on different types of factor Xa inhibitors)

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Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 7: Major bleeding (subgroup analysis based on different types of factor Xa inhibitors)

Figures and Tables -
Analysis 2.7

Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 7: Major bleeding (subgroup analysis based on different types of factor Xa inhibitors)

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Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 8: Recurrent venous thromboembolism (sensitivity analysis by including only studies at low risk of bias)

Figures and Tables -
Analysis 2.8

Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 8: Recurrent venous thromboembolism (sensitivity analysis by including only studies at low risk of bias)

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Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 9: Major bleeding (sensitivity analysis by including only studies at low risk of bias)

Figures and Tables -
Analysis 2.9

Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 9: Major bleeding (sensitivity analysis by including only studies at low risk of bias)

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Summary of findings 1. Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation for the treatment of pulmonary embolism

Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation for the treatment of pulmonary embolism

Patient or population: people with a pulmonary embolism, confirmed by standard imaging techniques
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 DTI

Recurrent PEa

 

Follow‐up: 

6 months

Study population

OR 1.02
(0.50 to 2.04)

1602
(1 RCT)

⊕⊕⊕⊝
Moderateb

The 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.

20 per 1000

20 per 1000
(10 to 40)

Recurrent VTEc

 

Follow‐up: 

6 months

Study population

OR 0.93
(0.52 to 1.66)

1602
(1 RCT)

⊕⊕⊕⊝
Moderateb

The 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.

31 per 1000

29 per 1000
(16 to 50)

DVTd

 

Follow‐up: 

6 months

Study population

OR 0.79
(0.29 to 2.13)

1602
(1 RCT)

⊕⊕⊕⊝
Moderateb

The 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.

11 per 1000

9 per 1000
(3 to 23)

All‐cause mortality

See comment

See comment

See comment

‐

RE‐COVER 2009 and RE‐COVER II 2014 did not report on all‐cause mortality.

Major bleedinge

 

Follow‐up: 

6 months

Study population

OR 0.50
(0.15 to 1.68)

1527
(1 RCT)

⊕⊕⊕⊝
Moderateb

The 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.

10 per 1000

5 per 1000
(2 to 17)

Health‐related quality of life

See comment

See comment

See comment

‐

RE‐COVER 2009 and RE‐COVER II 2014 did not measure health‐related quality of life.

*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; CTPA: computed tomographic pulmonary angiography; DVT: deep vein thrombosis; ISTH: International Society on Thrombosis and Haemostasis; OR: odds ratio; PE: pulmonary embolism; RCT: randomised controlled trial; V/Q: ventilation/perfusion; 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

aConfirmed by V/Q lung scanning, pulmonary angiography, or CTPA
bWe downgraded one level for imprecision due to the low number of events. The possibility of publication bias is not excluded but we did not consider it sufficient to downgrade the certainty of evidence.
cVTE includes clinically overt DVT and PE. Clinically overt DVT, confirmed by standard imaging techniques (venography, impedance plethysmography, whole‐leg compression ultrasound, proximal compression ultrasound); or clinically overt PE, confirmed by V/Q lung scanning, pulmonary angiography, or CTPA.
dClinically overt DVT confirmed by standard imaging techniques (venography, impedance plethysmography, whole‐leg compression ultrasound, proximal compression ultrasound). 
eAs defined by the ISTH (Schulman 2005): 1. Fatal bleeding, and/or 2. symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra‐articular or pericardial, or intramuscular with compartment syndrome, and/or 3. bleeding causing a fall in haemoglobin level of 20 g/L (1.24 mmol/L) or more, or leading to transfusion of two or more units of whole blood or packed red cells.

Figures and Tables -
Summary of findings 1. Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation for the treatment of pulmonary embolism
Navigate to table in Review
Summary of findings 2. Oral factor Xa inhibitors versus conventional anticoagulation for the treatment of pulmonary embolism

Oral factor Xa inhibitors versus conventional anticoagulation for the treatment of pulmonary embolism

Patient or population: people with a pulmonary embolism, confirmed by standard imaging techniques
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 inhibitors

Recurrent PEa

 

Follow‐up: 

0 to 12 months

Study population

OR 0.92
(0.66 to 1.29)

8186
(3 RCTs)

⊕⊕⊕⊝

Moderateb 

‐

18 per 1000

16 per 1000
(12 to 23)

Recurrent VTEc

 

Follow‐up: 

0 to 12 months

Study population

OR 0.83
(0.66 to 1.03)

11,416
(8 RCTs)

⊕⊕⊕⊝
Moderateb

 

2 of 8 studies reported no events

32 per 1000

26 per 1000
(21 to 33)

DVTd

 

Follow‐up: 

5 days to 12 months

Study population

OR 0.77
(0.48 to 1.25)

8151
(2 RCTs)

⊕⊕⊕⊝
Moderateb

‐

10 per 1000

7 per 1000
(5 to 12)

All‐cause mortality

 

Follow‐up: 

0 to 12 months

Study population

OR 1.16
(0.79 to 1.70)

4817
(1 RCT)

⊕⊕⊕⊝
Moderateb

‐

21 per 1000

24 per 1000
(16 to 35)

Major bleedinge

 

Follow‐up: 

0 to 12 months

Study population

OR 0.71
(0.36 to 1.41) 

11,447
(8 RCTs)

⊕⊕⊝⊝
Lowb,f

2 of 8 studies reported no events

23 per 1000

16 per 1000
(8 to 32)

Health‐related quality of life

See comment

See comment

See comment

‐

The studies did not measure health‐related quality of life.

*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; CTPA: computed tomographic pulmonary angiography; DVT: deep vein thrombosis; ISTH: International Society on Thrombosis and Haemostasis; OR: odds ratio; PE: pulmonary embolism; RCT: randomised controlled trial; V/Q: ventilation/perfusion; 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

aConfirmed by V/Q lung scanning, pulmonary angiography, or CTPA.
bWe downgraded one level for imprecision due to the low number of events. The possibility of publication bias is not excluded but we did not consider it sufficient to downgrade the certainty of evidence.
cVTE includes clinically overt DVT and PE. Clinically overt DVT, confirmed by standard imaging techniques (venography, impedance plethysmography, whole‐leg compression ultrasound, proximal compression ultrasound); or clinically overt PE, confirmed by V/Q lung scanning, pulmonary angiography, or CTPA.
dClinically overt DVT confirmed by standard imaging techniques (venography, impedance plethysmography, whole‐leg compression ultrasound, proximal compression ultrasound). 
eAs defined by the ISTH (Schulman 2005): 1. Fatal bleeding, and/or 2. symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra‐articular or pericardial, or intramuscular with compartment syndrome, and/or 3. bleeding causing a fall in haemoglobin level of 20 g/L (1.24 mmol/L) or more, or leading to transfusion of two or more units of whole blood or packed red cells.
fWe downgraded one level for serious inconsistency (I2 = 79% due to clinical heterogeneity).

Figures and Tables -
Summary of findings 2. Oral factor Xa inhibitors versus conventional anticoagulation for the treatment of pulmonary embolism
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Comparison 1. Oral DTIs versus conventional anticoagulation

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1.1 Recurrent pulmonary embolism Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

1.2 Recurrent venous thromboembolism Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

1.3 Deep vein thrombosis Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

1.4 Major bleeding Show forest plot

1

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 1. Oral DTIs versus conventional anticoagulation
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Comparison 2. Oral factor Xa inhibitors versus conventional anticoagulation

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

2.1 Recurrent pulmonary embolism Show forest plot

3

8186

Odds Ratio (M‐H, Random, 95% CI)

0.92 [0.66, 1.29]

2.2 Recurrent venous thromboembolism Show forest plot

8

11416

Odds Ratio (M‐H, Random, 95% CI)

0.83 [0.66, 1.03]

2.2.1 Non‐cancer associated pulmonary embolism

6

9898

Odds Ratio (M‐H, Random, 95% CI)

0.89 [0.68, 1.17]

2.2.2 Cancer associated pulmonary embolism

3

1518

Odds Ratio (M‐H, Random, 95% CI)

0.65 [0.42, 1.01]

2.3 Deep vein thrombosis Show forest plot

2

8151

Odds Ratio (M‐H, Random, 95% CI)

0.77 [0.48, 1.25]

2.4 All‐cause mortality Show forest plot

3

Odds Ratio (M‐H, Random, 95% CI)

Totals not selected

2.5 Major bleeding Show forest plot

8

11447

Odds Ratio (M‐H, Random, 95% CI)

0.71 [0.36, 1.41]

2.5.1 Non‐cancer associated pulmonary embolism

6

10152

Odds Ratio (M‐H, Random, 95% CI)

0.45 [0.19, 1.06]

2.5.2 Cancer associated pulmonary embolism

2

1295

Odds Ratio (M‐H, Random, 95% CI)

1.51 [0.84, 2.71]

2.6 Recurrent venous thromboembolism (subgroup analysis based on different types of factor Xa inhibitors) Show forest plot

8

11416

Odds Ratio (M‐H, Random, 95% CI)

0.82 [0.66, 1.04]

2.6.1 Apixaban

3

2459

Odds Ratio (M‐H, Random, 95% CI)

0.86 [0.54, 1.35]

2.6.2 Rivaroxaban

3

4981

Odds Ratio (M‐H, Random, 95% CI)

1.14 [0.75, 1.71]

2.6.3 Edoxaban

2

3976

Odds Ratio (M‐H, Random, 95% CI)

0.66 [0.48, 0.92]

2.7 Major bleeding (subgroup analysis based on different types of factor Xa inhibitors) Show forest plot

8

11447

Odds Ratio (M‐H, Random, 95% CI)

0.71 [0.36, 1.41]

2.7.1 Apixaban

3

2503

Odds Ratio (M‐H, Random, 95% CI)

0.36 [0.07, 1.91]

2.7.2 Rivaroxaban

3

4968

Odds Ratio (M‐H, Random, 95% CI)

0.49 [0.31, 0.79]

2.7.3 Edoxaban

2

3976

Odds Ratio (M‐H, Random, 95% CI)

1.44 [0.80, 2.58]

2.8 Recurrent venous thromboembolism (sensitivity analysis by including only studies at low risk of bias) Show forest plot

6

8992

Odds Ratio (M‐H, Random, 95% CI)

0.78 [0.54, 1.14]

2.9 Major bleeding (sensitivity analysis by including only studies at low risk of bias) Show forest plot

6

8979

Odds Ratio (M‐H, Random, 95% CI)

0.91 [0.42, 1.97]
Figures and Tables -
Comparison 2. Oral factor Xa inhibitors versus conventional anticoagulation
Navigate to table in Review