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نقش مهار کننده‌های خوراکی مستقیم ترومبین یا مهار کننده‌های خوراکی فاکتور Xa برای درمان آمبولی ریوی

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Information

DOI:
https://doi.org/10.1002/14651858.CD010957.pub2Copy DOI
Database:
  1. Cochrane Database of Systematic Reviews
Version published:
  1. 04 December 2015see what's new
Type:
  1. Intervention
Stage:
  1. Review
Cochrane Editorial Group:
  1. Cochrane Vascular Group

Copyright:
  1. Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Authors

  • Lindsay Robertson

    Correspondence to: Department of Vascular Surgery, Freeman Hospital, Newcastle upon Tyne, UK

    [email protected]

    [email protected]

  • Patrick Kesteven

    Department of Haematology, Freeman Hospital, Newcastle upon Tyne, UK

  • James E McCaslin

    Northern Vascular Centre, Freeman Hospital, Newcastle upon Tyne, UK

Contributions of authors

LR: drafted the protocol, selected studies for inclusion, extracted data, assessed the quality of studies, performed data analysis and wrote the review.
PK: commented on the protocol, selected studies for inclusion, extracted data, assessed the quality of the studies and commented on the review.
JM: selected studies for inclusion, extracted data, assessed the quality of the studies and commented on the review.

Sources of support

Internal sources

  • No sources of support supplied

External sources

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

    The Cochrane Vascular editorial base is supported by the Chief Scientist Office.

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

    This project was supported by the NIHR, via Cochrane Programme Grant funding to Cochrane Vascular. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health

Declarations of interest

LR: none known.
PK: I have received consultancy fees for attendance at advisory boards of Boehringer‐Ingelheim, Bayer and Daiitchi‐Sankyo and payment from Bayer for lectures at the 2013 anticoagulation master class. My institution was paid travel/accommodation/meeting expenses by Boehringer‐Ingelheim for my attendance at the 2013 ISTH meeting and staff and NHS costs by Boehringer‐Ingelheim and Daiitchi‐Sankyo for involvement in phase III trials of novel anticoagulants in venous thrombosis. Since Summer 2014 I have declined all invitations to advisory boards, or lectures on behalf of the pharmaceutical industry.
JM: I received travel, course fees, accommodation and meals from Medtronic as part of the Medtronic University program. This is an educational program, and includes registration and attendance at the European Vascular Course 2012. No financial remuneration was received by myself, other than costs of travel, accommodation, course fees and meals.
I received sponsorship to attend the Vascular Society annual meeting 2012 and 2014 in the form of registration fees and accommodation/travel costs.
I received sponsorship to attend a stenting master class, the Verve clinical meeting in 2013, and a technology forum in Phoenix, Arizona from Gore Medical. This was in the form of travel, accommodation and meals. No other financial remuneration was received.
I received sponsorship to attend the LINC 2015 meeting in Leipzig, Germany from Abbott Medical in the form of registration, accommodation, travel and meals.
I am a co‐founder of UKETS, a trainee initiative, which receives funding through sponsorship from endovascular technology and simulation companies. The majority of this is non‐financial (i.e. the companies supply trainers on the courses or allow use of their simulators), although some direct financial input is received from Vascutek and Mentice and is used to run events. No profit is derived from this initiative.
Medtronic, Gore Medical, Abbott Medical, Vascutek and Mentice do not manufacture any pharmaceuticals, including anticoagulants.

Acknowledgements

We would like to thank Dr Karen Welch for searching the Cochrane Vascular Specialised Register and the Cochrane Central Register of Controlled Trials. We would also like to thank Dr Marlene Stewart, Managing Editor of Cochrane Vascular, for her assistance and advice in completing this review

Version history

Published

Title

Stage

Authors

Version

2023 Apr 14

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

Review

Meixuan Li, Jing Li, Xiaoqin Wang, Xu Hui, Qi Wang, Shitong Xie, Peijing Yan, Jinhui Tian, Jianfeng Li, Ping Xie, Kehu Yang, Liang Yao

https://doi.org/10.1002/14651858.CD010957.pub3

2015 Dec 04

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

Review

Lindsay Robertson, Patrick Kesteven, James E McCaslin

https://doi.org/10.1002/14651858.CD010957.pub2

2014 Feb 03

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

Protocol

Lindsay Robertson, Patrick Kesteven

https://doi.org/10.1002/14651858.CD010957

Differences between protocol and review

In a change from the protocol (Robertson 2014b), we excluded studies where treatment was for less than three months because a meta‐analysis of venous thromboembolism treatment strategies has demonstrated an increased rate of recurrence after less than three months anticoagulation but no significant difference with various longer periods of treatment (Boutitie 2011).

Keywords

MeSH

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.

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

'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.

'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.

Comparison 1 Oral DTI versus standard anticoagulation, Outcome 1 Recurrent pulmonary embolism.
Figures and Tables -
Analysis 1.1

Comparison 1 Oral DTI versus standard anticoagulation, Outcome 1 Recurrent pulmonary embolism.

Comparison 1 Oral DTI versus standard anticoagulation, Outcome 2 Recurrent venous thromboembolism.
Figures and Tables -
Analysis 1.2

Comparison 1 Oral DTI versus standard anticoagulation, Outcome 2 Recurrent venous thromboembolism.

Comparison 1 Oral DTI versus standard anticoagulation, Outcome 3 Deep vein thrombosis.
Figures and Tables -
Analysis 1.3

Comparison 1 Oral DTI versus standard anticoagulation, Outcome 3 Deep vein thrombosis.

Comparison 1 Oral DTI versus standard anticoagulation, Outcome 4 Major bleeding.
Figures and Tables -
Analysis 1.4

Comparison 1 Oral DTI versus standard anticoagulation, Outcome 4 Major bleeding.

Comparison 2 Oral factor Xa versus standard anticoagulation, Outcome 1 Recurrent pulmonary embolism.
Figures and Tables -
Analysis 2.1

Comparison 2 Oral factor Xa versus standard anticoagulation, Outcome 1 Recurrent pulmonary embolism.

Comparison 2 Oral factor Xa versus standard anticoagulation, Outcome 2 Recurrent venous thromboembolism.
Figures and Tables -
Analysis 2.2

Comparison 2 Oral factor Xa versus standard anticoagulation, Outcome 2 Recurrent venous thromboembolism.

Comparison 2 Oral factor Xa versus standard anticoagulation, Outcome 3 Deep vein thrombosis.
Figures and Tables -
Analysis 2.3

Comparison 2 Oral factor Xa versus standard anticoagulation, Outcome 3 Deep vein thrombosis.

Comparison 2 Oral factor Xa versus standard anticoagulation, Outcome 4 All‐cause mortality.
Figures and Tables -
Analysis 2.4

Comparison 2 Oral factor Xa versus standard anticoagulation, Outcome 4 All‐cause mortality.

Comparison 2 Oral factor Xa versus standard anticoagulation, Outcome 5 Major bleeding.
Figures and Tables -
Analysis 2.5

Comparison 2 Oral factor Xa versus standard anticoagulation, Outcome 5 Major bleeding.

Summary of findings for the main comparison. Oral direct thrombin inhibitors (DTIs) versus standard anticoagulation for the treatment of pulmonary embolism

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

Patient or population: patients with a pulmonary embolism, confirmed by standard imaging techniques
Setting: hospital
Intervention: oral direct thrombin inhibitors (DTIs)
Comparison: standard anticoagulation

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with standard anticoagulation

Risk with Oral DTI

Recurrent pulmonary embolism1

Study population

OR 1.02
(0.50 to 2.04)

1602
(1 RCT)

⊕⊕⊕⊕
HIGH2 3

The data from the 2 RECOVER studies were taken from 1 pooled analysis and are therefore shown as 1 study

20 per 1000

20 per 1000
(10 to 40)

Recurrent venous thromboembolism
4

Study population

OR 0.93
(0.52 to 1.66)

1602
(1 RCT)

⊕⊕⊕⊕
HIGH2 3

The data from the 2 RECOVER studies were taken from 1 pooled analysis and are therefore shown as 1 study

31 per 1000

29 per 1000
(16 to 50)

Deep vein thrombosis5

Study population

OR 0.79
(0.29 to 2.13)

1602
(1 RCT)

⊕⊕⊕⊕
HIGH2 3

The data from the 2 RECOVER studies were taken from 1 pooled analysis and are therefore shown as 1 study

11 per 1000

9 per 1000
(3 to 23)

All‐cause mortality

See comment

See comment

See comment

The 2 RECOVER studies did not report on all‐cause mortality

Major bleeding6

Study population

OR 0.50
(0.15 to 1.68)

1527
(1 RCT)

⊕⊕⊕⊕
HIGH2 3

The data from the 2 RECOVER studies were taken from 1 pooled analysis and are therefore shown as 1 study

10 per 1000

5 per 1000
(2 to 17)

Health‐related quality of life

See comment

See comment

See comment

The 2 RECOVER 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; OR: odds ratio; PE: pulmonary embolism; RCT: randomised controlled trial; VTE: venous thromboembolism

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: 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 quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1Confirmed by ventilation–perfusion lung scanning, angiography or spiral computed tomography of pulmonary arteries.
2Risk of bias was 'unclear' for random sequence generation but we did not consider it sufficient to downgrade the quality of evidence.
3The possibility of publication bias is not excluded but we did not consider it sufficient to downgrade the quality of evidence.
4Clinically overt DVT, confirmed by standard imaging techniques including proximal leg vein ultrasound scan or D‐dimer test, or both; or clinically overt pulmonary embolism, confirmed by ventilation–perfusion lung scanning, angiography or spiral computed tomography of pulmonary arteries.
5Clinically overt DVT confirmed by standard imaging techniques (proximal leg vein ultrasound scan, venography) or D‐dimer test, or both.
6As 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 points 1 to 3.

Figures and Tables -
Summary of findings for the main comparison. Oral direct thrombin inhibitors (DTIs) versus standard anticoagulation for the treatment of pulmonary embolism
Summary of findings 2. Oral factor Xa inhibitors versus standard anticoagulation for the treatment of pulmonary embolism

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

Patient or population: patients with a pulmonary embolism, confirmed by standard imaging techniques
Setting: hospital
Intervention: oral factor Xa inhibitors
Comparison: standard anticoagulation

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with standard anticoagulation

Risk with oral factor Xa

Recurrent pulmonary embolism1

Study population

OR 1.08
(0.46 to 2.56)

4509
(2 RCTs)

⊕⊕⊕⊝
MODERATE 2 3 4

22 per 1000

24 per 1000
(10 to 55)

Recurrent venous thromboembolism5

Study population

OR 0.85
(0.63 to 1.15)

6295
(3 RCTs)

⊕⊕⊕⊕
HIGH 2 4

24 per 1000

20 per 1000
(15 to 27)

Deep vein thrombosis6

Study population

OR 0.72
(0.39 to 1.32)

4509
(2 RCTs)

⊕⊕⊕⊕
HIGH 4

11 per 1000

8 per 1000
(4 to 15)

All‐cause mortality

Study population

OR 1.16
(0.79 to 1.70)

4817
(1 RCT)

⊕⊕⊕⊝
MODERATE 2 4 7

16 per 1000

19 per 1000
(13 to 27)

Major bleeding8

Study population

OR 0.97
(0.59 to 1.62)

4507
(2 RCTs)

⊕⊕⊕⊕
HIGH 2 4

14 per 1000

13 per 1000
(8 to 22)

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; OR: odds ratio; PE: pulmonary embolism; RCT: randomised controlled trial; VTE: venous thromboembolism

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: 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 quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1Confirmed by ventilation–perfusion lung scanning, angiography or spiral computed tomography of pulmonary arteries.
2Risk of bias was 'unclear' for random sequence generation but we did not consider it sufficient to downgrade the quality of evidence.
3Statistical heterogeneity was found for this outcome and could not be explained.
4The possibility of publication bias is not excluded but we did not consider it sufficient to downgrade the quality of evidence as only two studies were included in this comparison.
5Clinically overt DVT, confirmed by standard imaging techniques including proximal leg vein ultrasound scan or D‐dimer test, or both; or clinically overt pulmonary embolism, confirmed by ventilation–perfusion lung scanning, angiography or spiral computed tomography of pulmonary arteries.
6Clinically overt DVT confirmed by standard imaging techniques (proximal leg vein ultrasound scan, venography) or D‐dimer test, or both.
7Quality of evidence downgraded to moderate as only one study was included.
8As 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 points 1 to 3.

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

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Recurrent pulmonary embolism Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2 Recurrent venous thromboembolism Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3 Deep vein thrombosis Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

4 Major bleeding Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Figures and Tables -
Comparison 1. Oral DTI versus standard anticoagulation
Comparison 2. Oral factor Xa versus standard anticoagulation

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Recurrent pulmonary embolism Show forest plot

2

4509

Odds Ratio (M‐H, Random, 95% CI)

1.08 [0.46, 2.56]

2 Recurrent venous thromboembolism Show forest plot

3

6295

Odds Ratio (M‐H, Fixed, 95% CI)

0.85 [0.63, 1.15]

3 Deep vein thrombosis Show forest plot

2

4509

Odds Ratio (M‐H, Fixed, 95% CI)

0.72 [0.39, 1.32]

4 All‐cause mortality Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

5 Major bleeding Show forest plot

2

4507

Odds Ratio (M‐H, Fixed, 95% CI)

0.97 [0.59, 1.61]

Figures and Tables -
Comparison 2. Oral factor Xa versus standard anticoagulation