Oral direct thrombin inhibitors or oral factor Xa inhibitors versus conventional anticoagulants for the treatment of pulmonary embolism
Information
- DOI:
- https://doi.org/10.1002/14651858.CD010957.pub3Copy DOI
- Database:
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- Cochrane Database of Systematic Reviews
- Version published:
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- 14 April 2023see what's new
- Type:
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- Intervention
- Stage:
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- Review
- Cochrane Editorial Group:
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Cochrane Vascular Group
- Copyright:
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- Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Authors
Contributions of authors
ML: selected studies for inclusion, extracted data, assessed the risk of bias of studies, contacted authors for missing data, performed data analysis and interpretation, created the summary of findings tables using the GRADE approach, and updated the review.
JL: selected studies for inclusion, extracted data, assessed the risk of bias of the studies, performed data analysis and interpretation, and commented on the review.
XW: selected studies for inclusion, extracted data, assessed the risk of bias of the studies, contacted authors for missing data, and commented on the review.
XH: selected studies for inclusion, extracted data, assessed the risk of bias of the studies and commented on the review.
QW: selected studies for inclusion, extracted data, and commented on the review.
SX: selected studies for inclusion, extracted data, and commented on the review.
PY: commented on the review.
JT: commented on the review.
JFL: provided clinical consultation on the whole process.
PX: provided clinical consultation on the whole process.
KY: commented on the review, and provided methodological guidance on the whole process.
LY: selected studies for inclusion, commented on the review, and provided methodological guidance on the whole process.
Sources of support
Internal sources
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‐, Other
No internal sources of support
External sources
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Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK
The Cochrane Vascular editorial base is supported by the Chief Scientist Office.
Declarations of interest
ML: none known.
JL: none known.
XW: none known.
XH: none known.
QW: none known.
SX: none known.
PY: none known.
JT: none known.
JFL: none known.
PX: none known.
KY: none known.
LY: none known.
Acknowledgements
The review authors would like to thank Lindsay Robertson, James McCaslin, and colleagues for their contributions to previous versions of this review.
The review authors would like to thank Dr Cathryn Broderick, Dr Marlene Stewart and other Cochrane Vascular editors for their assistance and advice in completing this review. We thank Candida Fenton for designing and running the searches. We thank Yanfang Ma for helping select studies for inclusion.
The review authors would like to thank Faith Armitage for copy editing the review.
The review authors and the Cochrane Vascular editorial base are grateful to the following peer reviewers, and those who wished to remain anonymous, for their time and comments: Martin H Ellis MD, Hematology Institute and Blood Bank, Meir Medical Center, Kfar Saba and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Daniel Schimmel MD, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
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 | |
| 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 | |
| 2014 Feb 03 | Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of pulmonary embolism | Protocol | Lindsay Robertson, Patrick Kesteven | |
Differences between protocol and review
2023 version
For this update, we used a random‐effects model for all analyses as we expected clinical heterogeneity across studies. This may be due to different oral factor Xa inhibitors (e.g. apixaban, rivaroxaban, edoxaban), different conventional thrombin inhibitors in the control group (e.g. warfarin, dalteparin), different treatment durations (e.g. three, six, or 12 months). We amended 'standard anticoagulation' to 'conventional anticoagulation' throughout for consistency. In response to peer reviewer comments, we carried out an additional subgroup analysis based on the different types of factor Xa inhibitors.
2015 version
In a change from the protocol (Robertson 2014b), we excluded studies where treatment lasted fewer than three months. This was because a meta‐analysis of venous thromboembolism treatment strategies demonstrated an increased rate of recurrence after fewer than three months of anticoagulation but no significant difference with various longer periods of treatment (Boutitie 2011).
Keywords
MeSH
Medical Subject Headings (MeSH) Keywords
Medical Subject Headings Check Words
Humans;
PICOs
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
Comparison 1: Oral DTIs versus conventional anticoagulation, Outcome 1: Recurrent pulmonary embolism
Comparison 1: Oral DTIs versus conventional anticoagulation, Outcome 2: Recurrent venous thromboembolism
Comparison 1: Oral DTIs versus conventional anticoagulation, Outcome 3: Deep vein thrombosis
Comparison 1: Oral DTIs versus conventional anticoagulation, Outcome 4: Major bleeding
Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 1: Recurrent pulmonary embolism
Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 2: Recurrent venous thromboembolism
Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 3: Deep vein thrombosis
Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 4: All‐cause mortality
Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 5: Major bleeding
Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 6: Recurrent venous thromboembolism (subgroup analysis based on different types of factor Xa inhibitors)
Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 7: Major bleeding (subgroup analysis based on different types of factor Xa inhibitors)
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)
Comparison 2: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 9: Major bleeding (sensitivity analysis by including only studies at low risk of bias)
| 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 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with conventional anticoagulation | Risk with oral DTI | |||||
| Recurrent PEa
Follow‐up: 6 months | Study population | OR 1.02 | 1602 | ⊕⊕⊕⊝ | 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 | |||||
| Recurrent VTEc
Follow‐up: 6 months | Study population | OR 0.93 | 1602 | ⊕⊕⊕⊝ | 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 | |||||
| DVTd
Follow‐up: 6 months | Study population | OR 0.79 | 1602 | ⊕⊕⊕⊝ | 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 | |||||
| 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 | 1527 | ⊕⊕⊕⊝ | 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 | |||||
| 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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aConfirmed by V/Q lung scanning, pulmonary angiography, or CTPA | ||||||
| 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 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with conventional anticoagulation | Risk with oral factor Xa inhibitors | |||||
| Recurrent PEa
Follow‐up: 0 to 12 months | Study population | OR 0.92 | 8186 | ⊕⊕⊕⊝ Moderateb | ‐ | |
| 18 per 1000 | 16 per 1000 | |||||
| Recurrent VTEc
Follow‐up: 0 to 12 months | Study population | OR 0.83 | 11,416 | ⊕⊕⊕⊝
| 2 of 8 studies reported no events | |
| 32 per 1000 | 26 per 1000 | |||||
| DVTd
Follow‐up: 5 days to 12 months | Study population | OR 0.77 | 8151 | ⊕⊕⊕⊝ | ‐ | |
| 10 per 1000 | 7 per 1000 | |||||
| All‐cause mortality
Follow‐up: 0 to 12 months | Study population | OR 1.16 | 4817 | ⊕⊕⊕⊝ | ‐ | |
| 21 per 1000 | 24 per 1000 | |||||
| Major bleedinge
Follow‐up: 0 to 12 months | Study population | OR 0.71 | 11,447 | ⊕⊕⊝⊝ | 2 of 8 studies reported no events | |
| 23 per 1000 | 16 per 1000 | |||||
| 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 | ||||||
| aConfirmed by V/Q lung scanning, pulmonary angiography, or CTPA. | ||||||
| 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 | |
| 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] |
