Supplementary appendix · A Khorana, Andres Munoz, Benjamin Brenner, Ajay Kakkar, Hanadi Rafii,...
Transcript of Supplementary appendix · A Khorana, Andres Munoz, Benjamin Brenner, Ajay Kakkar, Hanadi Rafii,...
Supplementary appendixThis appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.
Supplement to: Farge D, Frere C, Connors JM, et al. 2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol 2019; published online Sept 3. http://dx.doi.org/10.1016/S1470-2045(19)30336-5.
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2019 International Clinical Practice Guidelines (ITAC-
CPGs) for the Treatment and Prophylaxis of Venous
Thromboembolism in Patients with Cancer
Dominique Farge*, Corinne Frere*, Jean M Connors, Cihan Ay, Alok
A Khorana, Andres Munoz, Benjamin Brenner, Ajay Kakkar, Hanadi
Rafii, Susan Solymoss, Dialina Brilhante, Manuel Monreal, Henri
Bounameaux, Ingrid Pabinger and James Douketis.
*equal contribution
Supplementary Appendix
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Table of Contents Guideline development methodology ............................................................................................. 3
Literature search strategy and article selection ............................................................................... 6
Data Extraction ............................................................................................................................. 16
Conclusions Tables ........................................................................................................................ 69
KHORANA Score and expanded models………………………………………………………………………………………..88
Prohibited concomitant medications in randomized controlled trials ............................................ 89
ITAC Advisory Panel ...................................................................................................................... 90
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Guideline development methodology The methodology used to prepare the current 2019 iteration of the International Initiative on
Thrombosis and Cancer (ITAC) Clinical Practice Guidelines (CPGs) for the treatment and prevention of
Venous Thromboembolism (VTE) in cancer patients was developed by the Institut National du Cancer
(INCa). This methodology was used for the first publication of the CPGs in 2013, and then for the CPGs
update published in 2016. Preparation of the 2019 CPGs was directed by 2 coordinators (Prof.
Dominique Farge and Prof. James Douketis) with 2 methodologists (Dr. Corinne Frere and Dr. Hanadi
Rafii) and, with the collaboration of all the steering committee working group of ITAC experts:
• Dominique Farge, MD, PhD, France (coordinator) • James Douketis, MD, Canada (coordinator) • Corinne Frere MD, PhD, France (methodologist) • Jean M Connors, MD, PhD, USA • Cian Ay, MD, Austria • Alok A Khorana, MD, USA • Andres Munoz, MD, Spain • Benjamin Brenner, MD, Israel • Ajay Kakkar, B.Sc., M.B.B.S., PhD, UK • Hanadi Rafii, MD, Lebanon (methodologist) • Susan Solymoss, MD, Canada • Dialina Brilhante, MD, Portugal • Manuel Monreal, MD, Spain • Henri Bounameaux, MD, Switzerland • Ingrid Pabinger, MD, PhD, Austria
Search strategy and selection criteria. The update literature search for all studies published between
January 2015 and December 2018 was performed by INCa using the Pubmed Central database with
the following subject headings: cancer, venous thromboembolism, anticoagulant drugs and devices,
and the Medline database using a detailed search strategy. Members of the working group had the
opportunity to add additional references that the bibliographic search did not identify. Other clinical
practice guidelines addressing overlapping clinical questions were consulted. The literature search was
limited to publications in English. Meta-analyses, systematic reviews, randomized clinical trials, or non-
randomized prospective or retrospective studies in the absence of randomized clinical trials, were
included. Editorials, letters to the editor, case reports, publications without an abstract, press releases
and animal studies were excluded. This review of the literature is added to the previous search of all
MEDLINE* and several other databases (eg EMBASE,CCTR), in French or English, which spanned
January 1996 to January 2015, and was reviewed in the first published 2013 International guidelines
in JTH (JTH 2013; 1:56-71 and JTH 2013; 11:71-80) and the 2016 update (Lancet oncology 2016; e462-
466), using the Grading of Recommendations Assessment, Development and Evaluation (GRADE)
methodology.
Articles were selected for potential inclusion based on article selection grids that were designed for
each clinical question during the development of the guideline methodology.
Critical appraisal and data extraction. Selected articles underwent a critical appraisal that included
an assessment of the articles’ methodological strength and clinical relevance, which was performed by
the two methodologist (CF and HR) and then approved by the rest of the working group.
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Data were extracted into evidence tables by two independent reviewers (CF and HR), and
discrepancies between the 2 methodologists were identified and resolved by a review of the data and
discussion.
Conclusion tables were assembled by the working group to guide the development of the
recommendations. These tables summarized the evidence for each clinical question based on the
critical appraisal and evidence tables. The conclusion table for each clinical question included the list
of studies with new evidence highlighted, a summary of findings, rankings of the study quality (low,
medium, high) based on study type, methodological strength, and sample size; the degree of
agreement between studies (consistency); and an assessment of the patient population (directness)—
ie, patients with cancer versus an unselected study population, which was recorded as a study
limitation, and publication bias. These elements were later used to rank the level of evidence according
to the GRADE scale. Any disagreements were successfully resolved by group discussion. All evidence
tables and conclusion tables were reviewed and approved on June 28th, 2018 and their final version
on December 4th, 2018 by all working group members.
Consensus development and grading system. Recommendations were drafted over three consensus
meetings (July 19th, 2018; September 24th 2018 and December 4th 2018). Prior to the first consensus
meeting, working group members were asked to evaluate each recommendation from the 2016
iteration of the guidelines against new published data summarized in the conclusion tables. The
working group members were to indicate whether the recommendation should remain unchanged or
formulate what update they thought should be made, and why. These responses were collected and
redistributed to the group for consideration prior to the consensus meeting.
Once drafted, the recommendations were ranked using two different scoring systems within the
Grading of Recommendations Assessment Development and Evaluation (GRADE) scale: 1) a quality of
evidence grade (A-D), and 2) a level of recommendation ranking that reflects the degree of confidence
that the benefits of adherence to a recommendation will outweigh any undesirable effects (Grade 1
guideline, strong; Grade 2 guideline, weak). In the absence of any clear scientific evidence, judgment
was based on the professional experience and consensus of the international experts within the
working group and defined as “Best Clinical Practice” (Guidance). Additional economic considerations
were taken into account during the development and ranking of the recommendations to offer
treatment alternatives when possible that address potential economic barriers to treatment.
The working group agreed a priori that if a consensus could not be reached, this would be reported in
the guidelines, with an explanation of the point or points of contention. No such conflict arose, and all
recommendations represent a consensus reached by the entirety of the group.
Review process The Guidelines were peer-reviewed in December 2018 by an advisory panel of 83
independent international experts, encompassing all medical and surgical specialties involved in the
management of patients with cancer, and by three patients advocate and nurses. The experts were
identified on the basis of their knowledge, clinical expertise, publication record, and contributions to
the field. As performed in the previous ITAC-CME CPGs iterations (JTH 2013; 1:56-71 - JTH 2013; 11:71-
80 -Lancet oncology 2016; e462-466), panel members were given an evaluation grid to rank their
agreement with the recommendations (nine point scale, from don’t agree to agree), and provide
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comments. This process enabled us to consider both practitioner and patient values and preferences.
Discrepancies in opinion between the reviewers and the members of the working group were resolved
by consensus during a final meeting. The International Society on Thrombosis and Haemostasis has
reviewed and endorsed the methodology used in creating these guidelines.
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Literature search strategy and article selection Literature search strategy
Q1: Initial treatment of established VTE (up to 10 days of anticoagulation) Q2: Early maintenance (3 to 6 months) and long-term (beyond 6 months) treatment of established VTE
Search equation Medline® (Ovid) Search description
1. exp neoplasms/ 2. (cancer$1 or carcinoma$1 or adenocarcinoma$1 or tumour$1 or tumor$1 or malignant$).ti. 3. 1 or 2
Search module Cancer
4. thrombosis/ 5. venous thrombosis/ 6. thromboembolism/ 7. Pulmonary Embolism/ 8. (thrombosis$ or DVT or (pulmonary adj1 embolism) or VTE or thromboembolism$).ti. 9. or/4-8 10. exp Thrombolytic Therapy/ 11. exp Antithrombins/ 12. exp Heparin, Low-Molecular-Weight/ 13. exp anticoagulants/ 14. ((novel or new) adj2 (anticoag$ or anti coag$)).mp. 15. ((new or novel or direct) adj4 (oral anticoag$ or oral anti coag$)).mp. 16. warfarin.mp. 17. vitamin K.mp. 18. tinzaparin.mp. 19. reviparin.mp. 20. Fondaparinux.mp. 21. dabigatran.mp. 22. rivaroxaban.mp. 23. apixaban.mp. 24. edoxaban.mp. 25. or/10-24
"Treatment of VTE venous Thromboembolism" (1)
26. thrombosis/dt, th 27. venous thrombosis/dt, th 28. thromboembolism/dt, th 29. pulmonary embolism/dt, th 30. ((thrombos$ or DVT or (pulmonary adj1 embolism) or VTE or thromboembolism$) and (treatment$1 or therapy or therapeutic)).ti. 31. or/26-30
"Treatment of VTE venous Thromboembolism" (2)
32. 3 and 9 and 25 33. 3 and 31 34. 32 or 33
"Treatment of VTE venous Thromboembolism" (1 ) or (2)
35. limit 34 to (human and (english or french) and ed=20101101-20160131) 36. editorial.pt. 37. letter.pt. 38. news.pt. 39. case reports.pt. 40. in-vitro.pt. 41. animal/ 42. or/36-41 43. 35 not 42
Limitations (date, language) and exclusion filters
44. randomized controlled trial.pt. 45. random allocation.de. 46. random$.ti. 47. double-blind method.de. 48. or/44-47
Search for randomized trials
49. meta-analysis.pt. 50. meta-analy$.ti. 51. metaanaly$.ti. 52. (systematic adj3 overview$).tw. 53. (systematic adj3 review$).tw. 54. (quantitative adj3 overview$).tw. 55. (quantitative adj3 review$).tw.
Search for Meta-analyses/systematic reviews
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56. or/49-55 57. 43 and 48 58. 43 and 56
Q3: Treatment of VTE recurrence – vena cava filters
In patients with cancer
Search equation Medline® (Ovid) Search description
1. exp neoplasms/ 2. (cancer$1 or carcinoma$1 or adenocarcinoma$1 or tumour$1 or tumor$1 or malignan$).ti. 3. 1 or 2
Search module Cancer
4. thrombosis/ 5. venous thrombosis/ 6. thromboembolism/ 7. Pulmonary Embolism/ 8. (thrombos$ or DVT or (pulmonary adj1 embolism) or VTE or thromboembol$).ti. 9. Venous Thromboembolism/ 10. or/4-9
Search module venous thromboembolism
11. Vena Cava Filters/ 12. (filter$1 adj (umbrella or vena cava)).ti. 13. or/11-12 14. 3 and 10 and 13
"Vena cava filters"
15. limit 14 to (human and (english or french) and ed=20101101-20160131) 16. editorial.pt. 17. letter.pt. 18. news.pt. 19. case reports.pt. 20. in-vitro.pt. 21. animal/ 22. or/16-21 23. 15 not 22
Limitations (date, language) and exclusion filters
24. randomized controlled trial.pt. 25. random allocation.de. 26. random$.ti. 27. double-blind method.de. 28. 24 or 25 or 26 or 27
Search for randomized trials
29. meta-analysis.pt. 30. meta-analy$.ti. 31. metaanaly$.ti. 32. (systematic adj3 overview$).tw. 33. (systematic adj3 review$).tw. 34. (quantitative adj3 overview$).tw. 35. (quantitative adj3 review$).tw. 36. or/29-35 37. 23 and 28 38. 23 and 36
Search for Meta-analyses/systematic reviews
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In patients without cancer
Search equation Medline® (Ovid) Search description
1. thrombosis/ 2. venous thrombosis/ 3. thromboembolism/ 4. Pulmonary Embolism/ 5. (thrombos$ or DVT or (pulmonary adj1 embolism) or VTE or thromboembol$).ti. 6. Venous Thromboembolism/ 7. or/1-6
Search module: venous thromboembolism
8. Vena Cava Filters/ 9. (filter$1 adj (umbrella or vena cava)).ti. 10. or/8-9 11. 7 and 10
"Vena cava filters"
12. limit 11 to (human and (english or french) and ed=20101101-20160131) 13. editorial.pt. 14. letter.pt. 15. news.pt. 16. case reports.pt. 17. in-vitro.pt. 18. animal/ 19. or/13-18 20. 12 not 19
Limitations (date, language) and exclusion filters
21. meta-analysis.pt. 22. meta-analy$.ti. 23. metaanaly$.ti. 24. (systematic adj3 overview$).tw. 25. (systematic adj3 review$).tw. 26. (quantitative adj3 overview$).tw. 27. (quantitative adj3 review$).tw. 28. or/21-27 29. 20 and 28
Search for Meta-analyses/systematic reviews
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Q4: Prophylaxis of VTE in surgical cancer patients Q5: Prophylaxis of VTE in medical cancer patients
Search equation Medline® (Ovid) Search description
1. exp neoplasms/ 2. (cancer$1 or carcinoma$1 or adenocarcinoma$1 or tumour$1 or tumor$1 or malignan$).ti. 3. 1 or 2
Search module Cancer
4. thrombosis/ 5. venous thrombosis/ 6. thromboembolism/ 7. Pulmonary Embolism/ 8. (thrombos$ or DVT or (pulmonary adj1 embolism) or VTE or thromboembol$).ti. 9. or/4-8
Search module Venous Thromboembolism
10. thrombosis/pc 11. venous thrombosis/pc [Prevention & Control] 12. thromboembolism/pc [Prevention & Control] 13. Pulmonary Embolism/pc [Prevention & Control] 14. 10 or 11 or 12 or 13 15. ((thrombos$ or DVT or VTE or thromboembol$ or (pulmonary adj1 embolism)) adj4 (recurrence or recurrent or second$) adj2 (risk$ or prevent$ or prophylaxy or prophylaxi$)).ti,ab. 16. (risk$ or prevent$ or prophylaxy or prophylaxi$).ti,ab. 17. ((thrombos$ or DVT or VTE or thromboembol$ or (pulmonary adj1 embolism)) adj4 (recurrence or recurrent or second$)).ti,ab. 18. 3 and 9 and 16 19. 3 and 15 20. 3 and 14 and 17 21. 18 or 19 or 20
"Venous thromboembolism prophylaxis"
22. editorial.pt. 23. letter.pt. 24. news.pt. 25. case reports.pt. 26. in vitro.pt. 27. animal/ 28. or/22-27 29. 21 not 28 30. limit 29 to (human and (english or french) and ed=20101101-20160131)
Limitations (date, language) and exclusion filters
31. randomized controlled trial.pt. 32. random allocation.de. 33. random$.ti. 34. double-blind method.de. 35. 31 or 32 or 33 or 34
Search for Randomized trials
36. meta-analysis.pt. 37. meta-analy$.ti. 38. metaanaly$.ti. 39. (systematic adj3 overview$).tw. 40. (systematic adj3 review$).tw. 41. (quantitative adj3 overview$).tw. 42. (quantitative adj3 review$).tw. 43. or/36-42
Search for Meta-analyses/systematic reviews
44. clinical trials, phase iii/ 45. clinical trial, phase iii.pt. 46. (phase III or phase 3).ti. 47. 44 or 45 or 46
Search for Phase III Randomized trials
48. exp "cohort studies"/ 49. prospective stud$.ti. 50. prospective studies/ 51. 48 or 49 or 50 52. 30 and 35 53. 30 and 43 54. 30 and 47 55. 30 and 51
Search for Prospective studies
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Q6: Treatment of established catheter-related thrombosis Q7: Prophylaxis of catheter-related thrombosis
Search equation Medline® (Ovid) Search description
1. exp neoplasms/ 2. (cancer$1 or carcinoma$1 or adenocarcinoma$1 or tumour$1 or tumor$1 or malignan$).ti. 3. 1 or 2
Search module Cancer
4. thrombosis/ 5. venous thrombosis/ 6. thromboembolism/ 7. Pulmonary Embolism/ 8. (thrombos$ or DVT or (pulmonary adj1 embolism) or VTE or thromboembol$).ti. 9. or/4-8
Search module Venous Thromboembolism
10. Catheterization/ 11. Catheterization, Central Venous/ 12. (Catheterization$ or CCV or (central adj1 venous) or catheter$).ti. 13. or/10-12 14. 3 and 9 and 13
Search module Catheter
15. limit 14 to (human and (english or french) and ed=20101101-20160131) 16. editorial.pt. 17. letter.pt. 18. news.pt. 19. case reports.pt. 20. in-vitro.pt. 21. animal/ 22. or/16-21 23. 15 not 22
Limitations (date, language) and exclusion filters
24. randomized controlled trial.pt. 25. random allocation.de. 26. random$.ti. 27. double-blind method.de. 28. 24 or 25 or 26 or 27
Search for Randomized trials
29. meta-analysis.pt. 30. meta-analy$.ti. 31. metaanaly$.ti. 32. (systematic adj3 overview$).tw. 33. (systematic adj3 review$).tw. 34. (quantitative adj3 overview$).tw. 35. (quantitative adj3 review$).tw. 36. or/29-35 37. 23 and 28 38. 23 and 36
Search for Meta-analyses/systematic reviews
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Thrombolytics
Search equation Medline® (Ovid) Search description
1. exp neoplasms/ 2. (cancer$1 or carcinoma$1 or adenocarcinoma$1 or tumour$1 or tumor$1 or malignan$).ti. 3. 1 or 2
Search module Cancer
4. thrombosis/ 5. venous thrombosis/ 6. thromboembolism/ 7. Pulmonary Embolism/ 8. (thrombos$ or DVT or (pulmonary adj1 embolism) or VTE or thromboembol$).ti. 9. Venous Thromboembolism/ 10. or/4-9
Search module Venous Thromboembolism
11. Thrombolytic Therapy/ or thrombolysis.ti. 12. 3 and 10 and 11
Search module Thrombolysis
13. limit 12 to (human and (english or french) and ed=20101101-20160131) 14. editorial.pt. 15. letter.pt. 16. news.pt. 17. case reports.pt. 18. in-vitro.pt. 19. animal/ 20. or/14-19 21. 13 not 20
Limitations (date, language) and exclusion filters
22. randomized controlled trial.pt. 23. random allocation.de. 24. random$.ti. 25. double-blind method.de. 26. 22 or 23 or 24 or 25
Search for Randomized trials
27. meta-analysis.pt. 28. meta-analy$.ti. 29. metaanaly$.ti. 30. (systematic adj3 overview$).tw. 31. (systematic adj3 review$).tw. 32. (quantitative adj3 overview$).tw. 33. (quantitative adj3 review$).tw. 34. or/27-33 35. 21 and 26 36. 21 and 34
Search for Meta-analyses/systematic reviews
Q8: Special situations
(See all above Medline® equations)
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Article Selection
Q1: Initial treatment of established VTE (up to 10 days of anticoagulation)
Inclusion criteria Exclusion criteria
Population Patients with: • cancer (solid tumors) • acute leukemia • multiple myeloma • lymphoma
Confirmed VTE (deep-vein thrombosis and pulmonary embolism)
Patients treated by all cancer-associated therapies: • chemotherapy • growth factors • hormonal therapy • targeted therapy (anti-angiogenics,
monoclonal antibodies) • surgery • radiotherapy
Initial treatment of VTE corresponds to the first 10 days of anticoagulation
Patients with a tumor thrombus, or a history of cancer in remission for more than 5 years
Patients with no VTE (prophylaxis) Catheter-related thrombosis Superficial-vein thrombosis
Intervention UFH VKA LMWH Fondaparinux Thrombolytic Vena cava filter External compression device
Drugs or devices that are not marketed
Outcomes Rates of VTE (de novo VTE or VTE extension) Major and minor bleeding Thrombocytopenia Death
Catheter-related thrombosis Superficial-vein thrombosis
Q2: Early maintenance (3 to 6 months) and long-term (beyond 6 months) treatment of established VTE
Inclusion criteria Exclusion criteria
Population Patients with: • cancer (solid tumors) • acute leukemia • myeloma • lymphoma
Confirmed VTE (deep-vein thrombosis and pulmonary embolism)
Patients treated by all cancer-associated therapies: • chemotherapy • growth factors • hormonal therapy • targeted therapy (anti-angiogenics,
monoclonal antibodies) • surgery • radiotherapy
Patients with tumor thrombus, or a history of cancer in remission for more than 5 years
Patients with no VTE (prophylaxis) Catheter-related thrombosis Superficial-vein thrombosis
Intervention VKA LMWH (long-term use) Idraparinux DOAC
Drugs or devices that are not marketed
Outcomes Rates of VTE: • de novo VTE • VTE extension
Major and minor bleeding Thrombocytopenia Death
Catheter-related thrombosis Superficial-vein thrombosis
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Q3: Treatment of VTE recurrence in cancer patients under anticoagulation
Inclusion criteria Exclusion criteria
Population Patients with: • cancer (solid tumor) • acute leukemia • multiple myeloma • lymphoma
Confirmed VTE (deep-vein thrombosis and pulmonary embolism)
Patients treated by all cancer-associated therapies: • chemotherapy • growth factors • hormonal therapy • targeted therapy (anti-angiogenics,
monoclonal antibodies) • surgery • radiotherapy
Patients with a tumor thrombus, or a history of cancer in remission for more than 5 years
Patients with no VTE (prophylaxis) Catheter-related thrombosis Superficial-vein thrombosis
Intervention VKA Vena cava filter DOACs
Drugs or devices that are not marketed
Outcomes Rate of VTE: • de novo VTE • VTE extension
Major and minor bleeding Thrombocytopenia Death
Catheter-related thrombosis Superficial-vein thrombosis
Q4: Prophylaxis of VTE in surgical cancer patients
Inclusion criteria Exclusion criteria
Population Cancer patients in a surgical setting with laparotomy or laparoscopy
Patients with a history of cancer in remission for more than 5 years
No cancer Patients with VTE Patients with a full dose of anticoagulant Surgery performed for non-cancer treatment
Intervention UFH LMWH Fondaparinux External compression device Duration of drug prophylaxis DOAC
Drugs or devices that are not marketed
Outcomes De novo VTE Major and minor bleeding Thrombocytopenia Death
Catheter-related thrombosis Superficial-vein thrombosis
Q5: Prophylaxis of VTE in medical cancer patients
Inclusion criteria Exclusion criteria
Population Hospitalized cancer patients Children with ALL treated with L-asparaginase Ambulatory patients treated with • chemotherapy • thalidomide or lenalidomide
Cancer in remission for more than 5 years Non-cancer patients Patients with VTE Patients treated with a full dose of anticoagulant
Intervention UFH LMVH Fondaparinux External compression device DOAC
Drugs or devices that are not marketed
Outcomes De novo VTE Catheter-related thrombosis
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Major and minor bleeding Thrombocytopenia Death
Superficial-vein thrombosis
Q6: Treatment of established catheter-related thrombosis
Inclusion criteria Exclusion criteria
Population Cancer patients with a central venous catheter: • totally implantable venous access system • tunneled catheter • prophetically inserted central catheter • with open-ended or valved distal extremity
Patients treated by all cancer-associated therapies: • chemotherapy • growth factors • hormonal therapy • targeted therapy (anti-angiogenics, monoclonal
antibodies) • surgery • radiotherapy
Cancer in remission for more than 5 years Central catheter inserted in non-cancer patients Dialysis catheter Peripheral intravenous catheter
Intervention LMWH VKA CVC removal Systemic thrombolytic DOAC
Catheter flushing with • normal saline or heparinized saline solution • thrombolytic • taurolidine-citrate lock solution
Outcomes Proven CRT: • de novo CRT • CRT extension • PE related to CRT
Toxicities: • major and minor bleeding • thrombocytopenia • death
Catheter obstruction without parietal thrombosis DVT of lower limbs PE not related to CRT Superficial-vein thrombosis
Q7: Prophylaxis of catheter-related thrombosis
Inclusion criteria Exclusion criteria
Population Cancer patients with a central venous catheter: • totally implantable venous access system • tunneled catheter • peripherically inserted central catheter • with open-ended or valved distal extremity
Cancer in remission for more than 5 years Central catheter inserted in non-cancer patients Dialysis catheter Peripheral intravenous catheter Patients with VTE or CRT Patients treated with full dose of anticoagulant
Intervention Low dose of VKA Low dose of UFH Low dose of LMWH Type of CVC + insertion site Thrombolytic
Catheter flushing with • normal saline or heparinized saline solution • thrombolytic • taurolidine-citrate lock solution • antibiotics
Full dose of anticoagulant Outcomes De novo proven CRT
PE related to CRT Toxicities: • major and minor bleeding • thrombocytopenia • death
Catheter obstruction without parietal thrombosis DVT of lower limbs PE not related to CRT Superficial-vein thrombosis
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Q8: Special situations
Inclusion criteria Exclusion criteria
Population Cancer patients with: • thrombocytopenia • brain tumors • renal failure
Pregnant women with cancer
Not applicable
Intervention Treatment and prophylaxis of: • DVT • PE • CRT
Exclusion criteria chosen for each specific question (Q1 to Q7)
Outcomes Selected endpoints chosen for each specific question (Q1 to Q7)
Excluded endpoints chosen for each specific question (Q1 to Q7)
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Data Extraction Update reference list
Q1: Initial treatment of established VTE
• RCT-randomized controlled trials
1. [Young 2018] Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). J Clin Oncol. 20 8 May 10:JCO2018788034.
2. [McBane 2018]. Apixaban, Dalteparin, in Active Cancer Associated Venous Thromboembolism, the ADAM VTE Trial. American Society of Hematology, 2018 December 2; San Diego
• Systematic reviews w/wo Meta-Analysis 3. [Robertson 2017] Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated
heparin for the initial treatment of venous thromboembolism. Cochrane Database Syst Rev. 2017 Feb 9;2:CD001100. 4. [Hakoum 2018] Anticoagulation for the initial treatment of venous thromboembolism in people with cancer.
Cochrane Database Syst Rev. 2018 Jan 24;1:CD006649.
• Comparative/observational – prospective/retrospective 5. [Muriel 2014] Survival effects of inferior vena cava filter in patients with acute symptomatic venous thromboembolism
and a significant bleeding risk. J Am Coll Cardiol. 2014 Apr 29;63(16):1675-83. 6. [Narayan 2016] The Impact of Cancer on the Clinical Outcome of Patients After Inferior Vena Cava Filter Placement: A
Retrospective Cohort Study. Am J Clin Oncol. 2016 Jun;39(3):294-301. 7. [Brunson 2016] Inferior vena cava filters in patients with cancer and venous thromboembolism (VTE): patterns of use
and outcomes. Thromb Res. 2016 Apr;140 Suppl 1:S132-41. 8. [Casanegra 2016] Retrievable Inferior Vena Cava Filters in Patients with Cancer: Complications and Retrieval Success
Rate. Int J Vasc Med. 2016;2016:6413541. 9. [Brunson 2017] Inferior vena cava filters in patients with cancer and venous thromboembolism (VTE) does not improve
clinical outcomes: A population-based study. Thromb Res. 2017 May; 153:57-64. 10. [Coombs 2017] Outcomes after inferior vena cava filter placement in cancer patients diagnosed with pulmonary
embolism: risk for recurrent venous thromboembolism. J Thromb Thrombolysis. 2017 Nov;44(4):489-493 11. [Stein 2018] Inferior Vena Cava Filters in Patients with Acute Pulmonary Embolism and Cancer. Am J Med. 2018
Apr;131(4): 442.e9-442.e12. 12. [Kang 2018] Effect of post-filter anticoagulation on mortality in patients with cancer-associated pulmonary embolism.
Int J Clin Oncol. 2018 May 17.
Q2: Early maintenance and long-term treatment of established VTE
• RCT-randomized controlled trials 13. [Amato 2016] Fondaparinux vs warfarin for the treatment of unsuspected pulmonary embolism in cancer patients. Drug
Des Devel Ther. 2016 Jun 23; 10:2041-6. 14. [Raskob 2018] Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N Engl J Med. 2018
Feb 15;378(7):615-62 15. [Young 2018] Comparison of an Oral Factor Xa Inhibitor with Low Molecular Weight Heparin in Patients With Cancer
With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). J Clin Oncol. 20 8 May 10: JCO2018788034. 16. [McBane 2018]. Apixaban, Dalteparin, in Active Cancer Associated Venous Thromboembolism, the ADAM VTE Trial.
American Society of Hematology, 2018 December 2; San Diego
• Systematic reviews w/wo Meta-Analysis 17. [Brunetti 2017] Direct oral anti-coagulants compared with vitamin-K inhibitors and low-molecular-weight-heparin for
the prevention of venous thromboembolism in patients with cancer: A meta-analysis study. Int J Cardiol. 2017 Mar 1;230: 214-221.
18. [Rojas-Hernandez 2017] Risk of intracranial hemorrhage associated with therapeutic anticoagulation for venous thromboembolism in cancer patients: a systematic review and meta-analysis. J Thromb Thrombolysis. 2017 Feb;43(2):233-240.
19. [Li 2018] Direct oral anticoagulant (DOAC) versus low-molecular-weight heparin (LMWH) for treatment of cancer associated thrombosis (CAT): A systematic review and meta-analysis. Thromb Res. 2018 Mar 2. pii: S0049-3848(18)30216-0.
20. [Kahale 2018a] Anticoagulation for the long-term treatment of venous thromboembolism in people with cancer. Cochrane Database Syst Rev. 2018 Jun 18;6:CD006650.
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21. [Al Yami 2018] Direct oral anticoagulants for the treatment of venous thromboembolism in patients with active malignancy: a systematic review and meta-analysis J Thromb Thrombolysis. 2018 Aug;46(2):145-153
22. [Xing 2018] Rivaroxaban versus enoxaparin for the prevention of recurrent venous thromboembolism in patients with cancer: A meta-analysis. Medicine (Baltimore). 2018 Aug;97(31): e11384.
23. [Vedovati 2018] Efficacy and safety of anticoagulant agents in patients with venous thromboembolism and cancer: A network meta-analysis. Thromb Res. 2018 Oct; 170:175-180.
• Comparative/observational – prospective/retrospective 24. [Francis 2015] Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the
DALTECAN Study. J Thromb Haemost. 2015 Jun;13(6):1028-35. 25. [Jara-Palomares 2017] Tinzaparin in cancer associated thrombosis beyond 6months: TiCAT study. Thromb Res. 2017
Sep; 157:90-96. 26. [Chai-Adisaksopha 2018] Vitamin K Antagonists After 6 Months of Low-Molecular-Weight Heparin in Cancer Patients
with Venous Thromboembolism. Am J Med. 2018 Apr;131(4):430-437.
Q3: Treatment of VTE recurrence – Vena Cava filters in patients with cancer
• Systematic reviews w/wo Meta-Analysis 27. [Rojas-Hernandez 2018] Role of vena cava filters for the management of cancer-related venous thromboembolism:
Systematic review and meta-analysis. Crit Rev Oncol Hematol. 2018 Oct; 130:44-50.
• Comparative/observational – prospective/retrospective 28. [Mellado 2016] Outcomes Associated with Inferior Vena Cava Filters Among Patients With Thromboembolic Recurrence
During Anticoagulant Therapy. JACC Cardiovasc Interv. 2016 Dec 12;9(23):2440-2448.
Q4: Prophylaxis of VTE in surgical cancer patients
• RCT-randomized controlled trials 29. [Nagata 2015] Randomized controlled trial of enoxaparin versus intermittent pneumatic compression for venous
thromboembolism prevention in Japanese surgical patients with gynecologic malignancy. J Obstet Gynaecol Res. 2015 Sep;41(9):1440-8.
30. [Dong 2018] Effect of low molecular weight heparin on venous thromboembolism disease in thoracotomy patients with cancer. J Thorac Dis. 2018 Mar;10(3):1850-1856.
31. [Jung 2018] Venous Thromboembolism Incidence and Prophylaxis Use After Gastrectomy Among Korean Patients with Gastric Adenocarcinoma: The PROTECTOR Randomized Clinical Trial. JAMA Surg. 2018 Oct 1;153(10):939-946.
• Systematic reviews w/wo Meta-Analysis 32. [Fagarasanu 2016] Role of Extended Thromboprophylaxis After Abdominal and Pelvic Surgery in Cancer Patients: A
Systematic Review and Meta-Analysis. Ann Surg Oncol. 2016 May;23(5):1422-30. 33. [Guo 2017] Perioperative Pharmacological Thromboprophylaxis in Patients with Cancer: A Systematic Review and Meta-
analysis. Ann Surg. 2017 Jun;265(6):1087-1093. 34. [Felder 2018] Prolonged thromboprophylaxis with low molecular weight heparin for abdominal or pelvic surgery.
Cochrane Database Syst Rev. 2018 Nov 27;11:CD004318 35. [Carrier 2018] Extended thromboprophylaxis with low-molecular weight heparin (LMWH) following abdominopelvic
cancer surgery. Am J Surg. 2018 Dec 16. pii: S0002-9610(18)31377-1.
• Comparative/observational – prospective/retrospective
36. [Pariser 2017] Extended Duration Enoxaparin Decreases the Rate of Venous Thromboembolic Events after Radical Cystectomy Compared to Inpatient Only Subcutaneous Heparin. J Urol. 2017 Feb;197(2):302-307.
37. [Kim 2017] Extended pharmacologic thromboprophylaxis in oncologic liver surgery is safe and effective. J Thromb Haemost. 2017 Nov;15(11):2158-2164.
38. [Schomburg 2018] Extended outpatient chemoprophylaxis reduces venous thromboembolism after radical cystectomy. Urol Oncol. 2018 Feb;36(2):77. e9-77.e13.
Q5: Prophylaxis of VTE in medical cancer patients
Supplementary appendix revised version 23 08 2019
18
• RCT-randomized controlled trials
39. [Khorana 2012] Dalteparin thromboprophylaxis in cancer patients at high risk for venous thromboembolism: A randomized trial. Thromb Res. 2017 Mar; 151:89-95.
40. [Ek 2018] Randomized phase III trial of low-molecular-weight heparin enoxaparin in addition to standard treatment in small-cell lung cancer: the RASTEN trial. Ann Oncol. 2018 Feb 1;29(2):398-404.
41. [Meyer 2018] Anti-tumour effect of low molecular weight heparin in localised lung cancer: a phase III clinical trial. Eur Respir J. 2018 Oct 4;52(4)
42. [Khorana 2019] Rivaroxaban Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer. N Engl J Med. 2019 Feb 21;380(8):720-728.
43. [Carrier 2019] Apixaban to Prevent Venous Thromboembolism in Patients with Cancer. N Engl J Med. 2019 Feb 21;380(8):711-719
Systematic reviews w/wo Meta-Analysis
44. [Di Nisio 2016] Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database Syst Rev. 2016 Dec 1;12:CD008500.
45. [Tun 2016] Benefit and risk of primary thromboprophylaxis in ambulatory patients with advanced pancreatic cancer receiving chemotherapy: a systematic review and meta-analysis of randomized controlled trials. Blood Coagul Fibrinolysis. 2016 Apr;27(3):270-4.
46. [Yu 2016] Adjuvant therapy with heparin in patients with lung cancer without indication for anticoagulants: A systematic review of the literature with meta-analysis. J Cancer Res Ther. 2016 Oct;12(Supplement):37-42.
47. [Al Ani 2016] Thromboprophylaxis in multiple myeloma patients treated with lenalidomide - A systematic review. Thromb Res.2016 May; 141:84-90.
48. [Fuentes 2017] Meta-analysis on anticoagulation and prevention of thrombosis and mortality among patients with lung cancer. Thromb Res. 2017 Jun; 154:28-34.
49. [Thein 2017] Primary thromboprophylaxis (PTP) in ambulatory patients with lung cancer receiving chemotherapy: A systematic review and meta-analysis of randomized controlled trials (RCTs). Asia Pac J Clin Oncol. 2018 Jun;14(3):210-216.
50. [Akl 2017] Parenteral anticoagulation in ambulatory patients with cancer. Cochrane Database Syst Rev. 2017 Sep 11;9:CD006652.
51. [Kahale 2017] Oral anticoagulation in people with cancer who have no therapeutic or prophylactic indication for anticoagulation. Cochrane Database Syst Rev. 2017 Dec 29;12:CD006466.
Q6: Treatment of established catheter-related thrombosis (CRT)
• Comparative/observational – prospective/retrospective 52. [Davies 2018] A prospective study of Rivaroxaban for central venous catheter associated upper extremity deep vein
thrombosis in cancer patients (Catheter 2). Thromb Res. 2018 Feb; 162:88-92.
Q7: Prophylaxis of CRT
• Systematic reviews w/wo Meta-Analysis 53. [Kahale 2018] Anticoagulation for people with cancer and central venous catheters. Cochrane Database Syst Rev. 2018
Jun 1;6:CD006468. 54. [Lv 2018] Risk associated with central catheters for malignant tumor patients: a systematic review and meta-analysis.
Oncotarget. 2018 Jan 12;9(15):12376-12388.
Q8: Questions for specific populations and specific clinical situations
Cancer patients with:
ü Brain Tumours
55. [Alshehri 2016] Venous thromboembolism prophylaxis in brain tumor patients undergoing craniotomy: a meta-
analysis. J Neurooncol. 2016 Dec;130(3):561-570. 56. [Zwicker 2016] A meta-analysis of intracranial hemorrhage in patients with brain tumors receiving therapeutic
anticoagulation. J Thromb Haemost. 2016 Sep;14(9):1736-40.
57. [Chai-Adisaksopha 2017] Outcomes of low-molecular-weight heparin treatment for venous thromboembolism in patients with primary and metastatic brain tumours. Thromb Haemost. 2017 Feb 28;117(3):589-594.
Supplementary appendix revised version 23 08 2019
19
ü Thrombocytopenia
58. [Samuelson Bannow 2018] Management of anticoagulation for cancer-associated thrombosis in patients with thrombocytopenia: A systematic review. Res Pract Thromb Haemost. 2018; Epub 2018 June 19.
59. [Khanal 2016] Venous thromboembolism in patients with hematologic malignancy and thrombocytopenia. Am J
Hematol. 2016 Nov;91(11): E468-E472.
ü Renal Failure 60. [Woodruf 2016] A post hoc analysis of dalteparin versus oral anticoagulant (VKA) therapy for the prevention of
recurrent venous thromboembolism (rVTE) in patients with cancer and renal impairment. J Thromb Thrombolysis.
2016 Nov;42(4):494-504.
61. [Bauersachs 2018] Renal Impairment, Recurrent Venous Thromboembolism and Bleeding in Cancer Patients with Acute Venous Thromboembolism-Analysis of the CATCH Study. Thromb Haemost. 2018 May;118(5):914-921.
ü Gender differences?
62. [Martín-Martos 2017] Gender differences in patients with venous thromboembolism and five common sites of cancer. Thromb Res. 2017 Mar;151 Suppl 1: S16-S20.
Supplementary appendix revised version 23 08 2019
20
Data extraction: CRITICAL APPRAISAL
References
Desi
gn
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finiti
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Desc
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dpoi
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met
hod
of
mea
sure
men
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Docu
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tatio
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of lo
st to
fo
llow
-up
Inte
nt- t
o-tr
eat
anal
ysis
Toxi
city
: da
ta -
grad
ing
Conf
lict o
f in
tere
st Comments
Q1. INITIAL TREATMENT (UP TO 10 DAYS) OF ESTABLISHED VTE (SPECIFIC CASES EXCLUDED) 1. [YOUNG 2018] RCT yes yes yes yes yes yes yes yes-yes yes SELECT-D
2. [MCBANE 2018] RCT yes yes yes yes yes - yes yes-yes yes ADAM-VTE
3. [ROBERTSON 2017] Meta-analysis
4. [HAKOUM 2018] Meta-analysis
5. [MURIEL 2014] PNRS yes -- no yes yes -- no yes-yes yes Patients from RIETE
6. [NARAYAN 2016] RNRS yes -- yes yes yes -- no no-no no Retrospective cohort study
7. [BRUNSON 2016] RNRS yes -- no yes yes -- no no-no yes Population-based retrospective cohort
8. [CASANAGRA 2016] RNRS yes -- no yes yes -- no yes-no yes Retrospective cohort study
9. [BRUNSON 2017] RNRS yes -- no yes yes -- no no-no yes Population-based retrospective cohort
10. [COOMBS 2017] RNRS yes -- no yes yes -- no no-no -- Small sample size
11. [STEIN 2018] RNRS yes -- no yes yes -- no no-no -- Analysis of administrative data
12. [KANG 2018] RNRS yes -- no yes yes -- no no-no -- Retrospective cohort study
Q2. EARLY MAINTENANCE TREATMENT (3 TO 6 MONTHS) AND LONG-TERM TREATMENT (BEYOND 6 MONTHS) OF ESTABLISHED VTE (SPECIFIC CASES EXCLUDED) 13. [AMATO 2016] RCT yes yes no yes yes yes yes yes-yes yes Small sample size
14. [RASKOB 2018] RCT yes yes yes yes yes yes yes yes-yes yes
15. [YOUNG 2018] RCT yes yes yes yes yes yes yes yes-yes yes SELECT-D
16. [MCBANE 2018] RCT yes yes yes yes yes - yes yes-yes yes ADAM-VTE
17. [BRUNETTI 2017] Meta-analysis
18. [ROJAS-HERNANDEZ 2017] Meta-analysis
19. [LI 2018] Meta-analysis
20. [KAHALE 2018 A] Meta-analysis
21. [AL YAMI 2018] Meta-analysis
22. [XING 2018] Meta-analysis
23. [VEDOVATI 2018] Meta-analysis
24. [FRANCIS 2015] PNRS yes -- no yes yes no no yes-no yes Prospective, open, single arm, multicentre study in patients
with CAT receiving long-term treatment with dalteparin
25. [JARA-PALOMARES 2018] PNRS yes -- yes yes yes no no yes-yes yes Prospective, open, single arm, multicentre study in patients
with CAT receiving long-term treatment with tinzaparin.
26. [CHAI-ADISAKSOPHA 2018] PNRS yes -- no yes yes -- no yes-yes yes Patients from RIETE
Supplementary appendix revised version 23 08 2019
21
References
Desi
gn
Endp
oint
def
initi
on
Desc
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n of
ra
ndom
izat
ion
Sam
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size
ca
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atio
n
Desc
riptio
n of
st
atis
tical
pla
n
Desc
riptio
n of
en
dpoi
nt m
etho
d
of m
easu
rem
ent
Docu
men
tatio
n
of lo
st to
follo
w-u
p
Inte
nt- t
o-tr
eat
anal
ysis
Toxi
city
: da
ta -
grad
ing
Conf
lict o
f int
eres
t
Comments
Q3. TREATMENT OF VTE RECURRENCE (SPECIFIC CASES EXCLUDED)- VENA CAVA FILTERS
27. [ROJAS-HERNANDEZ 2018] Meta-analysis
28. [MELLADO 2016] PNRS yes -- no yes yes -- no yes-yes yes Patients from RIETE
Q4. PROPHYLAXIS OF VTE IN SURGICAL CANCER PATIENTS (SPECIFIC CASES EXCLUDED) 29. [NAGATA 2015] RCT yes no yes yes yes no yes yes-yes yes
30. [DONG 2018] RCT yes no yes yes yes no yes yes-no yes Small sample size – short follow-up (7 days post surgery)
31. [JUNG 2018] RCT yes yes yes yes yes no yes yes-no yes
32. [FAGARASANU 2016] Meta-analysis
33. [GUO 2017] Meta-analysis
34. [FELDER 2018] Meta-analysis
35. [CARRIER 2018] Meta-analysis
36. [PARISER 2017] RNRS yes -- no yes yes -- no no-no --
Q4. PROPHYLAXIS OF VTE IN SURGICAL CANCER PATIENTS (SPECIFIC CASES EXCLUDED)-CONTINUED
37. [KIM 2017] RNRS no -- no yes yes -- no yes-no Heterogeneous population
38. [SCHOMBURG 2018] RNRS yes -- no yes yes -- no no-no --
Q5. PROPHYLAXIS IN MEDICAL CANCER PATIENTS (SPECIFIC CASES EXCLUDED) 39. [KHORANA 2017] RCT yes yes yes yes yes no yes yes-yes yes
40. [EK 2018] RCT yes yes yes yes yes yes yes yes-yes yes RASTEN trial in SCLG
41. [MEYER 2018] RCT yes yes yes yes yes yes yes yes-yes yes TILT trial in NSCLG
42. [KHORANA 2019] RCT yes yes yes yes yes yes yes yes-yes CASSINI trial
43. [CARRIER 2019] RCT yes yes yes yes yes yes yes yes-yes AVERT trial
44. [DI NISIO 2016] Meta-analysis
45. [TUN 2016] Meta-analysis
46. [YU 2016] Meta-analysis
47. [AL-ANI 2016] Meta-analysis
48. [FUENTES 2017] Meta-analysis
49. [THEIN 2017] Meta-analysis
50. [AKL 2017] Meta-analysis
51. [KAHALE 2017] Meta-analysis
Q6. TREATMENT OF ESTABLISHED CATHETER-RELATED THROMBOSIS (CRT) 52. [DAVIES 2018] PNRS yes -- no yes yes no no yes-yes yes PICC and PACC are mixed
Q7. PROPHYLAXIS OF CRT 53. [KAHALE 2018 B] Meta-analysis
54. [LV 2018] Meta-analysis
Supplementary appendix revised version 23 08 2019
22
RS, Randomized Study; PNRS/RNRS, Prospective/retrospective Non-Randomized Study; RCT, Randomized Controlled Trial; RDBT, Randomized Double-Blind Trial
Q8. SPECIFIC CASES: ALL THESE SPECIFIC CASES WHICH WERE NOT STUDIED IN THE ABOVE CLINICAL QUESTIONS BRAIN TUMOURS 55. [ALSHERI 2016] brain tumor Meta-analysis
56. [ZWICKER 2016] brain tumor Meta-analysis
57. [CHAI-ADISAKSOPHA 2017] brain tumor RNRS yes -- no yes yes -- no yes-yes yes
THROMBOCYTOPENIA 58. [SAMUELSON BANNOW 2018] Meta-analysis (Appendix 3; XX-XX)
59. [KHANAL 2016] RNRS yes -- no yes yes -- no yes-no yes
RENAL FAILURE 60. [WOODRUF 2016] renal
failure RCT yes yes yes yes yes yes yes yes-yes yes Post hoc analysis using data from the CLOT study
61. [BAUERSACHS 2018] RCT yes yes yes yes yes yes yes yes-yes yes Post hoc analysis using data from the CATCH study
SEX DIFFERENCES 62. [MARTIN-MARTOS 2017] PNRS yes -- no yes yes -- no yes-yes yes Patients from RIETE
Supplementary appendix revised version 23 08 2019
23
Data Extraction: TABLES
Reference Inclusion period
Number of patients
analyzed/included
Follow-up Population Intervention VTE incidence Toxicity Death
[Young 2018] SELECT-D prospective,
randomised, open
label, multicentre
pilot trial
406/406 patients 6
months Patients >18 years with active cancer and DVT,
pulmonary embolism or both.
Active cancer was defined as a diagnosis of
cancer (other than basal-cell or squamous-cell
skin carcinoma) in the previous 6 months, any
treatment for cancer within the previous 6
months, recurrent or metastatic cancer, or
cancer not in complete remission
(hematologic malignancy).
Arm A: rivaroxaban 15mg twice
daily for 3 weeks then
20mg once daily, for 6
months in total
Arm B: dalteparin 200 IU/kg sc
daily for 30 days,
followed by 150 IU/Kg
sc daily Treatment for at least 6
months
Recurrent VTE Arm A: 8/203(4%)
Arm B: 18/203 (11%)
HR, 0.43;
95% CI, 0.19 to 0.99
Major bleeding Arm A: 11/203 (6.0%)
Arm B: 6/203 (4.0%)
HR, 1.83; 95% CI, 0.68 to 4.96
Clinically relevant non-major bleeds (CRNMB) Arm A: 25/203 (13.0%)
Arm B: 7/203 (4.0%)
HR, 3.76;95% CI, 1.63 to 8.69
Overall survival at 6 months Arm A:75% (95% CI, 69% to
81%)
Arm B:70%
(95% CI, 63% to 76%)
[Mc Bane 2018] ADAM-VTE Phase IV,
multicenter,
randomized,
open label,
superiority trial
287/300 6
months
Patients >18 years with active cancer and acute
VTE objectively demonstrated by an imaging
study
Active cancer was defined as proven cancer with
metastatic disease and/or any evidence of
cancer on computerized tomography (CT) or
positron emission tomography (PET) imaging;
Arm A: Apixaban 10 mg twice
daily for 7 days
followed by 5 mg twice
daily thereafter, for 6
months
Arm B: dalteparin 200 IU/kg sc
daily for 30 days,
followed by 150 IU/Kg
sc daily thereafter, for 6 months
Recurrent VTE Arm A: 5/145 (3.4%)
Arm B: 20/142 (14.1%)
HR, 0.26; 95% CI, 0.09–
0.80; p=0.0182
Major bleeding Arm A: 0/145 (0%)
Arm B: 3/142 (2.1%)
p=0.9956
Major and clinically relevant non-major bleeds (CRNMB) Arm A: 9%
Arm B: 9%
Overall survival at 6 months Arm A: 15.9%
Arm B: 10.6%
HR, 1.36; 95% CI, 0.79–2.35
Table1 Initial treatment of VTE – RCT
Supplementary appendix revised version 23 08 2019
24
References [Robertson 2017] [Hakoum 2018]
Bibliographic search Cochrane Vascular Specialised Register (searched 15 September 2016)– constructed from
MEDLINE, EMBASE, CINAHL, AMED; and through hand-searching relevant journals.
Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8) in the Cochrane
Library (searched 15 September 2016).
Cochrane Central Register of Controlled Trials (CENTRAL) (2018, Issue 1), MEDLINE
(viaOvid, starting 1946ID), Embase (starting 1980; accessed via Ovid), handsearching of
conference proceedings; checking of references of included studies; use of the ’related
citation’ feature in PubMed; and a search for ongoing studies.
This update of the systematic review was based on the findings of a literature search
conducted on 14 January 2018.
Included studies 29 studies (10390 patients)
LMWH-fixed dose (once or twice delay)
Compared to UFH adjusted dose - IV or SC
[FIESSINGER 1996] [HULL 1992] [LINDMARKER1994] [LUOMANMAKI 1996] [SIMONNEAU 1997] [BELCARO 1999] [BREDDIN 2001] [COLUMBUS 1997] [DECOUSUS 1998] [FAIVRE1988] [FINDIK 2002] [GALILEI 2004] [GOLDHABER 1998] [HARENBERG 2000] [KIRCHMAIER 1998] [KOOPMAN 1996] [LEVINE 1996] [LOPACIUK1992] [NINET 1991] [PRANDONI 1992] [RIESS 2003] [SIMONNEAU 1993] [MERLI 2001] [KAKKAR 2003] [LEIZOROVICZ 2011] [MEYER 1995] [MORENO-PALOMARES 2001] [PÉREZ DE LLANO 2003] [THERY 1992]
15 RCTs (1615 participants with cancer and VTE) 13 studies compared LMWH with UFH (1025 participants) [BREDDIN 2001] [BULLER 1997] [DUROUX 1991] [HULL 1992] [KOOPMAN 1996] [LEVINE 1996] [MERLI 2001] [PRANDONI 1992] [PRANDONI 2004] [SIMONNEAU 1993] [SIMONNEAU 1997] [LINDMARKER 1994] [LOPACIUK 1992] 1 study compared fondaparinux with UFH and LMWH (477 participants) [VAN DOORMAAL 2009] 1 study compared dalteparin with tinzaparin (113 participant) [WELLS 2005]
Primary endpoint Symptomatic recurrent VTE (DVT or PE) during the initial treatment and during follow-up. All-cause mortality
Secondary endpoint Number of participants in whom the thrombus size reduced based on pre- and post-
treatment venograms.
Major bleeding during initial treatment or within 48 hours after treatment cessation.
Overall mortality at the end of follow-up.
Symptomatic recurrent DVT
Symptomatic recurrent PE
Major bleeding
Minor bleeding
Postphlebitic syndrome
Quality of life
Thrombocytopenia
Results General population Symptomatic recurrent VTE no difference between LMWH and UFH at 1 one month’s follow-up : Peto OR 0.90, 95% CI
0.56 -1.44; participants, 1741; studies, 4; P = 0.65
statistically significant reduction with LMWH:
during the initial treatment period: Peto OR 0.69, 95% CI 0.49-0.98; moderate-quality
evidence; participants, 6238; studies, 18; P = 0.04
at the end of follow-up: Peto OR 0.72, 95% CI 0.59-0.88; participants,9489; studies,22; P =
0.0005
at 3 months’ follow-up: Peto OR 0.71, 95% CI 0.56-0.90; moderate-quality evidence;
participants, 6661; studies, 16; P =0.005
at 6 months’ follow-up: PetoOR 0.68, 95%CI 0.48-0.96; participants, 2841; studies, 7; P =
0.03
Patient or population: patients with cancer with the initial treatment of VTE
Settings: inpatient or outpatient
Intervention: LMWH
Comparison: UFH
Reduced mortality with LMWH at 3 months: RR 0.66, 95% CI 0.40-1.10; risk difference (RD)
57 fewer per 1000, 95% CI 101 fewer to 17 more (moderate certainty evidence).
No beneficial/detrimental effect of LMWH over UFH on Recurrent VTE at 3 months
RR=0.69, 95% CI 0.27-1.76; RD 30 fewer per 1000,95% CI 70 fewer to 73 more (moderate
certainty evidence).
Patient or population: patients with cancer with the initial treatment of VTE
Table 2: Initial treatment of VTE: Short-term LMWH versus Short-term UFH followed by VKA - Meta-analyses of cancer patient subpopulations
Supplementary appendix revised version 23 08 2019
25
Reduction in thrombus size with LMW: Peto OR 0.71, 95% CI 0.61-0.82; moderate-quality
evidence; participants, 2909; studies, 16; P < 0.00001. Moderate heterogeneity in this
analysis (I² = 56%).
Of the individual LMWH preparations, better venographic outcome observed for
ardeparin (Peto OR 0.37, 95% CI 0.14-0.99), enoxaparin (Peto OR 0.34, 95% CI 0.17-0.71),
reviparin (Peto OR 0.59, 95% CI 0.43-0.80), certoparin (Peto OR 0.70, 95% CI 0.50-0.98)
and bemiparin (Peto OR 0.42, 95% CI 0.24- 0.74).
Reduction in major bleeding during initial treatment or within 48 hours after treatment cessation with LMWH: Peto OR 0.69, 95% CI 0.50-0.95; participants, 8780; studies, 25;
moderate-quality evidence; P = 0.02.
no difference between the LMWH preparations (P = 0.10).
Overall mortality at the end of follow-up
No difference in overall mortality at the end of follow-up between participants treated
with LMWH and UFH: Peto OR 0.84, 95% CI 0.70-1.01; moderate-quality evidence;
participants, 9663; studies, 24; P = 0.07
Patients with malignancy
reduction in overall mortality in participants with cancer who were treated with LMWH
(Peto OR 0.53, 95% CI 0.33-0.85; participants, 446; studies, 6 ; P =0.009)
Settings: inpatient or outpatient
Intervention: fondaparinux
Comparison: heparin (UFH or LMWH)
No difference in mortality: RR 1.25, 95% CI 0.86-1.81; RD 43 more per 1000, 95% CI 24
fewer to 139 more (moderate certainty evidence)
No difference in recurrent VTE: RR 0.93, 95% CI 0.56-1.54; RD 8 fewer per 1000, 95% CI 52
fewer to 63 more (moderate certainty evidence)
Major bleeding: RR 0.82; 95% CI 0.40- 1.66; RD 12 fewer per 1000, 95% CI 40 fewer to 44
more (moderate certainty evidence)
Minor bleeding: RR 1.53, 95% CI 0.88-2.66; RD42 more per 1000, 95%CI 10 fewer to 132
more (moderate certainty evidence)
Dalteparin vs Tinzaparin
No difference in mortality: RR 0.86, 95% CI 0.43-1.73; RD 33 fewer per 1000, 95% CI 135
fewer to 173 more (low certainty evidence)
No difference in VTE recurrence: RR 0.44, 95% CI 0.09-2.16; RD 47 fewer per 1000, 95% CI
77 fewer to 98 more (low certainty evidence)
Major bleeding: RR 2.19, 95% CI 0.20-23.42] RD 20 more per 1000, 95% CI 14 fewer to 380
more (low certainty evidence)
Minor bleeding: RR 0.82, 95% CI 0.30-2.21; RD 24 fewer per 1000, 95% CI 95 fewer to 164
more (low certainty evidence).
Authors’ conclusions Moderate-quality evidence that fixed dose LMWH reduced the incidence of recurrent
thrombotic complications and occurrence of major haemorrhage during initial treatment
and low-quality evidence that fixed dose LMWH reduced thrombus size when compared
to UFH for the initial treatment of VTE.
No difference in overall mortality between participantstreated with LMWH and those
treated with UFH (moderate-quality evidence).
In cancer patients: reduced mortality at the end of follow-up with LMWH versus UFH.
LMWH is possibly superior to UFH in the initial treatment of VTE in people with cancer.
Additional trials focusing on patient important outcomes will further inform the questions
addressed in this review. The decision for a person with cancer to start LMWH
therapy should balance the benefits and harms and consider the person’s values and
preferences.
Supplementary appendix revised version 23 08 2019
26
Reference Inclusion period
Number of patients analyzed/included Follow-up Population Intervention VTE incidence Toxicity Death
[Muriel 2014]
Propensity score-
matched cohort study
Patients from RIETE
688 patients with
VTE
30 days Patients with acute
symptomatic VTE with
or without cancer
(approximatively 30-
40% of cancer patients)
Group A: 344 patients
treated with filters
Group B: 344 patients
treated without
filters.
Recurrent VTE Group A: 21/344 (6.1%)
Group B: 2/344 (0.6%) OR 11.12, 95% CI 2.56–48.19; p<0.001
Major bleeding Group A: 13/344 (3.8%)
Group B: 18/344 (5.2%) OR 0.71, 95% CI 0.35–1.46; p=0.35
Death Group A: 23/344 (6.6%)
Group B: 35/344 (10.2%) OR 0.63, 95% CI 0.36–1.12; p=0.12
PE-related death Group A: 6/344 (1.7%)
Group B: 17/344 (4.9%) OR 0.35, 95% CI 0.15–0.43; p=0.03
[Narayan 2016]
retrospective cohort
study of consecutive
patients who
received filters (2002-
2006) at Johns
Hopkins
702 patients: 246
with cancer and 456
without cancer
Patients who received
an IVC filter
Group A: patients with
active Cancer Among 246 cancer
patients, 38.6% of
patients received
anticoagulation after
filter placement
Group B: patients
without active cancer
among 456 non-cancer
patients, 33.3% of
patients received
anticoagulation
Development of VTE (DVT, IVC thrombosis or PE) after IVC filter placement Group A: 13.4% Group B: 7.7%
RR 2.0, 95% CI 1.2-3.3 Development of DVT Group A: 10.6% Group B: 6.8%
RR 1.7, 95% CI 1.0-3.1 Development of PE Group A: 4.1% Group B: 1.8%
RR 2.7, 95% CI 1.0-7.5
Survival at 30 days Group A: 78% Group B: 86%
Survival at 1 year Group A: 36% Group B: 71%
Survival at 5 years Group A: 15% Group B: 52%
[Brunson 2016]
retrospective cohort
California Patient
Discharge Database
Jan 2005 -Dec 2009
14000 patients with
active cancer and
acute VTE: 2747
patients with IVC
filters
and 11253 patients
without IVC filter
Propensity score
methodology used
to balance the IVCF
and no-IVCF groups
180 days Patients aged ≥18 years
who were hospitalized
between January 2005
and December 2009
with acute VTE and
active cancer
Group A: IVCF Group B: no-IVCF
Data on anticoagulation
use not available
Subsequent PE within 180 days IVCF vs. no-IVCF:
HR 0.81, 95% CI 0.60-1.08
Patients with a diagnosis of brain
cancer were 1.9-fold more likely to
have a recurrent PE compared to most
solid tumors with a perceived
low risk of bleeding.
Subsequent DVT within 180 days HR 1.56, 95% CI 1.26-1.92
Subsequent Major Bleeding within 180 days of discharge or less from index admission discharge IVCF vs. no-IVCF:
HR 1.20, 95% CI 1.04-1.38
Short-term mortality (death ≤ 30 days) from the index admission date IVCF vs. no-IVCF:
HR 1.12, 95% CI 0.99-1.26
Metastatic disease (HR 1.79, 95% CI:
1.52-2.10) and risk of mortality
strong predictors of short-term
mortality.
Table 3: Initial treatment of VTE: Comparative/observational – prospective/retrospective
Supplementary appendix revised version 23 08 2019
27
[Casanegra 2016]
Retrospective review
of 251 consecutive
patients with RIVCF in
a single institution
Jan 2010 -Dec 2012
251/267
consecutive
patients: 87
patients with active
cancer and 164
patients without
active cancer
Median follow-
up of 5.4
months (164
days, IQR: 34–
385).
Consecutive adult
subjects with a
retrievable IVC
filter placed.
Active cancer was
defined as metastatic
disease or any
cancer treatment within
6 months before the
filter placement,
excluding
nonmelanoma cancers
of the skin
Group A: patients with
active Cancer Group B: patients
without active cancer
New PE Group A: 5% Group B: 0.6%,
P= 0.05
DVT recurrences Group A: 13% Group B: 17%
P=ns
Retrieval rate at 6 months Group A: 49% Group B: 64%
P=ns
- Death during follow up Group A: 55% Group B: 26%
p< 0.01
[Brunson 2017]
Population-based
retrospective cohort
study
Jan 2005 -Dec 2009
14000 patients with
active cancer and
acute VTE: 2747
patients with IVC
filters (only 21% of
these IVCF patients
had an apparent
indication for filter
use because of
acute bleeding or
undergoing
major surgery) and
11253 patients
without IVC filter
Propensity score
methodology used
to balance the IVCF
and no-IVCF groups
Median follow-
up time (time
from index
acute VTE to
death or end of
study) 10.7
months.
Patients aged ≥18 years
who were hospitalized
between January 2005
and December 2009
with acute VTE and
active cancer in a non-
federal California
hospital
Group A: IVCF Group B: no-IVCF
Data on anticoagulation
use not available
Subsequent PE within 180 days Group A: 2.6% Group B: 3.4%
HR 0.81, 95% CI 0.52–1.27, p=0.3608
Subsequent DVT within 180 days Group A: 5.6% Group B: 3.9%
HR 2.10, 95% CI 1.53–2.89, p<0.0001
Active bleeding within 180 days of discharge Group A: 10.9% Group B: 8.6%
HR 1.24, 95% CI 1.03–1.49, p=0.0243
death at 30 days Group A: 15.1% Group B: 17.8%
HR 1.12, 95% CI 0.99–1.26, p=0.08
death ≤60 days
HR 1.23, 95% CI 1.13–1.35
death ≤90 days HR 1.26, 95% CI 1.16–1.37
[Coombs 2017]
retrospective, single
institution study
2008-2009
1270 consecutive
patients with
cancer-associated
pulmonary
embolism (PE):
317 patients with
inferior vena cava
(IVC) filters / 953
patients without
IVC filter
12 months
following the
index PE
diagnosis.
Patients with lung,
colorectal, gynecologic,
hematologic
malignancies, or
primary central nervous
system (CNS) tumors
Arm A: IVC filter
placement within 30
days following the index
PE event or prior to the
index PE in the setting
of prior DVT
Arm B: no IVC filter
placement
All recurrent VTE: Arm A: 37/317 (11.9%)
Arm B: 73/953 (7.7%) P=0.086
Recurrent DVT: Arm A: 26/317 (8.2%)
Arm B: 40/953 (4.2%) P=0.033
Recurrent PE: Arm A: 11/317 (3.5%)Arm B: 33/953 (3.5%) P=0.99
- Median Overall survival Arm A: 7.2 months
Arm B: 13.2 months
p < 0.001 by log-rank testing
HR 1.26; 95% CI 1.09–1.47, p = 0.002
Supplementary appendix revised version 23 08 2019
28
[Stein 2018]
Analysis of
administrative data
from the Premier
Healthcare Database,
2010-2014
6589 patients
(18.8%) with vena
cava filter, and
28,445 patients
(81.2%)without
vena cava filter
3 months patients aged ≥18 years
who were hospitalized
2010 through 2014 with
stable pulmonary
embolism and solid
malignant tumors
identified on the basis
of International
Classification of
Disease, Ninth Revision,
Clinical Modification
codes
Group A: with vena
cava filter
Group B: without vena
cava filter
- - All-Cause In-Hospital Mortality All patients Group A: 532/6589 (8.1%)
Group B: 3175 /28,445 (11.2%)
RR 0.72, 95% CI, 0.66-0.79; P <0.0001
Patients older than 60 years Group A: 346/4648 (7.4%)
Group B: 2216/19,847 (11.2%)
RR 0.67, 95% CI, 0.60-0.74; P <0.0001
Three-Month All-Cause Mortality All patients Group A: 1049/6589 (15.9%)
Group B: 4993/28,445 (17.6%)
RR 0.92, 95% CI, 0.85-0.96; P=0.0017
Patients older than 60 years Group A: 704/4648 (15.1%)
Group B: 3444/19,847(17.4%)
RR 0.86, 95% CI, 0.80-0.92; P <0.0001
[Kang 2018]
Retrospective cohort
study
180 patients having
a diagnosis of active
cancer and an IVC
filter inserted
because of PE
Patients aged ≥18 years
with pulmonary
embolism (PE) at Asan
Medical Center, a 2700-
bed tertiary care center
in South Korea,
between January 2010
and May 2016
Group A: 143 patients
receiving post-filter
anticoagulation
treatment
(warfarin,53.8%;
LMWH, 27.3%; DOACs,
16.1%)
Group B: 37 patients
not receiving post-filter
anticoagulation
treatment
Survival time
Group A: median survival time
85 days (range :3–2411 days)
Group B: median survival time
78 days (range :1–892 days)
P= 0.300
PE-related death Group A: 12 (10.5%))
Group B: 4 (11.8%)
Bleeding -related death Group A: 2 (1.4%)
Group B: 0 (0%)
Anticoagulation not protective in
terms of mortality at 90 days :
adjusted HR 0.894 95% CI 0.525-1.523
Supplementary appendix revised version 23 08 2019
29
Reference Inclusion period
Number of patients
analyzed/included Follow-up Population Intervention VTE incidence Toxicity Death
[Amato 2016] randomized,
prospective,
single-blind, and
parallel group
study
64/64 patients 1 year Patients with active primary cancer
and being in anticancer treatment,
with asymptomatic pulmonary
embolism (APE) diagnosed on
computer tomography
Arm A: fondaparinux 7.5 mg SC once
daily for 90 days Arm B: warfarin for 90 days (dose-
adjusted to achieve an
international normalized ratio
of 2.0–3.0)
Persistence of APE after 90 days Arm A: 4/32 (12.5%)
Arm B: 14/32(43.75%)
P<0.01
Recurrent PE at 1 year Arm A: 6/32 (18.75%)
Arm B: 7/32(21.8%)
P = 0.32
Thrombotic events in other locations at 1 year Arm A: 6/32(18.75%)
Arm B: 6/32 (18.75%)
P = 0.46
Major bleeding Arm A: 3/32 (9.3%)
Arm B: 6/32(18.75%)
P<0.01
Minor bleeding Arm A: 4/32 (12.5%)
Arm B: 5/32(15.6%)
P = 0.12
Overall motality Arm A: 3/32 (9.3%)
Arm B: 4/32(12.5%)
P = 0.47
[Raskob 2018] HOKUSAI CANCER VTE open-label
randomized Jul 2015 - Dec
2016
1050/1050
patients
12 months or
until the end of
the trial
(minimum
follow-up, 9
months)
Patients >18 years with active
cancer and DVT, pulmonary
embolism or both
Active cancer defined as cancer
diagnosed within the previous 6
months; recurrent, regionally
advanced, or metastatic
cancer; cancer for which treatment
had been
administered within 6 months
before randomization;
or hematologic cancer that was not
in complete remission.
Arm A: LMWH at therapeutic doses for
5 days, then edoxaban 60 mg
daily with or without food (30
mg daily if creatinine clearance
of 30 to 50 ml per minute or
body £60 kg or concomitant
treatment with potent P-
glycoprotein inhibitors) Arm B: dalteparin 200 IU/kg sc daily for
30 days with a maximum daily
dose of
18,000 IU, followed by 150
IU/kg sc daily Treatment for at least6 months
and up to 12 months
Recurrent VTE Arm A: 41/525 (7.9%)
Arm B: 59/525 (11.3%)
p=0.09
Major bleeding Arm A: 36/525 (6.9%)
Arm B: 21/525 (4.0%)
p=0.04
Arm A: 206/525 (39.5%)
Arm B: 192/525 (36.6%)
No differences in cause of death
between two arms (cancer
progression main cause).
Table 4: Early maintenance and long-term treatment of established VTE – RCT
Supplementary appendix revised version 23 08 2019
30
[Young 2018] SELECT-D prospective,
randomised,
open label,
multicentre pilot
trial
406/406 patients 6 months Patients >18 years with active
cancer and DVT, pulmonary
embolism or both.
Active cancer was defined as a
diagnosis of cancer (other than
basal-cell or squamous-cell skin
carcinoma) in the previous 6
months, any treatment for cancer
within the previous 6 months,
recurrent or metastatic cancer, or
cancer not in complete remission
(hematologic malignancy).
Arm A: rivaroxaban 15mg twice daily
for 3 weeks then 20mg once
daily, for 6 months in total
Arm B: dalteparin 200 IU/kg sc daily for
30 days,
followed by 150 IU/Kg sc daily Treatment for at least 6
months
Recurrent VTE Arm A: 8/203(4%)
Arm B: 18/203 (11%)
HR, 0.43;
95% CI, 0.19 to 0.99
Major bleeding Arm A: 11/203 (6.0%)
Arm B: 6/203 (4.0%)
HR, 1.83; 95% CI, 0.68 to 4.96
Clinically relevant non-major bleeds (CRNMB) Arm A: 25/203 (13.0%)
Arm B: 7/203 (4.0%)
HR, 3.76;95% CI, 1.63 to 8.69
Overall survival at 6 months Arm A:75% (95% CI, 69% to
81%)
Arm B:70%
(95% CI, 63% to 76%)
[Mc Bane 2018] ADAM-VTE Phase IV,
multicenter,
randomized,
open label,
superiority trial
287/300 6 months Patients >18 years with active
cancer and acute VTE objectively
demonstrated by an imaging study
Active cancer was defined as
proven cancer with metastatic
disease and/or any evidence of
cancer on computerized
tomography (CT) or positron
emission tomography (PET)
imaging;
Arm A: apixaban 10 mg twice daily for
7 days followed by 5 mg twice
daily thereafter, for 6 months
Arm B: dalteparin 200 IU/kg sc daily for
30 days,
followed by 150 IU/Kg sc daily thereafter, for 6 months
Recurrent VTE Arm A: 5/145 (3.4%)
Arm B: 20/142 (14.1%)
HR, 0.26; 95% CI, 0.09–
0.80; p=0.0182
Major bleeding Arm A: 0/145 (0%)
Arm B: 3/142 (2.1%)
p=0.9956
Major and clinically relevant non-major bleeds (CRNMB) Arm A: 9%
Arm B: 9%
Overall survival at 6 months Arm A: 15.9%
Arm B: 10.6%
HR, 1.36; 95% CI, 0.79–2.35
Supplementary appendix revised version 23 08 2019
31
References Bibliographic search Included studies Primary endpoint Secondary endpoint Statistical tests Results
[Brunetti 2017]
Unrestricted search in
MEDLINE and PUBMED
through December 15,
2015
9 studies (n=1952 cancer patients):
7 studies compared DOACs with
conventional anticoagulation (heparin/VKA)
for treatment of VTE [SCHULMAN2009] [SCHULMAN2014] [SCHULMAN2013] [BÜLLER2013] [AGNELLI2013] [BAUERSACHS2010] [BÜLLER2012]
2 studies compared DOACs with LMWH for
VTE prophylaxis in patients hospitalized for
an acute disease [COHEN 2013] [GOLDHABERG 2011]
Recurrent VTE
Bleeding
- Pooled OR were determined
using Mantel-Haenszel method
Cochran c2 test and I2 statistic to
assess heterogeneity between
studies. Statistically significant
heterogeneity was considered
to be present when p < 0.10 and
I2 > 50%
Funnel plots were used to
assess for publication bias.
Recurrent VTE treated with DOACs: 55/1010 patients (5.4%)
treated with comparator (LMWH or VKA):
56/942 patients (5.9%)
0R, 0.79; 95% CI 0.53–1.17; I², 0%
Subgroup analysis:
DOAC vs. VKA (7 studies, 1251 patients) :
0R, 0.67; 95% CI 0.52–1.75
DOACs vs. LMWH (2 studies, 701 patients) :
0R, 0.96; 95% CI 0.52–1.75
Bleeding treated with DOACs: 102/ 943 patients (10.8%)
treated with comparator (LMWH or VKA):
96/875 patients (11.0%)
0R, 0.96; 95% CI 00.71–1.37; I², 43.9%
Subgroup analysis:
DOAC vs. VKA (6 studies, 1116 patients):
0R, 0.83; 95% CI 0.60–1.15
DOACs vs. LMWH (2 studies, 703 patients):
0R, 2.72; 95% CI 1.05–7.01; p=0.039
[Rojas-Hernandez 2017]
Systematic review
following the instructions
given in the Cochrane
Handbook for Systematic
Reviews
(http://www.cochrane-
handbook.org) and the
Preferred Reporting Items
for Systematic Reviews and
Meta-Analyses (PRISMA).
The PROSPERO registration
number CRD42015024143.
5 RCTs evaluating LMWH vs. VKA in cancer
patient with VTE, 2089 patients
[MEYER 2002] [LEE 2003] [HULL 2006] [LEE 2015] [DEITCHER 2006]
Incidence of ICH All major bleeding
and the time to
ICH and major
bleeding. Major
bleeding events
defined according
to the
International
Society on
Thrombosis and
Haemostasis
definition
Risk ratios (RR) and risk
difference (RD), if appropriate
Heterogeneity was
analyzed using a χ2 test on N-1
degrees of freedom, with
an alpha of 0.05 used for
statistical significance, and with
the I² test.
When statistical homogeneity
was observed, results pooled
using the fixed-effect method
Risk of ICH LMWH: 2/543 (0.36 %)
VKA: 5/539 (0.92 %)
RR 0.494, 95 % CI 0.105- 2.331
RD −0.004, 95 % CI−0.013,0.006
Risk of major bleeding LMWH vs. VKA:
RR 0.853, 95 % CI 0.549, 1.327
RD −0.003, 95 % CI −0.018-0.013
Table 5: Early maintenance and long-term treatment of established VTE – Systematic reviews with or without Meta-analysis
Supplementary appendix revised version 23 08 2019
32
[Li 2018] MEDLINE, EMBASE, and
Cochrane Central library
[2007-017]
Hand search of the
American Society of Clinical
Oncology and the American
Society of Hematology
annual meeting abstracts in
2017.
Systematic search strategy
available on-line
(PROSPERO:
CRD42017080898)
9 observational retrospective studies + 2
prospective RCTs of cancer patients.
Only the 2 prospective RCTs of cancer
patients (n=1452) with acute symptomatic
VTE (DVT and/or PE) that were randomized
to receive LMWH alone, or LMWH followed
by DOAC [RASKOB 2018] [YOUNG 2017] were included in the metanalysis.
6-month
incidence of
recurrent VTE
6-month
incidence of major
bleeding
Incidence of
clinically relevant
non-major
bleeding (CRNMB)
All cause mortality
All analyses performed on
intent-to-treat basis.
Relative risks using random
effects model
I2 statistic to assess
heterogeneity between studies
Recurrent VTE treated with DOACs: 42/725 (5.7%)
standard treatment: 64/727 (8.8%)
RR, 0.65; 95% CI 0.42–1.01; I², 17%
Major bleeding treated with DOACs: 40/725 (5.5%)
standard treatment: 23/727 (3.2%)
RR, 1.74; 95% CI 1.05–2.88; I², 0%
CRNMB treated with DOACs: 89/725 (12.3%)
standard treatment: 49/727 (6.7%)
RR, 2.31; 95% CI: 0.85–6.28; I², 78%
All cause mortality treated with DOACs: 188/725 (2.6%)
standard treatment: 181/727 (2.49%)
RR, 1.03; 95% CI 0.85–1.26; I², 15%
[Kahale 2018 a]
Cochrane Central Register
of Controlled Trials
(CENTRAL;2016, Issue 1),
MEDLINE (Ovid), Embase
(Ovid).
Handsearching conference
proceedings; checking
references of included
studies; use of the ’related
citation’ feature in PubMed
Search for ongoing studies
in trial registries.
Last search date 14 May
2018
16 RCTs, 5167 people with cancer and VTE.
8 studies enrolling 2327 participants
compared LMWH vs. VKA [CESARONE 2003] [DEITCHER 2006 (ONCENOX)] [HULL 2006] [LEE 2003 (CLOT)] [LEE 2015 (CATCH) ] [LOPEZ-BERET 2001] [MEYER 2002 (CANTHANOX)] [ROMERA 2009]
5 studies enrolling 982 participants
compared DOACs vs. VKA [AGNELLI 2015 (AMPLIFY)] [MAZILU 2014 (OVIDIUS) ] [PRINS 2014 (EINSTEIN)] [RASKOB 2016 (HOKUSAI)] [SCHULMAN 2015 (RECOVER I-II)]
2 studies enrolling 1455 participants
compared DOACs vs. LMWH [RASKOB 2018 (HOKUSAI)] [YOUNG 2018 (SELECT-D) ]
1 RCT with 284 participants compared
Idraparinux vs. VKA [VAN DOORMAAL 2010]
All-cause
mortality
Symptomatic
recurrent VTE
Major bleeding
Minor bleeding
Thrombocytopenia
Health-related
quality of life
Postphlebitic
syndrome
Hazard ratios (HRs) for time-to-
event data and risk ratios (RRs)
for dichotomous data, with 95%
confidence intervals (CI)
Certainty of the evidence at the
outcome level following the
GRADE approach
Risk of bias at the study level
using Cochrane’s ’Risk of
bias’ tool.
Heterogeneity between studies
assessed by inspection of
forest plots, I² test, and formal
statistical test of the significance
of the heterogeneity.
All cause mortality LMWH vs. VKA
RR 1.00, 95% CI 0.88 to 1.13; RD 0 fewer per
1000, 95% CI 45 fewer to 48 more; moderate-
certainty evidence; I²=0%
DOACs vs. VKA
RR 0.93, 95% CI 0.71 to 1.21; RD 12 fewer per
1000, 95% CI 51 fewer to 37 more; low-
certainty evidence; I²=0%
DOACs vs. LMWH
1.07, 95% CI 0.92 to 1.25; RD 27 more per
1000, 95% CI 30 fewer to 95 more; low-
certainty evidence; I²=27%
Idraparinux vs. VKA
RR 1.11, 95% CI 0.78 to 1.59; RD 31 more per
1000, 95% CI 62 fewer to 167 more; moderate-
certainty evidence
Symptomatic recurrent VTE LMWH vs. VKA
RR 0.58, 95% CI 0.43 to 0.77; RD 53 fewer per
1000, 95% CI 29 fewer to 72 fewer, moderate-
certainty evidence; I²=0%
DOACs vs. VKA
RR 0.66, 95% CI 0.33 to 1.31; RD 14 fewer per
1000, 95% CI 27 fewer to 12
more; low-certainty evidence; I²=0%
DOACs vs. LMWH
Supplementary appendix revised version 23 08 2019
33
RR 0.69, 95% CI 0.47 to 1.01; RD 36 fewer per
1000, 95% CI 62 fewer to 1 more; low-certainty
evidence; I²=52%
Idraparinux vs. VKA
RR 0.46, 95% CI 0.16 to 1.32; RD 42
fewer per 1000, 95% CI 65 fewer to 25 more;
low-certainty evidence
Major bleeding LMWH vs. VKA
RR 1.09, 95% CI 0.55 to 2.12; RD 4 more per
1000, 95% CI 19 fewer to 48 more, moderate-
certainty evidence; I²=46%
DOACs vs. VKA
RR 0.77, 95% CI 0.38 to 1.57, RD 8 fewer per
1000, 95% CI 22 fewer to 20 more;
low-certainty evidence; I²=0%
DOACs vs. LMWH
RR 1.71, 95% CI 1.01 to 2.88; RD 29 more per
1000, 95% CI 0 fewer to 78 more; low-certainty
evidence; I²=0%
Idraparinux vs. VKA
RR 1.11, 95% CI 0.35 to 3.56; RD 4 more
per 1000, 95% CI 25 fewer to 98 more; low-
certainty evidence
Minor bleeding LMWH vs. VKA
RR 0.78, 95% CI 0.47 to 1.27; RD 38 fewer per
1000, 95% CI 92 fewer to 47 more; low-
certainty evidence; I²=78%
DOACs vs. VKA
RR 0.84, 95% CI 0.58 to 1.22; RD 21 fewer per
1000, 95% CI 54 fewer to 28 more; low
certainty evidence; I²=14%
DOACs vs. LMWH
RR 1.31, 95% CI 0.95 to 1.80; RD 35 more per
1000, 95% CI 6 fewer to 92 more; low-certainty
evidence; I²=88%
Thrombocytopenia LMWH vs. VKA
RR 0.94, 95% CI 0.52 to 1.69
Supplementary appendix revised version 23 08 2019
34
[Al Yami 2018] MEDLINE
through December 26,
2017 for studies evaluating
the use of DOACs in
patients with cancer and
reporting VTE recurrence
and bleeding events.
Search was limited to peer
reviewed, phase III
randomized-controlled
trials (RCTs) and
post-hoc analyses of RCTs
8 studies
One study evaluated the use of apixaban in
patients with cancer [AGNELLI 2013].
3 studies evaluated dabigatran
[SCHULMAN2009] [SCHULMAN2014] [SCHULMAN2013]; 2 of them reported their
results as a pooled analysis in cancer
patients [ERIKSSON 2013]
2 studies evaluated Rivaroxaban
[BAUERSACHS2010] [BÜLLER2012]
2 studies evaluated Edoxaban [RASKOB 2016] [RASKOB 2018]
Venous
thromboembolism
recurrence
Major bleeding or
clinically relevant
non-major
(CRNM) bleeding
Major bleeding
Risk ratio (RR) and
corresponding 95% confidence
interval (CI were determined
using Mantel–Haenszel random-
effects model RR
I2 statistic to assess
heterogeneity between studies.
values < 25 were defined as
low, values between 25 and 50
as moderate, > 75% as high-
level heterogeneity
Recurrent VTE DOACs vs. LMWH or warfarin:
RR, 0.64; 95% CI 0.46–0.88
Major or CRNM bleeding DOACs vs. LMWH or warfarin:
RR, 1.00; 95% CI 0.75–1.33
Major bleeding DOACs vs.LMWH or warfarin:
RR, 1.31; 95% CI 0.71–2.44
[Xing 2018] Medline/PubMed and
EMBASE, from inception
through January, 2018
4 studies (n=667 cancer patients)
[NICKLAUS 2018] [SIGNORELLI 2017] [ALZGHARI 2017] [PRINS 2014]
Venous
thromboembolism
recurrence
Major bleeding
Death
Risk ratio (RR) and
corresponding 95% confidence
interval (CI were determined
using Mantel–Haenszel random-
effects model RR.
I2 statistic to assess
heterogeneity between studies.
Funnel plot to indicate the
publication bias
Recurrent VTE Rivaroxaban vs. enoxaparin:
RR, 0.55; 95% CI: 0.28–1.06; I2, 0%
Major bleeding Rivaroxaban vs. enoxaparin:
RR, 0.84; 95% CI: 0.39–1.83; I2, 0%
Death Rivaroxaban vs. enoxaparin:
RR, 0.51; 95% CI: 0.15–1.80; I2, 89%
[Vedovati 2018] Unrestricted search in
MEDLINE and EMBASE
through February 28th,
2018.
12 studies (n=4720 cancer patients)
[MEYER2002] [LEE 2003] [DEITCHER 2006] [HULL 2006] [ROMERA 2009] [PRINS 2014] [AGNELLI 2015] [LEE 2015] [SCHULMAN 2015] [RASKOB 2016] [RASKOB [2018] [YOUNG 2018]
Venous
thromboembolism
recurrence
Major bleeding
Bayesian arm
based random effect network
meta-analysis
I2 statistic to assess
heterogeneity between studies.
values < 25 were defined as
low, values between 25 and 50
as moderate, > 75% as high-
level heterogeneity
Recurrent VTE LMWHs vs. DOACs:
RR, 1.3; 95% CI: 0.9-2.0
VKAs vs. LMWHs:
RR, 1.5; 95% CI: 1.0-2.0
VKAs vs. DOACs:
RR, 2.0; 95% CI: 1.3-3.0; I2, 0%
Major bleeding LMWHs vs. DOACs:
RR, 0.7; 95% CI: 0.4-1.3
VKAs vs. LMWHs:
RR, 1.0; 95% CI: 0.6-1.6
VKAs vs. DOACs:
RR, 0.7; 95% CI: 0.4-1.2
I2, 23.2%
Supplementary appendix revised version 23 08 2019
35
Reference Inclusion period
Number of patients
analyzed/included
Follow-up Population Intervention VTE incidence Toxicity Death
[Francis 2015] International, multicenter,
single-arm, open-label
study in cancer patients
receiving treatment with
dalteparin for longer than
6 months and up to a year
334/344 until death or end
of study (12
months)
Patients ≥ 18 years with
active cancer diagnosed
within 6 months before
enrollment, or receiving
chemotherapy within the
previous 6 months, or had
documented
recurrent or metastatic
cancer with a
newly diagnosed
symptomatic proximal DVT,
PE, or both.
Observational study to
assess the rate of major
bleeding between 6 and 12
months when receiving
treatment with dalteparin
Incidence of adjudicated new or recurrent venous thromboembolism (deep vein thrombosis/pulmonary embolism) M7-12: 8/194 (4.1 %;95% CI 1.8 to
8.0%)
M1-6: 29/334 (8.7 %; 95% CI 5.9 to
12.2%)
Overall 37/334 (11.1 %; 95% CI 7.9 to
14.9%)
Major bleeding (n/subject months at risk) M7-12: 8/1086 (0.7 %;95% CI 0.3 to
1.4%)
M1-6: 26/1571 4 (1.7 %; 95% CI
1.1to 2.4%)
Overall 34/2657 (1.3 %; 95% CI 0.9t
o 1.89%)
116/334 patients
(33.8%)
[Jara Palomares 2017] Prospective, open, single
arm, multicentre study in
patients with CAT
receiving long-term
treatment with tinzaparin
247/295 until death or end
of study (12
months)
Patients with active cancer
and symptomatic, acute,
confirmed VTE (DVT or PE
or both). Active cancer was
defined as 1) diagnosis of
cancer in the 6 months
prior to inclusion in the
study (excluding basal or
squamous cell skin
carcinoma) or 2) having
received any oncological
treatment within the
previous 6 months, or
3) presence of metastasis
or cancer recurrence
Observational Overall 13/247 (5.3%; 95% CI 2.8
to 8.8%)
M1-6: 11/247 (4.5%; 95% CI 2.2 to
7.8%)
M7-12: 2/184 (1.1%;95% CI 0.1 to
3.9%)
Major bleeding M1-12: 12/247 (4.9%;
0.5%/pt/month)
M1-6: 7 (2.8%; 0.5%/pt/month)
M7-12: 5 (2.1%; 0.5%/pt-month)
Clinically relevant non major bleeding M1-12: 18/247 (7.2%;
0.9%/pt/month)
M1-6: 12 (4.8%; 0.6%/pt/month)
M7-12: 6 (2.4%; 0.8%/pt-month)
M1-6: 39/247
(15.8%; 95% CI
11.5 to 21%)
M1-M12: 62/247
(25.1%; 95% CI
19.8 to 31%)
[Chai-Adisaksopha 2018] Propensity score-matched
cohort study
Patients from RIETE
964/964 Median duration
of follow-up from
diagnosis of VTE
11.9 months (IQR
8.0-19.7 months).
Patients with active cancer
and symptomatic, acute,
confirmed VTE (DVT or PE
or both). Active cancer was
defined as newly (<3
months before) diagnosed
cancer, metastatic cancer,
or cancer that was being
treated (ie, surgery,
chemotherapy,
radiotherapy, support
therapy, or combined
therapies).
Patients were required to
have been treated for VTE
with LMWH for 6 months.
Propensity score matching
Group A: beyond 6 months,
482 patients continued to
receive LMWH
Group B: beyond 6
months, 482 patients were
switched to VKA
Recurrent DVT LMWH: 17/482 (2.97 Events per 100
Patient-Years)
VKA: 12/482 (1.68 Events per 100
Patient-Years)
long-term LMWH vs LMWH then
warfarin: RR 1.41; 95% CI 0.68-2.93
Recurrent PE LMWH :11/482 (1.92 Events per 100
Patient-Years)
VKA: 15/482 (1.96 Events per 100
Patient-Years)
Major bleeding LMWH: 18/482 (3.73%)
VKA: 20/482 (4.14%)
long-term LMWH vs LMWH then
warfarin: RR 0.96; 95% CI 0.51-1.79
Non major bleeding LMWH: 15/482 (3.11%)
VKA: 13/482 (2.69%)
long-term LMWH vs LMWH then
warfarin: RR 1.15; 95% CI 0.55-2.40
Death
LMWH: 79/482
(16.4%)
VKA: 50/482
(10.4%)
Most common
cause of death:
cancer-related.
Table 6: Early maintenance and long-term treatment of established VTE – prospective/retrospective
Supplementary appendix revised version 23 08 2019
36
References Bibliographic search Included studies Primary endpoint
Secondary endpoint Statistical tests Results
[Rojas-Hernandez 2018]
MEDLINE (OVID),
EMBASE, LILACS and the
Cochrane Central Register
of Controlled Trials
(CENTRAL) from inception
to March 2018.
PROSPERO registration
number CRD42016052213.
7 studies (n=1952 cancer patients):
[BARGINEAR 2012] [BARGINEAR 2009] [BRAILOVSKY 2014] [COOMBS 2015] [BRUNSON 2017] [MURIEL 2014] [KHAN 2016]
Recurrent VTE
Overall survival
Adverse effects
RR with 95% CI
I2 statistic to assess
heterogeneity between studies;
values of 25%, 50%, and 75% in
the I2 test corresponding to low,
medium, and high levels of
heterogeneity.
Recurrent VTE VCF vs. anticoagulation :
RR, 2.53; 95% CI 1.35–4.75; I2=76%
Overall Survival A meta-analysis could not be performed but
there was a trend against VCF
Bleeding VCF vs. anticoagulation :
RR 0.5; 95% CI 0.00-55.12
long-term LMWH vs LMWH then
warfarin: RR 0.73; 95% CI 0.34-1.58
Recurrent VTE long-term LMWH vs LMWH then
warfarin: HR 1.34; 95% CI 0.73-2.45;
P = 0.34
Fatal bleeding LMWH: 2/482 (0.62%)
VKA: 3/482 (0.41%)
long-term LMWH vs LMWH then
warfarin: RR 1.50; 95% CI 0.25-8.93
Reference Inclusion period
Number of patients analyzed/included Follow-up Population Intervention VTE incidence Toxicity Death
[Mellado 2016]
Propensity score-
matched cohort study
Patients from RIETE
Matched cohort: 65
patients with DVT
recurrence
and 139 patients
with PE recurrence
with IVC filter
placement for VTE
recurrence in the
first 3 months of
30 days after
VTE recurrence
Patients with
symptomatic,
objectively confirmed
DVT or PE with or
without cancer
(approximatively 40% of
cancer patients)
Patients with DVT recurrence Group A: 17 patients
treated with IVC filter
Group B: 49 patients
treated without
IVC filter
Patients with DVT recurrence Nonfatal recurrent VTE Group A: 2/17 (11.8%)
Group B: 2/49 (4.1%) OR 3.30, 95% CI 0.36–29.41; p= 0.29
Patients with PE recurrence Nonfatal recurrent VTE Group A: 2/48 (4.2%)
Patients with DVT recurrence Major bleeding Group A: 0/17 (0%)
Group B: 2/49 (4.1%) Patients with PE recurrence Major bleeding Group A: 2/48 (4.2%)
Group B: 3/91 (3.3%)
Patients with DVT recurrence Death Group A: 3/17 (17.7%)
Group B: 6/49 (12.2%) OR 1.49, 95% CI 0.39–5.67; p= 0.56
PE-related death Group A: 0/17 (0%)
Group B: 0/49 (0%)
Table 8: Treatment of VTE in patients with cancer – Vena Cava filters – prospective/retrospective
Table 7: Treatment of VTE in patients with cancer – Vena Cava filters – Systematic reviews with or without Meta-analysis
Supplementary appendix revised version 23 08 2019
37
anticoagulant
therapy
Patients with PE recurrence Group A: 48 patients
treated with IVC filter
Group B: 91 patients
treated without IVC
filter
Group B: 2/91 (2.2%) OR 2.13, 95% CI 0.18–25.81; p= 0.55
OR 1.11, 95% CI 0.19–6.63; p= 0.91 Patients with PE recurrence Death Group A: 1/48 (2.1%)
Group B: 23/91 (25.3%) OR 0.06, 95% CI 0.01–0.69; p= 0.02
PE-related death Group A: 1/48 (2.1%)
Group B: 16/91 (17.6%) OR 0.12, 95% CI 0.01–1.29; p= 0.08
Supplementary appendix revised version 23 08 2019
38
Reference Inclusion period
Number of patients
analyzed/included
Follow-up Population Intervention VTE incidence Toxicity Death
[Nagata 2015] prospective,
randomized controlled
trial
30/45 patients 11 days
post
surgery
Women ≥ 40 years
with a weight of 40 kg or more, and who
were undergoing major abdominal or
pelvic surgery for diagnosed or
suspected gynecologic malignancy
Arm A: IPC immediately prior to
surgery, followed by
postoperatively enoxaparin 20mg
injected SC every 12 h
Arm B: IPC immediately prior to
surgery, followed by IPC until full
ambulation
VTE Arm A: 1/15 (6.7%)
Arm B: 5/14 (35.7%)
P=0.08
PE Arm A: 0
Arm B: 3/14 (21.4%)
P=0.10
DVT Arm A: 1/16 (6.3%)
Arm B: 3/14 (21.4%)
P=0.32
Decrease in hemoglobin concentration > 2 g/dL from the morning of postoperative day 2 Arm A: 2/16 12.5%)
Arm B: 1/14 (7.1%)
P=1.0
-
[Dong 2018] prospective,
randomized controlled
trial
Oct 2010 - Sep 2011
90/111 patients 7 days
post
surgery
Patients >18 years and < 80 years
undergoing thoracotomy
Arm A: IPC for 30 minutes, bid and
ES, followed by postoperatively sc
nadroparin 2850 IU od for 7 days
Arm B: IPC for 30 minutes, bid
and ES
PE Arm A: 7/40(17.50%)
Arm B: 4/50 (8.0%)
p=ns
DVT Arm A: 2/40 (5%)
Arm B: 4/50 (8.0%)
p=ns
No difference in hemoglobin
levels, platelet count at day 7
post surgery
-
[Jung 2018] prospective, single
center (Seoul St Mary’s
Hospital in
Seoul, South Korea),
randomized controlled
trial
August 2011- March
2015
341/341 patients 30 days
post
surgery
Patients with histologically
confirmed gastric adenocarcinoma
presenting to a
Arm A: IPC alone initiated
preoperatively and continued
until discharge
Arm B: IPC alone initiated
preoperatively and continued
until discharge + LMWH
administered after surgery once
daily at a daily dose of 40 mg
beginning on the day of surgery.
VTE Arm A : 3.6%; 95%CI,
2.05-6.14%
Arm B : 0.6%; 95%CI,
0.17-2.18%
P= 0.008
DVTs detected by DUS, Arm A: 3.3%
Arm B: 0.6%
P=0.007
PE Arm A: 0.3%
Arm B: 0%
Bleeding Arm A: 1.2%
Arm B: 9.1%
P<0.001
-
Table 9: Prophylaxis of VTE in surgical cancer patients- RCT
Supplementary appendix revised version 23 08 2019
39
3.6%; 95%CI, 2.05%-
6.14%vs 0.6%; 95%CI,
0.17%-2.18%; P = .008).
References Bibliographic search Included studies Primary endpoint Secondary endpoint Statistical tests Results Authors’ conclusions
[Fagarasanu 2016]
Cochrane Central Register of
Controlled Trials, MEDLINE,
and EMBASE, from inception
through May 2015.
Priori protocol registered at
PROSPERO (CRD42014014465)
7 studies (3RCTs and 4 prospective studies), providing rates of relevant
outcomes in 4807 patients undergoing major abdominal or
pelvic surgery for cancer receiving
perioperative standard-extended
thromboprophylaxis (ETP, 2-6
weeks) compared with those
receiving conventional
thromboprophylaxis (CTP, <2
weeks)
[BERGQVIST 2002] [KAKKAR 2010] [VEDOVATI 2014] [SCHMELER 2012] [SAMAMA 2013] [IBRAHIM 2014] [KUKREJA 2015]
DVT (symptomatic or
screened)
PE
Mortality
Major bleeding
- Overall estimated
effect size and
variation expressed
as RR with a 95 % CI
DerSimonian and
Laird random effects
model assumption to
adjust for within and
between-study
heterogeneity
Heterogeneity
between trials
assessed with I2
Funnel plot to assess
publication bias
All VTE (7 studies) ETP: 59/2292 (2.6 %)
CTP: 124/2209 (5.6 %)
RR 0.44, 95 % CI 0.28–
0.70, number needed to
treat (NNT)=39
Proximal DVT (5 studies) ETP: 14/966 (1.4 %)
CTP: 24/862 (2.8 %)
RR 0.46, 95 % CI 0.23–
0.91, NNT=71
Distal DVT (2 RCTs) ETP vs. CTP : RR 0.63, 95
% CI 0.32–1.22, NNT=30
All but one asymptomatic
PE ETP: 8/966 (0.8 %)
CTP: 11/862 (1.3 %)
RR 0.56, 95 % CI 0.23–
1.40, NNT=200
Major bleeding (4 studies) ETP: 14/787 (1.8 %)
CTP: 7/713 (1.0 %)
RR 1.19, 95 % CI 0.47–
2.97, NNT=125
Routine
pharmacological
thromboprophylaxis
for cancer patients
undergoing surgery
needs to be carefully
considered, because
although
thromboprophylaxis
is associated with
lower VTE events,
there is a higher
incidence of clinically
significant bleeding
events.
If pharmacological
thromboprophylaxis
is to be used,
extended
thromboprophylaxis
started
preoperatively with
LWMH might be the
most effective
strategy.
Table 10: Prophylaxis of VTE in surgical cancer patients- Systematic reviews with or without meta-analysis
Supplementary appendix revised version 23 08 2019
40
Mortality at 3 months ETP: 30/720 (4.2 %)
CTP: 23/643 (3.6 %)
RR 0.79, 95 % CI 0.47-
1.33, NNT=167
[Guo 2017] PubMed, Embase, and the
Cochrane Library from January
1, 1950 to March 31, 2016
Searching the ClinicalTrials.gov
website for randomized trials
that were registered as
completed
39 studies (16,366 patients with cancer): 20 studies (6238 patients)
provided data for patients with
cancer receiving perioperative
pharmacological
thromboprophylaxis compared
with those without
pharmacological
thromboprophylaxis; 13 studies
(8043 participants) provided
relevant outcome data for
participants with cancer receiving
perioperative UFH compared with
those receiving LMWH; 6 studies
provided rates of relevant outcome
for patients with malignancy
receiving perioperative standard-
extended thromboprophylaxis (at
least 4 weeks (compared with
those receiving conventional
thromboprophylaxis (2 weeks)
[MARASSI 1993] [AILAWADI 2001] [FRIIS 2004] [SHUKLA 2008] [VIVARELLI 2010] [SAKON 2010] [PATEL 2011] [GAVRIEL 2012] [TSUTSUMI 2012] [SANDADI 2012] [MITA 2012] [KEITH 2013] [YAMASHITA 2014] [SONG 2014] [BOUCHARD-FORTIER 2014] [SUNG 2014] [YAMAOKA 2015] [NAGATA 2015] [KIMURA 2016] [ONARHEIM 1986] [FRICKER 1988] [EFS GROUP 1988] [DAHAN 1989] [GALLUS 1993] [GODWIN 1993] [HEILMANN 1998] [ENOXACAN 1997] [BAYKAL 2001]
Rates of DVT
Incidence of PE
Incidence of bleeding
Mortality
- Risk ratios (RRs) and
95% confidence
intervals (CIs) for
dichotomous data
Heterogeneity
between trials
assessed with I2 : I2
less than 25% judged
as showing low
heterogeneity, I2=
25% -50% judged as
showing moderate
heterogeneity, I2
greater than 50%
judged as showing
substantial
heterogeneity.
Funnel plot to assess
publication bias
Pharmacological Thromboprophylaxis vs. No Pharmacological Thromboprophylaxis
Rates of DVT (20 studies, 6201 patients) Pharmacological
Thromboprophylaxis:
42/3443 (0.5%)
No Pharmacological
Thromboprophylaxis:
15/2758 (1.2%)
RR 0.51, 95% CI 0.27–
0.94, p=0.03
Rates of PE (19 studies, 6140 patients) Pharmacological
Thromboprophylaxis:
10/3412
No Pharmacological
Thromboprophylaxis:
9/2728
RR 1.77, 95% CI 0.76–
4.14, p=0.19
Rates of bleeding (13 studies, 4316 patients) Pharmacological
Thromboprophylaxis:
57/2116
No Pharmacological
Thromboprophylaxis:
1766/2200
RR 2.51, 95% CI 1.79–
3.51, p<0.00001
UFH vs. LMWH
Routine
pharmacological
thromboprophylaxis
for cancer patients
undergoing surgery
needs to be carefully
considered, because
although
thromboprophylaxis
is associated with
lower VTE events,
there is a higher
incidence of clinically
significant bleeding
events.
If pharmacological
thromboprophylaxis
is to be used,
extended
thromboprophylaxis
started
preoperatively with
LWMH might be the
most effective
strategy.
Supplementary appendix revised version 23 08 2019
41
[BONCINELLI 2001] [MCLEOD 2001] [DEBERNARDO JR 2005] [CHANGOLKAR 2014] [BERGQVIST 2002] [KAKKAR 2010] [SCHMELER 2013] [VEDOVATI 2014] [KUKREJA 2015] [VASQUEZ 2015]
DVT (12 studies, 7719 patients) LMWH : 164/2717
patients
UFH : 75/5002 patients
RR 0.81, 95% CI 0.66–
1.00, P = 0.05, I²=0%
PE (12 studies, 7719 patients) LMWH : 28/2721 patients
UFH : 48/4998 patients
RR 0.98, 95% CI 0.45–
2.13, P = 0.96, I²=33%
Bleeding (7 studies, 6593 patients) LMWH: 270/2142
patients
UFH: 320/4451 patients
RR 0.73, 95% CI 0.49–
1.08, P = 0.11, I²=75%
Standard Extended Thromboprophylaxis Versus Conventional Thromboprophylaxis DVT (6 studies, 1948 patients) conventional: 69/969
patients
extended: 42/979
patients
RR 0.57, 95% CI 0.39-
0.83, P=0.003, I²=0%
PE (6 studies, 1948 patients) conventional: 13/969
patients
extended:9/979 patients
RR 0.66, 95% CI 0.29–
1.52, P = 0.33; I²=0%
Bleeding (4 studies, 1165 patients) conventional: 15/627
patients
Supplementary appendix revised version 23 08 2019
42
extended: 22/538
patients
RR 1.48, 95% CI 0.78–2.8
P=0.23 I²=0%
[Felder 2018] Cochrane Central Register of
Controlled Trials, MEDLINE,
Embase, LILACS and registered
trials (Clinicaltrials.gov October
28, 2017 and World Health
Organization International
Clinical Trials Registry
Platform (ICTRP) 28 October
2017).
Abstract books from major
congresses addressing
thromboembolism
handsearched from
1976 to 28 October 2017, as
reference lists from relevant
studies
7 RCTs (1728 participants) evaluating prolonged
thromboprophylaxis with LMWH
compared with control or placebo.
[BERGQVIST 2002] [JØRGENSEN 2002] [LAUSEN 1998] [RASMUSSEN 2006] [KAKKAR 2010] [SAKON 2010] [VEDOVATI 2014]
Incidence of overall
VTE after major
abdominal or pelvic
surgery as assessed
by objective means
(venography,
ultrasonography,
pulmonary
ventilation/perfusion
scintigraphy, spiral
computed
tomography (CT) scan
or autopsy)
Incidence of all DVT
Incidence of proximal
DVT
Incidence of
symptomatic DVT
Bleeding
Mantel Haentzel
(MH) odds ratios (OR)
with 95% confidence
intervals (CIs). As the
included studies were
relatively clinically
homogeneous, we
applied a fixed-effect
model.
A P value < 0.05was
considered to
represent statistical
significance.
Cochrane’s tool for
assessing risk of bias
Incidence of overall VTE after major abdominal or pelvic surgery (7 studies,
n = 1728) Control group: 13.2%
Patients receiving out-of-
hospital LMWH: 5.3%
OR 0.38, 95% CI 0.26-
0.54; I2 = 28%; moderate-
quality evidence.
Incidence of all DVT after major abdominal or pelvic surgery (7 studies,
n = 1728)
Patients receiving out-of-
hospital LMWH vs.
control group
OR 0.39, 95% CI 0.27-
0.55; I2 = 28%; moderate-
quality evidence
incidence of proximal DVT after major abdominal or pelvic surgery (7 studies, n =
1728)
Patients receiving out-of-
hospital LMWH vs.
control group
OR 0.22, 95% CI 0.10-
0.47; I2 =0%; moderate-
quality evidence.
incidence of symptomatic DVT after major abdominal or pelvic surgery (7 studies,
n = 1728)
control group: 1.0%
prolonged
thromboprophylaxis:
0.1%
Prolonged
thromboprophylaxis
with LMWH
significantly reduces
the risk of VTE
compared to
thromboprophylaxis
during hospital
admittance only,
without increasing
bleeding
complications after
major abdominal or
pelvic surgery. This
finding also holds
true for DVT alone,
and for both
proximal and
symptomatic DVT.
The quality of the
evidence is moderate
and provides
moderate support for
routine use of
prolonged
thromboprophylaxis.
Supplementary appendix revised version 23 08 2019
43
OR 0.30, 95% CI 0.08-
1.11; I2 = 0%; moderate-
quality evidence.
incidence of bleeding (7
studies, n = 2239)
control group: 2.8%
LMWH group: 3.4%
OR 1.10, 95% CI 0.67-
1.81; I2 = 0%; moderate-
quality evidence).
[Carrier 2018] Pubmed, Medline, EMBASE,
the Cochrane Central Register
of Controlled Trials (all time to
July 2017), in addition to the
American Society of
Hematology, the International
and the North American
Societies on Thrombosis and
Haemostasis, and the
Mediterranean League against
Thrombosis conference
databases (July 2015 to July
2017) searched using the
terms surgery, cancer,
thromboprophylaxis and
clinical study (or respective
aliases) while following
Cochrane Intervention Review
methodological
Supplemental bibliographic
search of recent review
articles and directed searches
for updated reports of specific
studies
6 RCTs
[BERGQVIST 2002] [JØRGENSEN 2002] [LAUSEN 1998] [RASMUSSEN 2006] [KAKKAR 2010] [VEDOVATI 2014]
7 meta-analysis
[FAGARASANU 2016] [GUO 2017] [BOTTARO 2008] [RASMUSSEN 2009] [AKL 2008] [RASMUSSEN 2003] [JØRGENSEN 2002]
5 non-randomized clinical trials
[SAMAMA 2014] [SCHEMELER 2013] [KUKREJA 2015] [PARISER 2017] [IBRAHIM 2014]
Rates of VTE, DVT and
PE
Incidence of bleeding
No meta-analysis
performed
Available evidence
showed significantly
reduced rates of VTE
for extended versus
standard LMWH
thromboprophylaxis
following
abdominopelvic
cancer surgery, with
some studies
showing trends
toward reduced rates
of symptomatic VTE
events. Many of
these studies showed
significantly reduced
rates of proximal DVT
and some showed
trends toward
reduced PE,
suggesting
potentially important
clinical benefits
Reference Inclusion period
Number of patients analyzed/included Follow-up Population Intervention VTE incidence Toxicity Death
Table 11: Prophylaxis of VTE in surgical cancer patients- – prospective/retrospective
Supplementary appendix revised version 23 08 2019
44
[Pariser 2017]
retrospective, single
institution study
January 2011-May
2014
402 patients were
included in analysis,
including 234
treated with
heparin alone
(January 2011 to
January 2013)
and 168 on the
extended duration
enoxaparin regimen
(January 2013 to
May 2014
90 days Patients undergoing
radical cystectomy
Arm A: subcutaneous
5000 U heparin given
before induction and
continued every 8 hours
postoperatively until
discharge home
Arm B: single dose of
subcutaneous heparin
before induction
followed by 40 mg
enoxaparin daily
postoperatively,
continued during
hospitalization and for
28 days after discharge.
VTE at 90 days: Arm A: 28/234(12%)
Arm B: 9/168 (5%)
P=0.024
DVT at 90 days: Arm A: 22/234(9%)
Arm B: 7/168 (4%)
P=0.045
PE at 90 days: Arm A: 10/234(4%)
Arm B: 4/168 (2%)
P=0.307
Post discharge VTE: Arm A: 14/234(6%)
Arm B: 3/168 (2%)
P=0.039
Extended duration enoxaparin regimen
associated with decreased odds of VTE
OR 0.33, 95% CI 0.14-0.76, p=0.009.
Postoperative blood transfusions: Arm A: 103/234(44%)
Arm B: 82/168 (49%)
P=0.342
-
[Kim 2017] prospective, single
institution study
August 2013 to April
2016
124 patients 5 years patients undergoing
liver resection for
malignancy receiving an
extended
pharmacologic
thromboprophylaxis
protocol
thromboembolic
deterrent hoses
and sequential
compression devices
activated
prior to anesthesia
induction, followed by
subcutaneous UFH
(5000 mg every 8 h),
converted to
daily subcutaneous
enoxaparin (40 mg)
between POD 1
and POD 3, and
continued on
enoxaparin for the
remainder
of the hospitalization. extended for 14 total
days from the day of
surgery, and after major
hepatectomy, in those
patients discharged
with a drain or with a
history
VTE: 0 (0%)
DVT: 0 (0%) PE: 0 (0%)
Bleeding event: 2/124 (1.6%)
Intraoperative transfusion: 7/124
(5.6%)
Postoperative transfusion: 10/124
(8.1%)
-
Supplementary appendix revised version 23 08 2019
45
of VTE, for a total of 28
days.
[Schomburg 2018] retrospective, single
institution study
January 2012-
December 2015
130 patients were
included in analysis,
including 51 treated
with heparin alone
(January 2011 to
January 2013)
and 79 on the
extended duration
enoxaparin regimen
(January 2013 to
May 2014
90 days Patients undergoing
radical cystectomy for
urothelial carcinoma
Arm A: single dose of
subcutaneous heparin.
given before induction
followed by
subcutaneous
heparin/LMWH until
discharge home
Arm B: single dose of
subcutaneous heparin.
given before induction
followed by
subcutaneous
heparin/LMWH for 30
days postoperatively
VTE at 90 days: Arm A: 17.6%
Arm B: 5.06%
P=0.021
extended prophylaxis associated with
decreased odds of VTE: OR 0.22, 95%CI
0.06–0.89; P=0.03
Bleeding complications: Arm A: 1/51 (2%)
Arm B: 3/79 (3.7%)
P=0.55
-
Supplementary appendix revised version 23 08 2019
46
Reference Inclusion period
Number of patients analyzed/included Follow-up Population Intervention VTE incidence Toxicity Death
[Khorana 2017- PHACS Study] Randomized,
multicenter clinical
trial
Aug 2009 - Dec 2013
98/98 12 weeks. Patients >18 years
planned for initiation of a
new systemic
chemotherapy regimen,
at high-risk for
developing VTE, based on
a Khorana risk score ≥3
VTE defined as
symptomatic lower
extremity DVT, PE and
upper extremity
thrombosis as well as
all unsuspected DVT and
PE.
Arm A: dalteparin 5000
units daily for 12 weeks
Arm B: observation arm
Limitations: the study did not accrue to its planned sample size (404 subjects to have 80% power to detect a 60% reduction in VTE) and, at time of termination, remained under-powered.
VTE Arm A: 6/50 (12%) Arm B: 10/48 (21%) HR 0.69, 95% CI 0.23-1.89
P=0.37
Clinically significant non-major bleeding or major bleeding Arm A: 7/50 (14%) Arm B: 1/48 (2%) HR 7.0, 95% CI 1.2-131.6
P= 0.025
Death from any cause: Arm A: 8/50(16%)
Arm B: 6/48 (13%)
[Ek 2018-RASTEN study] randomized,
multicenter, open-
label trial
2008–2016
377/390 6 months Patients with newly
diagnosed small-cell lung
cancer (SCLC) of all
stages
Arm A: standard cancer
treatment + enoxaparin at a
supraprophylactic dose
(1 mg/kg)
Arm B: standard cancer
treatment (control arm)
VTE Arm A: 5/186 (2.7%) Arm B: 16/191 (8.4%) HR 0.31, 95% CI 0.11–0.84
P=0.02
Pulmonary bleeding Arm A: 14/186 (8%) Arm B: 3/191 (2%) Bleeding, other sites Arm A: 13/186 (7%) Arm B: 5/191 (3%)
1-year survival overall survival Arm A: 48% Arm B: 47% HR 0.98, 95% CI 0.74–1.30
P = 0.92
[MEYER 2018-TILT study] randomized,
multicenter, open-
label trial
2007–2013
377/390 Median follow-
up 5.7 years
Patients with completely
resected stage I, II or IIIA
NSCLC
Arm A: subcutaneous
tinzaparin 100 IU/kg once a
day for 12 weeks
Arm B: no treatment on
top of standard of care.
(control arm°
VTE Arm A: 18/377 (6.7%) Arm B: 20/390 (7.1%) SHR 0.95, 95% CI 0.68-1.32
P=0.75
Serious non-fatal bleeding
Arm A: 1
Arm B: 0
Minor bleeding Arm A: 1 (0.4%)
Arm B: 19 (7.1%)
P < 0.001
Overall survival Arm A: 68.2%, 95% CI, 62.5%-
74.4%
Arm B : 74.2%, 95% CI, 68.9%-
79.9% HR, 1.24; 95% CI, 0.92-1.68;
P=0.17
[KHORANA 2019-CASSINI study] double-blind,
randomized, placebo-
controlled, parallel-
group, multicenter
study
841/1080 6 months Adult ambulatory
patients with various
cancers initiating a new
systemic regimen and at
increased risk for VTE
(defined as Khorana
score ≥ 2).
Arm A: rivaroxaban 10 mg
once daily up to day 180
Arm B: placebo up to day
180
VTE at 6 months Arm A: 25/420 (5.95%) Arm B: 37/421 patients (8.79%) HR, 0.66; 95% CI, 0.40-1.09;
p=0.101; NNT=35
VTE during the on-treatment period Arm A: 11/420 (2.62%) Arm B: 27/421 (6.41%) HR 0.40, 95% CI 0.20 to 0.80,
p=0.007; NNT=26
Major bleeding Arm A: 8/405 (1.98%)
Arm B: 4/404 (0.99%) HR, 1.96; 95% CI, 0.59-6.49;
p=0.265; NNH=101).
Clinically relevant non-major bleeding Arm A: 2.72%
Arm B: 1.98% HR, 1.96; 95% CI, 0.59-6.49;
p=0.265; NNH=101.
All-cause mortality Arm A: 20.0%
Arm B: 23.8% HR, 0.83, 95% CI 0.62-1.11;
p=0.213.
Table 12: Prophylaxis of VTE in medical cancer patients - Randomized Controlled Trials
Supplementary appendix revised version 23 08 2019
47
[CARRIER 2019 AVERT study] double-blind,
randomized, placebo-
controlled,
multicenter study
563/574 6 months Ambulatory cancer
patients receiving
chemotherapy who are
at high-risk for VTE (as
defined by a Khorana
score of ≥2)
Arm A: apixaban 2.5 mg
twice daily up to day 180
Arm B: placebo up to day
180
VTE at 6 months Arm A: 12/288 (4.2%)
Arm B: 28/275 (10.2%)
HR, 0.41; 95% CI, 0.26-0.65;
P<0.001
Major bleeding Arm A: 10/288(3.5%)
Arm B: 5/275(1.8%)
HR, 2.00; 95% CI, 1.01-3.95;
p=0.046
Clinically relevant non-major bleeding Arm A: 21/288 (7.3%)
Arm B: 15/276 (5.5%)
HR, 1.28; 95% CI, 0.89-1.84
All-cause mortality Arm A: 35/288 (12.2%) Arm B: 27/275 (9.8%)
HR, 1.29; 95% CI, 0.98–1.71
Supplementary appendix revised version 23 08 2019
48
References Bibliographic search Included studies Primary
endpoint
Secondary
endpoint Statistical tests Results Authors’ conclusions
[Di Nisio 2016] Cochrane Vascular Group
Specialised Register (June 2016)
)– constructed from MEDLINE,
EMBASE, CINAHL, AMED; and
through hand-searching relevant
journals
Cochrane Central Register of
Controlled Trials (CENTRAL)
(2016, Issue 5).
12352 ambulatory cancer patients 26 RCT comparing any oral
or parental anticoagulant
(UFH, LMWH, uLMWH,
VKAs) to no intervention or
placebo or two different
anticoagulants in 12352
patients with cancer
receiving chemotherapy
[AGNELLI2012] [AGNELLI2009] [ALTINBAS 2004] [ELIT 2012] [HAAS 2012] [KAKKAR 2004] [KHORANA 2015] [KLERK 2005] [LAROCCA 2012] [LECUMBERRI 2013] [MACBETH 2016] [MARAVEYAS 2012] [PALUMBO 2011] [PELZER2015] [PERRY 2010] [SIDERAS 2006] [VADHAN-RAJ 2013] [VANDOORMAAL 2011] [ZWICKER 2013] [LEBEAU 1994] [CHAHINIAN 1989] [LEVINE 1994] [MAURER 1997 [PALUMBO 2011] [ZACHARSKI 1981] [MITCHELL 2003] [LEVINE 2012]
symptomatic
VTE,
objectively
verified
major
bleeding
symptomatic PE
symptomatic DVT
unsuspected
(incidental) VTE
overall VTE
clinically relevant
bleeding (major
and clinically
relevant non-
major bleeding)
minor bleeding
one-year overall
mortality
arterial
thromboembolic
events;
superficial venous
thrombosis
quality of life
any serious
adverse event.
When possible, authors extracted
the results from an intention-to-
treat analysis
Risk ratios for dichotomous
variables determining a 95%
confidence interval (CI) for each
estimate
Inverse-variance random effects
model used to combine trials
(DerSimonian and Laird method)
In the case of statistically
significant overall estimates,
number needed to treat for an
additional beneficial outcome
(NNTB) or number needed to
treat for an additional harmful
outcome (NNTH)
Assessed heterogeneity between
trials through Tau2 statistic (low
heterogeneity >0.04; moderate
>0.09; high >0.16)
Assessed bias using funnel plots
LMWH compared to no thromboprophylaxis Symptomatic VTE significant reduction in
symptomatic VTE with LMWH:
RR 0.54, 95% CI 0.38-0.75; 9
studies; 3284 participants
Tau2=0
NNTB 30; 95% CI 23-56 assuming
a background risk of 71
symptomatic VTE events per
1000 patients
Major bleeding No statistically significant
difference:
RR 1.44, 95% CI 0.98-2.11; 6356
participants; 13 studies
Symptomatic PE significant reduction in
symptomatic PE with LMWH:
RR 0.59, 95% CI 0.40-0.86; 5226
participants; 7 studies Tau2=0
NNTB 174, 95% CI 119-510
Symptomatic DVT significant reduction in
symptomatic DVT
RR 0.49, 95% CI 0.35-0.67; 310
participants; 8 studies;
Tau2=0
NNTB 68, 95% CI 53-105
Overall VTE significant reduction in overall
VTE
RR 0.59, 95% CI 0.48-0.73; 5366
participants; 9 studies
Tau2=0
NNTB 25, 95% CI 20-38
Primary thromboprophylaxis
with LMWH significantly
reduced the incidence of
symptomatic VTE in
ambulatory cancer patients
treated with chemotherapy
The risk of major bleeding
associated with LMWH, while
not reaching statistical
significance, suggest caution
and mandate additional
studies to determine the risk-
to-benefit ratio of LMWH in
this setting.
Although the results are
promising, routine use of
prophylaxis in ambulatory
cancer patients cannot be
recommended until the safety
issue (i.e increased bleeding
risk) are adequately
addressed.
Table 13: Prophylaxis of VTE in medical cancer patients – Systematic reviews with or without Meta-analyses
Supplementary appendix revised version 23 08 2019
49
Clinically relevant bleeding
significant increase in clinically
relevant bleeding with LMWH
RR 3.40, 95%CI 1.20-9.63; 3105
participants; 4 studies;
Tau²= 0.73
no statistically significant benefit
or harm for incidental VTE, minor
bleeding, 1-year mortality,
symptomatic arterial
thromboembolism, superficial
venous thrombosis, or serious
adverse events
LMWH compared to warfarin or aspirin in participants with multiple myeloma significant reduction in
symptomatic VTE compared to
warfarin
RR 0.33, 95% CI 0.14-0.83
no statistically significant
difference compared to aspirin
RR 0.51, 95% CI 0.22-1.17
Major bleeding was observed in
none of the participants treated
with LMWH or warfarin and in
less than 1% of those treated
with aspirin.
UFH compared to no thromboprophylaxis Only one study, no report on VTE
or major bleeding.
warfarin compared to placebo or no thromboprophylaxis no statistically significant
reduction of symptomatic VTE RR
0.15, 95% CI 0.02-1.20
Antithrombin compared to no antithrombin
Supplementary appendix revised version 23 08 2019
50
one study involving paediatric
patients, no significant effect on
VTE or on major bleeding when.
Apixaban compared to placebo one phase II dose-finding study
suggested a low rate of major
bleeding (2.1% versus 3.4%) and
symptomatic VTE (1.1% versus
13.8%) with apixaban in
comparison with placebo.
.
[Tun 2016] Literature search using MEDLINE
and EMBASE databases up to
May 2015
2 RCTs, 738 ambulatory
advanced pancreatic cancer
(APC) patients receiving
chemotherapy and a
subgroup of another 2 RCTs
[PELZER 2015] [MARAYEVAS 2012] [AGNELLI 2009] [AGNELLI 2012]
Incidence
rates of
symptomatic
VTE
Incidence rates
of major bleeding
Mantel-Haenszel method was
used to estimate the pooled
event-based risk ratio as well as
the pooled absolute risk
difference with 95% confidence
interval (CI)
Fixed effects model because no
significant heterogeneity among
included studies
VTE Crude VTE incidence
LMWH group: 2.1 %
Control group : 11.2%
RR 0.18, 95% CI 0.083-0.39,
P < 0.0001
Absolute risk difference in VTE -
0.092, 95% CI -0.127 to -0.057;
P < 0.0001
Estimated number needed to
treat of 11 patients to prevent
one symptomatic VTE event.
Major bleeding LMWH group: 4.1 %
Control group: 3.3%
pooled risk ratio 1.25, 95% CI,
0.48-3.3, P = 0.65
These findings are encouraging
to deploy PTP in APC patients
receiving chemotherapy,
uncertainties remain as to its
survival benefit, optimal PTP
duration, type and dose of
LMWH, and costs of care.
Therefore, adequately
powered randomized phase III
studies are warranted to
address these questions.
[Yu 2016] Literature search using PubMed,
Embase, and The Cochrane
Central Register of Controlled
Trials database
1393 participants from 6
studies with 753 patients in
the heparin group, and 640
patients in the control
group.
The intervention was UFH in
one study [Lebeau 1994] and
LMWH in 5 studies
[ALTINBAS 2004], [LECUMBERRI 2013], [ VAN DOORMAAL 2011], [AGNELLI 2009], [HAAS 2012] Four studies reported
survival outcomes.
Survival
Outcome
symptomatic DVT,
Symptomatic
pulmonary
embolism, and all
reported
thromboembolic
events, adverse
effects including
major bleeding,
minor bleeding,
and
Thrombocytopenia
Hazard Ratio (HR) between the
survival distributions to estimate
the survival outcome
I² statistics to quantify the
heterogeneity across the studies
Survival Heparin vs. control :
All : HR 0.71 , 95% CI 0.60-0.84,
limited-stage SCLC : HR 0.57, 95%
CI 0.43-0.77,
VTE RR 0.46, 95% CI 0.27-0.80
Bleeding RR 1.53, 95% CI 0.96-2.45,
Major bleeding RR 1.43, 95% CI 0.59-3.45
Thrombocytopenia
Administration of heparin
(mainly LMWH) as primary
thromboprophylaxis for lung
cancer patients without
indication for anticoagulants
was associated with a
significant survival benefit,
particularly in limited-stage
SCLC.
Supplementary appendix revised version 23 08 2019
51
RR 0.86, 95% CI 0.66-1.12
[Al-Ani 2016] MEDLINE (1946 to 2015),
EMBASE (1946 to 2015),
CENTRAL (1946 to 2015) using
an OVID interface (1946 to 2015)
(Appendix). Hand search of
journals and of the American
Society of Hematology (ASH) and
the American Society of
Oncology (ASCO) Conference
proceedings (1946–2015)
6 studies, 1125 patients with
newly diagnosed multiple
myeloma (NDMM) or
relapsed refractory multiple
myeloma (RRMM), treated
with lenalidomide
[KLEIN 2008] [ZONDER 2010] [LAROCCA 2011] [STEWART 2015] [PALUMBO 2012] [RAJKUM 2010]
Incidence
rates of
symptomatic
VTE
Incidence rates of
all bleeding
Incidence rates of
major bleeding
RR with 95% CI
Methodological quality of the
selected prospective or
retrospective cohort studies was
assessed according to Newcastle-
Ottawa Quality Assessment
Scale,
risk of bias of RCTs assessed
according to risk of bias
assessment tool from the
Cochrane Handbook
Risk of VTE in patients
NDMM patient receiving ASA:
98/915 (10.7%)
NDMM and RRMM patients
receiving LMWH: 3/211 (1.4%)
Significantly higher VTE risk for
patients receiving lenalidomide
plus high-dose dexamethasone
on ASA prophylaxis compared to
lenalidomide plus low-dose
dexamethasone: RR 2.5, 95% CI
1.68–3.96, P =0.0001
Significantly higher risk of VTE in
patients receiving lenalidomide
and dexamethasone alone
compared to those on Mephalan
prednisolone and lenalidomide
while on ASA prophylaxis:
RR 6.4, 95% CI 4.11–9.91,
p=0.0001
Aspirin may not confer
appropriate
thromboprophylaxis in
patients receiving
lenalidomide plus high-dose
dexamethasone, but may be a
safe option in patients
receiving.
Mephalan prednisolone and
lenalidomide
The IMWG VTE risk
stratification criteria should be
validated, incorporating
the thromboprophylaxis
option accordingly.
More studies comparing the
efficacy and safety of ASA to
LMWH are warranted.
[Fuentes 2017] Ovid, Scopus, DARE, CINAHL,
MEDLINE, EMBASE, EBM
reviews-Cochrane database of
systematic reviews, EBM
reviews-ACP journal, and EBM
Reviews-Databases for relevant
studies following the Preferred
Reporting Items for Systematic
Reviews and Meta-Analyses
(PRISMA) guidelines from 1945
to 2016
5107 lung cancer patients
from 11 RCTs comparing any
oral or parental
anticoagulant (UFH, LMWH,
uLMWH, VKAs) to no
intervention or placebo
(7 studies on SCLC, 1 studies
on NSCLC and one study on
both SCLC and NSCLC)
[STANFORD 1979] [ZACHARSKI 1981] [CHAHINIAN 1989] [LEBEAU 1994] [MAURER 1997] [MAURER 2004] [VAN DOORMAAL 2011] [AGNELLI 2012] [HAAS 2012] [LECUMBERRI 2013]
VTE safety outcome,
major bleedings
all-cause mortality
OR and the random-effects
I2 and Q statistics to assess
heterogeneity between studies
(considered high heterogeneity I2
75% or greater)
Random-effects model presented
in cases of significant
heterogeneity
Funnel plots to detect publication
bias
VTE: 6%
LMWH vs. control (5 studies) : OR
0.50, 95% CI 0.38–0.66, I²= 0%
Bleedings: 20% (8 studies):
Any thromboprophylaxis : OR
3.06, 95% CI 1.64–5.72,; I²=
64.4%
LMWH: OR 2.03,; 95% CI 0.78–
5.25,; I²= 71.1%
warfarin: OR 5.42, 95% CI 3.48–
8.45, I²=45.7%
Mortality (8 studies):
Any thromboprophylaxis : OR
0.75, 95% CI 0.58–0.96, I²= 18.4%
LMWH: OR 0.74, 95% CI 0.49–
1.11, I²= 56.9%
warfarin: OR 0.75, 95% C: 0.47–
1.21, I²= 0%
Primary VTE prophylaxis with
LMWH reduces the occurrence
of VTE among ambulatory
patients with lung cancer with
a small but relevant
improvement, without
apparent increase in bleeding
risk.
Supplementary appendix revised version 23 08 2019
52
[MAC BETH 2016]
No significant statistical
difference when studies were
combined by the type of lung
cancer:
NSCLC : OR 0.80, 95% CI 0.64–
1.00, I²=0%
SCLC : OR 0.49, 95% CI 0.23–
1.02, I²= 38.9%
[Thein 2017] MEDLINE and EMBASE through
June 30, 2016.
4315 lung cancer patients
from 6 RCTs comparing
LMWH to no intervention or
placebo [ALTINBAS 2004] [AGNELLI 2009] [HAAS 2012] [AGNELLI 2012] [LECUMBERRI 2013] [MAC BETH 2016]
VTE major bleeding
events, CRNM
bleeding events
survival outcome
Risk ratios (RRs) and 95%
confidence intervals (CIs) for
dichotomous data were
estimated using the Mantel-
Haenszel method
fixed effects model was applied
as there was no significant
heterogeneity among the
included studies.
VTE LMWH group: 89/2221(4.0%)
Control group: 166 /2094 (7.9%)
RR 0.51, 95% CI 0.397–0.654, P <
0.001
Major bleeding (4 RCTS) LMWH group 1.5%
Control group: 1.0%
RR 1.468, 95% CI 0.785–2.746, P
= 0.229
CRNM bleeding (4 RCTS) LMWH group: 5.57%
Control group: 1.67%
RR 3.253; 95% CI 2.092–5.059; P
< 0.001
Survival outcome (2RCTs) HR 1.020; 95% CI 0.938–1.109, P
= 0.648
Routine thromboprophylaxis
for ambulatory lung cancer
patients receiving
chemotherapy is not
recommended and further
studies are necessary to define
a subset of ambulatory LC
patients receiving
chemotherapy who may
benefit from PTP
[Akl 2017] Cochrane Central Register of
Controlled Trials (CENTRAL)
(2016, Issue 1), MEDLINE (1946
to February 2016; ccessed via
OVID) and Embase (1980 to
February 2016; ccessed via
OVID); handsearching of
conference proceedings;
checking of references of
included studies; use of the
’related citation’ feature in
PubMed; search for ongoing
studies in trial registries. T
based on the findings of a
literature search conducted on
14 August 2017.
19 RCTs (includes 9650 ambulatory patients with
cancer) assessing the
benefits and risks of
parenteral anticoagulation
(LMWH or UFH) in
ambulatory patients with
cancer. For the most part,
these patients were
undergoing chemo-,
hormonal-, or radiotherapy
and had no indication of
anticoagulation treatment.
[AGNELLI2009] [AGNELLI2012] [ALTINBAS2004] [HASS2012
All-cause
mortality;
pre-specified
at 12
months, 24
months
and over the
duration of
the trial.
Symptomatic DVT
PE
Major bleeding
Minor bleeding
Health-related
quality of life
Thrombocytopenia
For time-to-event data (survival
data), the authors abstracted the
log(HR) and its variance (of if not
reported, they estimated the
log(HR) and variance from the
Kaplan-Meier survival curves
using the method of Parmar.
Log(HR)s were pooled using
random effects model of
DerSimonian and Laird
For dichotomous data, calculated
risk ratio (RR) for each study and
pooled results using random-
effects model
Assessed risk of bias for each
study using the Cochrane
Collaboration’s Risk of Bias tool
Mortality at 12-mo (18 studies, 9575 participants): no effect on mortality rates
RR 0.98, 95% CI 0.93-1.03
risk difference (RD) 10 fewer per
1000, 95% CI 35 fewer to 15
more
I² = 31%
Mortality at 24-mo (14 studies, 5229 participants): no effect on mortality
RR 0.99, 95% CI 0.96-1.01
RD 8 fewer per 1000; 95% CI 31
fewer to 8 more
I² = 27%
Heparin appears to have no
effect on mortality at 12
months and 24 months. It
reduces symptomatic VTE and
likely increases major
and minor bleeding. Future
research should further
investigate the survival benefit
of different types of
anticoagulants in patients with
different types and stages of
cancer. The decision for a
patient with cancer to start
heparin therapy should
balance the benefits and
Supplementary appendix revised version 23 08 2019
53
TOPIC-1] [HAAS2012 TOPIC-2] [KAKKAR2004] [KLERK2005] [LEBEAU1994] [LECUMBERRI2013] [MARAVEYAS2012] [PERRY2010] [SIDERAS2006] [VANDOORMAAL2011] [WEBER2008] [KHORANA 2017 (PHACS)] [MACBETH 2016] [Pelzer 2015] [VADHAN-RAJ 2013] [ZWICKER 2013 MICRO TEC].
Assessed heterogeneity between
trials through visual inspection of
forest plots, I2 statistic
Funnel plots to assess for
publication bias
Excluded participants considered
to have missing data
All-cause mortality - time-to-event analysis (5 studies, 8388 participants) no effect on the risk of death
HR 0.93, 95% CI 0.84-1.03
I² = 64%
Symptomatic VTE (16RCTs, 9036 participants heparin reduces the risk of
symptomatic VTE compared to
no heparin:
RR 0.56, 95% CI 0.47-0.68
RD 30 fewer per 1000; 36 fewer
to 22 fewer
I² = 0%
Major bleeding (18 RCTs, 9592 participants) heparin likely increases the risk
of major bleeding compared to
no heparin
RR 1.30, 95% CI 0.94-1.79
RD 4 more per 1000; 95% CI 1
fewer to 11 more
I² = 0%
Minor bleeding (16RCTs, 9245 participants) heparin causes an increase in the
risk of minor bleeding compared
to no heparin:
RR 1.70, 95% CI 1.13-2.55
RD 17 more per 1000; 3 more to
37 more
I² = 53%
Thrombocytopenia (12 RCTs, 5832 participants) failed to show or to exclude a
beneficial or detrimental effect
of heparin on the risk of
thrombocytopenia compared to
no heparin
RR 0.69, 95% CI 0.37-1.27
downsides, and should
integrate the patient’s values
and preferences
Supplementary appendix revised version 23 08 2019
54
RD 33 fewer per 1000; 95% CI 66
fewer to 28 more
I² = 83%
[Kahale 2017] Cochrane Central Register of
Controlled Trials (CENTRAL)
(2016, Issue 1), MEDLINE (Ovid)
and Embase (Ovid);
handsearching of conference
proceedings; checking of
references of included studies;
searching for ongoing studies;
and using the ’related citation’
feature in PubMed.
Literature search conducted on
14 December 2017.
1486 ambulatory cancer patients
7 RCT comparing the efficacy
and safety of VKA (6 used
warfarin, 1 used apixaban)
with no intervention or
placebo in 1486 patients
with cancer without clinical
evidence of VTE
[CHAHINIAN1989] [LEVINE1994] [LEVINE2012] [MAURER1997] [STANFORD1979] [ZACHARSKI1984] [CIFTCI 2012]
All-cause
mortality
Symptomatic DVT
PE
Major bleeding
Minor bleeding
Health-related
quality of life
(HRQoL)
Extracted outcome data
necessary to conduct intention-
to-treat analyses
Assessed risk of bias for each
study using the Cochrane
Collaboration’s Risk of Bias tool
Excluded participants considered
to have missing data
Assessed heterogeneity between
trials by visual inspection of
forest plots, I2 test
Funnel plots used to assess
publication bias
Calculated risk ratio (RR) for each
study and pooled results using
random-effects model
Mortality at 6 months (3 RCTs, 964 participants) VKA vs. no VKA
RR 0.93, 95% CI 0.77-1.1
I2=6%
Mortality at 1 year (5 RCTs, 1281 participants) VKA vs. no VKA
RR 0.95, 95% CI 0.87-1.03
risk difference (RD) 29 fewer per
1000, 95% CI 75 fewer to 17
more; moderate certainty
evidence
I2=0%
Mortality at 2 years (2 RCTs, 528 participants) VKA vs. no VKA
RR 0.95, 95% CI 0.70-1.30
I2=93%
Mortality at 5 years (1 RCT, 344 participants) VKA vs. no VKA
RR 0.93, 95% CI 0.83-1.03
Symptomatic DVT (1 study, 315 participants) VKA vs. no VKA
RR 0.08, 95% CI 0.00-1.42
RD 35 fewer per 1000, 95% CI 38
fewer to 16 more; low certainty
evidence
PE (1 study, 315 participants) VKA vs. no VKA
RR 1.05, 95% CI 0.07-16.58
The existing evidence does not
show a mortality benefit from
oral anticoagulation in people
with cancer but suggests an
increased risk
for bleeding.
Supplementary appendix revised version 23 08 2019
55
RD 0 fewer per 1000, 95% CI 6
fewer to 98 more; very low
certainty evidence
Major bleeding (1 study, 92 participants) VKA vs. no VKA
RR 2.93, 95% CI 1.86-4.62
RD 107 more per 1000, 95% CI 48
more to 201 more; moderate
certainty evidence
Minor bleeding (1 study, 92 participants) VKA vs. no VKA
RR 3.14, 95% CI 1.8-5.32
RD 167 more per 1000, 95% CI 66
more to 337 more; moderate
certainty evidence
Health-related QoL no data
Supplementary appendix revised version 23 08 2019
56
Reference Inclusion period
Number of patients analyzed/included Follow-up Population Intervention VTE incidence Toxicity Death
[Davies 2018]
prospective multicentre
cohort study.
December 2012 and
January 2016
70/70 6 months Patients older than 18
years with active cancer
(ie. receiving active
treatment, having
metastatic disease or
having been diagnosed
within the past 2 years)
not including non-
melanoma skin cancer,
and symptomatic
proximal UEDVT (axillary
or more proximal) with
orwithout PE, associated
with a CVC
Rivaroxaban at a dose of 15
mg orally twice daily for 3
weeks, followed by 20 mg
daily for 9 weeks
Preservation of line function at 3 months: 70/70 (100%)
Recurrence of DVT/PE: 1/70 (1.43%,
95% CI 0.25- 7.66)
Bleeding events: 11 bleeding
events in 9 patients/70 (12.85%,
95%CI 6.9 -22.7)
Death: 1/70
Table 14: Treatment of established catheter-related thrombosis (CRT)- Comparative/observational – prospective/retrospective studies
Supplementary appendix revised version 23 08 2019
57
References Bibliographic search Included studies Primary endpoint Secondary endpoint Statistical tests Results Authors’ conclusions
[Kahale 2018 b]
Cochrane Central
Register of Controlled
Trials (CENTRAL),
MEDLINE (Ovid;
starting 1966), and
Embase (Ovid; starting
1980); conference
proceedings of the
American Society of
Clinical Oncology
(ASCO, starting with its
first volume, 1982 up to
May 2018) and of the
American Society of
Hematology (ASH,
starting with its 2003
issue up to May 2018);
ClinicalTrials.gov and
World Health
Organization
International Clinical
Trials Registry Platform
for ongoing studies.
Search conducted in
May 2018
13 RCTs comparing the effects of
any dose of UFH, LMWH, VKA with
no intervention or placebo (or
comparison of two different
anticoagulants) in 3420 patients
with cancer and central venous
catheterization. Seven RCTs
compared LMWH to no LMWH (six
in adults and one in children), 6
RCTs compared VKA to no VKA (five
in adults and one in children), and 3
RCTs compared LMWH to VKA in
adults.
Patients had no clinical evidence of
VTE at time of enrolment
[BERN1990] [COUBAN 2005] [DE CICCO 2009] [HEATON 2002] [KARTHAUS 2006] [LAVAU-DENES 2013] [MASSICOTTE 2003] [MISMETTI 2003] [MONREAL 1996] [NIERS 2007] [RUUD 2006] [VERSO 2005] [YOUNG 2009]
All-cause mortality
Catheter-related
thrombosis.
Non-catheter-related
thrombosis.
PE events
Major bleeding
Minor bleeding
Catheter-related
infection
Thrombocytopenia
Health-related quality of
life (HRQoL)
Premature CVC removal.
HIT
HIT with thrombosis
When possible, meta-
analyses were conducted
using the random-effects
model
Extracted outcome data
necessary to conduct
intention-to-treat
analyses
Assessed methodological
quality of studies using
the Risk of Bias
Assessment Tool form
the Cochrane Handbook
for randomized trials
Excluded patients
considered to have
missing data from
primary meta-analysis
Assessed heterogeneity
between trials through
visual inspection of
forest plots, I2 statistic
All cause mortality: LMWH versus no LMWH (5
RCTs, 1236 participants)
RR 0.82, 95% CI 0.53 to 1.26;
RD 14 fewer per 1000, 95% CI
36 fewer to 20 more; I2=0%
VKA versus no VKA (4 RCTs,
701 participants)
RR 0.99, 95% CI 0.64 to 1.55;
RD 1 fewer per 1000, 95% CI
34 fewer to 52 more; I2=0%
LMWH versus VKA (3 RCTs,
571 participants)
RR 0.94, 95% CI 0.56 to 1.59;
RD 6 fewer per 1000, 95% CI
41 fewer to 56 more; I2=0%
Symptomatic catheter-related thrombosis: LMWH versus no LMWH (5
RCTs, 1089 participants)
RR 0.43, 95% CI 0.22 to 0.81;
RD 38 fewer per 1000, 95% CI
52 fewer to 13 fewer;
moderate-certainty evidence;
I2=2%
VKA versus no VKA (4 RCTs,
1271 participants)
RR 0.61, 95% CI 0.23 to 1.64;
RD 31 fewer per
1000, 95% CI 62 fewer to 51
more; I2=70%
LMWH versus VKA (2 RCTs,
327 participants)
RR 1.83, 95% CI 0.44 to 7.61;
RD 15 more per 1000, 95% CI
10 fewer to 122 more; I2=0%
Pulmonary embolism LMWH versus no LMWH
No conclusive
evidence for the effect
of LMWH on mortality,
the effect of VKA on
mortality and catheter-
related VTE, and the
effect of LMWH
compared to VKA on
mortality and catheter-
related VTE.
Moderate-certainty
evidence that LMWH
reduces catheter-related
VTE compared to no
LMWH.
People with cancer with
CVCs considering
anticoagulation should
balance the possible
benefit of reduced
thromboembolic
complications with the
possible harms and
burden of
anticoagulants.
Table 15: Prophylaxis of catheter-related deep vein thrombosis –Systematic reviews with or without meta-analysis
Supplementary appendix revised version 23 08 2019
58
No data
VKA versus no VKA
No data
LMWH versus VKA (2 RCTs,
327 participants)
RR 1.70, 95% CI 0.74 to 3.92;
RD 35 more per 1000, 95% CI
13 fewer to 144 more
Major bleeding : LMWH versus no LMWH (4
RCTs, 1018 participants)
RR 1.49, 95% CI 0.06 to 36.28;
RD 0 fewer per 1000, 95% CI 1
fewer to 35 more; I2=0
VKA versus no VKA (1 study,
751 participants)
RR 7.14, 95% CI 0.88 to 57.78;
RD 12 more per 1000, 95% CI 0
fewer to 110 more
LMWH versus VKA (1 study, 60
participants)
RR 3.11, 95% CI 0.13 to 73.11;
RD 2 more per 1000, 95%CI 1
fewer to 72 more
Minor bleeding: LMWH versus no LMWH (2
RCTs, 544 participants)
RR 1.35, 95% CI, 0.62 to 2.92;
RD 14 more per 1000, 95% CI
16 fewer to 79 more; I2=0
VKA versus no VKA (2 studies,
1126 participants)
RR 0.69, 95% CI 0.38 to 1.26;
RD 15 fewer per 1000, 95% CI
30 fewer to 13 more; I2=0
LMWH versus VKA (1 study,
234 participants)
RR 0.95, 95% CI 0.20 to 4.61;
RD 1 fewer per 1000, 95% CI
21 fewer to 95 more
Supplementary appendix revised version 23 08 2019
59
Catheter-related infection : LMWH versus no LMWH (2
RCTs, 474 participants)
RR 0.97, 95% CI 0.52 to 1.79;
RD 3 fewer per 1000, 95% CI
44 fewer to 73 more; I2=0
VKA versus no VKA (1 study,
88 participants)
RR 1.17, 95% CI 0.74 to 1.85;
RD 71 more per 1000, 95% CI
109 fewer to 356 more
LMWH versus VKA
No data
Thrombocytopenia : LMWH versus no LMWH (4
RCTs, 1002 participants)
RR 1.03, 95% CI 0.80 to 1.33;
RD 5 more per 1000, 95% CI 35
fewer to 58 more; I2=0
VKA versus no VKA
No data
LMWH versus VKA (2 RCTs,
327 participants)
RR 1.69, 95% CI 1.20 to 2.39;
RD 149 more per 1000, 95%
CI 43 fewer to 300 more;
moderate-certainty evidence;
I2=0
Health-related quality of life (HRQoL) No data
Premature CVC removal VKA versus no VKA (1 study)
RR 0.82, 95% CI 0.30 to 2.24;
RD 29 fewer per 1000,
95% CI 114 fewer to 202 more
HIT No data
HIT with thrombosis
Supplementary appendix revised version 23 08 2019
60
No data
[Lv 2018]
Preferred Reporting
Items for Systematic
Reviews and Meta-
Analyses (PRISMA)
methodology
Literature search using
PubMed through 2017
Conference Papers
Index provided
by ProQuest (1982–
2017), Biosis (1926–
2017), and Scopus
(1996–2017) to collate
conference posters and
abstracts
15 articles (n = 6579) showed the
details of CICC with
pharmacological deep venous
thrombosis
(DVT) prophylaxis compared with
placebo or other drugs, such as
heparin drugs, warfarin and other
thrombolytic drugs [BORAKS 1998] [RATCLIFFE 1999] [HEATON 2002] [MISMETTI 2003] [CORTELEZZIA 2003] [ABDELKEFI 2005] [COUBAN 2005] [VERSO 2005] [KARTHAUS 2006] [FAGNANI 2007] [NIERS 2007] [VAN RODEN 2008] [DE CICCO 2009] [YOUNG 2009] [LAVAU-DENES 2013]
7 of 15 studies with
pharmacological deep vein
thrombosis
prophylaxis data provided the
information about the
compared mortality rate of the
patients, including cancer
patients, haematological
malignancies and a mixture of
the two.
Mortality Incidence of VTE Odds ratio (OR)
Random effect model to
evaluate most of
treatment effects which
are different among all
studies Fixed effect
model occasionally for
some analysis when the
treatment effects were
deemed to be the same
and that differences in
results were just due to
random probability.
Incidence rate of patients
with VTE
Cochrane’s Q statistic
and the I² statistic to deal
with the heterogeneity
among studies
Harbord’s test to assess
publication bias for
studies
VTE CICCs vs. PICCs :
OR 0.45, 95% CI 0.32–0.62, p <
0.0001, I² = 0%, Tau²=0
Prophylaxis vs. no prophylaxis
OR 0.67, 95% CI 0.48–0.93, p =
0.02, I² = 57%, Tau²=0.24
Mortality Prophylaxis vs. no prophylaxis
(CICCs)
OR 0.95, 95% CI:0.55-1.63,
Z=0.19, p=0.85, I²=75%,
Tau²=0.36
warfarin vs. no warfarin
(CICCs)
RR 0.66, 95% CI 0.45–0.97,
Z=2.09 (p= 0.04)
PICCs are
associated with a higher
risk of deep vein
thrombosis,
when compared with
CICCs
Pharmacological
thromboprophylaxis is a
beneficial factor in
decreasing
the incidence of
thrombosis and warfarin
may decrease the risk of
mortality of malignant
tumor patients with
CICCs.
Supplementary appendix revised version 23 08 2019
61
References Bibliographic search Included studies Primary endpoint
Secondary endpoint Statistical tests Results Authors’ conclusions
[Alsheri 2016] PubMed, EMBASE, and
Cochrane Library databases
through October 2014.
An additional supplementary
search was performed at the
time of manuscript review,
through June 30, 2016
10 RCTs reporting 212 VTE
events among 1263
participants with brain tumor
patients undergoing
craniotomy
[AGNELLI. 1998] [BUCCI 1989] [CERRATO1978] [CONSTANTINI2001] [DICKINSON1998] [GOLDHABER 2002] [MACDONALD 2003] [NURMOHAMED1996] [SKILLMAN 1978] [TURPIE1977]
efficacy and
safety of different methods of
prophylaxis in brain tumor
patients undergoing craniotomy
Fixed-effects model
using the inverse
variance method to
obtain the overall
relative risk (RR)
estimates and the 95
% confidence
intervals
Random-effects
model according
to the method of
DerSimonian and
Laird accounting
for variation between
studies
Peto OR
Forest plots
to visualize the
individual and
summary estimates.
Heterogeneity among
studies by using the
Cochran’s Q-test (p <
0.10) and the I²
(considered as high if
I²>50 % )
Rates of VTE (10 studies) Various prophylactic measures
vs. control: RR 0.61, 95 % CI:
0.47-0.79 (fixed-effects model);
I²=28 %
UFH vs.placebo: RR 0.27, 95 %
CI: 0.10–0.73
LMWH combined with
mechanical prophylaxis vs.
mechanical prophylaxis
alone: RR 0.61, 95 % CI: 0.46–
0.82
mechanical prophylaxis vs.
placebo: Peto OR 0.30, 95 % CI
0.11-0.87
Rates of Bleeding (5 studies) Various prophylactic measures
vs. controls: RR 2.02, 95 % CI
1.14–3.58 (fixed-effects model);
I²=0
Statistically significant
VTE risk reduction
among brain tumor
patients receiving
prophylaxis, with
chemical prophylaxis
showing the strongest
risk reduction, but
increased risk of post-
operative minor
hemorrhage while the
risk of major
hemorrhage was not
increased with chemical
prophylaxis.
[Zwicker 2016]
PubMed, EMBASE, Google
Scholar, bibliographies
of relevant reviews and
conference abstracts
(American Society of
Hematology, International
Society of Thrombosis
and Hemostasis, and
American Society of Clinical
Oncology).
9 studies (retrospective cohorts)
[RUF 1983] [OLIN 1987] [CHOUCAIR 1987] [SHIFF 1994] [PAN2009] [NORDEN 2012] [ALVARADO 2012] [KHOURY 2015] [DONATO 2015]
odds ratio (OR)
of ICH in patients with brain
tumors receiving anticoagulation
compared with those not
receiving anticoagulation.
odds ratio of
ICH for: patients on
anticoagulation with
brain metastases
or primary brain
tumors; a renal cell
carcinoma/melanoma
subgroup; and low-
molecular-weight
heparin vs.
warfarin
Calculating the odds ratio using a
random effects model.
Heterogeneity across studies
estimated by means of the I²
statistic calculated from the Q
statistic.
A summary analysis across
studies planned only if the I2
ICH in patients with brain tumors anticoagulation vs. no
anticoagulation
OR 2.13, 95% CI 1.00–
4.57, P = 0.051; I²= 46%
LMWH vs. warfarin
OR 0.75, 95% CI 0.24–
2.33, P = 0.62; I²= 0%
Table 16: Specific populations and specific clinical situations: Patients with brain cancer –Systematic reviews with or without Meta-Analysis
Supplementary appendix revised version 23 08 2019
62
Protocol and systematic
search strategy of the review
documented online
(CRD42016036195)
at the International
Prospective Register of
Systematic Reviews Registry
(PROSPERO).
was not considered high (i.e. less
than 50%).
ICH in patients with brain metastases (3 studies) anticoagulation vs. no
anticoagulation
OR 1.07, 95% CI 0.61–
1.88, P = 0.81; I² = 0%
Melanoma or renal cell
carcinoma receiving
anticoagulation vs. no
anticoagulation
OR 2.30, 95% CI 0.80–
6.59, P = 0.12; I²= 0%
ICH in patients with primary brain tumors (5 studies) anticoagulation vs. no
anticoagulation
OR 3.75, 95% CI 1.42–
9.95, P = 0.01; I² = 33%.
Supplementary appendix revised version 23 08 2019
63
Reference Inclusion period
Number of patients analyzed/included Follow-up Population Intervention VTE incidence Toxicity Death
[Chai-Adisaksopha 2017]
retrospective chart review
conducted at Juravinski Cancer
Center, McMaster University,
Hamilton, Canada
January 2010-January 2014
364: 182 VTE
patients with non-
brain tumours
(controls) and 182
patients with brain
tumours .
Variable (see
intervention)
Controls: patients with
objectively proven VTE
and cancer diagnosed
within the previous six
months of VTE
diagnosis, not known to
have an intracranial
tumour, and planned to
receive extended
duration LMWH
Brain tumors: patients
with objectively proven
VTE and brain tumour
diagnosed within the
previous six months of
VTE diagnosis, not
known to have an
intracranial tumour, and
planned to receive
extended duration
LMWH
Group A: controls
(non-brain tumours)
Group B: patients with
brain tumours
Recurrent VTE (events/100 patient-years): Group A: 13.5, 95% CI 9.3–19.7
Group B: 11.0, 95% CI 6.7–17.9
HR 0.67, 95 % CI 0.35–1.30
P=0.43
Major bleeding (events/100 patient-years):
Group A: 5.0, 95% CI 2.8–9.2
Group B: 12.4, 95% CI 47.8–19.7
P=0.21
Clinical relevant non major bleeding (events/100 patient-years):
Group A: 8.7, 95% CI 5.5–13.8
Group B: 11.0, 95% CI 6.7–17.9
P=0.23
-
Table 17: Specific populations and specific clinical situations: Patients with brain cancer - prospective/retrospective
Supplementary appendix revised version 23 08 2019
64
References Bibliographic search Included studies Primary endpoint Safety endpoint Statistical tests Results Authors’ conclusions
[Samuelson Bannow 2018]
Medline (inception to
September 2017)
Systematic review
registered on
PROSPERO (registration
number
CRD42017077127).
2 studies
[KOPOLOVIC 2015] [KHANAL 2016]
Recurrent VTE
defined as
symptomatic,
imaging-confirmed
progression of index
thrombosis or
thrombosis at a new
site
Major Bleeding defined
as per the ISTH
definition
No meta-analysis
performed
Recurrent VTE in patients with thrombocytopenia: Prophylactic dose
LMWH:15/49 (31%)
Therapeutic dose LMWH:7/44
(16%)
Observational: 10/26/38%)
Major bleeding: Prophylactic dose LMWH:
10/49 (20%)
Therapeutic dose LMWH: 6/44
(14%)
Observational:2/26 (8%)
Available data do not support one management strategy over another to treat CAT patients with thrombocytopenia.
Table 18: Specific populations and specific clinical situations: Patients with thrombocytopenia – systematic review with or without Meta-Analysis
Supplementary appendix revised version 23 08 2019
65
Reference Inclusion period
Number of patients
analyzed/included Follow-up Population Intervention VTE incidence Toxicity Death
[Khanal 2016]
single-center retrospective study
1999- 2014
128/128
Median follow-up
44.1 months in
patients without
thrombocytopenia.
Median follow-up
24.6 months in
patients with
thrombocytopenia.
Adult patients with
hematologic
malignancies and VTE:
47 patients with a
platelet count< <50
x109/L and 81 patients
with a platelet
count>50 x109/L
Group A:
Prophylactic dose
LMWH
Group B: Therapeutic
dose LMWH
Group C: Coumadin
Group D: DOACs
Group E: IVC filter
Group F: Observation
Recurrent VTE Patients with thrombocytopenia
Group A: 3/22
Group B: 4/14
Group C: 1/1
Group D: 0/0
Group E: 0/1
Group F: 2/8
Patients without thrombocytopenia
Group A: 2/2
Group B: 9/34
Group C: 6/38
Group D:0/5
Group E: 0/0
Group F: 1/2
Clinically significant bleeding Patients with thrombocytopenia
Group A: 1/22
Group B: 4/14
Group C: 0/1
Group D: 0/0
Group E: 0/1
Group F: 0/8
Patients without thrombocytopenia
Group A: 0/2
Group B: 5/34
Group C: 0/38
Group D:0/5
Group E: 0/0
Group F: 0/2
-
Table 19: Specific populations and specific clinical situations: Patients with thrombocytopenia - prospective/retrospective
Supplementary appendix revised version 23 08 2019
66
Reference Inclusion period
Number of patients
analyzed/included
Follow-up Population Intervention VTE incidence Toxicity Death
[Woodruf 2016] Post hoc analysis using
data from the CLOT study
162/676 (24 %)
patients who
had renal
impairment at
baseline (CrCl<60 l/min
calculated using
the Cockcroft–
Gault formula)
6 months Adult cancer patients
with DVT or PE
Mean age: 62.5 years
Metastatic: 67.3%
Hemopathy:10.3 %
Arm A (control arm):
dalteparin 200 IU/kg
SC x1/day for 5-7 days +
warfarin or acenocoumarol
per os
Arm B: dalteparin (200
IU/kg SC x1/day
for 1 month then 150 IU/kg
SC x1/day for
5 months)
Recurrent VTE VKA 15/88 (17.0 %)
LMWH 2/74 (2.7 %)
LMWH vs. VKA: HR 0.15, 95 % CI 0.03–
0.65, p = 0.01
Any bleeding VKA 21/87 (24.1 %)
LMWH 15/74 (20.3 %)
LMWH vs. VKA: HR 0.781, 95 % CI
0.402–1.517,p = 0.47
Major bleeding VKA 6/87 (6.9 %)
LMWH 7/74 (9.5 %)
LMWH vs. VKA: HR 1.287, 95 % CI
0.432–3.834, p = 0.65
VKA 43/88
(48.9%)
LMWH 36/74
(48.6 %)
[Bauersachs 2018] Secondary analysis using
data from the CATCH
study
131/864 (15 %)
patients who
had renal
impairment (RI)
at baseline
(eGFR <
60mL/min/1.73
m²)
30 days after last
dose
Patients >18 years with
active cancer and DVT,
pulmonary embolism or
both
Active cancer defined by
histological or cytological
confirmation of malignancy
(excluding basal cell
carcinoma or non-
melanoma skin cancer)
Arm A: tinzaparin 175 IU/kg, sc
daily
Arm B: Warfarin (INR 2.0-3.0;
overlapping with Tinzaparin
for first 5-10 days)
Treatment for up to 6
months
Recurrent VTE patients with RI: 18/131 (13.7%)
patients without RI: 58/733 (7.9%)
RR 1.74, 95% CI 1.06-2.85
(no statistically significant differences
in recurrent VTE rates between the
tinzaparin and warfarin groups for
patients with RI: RR 0.90, 95% C 0.38-
2.12 or without RI: RR 0.65, 95% CI
0.39-1.08
Clinically Relevant Bleeding patients with RI: 25/131 (19.1%)
patients without RI: 105/733
(14.3%) RR 2.98, 95% CI 1.29- 6.90)
(no statistically significant
differences in recurrent VTE rates
between the tinzaparin and
warfarin groups for patients with
RI: RR 0.60, 95% CI 0.29-1.23 or
without RI : RR 0.80, 95% CI 0.56-
1.14)
Major bleeding patients with RI: 8/131 (6.1%)
patients without RI: 15/733 (2.0%)
RR 2.98, 95% CI 1.29- 6.90)
(no statistically significant
differences in recurrent VTE rates
between the tinzaparin and
warfarin groups for patients with
RI: RR 0.54, 95% CI 0.13-2.16 or
without RI: RR 1.60, 95% CI 0.57-
4.44)
patients with RI: 48/119 (40.3%)
patients without
RI: 226/671
(33.7%)
RR 1.20, 95% CI
0.94, 1.53
Table 20: Specific populations and specific clinical situation: Renal failure – RCT –randomized controlled trials
Supplementary appendix revised version 23 08 2019
67
Reference Inclusion period
Number of patients analyzed/included Follow-up Population Intervention VTE incidence Toxicity Death
[Martín-Martos 2017]
Prospective cohort study RIETE
Registry
March 2001 –January 2016
5135/5135
Women: 2005
(39%)
Men: 3130 (61%)
Variable (see
intervention)
5235 patients with
active cancer and
symptomatic, acute DVT
or PE confirmed by
objective tests. Patients
were excluded if they
were currently
participating in a
therapeutic clinical trial
with blinded therapy.
1,727 (16%) lung
cancers, 1,592 (14%)
colorectal cancers, 840
(7.6%) hematologic
malignancies, 517
(4.7%) pancreatic
cancers and 459 (4.2%)
gastric cancers.
Patients were
managed according to
their local
participating hospital
(no standardization of
anticoagulation
treatment)
Agents: LMWH, UFH,
thrombolytics, VCF,
VKA, fondaparinux
Mean treatment
duration:
Women: 152±233
days
Men: 149±226 days
Anticoagulation
treatment type
balanced between the
two groups
Recurrent PE (events/100 patient-years): Women: 59/2005 (6.99, 95% CI 5.33–
9.03)
Men: 73/3130 (5.67, 95% CI 4.44–
7.13)
RR 1.24, 95% CI 0.88–1.74
Recurrent DVT (events/100 patient-years): Women: 71/2005 (8.42, 95% CI 6.58–
10.6)
Men: 99/3130 (7.69, 95% CI 6.25–
9.36)
RR 1.10, 95% CI 0.81–9.28
Recurrent VTE (events/100 patient-years): Women: 130/2005 (15.4, 95% CI
12.9–18.3)
Men: 172/3130 (13.4, 95% CI 11.4–
15.5)
RR 1.16, 95% CI 0.92–1.59
Major bleeding (events/100 patient-years): Recurrent VTE (events/100 patient-years): Women: 83/2005 (83, 95% CI
7.84–12.2)
Men: 137/3130 (10.6, 95% CI
8.93–12.6)
RR 0.93, 95% CI 0.90–1.22
Overall deaths
Women: 650/2005
(77.1, 95% CI 71.3–
83.3)
Men: 1,099 /3130
(85.3; 95% CI 80.4–
90.5)
RR 0.90, 95% CI
0.82–0.99
Women had a
lower mortality
rate
Table 21: Specific populations and specific clinical situations: Patients with cancer – consideration of gender
Supplementary appendix revised version 23 08 2019
68
Conclusions Tables Chapter 1 Q1 Initial treatment of established VTE (up to 10 days of anticoagulation) – BIBLIOGRAPHIC TABLE
HTA questions Studies included
HTA 1: UFH followed by VKA
6 retrospective studies [Moore 1981] [Clarke Pearson 1983] [Calligaro 1991] [Chan 1992] [Debourdeau 1996] [Elting 2004] 2 control arms of randomized studies [Hull 2006] [van Doormaal 2009]
HTA 2: LMWH followed by VKA 5 control arms of randomized studies [Meyer 2002] [Lee 2003] [Deitcher 2006] [Romera 2009] [van Doormaal 2009]
HTA 3: LMWH vs. UFH
9 meta-analyses not specific to cancer patients (5%–22% cancer) [Lensing 1995] [Siragusa 1996] [Hettiaratchi 1998] [Gould 1999] [Dolovich 2000] [Rocha 2000] [Quilan 2004] [Mismetti 2005] [Robertson 2017] 5 cancer-specific meta-analyses [Akl 2008] [Akl 2011] [Akl 2014] [Erkens 2010] [Hakoum 2018]
HTA 4: LMWH vs. DOACs 2 randomized controlled trials [Young 2018] [McBane 2018]
HTA 5: Fondaparinux Analysis of the subgroup of cancer patients included in 2 randomized controlled trials [van Doormaal 2009] [Akl 2008] [Akl 2011] [Akl 2014] [Hakoum 2018]
HTA 6: Thrombolytics 1 retrospective study of cancer patients included in a prospective trial [Mikkola 1997]
HTA 7: Vena cava filters
23 retrospective studies – cancer population [Cohen 1991] [Calligaro 1991] [Cohen 1992] [Levin 1993] [Hubbard 1994] [Schiff 1994] [Schwarz 1996] [Greenfield 1997] [Ihnat 1998] [Schleich 2001] [Jarrett 2002] [Wallace 2004] [Zerati 2005] [Schunn 2006] [Stein 2013] [Muriel 2014] [Narayan 2016] [Brunson 2016] [Casanegra 2016] [Brunson 2017] [Coombs 2017] [Stein 2018] [Kang 2018] 2 randomized studies [Barginear 2012] [Mismetti 2015]
Q1 Initial treatment of established VTE (up to 10 days of anticoagulation) – CONCLUSIONS Q1.1: UFH followed by VKA
Studies
6 retrospective studies [Moore 1981] [Clarke Pearson 1983] [Calligaro 1991] [Chan 1992] [Debourdeau 1996] [Elting 2004] 2 control arms of randomized studies [Hull 2006] [Vandoormaal 2009]
Agreement Yes Quality of evidence Moderate (retrospective + large effect)
Results Retrospective studies: high complication rate with 11%–38% relapse and 8%–35% major bleeding Control arm of randomized studies (UFH + VKA): 10%–17.2% relapses and 6.3%–7% major bleeding at 3 months under treatment
Conclusion Treatment of VTE in cancer patients with UFH followed by VKA is associated with a high rate of relapse and bleeding.
Q1.2: LMWH followed by VKA
Studies 5 control arms of randomized studies [Meyer 2002] [Lee 2003] [Deitcher 2006] [Romera 2009] [van Doormaal 2009]
Agreement Yes Quality of evidence High (randomized + consistency)
Results
In the “cancer” population: at 6 months’ high rate of relapse (2%–16.9%) and major bleeding (2.7%–16%) in patients with cancer vs. patients without cancer In the control arm of prospective studies (LMWH + VKA): 6.7%–16.9% relapses and 2.9%–16% major bleeding at 6 months
Conclusion Treatment of VTE in cancer patients with LMWH followed by VKA is associated with a high rate of
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relapse and bleeding. Using indirect comparison, the rate of major bleeding and relapse of VTE in cancer patients treated with LMWH and VKA appears lower than the rate with UFH + VKA and is increased in “cancer patients” compared to “non-cancer patients.”
Q1.3: LMWH vs. UFH
Studies
9 meta-analyses not specific to cancer patients (5%–22% cancer) [Lensing 1995] [Siragusa 1996] [Hettiaratchi 1998] [Gould 1999] [Dolovich 2000] [Rocha 2000] [Quilan 2004] [Mismetti 2005] [Robertson 2017] 5 cancer-specific meta-analyses [Akl 2008] [Akl 2011] [Akl 2014] [Erkens 2010] [Hakoum 2018]
Agreement Yes Quality of evidence Moderate (indirectness)
Results
Meta-analyses in the general population • Decrease of relapse rate (4/9 meta-analyses) for LMWH • Decrease of major bleeding (6/8 meta-analyses) for LMWH • Few specific data except for survival in patients treated by LMWH [Siragusa 1996] [Gould 1999] • Reduction in overall mortality in participants with cancer who were treated with LMWH [Siragusa 1996]
[Robertson 2017]
Meta-analysis in cancer patients: Reduced mortality at 3 months or at the end of follow-up. The rates of recurrence were not statistically different between LMWH and UFH.
Conclusion There is moderate evidence to demonstrate the superiority of LMWH over UFH in the initial treatment of VTE in cancer patients. LMWH appears superior in reducing the rate of mortality and the incidence of recurrent VTE at 3 months compared to UFH in the initial treatment of VTE in cancer patients. Q1.4: LMWH vs. DOACS
Studies 2 randomized controlled trials [Young 2018] [McBane 2018]
Agreement Yes Quality of evidence High
Results
1 specific RCT comparing rivaroxaban vs LMWH in cancer patients [Young 2018] • non-inferior in terms of VTE recurrence rates and overall survival at 6 months • associated with higher rates of CRNM bleeding 1 specific RCT comparing apixaban vs LMWH in cancer patients [McBane 2018] • no difference in major bleeding or CRNM bleeding • decreased rates of VTE recurrence in the apixaban arm (3.4% vs. 14.1% in the LMWH arm)
Q1.5: Fondaparinux
Studies Analysis of the subgroup of cancer patients included in 2 randomized controlled trials [van Doormaal 2009] [Akl 2008] [Akl 2011] [Akl 2014] [Hakoum 2018]
Agreement Impossible to determine Quality of evidence Low
Results Analysis of cancer patients in randomized controlled trials For the initial treatment, the rate of recurrence is lower with fondaparinux than with UFH, but higher than enoxaparin with the same rate of bleeding.
Conclusion There are insufficient data to adequately compare the efficacy and safety of fondaparinux, UFH and LMWH for the initial treatment of thrombosis in cancer patients.
Q1.6: Thrombolytics
Studies 1 a posteriori analysis of 5 randomized trials (57 patients) [Mikkola 1997]
Agreement Impossible to determine
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Quality of evidence Very low (observational, serious limitations, serious imprecision) Results In cancer patients, thrombolysis was associated with a 6% relapse rate and a 12% rate of major bleeding
Conclusion Due to lack of data, the indications for thrombolytics cannot be specified in cancer patients. Q1.7: Vena cava filters
Studies
1 randomized controlled study – not specific to cancer [Mismetti 2015] 1 randomized study – cancer population [Barginear 2012] 23 retrospective studies – cancer population [Cohen 1991] [Calligaro 1991] [Cohen 1992] [Levin 1993] [Hubbard 1994] [Schiff 1994] [Schwarz 1996] [Greenfield 1997] [Ihnat 1998] [Schleich 2001] [Jarrett 2002] [Wallace 2004] [Zerati 2005] [Schunn 2006] [Stein 2013] [Muriel 2014] [Narayan 2016] [Brunson 2016] [Casanegra 2016] [Brunson 2017] [Coombs 2017] [Stein 2018] [Kang 2018]
Agreement Heterogeneity across retrospective studies
Quality of evidence
General population Randomized – indirectness (moderate) Cancer population Randomized – serious limitations (very low) Observational - Low or moderate (serious imprecision, serious indirectness, very large effect)
Results
General population [Mismetti 2015] - randomized study (n=199) At 3- and 6-month follow-up, the rate of recurrent PE doubled with vena cava filters, although this effect was not significant. No differences in other endpoints, including rates of symptomatic DVT, major bleeding, 3- and 6-month mortality, and filter complications Cancer population 15 previous observational studies – heterogeneity/inconsistency. New [Muriel 2014] [Narayan 2016] [Brunson 2016] [Casanegra 2016] [Brunson 2017] [Coombs 2017] [Stein 2018] [Kang 2018] Muriel 2014] [Narayan 2016] [Brunson 2016] [Casanegra 2016] [Brunson 2017] [Coombs 2017] [Stein 2018] [Kang 2018] The efficacy of vena cava filters is not proven in cancer patients
Conclusion Recurrent VTE (non-fatal DVT, non-fatal PE) are increased after IVC placement with no significant improvement in overall survival. Active bleeding within 3 months of discharge or less appeared to be increased when anticoagulation is resumed.
Evidence is lacking to recommend their use in the case of VTE recurrence. Cancer is neither a specific indication nor a special contraindication to vena cava filter placement.
Chapter 2
Q2 Early maintenance (up to 6 months) and long-term (beyond 6 months) treatment of established VTE – BIBLIOGRAPHIC TABLE
HTA questions Studies included
HTA 1: Early maintenance and long-term use of LMWH (includes dose comparison for LMWH, and LMWH vs. fondaparinux)
8 randomized controlled trials [Lopez-Beret 2001] [Meyer 2002] [Lee 2003] [Deitcher 2006] [Hull 2006] [Romera 2009] [Lee 2015–CATCH] [Amato 2016] 11 meta-analyses [Ioro 2003] [Ferretti 2006] [Louzada 2009] [Akl 2008B] [Akl 2008C] [Noble 2008] [Laporte 2012] [Akl 2014] [Romera-Villegas 2010] [Rojas-Henandez 2017] [Kahale 2018a] 1 prospective study [Pesavento 2015]
HTA 3: Duration of treatment
1 specific randomized controlled trial [Napolitano 2014] [Farge 2015] 2 prospective studies [Francis 2015] [Jara-Palomares 2018]
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HTA 4: The DOACs in the treatment of established VTE
6 randomized studies (4 cancer subgroup analyses) [Bauersachs 2010/Buller 2012–Prins 2013] [Schulman 2009/2014–Schulman 2015] [Agnelli
2013–Agnelli 2015] [Buller 2013–Raskob 2013] 3 specific randomized controlled trials [Raskob 2018] [Young 2018] [McBane 2018] 13 meta-analyses [Vedovati 2015] [Vanes 2014] [Vanderhulle 2014] [Larsen 2014] [Carrier 2014] [Posch 2015] [Gomez-Outes 2014] [Brunetti 2017] [Li 2018] [Kahale 2018 A] [Al Yami 2018] [Xing 2018] [Verdocati 2018]
Q2 Early maintenance (up to 6 months) and long-term (beyond 6 months) treatment of established VTE – CONCLUSIONS Q2.1: Early maintenance treatment (3 to 6 months) and long-term treatment by use of LMWH
Studies
8 randomized controlled trials [Lopez-Beret 2001] [Meyer 2002] [Lee 2003] [Deitcher 2006] [Hull 2006] [Romera 2009] [Lee 2015–CATCH] [Amato 2016] 11 meta-analyses [Ioro 2003] [Ferretti 2006] [Louzada 2009] [Akl 2008B] [Akl 2008C] [Noble 2008] [Laporte 2012] [Akl 2014] [Romera-Villegas 2010] [Rojas-Henandez 2017] [Kahale 2018a] 1 prospective study [Pesavento 2015]
Agreement Yes, except studies with low number of patients [Deitcher 2006] [Romera 2009] Coherent data for cancer patients (3/5 good-quality trials and meta-analyses)
Quality of evidence High (randomized, meta-analysis, consistency)
Results
Meta-analyses Early maintenance treatment (10 days to 3 months) and long-term treatment by LMWH alone (up to 6 months) vs. heparins (UFH/LMWH) with early VKA in cancer patients with VTE decreases the recurrence rate by 50% with no increase in bleeding risk or any effect on the mortality rate. [Kahale 2018a] metanalysis showed that the long-term treatment of VTE by LMWHs in people with cancer compared to VKAs probably produce an important reduction in VTE with no beneficial or harmful effect on major or minor bleeding (including ICH) nor on thrombocytopenia. [Romera-Villegas 2010] Studies using full and moderate doses of LMWH (3-month treatment) showed significantly reduced rates of VTE at 1-year follow-up compared to VKA, whereas low doses did not. Full LMWH treatment doses had similar rates of bleeds as low and moderate doses.
Conclusion LMWH should be used for a minimum of 3 months to treat established VTE in cancer patients. While the two largest studies in this setting treated patients for 6 months, the strength of the evidence for treatment up to 6 months is low.
Q2.2: Duration of anticoagulation
Studies
1 specific randomized controlled trial [Napolitano 2014] 1 observational study [Farge 2015] 2 prospective studies [Francis 2015] [Jara-Palomares 2018]
Agreement Impossible to determine because of only one specific study Quality of evidence Moderate (one RCT with serious indirectness, 2 observational specific studies with large sample size)
Results
Patients with residual VTE are at higher risk of VTE recurrence compared to patients without residual VTE, regardless of whether they received extended prophylaxis with LMWH or not. LMWH did not significantly reduce the incidence of recurrent VTE during the 6 months of extended anticoagulation among patients with residual VTE at 6 months. [Napolitan 2014] There is no study comparing 3 and 6 months of LMWH, but two specific RCTs used a 6-month regimen and 2 prospective observational single arm cohorts used a 12 months regimen with no increase in major bleeding at 6 and 12 months.
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Conclusion Early maintenance treatment (up to 6 months) and long-term treatment by LMWH alone (beyond 6 months up to 1 year) are validated in cancer patients It is important to distinguish between the duration of anticoagulation and the duration of LMWH treatment Q2.3: Treatment and management of acute VTE with DOACs
Studies
6 randomized studies in the general population (4 cancer subgroup analyses) [Bauersachs 2010/Buller 2012–Prins 2013] [Schulman 2009/2014–Schulman 2015] [Agnelli 2013–Agnelli 2015] [Buller 2013–Raskob 2013] 3 specific randomized controlled trial in cancer patients comparing DOACs vs LMWH [Raskob 2018] [Young 2018] [McBane 2018] 8 meta-analyses of the cancer subgroup included in RCTs in the general population [Vedovati 2015] [Vanes 2014] [Vanderhulle 2014] [Larsen 2014] [Carrier 2014] [Posch 2015] [Gomez-Outes 2014] [Brunetti 2017] 3 specific meta-analyses of 5 meta-analyses of studies comparing DOACs vs LMWH in cancer patients [Li 2018] [Kahale 2018 A] [Ay Ayami 2018] [Xing 2018] [Verdovati 2018]
Agreement Yes
Quality of evidence High
Results
6 randomized studies in the general population (4 cancer subgroup analyses) + 8 Meta-analyses + 1 Network meta-analysis [Posch 2015] found that DOACs are non-inferior to LMWH/VKA in terms of rate of VTE recurrence with comparable or reduced bleeding rates relative to VKA 3 specific RCT (n=1755 pts) + 5 meta-analyses comparing DOACs for at least 6 months (1 RCT) and up to 12 month (1 RCT) vs LMWH in cancer patients found that long term treatment with DOACs as compared to LMWH up to 6 months is superior[Young 2018] [McBane 2018] or non-inferior in terms of VTE recurrence rates and overall survival at 6 months and associated with similar [McBane 2018] or higher rates of major bleeding [Raskob 2018] or of CRNMB [Young 2018]
Conclusion The subgroup analyses in the DOAC clinical trials and meta-analyses of cancer patient subgroups conclude that for treatment of established VTE in cancer patients specifically, DOACs are non-inferior to VKA in both in terms of VTE recurrence and bleeding risk. In 2 RCTs, DOACs were non-inferior to LMWH to prevent recurrent VTE but were associated with a significant increase in major bleeding and a trend toward more CRNB.
Chapter 3
Q3 Treatment of VTE recurrence in cancer patients under anticoagulation – BIBLIOGRAPHIC TABLE
HTA questions Studies included
HTA 1: Recurrence in patients treated with LMWH or VKA
1 specific retrospective study [Carrier 2009]
HTA 2: Vena cava filters
17 retrospective studies [Cohen 1991] [Calligaro 1991] [Cohen 1992] [Levin 1993] [Hubbard 1994] [Schiff 1994] [Schwarz 1996] [Greenfield 1997] [Ihnat 1998] [Schleich 2001] [Jarrett 2002] [Wallace 2004] [Zerati 2005] [Schunn 2006] [Matsuo 2013] [Abtahian 2014] [Mellado 2016] 2 systematic review [Angel 2011] [Rojas-Hernandez 2018]
The results of the bibliographic search for vena cava filters (VCFs) are also shown in a previous chapter. In these studies, the main indications of insertion of VCFs were recurrence of VTE and contraindication to anticoagulation. In some cases, VCFs were inserted as a primary treatment of VTE.
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Treatment of VTE recurrence in cancer patients under anticoagulation – CONCLUSIONS
Q3.1: Patients treated with LMWH or VKA
Studies 1 specific retrospective study [Carrier 2009]
Agreement Not applicable
Quality of evidence Very low (observational study + very serious indirectness)
Results
In the case of recurrence of VTE, there is only one specific study with two therapeutic options: • in patients treated with VKA: switch from VKA to LMWH • in patients treated with LMWH: increase LMWH
The results appear to be similar to those obtained in cancer patients without VTE recurrence
Q3.2: Vena cava filters
Studies
17 retrospective studies [Cohen 1991] [Calligaro 1991] [Cohen 1992] [Levin 1993] [Hubbard 1994] [Schiff 1994] [Schwarz 1996] [Greenfield 1997] [Ihnat 1998] [Schleich 2001] [Jarrett 2002] [Wallace 2004] [Zerati 2005] [Schunn 2006] [Matsuo 2013] [Abtahian 2014] [Mellado 2016] 2 systematic review [Angel 2011] [Rojas-Hernandez 2018]
Agreement Impossible to determine heterogeneity
Quality of evidence Very low (observational, serious limitations, serious imprecision)
Results The efficacy of vena cava filters is not proven in cancer patients. Cancer is neither a specific indication nor a special contraindication to vena cava filters
Conclusion In the case of recurrence of VTE or PE in cancer patients, three therapeutic options have been studied: 1. Increased dose of LMWH in patients treated with LMWH 2. Switch from VKA to LMWH or DOACS in patients treated with VKA 3. Switch from DOACS to LMWH in patients treated with DOACs 4. Vena cava filter insertion
There is no data concerning the use of DOACS in this setting. There is insufficient evidence to determine if one option is superior to the others.
Chapter 4 Q4 Prophylaxis of VTE in surgical cancer patients – BIBLIOGRAPHIC TABLE
HTA questions Studies included
HTA 1: LMWH or UFH vs. placebo or no treatment
1 randomized controlled study [Shukla 2008] 3 meta-analyses [Mismetti 2001] [Einstein 2007] [Guo 2017] 1 systematic review [Rahn 2011]
HTA 2: LMWH vs. UFH
2 randomized controlled trials [Haas 2005] [Kakkar 1997] 4 meta-analyses [Mismetti 2001] [Akl 2008] [Akl 2014] [Guo 2017]
HTA 3: Comparison of drugs 2 randomized controlled trials Fondaparinux vs. dalteparin [Agnelli 2005] Nadroparin vs. enoxaparin [Simonneau 2006]
HTA 4: Dose of LMWH 1 randomized controlled trial Dalteparin 2500 IU vs. 5000 IU [Bergqvist 1995] [Balibrea 2007]
HTA 5: Extended duration 1 retrospective study [Pariser 2017] 1 prospective study [Schomburg 2017] 3 randomized controlled trials – not specific to cancer [Lausen 1998] [Rasmussen 2006] [Bergqvist 2002]
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2 randomized controlled trials – cancer patient population [Kakkar 2010] [Vedovati 2014] 4 meta-analysis [Akl 2008E] [Faragasanu 2016] [Guo 2017] [Felder 2018] 1 systematic review without metanalysis [Carrier 2018]
HTA 6: Vena cava filters 1 prospective study [Matsuo 2013]
HTA 7: External compression devices
7 randomized controlled trials [Turpie 1989] [Dickinson 1998] [Maxwell 2001] [Song 2014] [Nagata 2015] [Dong 2018] [Jung 2018] 1 meta-analysis in neurosurgical patients [Collen 2008]
Q4 Prophylaxis of VTE in surgical cancer patients – CONCLUSIONS Q4.1: LMWH or UFH compared to placebo or no treatment
Studies
1 randomized controlled study [Shukla 2008] 3 meta-analyses [Mismetti 2001] [Einstein 2007] [Guo 2017] 1 systematic review [Rahn 2011]
Agreement Yes
Quality of evidence High (randomized trials, meta-analysis)
Results
In the RCT, there was no difference between LMWH and placebo in the rates of recurrence and bleeding. Three meta-analyses of older RCTs were identified, one conducted in general surgery patients, and two focusing on patients undergoing gynecologic surgery. Overall, LMWH and UFH were superior to placebo or no prophylaxis in preventing postoperative VTE in cancer patients. In one older meta-analysis and in one recent meta-analysis [Guo 2017] the rate of any bleeding was higher with LMWH than with placebo or no treatment.
Q4.2: LMWH vs. UFH
Studies
2 randomized controlled trials [Haas 2005] [Kakkar 1997] 4 meta-analyses [Mismetti 2001] [Akl 2008] [Akl 2014] [Guo 2017]
Agreement Yes
Quality of evidence High
Results
In the clinical studies, LMWH and UFH showed the same efficacy with a trend towards less bleeding with LMWH In the meta-analyses, UFH given three times a day was as effective as LMWH [Akl 2008D], but LMWH once a day appeared to be superior to UFH twice a day. The rate of bleeding was the same with UFH and LMWH. [Akl 2014] consistent with [Akl 2008]
Conclusion LMWH and UFH are superior to placebo or no prophylaxis in the prevention of postoperative VTE in cancer patients. • UFH x3/day is as effective as LMWH x1/day • LMWH x1/day seems superior to UFH x2/day There are no data to conclude on the superiority of one type of LMWH over another one.
Q4.3: Comparison of drugs
Studies 2 randomized controlled trials Fondaparinux vs. dalteparin [Agnelli 2005] Nadroparin vs. enoxaparin [Simonneau 2006]
Agreement Not applicable
Quality of evidence Low (randomized, indirectness for one study, imprecision because of a non-inferiority study with a secondary endpoint)
Results Nadroparin (2850 IU) is at least as effective as enoxaparin (4000 IU) with less major bleeding
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In one study including two-thirds of cancer patients, fondaparinux compared to dalteparin is associated with less VTE recurrence and with a trend towards an increase in bleeding.
Conclusion There is insufficient evidence to conclude on the superiority of fondaparinux over dalteparin (1 study with two-thirds of cancer patients) or on the superiority of nadroparin over enoxaparin (1 study showing the same rate of venous thromboembolic events but with a difference in the rate of bleeding events).
Q4.4: Dose of LMWH
Studies 1 randomized controlled trial Dalteparin 2500 IU vs. 5000 IU [Bergqvist 1995] Bemiparin 3500 IU vs 2500 IU [Balibrea 2007]
Agreement Not applicable
Quality of evidence High (one randomized study but with a large effect size)
Results For prophylaxis a high dose of LMWH is superior to a low dose
Conclusion One study (1957 patients) with a large effect size showed that a high dosage of LMWH is superior to a low dosage of LMWH in the prevention of VTE in surgical cancer patients. A second retrospective multicenter cohort study (197 patients) reported a lower incidence of VTE with Bemiparin 3500 IU compared to Bemiparin 2500 IU, although this difference did not reach statistical significance. There was no difference in bleeding rates between the two doses.
Q4.5: Extended duration of prophylaxis
Studies
1 retrospective study [Pariser 2017] 1 prospective study [Schomburg 2017] 3 randomized controlled trials – not specific to cancer [Lausen 1998] [Rasmussen 2006] [Bergqvist 2002] 2 randomized controlled trials – cancer patient population [Kakkar 2010] [Vedovati 2014] 4 meta-analysis [Akl 2008E] [Faragasanu 2016] [Guo 2017] [Felder 2018] 1 systematic review without metanalysis [Carrier 2018]
Agreement
Despite 2 negative studies (but one was stopped before the calculated number of patients was achieved), 3 RCTS, 1 recent retrospective study [Pariser 2017], 1 recent prospective study [Schomburg 2017] and 2 recent meta-analysis [Faragasanu 2016] [Guo 2017]showed a significant decreased in all VTE with extended duration of prophylaxis.
Quality of evidence Moderate (randomized trials+ meta-analysis)
Results
A trend toward higher risk of bleeding was reported in one study [Bergqvist 2002] Two RCTs in cancer patients showed that extended LMWH treatment (28 days versus 8 days) in pts undergoing major abdominal surgery [Kakkar 2010, 1251 patients] or laparoscopic surgery [Vedovati 2014, 225 patients].was associated with a decreased rate of proximal DVT, without increasing the rate of major or minor bleeding 1 recent retrospective study [Pariser 2017] reported a significantly lower rate of VTE at 90 days with extended
duration of prophylaxis (5, vs. 12% p=0.024) 1 recent prospective study [Schomburg 2017] reported a significantly lower rate of VTE at 90 days with
extended duration of prophylaxis (5.06% vs. 17.6%, p=0.021)
3 recent meta-analysis [Faragasanu 2016] [Guo 2017] [Felder 2018] and 1 systematic review without meta-analysis [Carrier 2018] showed a significant decreased in all VTE with extended duration of prophylaxis
Conclusion Four weeks of LMWH reduced the rate of postoperative VTE after major laparotomy/laparoscopic surgery in cancer patients. The superiority of extended duration of LMWH (4 weeks) can be generalized to all cancer patients undergoing major abdominal or laporoscopy surgery for cancer, but should be considered in selected patients without a high risk of bleeding.
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Q4.6: Vena cava filters
Studies 1 prospective study [Matsuo 2013]
Agreement Impossible to determine
Quality of evidence Very low (observational/prospective, one study with limitations)
Results
(274 patients with ovarian cancer undergoing primary cytoreductive surgery) The cumulative risk of metastasis or disease progression was 45.2% in patients with inferior vena cava filter versus 13.6% in patients without filter placement. Median survival in the two groups was 5.7 months in patients with filters and 15.3 months in patients without filters (p<0.001).
Conclusion Inferior vena cava filter placement in patients with ovarian cancer undergoing primary cytoreductive surgery may be associated with increased risk of distant metastasis and decreased survival.
Q4.7: External compression devices
Studies
7 randomized controlled trials [Turpie 1989] [Dickinson 1998] [Maxwell 2001] [Song 2014] [Nagata 2015] [Dong 2018] [Jung 2018] 1 meta-analysis in neurosurgical patients [Collen 2008]
Agreement Not applicable (different external compression devices were used)
Quality of evidence Low (randomized but serious study limitations due to the differences in study design, study population and the external compression device used, inconsistency and imprecisions, so move down two grades)
Results
• To prevent VTE in major abdominal or pelvic surgery for gynecologic malignancies, ECD and LMWH appeared equivalent. [Song 2014] In 217 patients with confirmed adenocarcinoma undergoing gastrectomy, there was no significant difference in the rate of VTE between IPC alone versus IPC+enoxaparin. However, a significant increase in the risk of bleeding was reported for the IPC with enoxaparin treatment arm For prophylaxis after surgery for brain tumors, GCS + IPC had the same efficacy as GCS alone, and both were superior to no prophylaxis
• In neurosurgical patients, LMWH were superior to ECD despite an increase of minor bleeding but with no increase in intracranial bleeding or in major bleeding 1 RCT in 30 chinese women undergoing major abdominal or pelvic surgery [Nagata 2015] found no significant difference in the rate of VTE between IPC alone vs. IPC + enoxaparin 1 RCT in 90 japanese patients undergoing thoracotomy [Dong 2018] found no significant difference in the rate of VTE between IPC alone vs. IPC +nadroparin 2850 IU od for 7 days 1 RCT in 682 korean patients with histologically confirmed gastric adenocarcinoma [Jung 2018] found a significant difference in the rate of VTE between IPC alone vs. IPC +LMWH 40 mg od
• •
Conclusion External compression devices (ECDs) are superior to no prophylaxis, but whether or not they are superior to LMWH may depend on the malignancy and/or type of surgery. There are insufficient data to conclude on the superiority of one type of ECD or one ECD regimen over others. Chapter 5 Q5 Prophylaxis of VTE in medical cancer patients – BIBLIOGRAPHIC TABLE
HTA questions Studies included
HTA 1: Hospitalized patients
4 prospective randomized studies – general population (safety and efficacy LMWH, UFH) [Bergmann 1996] [Harenberg 1996] [Lechler 1996] [Kleber 2003] [Haas 2011] 4 randomized double-blind studies – general population (compared to placebo) [Dahan 1986] [Samama 1999] [Leizorovicz 2004] [Cohen 2006] [Cohen 2013-MAGELLAN] 1 meta-analysis (cancer patient subgroups) [Carrier 2014]
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HTA 2: Ambulatory patients treated with chemotherapy
14 randomized double-blind trials [Haas 2012] [Agnelli 2009] [Perry 2010-PRODIGE] [Barni 2011-PROTECHT] [Agnelli 2012- SAVE ONCO] [Macbeth 2015-FRAGMATIC] [Haas 2012-TOPIC] [Maraveyas 2012-FRAGEM] [Levine 2012-ADVOCATE] [Pelzer 2015- CONKO 004] [Khorana 2017-PHACS] [Ek 2018-RASTEN] [Meyer 2018-TILT] [Khorana 2018-CASSINI] [Carrier 2018 B-AVERT] 15 meta-analyses [Ben-Aharon 2014] [Dinisio 2014] [Phan 2014] [Che 2013] [Akl 2014] [Akl 2014-VKA] [Sanford 2014] [Zhang 2013] [Dinisio 2016] [Tun 2016] [Yu 2016] [Fuentes 2017] [Thein 2017] [Akl 2017] [Kahale 2017]
HTA 3: Patients treated with thalidomide or lenalidomide
2 randomized studies [Larocca 2012] [Palumbo 2011] 2 retrospective studies [Zangari 2004] [Ikhlaque 2006] 1 systematic review [Al-Ani 2016] 3 meta-analyses [Elaccaoui 2007] [Hicks 2008] [Carrier 2011]
Q5 Prophylaxis of VTE in medical cancer patients – CONCLUSIONS Q5.1: Hospitalized cancer patients
Studies
4 prospective randomized studies [Bergmann 1996] [Harenberg 1996] [Lechler 1996] [Kleber 2003] 4 randomized double-blind studies [Dahan 1986] [Samama 1999] [Leizorovicz 2004] [Cohen 2006] [Cohen 2013-MAGELLAN] 1 meta-analysis (cancer patient subgroups, n=307) [Carrier 2014]
Agreement Yes
Quality of evidence General population: moderate (randomized studies but indirectness) Cancer patients: low (only one meta-analysis, small sample size, n=307)
Results
For primary prophylaxis of VTE in hospitalized medical cancer patients – general population: • LMWH and UFH have a similar efficacy and safety • LMWH and fondaparinux are superior to placebo with a non-significant trend towards increased
bleeding (except for enoxaparin 40 mg and fondaparinux) • the rate of cancer patients included in these studies varies from 5% to 15% • no study reports a difference of efficacy between cancer and non-cancer patients For primary prophylaxis of VTE in hospitalized medical cancer patients – cancer patient subgroup analysis (n-307) • LMWH prophylaxis did not significantly reduce the relative risk of VTE recurrence relative to placebo
in hospitalized cancer patients • the rates of major and minor bleeding were not reported according to cancer status in the studies
analyzed For primary prophylaxis of VTE in hospitalized medical cancer patients – with the DOACs specifically, in cancer patient subgroup analysis • [Cohen 2013-MAGELLAN, 125 patients] Thromboprophylaxis with rivaroxaban tended to be less
effective than enoxaparin in cancer patients, but this did not reach significance. Rivaroxaban increased the risk of bleeds in patients with active cancer.
Conclusions Primary prophylaxis with UFH, LMWH and fondaparinux has been shown to be effective in studies, including hospitalized cancer patients (5% to 15% cancer patients) with reduced mobility. Meta-analysis of cancer patient subgroups suggests that effects may be different in cancer patients overall; no significant difference in VTE recurrence relative to placebo.
Q5.2: Ambulatory patients treated with chemotherapy
Studies
14 randomized double-blind trials [Haas 2012] [Agnelli 2009] [Perry 2010-PRODIGE] [Barni 2011-PROTECHT] [Agnelli 2012- SAVE ONCO] [Macbeth 2015-FRAGMATIC] [Haas 2012-TOPIC] [Maraveyas 2012-FRAGEM] [Levine 2012-ADVOCATE] [Pelzer 2015- CONKO 004] [Khorana 2017-PHACS] [Ek 2018-RASTEN] [Meyer 2018-TILT] [Khorana 2019-CASSINI] [Carrier 2019-AVERT] 15 meta-analyses [Ben-Aharon 2014] [Dinisio 2014] [Phan 2014] [Che 2013] [Akl 2014] [Akl 2014-VKA] [Sanford 2014] [Zhang 2013] [Dinisio 2016] [Tun 2016] [Yu 2016] [Fuentes 2017] [Thein 2017] [Akl 2017] [Kahale 2017]
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Agreement Results depend on the type of cancer
Quality of evidence Moderate in unselected cancer patients; Strong in pancreatic and lung cancer patient studies
Results
• Primary prophylaxis with LMWH in cancer patients treated with chemotherapy decreases the rate of VTE without an excess of bleeding in patients with locally advanced or metastatic pancreatic cancers and with locally advanced or metastatic lung cancers (at subtherapeutic dosages). In patients with advanced pancreatic cancer undergoing chemotherapy, [Tun 2016] meta-analysis of 4 RCTs found a crude VTE incidence of 2.1 and 11.2% in LMWH and in control groups, respectively (risk ratio, 0.18; 95% CI, 0.083-0.39; P < 0.0001) with no significant difference in the rate of major bleedings across groups.
• [Ek 2018-RASTEN] LMWH was not found to increase overall survival in patients with SCLC. Risk of VTE was decreased from 8.4% to 2.7% with LMWH with an increase in pulmonary bleeding and other sites in the LMWH treatment arm. [Meyer 2018-TILT] LMWH was not found to increase overall survival in patients with NSCLC. Risk of VTE was not decreased with LMWH compared to control arm (no treatment). Two out of three recent meta-analysis [Fuentes 2017] [Thein 2017] found no significant improvement in overall survival in lung cancer patients receiving LMWH. Primary VTE prophylaxis with LMWH reduced the occurrence of VTE (small but significant improvement) among ambulatory patients with lung cancer without increased bleeding in one metanalysis [Fuentes 2017] and with an increase in CRNMB in one metanalysis [Thein 2017].
• Primary prophylaxis with LMWH has no effect on VTE in patients with metastatic breast cancer [Haas 2012-TOPIC] and increases non-significantly intracranial bleeding in patients with a brain tumor [Perry 2010-PRODIGE]
• [Khorana 2017-PHACS] randomized 98 participants with cancer and a Khorana risk score ≥ 3 to subcutaneous dalteparin or observation for a period of 12 weeks. Thromboprophylaxis with LMWH reduced the risk of VTE (12% vs. 21%) but increase the rate of CNMB (14% vs. 2.1%)
• [Barni 2011] assessed the benefit-to-risk ratio of thromboprophylaxis with LMWH according to type of chemotherapy (1150 patients). The highest rates of VTE were with gemcitabine- (8.1%) or cisplatin-based chemotherapy (7.0%). Further, the risk VTE increased to 10.2% when gemcitabine was combined with cisplatin or carboplatin. Thromboprophylaxis with LMWH reduced the risk of VTE by 68% in patients receiving gemcitabine, and 78% in patients receiving combination chemotherapy (gemcitabine and a platinum-based agent)
• [Kahale 2017] updated meta-analysis from the previous [Akl 2014] compared safety and efficacy of VKA vs. placebo which showed no effect on mortality at 6 months, 1, 2 and 5 years. One study (n=315 participants) showed low certainty evidence for a decrease in symptomatic VTE and very low certainty evidence for a decrease in PE with VKA but VKA produced significant increase in the rate of major bleeding and minor bleeding
• [Levine 2012-ADVOCATE] Apixaban at prophylactic doses in ambulatory patients with advanced or metastatic cancer receiving first and second-line chemotherapy over a 3-month period (125 patients): 5 mg (Arm A), 10 mg (Arm B), or 20 mg (Arm C). The incidence of VTE was 10.3% (3 episodes) in the placebo group. No VTE events occurred with apixaban. No major bleeding events were reported in Arm A or B, or the placebo arm but a 6.3% rate of major bleeding events in treatment arm C
• [Khorana 2019-CASSINI] randomized 841 ambulatory cancer patients initiating a systematic chemotherapy and at intermediate-high risk of VTE (defined as Khorana score ≥2) to rivaroxaban 10 mg once daily or placebo for 6 months. Rivaroxaban reduced the rate of VTE during the on-treatment period (2.63% vs. 6.41%; p=0.007) without further increase in major and clinically relevant non-major bleeding (p=0.265 and p=0.53, respectively).
• [Carrier 2019-AVERT] randomized 574 ambulatory cancer patients initiating a systematic chemotherapy and at intermediate-high risk of VTE (defined as Khorana score ≥2) to apixaban 2.5 mg twice daily or placebo for 6 months. Apixaban reduced the rate of VTE (4.3% vs. 10.2%, p<0.001) with a further increase in major bleeding (3.5% vs. 1.8%, p=0.046)
Conclusions In cancer patients treated with chemotherapy: Earlier isolated trials Prophylaxis with LMWH (at subtherapeutic dosages) have a benefit in patients with locally advanced or metastatic pancreatic or locally advanced or metastatic lung cancers, has no effect on VTE in patients with metastatic breast cancer and may increase bleeding risk particularly in the presence of thrombocytopenia and for patients with a brain tumor
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New DOACs RCTs The CASSINI [Khorana 2019-CASSINI] and AVERT [Carrier 2019-AVERT] trials indicate a net clinical benefit of initiating anticoagulant prophylaxis with a DOAC (rivaroxaban 10 mg daily or apixaban 2.5 mg twice-daily) in selected cancer patients (Khorana score ≥2) initiating chemotherapy.
New meta-analyses [Dinisio 2016] [Akl 2017] [Kahale 2017] Parenteral prophylaxis in ambulatory cancer patients receiving chemotherapy has robust effects on the risk of VTE. Broad confidence intervals are observed around these estimates, suggesting considerable variability in bleed risk among the study populations, presumable owing to different cancer types, cancer treatments, and patient characteristics. VKA prophylaxis in ambulatory cancer patients receiving chemotherapy does not appear to reduce risk of VTE, but significantly increases risk of bleeds. Chemotherapy regimens with gemcitabine, platinum analogues, or their combination put patients at higher risk of VTE. The clinical benefits of LMWH thromboprophylaxis in these patients may outweigh the risks.
Q5.3: Patients treated with thalidomide or lenalidomide
Studies
2 randomized studies [Larocca 2012] [Palumbo 2011] 2 retrospective studies [Zangari 2004] [Ikhlaque 2006] 1 systematic review [Al-Ani 2016] 3 meta-analyses [Elaccaoui 2007] [Hicks 2008] [Carrier 2011]
Agreement Yes
Quality of evidence Low (one randomized study with serious limitations and imprecision; meta-analyses did not take into account this study)
Results Prophylactic doses of LMWH or aspirin (100 mg/day) or warfarin to maintain INR within the therapeutic range reduced the risk of thromboembolic events among multiple myeloma patients treated with lenalidomide or thalidomide with no increase in bleeding risk
Conclusions Overall, the available evidence includes two retrospective studies investigating the risks and benefits of VTE prophylaxis in cancer patients treated with thalidomide [Zangari 2004] [Ikhlaque 2006], two prospective randomized studies comparing aspirin, LMWH and warfarin for VTE prophylaxis in patients with myeloma [Larocca 2012] [Palumbo 2011], 1 systematic review comparing the efficacy of aspirin or LMWH prophylaxis in patients with myeloma using lenalidomide-based therapy [Al-Ani 2016] and three meta-analyses of anticoagulation in patients with myeloma [Elaccaoui 2007] [Hicks 2008] [Carrier 2011]. Together, these studies showed that the rate of VTE occurrence is very high in patients treated with IMiDs (thalidomide and lenalidomide) combined with steroids and/or chemotherapy (doxorubicin). Prophylactic doses of LMWH, aspirin (100 mg/day) or warfarin reduced the risk of VTE in multiple myeloma patients treated with lenalidomide or thalidomide, without increasing the incidence of bleeding complications. Notably, none of the studies included a placebo group.
Chapter 6
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Q6 Treatment of established catheter-related thrombosis – BIBLIOGRAPHIC TABLE
HTA questions Studies included
HTA 1: Treatment of CVC thrombosis: LMWH, VKA (includes
drug comparison), DOACs
3 prospective non-randomized studies [Savage 1999] [Kovacs 2007] [Davies 2018] 3 retrospective studies [Tran 2010] [Delluc 2015] [Oliver 2015] 1 meta-analysis [Akl 2014]
HTA 3: Treatment of CVC thrombosis: thrombolytic therapy
2 retrospective studies [Pucheu 1996] [Schindler 1999]
HTA 2: Treatment of CVC thrombosis: CVC removal
1 retrospective study [Frank 2000]
Q6 Treatment of established catheter-related thrombosis – CONCLUSIONS Q6.1: LMWH, VKA, DOACs
Studies
3 prospective non-randomized studies [Savage 1999] [Kovacs 2007] [Davies 2018] 3 retrospective studies [Tran 2010] [Delluc 2015] [Oliver 2015] 2 prospective non-randomized studies [Savage 1999] [Kovacs 2007] 3 retrospective study [Tran 2010] [Delluc 2015] [Oliver 2015] 1 meta-analysis [Akl 2014]
Agreement Not applicable, poor quality (39, 46, 64 patients; new studies 99 and 21 patients)
Quality of evidence Very low (observational studies, serious limitations, serious imprecision)
Results
[Delluc 2015] (99 patients) The majority of patients (73%) were treated with full-dose LMWH for 1 month, followed by an intermediate dose. The rate of VTE recurrence was 0% in this treatment group; 11% of patients received a preventative dose of LMWH. In this group, the rate of VTE recurrence was 15.4% [Oliver 2015] (21 patients) No difference in the rate of VTE resolution between no anticoagulation, high-, low-dose enoxaparin. The rate of morality was 33% in the anticoagulant treatment group, compared to 71% in the no anticoagulant treatment group. HR remained <1 after adjustments for leukemia type and cytogenetics [Akl 2014] Heparin associated with reduction in symptomatic DVT. No differences in major bleeding, minor bleeding, mortality, or thrombocytopenia. Same profile reported for VKA, but quality of evidence was ranked as low [Davies 2018] assessed rivaroxaban monotherapy for preservation of line function and safety outcomes of VTE recurrence, bleeding risk and death in 47 women with cancer who develop upper extremity deep vein thrombosis (UEDVT) due to CVC. Preservation of line function was 100% at 12 weeks. The risk of recurrent VTE at 12 weeks was 1.43%, with one episode of fatal PE. 9 patients (12.9%) experienced 11 total bleeding episodes.
Conclusion
There are insufficient data to determine the efficacy and tolerance of LMWH, VKA and DOACS for treating CVC-VTE. Q6.2: Catheter removal
Studies 1 retrospective study [Frank 2000]
Agreement Not applicable
Quality of evidence Very low (observational study, serious limitations)
Results There are insufficient data to conclude on the efficacy and tolerance of CVC withdrawal for treating CVC-VTE. There are no data on the optimal timing between withdrawal and the initiation of anticoagulant therapy
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Q6.3: Thrombolytics
Studies 2 retrospective studies [Pucheu 1996] [Schindler 1999]
Agreement Yes
Quality of evidence Very low (observational studies, serious limitations, very serious imprecision)
Results There are insufficient data to determine the efficacy and tolerance of systemic or localized thrombolytic therapy for treatment of CVC-VTE. Nonetheless, thrombolysis can be used even with intensive chemotherapy
Conclusions There is no evidence in cancer patients with catheter-related thrombosis to support: • the withdrawal of a non-infected, functioning, well-positioned CVC • the use of LMWH + VKA or long-term LMWH or DOACs • thrombolytic therapy via the catheter or systemic thrombolysis
Chapter 7 Q7 Prophylaxis of catheter-related thrombosis – BIBLIOGRAPHIC TABLE
HTA questions Studies included
Safety and efficacy of different anticoagulants in CVC-related VTE treatment:
HTA 1: VKA
6 randomized controlled trials [Bern 1990] [Couban 2005] [Heaton 2002] [Ruud 2006] [Young 2009] [Decicco 2009] 7 meta-analyses [Carrier 2007] [Akl 2007] [Rawson 2007] [Kirkpatrick 2007] [Chaukiyal 2008] [Akl 2008f] [Kahale 2018b]
HTA 2: UFH 1 randomized study [Abdelkefi 2004]
HTA 3: LMWH
6 randomized trials [Monreal 1996] [Mismetti 2003] [Verso 2005] [Karthaus 2006] [Niers 2007] [Decicco 2009] 8 meta-analyses [Carrier 2007] [Akl 2007] [Rawson 2007] [Kirkpatrick 2007] [Chaukiyal 2008] [Schoot 2013] [Kahale 2018b]
HTA 4: Drug comparison
1 randomized study [Lavau-Denes 2013] 1 meta-analyses [Kahale 2018b]
HTA 5: Thrombolytics
1 non-randomized prospective study [Kalmanti 2002] 1 randomized double-blind study [van Rooden 2008]
HTA 6: Type of CVC and insertion techniques
3 meta-analysis [Saber 2010] [Chopra 2013] [Lv 2018] 3 randomized trials [Biffi 2001] [Carlo 2004] [Biffi 2009] 4 prospective non-randomized trials [Labourey 2004] [Lee 2006] [Luciani 2001] [Nightingale 1997] 6 retrospective studies [Eastridge 1995] [Craft 1996] [Cadman 2004] [Caers 2005] [Morazin 2005] [Mclean 2005]
Q7 Prophylaxis of catheter-related thrombosis – CONCLUSIONS Q7.1: VKA
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Studies
6 randomized controlled trials [Bern 1990] [Couban 2005] [Heaton 2002] [Ruud 2006] [Young 2009] [Decicco 2009] 7 meta-analyses [Carrier 2007] [Akl 2007] [Rawson 2007] [Kirkpatrick 2007] [Chaukiyal 2008] [Akl 2008f] [Kahale 2018b]
Agreement Yes 4 randomized trials in agreement 4 meta-analyses in agreement
Quality of evidence High
Results
VKA low-dose In the RCTs: similar CRT rate with and without VKA prevention (5% symptomatic CRT) One positive study on asymptomatic CRT with VKA started before CVC insertion [Decicco 2009] The most recent meta-analysis [Kahale 2018b] did not confirm or exclude a beneficial or detrimental effect of low-dose VKA compared to no VKA on mortality, symptomatic catheter-related VTE, major bleeding, minor bleeding, premature catheter removal and catheter-related infection Low-intensity VKA (INR 1.5 to 2) One randomized study (1570 patients included and evaluated) showing a decrease of symptomatic CRT with an increased risk of bleeding [Young 2009]
Q7.2: UFH
Studies 1 randomized study [Abdelkefi 2004]
Agreement Not applicable
Quality of evidence Moderate (randomized, serious study limitation)
Results Continuous intravenous infusion of UFH may decrease the incidence of symptomatic and asymptomatic CRT as diagnosed by Doppler US in bone marrow transplant recipients (adults and children)
Q7.3: LMWH
Studies
6 randomized trials [Monreal 1996] [Mismetti 2003] [Verso 2005] [Karthaus 2006] [Niers 2007] [Decicco 2009] 8 meta-analyses [Carrier 2007] [Akl 2007] [Rawson 2007] [Kirkpatrick 2007] [Chaukiyal 2008] [Schoot 2013] [Kahale 2018b]
Agreement Yes
Quality of evidence High
Results
The randomized trials showed no excess in major bleeding, but no benefit in preventing symptomatic VTE in the superior vena cava Meta-analyses indicated a trend towards reduction of asymptomatic CRT or all CRT (asymptomatic and symptomatic) using different comparisons (VKA + LMWH vs. no treatment) The most recent meta-analysis [Kahale 2018b] found moderate-certainty evidence that LMWH reduced catheter-related thrombosis compared to no LMWH (risk ratio 0.43, 95% CI 0.22-0.81) without increase in major or minor bleedings.
Q7.4: Drug comparison
Studies
1 randomized study [Lavau-Denes 2013] 1 meta-analyse [Kahale 2018b]
Agreement Yes
Quality of evidence Low
Results
[Lavau-Denes 2013] (420 patients) 3-month anticoagulant treatment period in patients on chemotherapy. LMWH and warfarin produced comparable reductions in catheter-related and non-related DVT. No increase overall increase in bleeding rate, results pooled for all drug types. A recent meta-analysis [Kahale 2018b] did not confirm or exclude a beneficial or detrimental effect of LMWH relative to VKA on mortality, symptomatic catheter-related VTE, PE, major bleeding, or minor bleeding. The meta-analyses showed that LMWH probably increased the risk of thrombocytopenia compared to VKA at three months of follow-up (RR 1.69, 95% CI 1.20- 2.39).
Q7.5: Thrombolytics
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Studies
1 non-randomized prospective study [Kalmanti 2002] 1 randomized double-blind study [van Rooden 2008]
Agreement Yes
Quality of evidence Low (only one randomized study, but limitations as one study included few patients and one study evaluated CRT as a secondary endpoint, inconsistency)
Results Neither study supported the use of fibrinolysis to prevent CRT in cancer patients
Conclusions For the prevention of CRT, when compared to no prophylaxis, there is no evidence to support: • the routine use of low dose of VKA (warfarin 1 mg) • the routine use of VKA to maintain an INR between 1.5 and 2 • the use of continuous IV UFH or fibrinolytics More studies are required to analyse the effect of routine use of LMWH Q7.6: Type of CVC and insertion techniques
Studies
3 meta-analysis [Saber 2010] [Chopra 2013] [Lv 2018] 3 randomized trials [Biffi 2001] [Carlo 2004] [Biffi 2009] 4 prospective non-randomized trials [Labourey 2004] [Lee 2006] [Luciani 2001] [Nightingale 1997] 6 retrospective studies [Eastridge 1995] [Craft 1996] [Cadman 2004] [Caers 2005] [Morazin 2005] [Mclean 2005]
Agreement Yes
Quality of evidence High (meta-analysis + consistency)
Results
Independent risk factors for CRT include: • Catheter tip location: SVC-RA junction or RA • Insertion site: jugular vein better than subclavian, right side better than left side • Type of catheter: valved tips = open-ended tips, implanted ports better than external
catheter • Past medical history of CVC • Doppler US guidance: no data [Chopra 2013] PICCs are associated with a higher risk of DVT than are central venous catheters, especially in critically ill patients or those with cancer [Lv 2018] PICCs are associated with a higher risk of deep vein thrombosis, when compared with CICCs
Conclusion The catheter should be located: • at the SVC-RA junction • in the jugular vein rather than the subclavian vein Implanted ports are better than a SC catheter. There is no evidence to support the use of Doppler US guidance to prevent CRT. Chapter 8 Q8 Special situations – BIBLIOGRAPHIC TABLE
HTA questions Studies included
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HTA 1: Treatment and prophylaxis of established VTE in patients with a brain tumor
5 non-randomized studies [Schmidt 2002] [Altschuler 1990] [Levin 1993] [Schiff 1994] [Chai-Adisaksopha 2017] 2 meta-analysis [Simonetti 2014] [Zwicker 2016] 1 double-blind randomized trial [Perry 2010-PRODIGE]
HTA 2: Prophylaxis of VTE in cancer patients undergoing neurosurgery
5 prospective randomized studies [Turpie 1989] [Cerrato 1978] [Constantini 2001] [Dickinson 1998] [Macdonald 2003] 4 randomized double-blind studies [Melon 1991] [Nurmohamed 1996] [Agnelli 1998] [Goldhaber 2002] 4 meta-analyses [Ioro 2001] [Collen 2008] [Salmaggi 2013] [Alsheri 2016]
HTA 3: Treatment and prophylaxis of VTE in cancer patients with thrombocytopenia
2 prospective studies [Babilonia 2014] [Falvo 2011] 2 retrospective studies [Kopolovic 2015] [Khanal 2016] 1 systematic review [Samuelson Bannow 2018]
HTA 4: Treatment and prophylaxis of VTE in cancer patients with renal failure
1 prospective study [Kooiman 2013] Analysis of the subgroup of cancer patient with renal failure Included in 2 randomized studies [Woodruf 2016] [Bauersachs 2018]
HTA 5: Gender differences 2 prospective studies [Martin-Martos 2015]
Q8 Special situations – CONCLUSIONS
Q8.1: Treatment and prophylaxis of established VTE in patients with a brain tumor
Studies
5 non-randomized studies [Chai-Adisaksopha 2017] (treatment) [Schmidt 2002] [Altschuler 1990] [Levin 1993] [Schiff 1994] (prophylaxis) 2 meta-analysis (treatment) [Simonetti 2014] [Zwicker 2016] 1 double-blind randomized trial (prophylaxis) [Perry 2010-PRODIGE]
Agreement Yes
Quality of evidence Low (1 RCT, observational, but consistent)
Results
Treatment: In patients with brain tumors, treatment of VTE with use of anticoagulation yield the same rate of VTE recurrence (0% to 12%) and bleeding (intracerebral bleeding 0% to 7%) as in other cancer patients without brain tumors.[Chai-Adisaksopha 2017] compared the rates of recurrent VTE and major bleeding in patients with cancer-associated VTE in the setting of primary or metastatic brain tumours and those without known brain tumours. The rate of recurrent VTE was not significantly different in patients with primary or metastatic brain tumours (11 per 100 patient-years, 95 % CI; 6.7–17.9) and in those without (13.5 per 100 patient-years, 95 % CI; 9.3–19.7) with higher rates of intracranial bleeds in patients with brain tumours compared to those without known brain tumours (4.4 % vs 0 %, p=0.004).) [Zwicker 2016] meta-analysis in patients with brain tumors receiving or not receiving therapeutic anticoagulation reported a 2.13 (95% CI, 1.00–4.56) OR for intracranial hemorrhage (ICH). In studies evaluating anticoagulation in patients with brain metastases, there was no apparent increased risk of ICH (OR, 1.07; 95% CI, 0.61–1.88%). In patients with glioma there was an increase in risk of ICH associated with the administration of anticoagulation (OR, 3.75; 95% CI, 1.42–9.95). Prophylaxis: [Perry 2010-PRODIGE] did not report a significant reduction in VTE occurrence, or improvement in mortality rate. LMWH was not associated with an increase in major bleeding but the 95% CI was very wide (HR 4.2, 95% CI 0.48 -36; p=0.22). [Simonetti 2014] meta-analysis reported that the rate of VTE was not significantly different across cancer treatments (p=0.091). The incidence of severe central nervous system (CNS) bleeding increased considerably with anticoagulant administration (0.6% vs. 8.2%, p<0.001).
Conclusion The results of anticoagulation for established VTE are the same in patients with and without brain tumors. VTE prophylaxis in patients with brain tumors may increase the risk of severe central nervous system bleeding.
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Q8.2: Prophylaxis of VTE in cancer patients undergoing neurosurgery: heparins
Studies
5 prospective randomized studies [Turpie 1989] [Cerrato 1978] [Constantini 2001] [Dickinson 1998] [Macdonald 2003] 4 randomized double-blind studies [Melon 1991] [Nurmohamed 1996] [Agnelli 1998] [Goldhaber 2002] 4 meta-analyses [Ioro 2001] [Collen 2008] [Salmaggi 2013] [Alsheri 2016]
Agreement Yes
Quality of evidence High
Results
For VTE prophylaxis after surgery for brain or spinal tumors in cancer patients: • LMWH and UFH (5000 IU sc/12 h) are associated with the same rates of VTE and bleeding and lead
to a 50% reduction in the risk of VTE without an excess of major bleeding but with a two-fold higher rate of minor bleeding
• GCS + IPC have the same efficacy as GCS alone • The reduction of VTE with ECD is about 60% when compared to no prophylaxis • LMWH are superior to ECD with a reduction of VTE from 20% to 40%, and an increase of minor
bleeding (relative risk: 2), with no increase in intracranial bleeding or major bleeding [Collen 2008] • Consistent with previous studies, [Salmaggi 2013] reported that mechanical prophylaxis reduced the
rate of VTE without increasing risk of bleeding. Concomitant use of intermittent pneumatic compression devices and LMWH significantly further reduced the rate of VTE compared to the use mechanical compression. Addition of LMWH was associated with a non-significant increase in major bleeding
• [Alsheri 2016] found a significant VTE risk reduction among brain tumor patients receiving prophylaxis with no increase in major bleeding. UFH alone showed a stronger reduction in VTE risk compared to placebo (RR = 0.27; 95 % CI: 0.10–0.73), and LMWH combined with mechanical prophylaxis showed a lower VTE risk as compared to mechanical prophylaxis alone (0.61; 95 % CI: 0.46–0.82).
Conclusion LMWH and UFH have a similar efficacy and safety (in terms of major bleeding and intracranial bleeding) and are superior to no treatment. In this setting, pharmacological prophylaxis should be started postoperatively. After surgery for brain or spinal tumors, adding LMWH to an intermittent compression device increases the risk of minor bleeding but not the risk of major or intracranial bleeding. Q8.3: Treatment and prophylaxis of VTE in cancer patients with thrombocytopenia
Studies
2 prospective studies [Babilonia 2014] [Falvo 2011] 2 retrospective studies [Kopolovic 2015] [Khanal 2016] 1 systematic review [Samuelson Bannow 2018]
Agreement Impossible to determine (different study designs)
Quality of evidence Low
Results
[Babilonia 2014] (93 cancer patients) assessed the safety and efficacy of LMWH administered at a lower dose (dalteparin 100 IU/Kg od for 6 months) for cancer patients with thrombocytopenia (platelet 20.109/L<count<50.109/L) compared to LMWH administered at the standard dose (dalteparin 200IU/Kg for 1 month followed by 150 U/kg for 5 months) in cancer patients with mild to no thrombocytopenia. The rate of failure to attain clot resolution or to prevent a new or recurrent VTE and the overall the rate of bleeding complications did not differ between the two groups [Falvo 2011] assessed whether LMWH or UFH conferred a higher risk of developing thrombocytopenia (24 401 LMWH/25 153 UFH) 6 months after starting LMWH or UFH. The incidence of thrombocytopenia was significantly greater with LMWH vs. UFH. [Kopolovic 2015] 74 patients with inoperable, advanced pancreatic cancer receiving first-line chemotherapy received either 1) no anticoagulant treatment (group A); 2) anticoagulation at standard doses (group B); or 3) partial anticoagulation (group C). Standard anticoagulant treatment at the full dose significantly reduced the rate of VTE. Treatment did not affect the rate of bleeding complications
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[Khanal 2016] compared the outcomes of 47 patients with thrombocytopenia (platelets <50 x109/L) and 81 patients without thrombocytopenia receiving anticoagulation for cancer-associated thrombosis. 14/47 patients with thrombocytopenia received therapeutic anticoagulation with LMWH and 22/47 received dose-modified LMWH (enoxaparin 40 mg daily during the period of significant thrombocytopenia). 4/14 patients receiving therapeutic anticoagulation and 3/22 patients receiving dose-modified LMWH had a recurrent VTE. 4/14 patients receiving therapeutic anticoagulation and 1/22 patients receiving dose-modified LMWH had a clinically significant bleeding. 1 systematic review [Samuelson Bannow 2018] highlighted a higher risk of recurrent VTE in cancer patient with thrombocytopenia but available data do not support one management strategy over another to treat cancer-associated thrombosis in patients with thrombocytopenia.
Q8.4: Treatment and prophylaxis of VTE in cancer patients with renal failure
Studies
1 prospective study [Kooiman 2013] Analysis of the subgroup of cancer patient with renal failure Included in 2 randomized studies [Woodruf 2016] [Bauersachs 2018]
Agreement Impossible to determine
Quality of evidence Low
Results
[Woodruf 2016] conducted a post hoc analysis using data from the CLOT study to compare the efficacy and safety of dalteparin vs. VKA for prevention of recurrent VTE in patients with cancer and renal impairment (CrCl<60 ml/min, n=162/676).Compared to VKA, dalteparin significantly reduced the risk of recurrent VTE in patients with cancer and renal impairment (p = 0.01) with a comparable safety profile. [Bauersachs 2018] conducted a secondary analysis using data from the CATCH study to assess the impact of renal impairment (GFR-MDR<60 ml/min/1.73m², n=131/864) on the efficacy and the safety (with respect to bleeding and mortality) of anticoagulation. Patients with cancer-associated thrombosis and renal impairment had a statistically significant increase in recurrent VTE and major bleeding compared to patients with, but no significant increase in CRB or mortality. No differences were observed between long-term tinzaparin therapy and warfarin.
Q8.5: Gender differences
Studies 2 prospective studies [Martin-Martos 2015] [Martin-Martos 2017
Agreement Impossible to determine
Quality of evidence Low
Results
In [Martin-Martos 2017], the RIETE database was used compare the rate of VTE recurrences, major bleeding and mortality in patients with lung, colorectal, pancreatic, hematologic or gastric cancer during the course of anticoagulation, according to gender (2005 female/3130 male). Women with VTE and lung, colorectal, pancreatic, haematological or gastric cancer experienced a similar rate of VTE recurrences, major bleeding or death during the course of anticoagulant therapy than men with similar cancers
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Table 22: Khorana score and expanded models
KHORANA score and expanded models
Khorana score
Vienna CATS score
PROTECHT score
CONKO score
Very high-risk tumors† +2 +2# +2 +2
High risk tumors‡ +1 +1 +1 +1
Hemoglobin <10 g/dl
Erythropoietin stimulating agents
+1 +1 +1 +1
White blood cell count >11 x 109/L +1 +1 +1 +1
platelet count ≥350 x 109/L +1 +1 +1 +1
BMI >35 kg/m2 +1 +1 +1 +1
D-dimer >1.44 µg/L +1
Soluble P-selectin >53.1 ng/L +1
Gemcitabine chemotherapy +1
Platinum-based chemotherapy +1
WHO performance status +1
†Very high-risk tumors: pancreatic, gastric; ‡high risk tumors: lung, lymphoma, bladder, testicular or gynecological; # The Vienna CATS score added primary brain tumor patients (glioma) to the list of very high-risk tumors; BMI, body mass index; WHO, world Health Organization
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Table 23: List of anticancer drugs that can potentially interfere with DOACs
Table 1. Prohibited concomitant medications in randomized controlled trials
TREATMENT OF ESTABLISHED VTE in cancer patients
Edoxaban (Hokusai VTE)
P-glycoprotein (P-gp) inhibitors: ritonavir, nelfinavir, indinavir, or saquinavir anticipated to continue during the study.
P-gp inhibitors: ketoconazole, itraconazole, erythromycin, azithromycin or clarithromycin at the time of randomization; subsequent use is was permitted (with appropriate dose reduction of edoxaban).
Rivaroxaban (SELECT-D)
Strong cytochrome P-450 (CYP) 3A4 inhibitor: human immunodeficiency virus protease inhibitors or systemic ketoconazole.
Strong CYP 3A4 inducers: rifampicin, carbamazepine, or phenytoin.
Strong P-gp inhibitors/ inducers
Use of rivaroxaban is not recommended with systemic azole-antimycotics (e.g. ketoconazole)
or HIV protease inhibitors (e.g. ritonavir). These active substances are strong inhibitors of
both CYP3A4 and P-gp and therefore may increase rivaroxaban plasma concentrations to a
clinically relevant degree (2.6 fold on average) which may lead to an increased bleeding risk.
Apixaban (ADAM VTE) CYP3A4 inducers: rifampin, rifabutin, carbamazepine, efavirenz, phenobarbital, phenytoin, fosphenytoin, primidone, and St. John’s Wort
PRIMARY PROPHYLAXIS of VTE in cancer patients
Rivaroxaban (CASSINI)
Combined P-gp and strong CYP3A4 inhibitors such as but not limited to ketoconazole, telithromycin or protease inhibitors) within 4 days before randomization, or planned use during the study.
Use of itraconazole within 7 days before randomization or planned use during the study.
Combined P-gp and strong CYP3A4 inducers such as but not limited to rifampin/rifampicin, rifabutin, rifapentine, phenytoin, phenobarbital, carbamazepine, or St. John's Wort within 2 weeks before randomization, or planned use during the study.
Apixaban (AVERT)
Use of medication contraindicated with apixaban.
Strong inhibitors of both CYP 3A4 and P-gp: ketoconazole, itraconazole, voriconazole, posaconazole, voriconazole and HIV protease inhibitors (e.g. ritonavir)
Strong CYP3A4 and P-gp inducers: rifampicin, phenytoin, carbamazepine, phenobarbital or St. John’s Wort
September 2, 2019
89
ITAC Advisory Panel
ITAC role COUNTRY SURNAME, First name Affiliation email Advisory Council
ARGENTINA
CASAIS, Patricia
Academia Nacional de Medicina de Buenos Aires Av. Gral. Las Heras 3092, C1425ASU CABA, Argentine
Advisory Council
AUSTRIA
POSCH, Florian
Medizinische Universität Graz Auenbruggerplatz 2 A-8036 Graz, Austria
Advisory Council
AUSTRIA
GARY, Thomas
Medizinische Universität Graz Auenbruggerplatz 2 A-8036 Graz, Austria
Advisory Council
AUSTRIA
FEISTRITZER, Clemens
Medizinische Universität Innsbruck Christoph-Probst-Platz 1 Innrain 52 A-6020 Innsbruck, Austria
Advisory Council
AUSTRIA
PREUSSER, Matthias
Klinische Abteilung für Onkologie Universitätsklinik für Innere Medizin I Medizinische Universität Wien Währinger Gürtel 18-20, 1090 Wien, Austria
Advisory Council
AUSTRIA
MAROSI- Christine
Medizinische Universität Wien Währinger Gürtel 18-20, 1090 Wien, Austria
Advisory Council BRAZIL
ROTHSCHILD, Cynthia
Fundação Faculdade de Medicina – ICESP Av. Dr. Arnaldo, 455 - Cerqueira César, São Paulo - SP, 01246-903, Brazil
September 2, 2019
90
Advisory Council CANADA
ROUSSIN, Andre
CHUM University of Montreal 1051 Rue Sanguinet, Montréal, QC H2X 3E4, Canada
Advisory Council CANADA
ALCINDOR, Thierry
McGill University 845 Rue Sherbrooke Ouest, Montréal, QC H3A 0G4, Canada
Advisory Council
CANADA
HULL, Russell D
University of Calgary 2500 University Drive NW Calgary, AB T2N 1N4 CANADA.
Advisory Council CANADA
TAGALAKIS, Vicky
McGill University 845 Rue Sherbrooke Ouest, Montréal, QC H3A 0G4, Canada
Advisory Council CANADA
BLOSTEIN, Mark
McGill University 845 Rue Sherbrooke Ouest, Montréal, QC H3A 0G4, Canada
Advisory Council CANADA
KOOLIAN, Maral
McGill University 845 Rue Sherbrooke Ouest, Montréal, QC H3A 0G4, Canada
Advisory Council
CHINA, HONG KONG
WONG, Raymond
The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, The People's Republic of China
Advisory Council
FRANCE
LE HELLO, Claire
CHU Saint Etienne Avenue Albert Raimond, 42270 Saint-Priest-en-Jarez, France
Advisory Council
FRANCE
HIJ, Adrian
Assistance Publique Hôpitaux de Paris, Hôpital Saint-Louis, A 1 Avenue Claude Vellefaux, 75010 Paris, France
Advisory Council
FRANCE
ANDRE, Thierry
Assistance Publique Hôpitaux de Paris, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75012 Paris, France
September 2, 2019
91
Advisory Council FRANCE
EMMERICH, Joseph
Hôpital Saint-Joseph 185 Rue Raymond Losserand, 75014 Paris, France
Advisory Council
FRANCE
MARJANOVIC, Zora
Assistance Publique Hôpitaux de Paris, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75012 Paris, France
Advisory Council
FRANCE
DURANT, Cécile
CHU de Nantes, 5 allée de l'île gloriette, 44093 Nantes Cedex, France
Advisory Council
FRANCE
CONNAULT, Jérôme
CHU de Nantes, 5 allée de l'île gloriette, 44093 Nantes Cedex, France
Advisory Council
FRANCE
DOUCET, Ludovic
Assistance Publique Hôpitaux de Paris, Hôpital Saint-Louis, A 1 Avenue Claude Vellefaux, 75010 Paris, France
Advisory Council
FRANCE
VILLIERS, Stéphane
Assistance Publique Hôpitaux de Paris, Hôpital Saint-Louis, A 1 Avenue Claude Vellefaux, 75010 Paris, France
Advisory Council
FRANCE
BENZIDIA, Ilham
Assistance Publique Hôpitaux de Paris, Hôpital Saint-Louis, A 1 Avenue Claude Vellefaux, 75010 Paris, France
Advisory Council
FRANCE
CARPENTIER, Antoine
Assistance Publique Hôpitaux de Paris, Hôpital Saint-Louis, A 1 Avenue Claude Vellefaux, 75010 Paris, France
Advisory Council
FRANCE
GRIS, Jean-Christophe
CHU de Nimes 4 Rue du Professeur Robert Debré, 30029 Nîmes, France
September 2, 2019
92
Advisory Council FRANCE
MESSAS, Emmanuel
Assistance Publique Hôpitaux de Paris, Hôpital Européen George Pompidou, 20 Rue Leblanc, 75015 Paris, France
Advisory Council FRANCE
BOURNET, Barbara
CHU de Toulouse, Hopital Rangueil, 1 Avenue Jean Poulhès, 31059 TOULOUSE cedex 9, France
Advisory Council FRANCE
BUSCAIL, Louis
CHU de Toulouse, Hopital Rangueil, 1 Avenue Jean Poulhès, 31059 TOULOUSE cedex 9, France
Advisory Council FRANCE
ASSENAT, Eric
St-Eloi University Hospital- Montpellier School of Medicine 80, avenue Augustin Fliche 34295 Montpellier, France
Advisory Council (nurse) FRANCE
NDOUR, Arlette
Assistance Publique Hôpitaux de Paris, Hôpital Saint-Louis, A 1 Avenue Claude Vellefaux, 75010 Paris, France
Advisory Council (pharmacist)
FRANCE
MADELAINE, Isabelle
Assistance Publique Hôpitaux de Paris, Hôpital Saint-Louis, A 1 Avenue Claude Vellefaux, 75010 Paris, France
Advisory Council
GERMANY
LANGER, Florian
University Medical Center Hamburg, Martinistraße 52, 20246 Hamburg, Germany
Advisory Council
GERMANY
BEYER-WESTENDORF, Jan
University Hospital Dresden Fetscherstraße 74, 01307 Dresden, Germany
Advisory Council
GERMANY
RIESS, Hanno
Charity University, Charitépl. 1, 1017, Berlin, Germany
September 2, 2019
93
Advisory Council
INDIA
CHAKRABARTTY, Joydeep
Vivekananda Institute of Medical Science, Kolkata, India
Advisory Council
INDIA
SASEEDHARAN, Sanjith
S.L Raheja Hospital Raheja Rugnalaya Marg, Mahim West, Mahim, Mumbai, Maharashtra 400016, India
Advisory Council
ISRAEL
MARTIN, Ellis
Meir medical center Tchernichovsky St 59, Kfar Saba, 4428164, Israël
Advisory Council
ISRAEL
BLICKSTEIN, Dorit
Rabin Medical Center Ze'ev Jabotinsky St 39, Petah Tikva, 4941492, Israël
Advisory Council (Patient)
ISRAEL
GIORA, Sharf
6 Ehud Manor street, Netanya, 4265941 , Israël
Advisory Council
ITALY
FALANGA, Anna
Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italia
Advisory Council
ITALY
MANDALA, Mario
Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italia
Advisory Council
ITALY
AGENO, Walter
University of Insubria Varese Via Ravasi, 2, 21100 Varese VA, Italia
Advisory Council
IVORY COAST
NGUESSAN, Michel
CHU de Treichville, Abidjan, Ivory Coast
Advisory Council
IVORY COAST
TOUSSAINT, Toutou
CHU de Treichville, Abidjan, Ivory Coast
Advisory Council
JAPAN
IKEZOE, Takayuki
Fukushima medical university Hikarigaoka, Fukushima, Fukushima Prefecture 960-1247, Japan
Advisory Council
JAPAN
YAMADA, Norizaku
Kuwana city medical center, �511-0061 Mie Prefecture, Kuwana, Kotobukicho, 3 Chome-1, Japan
Advisory Council
LEBANON
BAZARBACHII, Ali
American University of Beirut P.O.Box 11-0236 / (Department) Riad El-Solh / Beirut 1107 2020, Lebanon
September 2, 2019
94
Advisory Council
LEBANON
SHAMSEDDINE, Ali
American University of Beirut P.O.Box 11-0236 / (Department) Riad El-Solh / Beirut 1107 2020, Lebanon
Advisory Council
LEBANON
TAHER, Ali
American University of Beirut P.O.Box 11-0236 / (Department) Riad El-Solh / Beirut 1107 2020, Lebanon
Advisory Council
PORTUGAL
AJAURO, Fernando
Centro Hospitalar de São João Alameda Prof. Hernâni Monteiro 4200–319 Porto, Portugal
Advisory Council PORTUGAL BOGALHO, Isabel
Instituto Superior Técnico, Portugal [email protected]
Advisory Council PORTUGAL
MACHADO, Duarte Henrique
Instituto Português de Oncologia Lisboa Francisco Gentil, IPOLFG R. Prof. Lima Basto, Lisboa, Portugal
Advisory Council PORTUGAL
CLEMENTE, Hugo, Alexandre
Instituto Português de Oncologia Lisboa Francisco Gentil, IPOLFG R. Prof. Lima Basto, Lisboa, Portugal
Advisory Council
PORTUGAL
LOPES DOS SANTOS, Luisa
Instituto Português de Oncologia Porto R. Dr. António Bernardino de Almeida 865, 4200-072 Porto, Portugal
Advisory Council
PORTUGAL
PAIS, Ana
Instituto Português de Oncologia Coimbra Francisco Gentil, IPOCFG, Portugal
September 2, 2019
95
Advisory Council
PORTUGAL
MOREIRA, Antonio
Instituto Português de Oncologia de Lisboa Francisco Gentil, IPOLFG, Portugal
Advisory Council
QATAR
HALIMA, El Omri
National Center for Cancer Care and Research (NCCCR) Hamad Medical Corporation PO Box 3050 Doha, Qatar
Advisory Council
QATAR
AL-ABOUDI, Kamal R
National Center for Cancer Care and Research (NCCCR) Hamad Medical Corporation PO Box 3050 Doha, Qatar
Advisory Council
REPUBLIC OF SINGAPORE
LEE, Lai Heng
Singapore General Hospital, Republic of Singapore
Advisory Council
RUSSIA
MAKATSARIYA, Alexander
Sechenov First Moscow Medical University Bol'shaya Pirogovskaya Ulitsa, 19с1, Moskva, Russia
Advisory Council RUSSIA
BITSADZE, Viktoria
Sechenov First Moscow Medical University Bol'shaya Pirogovskaya Ulitsa, 19с1, Moskva, Russia
Advisory Council
RUSSIA
KHRIZROEVA, Jamilya
Sechenov First Moscow Medical University Bol'shaya Pirogovskaya Ulitsa, 19с1, Moskva, Russia
Advisory Council
SERBIA
ANTIC, Darko
Clinic for Hematology, Clinical Centre Serbia, Belgrade, Serbia; Medical Faculty, University of Belgrade, Belgrade, Serbia
September 2, 2019
96
Advisory Council SPAIN
FONT, Carme
Hospital Clinic de Barcelona Barcelona, Spain
Advisory Council
SPAIN
TRUJILLO-SANTOS, Javier
Universidad Católica de Murcia Av. de los Jerónimos, 135, 30107 Guadalupe, Murcia, Spain
Advisory Council
SPAIN
RUEDA-CAMINO, José Antonio
Hospital Universitario de Fuenlabrada C/ Camino del Molino, 2 28942 - Fuenlabrada Madrid, Spain
Advisory Council
SPAIN
LECUMBERRI, Ramos
Clinica Universidad de Navarra Av. de Pío XII, 36, 31008 Pamplona, Navarra, Spain
Advisory Council
SPAIN
RUIZ-ARTACHO, Pedro
Clínica Universidad de Navarra, Madrid Av. de Pío XII, 36, 31008 Pamplona, Navarra, Spain
Advisory Council
SPAIN
GALLARDO, Enrique
Hospital Universitari Parc Taulí Parc Taulí, 1 08208 Sabadell, Spain
[email protected] [email protected]
Advisory Council
SPAIN
OTERO-CANDELERA, Remedios
Hospital Universitario Virgen del Rocio Av. Manuel Siurot, S/n, 41013 Sevilla, Spain
Advisory Council
SPAIN
ARCELUS, Juan I.
University of Granada, Avda. del Hospicio, 18071 Granada, Spain
Advisory Council SPAIN PACHON OLMOS, Vanessa Hospital Ramon y Cajal [email protected]
September 2, 2019
97
Ctra. Colmenar Viejo Km. 9100 28034 Madrid, Spain
Advisory Council
SPAIN
JUAN-PALOMARES, Luis
Hospital Universitario Virgen del Rocio Av. Manuel Siurot, S/n, 41013 Sevilla, Spain
Advisory Council
SWITZERLAND
STRICKER, Hans
Ospedale La Carità Via dell'Ospedale 1, 6600 Locarno, Switzerland
Advisory Council
SWITZERLAND
RIGHINI Marc
University Hospitals of Geneva, Switzerland Rue Gabrielle-Perret-Gentil 4, 1205 Genève, Switzerland
Advisory Council
THAILAND
ANGCHAISUKSIRI, Pantep
Division of Hematology, Department of Medicine Ramathibodi Hospital, Mahidol University Bangkok, Thailand
Advisory Council
TURKEY
DEMIR, Ahmet Muzaffer
Trakya university medical school rakya Ünv. Balkan Yerleşkesi, 22130 İskender Köyü/Edirne Merkez/Edirne, Turkey
Advisory Council
UK
MARAYEVAS, Anthony
Hull York Medical School John Hughlings Jackson Building, University Rd, Heslington, York YO10 5DD, UK
Advisory Council
UNITED MEXICAN STATES
CESARMAN, Gabriela
National Cancer Inst, Mexico, United Mexican States
Advisory Council UNITED MEXICAN STATES
MEILLON, Luis
Hematology Deparment, Hospital de Especialidades, Centro Médico Nacional Siglo XXI; Universidad Nacional Autónoma de México United Mexican States
September 2, 2019
98
Advisory Council URUGUAY
GUILLERMO, Cecilia
Universidad de la República Oriental del Uruguay, Montevideo, Uruguay
Advisory Council
USA
FRANCIS, Charles
University of Rochester 601 Elmwood Ave., Rochester, NY 14642, USA
Advisory Council
USA
BAUER, Kenneth A
Harvard Medical School 25 Shattuck St, Boston, MA 02115, USA
Advisory Council
USA
KEY, Nigel S
The University of North Carolina at Chapel Hill 250 E. Franklin Street Chapel Hill, N.C. , USA
Advisory Council USA
SOFF, Gerald
Memorial Sloan Kettering Cancer Center, UNew-York, SA
Advisory Council USA
LIEBMAN, Howard
University of Southern California, Los Angeles, USA
Advisory Council (patient)
USA
HOKANSON, Robert