Supplementary appendix · A Khorana, Andres Munoz, Benjamin Brenner, Ajay Kakkar, Hanadi Rafii, Susan Solymoss, Dialina Brilhante, Manuel Monreal, Henri Bounameaux, Ingrid Pabinger

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.

Supplementary appendix revised version 23 08 2019

1

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


2

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.


4

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


5

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.


6

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


7

56. or/49-55 57. 43 and 48 58. 43 and 56

Q3: Treatment of VTE recurrence – vena cava filters

In patients with cancer


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


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"



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



8

In patients without cancer



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"



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



9

Q4: Prophylaxis of VTE in surgical cancer patients Q5: Prophylaxis of VTE in medical cancer patients




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)



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


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


10

Q6: Treatment of established catheter-related thrombosis Q7: Prophylaxis of catheter-related thrombosis




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


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








11

Thrombolytics






11. Thrombolytic Therapy/ or thrombolysis.ti. 12. 3 and 10 and 11

Search module Thrombolysis







Q8: Special situations

(See all above Medline® equations)


12

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


Population Patients with: • cancer (solid tumors) • acute leukemia • myeloma • lymphoma




Patients with tumor thrombus, or a history of cancer in remission for more than 5 years


Intervention VKA LMWH (long-term use) Idraparinux DOAC


Outcomes Rates of VTE: • de novo VTE • VTE extension

Major and minor bleeding Thrombocytopenia Death



13

Q3: Treatment of VTE recurrence in cancer patients under anticoagulation


Population Patients with: • cancer (solid tumor) • acute leukemia • multiple myeloma • lymphoma




Patients with a tumor thrombus, or a history of cancer in remission for more than 5 years


Intervention VKA Vena cava filter DOACs


Outcomes Rate of VTE: • de novo VTE • VTE extension



Q4: Prophylaxis of VTE in surgical cancer patients


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


Outcomes De novo VTE Major and minor bleeding Thrombocytopenia Death


Q5: Prophylaxis of VTE in medical cancer patients


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


Outcomes De novo VTE Catheter-related thrombosis


14


Superficial-vein thrombosis

Q6: Treatment of established catheter-related thrombosis


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


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


15

Q8: Special situations


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)


16

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.


17

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


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.


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.


20

Data extraction: CRITICAL APPRAISAL

References

Desi

gn

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finiti

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dpoi

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met

hod

of

mea

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men

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Docu

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of lo

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llow

-up

Inte

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o-tr

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anal

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Toxi

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: da

ta -

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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


21

References

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gn

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oint

def

initi

on

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riptio

n of

ra

ndom

izat

ion

Sam

ple

size

ca

lcul

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


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


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


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


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.


26


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]


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


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


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



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


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


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,


and May 2016

Group A: 143 patients

receiving post-filter

anticoagulation

treatment

(warfarin,53.8%;

LMWH, 27.3%; DOACs,

16.1%)


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


29


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


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


Arm B: 59/525 (11.3%)

p=0.09


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


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


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


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


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


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%)


RR, 1.74; 95% CI 1.05–2.88; I², 0%

CRNMB treated with DOACs: 89/725 (12.3%)


RR, 2.31; 95% CI: 0.85–6.28; I², 78%

All cause mortality treated with DOACs: 188/725 (2.6%)


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]


compared DOACs vs. VKA [AGNELLI 2015 (AMPLIFY)] [MAZILU 2014 (OVIDIUS) ] [PRINS 2014 (EINSTEIN)] [RASKOB 2016 (HOKUSAI)] [SCHULMAN 2015 (RECOVER I-II)]


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


1000, 95% CI 51 fewer to 37 more; low-


DOACs vs. LMWH

1.07, 95% CI 0.92 to 1.25; RD 27 more per



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


1000, 95% CI 29 fewer to 72 fewer, moderate-


DOACs vs. VKA


1000, 95% CI 27 fewer to 12

more; low-certainty evidence; I²=0%

DOACs vs. LMWH


33


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


1000, 95% CI 19 fewer to 48 more, moderate-


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



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




DOACs vs. VKA


1000, 95% CI 54 fewer to 28 more; low


DOACs vs. LMWH



evidence; I²=88%

Thrombocytopenia LMWH vs. VKA

RR 0.94, 95% CI 0.52 to 1.69


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


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.



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



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%


35


Number of patients

analyzed/included


[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%)


warfarin: RR 0.96; 95% CI 0.51-1.79

Non major bleeding LMWH: 15/482 (3.11%)

VKA: 13/482 (2.69%)


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


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


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


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%)


warfarin: RR 1.50; 95% CI 0.25-8.93



[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


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


37

anticoagulant

therapy

Patients with PE recurrence Group A: 48 patients

treated with IVC filter


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


38


Number of patients

analyzed/included


[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,


trial

Oct 2010 - Sep 2011


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),


trial

August 2011- March

2015


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


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


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.


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


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)


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)


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.


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



Table 11: Prophylaxis of VTE in surgical cancer patients- – prospective/retrospective


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%)

-


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

-


46



[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


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


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


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


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


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.


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.


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


(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


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].


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


54

RD 33 fewer per 1000; 95% CI 66

fewer to 28 more

I² = 83%

[Kahale 2017] Cochrane Central Register of


(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


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.


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


56



[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


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;



LMWH versus VKA (3 RCTs,

571 participants)

RR 0.94, 95% CI 0.56 to 1.59;



Symptomatic catheter-related thrombosis: LMWH versus no LMWH (5


RR 0.43, 95% CI 0.22 to 0.81;


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%


327 participants)

RR 1.83, 95% CI 0.44 to 7.61;

RD 15 more per 1000, 95% CI


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


58

No data

VKA versus no VKA

No data


327 participants)

RR 1.70, 95% CI 0.74 to 3.92;


13 fewer to 144 more

Major bleeding : LMWH versus no LMWH (4


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


RR 1.35, 95% CI, 0.62 to 2.92;


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;



LMWH versus VKA (1 study,

234 participants)

RR 0.95, 95% CI 0.20 to 4.61;


21 fewer to 95 more


59

Catheter-related infection : LMWH versus no LMWH (2


RR 0.97, 95% CI 0.52 to 1.79;



VKA versus no VKA (1 study,

88 participants)

RR 1.17, 95% CI 0.74 to 1.85;


109 fewer to 356 more

LMWH versus VKA

No data

Thrombocytopenia : LMWH versus no LMWH (4


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


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


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.


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


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%.


63



[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


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


65


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


66


Number of patients

analyzed/included


[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


67



[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


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


69

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


70

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 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]


71

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.


72

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 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 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


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]


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]


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]


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 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 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]


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


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


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]


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


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


83

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



84

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


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)


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


86

[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]



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



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


87

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

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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

[email protected]

Advisory Council

AUSTRIA

POSCH, Florian

Medizinische Universität Graz Auenbruggerplatz 2 A-8036 Graz, Austria

[email protected]

Advisory Council

AUSTRIA

GARY, Thomas

Medizinische Universität Graz Auenbruggerplatz 2 A-8036 Graz, Austria

[email protected]

Advisory Council

AUSTRIA

FEISTRITZER, Clemens

Medizinische Universität Innsbruck Christoph-Probst-Platz 1 Innrain 52 A-6020 Innsbruck, Austria

[email protected]

Advisory Council

AUSTRIA

PREUSSER, Matthias

Klinische Abteilung für Onkologie Universitätsklinik für Innere Medizin I Medizinische Universität Wien Währinger Gürtel 18-20, 1090 Wien, Austria

[email protected]

Advisory Council

AUSTRIA

MAROSI- Christine

Medizinische Universität Wien Währinger Gürtel 18-20, 1090 Wien, Austria

[email protected]

Advisory Council BRAZIL

ROTHSCHILD, Cynthia

Fundação Faculdade de Medicina – ICESP Av. Dr. Arnaldo, 455 - Cerqueira César, São Paulo - SP, 01246-903, Brazil

[email protected]

September 2, 2019

90

Advisory Council CANADA

ROUSSIN, Andre

CHUM University of Montreal 1051 Rue Sanguinet, Montréal, QC H2X 3E4, Canada

[email protected]


ALCINDOR, Thierry

McGill University 845 Rue Sherbrooke Ouest, Montréal, QC H3A 0G4, Canada

[email protected]

Advisory Council

CANADA

HULL, Russell D

University of Calgary 2500 University Drive NW Calgary, AB T2N 1N4 CANADA.

[email protected]


TAGALAKIS, Vicky


[email protected]


BLOSTEIN, Mark


[email protected]


KOOLIAN, Maral


[email protected]

Advisory Council

CHINA, HONG KONG

WONG, Raymond

The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, The People's Republic of China

[email protected]

Advisory Council

FRANCE

LE HELLO, Claire

CHU Saint Etienne Avenue Albert Raimond, 42270 Saint-Priest-en-Jarez, France

[email protected]

Advisory Council

FRANCE

HIJ, Adrian

Assistance Publique Hôpitaux de Paris, Hôpital Saint-Louis, A 1 Avenue Claude Vellefaux, 75010 Paris, France

[email protected]

Advisory Council

FRANCE

ANDRE, Thierry

Assistance Publique Hôpitaux de Paris, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75012 Paris, France

[email protected]

September 2, 2019

91

Advisory Council FRANCE

EMMERICH, Joseph

Hôpital Saint-Joseph 185 Rue Raymond Losserand, 75014 Paris, France

[email protected]

Advisory Council

FRANCE

MARJANOVIC, Zora

Assistance Publique Hôpitaux de Paris, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75012 Paris, France

[email protected]

Advisory Council

FRANCE

DURANT, Cécile

CHU de Nantes, 5 allée de l'île gloriette, 44093 Nantes Cedex, France

[email protected]

Advisory Council

FRANCE

CONNAULT, Jérôme

CHU de Nantes, 5 allée de l'île gloriette, 44093 Nantes Cedex, France

[email protected]

Advisory Council

FRANCE

DOUCET, Ludovic


[email protected]

Advisory Council

FRANCE

VILLIERS, Stéphane


[email protected]

Advisory Council

FRANCE

BENZIDIA, Ilham


[email protected]

Advisory Council

FRANCE

CARPENTIER, Antoine


[email protected]

Advisory Council

FRANCE

GRIS, Jean-Christophe

CHU de Nimes 4 Rue du Professeur Robert Debré, 30029 Nîmes, France

[email protected]

September 2, 2019

92


MESSAS, Emmanuel

Assistance Publique Hôpitaux de Paris, Hôpital Européen George Pompidou, 20 Rue Leblanc, 75015 Paris, France

[email protected]


BOURNET, Barbara

CHU de Toulouse, Hopital Rangueil, 1 Avenue Jean Poulhès, 31059 TOULOUSE cedex 9, France

[email protected]


BUSCAIL, Louis

CHU de Toulouse, Hopital Rangueil, 1 Avenue Jean Poulhès, 31059 TOULOUSE cedex 9, France

[email protected]


ASSENAT, Eric

St-Eloi University Hospital- Montpellier School of Medicine 80, avenue Augustin Fliche 34295 Montpellier, France

[email protected]

Advisory Council (nurse) FRANCE

NDOUR, Arlette


[email protected]

Advisory Council (pharmacist)

FRANCE

MADELAINE, Isabelle


[email protected]

Advisory Council

GERMANY

LANGER, Florian

University Medical Center Hamburg, Martinistraße 52, 20246 Hamburg, Germany

[email protected]

Advisory Council

GERMANY

BEYER-WESTENDORF, Jan

University Hospital Dresden Fetscherstraße 74, 01307 Dresden, Germany

[email protected]

Advisory Council

GERMANY

RIESS, Hanno

Charity University, Charitépl. 1, 1017, Berlin, Germany

[email protected]

September 2, 2019

93

Advisory Council

INDIA

CHAKRABARTTY, Joydeep

Vivekananda Institute of Medical Science, Kolkata, India

[email protected]

Advisory Council

INDIA

SASEEDHARAN, Sanjith

S.L Raheja Hospital Raheja Rugnalaya Marg, Mahim West, Mahim, Mumbai, Maharashtra 400016, India

[email protected]

Advisory Council

ISRAEL

MARTIN, Ellis

Meir medical center Tchernichovsky St 59, Kfar Saba, 4428164, Israël

[email protected]

Advisory Council

ISRAEL

BLICKSTEIN, Dorit

Rabin Medical Center Ze'ev Jabotinsky St 39, Petah Tikva, 4941492, Israël

[email protected]

Advisory Council (Patient)

ISRAEL

GIORA, Sharf

6 Ehud Manor street, Netanya, 4265941 , Israël

[email protected]

Advisory Council

ITALY

FALANGA, Anna

Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italia

[email protected]

Advisory Council

ITALY

MANDALA, Mario

Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italia

[email protected]

Advisory Council

ITALY

AGENO, Walter

University of Insubria Varese Via Ravasi, 2, 21100 Varese VA, Italia

[email protected]

Advisory Council

IVORY COAST

NGUESSAN, Michel

CHU de Treichville, Abidjan, Ivory Coast

[email protected]

Advisory Council

IVORY COAST

TOUSSAINT, Toutou

CHU de Treichville, Abidjan, Ivory Coast

[email protected]

Advisory Council

JAPAN

IKEZOE, Takayuki

Fukushima medical university Hikarigaoka, Fukushima, Fukushima Prefecture 960-1247, Japan

[email protected]

Advisory Council

JAPAN

YAMADA, Norizaku

Kuwana city medical center, �511-0061 Mie Prefecture, Kuwana, Kotobukicho, 3 Chome-1, Japan

[email protected]

Advisory Council

LEBANON

BAZARBACHII, Ali

American University of Beirut P.O.Box 11-0236 / (Department) Riad El-Solh / Beirut 1107 2020, Lebanon

[email protected]

September 2, 2019

94

Advisory Council

LEBANON

SHAMSEDDINE, Ali


[email protected]

Advisory Council

LEBANON

TAHER, Ali


[email protected]

Advisory Council

PORTUGAL

AJAURO, Fernando

Centro Hospitalar de São João Alameda Prof. Hernâni Monteiro 4200–319 Porto, Portugal

[email protected]

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

[email protected]

Advisory Council PORTUGAL

CLEMENTE, Hugo, Alexandre

Instituto Português de Oncologia Lisboa Francisco Gentil, IPOLFG R. Prof. Lima Basto, Lisboa, Portugal

[email protected]

Advisory Council

PORTUGAL

LOPES DOS SANTOS, Luisa

Instituto Português de Oncologia Porto R. Dr. António Bernardino de Almeida 865, 4200-072 Porto, Portugal

[email protected]

Advisory Council

PORTUGAL

PAIS, Ana

Instituto Português de Oncologia Coimbra Francisco Gentil, IPOCFG, Portugal

[email protected]

September 2, 2019

95

Advisory Council

PORTUGAL

MOREIRA, Antonio

Instituto Português de Oncologia de Lisboa Francisco Gentil, IPOLFG, Portugal

[email protected]

Advisory Council

QATAR

HALIMA, El Omri

National Center for Cancer Care and Research (NCCCR) Hamad Medical Corporation PO Box 3050 Doha, Qatar

[email protected]

Advisory Council

QATAR

AL-ABOUDI, Kamal R

National Center for Cancer Care and Research (NCCCR) Hamad Medical Corporation PO Box 3050 Doha, Qatar

[email protected]

Advisory Council

REPUBLIC OF SINGAPORE

LEE, Lai Heng

Singapore General Hospital, Republic of Singapore

[email protected]

Advisory Council

RUSSIA

MAKATSARIYA, Alexander

Sechenov First Moscow Medical University Bol'shaya Pirogovskaya Ulitsa, 19с1, Moskva, Russia

[email protected]

Advisory Council RUSSIA

BITSADZE, Viktoria


[email protected]

Advisory Council

RUSSIA

KHRIZROEVA, Jamilya


[email protected]

Advisory Council

SERBIA

ANTIC, Darko

Clinic for Hematology, Clinical Centre Serbia, Belgrade, Serbia; Medical Faculty, University of Belgrade, Belgrade, Serbia

[email protected] [email protected]

September 2, 2019

96

Advisory Council SPAIN

FONT, Carme

Hospital Clinic de Barcelona Barcelona, Spain

[email protected]

Advisory Council

SPAIN

TRUJILLO-SANTOS, Javier

Universidad Católica de Murcia Av. de los Jerónimos, 135, 30107 Guadalupe, Murcia, Spain

[email protected]

Advisory Council

SPAIN

RUEDA-CAMINO, José Antonio

Hospital Universitario de Fuenlabrada C/ Camino del Molino, 2 28942 - Fuenlabrada Madrid, Spain

[email protected]

Advisory Council

SPAIN

LECUMBERRI, Ramos

Clinica Universidad de Navarra Av. de Pío XII, 36, 31008 Pamplona, Navarra, Spain

[email protected]

Advisory Council

SPAIN

RUIZ-ARTACHO, Pedro

Clínica Universidad de Navarra, Madrid Av. de Pío XII, 36, 31008 Pamplona, Navarra, Spain

[email protected]

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

[email protected]

Advisory Council

SPAIN

ARCELUS, Juan I.

University of Granada, Avda. del Hospicio, 18071 Granada, Spain

[email protected]

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

[email protected]

Advisory Council

SWITZERLAND

STRICKER, Hans

Ospedale La Carità Via dell'Ospedale 1, 6600 Locarno, Switzerland

[email protected]

Advisory Council

SWITZERLAND

RIGHINI Marc

University Hospitals of Geneva, Switzerland Rue Gabrielle-Perret-Gentil 4, 1205 Genève, Switzerland

[email protected]

Advisory Council

THAILAND

ANGCHAISUKSIRI, Pantep

Division of Hematology, Department of Medicine Ramathibodi Hospital, Mahidol University Bangkok, Thailand

[email protected]

Advisory Council

TURKEY

DEMIR, Ahmet Muzaffer

Trakya university medical school rakya Ünv. Balkan Yerleşkesi, 22130 İskender Köyü/Edirne Merkez/Edirne, Turkey

[email protected]

Advisory Council

UK

MARAYEVAS, Anthony

Hull York Medical School John Hughlings Jackson Building, University Rd, Heslington, York YO10 5DD, UK

[email protected]

Advisory Council

UNITED MEXICAN STATES

CESARMAN, Gabriela

National Cancer Inst, Mexico, United Mexican States

[email protected]

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

[email protected]

September 2, 2019

98

Advisory Council URUGUAY

GUILLERMO, Cecilia

Universidad de la República Oriental del Uruguay, Montevideo, Uruguay

[email protected]

Advisory Council

USA

FRANCIS, Charles

University of Rochester 601 Elmwood Ave., Rochester, NY 14642, USA

[email protected]

Advisory Council

USA

BAUER, Kenneth A

Harvard Medical School 25 Shattuck St, Boston, MA 02115, USA

[email protected]

Advisory Council

USA

KEY, Nigel S

The University of North Carolina at Chapel Hill 250 E. Franklin Street Chapel Hill, N.C. , USA

[email protected]

Advisory Council USA

SOFF, Gerald

Memorial Sloan Kettering Cancer Center, UNew-York, SA

[email protected]

Advisory Council USA

LIEBMAN, Howard

University of Southern California, Los Angeles, USA

[email protected]

Advisory Council (patient)

USA

HOKANSON, Robert

[email protected]

Documents

Supplementary appendix · A Khorana, Andres Munoz, Benjamin Brenner, Ajay Kakkar, Hanadi Rafii, Susan Solymoss, Dialina Brilhante, Manuel Monreal, Henri Bounameaux, Ingrid Pabinger