Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2020 Dec 18;12(12):CD008500.
doi: 10.1002/14651858.CD008500.pub5.

Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy

Anne Ws Rutjes  1 , Ettore Porreca  2 , Matteo Candeloro  3 , Emanuele Valeriani  3 , Marcello Di Nisio  4   5
Affiliations
Meta-Analysis

Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy

Anne Ws Rutjes et al. Cochrane Database Syst Rev. .

Abstract

Background: Venous thromboembolism (VTE) often complicates the clinical course of cancer. The risk is further increased by chemotherapy, but the trade-off between safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain. This is the third update of a review first published in February 2012.

Objectives: To assess the efficacy and safety of primary thromboprophylaxis for VTE in ambulatory cancer patients receiving chemotherapy compared with placebo or no thromboprophylaxis, or an active control intervention.

Search methods: For this update, the Cochrane Vascular Information Specialist searched the Cochrane Vascular, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 3 August 2020. We also searched the reference lists of identified studies and contacted content experts and trialists for relevant references.

Selection criteria: Randomised controlled trials comparing any oral or parenteral anticoagulant or mechanical intervention to no thromboprophylaxis or placebo, or comparing two different anticoagulants.

Data collection and analysis: We extracted data on risk of bias, participant characteristics, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively. We applied GRADE to assess the certainty of evidence.

Main results: We identified six additional randomised controlled trials (3326 participants) for this update, bringing the included study total to 32 (15,678 participants), all evaluating pharmacological interventions and performed mainly in people with locally advanced or metastatic cancer. The certainty of the evidence ranged from high to very low across the different outcomes and comparisons. The main limiting factors were imprecision and risk of bias. Thromboprophylaxis with direct oral anticoagulants (direct factor Xa inhibitors apixaban and rivaroxaban) may decrease the incidence of symptomatic VTE (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.18 to 1.06; 3 studies, 1526 participants; low-certainty evidence); and probably increases the risk of major bleeding compared with placebo (RR 1.74, 95% CI 0.82 to 3.68; 3 studies, 1494 participants; moderate-certainty evidence). When compared with no thromboprophylaxis, low-molecular-weight heparin (LMWH) reduced the incidence of symptomatic VTE (RR 0.62, 95% CI 0.46 to 0.83; 11 studies, 3931 participants; high-certainty evidence); and probably increased the risk of major bleeding events (RR 1.63, 95% CI 1.12 to 2.35; 15 studies, 7282 participants; moderate-certainty evidence). In participants with multiple myeloma, LMWH resulted in lower symptomatic VTE compared with the vitamin K antagonist warfarin (RR 0.33, 95% CI 0.14 to 0.83; 1 study, 439 participants; high-certainty evidence), while LMWH probably lowers symptomatic VTE more than aspirin (RR 0.51, 95% CI 0.22 to 1.17; 2 studies, 781 participants; moderate-certainty evidence). Major bleeding was observed in none of the participants with multiple myeloma treated with LMWH or warfarin and in less than 1% of those treated with aspirin. Only one study evaluated unfractionated heparin against no thromboprophylaxis, but did not report on VTE or major bleeding. When compared with placebo or no thromboprophylaxis, warfarin may importantly reduce symptomatic VTE (RR 0.15, 95% CI 0.02 to 1.20; 1 study, 311 participants; low-certainty evidence) and may result in a large increase in major bleeding (RR 3.82, 95% CI 0.97 to 15.04; 4 studies, 994 participants; low-certainty evidence). One study evaluated antithrombin versus no antithrombin in children. This study did not report on symptomatic VTE but did report any VTE (symptomatic and incidental VTE). The effect of antithrombin on any VTE and major bleeding is uncertain (any VTE: RR 0.84, 95% CI 0.41 to 1.73; major bleeding: RR 0.78, 95% CI 0.03 to 18.57; 1 study, 85 participants; very low-certainty evidence).

Authors' conclusions: In ambulatory cancer patients, primary thromboprophylaxis with direct factor Xa inhibitors may reduce the incidence of symptomatic VTE (low-certainty evidence) and probably increases the risk of major bleeding (moderate-certainty evidence) when compared with placebo. LMWH decreases the incidence of symptomatic VTE (high-certainty evidence), but increases the risk of major bleeding (moderate-certainty evidence) when compared with placebo or no thromboprophylaxis. Evidence for the use of thromboprophylaxis with anticoagulants other than direct factor Xa inhibitors and LMWH is limited. More studies are warranted to evaluate the efficacy and safety of primary prophylaxis in specific types of chemotherapeutic agents and types of cancer, such as gastrointestinal or genitourinary cancer.

Trial registration: ClinicalTrials.gov NCT00951574 NCT00694382 NCT02048865 NCT00239980 NCT00876915 NCT02555878 NCT00551928 NCT00324558 NCT00320255 NCT00519805 NCT00462852 NCT00475098 NCT00785421 NCT00966277 NCT00908960 NCT00662688 NCT00771563.

PubMed Disclaimer

Conflict of interest statement

AWSR: none. EP: none. MC: none. EV: none. MDN: has declared that he has received consultancy fees from Bayer, Daiichi Sankyo, LEO Pharma, BMS‐Pfizer and Aspen, outside of the submitted work.

When the previous version of this review was published(Di Nisio 2016), the authors declared the below conflicts of interest. From 29 October 2020, the above conflicts of interest were declared. These conflicts applied during the period that the review update was in preparation.

MDN: I have received consultancy fees from Bayer, Grifols, and Daiichi Sankyo not related to the present review. EP: none known MC: none known MDT: none known IR: none known AWSR: none known

Figures

1
1
Study flow diagram. RCT: randomised controlled trial; VTE: venous thromboembolism.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Funnel plot of comparison: 1 Anticoagulants versus control: symptomatic venous thromboembolism (VTE), outcome: 1.2 Symptomatic VTE: low‐molecular weight heparin versus no thromboprophylaxis.
4
4
Funnel plot of comparison: 2 Anticoagulants versus control: major bleeding, outcome: 2.2 Major bleeding: low‐molecular weight heparin versus no thromboprophylaxis.
1.1
1.1. Analysis
Comparison 1: Anticoagulants versus control: symptomatic venous thromboembolism, Outcome 1: Symptomatic VTE: DOAC vs placebo
1.2
1.2. Analysis
Comparison 1: Anticoagulants versus control: symptomatic venous thromboembolism, Outcome 2: Symptomatic VTE: LMWH vs no thromboprophylaxis
1.3
1.3. Analysis
Comparison 1: Anticoagulants versus control: symptomatic venous thromboembolism, Outcome 3: Symptomatic VTE: prophylactic vs intermediate or therapeutic LMWH
1.4
1.4. Analysis
Comparison 1: Anticoagulants versus control: symptomatic venous thromboembolism, Outcome 4: Symptomatic VTE: LMWH vs aspirin
1.5
1.5. Analysis
Comparison 1: Anticoagulants versus control: symptomatic venous thromboembolism, Outcome 5: Symptomatic VTE: LMWH vs warfarin
1.6
1.6. Analysis
Comparison 1: Anticoagulants versus control: symptomatic venous thromboembolism, Outcome 6: Symptomatic VTE: semuloparin vs placebo
1.7
1.7. Analysis
Comparison 1: Anticoagulants versus control: symptomatic venous thromboembolism, Outcome 7: Symptomatic VTE: vitamin K antagonists vs placebo
1.8
1.8. Analysis
Comparison 1: Anticoagulants versus control: symptomatic venous thromboembolism, Outcome 8: Symptomatic VTE: warfarin vs aspirin
2.1
2.1. Analysis
Comparison 2: Anticoagulants versus control: major bleeding, Outcome 1: Major bleeding: DOAC vs placebo
2.2
2.2. Analysis
Comparison 2: Anticoagulants versus control: major bleeding, Outcome 2: Major bleeding: LMWH vs no thromboprophylaxis
2.3
2.3. Analysis
Comparison 2: Anticoagulants versus control: major bleeding, Outcome 3: Major bleeding: prophylactic vs intermediate or therapeutic LMWH
2.4
2.4. Analysis
Comparison 2: Anticoagulants versus control: major bleeding, Outcome 4: Major bleeding: LMWH vs aspirin
2.5
2.5. Analysis
Comparison 2: Anticoagulants versus control: major bleeding, Outcome 5: Major bleeding: LMWH vs warfarin
2.6
2.6. Analysis
Comparison 2: Anticoagulants versus control: major bleeding, Outcome 6: Major bleeding: semuloparin vs placebo
2.7
2.7. Analysis
Comparison 2: Anticoagulants versus control: major bleeding, Outcome 7: Major bleeding: vitamin K antagonists vs no thromboprophylaxis
2.8
2.8. Analysis
Comparison 2: Anticoagulants versus control: major bleeding, Outcome 8: Major bleeding: warfarin vs aspirin
3.1
3.1. Analysis
Comparison 3: Anticoagulants versus control: symptomatic pulmonary embolism, Outcome 1: Symptomatic PE: DOAC vs placebo
3.2
3.2. Analysis
Comparison 3: Anticoagulants versus control: symptomatic pulmonary embolism, Outcome 2: Symptomatic PE: LMWH vs no thromboprophylaxis
3.3
3.3. Analysis
Comparison 3: Anticoagulants versus control: symptomatic pulmonary embolism, Outcome 3: Symptomatic PE: prophylactic vs intermediate or therapeutic LMWH
3.4
3.4. Analysis
Comparison 3: Anticoagulants versus control: symptomatic pulmonary embolism, Outcome 4: Symptomatic PE: LMWH vs aspirin
3.5
3.5. Analysis
Comparison 3: Anticoagulants versus control: symptomatic pulmonary embolism, Outcome 5: Symptomatic PE: LMWH vs warfarin
3.6
3.6. Analysis
Comparison 3: Anticoagulants versus control: symptomatic pulmonary embolism, Outcome 6: Symptomatic PE: semuloparin vs placebo
3.7
3.7. Analysis
Comparison 3: Anticoagulants versus control: symptomatic pulmonary embolism, Outcome 7: Symptomatic PE: vitamin K antagonists vs placebo
3.8
3.8. Analysis
Comparison 3: Anticoagulants versus control: symptomatic pulmonary embolism, Outcome 8: Symptomatic PE: warfarin vs aspirin
4.1
4.1. Analysis
Comparison 4: Anticoagulants versus control: fatal PE, Outcome 1: Fatal PE: LMWH vs no thromboprophylaxis
5.1
5.1. Analysis
Comparison 5: Anticoagulants versus control: symptomatic deep vein thrombosis, Outcome 1: Symptomatic DVT: DOAC vs placebo
5.2
5.2. Analysis
Comparison 5: Anticoagulants versus control: symptomatic deep vein thrombosis, Outcome 2: Symptomatic DVT: LMWH vs no thromboprophylaxis
5.3
5.3. Analysis
Comparison 5: Anticoagulants versus control: symptomatic deep vein thrombosis, Outcome 3: Symptomatic DVT: prophylactic vs intermediate or therapeutic LMWH
5.4
5.4. Analysis
Comparison 5: Anticoagulants versus control: symptomatic deep vein thrombosis, Outcome 4: Symptomatic DVT: LMWH vs aspirin
5.5
5.5. Analysis
Comparison 5: Anticoagulants versus control: symptomatic deep vein thrombosis, Outcome 5: Symptomatic DVT: LMWH vs warfarin
5.6
5.6. Analysis
Comparison 5: Anticoagulants versus control: symptomatic deep vein thrombosis, Outcome 6: Symptomatic DVT: semuloparin vs placebo
5.7
5.7. Analysis
Comparison 5: Anticoagulants versus control: symptomatic deep vein thrombosis, Outcome 7: Symptomatic DVT: vitamin K antagonists vs placebo
5.8
5.8. Analysis
Comparison 5: Anticoagulants versus control: symptomatic deep vein thrombosis, Outcome 8: Symptomatic DVT: warfarin vs aspirin
6.1
6.1. Analysis
Comparison 6: Anticoagulants versus control: any venous thromboembolism, Outcome 1: Any VTE: DOAC vs placebo
6.2
6.2. Analysis
Comparison 6: Anticoagulants versus control: any venous thromboembolism, Outcome 2: Any VTE: LMWH vs no thromboprophylaxis
6.3
6.3. Analysis
Comparison 6: Anticoagulants versus control: any venous thromboembolism, Outcome 3: Any VTE: prophylactic vs intermediate vs therapeutic LMWH
6.4
6.4. Analysis
Comparison 6: Anticoagulants versus control: any venous thromboembolism, Outcome 4: Any VTE: semuloparin vs placebo
7.1
7.1. Analysis
Comparison 7: Anticoagulants versus control: 1‐year overall mortality, Outcome 1: 1‐year overall mortality: LMWH vs no thromboprophylaxis
7.2
7.2. Analysis
Comparison 7: Anticoagulants versus control: 1‐year overall mortality, Outcome 2: 1‐year overall mortality: semuloparin vs placebo
7.3
7.3. Analysis
Comparison 7: Anticoagulants versus control: 1‐year overall mortality, Outcome 3: 1‐year overall mortality: UFH vs no thromboprophylaxis
8.1
8.1. Analysis
Comparison 8: Anticoagulants versus control: clinically relevant bleeding, Outcome 1: Clinically relevant bleeding: DOAC vs placebo
8.2
8.2. Analysis
Comparison 8: Anticoagulants versus control: clinically relevant bleeding, Outcome 2: Clinically relevant bleeding: LMWH vs no thromboprophylaxis
8.3
8.3. Analysis
Comparison 8: Anticoagulants versus control: clinically relevant bleeding, Outcome 3: Clinically relevant bleeding: prophylactic vs intermediate vs therapeutic LMWH
8.4
8.4. Analysis
Comparison 8: Anticoagulants versus control: clinically relevant bleeding, Outcome 4: Clinically relevant bleeding: semuloparin vs placebo
8.5
8.5. Analysis
Comparison 8: Anticoagulants versus control: clinically relevant bleeding, Outcome 5: Clinically relevant bleeding: UFH vs no thromboprophylaxis
9.1
9.1. Analysis
Comparison 9: Anticoagulants versus control: incidental venous thromboembolism, Outcome 1: Incidental VTE: DOAC vs placebo
9.2
9.2. Analysis
Comparison 9: Anticoagulants versus control: incidental venous thromboembolism, Outcome 2: Incidental VTE: LMWH vs no thromboprophylaxis
9.3
9.3. Analysis
Comparison 9: Anticoagulants versus control: incidental venous thromboembolism, Outcome 3: Incidental VTE: prophylactic vs intermediate or therapeutic LMWH
9.4
9.4. Analysis
Comparison 9: Anticoagulants versus control: incidental venous thromboembolism, Outcome 4: Incidental VTE: semuloparin vs placebo
10.1
10.1. Analysis
Comparison 10: Anticoagulants versus control: minor bleeding, Outcome 1: Minor bleeding: LMWH vs no thromboprophylaxis
10.2
10.2. Analysis
Comparison 10: Anticoagulants versus control: minor bleeding, Outcome 2: Minor bleeding: prophylactic vs intermediate or therapeutic LMWH
10.3
10.3. Analysis
Comparison 10: Anticoagulants versus control: minor bleeding, Outcome 3: Minor bleeding: LMWH vs aspirin
10.4
10.4. Analysis
Comparison 10: Anticoagulants versus control: minor bleeding, Outcome 4: Minor bleeding: LMWH vs warfarin
10.5
10.5. Analysis
Comparison 10: Anticoagulants versus control: minor bleeding, Outcome 5: Minor bleeding: UFH vs no thromboprophylaxis
10.6
10.6. Analysis
Comparison 10: Anticoagulants versus control: minor bleeding, Outcome 6: Minor bleeding: vitamin K antagonists vs placebo
10.7
10.7. Analysis
Comparison 10: Anticoagulants versus control: minor bleeding, Outcome 7: Minor bleeding: warfarin vs aspirin
11.1
11.1. Analysis
Comparison 11: Anticoagulants versus control: symptomatic arterial thromboembolism, Outcome 1: Symptomatic arterial thromboembolism: DOAC vs placebo
11.2
11.2. Analysis
Comparison 11: Anticoagulants versus control: symptomatic arterial thromboembolism, Outcome 2: Symptomatic arterial thromboembolism: LMWH vs no thromboprophylaxis
11.3
11.3. Analysis
Comparison 11: Anticoagulants versus control: symptomatic arterial thromboembolism, Outcome 3: Symptomatic arterial thromboembolism: LMWH vs aspirin
11.4
11.4. Analysis
Comparison 11: Anticoagulants versus control: symptomatic arterial thromboembolism, Outcome 4: Symptomatic arterial thromboembolism: LMWH vs warfarin
11.5
11.5. Analysis
Comparison 11: Anticoagulants versus control: symptomatic arterial thromboembolism, Outcome 5: Symptomatic arterial thromboembolism: vitamin K antagonists vs placebo
11.6
11.6. Analysis
Comparison 11: Anticoagulants versus control: symptomatic arterial thromboembolism, Outcome 6: Symptomatic arterial thromboembolism: warfarin vs aspirin
12.1
12.1. Analysis
Comparison 12: Anticoagulants versus control: superficial venous thrombosis, Outcome 1: Superficial venous thrombosis: LMWH vs no thromboprophylaxis
12.2
12.2. Analysis
Comparison 12: Anticoagulants versus control: superficial venous thrombosis, Outcome 2: Superficial venous thrombosis: LMWH vs aspirin
13.1
13.1. Analysis
Comparison 13: Anticoagulants versus control: serious adverse events, Outcome 1: Serious adverse events: DOAC vs placebo
13.2
13.2. Analysis
Comparison 13: Anticoagulants versus control: serious adverse events, Outcome 2: Serious adverse events: LMWH vs no thromboprophylaxis
13.3
13.3. Analysis
Comparison 13: Anticoagulants versus control: serious adverse events, Outcome 3: Serious adverse events: semuloparin vs placebo
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Agnelli 2009 {published data only}
    1. Agnelli G, Gussoni G, Bianchini C, Verso M, Mandala M, Cavanna L, et al. Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncology 2009;10(10):943-9. - PubMed
    1. Agnelli G, Tonato M. Nadroparin for prevention of thromboembolic events in cancer patients receiving chemotherapy: a randomized placebo-controlled double-blind study. Supportive Care in Cancer 2009;17:857-1039.
    1. Barni S, Bonizzoni E, Verso M, Gussoni G, Petrelli F, Perrone T, et al. The effect of low-molecular-weight heparin in cancer patients: the mirror image of survival? Blood 2014;124:155-6. - PMC - PubMed
    1. Barni S, Labianca R, Agnelli G, Bonizzoni E, Mandalà M, Verso M, et al. Thromboembolic risk related to type of chemotherapy and efficacy of nadroparin in cancer outpatients with metastatic or locally advanced cancer. Supportive Care in Cancer 2011;19 (Suppl 2):S206.
    1. Barni S, Labianca R, Agnelli G, Bonizzoni E, Verso M, Mandala M, et al. Chemotherapy-associated thromboembolic risk in cancer outpatients and effect of nadroparin thromboprophylaxis: results of a retrospective analysis of the PROTECHT study. Journal of Translational Medicine 2011;9:179. - PMC - PubMed
Agnelli 2012 {published data only}
    1. Agnelli G, George D, Fisher WD, Kakkar AK, Lassen MR, Mismetti P, et al. Ultra-low-molecular-weight heparin (ULMWH) semuloparin for prevention of venous thromboembolism (VTE) in cancer patients receiving chemotherapy: consistent beneficial effect across cancer stage and location subgroups. European Journal of Cancer 2011;47:S222.
    1. Agnelli G, George DJ, Kakkar AK, Fisher W, Lassen MR, Mismetti P, et al, for the SAVE-ONCO Investigators. Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. New England Journal of Medicine 2012;366(7):601-9. - PubMed
    1. Hull RD. Semuloparin reduced venous thromboembolism in patients receiving chemotherapy for cancer. Annals of Internal Medicine 2012;156:JC6-5. - PubMed
    1. NCT00694382. A multinational, randomized, double blind, placebo-controlled study to evaluate the efficacy and safety of AVE5026 in the prevention of venous thromboembolism (VTE) in cancer patients at high risk for VTE and who are undergoing chemotherapy. clinicaltrials.gov/show/NCT00694382 (first received 7 May 2008).
Altinbas 2004 {published data only}
    1. Altinbas M, Coskun HS, Er O, Ozkan M, Eser B, Unal A, et al. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. Journal of Thrombosis and Haemostasis 2004;2(8):1266-71. - PubMed
Campos‐Cabrera 2018 {published data only}
    1. Campos-Cabrera G, Mendez-Garcia E, Campos-Cabrera S, Campos-Villagomez JL, Campos-Cabrera V. Rivaroxaban or aspirin as thromboprophylaxis in multiple myeloma. Blood 2018;132(Suppl 1):5068. [DOI: 10.1182/blood-2018-99-111579] - DOI
Carrier 2019 {published data only}
    1. Carrier M, Abou-Nassar K, Mallick R, Tagalakis V, Shivakumar S, Schattner A, et al. Apixaban to prevent venous thromboembolism in patients with cancer. New England Journal of Medicine 2019;380:711-9. - PubMed
    1. Castellucci L, Carrier M, Mallick R, Wells P. Bleeding in the prevention of cancer-associated venous thromboembolism: secondary analysis of the AVERT study. Research and Practice in Thrombosis and Haemostasis 2019;3 (Suppl 1):719.
    1. Kimpton M, Wells PS, Carrier M. Apixaban for the prevention of venous thromboembolism in high-risk ambulatory cancer patients receiving chemotherapy: rational and design of the AVERT trial. Thrombosis Research 2018;164:S124-9. - PubMed
    1. Knoll W, Mallick R, Wells P, Carrier M. Safety and efficacy of apixaban thromboprophylaxis in cancer patients with metastatic disease: a subgroup analysis of the avert trial. Blood 2019;134 (Suppl 1):1140. - PubMed
    1. Miranda S, Benhamou Y, Wells P, Carrier M. Safety of primary thromboprophylaxis using apixaban in ambulatory cancer patients with intracranial metastatic disease or primary brain tumors. Thrombosis and Haemostasis 2019;119(11):1886-7. - PubMed
Chahinian 1989 {published data only}
    1. Chahinian AP, Propert KJ, Ware JH, Zimmer B, Perry MC, Hirsh V, et al. A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B. Journal of Clinical Oncology 1989;7(8):993-1002. - PubMed
Ek 2018 {published data only}
    1. Ek L, Gezelius E, Bergman B, Bendahl PO, Anderson H, Sundberg J, et al. Randomized phase III trial of low-molecular-weight heparin enoxaparin in addition to standard treatment in small-cell lung cancer: the RASTEN trial. Annals of Oncology 2018;29(2):398-404. - PMC - PubMed
    1. Gezelius E, Bendahl P, Goncalves de Oliveira K, Ek L, Bergman B, Sundberg J, et al. Low-molecular-weight heparin adherence and effects on survival within a randomised phase III lung cancer trial (RASTEN). European Journal of Cancer 2019;118:82-90. - PubMed
    1. Gezelius E, Ek L, Bergman B, Bendahl P, Anderson H, Falkmer U, et al. Randomized phase III trial of enoxaparin in addition to standard treatment in small cell lung cancer: the RASTEN trial. Journal of Thoracic Oncology 2017;12(11):S2045-6. - PMC - PubMed
    1. Gezelius E, Flou Kristensen A, Bendahl PO, Hisada Y, Risom Kristensen S, Ek L, et al. Coagulation biomarkers and prediction of venous thromboembolism and survival in small cell lung cancer: a sub-study of RASTEN – a randomized trial with low molecular weight heparin. PloS One 2018;13(11):e0207387. - PMC - PubMed
    1. NCT00717938. A study of standard treatment +/- enoxaparin in small cell lung cancer (RASTEN). clinicaltrials.gov/ct2/show/NCT00717938 (first received 16 July 2008).
Elit 2012 {published data only}
    1. Elit LM, Lee AY, Parpia S, Swystun LL, Liaw PC, Hoskins P, et al. Dalteparin low molecular weight heparin (LMWH) in ovarian cancer: a phase II randomized study. Thrombosis Research 2012;130:894-900. - PubMed
    1. NCT00239980. A phase II randomized study of Fragmin in ovarian cancer: utility on survival (FOCUS). clinicaltrials.gov/show/NCT00239980 (first received 13 October 2005).
Greiner 2019 {published data only}
    1. Greiner J, Schrappe M, Claviez A, Zimmermann M, Niemeyer C, Kolb R, et al. THROMBOTECT – a randomized study comparing low molecular weight heparin, antithrombin and unfractionated heparin for thromboprophylaxis during induction therapy of acute lymphoblastic leukemia in children and adolescents. Haematologica 2019;104(4):756-65. - PMC - PubMed
Haas 2012 {published data only}
    1. Freund M, Kakkar AK, Haas S, Heilmann L, von-Tempelhoff GF, Brom J, et al. A randomized trial of the low molecular weight of heparin certoparin against placebo in the long-term prevention of venous thromboembolism in patients with metastatic breast cancer. Blood 2003;102(11 (Pt1)):210a.
    1. Gatzemeier U, Freund M, Haas S, Kakkar A, Zatloukai P, Kelbel C, et al. Prevention of thromboembolic complications with the low-molecular-weight heparin certoparin in non-small-cell lung carcinoma (TOPIC-2). Lung Cancer (Amsterdam, Netherlands) 2005;49:S56.
    1. Haas SK, Freund M, Heigener D, Heilmann L, Kemkes-Matthes B, Tempelhoff GF, TOPIC Investigators. Low-molecular-weight heparin versus placebo for the prevention of venous thromboembolism in metastatic breast cancer or stage III/IV lung cancer. Clinical and Applied Thrombosis Hemostasis 2012;18(2):159-65. - PubMed
    1. Haas SK, Kakkar AK, Kemkes-Matthes B, Freund M, Gatzemeier U, Heilmann L, et al. Prevention of venous thromboembolism with low-molecular-weight heparin in patients with metastatic breast or lung cancer – results of the TOPIC studies. Journal of Thrombosis and Haemostasis 2005;3(1):Abstract OR059.
    1. Verso M, Gussoni G, Agnelli G. Prevention of venous thromboembolism in patients with advanced lung cancer receiving chemotherapy: a combined analysis of the PROTECHT and TOPIC-2 studies. Journal of Thrombosis and Haemostasis 2010;8(7):1649-51. - PubMed
Kakkar 2004 {published data only}
    1. Kakkar AK, Levine MN, Kadziola Z, Lemoine NR, Low V, Patel HK, et al. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). Journal of Clinical Oncology 2004;22(10):1944-8. - PubMed
Khorana 2017 {published data only}
    1. Khorana AA, Francis CW, Kuderer N, Carrier M, Ortel TL, Wun T, et al. Dalteparin thromboprophylaxis in cancer patients at high risk for venous thromboembolism: a randomized trial. Blood 2015;126:427. - PubMed
    1. Khorana AA, Francis CW, Kuderer NM, Carrier M, Ortel TL, Wun T, et al. Dalteparin thromboprophylaxis in cancer patients at high risk for venous thromboembolism: a randomized trial. Thrombosis Research 2017;151:89-95. - PubMed
    1. NCT00876915. A prospective randomized multicenter study of dalteparin prophylaxis in high-risk ambulatory cancer patients. clinicaltrials.gov/show/NCT00876915 (first received 31 March 2009).
Khorana 2019 {published data only}
    1. Anonymous. CASSINI trial data on preventing blood clots in cancer patients. Oncology Times 2019;41:19.
    1. Khorana A, McNamara M, Kakkar A, Streiff M, Riess H, Vijapurkar U, et al. Assessing full benefit of rivaroxaban prophylaxis in high-risk ambulatory patients with cancer: thromboembolic events in the randomized CASSINI trial. TH Open 2020;4(2):E107-12. - PMC - PubMed
    1. Khorana A, Soff G, Kakkar A, Vadhan-Raj S, Riess H, Wun T, et al. Rivaroxaban thromboprophylaxis in high-risk ambulatory cancer patients receiving systemic therapy: results of a randomized clinical trial (CASSINI). Blood 2018;132 (Suppl 1):LBA-1.
    1. Khorana AA, Soff GA, Kakkar AK, Vadhan‑Raj S, Riess H, Wun T, et al. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. New England Journal of Medicine 2019;380:720-8. - PubMed
    1. Khorana AA, Vadhan-Raj S, Kuderer NM, Wun T, Liebman H, Soff G, et al. Rivaroxaban for preventing venous thromboembolism in high-risk ambulatory patients with cancer: rationale and design of the CASSINI trial. Thrombosis and Haemostasis 2017;117:2135-45. - PMC - PubMed
Klerk 2005 {published data only}
    1. Klerk CP, Smorenburg SM, Otten HM, Lensing AW, Prins MH, Piovella F, et al. The effect of low molecular weight heparin on survival in patients with advanced malignancy. Journal of Clinical Oncology 2005;23(10):2130-5. - PubMed
Larocca 2012 {published data only}
    1. Cavallo F, Caravita T, Di Raimondo F, Ciccone G, Lupo B, Marcatti M, et al. A phase III study of enoxaparin vs aspirin as thromboprophylaxis for patients with newly diagnosed of multiple myeloma treated with lenalidomide-based regimens. Haematologica 2011;96:S30.
    1. Cavallo F, Di Raimondo F, Harda I, Lupo B, Romano A, Catalano L, et al. A phase III study of enoxaparin vs aspirin as thromboprophylaxis for newly diagnosed myeloma patients treated with lenalidomide-based regimen. Blood 2010;116:Abstract 1092.
    1. Larocca A, Caravita TT, Di Raimondo F, Cavallo F, Cascavilla N, Galli M, et al. Thromboprophylaxis for newly diagnosed myeloma patients treated with lenalidomide-based regimens: an interim analysis of a prospective, randomized study of enoxaparin vs aspirin. Haematologica 2013;95:S40.
    1. Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, et al. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood 2012;119(4):933-9. - PubMed
Lebeau 1994 {published data only}
    1. Lebeau B, Chastang C, Brechot J-M, Capron F, Dautzenberg B, Delaisements C, et al. Subcutaneous heparin treatment increases survival in small cell lung cancer. "Petites Cellules" Group. Cancer 1994;74(1):38-45. - PubMed
Lecumberri 2013 {published data only}
    1. Lecumberri R, Lopez VG, Font A, Gonzalez BE, Gurpide A, Gomez CJ, et al. Adjuvant therapy with bemiparin in patients with limited-stage small cell lung cancer: results from the ABEL study. Thrombosis Research 2013;132:666-70. - PubMed
    1. NCT00324558. Multicenter, randomized, open and sequential study to evaluate the efficacy and safety of bemiparin administration on the response to treatment in patients diagnosed with limited small cell lung cancer. clinicaltrials.gov/show/NCT00324558 (first received 9 May 2006).
Levine 1994 {published data only}
    1. Dickson L, Levine M, Gent M. Efficacy of double-blinding in a randomized controlled trial (RCT) of low dose warfarin to prevent thromboembolic disease in patients with metastatic breast cancer. Controlled Clinical Trials 1993;14(5):462.
    1. Levine M, Hirsh J, Gent M, Arnold A, Warr D, Falanga A, et al. Double-blind randomised trial of very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet 1994;343(8902):886-9. - PubMed
Levine 2012 {published data only}
    1. Levine MN, Deitchman D, Julian J, Liebman H, Escalante C, O'Brien MC, et al. A randomized phase II trial of a new anticoagulant, apixaban, in metastatic cancer. Journal of Clinical Oncology 2009;27(15):e20514.
    1. Levine MN, Gu C, Liebman HA, Escalante CP, Solymoss S, Deitchman D, et al. A randomized phase II trial of Apixaban for the prevention of thromboembolism in patients with metastatic cancer. Journal of Thrombosis and Haemostasis 2012;10(5):807-14. - PubMed
    1. Levine MN, Liebman HA, Esclanate CP, Julian JA, Deitchman D, O'Brien MC, et al. Randomized phase II trial of an oral factor Xa inhibitor in patients with metastatic cancer on chemotherapy. Thrombosis Research 2010;125 (Suppl 2):S161-2.
    1. Liebman H, Levine MN, Deitchman D, Julian J, Escalante CP, O'Brien MC, et al. Apixaban in patients with metastatic cancer: a randomized phase II feasibility study. Journal of Thrombosis and Haemostasis 2009;7 Suppl 2:Abstract PP-WE-489. - PubMed
    1. NCT00320255. A randomized, double-blind, placebo-controlled study of apixaban for the prevention of thromboembolic events in patients undergoing treatment for advanced cancer: a phase 2 pilot study. clinicaltrials.gov/show/NCT00320255 (first received 28 April 2006).
Macbeth 2016 {published data only}
    1. Griffiths GO, Burns S, Noble SI, Macbeth FR, Cohen D, Maughan TS. FRAGMATIC: a randomised phase III clinical trial investigating the effect of fragmin added to standard therapy in patients with lung cancer. BMC Cancer 2009;9:355. - PMC - PubMed
    1. Macbeth F, Carter B, Noble S, Hood K. Further results of the FRAGMATIC trial of thromboprophylaxis in lung cancer. Translational Lung Cancer Research 2016;5:347-9. - PMC - PubMed
    1. Macbeth F, Noble S, Evans J, Ahmed S, Cohen D, Hood K, et al. Randomized phase III trial of standard therapy plus low molecular weight heparin in patients with lung cancer: FRAGMATIC trial. Journal of Clinical Oncology 2016;34:488-94. - PubMed
    1. Macbeth F, Noble S, Griffiths G, Chowdhury R, Rolfe C, Hood K, et al. Preliminary results from the fragmatic trial: a randomised phase iii clinical trial investigating the effect of fragmin added to standard therapy in patients with lung cancer. Journal of Thoracic Oncology 2013;8(Suppl 2):O27.02.
    1. NCT00519805. Dalteparin in preventing blood clots in patients with lung cancer. clinicaltrials.gov/show/NCT00519805 (first received 23 August 2007).
Maraveyas 2012 {published data only}
    1. Maraveyas A, Ettelaie C, Echrish H, Li C, Gardiner E, Greenman J, et al. Weight-adjusted dalteparin for prevention of vascular thromboembolism in advanced pancreatic cancer patients decreases serum tissue factor and serum-mediated induction of cancer cell invasion. Blood Coagulation and Fibrinolysis 2010;21(5):452-8. - PubMed
    1. Maraveyas A, Waters J, Roy R, Fyfe D, Propper D, Lofts F, et al. Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. European Journal of Cancer 2012;48(9):1283-92. - PubMed
    1. Maraveyas A, Waters J, Roy R, Propper D, Fyfe D, Lofts F, et al. Gemcitabine with or without prophylactic weight-adjusted dalteparin in patients with advanced or metastatic pancreatic cancer (APC): a multicentre, randomised phase IIB trial (the UK FRAGEM study). European Journal of Cancer Supplements 2009;7(2):362.
    1. NCT00462852. A phase II randomised study of chemo-anticoagulation (gemcitabine-dalteparin) vs chemotherapy alone (Gemcitabine) for locally advanced and metastatic pancreatic adenocarcinoma. clinicaltrials.gov/show/NCT00462852 (first received 18 April 2007).
Maurer 1997 {published data only}
    1. Maurer LH, Herndon JE II, Hollis DR, Aisner J, Carey RW, Skarin AT, et al. Randomized trial of chemotherapy and radiation therapy with or without warfarin for limited-stage small-cell lung cancer: a Cancer and Leukemia Group B study. Journal of Clinical Oncology 1997;15(11):3378-87. - PubMed
Meyer 2018 {published data only}
    1. Meyer G, Besse B, Doubre H, Charles-Nelson A, Aquilanti S, Izadifar A, et al. Anti-tumour effect of low molecular weight heparin in localised lung cancer: a phase III clinical trial. European Respiratory Journal 2018;52:1801220. - PubMed
    1. Meyer G, Besse B, Doubre H, Charles-Nelson A, Aquilanti S, Izadifar A, et al. Effect of low molecular weight heparin on survival of patients with resected non-small cell lung cancer: the Tinzaparin in Lung Tumors (TILT) randomized phase III trial. Research and Practice in Thrombosis and Haemostasis 2017;1(Suppl 1):S212.
    1. NCT00475098. Effect of low molecular weight heparin: Tinzaparin in Lung Tumours (TILT). clinicaltrials.gov/ct2/show/NCT00475098 (first posted 17 May 2007).
Mitchell 2003 {published data only}
    1. Mitchell L, Andrew M, Hanna K, Abshire T, Halton J, Wu J, et al. Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving l-asparaginase for acute lymphoblastic leukemia. Results of the PAARKA study. Thrombosis and Haemostasis 2003;90(2):235-44. - PubMed
Palumbo 2011 {published data only}
    1. Cavo M, Palumbo A, Bringhen S, Di RF, Patriarca F, Rossi D, et al. Phase III study of enoxaparin versus aspirin versus low dose warfarin as thromboprophylaxis for patients with newly diagnosed multiple myeloma treated up front with thalidomide-containing regimens. Haematologica 2010;95 Suppl 2:391, Abstract 0941.
    1. Cavo M, Palumbo A, Bringhen S, Falcone A, Musto P, Ciceri F, et al. A phase III study of enoxaparin versus low-dose warfarin versus aspirin as thromboprophylaxis for patients with newly diagnosed multiple myeloma treated up-front with thalidomide-containing regimens. Blood 2008;110:3017.
    1. Cavo M, Palumbo A, Bringhen S, Falcone A, Musto P, Ciceri F, et al. A phase III study of enoxaparin versus low-dose warfarin versus aspirin as thromboprophylaxis for patients with newly diagnosed multiple myeloma treated up-front with thalidomide-containing regimens. Haematologica 2009;94:s4.
    1. Magarotto V, Brioli A, Patriarca F, Rossi D, Petrucci MT, Nozzoli C, et al. Enoxaparin, aspirin, or warfarin for the thromboprophylaxis in newly diagnosed myeloma patients receiving thalidomide: a randomized controlled trial. XI Congress of the Italian Society of Experimental Hematology; 2010 Oct 6-8; Turin, Italy.
    1. Palumbo A, Cavo M, Bringhen S, Patriarca F, Rossi D, Petrucci MT, et al. A phase III study of enoxaparin versus aspirin versus low-dose warfarin as thromboprophylaxis for patients with newly diagnosed multiple myeloma treated up-front with thalidomide based-regimens. Haematologica 2009;94 Suppl 2:213.
Pelzer 2015 {published data only}
    1. NCT00785421. Chemotherapy with or without enoxaparin in pancreatic cancer (PROSPECT). clinicaltrials.gov/ct2/show/NCT00785421 (first received 5 November 2008).
    1. Pelzer U, Deutschinoff G, Opitz B, Stauch M, Reitzig P, Hahnfeld S, et al. A prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy. First results of the CONKO-004 trial. Onkologie-DGHO meeting; 2009 Oct 2-6; Mannheim, Germany. Abstract 580.
    1. Pelzer U, Deutschinoff G, Opitz B, Stauch M, Reitzig P, Hahnfeld S, et al. The impact of low molecular weight heparin in first-line pancreatic cancer treatment – final results of the CONKO-004 trial. Onkologie 2010;33(6):200.
    1. Pelzer U, Hilbig A, Stieler J, Roll L, Riess H, Dörken B, et al. A prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy (PROSPECT – CONKO 004). Onkologie 2005;28 Suppl 3:Abstract 151. - PMC - PubMed
    1. Pelzer U, Hilbig A, Stieler JM, Bahra M, Sinn M, Gebauer B, et al. Intensified chemotherapy and simultaneous treatment with heparin in outpatients with pancreatic cancer – the CONKO 004 pilot trial. BMC Cancer 2014;14:204. - PMC - PubMed
Perry 2010 {published data only}
    1. NCT00135876. Dalteparin low molecular weight heparin for primary prophylaxis of venous thromboembolism in brain tumour patients. clinicaltrials.gov/ct2/show/NCT00135876 (first received 26 August 2005).
    1. Perry JR, Julian JA, Laperriere NJ, Geerts W, Agnelli G, Rogers LR, et al. PRODIGE: a randomized placebo-controlled trial of dalteparin low-molecular-weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma. Journal of Thrombosis and Haemostasis 2010;8(9):1959-65. - PubMed
    1. Perry JR, Rogers L, Laperriere N, Julian J, Geerts W, Agnelli G, et al. PRODIGE: a phase III randomized placebo-controlled trial of thromboprophylaxis using dalteparin low molecular weight heparin (LMWH) in patients with newly diagnosed malignant glioma. Journal of Clinical Oncology 2007;25(18 Suppl):2011.
Sideras 2006 {published data only}
    1. Sideras K, Schaefer PL, Okuno SH, Sloan JA, Kutteh L, Fitch TR, et al. Low-molecular-weight heparin in patients with advanced cancer: a phase 3 clinical trial. Mayo Clinic Proceedings 2006;81(6):758-67. - PubMed
Vadhan‐Raj 2013 {published data only}
    1. NCT00966277. Randomized clinical trial of dalteparin for primary venous thromboembolism (VTE) prophylaxis in pancreatic cancer patients undergoing chemotherapy treatment. clinicaltrials.gov/show/NCT00966277 (first received 25 August 2009).
    1. Vadhan-Raj S, Zhou X, Varadhachary GR, Milind J, Fogelman D, Shroff R, et al. Randomized controlled trial of dalteparin for primary thromboprophylaxis for venous thromboembolism (VTE) in patients with advanced pancreatic cancer (APC): risk factors predictive of VTE. 55th Annual Meeting of the American Society of Hematology; 2013 Dec 7-10; New Orleans, LA.
    1. Vadhan-Raj S, Zhou X, Varadhachary GR, Milind J, Fogelman D, Shroff R, et al. Randomized controlled trial of dalteparin for primary thromboprophylaxis for venous thromboembolism (VTE) in patients with advanced pancreatic cancer (APC): risk factors predictive of VTE. Blood 2013;122(21):580.
van Doormaal 2011 {published data only}
    1. Doormaal FF, Di Nisio M, Otten H-M, Richel DJ, Prins M, Buller HR. Randomized trial of the effect of the low molecular weight heparin nadroparin on survival in patients with cancer. Journal of Clinical Oncology 2011;29(15):2071-6. - PubMed
Zacharski 1981 {published data only}
    1. Zacharski LR, Henderson WG, Rickles FR, Forman WB, Cornell CJ Jr, Forcier RJ, et al. Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate. Final report of VA Cooperative Study #75. Cancer 1984;53(10):2046-52. - PubMed
    1. Zacharski LR, Henderson WG, Rickles FR, Forman WB, Cornell CJ Jr, Forcier RJ, et al. Effect of warfarin on survival in small cell carcinoma of the lung. Veterans Administration Study No. 75. JAMA 1981;245(8):831-5. - PubMed
Zwicker 2013 {published data only}
    1. NCT00908960. Enoxaparin thromboprophylaxis in cancer patients with elevated tissue factor bearing microparticles. clinicaltrials.gov/ct2/show/NCT00908960 (first received 12 December 2013).
    1. Zwicker J, Liebman HA, Bauer KA, Caughey T, Rosovsky R, Mantha S, et al. A randomized-controlled phase II trial of primary thromboprophylaxis with enoxaparin in cancer patients with elevated tissue factor bearing microparticles (The Microtec Study). Journal of Thrombosis and Haemostasis 2013;11 (Suppl s3):6. - PMC - PubMed
    1. Zwicker JI, Liebman HA, Bauer KA, Caughey T, Campigotto F, Rosovsky R, et al. Prediction and prevention of thromboembolic events with enoxaparin in cancer patients with elevated tissue factor-bearing microparticles: a randomized-controlled phase II trial (the Microtec study). British Journal of Haematology 2013;160(4):530-7. - PMC - PubMed

References to studies excluded from this review

Baz 2005 {published data only}
    1. Baz R, Li L, Kottke-Marchant K, Srkalovic G, McGowan B, Yiannaki E, et al. The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma. Mayo Clinic Proceedings 2005;80(12):1568-74. - PubMed
Bergqvist 1983 {published data only}
    1. Bergqvist D, Lindblad B. Is it possible to potentiate the thromboprophylactic effect of dextran with elastic compression stockings? Thrombosis and Haemostasis 1983;50(1):247 Abstract 0777.
Bocharov 2011 {published data only}
    1. Bocharov AV, Cherenkov VG, Ukhanov AP, Chentsov VI. Potential endovascular prophylaxis for pulmonary thromboembolism in the combined treatment of cancer patients. Voprosy Onkologii 2011;57:513-6. - PubMed
Eichinger 2008 {published data only}
    1. Eichinger S, Traby L, Kaider A, Quehenberger P, Kyrle PA. Prevention of venous thrombosis in cancer patients: a randomized, double-blind study comparing two different dosages of low-molecular weight heparin. Blood 2008;112(11):690 Abstract 1977.
Groen 2019 {published data only}
    1. Groen HJ, Heijden EH, Klinkenberg TJ, Biesma B, Aerts J, Verhagen A, et al. Randomised phase 3 study of adjuvant chemotherapy with or without nadroparin in patients with completely resected non-small-cell lung cancer: the NVALT-8 study. British Journal of Cancer 2019;121(5):372-7. - PMC - PubMed
Haas 2011 {published data only}
    1. Haas S, Schellong SM, Tebbe U, Gerlach H-E, Bauersachs R, Melzer N, et al. Heparin based prophylaxis to prevent venous thromboembolic events and death in patients with cancer – a subgroup analysis of CERTIFY. BMC Cancer 2011;11:316. - PMC - PubMed
Heilmann 1995 {published data only}
    1. Heilmann L, Schneider D, Herrle B, von Tempelhoff G-F, Manstein J, Wolf H. A prospective randomized trial of low molecular weight heparin (LMWH) versus unfractionated heparin (UFH) in patients with gynecologic cancer. Thrombosis and Haemostasis 1995;73(6):974 Abstract No 286.
Hills 1972 {published data only}
    1. Hills NH, Pflug JJ, Jeyasingh K, Boardman L, Calnan JS. Prevention of deep vein thrombosis by intermittent pneumatic compression of calf. British Medical Journal 1972;1(5793):131-5. - PMC - PubMed
Kessler 2011 {published data only}
    1. Kessler P, Pour L, Gregora E, Zemanova M, Penka M, Brejcha M, et al, Czech Myeloma Group. Low molecular weight heparins for thromboprophylaxis during induction chemotherapy in patients with multiple myeloma. Klinicka Onkologie 2011;24(4):281-6. - PubMed
    1. Kessler P. Prophylaxis and treatment of venous thromboembolism in patients with multiple myeloma. Onkologie 2011;5(3):160-2.
Macintyre 1974 {published data only}
    1. Macintyre MC, Vasilescu C, Jones DR. Heparin versus dextran in the prevention of deep-vein thrombosis. A multi-unit controlled trial. Lancet 1974;2(7873):118-20. - PubMed
Maxwell 2000 {published data only}
    1. Maxwell GL. A prospective randomized trial comparing external pneumatic compression stockings (EPC) to the low molecular weight heparin (LMWH) dalteparin in the prevention of thromboembolic events (TE) among gynecologic oncology patients. Proceedings of the American Society of Clinical Oncology 2000;19:388a, Abstract 1535.
Meister 2008 {published data only}
    1. Meister B, Kropshofer G, Klein Franke A, Strasak AM, Hager J, Streif W. Comparison of low-molecular-weight heparin and antithrombin versus antithrombin alone for the prevention of symptomatic venous thromboembolism in children with acute lymphoblastic leukemia. Pediatric Blood and Cancer 2008;50(2):298-303. - PubMed
Minnema 2004 {published data only}
    1. Minnema MC, Breitkreutz I, Auwerda JJ, van-der Holt B, Cremer FW, van-Marion AM, et al. Prevention of venous thromboembolism with low molecular-weight heparin in patients with multiple myeloma treated with thalidomide and chemotherapy. Leukemia 2004;18(12):2044-6. - PubMed
NCT00004875 {unpublished data only}
    1. NCT00004875. Heparin or enoxaparin in patients with cancer. clinicaltrials.gov/show/NCT00004875 (first received 7 March 2000).
NCT00031837 {unpublished data only}
    1. NCT00031837. A prospective randomized controlled multicenter study of the effect of dalteparin on quality of life in unresectable pancreatic cancer. clinicaltrials.gov/show/NCT00031837 (first received 8 March 2002).
NCT00662688 {unpublished data only}
    1. NCT00662688. Chemotherapy with or without dalteparin in treating patients with metastatic pancreatic cancer (PAM07). clinicaltrials.gov/show/NCT00662688 (first received 18 April 2008).
NCT00790452 {unpublished data only}
    1. NCT00790452. A randomized phase II trial of aspirin for primary prophylaxis of venous thromboembolism in glioblastoma. clinicaltrials.gov/show/NCT00790452 (first received 7 November 2008).
NCT04106700 {published data only}
    1. NCT04106700. Prophylaxis with apixaban in transplant eligible patients with multiple myeloma receiving induction therapy with IMiDs. clinicaltrials.gov/ct2/show/NCT04106700 (first received 27 September 2019).
NCT04352439 {published data only}
    1. NCT04352439. Aspirin for prevention of venous thromboembolism among ovarian cancer patients receiving neoadjuvant chemotherapy. clinicaltrials.gov/ct2/show/NCT04352439 (first received 20 April 2020).
Niesvizky 2007 {published data only}
    1. Niesvizky R, Martinez-Banos D, Jalbrzikowski J, Christos P, Furst J, De Sancho M, et al. Prophylactic low-dose aspirin is effective antithrombotic therapy for combination treatments of thalidomide or lenalidomide in myeloma. Leukemia and Lymphoma 2007;48(12):2330-7. - PubMed
Paydas 2008 {published data only}
    1. Paydas S. Tailored thromboprophylaxis for patients with multiple myeloma treated by IMIDs. Leukemia and Lymphoma 2008;49(8):1644-5. - PubMed
Poniewierski 1988 {published data only}
    1. Poniewierski M, Barthels M, Kuhn M, Poliwoda H. Efficacy of low molecular weight heparin (Fragmin) for thromboprophylaxis in medical patients: a randomized double blind trial. Medizinische Klinik 1988;83(7):241-5. - PubMed
    1. Poniewierski M, Barthels M, Poliwoda H. The safety and efficacy of a low molecular weight heparin (fragmin) in the prevention of deep vein thrombosis in medical patients: a randomized double-blind trial. Thrombosis and Haemostasis 1987;58(1):119 Abstract 425.
Rajan 1995 {published data only}
    1. Rajan R, Gafni A, Levine M, Hirsh J, Gent M. Very low-dose warfarin prophylaxis to prevent thromboembolism in women with metastatic breast cancer receiving chemotherapy: an economic evaluation. Journal of Clinical Oncology 1995;13(1):42-6. - PubMed
Salat 1990 {published data only}
    1. Salat C, Breitruck H, Reinhardt B, Hiller E. Thromboprophylaxis with low molecular weight heparin (LMWH) and conventional low dose heparin in patients with malignant diseases. Blut 1990;61(2-3):142.
Sideras 2007 {published data only}
    1. Sideras K, Schaefer PL, Okuno SH. Low-molecular-weight heparin in patients with advanced cancer: a phase 3 clinical trial. Journal of Vascular Surgery 2007;45(4):861. - PubMed
Storrar 2019 {published data only}
    1. Storrar NP, Mathur A, Johnson PR, Roddie PH. Safety and efficacy of apixaban for routine thromboprophylaxis in myeloma patients treated with thalidomide- and lenalidomide-containing regimens. British Journal of Haematology 2019;185:142-4. - PubMed
Weber 2008 {published data only}
    1. Weber C, Merminod T, Herrmann FR, Zulian GB. Prophylactic anti-coagulation in cancer palliative care: a prospective randomised study. Support Care in Cancer 2008;16(7):847-52. - PubMed
Welti 1981 {published data only}
    1. Welti H. Thrombo-embolytic prophylaxis using physiotherapy with and without low doses of heparin in gynecology and obstetrics. Results of a controlled and randomized multi-cancer study. Revue Medicale de la Suisse Romande 1981;101(11):925-34. - PubMed
Zangari 2003 {published data only}
    1. Zangari M, Barlogie B, Saghafifar F, Eddlemon P, Jacobson J, Lee CK, et al. Effect of anticoagulation on development and recurrence of deep vein thrombosis (DVT) in multiple myeloma patients treated with chemotherapy and thalidomide (total therapy II). Hematology Journal 2003;4 Suppl 1:S248.
Zwicker 2019 {published data only}
    1. Zwicker JI, Schlechter BL, Stopa JD, Liebman HA, Aggarwal A, Puligandla M, et al. Targeting protein disulfide isomerase with the flavonoid isoquercetin to improve hypercoagulability in advanced cancer. JCI Insight 2019;4:e125851. - PMC - PubMed

References to studies awaiting assessment

Ciftci 2012 {published data only}
    1. Ciftci A, Altiay G. The effect of warfarin on survival in patients with lung cancer. Journal of Thoracic Oncology 2012;7:S122.
NCT00771563 {published data only}
    1. NCT00771563. Enoxaparin low molecular weight heparin (LMWH) in advanced non small cell lung cancer: effect on survival and symptom control in patients undergoing first line chemotherapy (SYRINGES). clinicaltrials.gov/ct2/show/NCT00771563 (first received 10 October 2008).

References to ongoing studies

ChiCTR‐TRC‐08000267 {unpublished data only}
    1. ChiCTR-TRC-08000267. The role of LMWH combined with TACE in hepatocellular carcinoma. chictr.org.cn/com/25/showproj.aspx?proj=9261 (first received 29 December 2008).
NCT00718354 {unpublished data only}
    1. NCT00718354. Overall survival of inoperable gastric/gastrooesophageal cancer subjects on treating with LMWH + chemotherapy (CT) vs standard CT (GASTRANOX). clinicaltrials.gov/ct2/show/NCT00718354 (first received 18 July 2008).
NCT01518465 {unpublished data only}
    1. NCT01518465. Dalteparin, lenalidomide, and low-dose dexamethasone in treating patients with previously untreated multiple myeloma. clinicaltrials.gov/ct2/show/NCT01518465 (first received 26 January 2012).
NCT02285738 {published data only}
    1. NCT02285738. Anti-platelet and statin therapy to prevent cancer-associated thrombosis. clinicaltrials.gov/ct2/show/NCT02285738 (first received 5 November 2014).
NCT02555878 {published data only}
    1. NCT02555878. Efficacy and safety of rivaroxaban prophylaxis compared with placebo in ambulatory cancer patients initiating systemic cancer therapy and at high risk for venous thromboembolism. clinicaltrials.gov/ct2/show/NCT02555878 (first received 18 September 2015).
NCT03090880 {unpublished data only}
    1. NCT03090880. Prophylaxis of venous thromboembolism in advanced lung cancer (PROVE). clinicaltrials.gov/ct2/show/NCT03090880 (first received 27 March 2017).
NCT03428373 {published data only}
    1. NCT03428373. ASA vs. rivaroxaban in newly diagnosed or relapsed and refractory multiple myeloma patients treated with Len-Dex combination therapy. clinicaltrials.gov/ct2/show/NCT03428373 (first received 9 February 2018).
O'Brien 2019 {unpublished data only}
    1. O'Brien SH, Li D, Mitchell LG, Hess T, Zee P, Yee DL, et al. PREVAPIX-ALL: apixaban compared to standard of care for prevention of venous thrombosis in paediatric acute lymphoblastic leukaemia (ALL) – rationale and design. Thrombosis and Haemostasis 2019;119:844-53. - PubMed

Additional references

Aikens 2013
    1. Aikens GB, Rivey MP, Hansen CJ. Primary venous thromboembolism prophylaxis in ambulatory cancer patients. Annals of Pharmacotherapy 2013;47(2):198-209. - PubMed
Ay 2010
    1. Ay C, Dunkler D, Marosi C, Chiriac AL, Vormittag R, Simanek R, et al. Prediction of venous thromboembolism in cancer patients. Blood 2010;116(24):5377-82. - PubMed
Ay 2017
    1. Ay C, Pabinger I, Cohen AT. Cancer-associated venous thromboembolism: burden, mechanisms, and management. Thrombosis and Haemostasis 2017;117:219-30. - PubMed
Cohen 2017
    1. Cohen AT, Katholing A, Rietbrock S, Bamber L, Martinez C. Epidemiology of first and recurrent venous thromboembolism in patients with active cancer. A population-based cohort study. Thrombosis and Haemostasis 2017;117:57-65. - PubMed
Connors 2014
    1. Connors JM. Prophylaxis against venous thromboembolism in ambulatory patients with cancer. New England Journal of Medicine 2014;370:2515-9. - PubMed
DerSimonian 1986
    1. DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials 1986;7:177-88. - PubMed
Di Nisio 2017
    1. Di Nisio M, Carrier M. Incidental venous thromboembolism: is anticoagulation indicated? Hematology 2017;1:121-7. - PMC - PubMed
EMEA 2012
    1. European Medicines Agency (EMEA). Withdrawal of the marketing authorisation application for Mulsevo (semuloparin sodium). www.emea.europa.eu/docs/en_GB/document_library/Medicine_QA/2012/07/WC500... (accessed 11 December 2012).
Farge 2019
    1. Farge D, Frere C, Connors JM, Ay C, Khorana AA, Munoz A, et al. 2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncology 2019;20(10):e566-81. - PubMed
George 2011
    1. George D, Agnelli G, Fisher W, Kakkar A, Lassen MR, Mismetti P, et al. Venous thromboembolism (VTE) prevention with semuloparin in cancer patients initiating chemotherapy: benefit-risk assessment by VTE risk in SAVE-ONCO. Blood 2011;118:Abstract 206.
Guyatt 2008
    1. Guyatt G, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336(7656):924-6. - PMC - PubMed
Harbord 2006
    1. Harbord RM, Egger M, Sterne JA. A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Statistics in Medicine 2006;25(20):3443-57. - PubMed
Heit 2015
    1. Heit JA. Epidemiology of venous thromboembolism. Nature Reviews. Cardiology 2015;12:464-74. - PMC - PubMed
Higgins 2003
    1. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327(7414):557-60. - PMC - PubMed
Higgins 2011
    1. Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Horsted 2012
    1. Horsted F, West J, Grainge MJ. Risk of venous thromboembolism in patients with cancer: a systematic review and meta-analysis. PLoS Medicine 2012;9(7):e1001275.18. - PMC - PubMed
Hutten 2000
    1. Hutten B, Prins M, Gent M, Ginsberg J, Tijsen JG, Büller HR. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. Journal of Clinical Oncology 2000;18(17):3078-83. - PubMed
Juni 2001
    1. Juni P, Altman DG, Egger M. Systematic reviews in health care: assessing the quality of controlled clinical trials. BMJ 2001;323(7303):42-6. - PMC - PubMed
Kaatz 2015
    1. Kaatz S, Ahmad D, Spyropoulos AC, Schulman S, Subcommittee on Control of Anticoagulation. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. Journal of Thrombosis and Haemostasis 2015;13:2119-26. - PubMed
Kahale 2018
    1. Kahale LA, Tsolakian IG, Hakoum MB, Matar CF, Barba M, Yosuico VE, et al. Anticoagulation for people with cancer and central venous catheters. Cochrane Database of Systematic Reviews 2018, Issue 6. Art. No: CD006468. [DOI: 10.1002/14651858.CD006468.pub6] - DOI - PMC - PubMed
Kahn 2012
    1. Kahn SR, Lim W, Dunn AS, Cushman M, Dentali F, Akl EA, et al. Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th edition: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(2 Suppl):e195S-226S. - PMC - PubMed
Kamphuisen 2014
    1. Kamphuisen PW, Beyer-Westendorf J. Bleeding complications during anticoagulant treatment in patients with cancer. Thrombosis Research 2014;133(S2):S49-55. - PubMed
Key 2020
    1. Key NS, Khorana AA, Kuderer NM, Bohlke K, Lee AY, Arcelus JI, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. Journal of Clinical Oncology 2020;38(5):496-520. - PubMed
Khorana 2008
    1. Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008;111(10):4902-7. - PMC - PubMed
Khorana 2009a
    1. Khorana AA, Connolly GC. Assessing risk of venous thromboembolism in the patient with cancer. Journal of Clinical Oncology 2009;27(29):4839-47. - PMC - PubMed
Khorana 2009b
    1. Khorana AA, Streiff MB, Farge D, Mandala M, Debourdeau P, Cajfinger F, et al. Venous thromboembolism prophylaxis and treatment in cancer: a consensus statement of major guidelines panels and call to action. Journal of Clinical Oncology 2009;27(29):4919-26. - PMC - PubMed
Khorana 2018
    1. Khorana AA, Francis CW. Risk prediction of cancer-associated thrombosis: appraising the first decade and developing the future. Thrombosis Research 2018;Suppl 1:S70-6. - PubMed
Kraaijpoel 2019
    1. Kraaijpoel N, Bleker SM, Meyer G, Mahé I, Muñoz A, Bertoletti L, et al. Treatment and long-term clinical outcomes of incidental pulmonary embolism in patients with cancer: an international prospective cohort study. Journal of Clinical Oncology 2019;37(20):1713-20. - PubMed
Lefebvre 2011
    1. Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JP, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration. Available from handbook.cochrane.org.
Maxwell 2012
    1. Maxwell WD, Bennett CL. Thromboprophylaxis guidelines in cancer with a primary focus on ambulatory patients receiving chemotherapy: a review from the southern network on adverse reactions (SONAR). Seminars in Thrombosis and Hemostasis 2012;38(8):759-67. - PMC - PubMed
Mulder 2019
    1. Mulder FI, Candeloro M, Kamphuisen PW, Di Nisio M, Bossuyt PM, Guman N, et al. The Khorana score for prediction of venous thromboembolism in cancer patients: a systematic review and meta-analysis. Haematologica 2019;104(6):1277-87. [DOI: 10.3324/haematol.2018.209114] - DOI - PMC - PubMed
National Comprehensive Cancer Network 2020
    1. National Comprehensive Cancer Network (NCCN). Clinical practice guideline in oncology: cancer-associated venous thromboembolic disease. www.nccn.org/professionals/physician_gls/default.aspx#detection (accessed 16 April 2020).
Otten 2004
    1. Otten H-M, Mathijssen J, ten Cate H, Soesan M, Inghels M, Richel DJ, et al. Symptomatic venous thromboembolism in cancer patients treated with chemotherapy. An underestimated phenomenon. Archives of Internal Medicine 2004;164(2):190-4. - PubMed
Prandoni 2002
    1. Prandoni P, Lensing AW, Piccioli A, Bernardi E, Simioni P, Girolami B, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002;100(10):3484-8. - PubMed
Review Manager 2014 [Computer program]
    1. Review Manager 5 (RevMan). Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
Rücker 2008
    1. Rücker G, Schwarzer G, Carpenter JR, Schumacher M. Undue reliance on I2 in assessing heterogeneity may mislead. BMC Medical Research Methodology 2008;8(1):79. - PMC - PubMed
Rutjes 2009
    1. Rutjes AW, Nüesch E, Sterchi R, Kalichman L, Hendriks E, Osiri M, et al. Transcutaneous electrostimulation for osteoarthritis of the knee. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No: CD002823. [DOI: 10.1002/14651858.CD002823.pub2] - DOI - PMC - PubMed
Rutjes 2012
    1. Rutjes AW, Juni P, da Costa BR, Trelle S, Nuesch E, Reichenbach S. Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis. Annals of Internal Medicine 2012;157(3):180-91. - PubMed
Schulman 2005
    1. Schulman S, Kearon C on behalf of the subcommittee on control of anticoagulation of the Scientific and Standardization committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. Scientific and Standardization Committee Communication. Journal of Thrombosis and Haemostasis 2005;3:692-4. - PubMed
Sorensen 2000
    1. Sorensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. New England Journal of Medicine 2000;343(25):1846-50. - PubMed
Stata 2019 [Computer program]
    1. Stata Statistical Software. Version 15.1. College Station, TX: StataCorp LP, 2019.
Sterne 2001
    1. Sterne JA, Egger M. Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis. Journal of Clinical Epidemiology 2001;54(10):1046-55. - PubMed
Thompson 1999
    1. Thompson SG, Sharp SJ. Explaining heterogeneity in meta-analysis: a comparison of methods. Statistics in Medicine 1999;18(20):2693-708. - PubMed
Timp 2013
    1. Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood 2013;122:1712-23. - PubMed
van Es 2014
    1. Es N, Bleker SM, Di Nisio M. Cancer-associated unsuspected pulmonary embolism. Thrombosis Research 2014;133(Suppl 2):S172-8. - PubMed
Verso 2012
    1. Verso M, Agnelli G, Barni S, Gasparini G, LaBianca R. A modified Khorana risk assessment score for venous thromboembolism in cancer patients receiving chemotherapy: the Protecht score. Internal and Emergency Medicine 2012;7(3):291-2. - PubMed

References to other published versions of this review

Di Nisio 2010
    1. Di Nisio M, Rutjes AW, Ferrante N, Otten HM, Porreca E, Cuccurullo F. Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database of Systematic Reviews 2010, Issue 5. Art. No: CD008500. [DOI: 10.1002/14651858.CD008500] - DOI - PubMed
Di Nisio 2012
    1. Di Nisio M, Porreca E, Ferrante N, Otten HM, Cuccurullo F, Rutjes AW. Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database of Systematic Reviews 2012, Issue 2. Art. No: CD008500. [DOI: 10.1002/14651858.CD008500.pub2] - DOI - PubMed
Di Nisio 2014
    1. Di Nisio M, Porreca E, Otten HM, Rutjes AW. Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database of Systematic Reviews 2014, Issue 8. Art. No: CD008500. [DOI: 10.1002/14651858.CD008500.pub3] - DOI - PubMed
Di Nisio 2016
    1. Di Nisio M, Porreca E, Candeloro M, De Tursi M, Russi I, Rutjes AW. Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database of Systematic Reviews 2016, Issue 12. Art. No: CD008500. [DOI: 10.1002/14651858.CD008500.pub4] - DOI - PMC - PubMed

Publication types

MeSH terms

Associated data