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Meta-Analysis
. 2016 Dec 1;12(12):CD008500.
doi: 10.1002/14651858.CD008500.pub4.

Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy

Marcello Di Nisio  1   2 , Ettore Porreca  1 , Matteo Candeloro  3 , Michele De Tursi  3 , Ilaria Russi  1 , Anne Ws Rutjes  4   5
Affiliations
Meta-Analysis

Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy

Marcello Di Nisio et al. Cochrane Database Syst Rev. .

Update in

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 second 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.

Search methods: For this update the Cochrane Vascular Information Specialist searched the Cochrane Vascular Group Specialised Register (June 2016). In addition, the Information Specialist searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 5). Clinical trials registries were searched up to June 2016.

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 methodological quality, participant characteristics, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively.

Main results: We identified five additional randomised controlled trials (2491 participants) in the updated search, considering in this update 26 trials with a total of 12,352 participants, all evaluating pharmacological interventions and performed mainly in people with locally advanced or metastatic cancer. The quality 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. One large trial of 3212 participants found a 64% (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.22 to 0.60) reduction of symptomatic VTE with the ultra-low molecular weight heparin (uLMWH) semuloparin relative to placebo, with no apparent difference in major bleeding (RR 1.05, 95% CI 0.55 to 2.00). When compared with no thromboprophylaxis, LMWH significantly reduced the incidence of symptomatic VTE (RR 0.54, 95% CI 0.38 to 0.75; no heterogeneity, Tau2 = 0.00%) with a non-statistically significant 44% higher risk of major bleeding events (RR 1.44, 95% CI 0.98 to 2.11). In participants with multiple myeloma, LMWH was associated with a significant reduction in symptomatic VTE compared with the vitamin K antagonist warfarin (RR 0.33, 95% CI 0.14 to 0.83), while the difference between LMWH and aspirin was not statistically significant (RR 0.51, 95% CI 0.22 to 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. Only one study evaluated unfractionated heparin against no thromboprophylaxis but did not report on VTE or major bleeding. When compared with placebo, warfarin was associated with a non-statistically significant reduction of symptomatic VTE (RR 0.15, 95% CI 0.02 to 1.20). Antithrombin, evaluated in one study involving paediatric patients, had no significant effect on VTE or on major bleeding when compared with no antithrombin. The direct oral factor Xa inhibitor apixaban was evaluated in a phase II dose-finding study that suggested a low rate of major bleeding (2.1% versus 3.4%) and symptomatic VTE (1.1% versus 13.8%) in comparison with placebo.

Authors' conclusions: In this second update, we confirmed that primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy. In addition, the uLMWH semuloparin, which is not commercially available, significantly reduced the incidence of symptomatic VTE. 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. Despite the encouraging results of this review, routine prophylaxis in ambulatory cancer patients cannot be recommended before safety issues are adequately addressed. We need additional studies investigating targeted primary prophylaxis in people with specific types or stages of cancer associated with a higher risk of VTE.

PubMed Disclaimer

Conflict of interest statement

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.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Forest plot of comparison: 1 Anticoagulants versus control: symptomatic VTE, outcome: 1.2 Symptomatic VTE: LMWH versus no thromboprophylaxis.
4
4
Funnel plot of comparison: 1 Anticoagulants versus control: symptomatic VTE, outcome: 1.2 Symptomatic VTE: LMWH versus no thromboprophylaxis.
5
5
Forest plot of comparison: 2 Anticoagulants versus control: major bleeding, outcome: 2.2 Major bleeding: LMWH versus no thromboprophylaxis.
6
6
Funnel plot of comparison: 2 Anticoagulants versus control: major bleeding, outcome: 2.2 Major bleeding: LMWH versus no thromboprophylaxis.
1.1
1.1. Analysis
Comparison 1 Anticoagulants versus control: symptomatic venous thromboembolism, Outcome 1 Symptomatic VTE: semuloparin 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: LMWH vs aspirin.
1.4
1.4. Analysis
Comparison 1 Anticoagulants versus control: symptomatic venous thromboembolism, Outcome 4 Symptomatic VTE: LMWH vs warfarin.
1.5
1.5. Analysis
Comparison 1 Anticoagulants versus control: symptomatic venous thromboembolism, Outcome 5 Symptomatic VTE: prophylactic vs intermediate or therapeutic LMWH.
1.6
1.6. Analysis
Comparison 1 Anticoagulants versus control: symptomatic venous thromboembolism, Outcome 6 Symptomatic VTE: vitamin K antagonists vs placebo.
1.7
1.7. Analysis
Comparison 1 Anticoagulants versus control: symptomatic venous thromboembolism, Outcome 7 Symptomatic VTE: warfarin vs aspirin.
1.8
1.8. Analysis
Comparison 1 Anticoagulants versus control: symptomatic venous thromboembolism, Outcome 8 Symptomatic VTE: apixaban vs placebo.
2.1
2.1. Analysis
Comparison 2 Anticoagulants versus control: major bleeding, Outcome 1 Major bleeding: semuloparin 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: LMWH vs aspirin.
2.4
2.4. Analysis
Comparison 2 Anticoagulants versus control: major bleeding, Outcome 4 Major bleeding: LMWH vs warfarin.
2.5
2.5. Analysis
Comparison 2 Anticoagulants versus control: major bleeding, Outcome 5 Major bleeding: prophylactic vs intermediate or therapeutic LMWH.
2.6
2.6. Analysis
Comparison 2 Anticoagulants versus control: major bleeding, Outcome 6 Major bleeding: vitamin K antagonists vs no thromboprophylaxis.
2.7
2.7. Analysis
Comparison 2 Anticoagulants versus control: major bleeding, Outcome 7 Major bleeding: warfarin vs aspirin.
2.8
2.8. Analysis
Comparison 2 Anticoagulants versus control: major bleeding, Outcome 8 Major bleeding: antithrombin vs placebo.
2.9
2.9. Analysis
Comparison 2 Anticoagulants versus control: major bleeding, Outcome 9 Major bleeding: apixaban vs placebo.
3.1
3.1. Analysis
Comparison 3 Anticoagulants versus control: symptomatic pulmonary embolism, Outcome 1 Symptomatic PE: semuloparin 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: LMWH vs aspirin.
3.4
3.4. Analysis
Comparison 3 Anticoagulants versus control: symptomatic pulmonary embolism, Outcome 4 Symptomatic PE: LMWH vs warfarin.
3.5
3.5. Analysis
Comparison 3 Anticoagulants versus control: symptomatic pulmonary embolism, Outcome 5 Symptomatic PE: prophylactic vs intermediate or therapeutic LMWH.
3.6
3.6. Analysis
Comparison 3 Anticoagulants versus control: symptomatic pulmonary embolism, Outcome 6 Symptomatic PE: vitamin K antagonists vs placebo.
3.7
3.7. Analysis
Comparison 3 Anticoagulants versus control: symptomatic pulmonary embolism, Outcome 7 Symptomatic PE: warfarin vs aspirin.
3.8
3.8. Analysis
Comparison 3 Anticoagulants versus control: symptomatic pulmonary embolism, Outcome 8 Symptomatic PE: apixaban vs placebo.
4.1
4.1. Analysis
Comparison 4 Anticoagulants versus control: symptomatic deep vein thrombosis, Outcome 1 Symptomatic DVT: semuloparin vs placebo.
4.2
4.2. Analysis
Comparison 4 Anticoagulants versus control: symptomatic deep vein thrombosis, Outcome 2 Symptomatic DVT: LMWH vs no thromboprophylaxis.
4.3
4.3. Analysis
Comparison 4 Anticoagulants versus control: symptomatic deep vein thrombosis, Outcome 3 Symptomatic DVT: LMWH vs aspirin.
4.4
4.4. Analysis
Comparison 4 Anticoagulants versus control: symptomatic deep vein thrombosis, Outcome 4 Symptomatic DVT: LMWH vs warfarin.
4.5
4.5. Analysis
Comparison 4 Anticoagulants versus control: symptomatic deep vein thrombosis, Outcome 5 Symptomatic DVT: prophylactic vs intermediate or therapeutic LMWH.
4.6
4.6. Analysis
Comparison 4 Anticoagulants versus control: symptomatic deep vein thrombosis, Outcome 6 Symptomatic DVT: vitamin K antagonists vs placebo.
4.7
4.7. Analysis
Comparison 4 Anticoagulants versus control: symptomatic deep vein thrombosis, Outcome 7 Symptomatic DVT: warfarin vs aspirin.
4.8
4.8. Analysis
Comparison 4 Anticoagulants versus control: symptomatic deep vein thrombosis, Outcome 8 Symptomatic DVT: apixaban vs placebo.
5.1
5.1. Analysis
Comparison 5 Anticoagulants versus control: incidental venous thromboembolism, Outcome 1 Incidental VTE: semuloparin vs placebo.
5.2
5.2. Analysis
Comparison 5 Anticoagulants versus control: incidental venous thromboembolism, Outcome 2 Incidental VTE: LMWH vs no thromboprophylaxis.
5.3
5.3. Analysis
Comparison 5 Anticoagulants versus control: incidental venous thromboembolism, Outcome 3 Incidental VTE: prophylactic vs intermediate or therapeutic LMWH.
6.1
6.1. Analysis
Comparison 6 Anticoagulants versus control: overall venous thromboembolism, Outcome 1 Overall VTE: semuloparin vs placebo.
6.2
6.2. Analysis
Comparison 6 Anticoagulants versus control: overall venous thromboembolism, Outcome 2 Overall VTE: LMWH vs no thromboprophylaxis.
6.3
6.3. Analysis
Comparison 6 Anticoagulants versus control: overall venous thromboembolism, Outcome 3 Overall VTE: prophylactic vs intermediate vs therapeutic LMWH.
6.4
6.4. Analysis
Comparison 6 Anticoagulants versus control: overall venous thromboembolism, Outcome 4 Overall VTE: antithrombin vs placebo.
7.1
7.1. Analysis
Comparison 7 Anticoagulants versus control: clinically relevant bleeding, Outcome 1 Clinically relevant bleeding: semuloparin vs placebo.
7.2
7.2. Analysis
Comparison 7 Anticoagulants versus control: clinically relevant bleeding, Outcome 2 Clinically relevant bleeding: LMWH vs no thromboprophylaxis.
7.3
7.3. Analysis
Comparison 7 Anticoagulants versus control: clinically relevant bleeding, Outcome 3 Clinically relevant bleeding: prophylactic vs intermediate vs therapeutic LMWH.
7.4
7.4. Analysis
Comparison 7 Anticoagulants versus control: clinically relevant bleeding, Outcome 4 Clinically relevant bleeding: apixaban vs placebo.
7.5
7.5. Analysis
Comparison 7 Anticoagulants versus control: clinically relevant bleeding, Outcome 5 Clinically relevant bleeding: UFH vs no thromboprophylaxis.
8.1
8.1. Analysis
Comparison 8 Anticoagulants versus control: minor bleeding, Outcome 1 Minor bleeding: LMWH vs no thromboprophylaxis.
8.2
8.2. Analysis
Comparison 8 Anticoagulants versus control: minor bleeding, Outcome 2 Minor bleeding: LMWH vs aspirin.
8.3
8.3. Analysis
Comparison 8 Anticoagulants versus control: minor bleeding, Outcome 3 Minor bleeding: LMWH vs warfarin.
8.4
8.4. Analysis
Comparison 8 Anticoagulants versus control: minor bleeding, Outcome 4 Minor bleeding: prophylactic vs intermediate or therapeutic LMWH.
8.5
8.5. Analysis
Comparison 8 Anticoagulants versus control: minor bleeding, Outcome 5 Minor bleeding: UFH vs no thromboprophylaxis.
8.6
8.6. Analysis
Comparison 8 Anticoagulants versus control: minor bleeding, Outcome 6 Minor bleeding: vitamin K antagonists vs placebo.
8.7
8.7. Analysis
Comparison 8 Anticoagulants versus control: minor bleeding, Outcome 7 Minor bleeding: warfarin vs aspirin.
8.8
8.8. Analysis
Comparison 8 Anticoagulants versus control: minor bleeding, Outcome 8 Minor bleeding: antithrombin vs placebo.
9.1
9.1. Analysis
Comparison 9 Anticoagulants versus control: 1‐year mortality, Outcome 1 1‐year mortality: semuloparin vs placebo.
9.2
9.2. Analysis
Comparison 9 Anticoagulants versus control: 1‐year mortality, Outcome 2 1‐year mortality: LMWH vs no thromboprophylaxis.
9.3
9.3. Analysis
Comparison 9 Anticoagulants versus control: 1‐year mortality, Outcome 3 1‐year mortality: UFH vs no thromboprophylaxis.
10.1
10.1. Analysis
Comparison 10 Anticoagulants versus control: symptomatic arterial thromboembolism, Outcome 1 Symptomatic arterial thromboembolism: LMWH vs no thromboprophylaxis.
10.2
10.2. Analysis
Comparison 10 Anticoagulants versus control: symptomatic arterial thromboembolism, Outcome 2 Symptomatic arterial thromboembolism: LMWH vs aspirin.
10.3
10.3. Analysis
Comparison 10 Anticoagulants versus control: symptomatic arterial thromboembolism, Outcome 3 Symptomatic arterial thromboembolism: LMWH vs warfarin.
10.4
10.4. Analysis
Comparison 10 Anticoagulants versus control: symptomatic arterial thromboembolism, Outcome 4 Symptomatic arterial thromboembolism: vitamin K antagonists vs placebo.
10.5
10.5. Analysis
Comparison 10 Anticoagulants versus control: symptomatic arterial thromboembolism, Outcome 5 Symptomatic arterial thromboembolism: warfarin vs aspirin.
11.1
11.1. Analysis
Comparison 11 Anticoagulants versus control: superficial venous thrombosis, Outcome 1 Superficial venous thrombosis: LMWH vs no thromboprophylaxis.
11.2
11.2. Analysis
Comparison 11 Anticoagulants versus control: superficial venous thrombosis, Outcome 2 Superficial venous thrombosis: LMWH vs aspirin.
12.1
12.1. Analysis
Comparison 12 Anticoagulants versus control: serious adverse events, Outcome 1 Serious adverse events: semuloparin vs placebo.
12.2
12.2. Analysis
Comparison 12 Anticoagulants versus control: serious adverse events, Outcome 2 Serious adverse events: LMWH vs no thromboprophylaxis.
12.3
12.3. Analysis
Comparison 12 Anticoagulants versus control: serious adverse events, Outcome 3 Serious adverse events: apixaban vs placebo.
See this image and copyright information in PMC

Update of

References

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    1. Palumbo A, Rus C, Cavallo F, Bertola A, Petrucci MT, Liberati AM, et al. Enoxaparin or aspirin for the prevention of recurrent thromboembolism in newly diagnosed myeloma patients treated with melphalan and prednisone plus thalidomide or lenalidomide. Haematologica 2006; Vol. 91 Suppl 1. - PubMed
Pelzer 2015 {published data only}
    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. 2009: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; Vol. 28 Suppl 3:Abstract 151.
    1. Pelzer U, Oettle H, Stauch M, Opitz B, Stieler J, Scholten T, et al. Prospective, randomized open trial of enoxaparin in patients with advanced pancreatic cancer undergoing first‐line chemotherapy. XXIst Congress of the International Society on Thrombosis and Haemostasis; 2007 Jul 6‐12; Geneva. 2007:Abstract P‐T‐488.
    1. Pelzer U, Opitz B, Deutschinoff G, Stauch M, Reitzig PC, Hahnfeld S, et al. Efficacy of prophylactic low‐molecular weight heparin for ambulatory patients with advanced pancreatic cancer: outcomes from the CONKO‐004 Trial. Journal of Clinical Oncology 2015;33:2028‐34. - PubMed
Perry 2010 {published data only}
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    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. 21 2013.
    1. Zhou X, Varadhachary GR, Milind J, Fogelman D, Shroff R, Bueso‐Ramos CE, 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, 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
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Zwicker 2013 {published data only}
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    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
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    1. Bergqvist D, Lindblad B. Is it possible to potentiate the thromboprophylactic effect of dextran with elastic compression stockings?. Thrombosis and Haemostasis 1983; Vol. 50, issue 1:247 Abstract 0777.
Bocharov 2011 {published data only}
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Eichinger 2008 {published data only}
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Gercor 2013 {unpublished data only}
    1. Groupe Cooperateur Multidisciplinaire en Oncologie. Chemotherapy with or without dalteparin in treating patients with metastatic pancreatic cancer (PAM07). clinicaltrials.gov/show/NCT00662688 (first received 18 April 2008).
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
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    1. Heilmann L, Schneider D, Herrle B, 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; Vol. 73, issue 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
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    1. Kessler P. Prophylaxis and treatment of venous thromboembolism in patients with multiple myeloma. Onkologie 2011;5(3):160‐2.
    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
Kwaan 2007 {unpublished data only}
    1. NCT00004875. Heparin or enoxaparin in patients with cancer. clinicaltrials.gov/show/NCT00004875 (first received 7 March 2000).
Levin 2008 {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).
Macintyre 1974 {published data only}
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    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; Vol. 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
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    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
Niesvizky 2007 {published data only}
    1. Niesvizky R, Martinez‐Banos D, Jalbrzikowski J, Christos P, Furst J, 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
Pandya 2002 {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).
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 1987 {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; Vol. 58, issue 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
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; Vol. 45, issue 4:861. - 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.

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. 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).
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.

References to ongoing studies

NCT00662688 {unpublished data only}
    1. NCT00662688. Chemotherapy with or without preventive anticoagulation for metastatic cancer of the pancreas. clinicaltrials.gov/ct2/show/NCT00662688?term=NCT00662688&rank=1 (first received 18 April 2008).
NCT00717938 {unpublished data only}
    1. NCT00717938. A study of standard treatment +/‐ enoxaparin in small cell lung cancer (RASTEN). clinicaltrials.gov/ct2/show/NCT00717938 (first received 16 July 2008).
NCT00718354 {unpublished data only}
    1. NCT00718354. Randomized, phase III‐b, multi‐centre, open‐label, parallel study of Enoxaparin (low molecular weight heparin) given concomitantly with chemotherapy vs chemotherapy alone in patients with inoperable gastric and gastro‐oesophageal cancer. clinicaltrials.gov/ct2/show/NCT00718354?term=NCT00718354&rank=1 (first received 16 July 2008).
NCT02048865 {published data only}
    1. NCT02048865. Apixaban for the prevention of venous thromboembolism in cancer patients (AVERT). clinicaltrials.gov/ct2/show/NCT02048865 (first received 27 January 2014).
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).

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