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Review
. 2018 Jun 19;6(6):CD006650.
doi: 10.1002/14651858.CD006650.pub5.

Anticoagulation for the long-term treatment of venous thromboembolism in people with cancer

Lara A Kahale  1 , Maram B Hakoum, Ibrahim G Tsolakian, Charbel F Matar, Irene Terrenato, Francesca Sperati, Maddalena Barba, Victor Ed Yosuico, Holger Schünemann, Elie A Akl
Affiliations
Review

Anticoagulation for the long-term treatment of venous thromboembolism in people with cancer

Lara A Kahale et al. Cochrane Database Syst Rev. .

Abstract

Background: Cancer increases the risk of thromboembolic events, especially in people receiving anticoagulation treatments.

Objectives: To compare the efficacy and safety of low molecular weight heparins (LMWHs), direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) for the long-term treatment of venous thromboembolism (VTE) in people with cancer.

Search methods: We conducted a literature search including a major electronic search of the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 1), MEDLINE (Ovid), and Embase (Ovid); handsearching conference proceedings; checking references of included studies; use of the 'related citation' feature in PubMed and a search for ongoing studies in trial registries. As part of the living systematic review approach, we run searches continually, incorporating new evidence after it is identified. Last search date 14 May 2018.

Selection criteria: Randomized controlled trials (RCTs) assessing the benefits and harms of long-term treatment with LMWHs, DOACs or VKAs in people with cancer and symptomatic VTE.

Data collection and analysis: We extracted data in duplicate on study characteristics and risk of bias. Outcomes included: all-cause mortality, recurrent VTE, major bleeding, minor bleeding, thrombocytopenia, and health-related quality of life (QoL). We assessed the certainty of the evidence at the outcome level following the GRADE approach (GRADE handbook).

Main results: Of 15,785 citations, including 7602 unique citations, 16 RCTs fulfilled the eligibility criteria. These trials enrolled 5167 people with cancer and VTE.Low molecular weight heparins versus vitamin K antagonistsEight studies enrolling 2327 participants compared LMWHs with VKAs. Meta-analysis of five studies probably did not rule out a beneficial or harmful effect of LMWHs compared to VKAs on mortality up to 12 months of follow-up (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.88 to 1.13; risk difference (RD) 0 fewer per 1000, 95% CI 45 fewer to 48 more; moderate-certainty evidence). Meta-analysis of four studies did not rule out a beneficial or harmful effect of LMWHs compared to VKAs on major bleeding (RR 1.09, 95% CI 0.55 to 2.12; RD 4 more per 1000, 95% CI 19 fewer to 48 more, moderate-certainty evidence) or minor bleeding (RR 0.78, 95% CI 0.47 to 1.27; RD 38 fewer per 1000, 95% CI 92 fewer to 47 more; low-certainty evidence), or thrombocytopenia (RR 0.94, 95% CI 0.52 to 1.69). Meta-analysis of five studies showed that LMWHs probably reduced the recurrence of VTE compared to VKAs (RR 0.58, 95% CI 0.43 to 0.77; RD 53 fewer per 1000, 95% CI 29 fewer to 72 fewer, moderate-certainty evidence).Direct oral anticoagulants versus vitamin K antagonistsFive studies enrolling 982 participants compared DOACs with VKAs. Meta-analysis of four studies may not rule out a beneficial or harmful effect of DOACs compared to VKAs on mortality (RR 0.93, 95% CI 0.71 to 1.21; RD 12 fewer per 1000, 95% CI 51 fewer to 37 more; low-certainty evidence), recurrent VTE (RR 0.66, 95% CI 0.33 to 1.31; RD 14 fewer per 1000, 95% CI 27 fewer to 12 more; low-certainty evidence), major bleeding (RR 0.77, 95% CI 0.38 to 1.57, RD 8 fewer per 1000, 95% CI 22 fewer to 20 more; low-certainty evidence), or minor bleeding (RR 0.84, 95% CI 0.58 to 1.22; RD 21 fewer per 1000, 95% CI 54 fewer to 28 more; low-certainty evidence). One study reporting on DOAC versus VKA was published as abstract so is not included in the main analysis.Direct oral anticoagulants versus low molecular weight heparinsTwo studies enrolling 1455 participants compared DOAC with LMWH. The study by Raskob did not rule out a beneficial or harmful effect of DOACs compared to LMWH on mortality up to 12 months of follow-up (RR 1.07, 95% CI 0.92 to 1.25; RD 27 more per 1000, 95% CI 30 fewer to 95 more; low-certainty evidence). The data also showed that DOACs may have shown a likely reduction in VTE recurrence up to 12 months of follow-up compared to LMWH (RR 0.69, 95% CI 0.47 to 1.01; RD 36 fewer per 1000, 95% CI 62 fewer to 1 more; low-certainty evidence). DOAC may have increased major bleeding at 12 months of follow-up compared to LMWH (RR 1.71, 95% CI 1.01 to 2.88; RD 29 more per 1000, 95% CI 0 fewer to 78 more; low-certainty evidence) and likely increased minor bleeding up to 12 months of follow-up compared to LMWH (RR 1.31, 95% CI 0.95 to 1.80; RD 35 more per 1000, 95% CI 6 fewer to 92 more; low-certainty evidence). The second study on DOAC versus LMWH was published as an abstract and is not included in the main analysis.Idraparinux versus vitamin K antagonistsOne RCT with 284 participants compared once-weekly subcutaneous injection of idraparinux versus standard treatment (parenteral anticoagulation followed by warfarin or acenocoumarol) for three or six months. The data probably did not rule out a beneficial or harmful effect of idraparinux compared to VKAs on mortality at six months (RR 1.11, 95% CI 0.78 to 1.59; RD 31 more per 1000, 95% CI 62 fewer to 167 more; moderate-certainty evidence), VTE recurrence at six months (RR 0.46, 95% CI 0.16 to 1.32; RD 42 fewer per 1000, 95% CI 65 fewer to 25 more; low-certainty evidence) or major bleeding (RR 1.11, 95% CI 0.35 to 3.56; RD 4 more per 1000, 95% CI 25 fewer to 98 more; low-certainty evidence).

Authors' conclusions: For the long-term treatment of VTE in people with cancer, evidence shows that LMWHs compared to VKAs probably produces an important reduction in VTE and DOACs compared to LMWH, may likely reduce VTE but may increase risk of major bleeding. Decisions for a person with cancer and VTE to start long-term LMWHs versus oral anticoagulation should balance benefits and harms and integrate the person's values and preferences for the important outcomes and alternative management strategies.Editorial note: this is a living systematic review (LSR). LSRs offer new approaches to review updating in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

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Conflict of interest statement

LAK: no conflicts of interest MBH: no conflicts of interests IGT: no conflicts of interests CFM: no conflicts of interests IT: no conflicts of interests FS: no conflicts of interests. MB: no conflicts of interests VEDY: no conflicts of interests HJS: panel member of the ASH VTE in Cancer patients, Vice‐Chair of the ASH VTE guidelines and played various leadership roles from 1999 until 2014 with ACCP VTE guidelines. EAA: served on the executive committee the ACCP Antithrombotic Therapy Guidelines published in 2016

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgments about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 1: All‐cause mortality (up to 6 months) (main analysis ‐ active cancer)
1.2
1.2. Analysis
Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 2: All‐cause mortality (time‐to‐event)
1.3
1.3. Analysis
Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 3: Recurrent venous thromboembolism (up to 6 months) (main analysis ‐ active cancer)
1.4
1.4. Analysis
Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 4: Recurrent venous thromboembolism (time‐to‐event)
1.5
1.5. Analysis
Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 5: Major bleeding (up to 6 months) (main analysis ‐ active cancer)
1.6
1.6. Analysis
Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 6: Minor bleeding (up to 6 months) (main analysis ‐ active cancer)
1.7
1.7. Analysis
Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 7: Thrombocytopenia (up to 6 months) (main analysis‐ active cancer)
2.1
2.1. Analysis
Comparison 2: Direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA), Outcome 1: All‐cause mortality (6‐12 months)
2.2
2.2. Analysis
Comparison 2: Direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA), Outcome 2: Recurrent venous thromboembolism (6‐12 months)
2.3
2.3. Analysis
Comparison 2: Direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA), Outcome 3: Major bleeding (6‐12 months)
2.4
2.4. Analysis
Comparison 2: Direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA), Outcome 4: Minor bleeding (6‐12 months)
3.1
3.1. Analysis
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 1: All‐cause mortality (6 months)
3.2
3.2. Analysis
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 2: Recurrent VTE (6 months)
3.3
3.3. Analysis
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 3: Major bleeding (6 months)
3.4
3.4. Analysis
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 4: Major GI bleeding (6 months)
3.5
3.5. Analysis
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 5: Major upper GI bleeding (6 months)
3.6
3.6. Analysis
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 6: Major lower GI bleeding (6 months)
3.7
3.7. Analysis
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 7: Major non‐GI bleeding (6 months)
3.8
3.8. Analysis
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 8: Minor bleeding (6 months)
3.9
3.9. Analysis
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 9: Minor GI bleeding (6 months)
3.10
3.10. Analysis
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 10: Minor upper GI bleeding (6 months)
3.11
3.11. Analysis
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 11: Minor lower GI bleeding (6 months)
3.12
3.12. Analysis
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 12: Minor non‐GI bleeding (6 months)
4.1
4.1. Analysis
Comparison 4: Idraparinux versus vitamin K antagonists (VKA), Outcome 1: All‐cause mortality (up to 6 months)
4.2
4.2. Analysis
Comparison 4: Idraparinux versus vitamin K antagonists (VKA), Outcome 2: Recurrent VTE (up to 6 months)
4.3
4.3. Analysis
Comparison 4: Idraparinux versus vitamin K antagonists (VKA), Outcome 3: Major bleeding (up to 6 months)
4.4
4.4. Analysis
Comparison 4: Idraparinux versus vitamin K antagonists (VKA), Outcome 4: Minor bleeding (up to 6 months)
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References

References to studies included in this review

Agnelli 2015 (AMPLIFY) {published data only}
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Lopez‐Beret 2001 {published data only}
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Mazilu 2014 (OVIDIUS) {published data only}
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McBane 2019 (ADAM‐VTE) {published data only}
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Meyer 2002 (CANTHANOX) {published data only}
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Prins 2014 (EINSTEIN) {published data only}
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Raskob 2016 (HOKUSAI) {published data only}
    1. Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. New England Journal of Medicine 2013;369:1406-15. - PubMed
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Raskob 2018 (HOKUSAI) {published data only}
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Romera 2009 {published data only}
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Schulman 2015 (RECOVER I‐II) {published data only}
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van Doormaal 2010 (Van Gogh DVT trial) {published data only}
    1. Doormaal FF, Cohen AT, Davidson BL, Decousus H, Gallus AS, Gent M, et al. Idraparinux versus standard therapy in the treatment of deep venous thrombosis in cancer patients: a subgroup analysis of the Van Gogh DVT trial. Thrombosis and Haemostasis 2010;104(1):86-91. - PubMed
Young 2018 (SELECT‐D) {published data only}
    1. Young A, Dunn J, Chapman O, Grumett J, Marshall A, Phillips J, et al. SELECT-D: anticoagulation therapy in selected cancer patients at risk of recurrence of venous thromboembolism. ASCO Annual Meeting Proceedings 2014;32(15 Suppl):TPS9661. - PubMed
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    1. Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol 2018 Jul 10 ;36(20):2017-2023. - PubMed

References to studies excluded from this review

Agnelli 2005 {published data only}
    1. Agnelli G, Bergqvist D, Cohen AT, Gallus AS, Gent M. Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery. British Journal of Surgery 2005;92(10):1212-20. - PubMed
Alikhan 2003 (MEDENOX) {published data only}
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    1. Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C, et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. New England Journal of Medicine 1999;341(11):793-800. - PubMed
Auer 2011 {published data only}
    1. Auer R, Scheer A, Wells PS, Boushey R, Asmis T, Jonker D, et al. The use of extended perioperative low molecular weight heparin (tinzaparin) to improve disease-free survival following surgical resection of colon cancer: a pilot randomized controlled trial. Blood Coagulation & Fibrinolysis 2011;22(8):760-2. - PubMed
Cohen 2006 {published data only}
    1. Cohen AT, Davidson BL, Gallus AS, Lassen MR, Prins MR, Tomkowski W, et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006;332(7537):325-9. - PMC - PubMed
Cohen 2007 (PREVENT) {published data only}
    1. Cohen AT, Davidson BL, Gallus AS, Lassen MR, Prins MH, Tomkowski W, et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006;332(7537):325-9. - PMC - PubMed
    1. Cohen AT, Turpie AG, Leizorovicz A, Olsson CG, Vaitkus PT, Goldhaber SZ. Thromboprophylaxis with dalteparin in medical patients: which patients benefit? Vascular Medicine 2007;12(2):123-7. - PubMed
    1. Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Vaitkus PT, Goldhaber SZ, PREVENT Medical Thromboprophylaxis Study Group. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 2004;110(7):874-9. - PubMed
Couban 2005 {published data only}
    1. Couban S, Goodyear M, Burnell M, Dolan S, Wasi P, Barnes D, et al. A randomized double-blind placebo-controlled study of low dose warfarin for the prevention of symptomatic central venous catheter-associated thrombosis in patients with cancer. In: Blood, American Society of Hematology 44th Annual Meeting. 2002:Abstract no 2769.
    1. Couban S, Goodyear M, Burnell M, Dolan S, Wasi P, Barnes D, et al. A randomized double-blind placebo controlled study of low dose warfarin for the prevention of symptomatic central venous catheter-associated thrombosis in patients with cancer. Journal of Thrombosis and Haemostasis 2003;1:Abstract no: P198. - PubMed
    1. Couban S, Goodyear M, Burnell M, Dolan S, Wasi P, Barnes D, et al. Randomized placebo-controlled study of low-dose warfarin for the prevention of central venous catheter-associated thrombosis in patients with cancer. Journal of Clinical Oncology 2005;23(18):4063-9. - PubMed
Eriksson 2005 {published data only}
    1. Eriksson H, Lundstrom T, Wahlander K, Clason SB, Schulman S. Prognostic factors for recurrence of venous thromboembolism (VTE) or bleeding during long-term secondary prevention of VTE with ximelagatran. Thrombosis and Haemostasis 2005;94(3):522-7. - PubMed
Farred 2004 {published data only}
    1. Farred J. Multifactorial etiology of cancer associated venous thrombosis: results from profiling of cancer patients recruited in a study of the secondary prevention of thrombosis with low molecular weight heparin. In: 40th Annual Meeting for the American Society for Clinical Oncology; 2004 Jun 5-8; New Orleans (LA). 2004.
Ferretti 2005 {published data only}
    1. Ferretti G, Bria E, Carlini P, Felici A, Giannarelli D, Ciccarese M, et al. Meta-analysis of the randomized comparisons between low-molecular weight heparin (LMWH) with oral anticoagulants (OA) for the long-term treatment of symptomatic venous thromboembolism (VTE): no difference in cancer-related mortality. Journal of Clinical Oncology 2005;23(16):765S. - PubMed
Ferretti 2006 {published data only}
    1. Ferretti G. Does low-molecular-weight heparin influence cancer-related mortality? Annals of Oncology 2006;17(10):1604-6. - PubMed
Fiessinger 2005 {published data only}
    1. Fiessinger JN, Huisman MV, Davidson BL, Bounameaux H, Francis CW, Eriksson H, et al. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis – a randomized trial. JAMA 2005;293(6):681-9. - PubMed
Haas 2011 {published data only}
    1. Bauersachs R, Schellong SM, Haas S, Tebbe U, Gerlach HE, Abletshauser C, et al. CERTIFY: prophylaxis of venous thromboembolism in patients with severe renal insufficiency. Thrombosis and Haemostasis 2011;105(6):981-8. - PubMed
    1. Haas S, Schellong SM, Tebbe U, Gerlach HE, Bauersachs R, Abletshauser C, et al. CERTIFY: certoparin versus UFH to prevent venous thromboembolic events in the patients with cancer. Hämostaseologie 2011;31(1):A10. - PubMed
    1. Haas S, Schellong SM, Tebbe U, Gerlach HE, 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(1):1. - PMC - PubMed
Hata 2016 {published data only}
    1. Hata K, Kimura T, Tsuzuki S, Ishii G, Kido M, Yamamoto T, et al. Safety of fondaparinux for prevention of postoperative venous thromboembolism in urological malignancy: a prospective randomized clinical trial. International Journal of Urology 2016;23(11):923-8. - PubMed
Hull 2007 {published data only}
    1. Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, et al. Self-managed long-term low-molecular-weight heparin therapy: the balance of benefits and harms. American Journal of Medicine 2007;120:72-82. - PubMed
Hull 2009 {published data only}
    1. Hull RD, Pineo GF, Brant R, Liang J, Cook R, Solymoss S, et al. Home therapy of venous thrombosis with long-term LMWH versus usual care: patient satisfaction and post-thrombotic syndrome. American Journal of Medicine 2009;122:762-9. - PubMed
Hyers 2005 {published data only}
    1. Hyers TM. Long-term anticoagulation prophylaxis following acute thromboembolism. Disease-a-Month 2005;51(2-3):158-65. - PubMed
Kakkar 2003 {published data only}
    1. Kakkar VV, Gebska M, Kadziola Z, Saba N, Carrasco P. Low-molecular-weight heparin in the acute and long-term treatment of deep vein thrombosis. Thrombosis and Haemostasis 2003;89(4):674-80. - PubMed
Kakkar 2010 (CANBESURE) {published data only}
    1. Kakkar VV, Balibrea J, Martinez-Gonzalez J, Prandoni P. Late breaking clinical trial: a randomised double blind trial to evaluate the efficacy and safety of prolonging the thromboprophylaxis with bemiparin in patients undergoing cancer abdominal or pelvic surgery (the CANBESURE study). International Society on Thrombosis and Haemostasis 2009;5(6):1223-9.
    1. Kakkar VV, Balibrea JL, Martinez-Gonzalez J, Prandoni P. Extended prophylaxis with bemiparin for the prevention of venous thromboembolism after abdominal or pelvic surgery for cancer: the CANBESURE randomized study. Journal of Thrombosis and Haemostasis : JTH 2010;8(6):1223-9. - PubMed
Kakkar 2014 (SAVE‐ABDO) {published data only}
    1. Kakkar AK, Agnelli G, Fisher WD, George D, Lassen MR, Mismetti P, et al, SAVE-ABDO Investigators. Preoperative enoxaparin versus postoperative semuloparin thromboprophylaxis in major abdominal surgery: a randomized controlled trial. Annals of Surgery 2014;259(6):1073-9. - PubMed
    1. Kakkar AK, Agnelli G, Fisher WD, George D, Mouret P, Lassen MR, et al. The ultra-low-molecular-weight heparin semuloparin for prevention of venous thromboembolism In patients undergoing major abdominal surgery. Blood 2010;116(21):188.
Khorana 2017 (PHACS) {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(23):427. - PubMed
    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. Thrombosis Research 2017;151:89-95. [DOI: ] - PubMed
King 2005 {published data only}
    1. King KM, Wong C, Nutescu E, Shord SS. Warfarin dose requirements in cancer and non-cancer. Pharmacotherapy 2005;25(3):468.
Kovacs 2005 {published data only}
    1. Kovacs MJ, Levine MN, Keeney M, Mackinnon KM, Lee AY. Anti-Xa effect of a low molecular weight heparin (dalteparin) does not accumulate in extended duration therapy for venous thromboembolism in cancer patients. Thrombosis and Haemostasis 2005;93(6):1185-8. - PubMed
Kucher 2005 {published data only}
    1. Kucher N, Quiroz R, McKean S, Sasahara AA, Goldhaber SZ, Kucher N, et al. Extended enoxaparin monotherapy for acute symptomatic pulmonary embolism. Vascular Medicine 2005;10(4):251-6. - PubMed
Larocca 2012 {published data only}
    1. Larocca A, Cavallo F, Bringhen S, Raimondo FD, Falanga A, Evangelista A, et al. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood 2012;119:933-9. - PubMed
Lee 2005 {published data only}
    1. Lee A, Levine M. Treatment of venous thromboembolism in cancer patients. Cancer Control 2005;12 Suppl 1:17-21. - PubMed
Lee 2006 {published data only}
    1. Lee AY. Dalteparin sodium in the management of thromboembolic disorder. Therapy 2006;3(4):461-73.
Levine 2003 {published data only}
    1. Levine MN, Lee AY, Kakkar AK. From Trousseau to targeted therapy: new insights and innovations in thrombosis and cancer. Thrombosis and Haemostasis 2003;1(7):1456-63. - PubMed
Macbeth 2016 (FRAGMATIC) {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(1):1. - 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(5):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 (R) added to standard therapy in patients with lung cancer. Journal of Thoracic Oncology 2013;8:S243.
    1. Noble S, Robbins A, Alikhan R, Hood K, Macbeth F. Prediction of venous thromboembolism in lung cancer patients receiving chemotherapy. Journal of Thrombosis and Haemostasis 2015;13:143.
Massicotte 2003 {published data only}
    1. Massicotte P, Julian JA, Gent M, Shields K, Marzinotto V, Szechtman B, et al. An open-label randomized controlled trial of low molecular weight heparin compared to heparin and coumadin for the treatment of venous thromboembolic events in children: the REVIVE trial. Thrombosis Research 2003;109(2-3):85-92. - PubMed
Murakami 2002 {published data only}
    1. Murakami M, Wiley LA, Cindrick-Pounds L, Hunter GC, Uchida T, Killewich LA. External pneumatic compression does not increase urokinase plasminogen activator after abdominal surgery. Vascular Surgery 2002;36(5):917-21. - PubMed
Nagata 2015 {published data only}
    1. Nagata C, Tanabe H, Takakura S, Narui C, Saito M, Yanaihara N, et al. Randomized controlled trial of enoxaparin versus intermittent pneumatic compression for venous thromboembolism prevention in Japanese surgical patients with gynecologic malignancy. Journal of Obstetrics and Gynaecology Research 2015;41(9):1440-8. - PubMed
Palumbo 2011 {published data only}
    1. Cavo M, Palumbo A, Bringhen S, Di Raimondo F, 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 upfront with thalidomide-containing regimens. Haematologica 2010;95:391.
    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;112(11):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;95:S1-S162.
    1. Palumbo A, Cavo M, Bringhen S, Zaccaria A, Spadano A, Palmieri S, et al. Enoxaparin versus aspirin versus low-fixed-dose of warfarin in newly diagnosed myeloma patients treated with thalidomide-containing regimens: a randomized, controlled trial. Haematologica 2008;93:362.
Pelzer 2015 (CONKO‐004) {published data only}02140505
    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. In: Onkologie – DGHO meeting. Vol. 580. October 2009:Abstract.
    1. Pelzer U, Hilbig A, Stieler J, Roll L, Riess H, Dorken B, et al. A prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy (PROSPECT – CONKO 004). Onkologie 2005;28(Suppl 3):54. - PMC - PubMed
    1. Pelzer U, Hilbig A, Stieler J, Roll L, Stauch M, Opitz B, et al. A prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy (PROSPECT-CONKO 004). ASCO Annual Meeting Proceedings 2006;24(18):4110.
    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
    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. In: XXIst Congress of the International Society on Thrombosis and Haemostasis; 2007 Jul 6-12; Geneva. 2007:P-T-488.
Pérez‐de‐Llano 2010 {published data only}
    1. Pérez-de-Llano LA, Leiro-Fernández V, Golpe R, Núñez-Delgado JM, Palacios-Bartolomé A, Méndez-Marote L, et al. Comparison of tinzaparin and acenocoumarol for the secondary prevention of venous thromboembolism: a multicentre, randomized study. Blood Coagulation Fibrinolysis 2010;21(8):744-99. - PubMed
Sakon 2010 {published data only}
    1. Sakon M, Kobayashi T, Shimazui T. Efficacy and safety of enoxaparin in Japanese patients undergoing curative abdominal or pelvic cancer surgery: results from a multicenter, randomized, open-label study. Thrombosis Research 2010;125(3):e65-70. - PubMed
Schulman 2003 {published data only}
    1. Schulman S, Wahlander K, Lundstrom T, Clason SB, Eriksson H, Investigators TI, et al. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. New England Journal of Medicine 2003;349(18):1713-21. - PubMed
Schulman 2006 {published data only}
    1. Schulman S, Lindmarker P, Holmström M, Lärfars G, Carlsson A, Nicol P, et al. Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months. Thrombosis & Haemostasis 2006;4(4):734-42. - PubMed
Schulman 2013 (RE‐MEDY) {published data only}
    1. Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. New England Journal of Medicine 2013;368(8):709-18. - PubMed
Siragusa 2010 {published data only}
    1. Siragusa S, Malato A, Mascheroni D, Ageno W, Bucherini E, Spadaro P, et al. The optimal duration of anticoagulant therapy in patients with cancer-related deep vein thrombosis: the advantage of using residual vein thrombosis (the Cancer-DACUS Study). Blood 2010;116(21):87-8.
Song 2014 {published data only}
    1. Song KY, Yoo HM, Kim EY, Kim JI, Yim HW, Jeon HM, et al. Optimal prophylactic method of venous thromboembolism for gastrectomy in Korean patients: an interim analysis of prospective randomized trial. Annals of Surgical Oncology 2014;21(13):4232-8. - PubMed
Suarez Alvarez 2003 {published data only}
    1. Suarez Alvarez CG, Garcia Canete J, Herrero Mendoza MD, Bellver Alvarez TM, Arboiro Pinel R. Treatment of deep vein thrombosis with low molecular weight heparins at home. Anales de Medicina Interna 2003;20(3):134-6. - PubMed
Vedovati 2014 {published data only}
    1. Becattini C, Rondelli F, Vedovati MC, Camporese G, Giustozzi M, Boncompagni M, et al. Incidence and risk factors for venous thromboembolism after laparoscopic surgery for colorectal cancer. Haematologica 2015;100(1):e35-8. - PMC - PubMed
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    1. Vedovati MC, Becattini C, Rondelli F, Boncompagni M, Camporese G, Balzarotti R, et al. A randomized study on 1 vs. 4 weeks prophylaxis for venous thromboembolism after laparoscopic surgery for colorectal cancer. Thrombosis and Haemostasis 2013;11:214. - PubMed
    1. Vedovati MC, Becattini C, Rondelli F, Boncompagni M, Camporese G, Balzarotti R, et al. A randomized study on 1-week versus 4-week prophylaxis for venous thromboembolism after laparoscopic surgery for colorectal cancer. Annals of Surgery 2014;259(4):665-9. - PubMed
Veiga 2000 {published data only}
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Verso 2008 {published data only}
    1. Agnelli G, Verso M, Bertoglio S, Ageno W, Bazzan M, Parise P, et al. A double-blind placebo-controlled randomized study on the efficacy and safety of enoxaparin for the prevention of upper limb deep vein thrombosis in cancer patients with central vein catheter. Journal of Clinical Oncology 2004;22:734S. - PubMed
    1. Verso M, Agnelli G, Bertoglio S, Di Somma FC, Paoletti F, Ageno W, et al. Enoxaparin for the prevention of venous thromboembolism associated with central vein catheter: a double-blind, placebo-controlled, randomized study in cancer patients. Journal of Clinical Oncology 2005;23(18):4057-62. - PubMed
    1. Verso M, Agnelli G, Kamphuisen PW, Ageno W, Bazzan M, Lazzaro A, et al. A double-blind placebo-controlled randomized study on the efficacy and safety of enoxaparin for the prevention of upper limb deep vein thrombosis in cancer patients with central vein catheter. Thrombosis and Haemostasis 2003;1:Abstract no: P0825.
    1. Verso M, Agnelli G, Kamphuisen PW, Ageno W, Bazzan M, Lazzaro A, et al. Risk factors for upper limb deep vein thrombosis associated with the use of central vein catheter in cancer patients. Internal and Emergency Medicine 2008;3(2):117-22. - PubMed
Zheng 2014 {published data only}
    1. Zheng H, Gao Y, Yan X, Gao M, Gao W. Prophylactic use of low molecular weight heparin in combination with graduated compression stockings in post-operative patients with gynecologic cancer. Zhonghua Zhong Liu za Zhi [Chinese Journal of Oncology] 2014;36(1):39-42. - PubMed
Zwicker 2013 (MICROTEC) {published data only}
    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). Thrombosis and Haemostasis 2013;11:6. - 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 ongoing studies

Kamphuisen 2010 (Longheva) {published data only}
    1. Kleinjan A, Di Nisio M, Kamphuisen PW, Buller HR, on behalf of the steering committee. Long-term treatment for cancer patients with deep vein thrombosis or pulmonary embolism – a randomized controlled trial. 5th ICTHIC Abstracts: Poster Sessions / Thrombosis Research 2010;125(PO-67):S184.
Karatas 2015 {published data only}
    1. Rivaroxaban in the treatment of venous thromboembolism (VTE) in cancer patients. Ongoing study. March 2016. Contact author for more information.
Meyer 2016 (CASTA‐DIVA) {published data only}
    1. Cancer associated thrombosis, a pilot treatment study using rivaroxaban (CASTA-DIVA). Ongoing study. September 2016. Contact author for more information.
Ryun Park 2017 (PRIORITY) {published data only}
    1. A randomized phase II study to compare the safety and efficacy of dalteparin vs. rivaroxaban for cancer-associated venous thromboembolism (PRIORITY). Ongoing study. May 2017. Contact author for more information.
Schrag 2016 (CANVAS) {published data only}
    1. Direct oral anticoagulants (DOACs) versus LMWH ± warfarin for VTE in cancer (CANVAS). Ongoing study. December 2016. Contact author for more information.

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References to other published versions of this review

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