Prevention of Deep Vein Thrombosis in Cancer Patients

ABSTRACT

Venous thromboembolism (VTE) in patients with cancer follows an aggressive course, and it is often resistant to traditional regimens of pharmacological prophylaxis and treatment. Anticoagulant-related bleeding is also common and can complicate VTE treatment as well as cancer therapy. Consequently, the most effective approach to reducing the burden of VTE and its associated morbidity and mortality is to provide appropriate prophylaxis. Few clinical trials have focused on the prevention of VTE in this high-risk patient population, and they consistently demonstrate the efficacy and safety of anticoagulant prophylaxis in reducing thrombotic complications. Currently, low-molecular-weight heparins and oral vitamin K antagonists are the most commonly used anticoagulants for primary prevention in patients with cancer, but compliance with consensus guidelines is poor. Novel anticoagulants with a convenient and favorable risk/benefit profile may help to improve prophylaxis utilization and treatment. This review will provide a summary of the evidence on the primary prevention of VTE in patients with cancer.

KEYWORDS

Neoplasm - deep vein thrombosis - thromboembolism - prophylaxis - low-molecular-weight heparin - heparin - warfarin

REFERENCES

• 1 Lee A Y, Levine M N. Venous thromboembolism and cancer: risks and outcomes.  Circulation. 2003;  107(Suppl 1) I17-I21
• 2 Blom J W, Doggen C J, Osanto S, Rosendaal F R. Malignancies, prothrombotic mutations, and the risk of venous thrombosis.  JAMA. 2005;  293 715-722
• 3 Prandoni P, Lensing A W, Piccioli A et al.. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis.  Blood. 2002;  100 3484-3488
• 4 Hutten B A, Prins M H, Gent M, Ginsberg J, Tijssen J G, Buller H R. 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.  J Clin Oncol. 2000;  18 3078-3083
• 5 Khorana A A, Francis C W, Culakova E, Fisher R I, Kuderer N M, Lyman G H. Thromboembolism in hospitalized neutropenic cancer patients.  J Clin Oncol. 2006;  24 484-490
• 6 Levitan N, Dowlati A, Remick S C et al.. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data.  Medicine (Baltimore). 1999;  78 285-291
• 7 Sorensen H T, Mellemkjaer L, Olsen J H, Baron J A. Prognosis of cancers associated with venous thromboembolism.  N Engl J Med. 2000;  343 1846-1850
• 8 Geerts W H, Pineo G F, Heit J A et al.. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.  Chest. 2004;  126(3 Suppl) 338S-400S
• 9 Haas S, Wolf H, Kakkar A K, Fareed J, Encke A. Prevention of fatal pulmonary embolism and mortality in surgical patients: a randomized double-blind comparison of LMWH with unfractionated heparin.  Thromb Haemost. 2005;  94 814-819
• 10 Kakkar A K, Haas S, Wolf H, Encke A. Evaluation of perioperative fatal pulmonary embolism and death in cancer surgical patients: the MC-4 cancer substudy.  Thromb Haemost. 2005;  94 867-871
• 11 Wells P S, Lensing A W, Hirsh J. Graduated compression stockings in the prevention of postoperative venous thromboembolism. A meta-analysis.  , [see comments] Arch Intern Med. 1994;  154 67-72
• 12 Clarke-Pearson D L, Creasman W T, Coleman R E, Synan I S, Hinshaw W M. Perioperative external pneumatic calf compression as thromboembolism prophylaxis in gynecologic oncology: report of a randomized controlled trial.  Gynecol Oncol. 1984;  18 226-232
• 13 Mismetti P, Laporte S, Darmon J Y, Buchmuller A, Decousus H. Meta-analysis of low molecular weight heparin in the prevention of venous thromboembolism in general surgery.  Br J Surg. 2001;  88 913-930
• 14 ENOXACAN Study Group . Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: a double- blind randomized multicentre trial with venographic assessment.  Br J Surg. 1997;  84 1099-1103
• 15 McLeod R S, Geerts W H, Sniderman K W et al.. Subcutaneous heparin versus low-molecular-weight heparin as thromboprophylaxis in patients undergoing colorectal surgery: results of the canadian colorectal DVT prophylaxis trial: a randomized, double-blind trial.  Ann Surg. 2001;  233 438-444
• 16 Agnelli G, Bergqvist D, Cohen A T, Gallus A S, Gent M. Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery.  Br J Surg. 2005;  92 1212-1220
• 17 Agnelli G, Bolis G, Capussotti L et al.. A clinical outcome-based prospective study on venous thromboembolism after cancer surgery: the @RISTOS project.  Ann Surg. 2006;  243 89-95
• 18 Bergqvist D, Agnelli G, Cohen A T et al.. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer.  N Engl J Med. 2002;  346 975-980
• 19 Rasmussen M S, Jorgensen L N, Wille-Jorgensen P et al.. Prolonged prophylaxis with dalteparin to prevent late thromboembolic complications in patients undergoing major abdominal surgery: a multicenter randomized open-label study.  J Thromb Haemost. 2006;  4 2384-2390
• 20 Bergqvist D, Burmark U S, Flordal P A et al.. Low molecular weight heparin started before surgery as prophylaxis against deep vein thrombosis: 2500 versus 5000 XaI units in 2070 patients.  , [see comments] Br J Surg. 1995;  82 496-501
• 21 Marras L C, Geerts W H, Perry J R. The risk of venous thromboembolism is increased throughout the course of malignant glioma: an evidence-based review.  Cancer. 2000;  89 640-646
• 22 Iorio A, Agnelli G. Low-molecular-weight and unfractionated heparin for prevention of venous thromboembolism in neurosurgery: a meta-analysis.  Arch Intern Med. 2000;  160 2327-2332
• 23 Nurmohamed M T, van Riel A M, Henkens C M et al.. Low molecular weight heparin and compression stockings in the prevention of venous thromboembolism in neurosurgery.  Thromb Haemost. 1996;  75 233-238
• 24 Agnelli G, Piovella F, Buoncristiani P et al.. Enoxaparin plus compression stockings compared with compression stockings alone in the prevention of venous thromboembolism after elective neurosurgery.  , [see comments] N Engl J Med. 1998;  339 80-85
• 25 Goldhaber S Z, Dunn K, Gerhard-Herman M, Park J K, Black P M. Low rate of venous thromboembolism after craniotomy for brain tumor using multimodality prophylaxis.  Chest. 2002;  122 1933-1937
• 26 Macdonald R L, Amidei C, Baron J et al.. Randomized, pilot study of intermittent pneumatic compression devices plus dalteparin versus intermittent pneumatic compression devices plus heparin for prevention of venous thromboembolism in patients undergoing craniotomy.  Surg Neurol. 2003;  59 363-372
• 27 Carman T L, Kanner A A, Barnett G H, Deitcher S R. Prevention of thromboembolism after neurosurgery for brain and spinal tumors.  South Med J. 2003;  96 17-22
• 28 Perry J, Rogers L, Laperriere N 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.  J Clin Oncol. 2007;  25(18S) , abstract 2011
• 29 Clarke-Pearson D L, Jelovsek F R, Creasman W T. Thromboembolism complicating surgery for cervical and uterine malignancy: incidence, risk factors, and prophylaxis.  Obstet Gynecol. 1983;  61 87-94
• 30 Oates-Whitehead R M, D'Angelo A, Mol B. Anticoagulant and aspirin prophylaxis for preventing thromboembolism after major gynaecological surgery.  Cochrane Database Syst Rev. 2003;  4 CD003679
• 31 Clarke-Pearson D L, Dodge R K, Synan I, McClelland R C, Maxwell G L. Venous thromboembolism prophylaxis: patients at high risk to fail intermittent pneumatic compression.  Obstet Gynecol. 2003;  101 157-163
• 32 Maxwell G L, Myers E R, Clarke-Pearson D L. Cost-effectiveness of deep venous thrombosis prophylaxis in gynecologic oncology surgery.  Obstet Gynecol. 2000;  95 206-214
• 33 Sawczuk I S, Williams D, Chang D T. Low molecular weight heparin for venous thromboembolism prophylaxis in urologic oncologic surgery.  Cancer Invest. 2002;  20 889-892
• 34 Cade J F, Clegg E A, Westlake G W. Prophylaxis of venous thrombosis after major thoracic surgery.  Aust N Z J Surg. 1983;  53 301-304
• 35 Mason D P, Quader M A, Blackstone E H et al.. Thromboembolism after pneumonectomy for malignancy: an independent marker of poor outcome.  J Thorac Cardiovasc Surg. 2006;  131 711-718
• 36 Levine M, Hirsh J, Gent M et al.. Double-blind randomised trial of a very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer.  , [see comments] Lancet. 1994;  343 886-889
• 37 Hass S. Prevention of VTE with LMWH in patients with metastatic breast or lung cancer-results of the TOPIC studies.  [abstract] J Thromb Haemost. 2005;  3(Suppl 1) OR059
• 38 Kakkar A K, Levine M N, Kadziola Z et al.. Low molecular weight heparin therapy with dalteparin and survival in advanced cancer: the Fragmin Advanced Malignancy Outcome Study (FAMOUS).  J Clin Oncol. 2004;  22 1944-1948
• 39 Klerk C P, Smorenburg S M, Otten H M et al.. The effect of low molecular weight heparin on survival in patients with advanced malignancy.  J Clin Oncol. 2005;  23 2130-2135
• 40 Marx G M, Steer C B, Harper P, Pavlakis N, Rixe O, Khayat D. Unexpected serious toxicity with chemotherapy and antiangiogenic combinations: time to take stock!.  J Clin Oncol. 2002;  20 1446-1448
• 41 Kabbinavar F, Hurwitz H I, Fehrenbacher L et al.. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer.  J Clin Oncol. 2003;  21 60-65
• 42 Kuenen B C, Rosen L, Smit E F et al.. Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors.  J Clin Oncol. 2002;  20 1657-1667
• 43 Desai A A, Vogelzang N J, Rini B I, Ansari R, Krauss S, Stadler W M. A high rate of venous thromboembolism in a multi-institutional phase II trial of weekly intravenous gemcitabine with continuous infusion fluorouracil and daily thalidomide in patients with metastatic renal cell carcinoma.  Cancer. 2002;  95 1629-1636
• 44 Zangari M, Anaissie E, Barlogie B et al.. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy.  Blood. 2001;  98 1614-1615
• 45 Rajkumar S V, Hayman S, Gertz M A et al.. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma.  J Clin Oncol. 2002;  20 4319-4323
• 46 Cohen A T, Davidson B L, Gallus A S et al.. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial.  BMJ. 2006;  332 325-329
• 47 Leizorovicz A, Cohen A T, Turpie A G, Olsson C G, Vaitkus P T, Goldhaber S Z. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients.  Circulation. 2004;  110 874-879
• 48 Samama M M, Cohen A T, Darmon J Y et al.. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group.  N Engl J Med. 1999;  341 793-800
• 49 Lee A Y, Levine M N, Butler G et al.. Incidence, risk factors, and outcomes of catheter-related thrombosis in adult patients with cancer.  J Clin Oncol. 2006;  24 1404-1408
• 50 Couban S, Goodyear M, Burnell M et al.. Randomized placebo-controlled study of low-dose warfarin for the prevention of central venous catheter-associated thrombosis in patients with cancer.  J Clin Oncol. 2005;  23 4063-4069
• 51 Young A M, Begum G, Billingham L J et al.. WARP-a multicentre prospective randomised controlled trial (RCT) of thrombosis prophylaxis with warfarin in cancer patients with central venous catheter (CVCs).  J Clin Oncol. 2005;  23(16S) , abstract 8004
• 52 Verso M, Agnelli G, Bertoglio S et al.. Enoxaparin for the prevention of venous thromboembolism associated with central vein catheter: a double-blind, placebo-controlled, randomized study in cancer patients.  J Clin Oncol. 2005;  23 4057-4062
• 53 Decousus H, Leizorovicz A, Parent F et al.. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prevention du Risque d'Embolie Pulmonaire par Interruption Cave Study Group.  N Engl J Med. 1998;  338 409-415
• 54 Elting L S, Escalante C P, Cooksley C et al.. Outcomes and cost of deep venous thrombosis among patients with cancer.  Arch Intern Med. 2004;  164 1653-1661
• 55 White R H, Zhou H, Kim J, Romano P S. A population-based study of the effectiveness of inferior vena cava filter use among patients with venous thromboembolism.  Arch Intern Med. 2000;  160 2033-2041
• 56 Anderson Jr F A, Tapson V F, Decousus H, Spyropoulos C, Turpie A GG, FitzGerald G A. for the IMPROVE Investigators . Multinational observational cohort study of practices in prevention of venous thromboembolism in acutely ill medical patients: a comparison with clinical study patient population.  Blood. 2003;  102 , abstract 1146
• 57 Arnold D M, Kahn S R, Shrier I. Missed opportunities for prevention of venous thromboembolism: an evaluation of the use of thromboprophylaxis guidelines.  Chest. 2001;  120 1964-1971
• 58 Tapson V F, Hyers T M, Waldo A L et al.. Antithrombotic therapy practices in US hospitals in an era of practice guidelines.  Arch Intern Med. 2005;  165 1458-1464
• 59 Kakkar A K, Levine M, Pinedo H M, Wolff R, Wong J. Venous thrombosis in cancer patients: insights from the FRONTLINE survey.  Oncologist. 2003;  8 381-388
• 60 Deitcher S R. Primary prevention of venous thromboembolic events (VTE) in cancer patients: an American survery study.  J Clin Oncol. 2004;  22(14S) abstract 8086