Management of VTE in Patients with Cancer

Long term anticoagulation for cancer patients with venous thromboembolism presents a significant problem for physicians. Warfarin therapy, with the INR kept in the 2-3 range, has long been the traditional treatment. However cancer patients often have issues that will make management of warfarin therapy difficult. For example, there are the issues of chemotherapy and its complications (thrombocytopenia, vomiting), invasive surgical procedures for which the anticoagulation must be reversed, hormonal agents and indwelling catheters. Poor nutrition, concomitant medication, infection and impaired liver function also present challenges in managing oral anticoagulant therapy.

Moreover, cancer patients are often resistant to oral anticoagulation, have a higher risk of recurrent VTE and have a higher risk of bleeding on anticoagulation therapy. Several studies have shown that patients with cancer have a 3-4 fold higher risk of recurrent VTE during anticoagulation therapy than do non-cancer patients, and that the risk increases with the extent of the cancer. This increased risk is likely as a consequence of the release of cancer pro-coagulants that are not inhibited by conventional anticoagulation.

The risk of bleeding in the cancer patients on anticoagulation may be as much as 5-6 times that of the patient without cancer. As with the risk of recurrent VTE, the risk of bleeding increases with the extent of the cancer. In one study, the cancer patient's bleeding rate was high across different INR levels. In contrast, the bleeding rate in patients without cancer was increased only when INR values were greater than 4.5.

Because cancer patients are at higher risk for VTE they should be treated aggressively, but this increases the risk of bleeding. Is there a solution to this issue?

Low molecular weight heparins (LMWHs) in full doses for the first month of treatment, followed by a dose ranging from 50% to 75% of the initial regimen, have the potential to provide more effective anticoagulation in cancer patients with venous thrombosis than the conventional treatment, and they are not associated with an increased hemorrhagic risk, even in patients with disseminated cancer. (With respect to the dosing when using LMWH alone, many hematologists feel that it should be given at full therapeutic dose throughout the treatment course).

In addition, LMWHs provide an anticoagulation that is easier to administer, more convenient with flexible dosing, and is not influenced by nutrition problems or liver impairment.

Because LMWHs are expensive and long term use is associated with osteoporosis, and because the rate of recurrent VTE and bleeding complications exceeds that of non-cancer patients only in those with advanced disease, warfarin treatment is still appropriate in many cancer patients.

It has been demonstrated that the risk of recurrent VTE, following discontinuation of anticoagulants is twice as high in cancer patients as in non cancer patients. Therefore, provided there is no contraindication, cancer patients should be continued on anticoagulant medications until they are cancer free, which in many cases means until the end of their lives.

Patients who have recurrent VTE while on oral anticoagulation present another problem. If the INR is suboptimal, the patient can be treated with heparin until the INR is raised to 2-3. If the patient is already in the therapeutic range of 2-3, options would be to increase the warfarin dosage to attain an INR of 3-3.5 (not the standard option), switch to subcutaneous standard heparin to maintain a therapeutic APTT, or switch to once daily weight based LMWH. The latter is the choice of many experts in the field.

A patient already receiving once-daily weight-based LMWH who has a recurrent event presents another sort of problem. If the patient is not receiving full dose therapy, the dose can be increased. If the patient is already on full dose therapy, an option may be to slightly increase the dose. However, a hematology consult would be appropriate in this situation.

It is of interest to note that several studies on the use of LMWH in cancer patients have demonstrated lower rates of cancer mortality. The reason for this is not clear, but perhaps LMWH interferes in some way with tumor growth and metastasis. Further study of this phenomenon is underway.

- John Hickey

Thanks to Dr. Andrea Kew, Staff Hematologist at the Queen Elizabeth 2 Healthsciences Centre in Halifax, Nova Scotia for reviewing the draft copy of this article.

1. Barbara A. Hutten, Martin H. Prins, Michael Gent, Jeff Ginsberg, Jan G. P. Tijssen, Harry R. Büller 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 JCO Sep 17 2000: 3078-3083. (Level 3 evidence)
 
2. Cosmi B, Palareti G, Moia M, Carpenedo M, Pengo V, Biasiolo A, Rampazzo P, Morstabilini G, Testa S. A comparison of the safety and efficacy of oral anticoagulation for the treatment of venous thromboembolic disease in patients with or without malignancy. Thromb Haemost. 2000 Nov;84(5):805-10. (Level 3 evidence)
 
3. Prandoni P, How I treat venous thromboembolism in patients with cancer. Blood. 2005 Dec 15;106(13):4027-33. Epub 2005 Aug 2. (Level 5 evidence - Review article)
 
4. Klerk CP, Smorenburg SM, Otten HM, Lensing AW, Prins MH, Piovella F, Prandoni P, Bos MM, Richel DJ, van Tienhoven G, Buller HR.The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol. 2005 Apr 1;23(10):2130-5. Epub 2005 Feb 7 (Level 1 evidence)
 
5. Kakkar AK, Levine MN, Kadziola Z, Lemoine NR, Low V, Patel HK, Rustin G, Thomas M, Quigley M, Williamson RC. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol. 2004 May 15;22(10):1944-8. (Level 1 evidence)
 
6. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349: 146-153.68. (Level 1 evidence)
 
7. Meyer G, Marjanovic Z, Valcke J, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer. Arch Intern Med. 2002;162:1729-1735 (Level 1 evidence)

You can search for abstracts of the above references by following this link: PubMed