Treating Venous Thromboembolism in Patients With Cancer

Caroline Piatek; Casey L O'Connell; Howard A Liebman

Disclosures

Expert Rev Hematol. 2012;5(2):201-209. 

In This Article

Treatment

Initial Treatment

LMWH is the preferred agent for the initial and long-term treatment of VTE in patients with cancer. This recommendation is primarily based on the findings of the CLOT study. This study, which included 676 patients, is the largest randomized clinical trial comparing an LMWH to vitamin K antagonists (VKA). Patients assigned to the VKA (warfarin or acenocoumarol) group initially received dalteparin for 5–7 days and continued with a VKA for 6 months with a target INR of 2.5 (therapeutic range 2.0–3.0). Patients assigned to the LMWH group were given dalteparin 200 IU/kg for the first month and then the dose was reduced to ~150 IU/kg for the remaining 5 months. Over the 6-month follow-up period, 9% of patients in the dalteparin group experienced a symptomatic recurrent VTE compared with 17% of patients in the VKA group, with a relative risk reduction of 52% (hazard ratio [HR]: 0.48; p = 0.002). There was no significant difference between the two groups in terms of bleeding complications or mortality. The need for dalteparin dose reduction after 1 month as well as in the setting of thrombocytopenia and renal insufficiency remains unclear. A total of 90% of patients enrolled had solid tumors in various sites including breast, colorectal, lung, genitourinary, gynecologic, pancreas and brain. A total of 14% of the patients in the dalteparin arm and 16% of the patients in the VKA arm with solid tumors were listed as 'other' for cancer type. The remaining 10% of patients enrolled had hematologic malignancies.[43]

Tinzaparin has also been compared with warfarin in a randomized treatment trial of VTE in cancer patients. In a multicenter, open-label, randomized trial, 3-month therapy with tinzaparin was compared with initial unfractionated heparin (UFH) followed by warfarin in 200 cancer patients with VTE. At 12 months, the rate of recurrent VTE in the tinzaparin-treated group was statistically lower than that of the warfarin-treated group (7 vs 16%; p = 0.044; risk ratio: 0.44). However, at the end of the 3 months of active treatment, there was no statistical difference in the VTE recurrence rates between the tinzaparin and warfarin arms suggesting only equivalence during active treatment.[44]

Unlike dalteparin, enoxaparin has not been demonstrated to be superior to warfarin. However, the enoxaparin studies were relatively small and may not have been adequately powered to detect a statistical difference. In one study comparing 3-month therapy with enoxaparin sodium (1.5 mg/kg subcutaneously once daily) with warfarin in 146 patients with cancer-associated thrombosis, the enoxaparin arm did not achieve statistical superiority for the combined outcome of major bleeding or recurrent VTE within 3 months (p = 0.09). The rate of recurrent VTE in the enoxaparin group was 2.9% compared with 4.2% in the warfarin group.[45] In another study, which compared 3-month therapy with enoxaparin alone versus initial enoxaparin followed by warfarin in the secondary prevention of VTE in 122 cancer patients, no trends or significance could be determined regarding recurrent VTE between treatment groups because of the low rate of recurrent VTE in the study (four events). The rate of recurrence in the enoxaparin group was 6.5% compared with 10% in warfarin group.[46]

A recent meta-analysis compared LMWH and oral VKA in the long-term treatment of cancer-associated thrombosis. It included the five randomized, controlled trials, including four of the above-mentioned studies by Lee et al., Hull et al., Meyer et al., Deitcher et al. and one additional study with nadroparin by Lopez-Beret et al.[43–48] In this meta-analysis, LMWH was found to be superior to VKA in the secondary prevention of VTE with relative risk reduction of approximately 50% (relative risk: 0.53; p = 0.007). However, LMWHs have not been shown to reduce the risk of fatal VTE compared with VKA therapy.[48]

A recent Cochrane review on initial treatment of VTE with anticoagulants in cancer patients found a statistically significant mortality reduction with the use of LMWH compared with UFH, but there was insufficient evidence to demonstrate superiority in reducing the recurrence of VTE.[49] It should still be noted that even with the use of LMWH treatment, as many as 10% of cancer patients will have a recurrent or progressive VTE during a 6-month treatment period.

Cost of VTE Treatment

The major limitation of LMWH is the associated cost. A Canadian pharmacoeconomic analysis was done based on the CLOT data to measure the economic value of dalteparin for long-term VTE treatment. The overall costs included the costs associated with drug acquisition, monitoring of therapy, adverse events associated with anticoagulation and recurrent VTE. Costs were calculated for the 6-month follow-up period of the original study, with a mean duration of 126.3 days of dalteparin in the experimental group and 8 days in the VKA group. Patients randomized to VKA therapy received treatment for a mean of 116.9 days. The overall costs were lower with VKA than dalteparin, with the cost primarily driven by drug acquisition (Can$2003 vs 4262; p < 0.001). When the patient's quality of life was also included in the analysis, dalteparin therapy was considered to be economically acceptable.[50]

Duration of VTE Treatment

Because cancer is an ongoing risk factor for VTE, the guidelines of the American College of Chest Physicians (ACCP) and ASCO recommend indefinite VTE treatment "as long as the cancer is active".[25,51] However, the optimal duration of anticoagulation beyond the initial 6-month treatment period is not well studied in cancer patients. Factors such as cost, injection-related discomfort and disposal of the medication may significantly influence patients' willingness to continue with LMWH as opposed to an oral VKA in the long-term treatment of VTE.

Recurrent VTE

ASCO guidelines recommend that patients who develop recurrent VTE despite adequate anticoagulant therapy should be treated with an anticoagulant from a different drug class. Alternatively, according to ASCO guidelines, an inferior vena cava (IVC) filter can be placed, but data supporting the use of IVC filters in cancer patients are lacking.[25] A recent study investigated the use of dose escalation of LMWH in cancer patients with recurrent VTE, suggesting that a higher dose of LMWH may be effective in cases where standard, weight-adjusted doses of LMWH or a VKA have failed.[52] An analysis of 93 patients enrolled in a single-arm trial of tinzaparin for the treatment of cancer-related VTE found a relative risk of 12.2 (95% CI: 1.4–143.8; two-sided p = 0.0088) for recurrent thrombosis when patients had a 1-month D-dimer higher than the pretreatment level.[53]

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