Lawrence LK Leung, MD
Stephen A Landaw, MD, PhD
INTRODUCTION — Patients with malignancy are in a hypercoagulable state. The spectrum of hemostatic abnormalities ranges from abnormal coagulation tests in the absence of clinical manifestations to massive, fatal venous thromboembolism (VTE).
The treatment of VTE in patients with malignancy will be discussed here. Prevention of VTE in patients with malignancy is discussed separately. (See “Hypercoagulable disorders associated with malignancy”, section on ‘Prevention of VTE’.)
OVERVIEW — Treatment of VTE with anticoagulants in cancer patients is associated with both benefit and a high rate of complications [1-8]. This was illustrated in a retrospective analysis of 1303 patients (264 with malignancy) in two randomized trials . The study evaluated the incidence of recurrent VTE and major bleeding with respect to the presence of malignancy and the achieved level of anticoagulation during a three-month period of treatment with oral anticoagulation. The following observations were made:
- The overall incidence of recurrent VTE was three times higher, and that of major bleeding 6.5 times higher, among those with malignancy.
- In the patients with malignancy, the incidence of recurrent VTE was 2.8 times higher in patients who were not adequately anticoagulated (ie, INR <2.0).
Similar conclusions were reached in two prospective studies [4,5]. In one, 842 patients with symptomatic DVT were treated with conventional anticoagulation; 21 percent had underlying malignancy. The incidences of recurrent thromboembolism and major bleeding during anticoagulant therapy were significantly higher in the patients with cancer, with relative risks of 3.2 and 2.2, respectively . Recurrence of DVT and bleeding were both directly related to the stage of the malignancy, occurred predominantly during the first month of treatment, and could not be explained by over- or under-anticoagulation.
In a study of 3805 cancer patients receiving anticoagulation for an index VTE event, 156 (4.1 percent) had major bleeding during the first three months of follow-up . On multivariate analysis, significant risk factors for bleeding included immobilization, presence of metastases, recent bleeding, and creatinine clearance <30 mL/min.
LMW HEPARIN VERSUS WARFARIN
Overview — The decision to anticoagulate a patient with cancer, VTE, and a limited life expectancy can be difficult because of the need for close laboratory monitoring if warfarin is used, as well as the high risks of recurrent VTE, bleeding, and death.
There are a number of theoretical reasons why heparin-containing products might be more effective than warfarin for this complication, which may or may not be associated with the anticoagulant properties of the heparins [10,11]. (See “Hypercoagulable disorders associated with malignancy”, section on ‘Mucin’.)
Only one major randomized clinical trial (the CLOT trial)  has convincingly shown that the use of long-term LMW heparin is more effective than warfarin in reducing the incidence of recurrent VTE in cancer patients without significantly increasing the risk of bleeding. Some of these studies are described below.
CLOT trial — A multicenter, international, randomized clinical trial (CLOT trial) compared six months of treatment with either dalteparin (200 international units/kg SQ once per day for the first month, followed by 150 international units/kg for the remaining five months) or warfarin (target INR 2.0 to 3.0) in 672 patients with cancer and acute symptomatic VTE . Dalteparin therapy was associated with a significant reduction in the cumulative rate of recurrent VTE at six months (9 versus 17 percent, hazard ratio 0.48, 95% CI 0.30-0.77).
Most of the recurrent thromboembolic events occurred during the first two months of therapy in both treatment groups. There were no significant differences in the rates of major bleeding (6 versus 4 percent), any bleeding (14 versus 19 percent), or overall mortality at six months (39 versus 41 percent) between the dalteparin and warfarin arms, respectively.
Based on the results of the CLOT trial, dalteparin (Fragmin®) was approved to reduce the recurrence of symptomatic VTE in patients with cancer. The recommended dose regimen is 200 international units/kg once/day SQ for the first month followed by 150 international units/kg SQ once/day for the subsequent five months, not to exceed a daily dose of 18,000 international units. No monitoring of blood anticoagulation tests is recommended or required for this usage [13,14].
Other trials — The CANTHANOX trial compared three months of therapy with either warfarin or the LMW heparin enoxaparin in cancer patients with proximal DVT, PE, or both . All patients received initial treatment with therapeutic doses of enoxaparin (1.5 mg/kg once daily for at least four days) and were randomly assigned to either continue enoxaparin at the same dose or to receive warfarin therapy. After 147 patients were accrued, the study was terminated early because of poor recruitment. Approximately one-half of the study patients had metastatic malignancy at randomization; these patients were equally distributed between the two treatment arms.
At three months, 15 of 75 patients (20 percent) in the warfarin arm had reached a primary endpoint of treatment failure (ie, symptomatic, recurrent VTE and/or major bleeding) compared with 7 of the 71 patients (10 percent) assigned to enoxaparin, a difference that did not reach statistical significance. The majority of the primary outcome events were major bleeding, reported in 12 and five patients, respectively. Of these bleeding events, six were fatal; all occurred in the warfarin treatment arm. The number of patients with recurrent VTE was similar in the enoxaparin and warfarin arms. The investigators concluded that warfarin was associated with a high bleeding risk in cancer patients with VTE and that prolonged treatment with LMWH may be as effective as and safer than oral anticoagulant therapy.
Meta-analyses — A number of meta-analyses have explored the effect of anticoagulation on VTE occurrence or recurrence, survival, and side effects (eg, bleeding, thrombocytopenia) in cancer patients with or without a prior episode of VTE [16-21].
- A 2008 Cochrane review of results in six randomized controlled trials in cancer patients receiving long-term treatment for VTE found no statistically significant survival benefit for LMW heparin over oral anticoagulation (vitamin K antagonists), a statistically significant reduction in VTE, and no significant difference in bleeding outcomes .
EFFECT ON SURVIVAL — Primary analysis of the data from the CLOT trial of cancer patients with idiopathic VTE showed no difference in survival with chronic LMW heparin compared with warfarin . A post-hoc analysis of the data indicated that, in patients with metastatic disease at initial presentation, there was no observable difference in mortality between the two treatment groups (72 versus 69 percent) . However, treatment with LMW heparin, as compared with warfarin, significantly reduced mortality at 12 months in the subgroup of patients without observable metastatic disease at initial presentation (20 versus 36 percent, hazard ratio 0.50, 95% CI 0.27-0.95).
This latter observation is consistent with results in three other trials (including the FAMOUS trial), in which the use of LMW heparin in patients without venous thromboembolism was associated with improved survival in those with a relatively good prognosis, and no improvement in survival in those with a poor prognosis or advanced disease [23-25]. The survival benefit in these trials persisted beyond the time of administration of LMW heparin [22-24], suggesting that LMW heparin may have a beneficial effect on tumor biology.
MANAGEMENT OF RECURRENT VTE — In the CLOT trial, 9 to 17 percent of cancer patients developed recurrent VTE over six months of follow-up, despite treatment with LMW heparin or a vitamin K antagonist (VKA), with a mortality of 40 percent . Management of these patients is problematic, with suggested options including insertion of an inferior vena cava filter or switching anticoagulation from a VKA to LMW heparin .
A retrospective study evaluated the effectiveness of escalating the dose of LMW heparin in patients with active cancer who developed an objectively documented episode of recurrent VTE while already receiving anticoagulation. Results included :
- Forty-seven patients were receiving LMW heparin. Of these, 15, 24, and 8 were receiving therapeutic dose (eg, dalteparin 200 U/kg once daily, tinzaparin 175 U/kg once daily, enoxaparin 1 mg/kg twice daily, or enoxaparin 1.5 mg/kg once daily), maintenance dose (75 to 80 percent of the therapeutic dose), or low dose (<75 percent of the therapeutic dose) therapy, respectively.Thirty-two of the 47 patients had their LMW heparin increased to a therapeutic dose; the 15 patients who had already been receiving a therapeutic dose received 120 percent of a therapeutic dose.
- Twenty-three patients were receiving a VKA. Of these, 11 and 8 had therapeutic (eg, INR >2.0) or subtherapeutic INR levels, respectively. The INR was not known for four patients. All of these patients were subsequently given a therapeutic dose of LMW heparin.
- Six patients (8.6 percent) had a second recurrent episode of VTE during the three-month follow-up period, at an event rate of 9.9/100 patient-years and a median time between the index and the second recurrent episode of 1.9 months (range: 0.6 to 3 months).All six were treated by increasing the weight-adjusted dose of LMW heparin by 20 to 25 percent for at least four weeks, and one also had an IVC filter placed. None of these patients had a further recurrent VTE event during the three-month follow-up period.
- Three patients had bleeding complications after their index episode of recurrent VTE. One patient with a malignant brain tumor had an intracranial bleed after the LMW heparin was increased to a therapeutic dose. Two had a minor bleeding episode while receiving therapeutic LMW heparin. Deaths on this study were not related to either recurrent VTE or bleeding.
Larger, prospective studies with longer follow-up are required before the safety and efficacy of dose escalation with LMW heparin for cancer patients with recurrent VTE can be adequately assessed.
FUTURE STUDIES — Many questions remain regarding optimal anticoagulant therapy for patients with malignancy. More studies are required to investigate the optimal dose/schedule of LMW heparin and duration of treatment in this population, including the use of anticoagulation in hospice settings .
Values and preferences — Because of the above-noted questions, as well as the fact that the cost of long-term prophylaxis for recurrent VTE with LMW heparin exceeds that of the vitamin K antagonists, the use of LMW heparin, as suggested below, should not be generalized to all patients with malignancy. Given the many issues involved in this decision (table 1), including patient values and preferences, possible out-of-pocket expenses, and potential side effects, warfarin is a reasonable choice for selected patients [13,29-31]. The CLOT trial included primarily ambulatory cancer patients with symptomatic VTE in the absence of other risk factors (eg, recent surgery, hospitalization, clots in association with central venous catheters); the presence of such concurrent risk factors could lead to a lower on-treatment recurrence risk with warfarin than was observed in the CLOT trial.
RECOMMENDATIONS — The following recommendations are consistent with the 2007 guidelines from the American Society of Clinical Oncology (ASCO), the 2007 clinical practice guidelines of the American College of Physicians and the American Academy of Family Physicians, the 2008 NCCN Guidelines, and the 2008 ACCP Guidelines [13,20,26,29,30,32-41].
- Anticoagulation for prophylaxis against recurrent VTE should generally be avoided if there is active bleeding and/or there are other contraindications to anticoagulant use (eg, recent surgery, pre-existing bleeding diathesis, platelet count <50,000/microL, coagulopathy) [26,30]. When anticoagulation is contraindicated, one treatment option is insertion of an inferior vena cava filter. (See “Treatment of lower extremity deep vein thrombosis”, section on ‘Inferior vena cava filter’.)
- For patients with malignancy, a reasonable quality of life and life expectancy, and venous thromboembolism, we suggest initial treatment with LMW heparin over the use of oral anticoagulants (Grade 2A). This was a Grade 1A recommendation in the 2008 ACCP Guidelines but has been down-graded to a Grade 2A suggestion since such patients may place a higher value on avoiding daily injections, and would thus prefer oral anticoagulation. (See ‘Values and preferences’ above.)Accordingly, a reasonable plan, and one that has been suggested in the 2008 ACCP Guidelines, is to initiate treatment with LMW heparin for the first three to six months. Because the risk of recurrent VTE is unacceptably high in patients with active cancer who stop anticoagulant therapy, we suggest that subsequent treatment with either LMW heparin or warfarin be given indefinitely or until the cancer is resolved (Grade 2C).It is advisable to frequently re-evaluate the risk-benefit ratio of ongoing anticoagulant therapy in individual patients, taking into consideration the overall clinical status of the patient, including the quality of life and life expectancy.
- Anticoagulation for VTE in patients with primary or secondary brain tumors is controversial and is discussed in detail separately. (See “Anticoagulant and antiplatelet therapy in patients with brain tumors”.)
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