Risk of Venous Thromboembolism with Thalidomide in Cancer Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract Background: Thalidomide, an oral angiogenesis inhibitor with immunomodulatory activity, is effective in the treatment of multiple myeloma, and also undergoing evaluation for other malignancies. The use of thalidomide is associated with significant side effects, including venous thromboembolism (VTE). Currently the overall risk of VTE with thalidomide is not well-defined. Objective: We conducted a systematic review and meta-analysis of published randomized controlled trials (RCT) to determine the risk of VTE with thalidomide in cancer patients, and assess whether it is affected by anti-thrombosis prophylaxis. Methods: We searched databases including PUBMED, the Web of Science (January, 1966–July, 2008), and abstracts presented at recent American Society of Clinical Oncology and American Society of Hematology conferences to identify relevant studies. Eligible studies included prospective RCT in which a standard anti-cancer therapy or placebo was employed with or without thalidomide with available data on VTE for analysis. The summary incidence, relative risk (RR), and 95% confidence interval (CI) were calculated using a random- or fixed-effects model based on the heterogeneity of the included studies. Results: From 17 RCTs, a total of 3977 patients with multiple myeloma and a variety of solid tumors (prostate, breast, renal cell, melanoma, ovarian) were included for analysis. The overall incidence of VTE was 11.7% (95% CI: 8.1–16.5%). Patients treated with thalidomide had a significantly increased risk of VTE with a RR of 2.4 (95% CI: 1.9–3.0, p<0.001) when compared to controls. The risk was significantly decreased with prophylaxis from a RR of 3.5 (95%CI: 2.5–4.9, p<0.001) in the absence of prophylaxis to 1.9 (95%CI: 1.4–2.5, p<0.001) in the presence of prophylaxis. The risk of VTE may vary with tumor types; in patients with multiple myeloma, the incidence and RR were 15.7% (95%CI: 10.9–22.1) and 3.1 (95%CI: 2.1–4.5, p<0.001) respectively; while for patients with solid tumors, the incidence and RR were 5.3% (95% CI 2.1–12.8) and 3.5 (95% CI: 1.1–10.6, p=0.028) respectively. Conclusion: Thalidomide therapy is associated with a significantly increased risk of VTE in cancer patients. The risk varies with anti-thrombosis prophylaxis and tumor type. It is strongly recommended to have surveillance for VTE in all patients receiving thalidomide, and prophylaxis to reduce the risk in patients with multiple myeloma.

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Use Of Novel Oral Anticoagulants For Treatment Of Venous Thromboembolism (VTE) In Patients With Malignancy: Meta-Analysis Of Randomized Controlled Trials

Blood ◽

10.1182/blood.v122.21.1150.1150 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1150-1150

Author(s):

Bo Jiang ◽

Qasim Malik ◽

Louis Romel Crevecoeur

Keyword(s):

Venous Thromboembolism ◽

Randomized Controlled Trials ◽

Cancer Patients ◽

Meta Analysis ◽

Oral Anticoagulants ◽

Novel Oral Anticoagulants ◽

Controlled Trials ◽

Current Standard ◽

Randomized Controlled ◽

Increased Risk

Abstract Use of Novel oral anticoagulants for treatment of venous thromboembolism (VTE) in patients with malignancy: meta-analysis of randomized controlled trials Background Venous thromboembolism (VTE) is a frequent complication of cancers. Patients with cancer have at least a 6 fold increased risk for VTE compared to those without cancer, and the diagnosis of VTE in cancer patient is associated with a 2-4 fold decreased survival during the first year. The mainstays of anticoagulant treatment in cancer patients remain unfractionated heparin, LMWH, and the Vitamin K antagonists (VKAs), with current guideline favoring the use of LMWH. Novel oral anticoagulants (NOAs) that directly inhibit factor Xa and thrombin, including dabigatran, rivaroxaban, and apixaban, represents a milestone in the prevention and treatment of VTE. However, there have been no clinical trials to test the efficacy of NOAs in cancer patients, therefore, use of these agents in cancer population is an extrapolation of published results with general population. Objectives Determine the efficacy of novel oral anticoagulants (thrombin inhibitor; dabigatran, and direct factor Xa inhibitors; rivaroxaban and apixaban) in VTE treatment in patients with cancer. Data source A systematic review was conducted using MEDLINE and EMBASE up to July 2013. Key words used included venous thromboembolism, pulmonary embolism, deep venous thrombosis, cancer, dabigatran, rivaroxaban, and apixaban. Due to the fact that no randomized controlled trials (RCTs) in cancer population, we combined data that were extracted from major RCTs that include cancer patients and performed a sub-group analysis. Results Three randomized controlled trials (RCTs) were reviewed, and a total of 550 patients with cancers were analyzed. NOAs are not inferior to the current standard anticoagulant therapy with enoxaparin followed by an adjusted-dose vitamin K antagonist, to prevent symptomatic recurrent venous thromboembolism. Odd ratio (OR) is 0.988 (95% CI, 0.51-1.94). There is no significant heterogeneity. The major bleeding events were not analyzed due to lack of sub-group data in the trials. Conclusion Cancer patients have different hemodynamics and unique features that make the treatment of VTE challenging. These includes: tumor-associated pro-coagulant, venous stasis and endothelial damage from chemotherapy and catheters, an increased risk of anticoagulant-related bleeding, and the complexity of anticoagulant control because of the occurrence of urgent procedures. The development of NOAs provided new modalities to treat VTEs in cancer patients, as it showed that NOAs is non-inferior to the current standard anticoagulant therapy. However, large scale randomized controlled trials specifically targeted cancer patients are needed. Disclosures: No relevant conflicts of interest to declare.

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