Full Length ArticleDalteparin thromboprophylaxis in cancer patients at high risk for venous thromboembolism: A randomized trial
Introduction
Venous thromboembolism (VTE), which includes both deep venous thrombosis (DVT) and pulmonary embolism (PE), is a highly prevalent complication of malignancy. The development of VTE in cancer patients is associated with several adverse consequences including worsened short- and long-term mortality, morbidity, potential hospitalization, need for long-term anticoagulation with attendant bleeding complications and high rates of recurrent VTE [1], [2]. In addition, VTE leads to significant consumption of health care resources; in one study of cancer patients, the adjusted mean incremental all-cause health care costs of VTE were $30,538 per patient [3].
Antithrombotic agents are safe and effective in preventing VTE in a variety of high-risk settings such as post-orthopedic surgery or acutely ill hospitalized medical patients [4], [5], [6], [7], [8], [9], [10], [11], [12]. Multiple randomized trials of thromboprophylaxis have been conducted recently focusing on ambulatory cancer patients receiving systemic therapy. These studies have generally demonstrated efficacy and safety of thromboprophylaxis. However, overall rates of VTE in largely unselected patients with cancer have been low such that absolute rates are only minimally decreased. This has precluded widespread adoption of outpatient prophylaxis in clinical practice. Indeed, routine outpatient thromboprophylaxis in ambulatory patients with cancer is not recommended by current guidelines [13], [14].
Although cancer patients have long been recognized to be high risk for VTE, rates vary widely within the cancer population. In 2008, we developed and validated a risk assessment tool to identify cancer patients at high risk for VTE while receiving systemic therapy, based on five simple clinical and laboratory variables (Table 1) [15]. This risk score has subsequently been externally validated in a multitude of prospective and retrospective cohort studies and is currently the only tool recommended by the American Society of Clinical Oncology guidelines for risk assessment [16], [17], [18]. Dalteparin is an approved low-molecular-weight heparin (LMWH) for the treatment of cancer-associated thrombosis, does not have significant interactions with chemotherapy (unlike warfarin) and has, in prior studies, been effective in prophylaxis of VTE associated with pancreas cancer [19]. We therefore conducted a randomized clinical trial of thromboprophylaxis with dalteparin in cancer patients initiating a new systemic therapy regimen and with a Khorana score of ≥ 3.
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Patients
Eligible patients had to have a histologic diagnosis of malignancy, be at the planned initiation of a new systemic chemotherapy regimen (either initial or after progression on prior chemotherapy), be 18 years of age or older and provide written, informed consent. Patients had to be at high-risk for developing VTE, based on a risk score of ≥ 3 [15]. The main exclusion criteria were active bleeding or high risk for bleeding in the opinion of the investigator; diagnosis of primary brain tumor,
Study population
A total of 117 subjects were enrolled, and 98 were randomized (Supplemental Fig. 1). Baseline characteristics of enrolled and randomized subjects are shown in Table 2. Nineteen enrolled patients were not randomized due to the presence of VTE on initial screening (N = 10), patient withdrawal (N = 5), change in treatment facility (N = 2) or other reasons (N = 2). Of the 98 randomized subjects, the mean age was 59 with 46% female and 54% male. The median Khorana score was 3 in both arms. For all
Discussion
We conducted a randomized trial of primary thromboprophylaxis in patients with malignancy receiving outpatient systemic therapy and considered high risk for VTE, as defined by a previously validated risk assessment tool. Unfortunately, the study did not accrue to its planned sample size and, at time of termination, remained under-powered. Dalteparin prophylaxis was associated with a non-significant 9% absolute risk reduction in VTE but at the expense of a significant increase in clinically
Authorship contributions
All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. A.A. Khorana made substantial contributions to the conception or design of the work; the acquisition, analysis, and interpretation of data for the work; drafting the work and revising it critically for important intellectual content; provided final approval of the version to be published and agreement to be accountable for all aspects of the
Acknowledgments
This study was sponsored by a grant (CWF) from the National Heart, Lung, and Blood Institute (R01HL95109). Dr. Khorana acknowledges additional research support from the National Cancer Institute (K23 CA120587), the Sondra and Stephen Hardis Chair in Oncology Research and the Scott Hamilton CARES Initiative. The authors are grateful for the efforts of members of the Data and Safety Monitoring Committee (Drs. Deepak Sahasrabudhe, Alissa Huston and Ollivier Hyrien) and the Bleeding Committee (Drs.
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