Randomized Controlled Trial Of Dalteparin For Primary Thromboprophylaxis For Venous Thromboembolism (VTE) In Patients With Advanced Pancreatic Cancer (APC): Risk Factors Predictive Of VTE

Risk of VTE is high in cancer patients, especially, in patients with APC. Treatment with chemotherapy further increases the risk. Purpose of the study was to evaluate the safety and efficacy of primary thromboprophylaxis with dalteparin in reducing the incidence of VTE in APC patients planned to start chemotherapy; and to determine the baseline risk factors/biomarkers predictive of VTE.

Patients with metastatic or locally advanced pancreatic cancer planned to start chemotherapy were randomized 1:1 to dalteparin vs control arms, stratified for the presence of metastasis and central venous catheter (CVC). The treatment arm received dalteparin 5000 U SQ daily for 16 weeks during chemotherapy and the control arm received chemotherapy alone. Bilateral compression ultrasound of the lower extremities was performed at baseline, and during study (weeks-8 and-16). In addition, blood was collected to identify biomarkers such as, plasma D-dimer levels, platelet activation markers (P-selectin), thrombin-antithrombin complex (TAT), prothrombin fragments 1 and 2 (F1+2), and cytokine levels. Univariate and multivariate logistic regression analysis of clinical and laboratory parameters were done to identify risk factors associated with the development of VTE.

Of 87 patients enrolled, 75 were randomized to dalteparin (38 patients) or control (37 patients) arms; 8 did not meet the eligibility criteria (including 6 found positive for incidental VTE on screening ultrasound), and 4 withdrew consents before randomization. There were 41 males and 34 females; with median age 52 (range, 36-77 years). Over half of the patients (55% dalteparin arm and 54% control arm) completed 16 weeks on study. All 75 patients were evaluable for response in an intent-to-treat analysis. During the study, the incidence of VTE was 22% [8/37 patients; 2 pulmonary emboli (PE) and 6 deep vein thrombosis (DVT)] on the control arm as compared to 5% (2/38 patients; both DVT) on the dalteparin arm (p = 0.02).

In the multivariate analysis, baseline plasma levels of D-dimer, ECOG performance status, presence of CVC, and prophylaxis with dalteparin were independent factors predictive of risk for VTE, as shown below.

There was no statistically significant difference in overall survival between the two arms; however, there were higher proportion of patients with elevated baseline D-dimer levels in the dalteparin arm than the control arm (≥ 5000 ng/mL 16% vs 3%). Elevated baseline D-dimer level (≥ 5000 ng/mL) was also predictive of the presence of silent or asymptomatic VTE at screening for study entry (p=0.001), suggesting its potential value in identifying patients with silent VTE. Treatment with dalteparin was well tolerated; the main adverse events included minimal bruising (5/34, 15%), or pain (2/34, 6%) at the injection sites. There were no clinically significant bleeding episodes in the dalteparin arm.

The results of this study showed that the incidence of VTE is very high in patients with APC. Primary thromboprophylaxis with dalteparin was well tolerated and was associated with 75% reduction in the incidence of VTE in ambulatory patients with locally advanced or metastatic cancer while receiving chemotherapy. Baseline risk factors such as elevated D-dimer levels may help identify high risk patients for primary thromboprophylaxis as well as patients with the presence of asymptomatic VTE.

Vadhan-Raj:Eisai: Research Funding. Off Label Use: Fragmin (Dalteparin): Prophylaxis of VTE in ambulatory cancer patients while receiving chemotherapy.