A Randomized Double-Blind Placebo-Controlled Study on Nadroparin for Prophylaxis of Thromboembolic Events in Cancer Patients Receiving Chemotherapy: The PROTECHT Study

Abstract

Abstract Background: Patients receiving chemotherapy (CHT) for cancer are at increased risk for thromboembolic events but clinical trials are required before any recommendations can be made about the use of antithrombotic prophylaxis in these patients. Patients and methods: A placebo-controlled, double-blind, multicenter, clinical outcome-based study (PROTECHT) was designed to evaluate the efficacy of the low molecular weight heparin nadroparin for prophylaxis of thromboembolic events in cancer patients receiving CHT. Patients with metastatic or locally advanced lung, breast, gastrointestinal (stomach, colon, rectum, pancreas), ovary or head and neck cancer with an ECOG performance status ≤2 were included in the study. Patients on adjuvant or neo-adjuvant CHT were excluded from the study. Eligible patients were randomized in a 2:1 ratio to receive subcutaneous injections of nadroparin, 3,800 anti-Xa IU once daily, or placebo. Treatment was started on the day of initiation of CHT (the first cycle or a new course) and planned for the overall duration of CHT or up to a maximum of 4 months. The primary study end-point was the composite of clinically overt venous or arterial thromboembolic events (deep vein thrombosis of the lower and upper limbs, visceral and cerebral venous thrombosis, pulmonary embolism, acute myocardial infarction, ischemic stroke, acute peripheral arterial thromboembolism, unexplained death of possible thromboembolic origin). Major bleeding was the main safety outcome measure. All study outcome events were evaluated by an independent Adjudication Committee unaware of treatment allocation. The results of one interim analysis of efficacy and two interim analyses of safety were reviewed by an independent Data and Safety Board. In the primary efficacy analysis the p value was adjusted for the interim analysis of efficacy. Results: The two treatment study groups were well balanced for demographic characteristics, cancer site and staging, CHT regimen and thromboembolic risk factors. The average study treatment duration was 90.3±41.2 and 93.9±39.8 days in the nadroparin and placebo groups, respectively. Overall, 1166 patients were randomized and 1150 received at least one dose of the study treatment (primary efficacy analysis and safety population). Cancer distribution was as follows: lung 279 patients (24.3%), colon 235 (20.4%), breast 165 (14.3%), ovary 143 (12.4%), stomach 98 (8.5%), rectum 87 (7.6%), pancreas 53 (4.6%), head and neck 36 (3.1%) and other 54 (4.7%). Sixteen of the 769 patients treated with nadroparin (2.1%) and 15 of the 381 patients treated with placebo (3.9%) had a thromboembolic event (interim-adjusted p value = 0.033, relative risk reduction 47.2%, NNT = 53.8). Venous thromboembolism accounted for 11 events in both the nadroparin and placebo patients. Fifteen of the thromboembolic events occurred in patients with lung cancer (4.0% and 8.8% in nadroparin and placebo patients, respectively; NNT = 22.7). Pancreatic cancer was associated with an overall rate of thromboembolic events of 7.5%. Five patients in the nadroparin group (0.7%) and none in the placebo group suffered a major bleeding (p= 0.177, NNH = 153.8). The incidence of minor bleeding was similar in the two treatment groups: 77 events in 57 patients (7.4%) and 38 events in 30 patients (7.9%) for nadroparin or placebo respectively. Conclusions: We conclude that nadroparin reduces the incidence of thromboembolic events in cancer patients receiving CHT. Future confirmatory studies should be focused on patients at high thromboembolic risk such as those with lung and pancreatic cancer.