Fast track — ArticlesNadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study
Introduction
Thromboembolic events are common in patients with cancer,1, 2 make patient management more complicated, and are associated with increased mortality.3, 4 Cancer cells can promote the activation of blood coagulation directly by generating thrombin, or indirectly by stimulating endothelial cells and circulating mononuclear cells to synthesise and express several procoagulant factors.5 The risk of thromboembolic events in cancer patients varies according to the type of malignancy and its disease stage, and it is increased by surgical and non-surgical cancer treatments.6 Cancer chemotherapy has been shown to both amplify the prothrombotic effect of cancer cells5 and to damage vessel walls directly, and is increasingly recognised as a risk factor for thromboembolic complications.7, 8
Thromboembolism is a frequent complication in hospitalised and bedridden patients with cancer,9 but fewer data are available for ambulatory patients with cancer. A pivotal study by Levine and colleagues10 showed warfarin prophylaxis was effective at reducing the risk of thromboembolism in patients with advanced breast cancer who were receiving chemotherapy. The clinical benefit was also assessed in patients with advanced lung cancer.11 However, there is a paucity of evidence from randomised studies regarding the clinical benefit of antithrombotic prophylaxis in patients with cancer who are undergoing chemotherapy. Consequently, the most recent guidelines of the American Society of Clinical Oncology12 and the Conference on Antithrombotic Therapy of the American College of Chest Physicians13 state that clinical trials are required before any recommendations can be made about the use of antithrombotic prophylaxis in ambulatory patients receiving chemotherapy for cancer, although the guidelines do recommend antithrombotic prophylaxis in hospitalised and bedridden patients with cancer.
The PROTECHT (PROphylaxis of ThromboEmbolism during CHemoTherapy) was a randomised, placebo-controlled, multicentre study aimed at assessing the efficacy of the low-molecular-weight heparin nadroparin for the prophylaxis of thromboembolic events in ambulatory patients receiving chemotherapy for metastatic or locally advanced solid cancer.
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Patients
Ambulatory patients older than 18 years of age who were receiving chemotherapy for metastatic or locally advanced lung, gastrointestinal (stomach, colon, or rectum), pancreatic, breast, ovarian, or head and neck cancer were recruited to the study at 62 centres across Italy between October, 2003, and May, 2007.
Patients on adjuvant or neoadjuvant chemotherapy were excluded from the study. Other exclusion criteria were: objectively confirmed venous or arterial thromboembolism in the past 3 months;
Results
Between October, 2003, and May, 2007, 1166 patients were recruited to the study at 62 study centres in Italy. 1150 patients received at least one dose of the study treatment and were included in the efficacy and safety analyses (figure 1). Patient characteristics, thromboembolic risk factors, cancer site, and chemotherapy regimens were well balanced between the two treatment groups (Table 1, Table 2).
The median duration of follow-up was 111 and 113 days in the nadroparin and placebo groups,
Discussion
This study shows that the low-molecular-weight heparin nadroparin almost halves the absolute rate of thromboembolic complications in ambulatory patients receiving chemotherapy for cancer (from 3·9% to 2·0%). This reduction in symptomatic outcomes is consistent with reductions attributable to low-molecular-weight heparin in the prevention of venous thromboembolism in several other clinical settings.13 The antithrombotic effect was most evident for deep-vein thrombosis and pulmonary embolism, and
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