Elsevier

The Lancet Oncology

Volume 10, Issue 10, October 2009, Pages 943-949
The Lancet Oncology

Fast track — Articles
Nadroparin 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

https://doi.org/10.1016/S1470-2045(09)70232-3Get rights and content

Summary

Background

Clinical trials are needed to assess the clinical benefit of antithrombotic prophylaxis in patients with cancer who are receiving chemotherapy, since these patients are at an increased risk of developing a thromboembolism. We did a trial to assess the clinical benefit 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.

Methods

Between October, 2003, and May, 2007, ambulatory patients with lung, gastrointestinal, pancreatic, breast, ovarian, or head and neck cancer were randomly assigned in a double-blind manner to receive subcutaneous injections of nadroparin (3800 IU anti-Xa once a day, n=779) or placebo (n=387), in a 2:1 ratio. Study treatment was given for the duration of chemotherapy up to a maximum of 4 months. The primary study outcome was the composite of symptomatic venous or arterial thromboembolic events, as assessed by an independent adjudication committee. All randomised patients who received at least one dose of study treatment were included in the efficacy and safety analyses (modified intention-to-treat population). The study is registered with ClinicalTrials.gov, NCT 00951574.

Findings

1150 patients were included in the primary efficacy and safety analyses: 769 patients in the nadroparin group and 381 patients in the placebo group. 15 (2·0%) of 769 patients treated with nadroparin and 15 (3·9%) of 381 patients treated with placebo had a thromboembolic event (single-sided p=0·02). Five (0·7%) of 769 patients in the nadroparin group and no patients in the placebo group had a major bleeding event (two-sided p=0·18). The incidences of minor bleeding were 7·4% (57 of 769) with nadroparin and 7·9% (30 of 381) with placebo. There were 121 (15·7%) serious adverse events in the nadroparin goup and 67 (17·6%) serious adverse events in the placebo group.

Interpretation

Nadroparin reduces the incidence of thromboembolic events in ambulatory patients with metastatic or locally advanced cancer who are receiving chemotherapy. Future studies should focus on patients who are at a high risk for thromboembolic events.

Funding

Italfarmaco SpA, Milan, Italy.

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.

Section snippets

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

References (32)

  • HT Sorensen et al.

    Prognosis of cancers associated with venous thromboembolism

    N Engl J Med

    (2000)
  • RL Bick

    Cancer-associated thrombosis

    N Engl J Med

    (2003)
  • A Falanga

    The incidence and risk of venous thromboembolism associated with cancer and non-surgical treatment

    Cancer Invest

    (2009)
  • HM Otten et al.

    Symptomatic venous thromboembolism in cancer patients treated with chemotherapy: an underestimated phenomenon

    Arch Intern Med

    (2004)
  • AA Khorana et al.

    Risk factors for chemotherapy-associated venous thromboembolism in prospective observational study

    Cancer

    (2005)
  • AA Khorana et al.

    Frequency, risk factors and trends for venous thromboembolism among hospitalized cancer patients

    Cancer

    (2007)
  • Cited by (0)

    For full list of investigators see webappendix

    View full text