Elsevier

Thrombosis Research

Volume 109, Issues 2–3, 25 January 2003, Pages 85-92
Thrombosis Research

Regular Article
An open-label randomized controlled trial of low molecular weight heparin compared to heparin and coumadin for the treatment of venous thromboembolic events in children: the REVIVE trial

https://doi.org/10.1016/S0049-3848(03)00059-8Get rights and content

Abstract

Objective(s): Venous thromboembolic events (VTE) are serious complications in children and for which the standard of care, unfractionated heparin followed by oral anticoagulation (UFH/OA), is problematic. The objective of REVIVE was to compare the efficacy and safety of a low molecular weight heparin (reviparin-sodium) to UFH/OA for the treatment of VTE in children. Study design: This multicenter, open-label study, with blinded central outcome adjudication, randomized patients with objectively confirmed VTE to receive either reviparin-sodium or UFH/OA. Dose adjustments were made using nomograms. The efficacy outcome was based on recurrent VTE and death due to VTE during the 3-month treatment period. The safety outcomes were major bleeding, minor bleeding and death. Due to slow patient accrual, REVIVE was closed prematurely. Results: At 3 months, with reviparin-sodium, 2/36 patients (5.6%) had recurrent VTE or death compared to 4/40 patients (10.0%) receiving UFH/OA (odds ratio=0.53; 95% CI=(0.05, 4.00); Fisher's exact test: 2P=0.677). There were 7 major bleeds, 2/36 (5.6%) in the reviparin-sodium group and 5/40 (12.5%) in UFH/OA group (odds ratio=0.41; 95% confidence interval 0.04, 2.76); Fisher's exact test: P=0.435). There were 5 deaths during the study period, 1 (2.8%) in the reviparin-sodium group and 4 (10.0%) in the UFH/OA group. All five deaths were unrelated to VTE but one was due to an intracranial hemorrhage in the UFH/OA group. Conclusions: Although limited by small sample size, REVIVE provides valuable information on the incidence of recurrent VTE, major bleeding and problematic issues associated with therapy of VTE in children.

Introduction

Increasing numbers of pediatric patients are developing venous thromboembolic events (VTE). These events are secondary complications of the successful treatment of previously lethal primary diseases, which include prematurity, congenital heart disease and cancer. The current standard of care for the treatment of VTE in children consists of unfractionated heparin (UFH) for a period of 7–10 days followed by oral anticoagulation (OA) for approximately 3 months. There are many problematic issues with the use of UFH and OA in children. For UFH, these include variable pharmacokinetics, need for venous access for both administration and monitoring, heparin-induced thrombocytopenia, and osteopenia with long-term use [1], [2], [3]. For OAs, problematic issues include the significant influences of age, diet, medications, and underlying diseases on dosing, which results in the need for frequent monitoring [4]. In addition, osteopenia occurs with long-term use of OAs in children [5]. These problems with conventional anticoagulation provided the rationale for investigations of other anticoagulants in children.

Low molecular weight heparins (LMWH) have several potential advantages over UFH/OAs for the treatment of VTE in children. These advantages include predictable pharmacokinetics, lack of influence of diet, medications or disease on the anticoagulant response, and reduced risk of heparin-induced thrombocytopenia as well as osteopenia [6], [7], [8], [9]. Based upon this information, a randomized controlled trial was conducted to compare LMWH to UFH/OAs for the treatment of VTE in children.

Section snippets

Study design

The REVIVE study was an open-label, multicenter, international randomized controlled trial in which parental consent (or informed consent for older children) was obtained from eligible patients. This study was approved by the Institutional Ethics Committee. They were then randomly assigned by a computer-derived protocol to initially receive 100 IU/kg of reviparin-sodium (Knoll, Germany) or UFH followed by OA therapy. The protocol mandated that the first dose of study medication be given within

Study patients

A total of 168 patients met the inclusion criteria; 60 (35.7%) of these had at least one exclusion criterion present (Table 1). The three main reasons for exclusion were treatment with therapeutic doses of UFH or LMWHs, anticipated lack of compliance and bleeding or risk of bleeding. Of the 108 eligible patients, informed consent was not obtained from 29 (26.9%) patients and for 1 patient the pharmacy was not able to provide the medication within the time restriction. The remaining 78 children

Discussion

REVIVE is the first multicenter, international randomized controlled trial comparing a LMWH, reviparin-sodium to UFH/OAs for the treatment of VTE during childhood. The study was closed early due to slow patient recruitment. Continuing the study to complete sample size would have taken so long that the study results would have been nongeneralizable. Although REVIVE was under-powered due to premature closure, reporting the results of REVIVE is important because of several significant scientific

Acknowledgements

This REVIVE trial was jointly funded by the Medical Research Council of Canada (MRC)/Pharmaceutical Manufacturers Association of Canada (PMAC) Health Program grant #COF-37621 and Knoll.

The authors wish to thank Lu Ann Brooker for editing this manuscript.

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