University of Michigan
Department of Pediatrics
Evidence-Based Pediatrics Web Site

Question

• Is coumadin safe and effective for venothrombotic events in children and adolescents?

Clinical Bottom Lines

1. There are currently well developed, well studied guidelines for antithrombotic therapy in adults based off of clinical trials, but this is not the case in the pediatric population.¹
2. Current antithrombotic therapy in children is extrapolated from adult studies. This can problematic as age significantly influences the maturation of the hemostatic system and therefore its interactions with different anticoagulants.
3. Oral anticoagulation can be problematic in the pediatric population due to concurrent medication use, erratic diets, and difficulty monitoring.
4. LMWH involves less monitoring, but involves injection and is also more expensive.
5. There was no difference in primary efficacy outcome of recurrent VTE at 3 months (p=0.677) and 6 months (p=0.435), and no difference in primary safety outcomes of major bleeding (p=0.435) or minor bleeding (p=0.053).
6. However, the study was limited by sample size (n=78) as it was terminated early.

Summary of Key Evidence

1. Open label, multi-center, randomized control trial
2. Inclusion criteria: children ≥ 60 days and ≤ 18 years old with DVR confirmed by either venography or Doppler US or PE confirmed by VQ scan or pulmonary angiogram.
3. Exclusion criteria: DVT in CNS, expected lack of compliance, treatment with high dose UFH, LMWH, or OA for more than 48hr at the time of randomization, a documented history of HIT, marked thrombocytopenia (plts <20K), active bleeding or high risk of bleeding with use of anticoagulation therapy, known contraindication to anticoagulation, severe untreated HTN (2x upper limit for normal for age sustained over 24hrs), severe renal dysfunction, severe hepatic disease, bacterial endocarditis, pregnancy, currently lactating, failure to provide informed consent.
4. Data collected at 3 months and 6 months
5. Primary efficacy outcome: Recurrent VTE at 3 months or 6 months
6. Primary safety outcome: Major (clinically significant overt bleeding that required immediate transfusion or any retroperitoneal, intracranial or intra-articular bleeding) or minor (bruising, oozing) bleeding.
7. Results: No statistically significant difference in efficacy or safety outcomes between OA and LMWH.
8. Power of study was poor as sample size was small and study terminated early.

Additional Comments

• Because the study was under powered and also a ‘negative’ study, the reader should be concerned about the possibility of a type II error. Type II error occurs when the study states there is no difference between the two groups, when in truth there really is a difference.
• This study is important as there are limited studies looking at the use of anticoagulation in children. Current therapy protocols are based on adult clinical trials and preference of pediatric hematologists.
• A larger study needs to be done to better compare different anticoagulation therapies.

Citation

1. Massicotte P, et al. 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. Thrombosis Research 2003;109:85-92.
2. Warfarin anticoagulation in children made easier. Thrombosis Research 2006;118:667-669.
3. Chan AK, et al. Venous thrombosis in children. Journal of Thrombosis and Haemostatsis 2003;1:143-1455.
4. Andrew M, et al. Guidelines for antithrombotic therapy in pediatric patients. J. Pediatr 1998;132:575-588.

CAT Author: Rebecca M. Northway, MD

CAT Appraisers: Robert Schumacher, MD

Date appraised: April 27, 2007