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Low molecular weight heparin for prevention of venous thromboembolism in patients with lower leg immobilization

M Testroote, W Stigter, H Janzing, D Visser

DOI:10.1002/14651858.CD006681

David K. Cundiff, MD
Date received: August 1, 2007
Cite this comment as: http://www.cochranefeedback.com/cf/cda/citation.do?id=9700#9700

The morbidity outcome endpoint is unclear:

“Morbidity - at least one of the following items: asymptomatic venous thrombosis (confirmed by venography or duplex); symptomatic deep venous thrombosis (confirmed by venography or duplex); pulmonary embolism (PE) (confirmed by ventilation-perfusion scan or CT scan); or any combination of these items, as a combined symptomatic venous thromboembolism (VTE) endpoint.”

It appears to mean the primary efficacy endpoint (morbidity) is the combination of asymptomatic and symptomatic venous thromboembolism. This would be inappropriate, since it would rely primarily on the more frequent surrogate endpoint asymptomatic VTE. Only a clinical endpoint should be used to measure efficacy. Even symptomatic VTE would be inappropriate as the primary outcome measure to determine recommendations, since it does not include adverse events. Fatal PE and fatal complications of the LMWH (bleeding and heparin induced thrombocytopenia with thrombosis [HITT]) combined would be the clinically relevant primary endpoint.

“Bleeding” is included among the adverse events in the outcome measures. Is this to be divided into major bleeding, fatal bleeding, and minor bleeding?

Rebound hypercoagulability will not be assessed unless the on study time includes two-three months after anticoagulant withdrawal in most patients.1, 2

RCTs will probably be too small to evaluate risk of HITT. Large observational studies should be analysed.

Because of excluding observational studies from consideration in the safety analysis, the bleeding complications will be very likely understated.

Without including data from large observational studies, any claim of safety and efficacy will not be generalizable to patients in general practice settings.

1. Cundiff DK. Commentary - Insufficient Evidence Supporting Low-Intensity Warfarin for Venous Thromboembolism (VTE) Prophylaxis. Medscape General Medicine™. 07/02/2003;http://www.medscape.com/viewarticle/457570.
2. Palareti G, Legnani C, Guazzaloca G, et al. Activation of blood coagulation after abrupt or stepwise withdrawal of oral anticoagulants--a prospective study. Thromb Haemost. 1994;72(2):222-226.