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Heparin Thromboprophylaxis in Medical-Surgical Critically Ill Patients: A Systematic Review and Meta-Analysis of Randomized Trials*

Alhazzani, Waleed MD1; Lim, Wendy MD1; Jaeschke, Roman Z. MD1,2; Murad, Mohammad Hassan MD3; Cade, Jack MD4; Cook, Deborah J. MD1,2

doi: 10.1097/CCM.0b013e31828cf104
Feature Articles

Objective: Venous thromboembolism prevention during critical illness is a widely used quality metric. The objective of this systematic review was to systematically review the efficacy and safety of heparin thromboprophylaxis in medical-surgical patients in the ICU.

Data Sources: We searched EMBASE, MEDLINE, the Cochrane Controlled Trials Register,, and personal files through May 2012.

Study Selection: Randomized trials in adult medical-surgical ICU patients comparing any heparin (unfractionated heparin or low-molecular-weight heparin) with each other or no anticoagulant prophylaxis, evaluating deep vein thrombosis, pulmonary embolism, major bleeding, or mortality.

Data Extraction: Independently, in duplicate, we abstracted trial characteristics, outcomes, and risk of bias.

Data Synthesis: Seven trials involved 7,226 patients. Any heparin thromboprophylaxis compared with placebo reduced rates of deep vein thrombosis (pooled risk ratio, 0.51 [95% CI, 0.41, 0.63]; p < 0.0001; I2 = 77%) and pulmonary embolism (risk ratio, 0.52 [95% CI, 0.28, 0.97]; p = 0.04; I2 = 0%) but not symptomatic deep vein thrombosis (risk ratio, 0.86 [95% CI, 0.59, 1.25]; p = 0.43). Major bleeding (risk ratio, 0.82 [95% CI, 0.56, 1.21]; p = 0.32; I2 = 50%) and mortality (risk ratio, 0.89 [95% CI, 0.78, 1.02]; p = 0.09; I2 = 0%) rates were similar. Compared with unfractionated heparin, low-molecular-weight heparin reduced rates of pulmonary embolism (risk ratio, 0.62 [95% CI, 0.39, 1.00]; p = 0.05; I2 = 53%) and symptomatic pulmonary embolism (risk ratio, 0.58 [95% CI, 0.34, 0.97]; p = 0.04) but not deep vein thrombosis (risk ratio, 0.90 [95% CI, 0.74, 1.08]; p = 0.26; I2 = 0%), symptomatic deep vein thrombosis (risk ratio, 0.87 [95% CI, 0.60, 1.25]; p = 0.44; I2 = 0%), major bleeding (risk ratio, 0.97 [95% CI, 0.75, 1.26]; p = 0.83; I2 = 0%), or mortality (risk ratio, 0.93 [95% CI, 0.82, 1.04]; p = 0.20; I2 = 31%).

Conclusions: Trial evidence to date suggests that any type of heparin thromboprophylaxis decreases deep vein thrombosis and pulmonary embolism in medical-surgical critically ill patients, and low-molecular-weight heparin compared with bid unfractionated heparin decreases pulmonary embolism and symptomatic pulmonary embolism. Major bleeding and mortality rates do not appear to be significantly influenced by heparin thromboprophylaxis in the ICU setting. Trial methodology, indirectness, and the heterogeneity and imprecision of some results temper inferences from this literature.

1Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

2Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada.

3Division of Preventive Medicine, Department of Medicine, Mayo Clinic, Rochester, MN.

4Department of Intensive Care Medicine, Royal Melbourne Hospital, Melbourne, Victoria, Australia.

* See also p. 2224.

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Supported, in part, by a grant from Hamilton Academy of Health Sciences of Ontario.

Dr. Lim has received grant support from Leo Pharma and honoraria for educational projects from Leo Pharma, Pfizer, and Octapharma and has also received the EJ Moran Campbell Internal Career Award from McMaster University. Dr. Cook is a Research Chair of the Canadian Institutes of Health Research. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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© 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins