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Failure of Anticoagulant Thromboprophylaxis

Risk Factors in Medical-Surgical Critically Ill Patients*

Lim, Wendy MD1; Meade, Maureen MD1,2; Lauzier, Francois MD3,4; Zarychanski, Ryan MD5,6; Mehta, Sangeeta MD7; Lamontagne, Francois MD8; Dodek, Peter MD9; McIntyre, Lauralyn MD10; Hall, Richard MD11,12; Heels-Ansdell, Diane MSc2; Fowler, Robert MD7; Pai, Menaka MD1; Guyatt, Gordon MD1,2; Crowther, Mark A. MD1,13; Warkentin, Theodore E. MD1,13; Devereaux, P. J. MD1,2; Walter, Stephen D. PhD2; Muscedere, John MD14; Herridge, Margaret MD7; Turgeon, Alexis F. MD3,15; Geerts, William MD16; Finfer, Simon MD17,18; Jacka, Michael MD19,20; Berwanger, Otavio MD21; Ostermann, Marlies MD22; Qushmaq, Ismael MD23; Friedrich, Jan O. MD7; Cook, Deborah J. MD1,2 for the PROphylaxis for ThromboEmbolism in Critical Care Trial Investigators, the Canadian Critical Care Trials Group, and the Australian and New Zealand Intensive Care Society Clinical Trials Group

doi: 10.1097/CCM.0000000000000713
Clinical Investigations
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Objectives: To identify risk factors for failure of anticoagulant thromboprophylaxis in critically ill patients in the ICU.

Design: Multivariable regression analysis of thrombosis predictors from a randomized thromboprophylaxis trial.

Setting: Sixty-seven medical-surgical ICUs in six countries.

Patients: Three thousand seven hundred forty-six medical-surgical critically ill patients.

Interventions: All patients received anticoagulant thromboprophylaxis with low-molecular-weight heparin or unfractionated heparin at standard doses.

Measurements and Main Results: Independent predictors for venous thromboembolism, proximal leg deep vein thrombosis, and pulmonary embolism developing during critical illness were assessed. A total of 289 patients (7.7%) developed venous thromboembolism. Predictors of thromboprophylaxis failure as measured by development of venous thromboembolism included a personal or family history of venous thromboembolism (hazard ratio, 1.64; 95% CI, 1.03–2.59; p = 0.04) and body mass index (hazard ratio, 1.18 per 10-point increase; 95% CI, 1.04–1.35; p = 0.01). Increasing body mass index was also a predictor for developing proximal leg deep vein thrombosis (hazard ratio, 1.25; 95% CI, 1.06–1.46; p = 0.007), which occurred in 182 patients (4.9%). Pulmonary embolism occurred in 47 patients (1.3%) and was associated with body mass index (hazard ratio, 1.37; 95% CI, 1.02–1.83; p = 0.035) and vasopressor use (hazard ratio, 1.84; 95% CI, 1.01–3.35; p = 0.046). Low-molecular-weight heparin (in comparison to unfractionated heparin) thromboprophylaxis lowered pulmonary embolism risk (hazard ratio, 0.51; 95% CI, 0.27–0.95; p = 0.034) while statin use in the preceding week lowered the risk of proximal leg deep vein thrombosis (hazard ratio, 0.46; 95% CI, 0.27–0.77; p = 0.004).

Conclusions: Failure of standard thromboprophylaxis using low-molecular-weight heparin or unfractionated heparin is more likely in ICU patients with elevated body mass index, those with a personal or family history of venous thromboembolism, and those receiving vasopressors. Alternate management or incremental risk reduction strategies may be needed in such patients.

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

2Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada.

3Research Center of the CHU de Québec, Population Health and Optimal Health Practices Research Unit, Québec, QC, Canada.

4Division of Critical Care, Department of Medicine, Québec, QC, Canada.

5Section of Critical Care, Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.

6Section of Hematology/Medical Oncology, Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.

7Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada.

8Division of Critical Care, Department of Medicine, Centre de Recherche Clinique Étiene-Le Bel, Université de Sherbrooke, Sherbrooke, QC, Canada.

9Division of Critical Care Medicine and Center for Health Evaluation and Outcome Sciences, St. Paul’s Hospital and University of British Columbia, Vancouver, BC, Canada.

10Department of Critical Care, University of Ottawa, Ottawa, ON, Canada.

11Department of Anesthesia, Queen Elizabeth II Health Sciences Centre,

12Department of Critical Care, Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada.

13Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.

14Department of Medicine, Queen’s University, Kingston, ON, Canada.

15Department of Anesthesiology, Québec, QC, Canada.

16Department of Medicine, University of Toronto, Toronto, ON, Canada.

17Malcolm Fisher Department of Intensive Care Medicine, Royal North Shore Hospital, Sydney, Australia.

18The George Institute for Global Health, University of Sydney, Sydney, Australia.

19Department of Critical Care, University of Alberta, Edmonton, AB, Canada.

20Department of Anesthesia, University of Alberta, Edmonton, AB, Canada.

21Department of Medicine, Research Institute-HCor, Hospital do Coracao, Sao Paolo, Brazil.

22Department of Intensive Care Medicine, Guys and St Thomas’ Hospital, London, United Kingdom.

23Department of Medicine, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia.

* See also p. 500.

Supported, in part, by the Canadian Institute of Health Research, the Heart and Stroke Foundation of Canada, and the Australian and New Zealand College of Anaesthetists Research Foundation. Pfizer Canada provided dalteparin for Canadian centers; Eisai provided dalteparin for centers in the United States. None of these groups played a role in the design, conduct, analysis, interpretation, or write-up of this trial.

Drs. Lim, Meade, Lamontagne, Mcintyre, Heels-Ansdell, Fowler, Pai, Guyatt, Devereaux, Turgeon, Geerts, Finfer, Jacka, Berwanger, Ostermann, Qushmaq, and Cook’s institutions received grant support from the Canadian Institutes for Health Research (CIHR), the Heart and Stroke Foundation of Canada, and the Australian and New Zealand College of Anaesthetists Research Foundation. Their institutions received provision of materials/support from Pfizer Canada (provided dalteparin for Canadian centers) and from Eisai (provided dalteparin for centers in the United States). Dr. Lim received grant support from Leo Pharma (unrestricted arms-length grant to provide low-molecular-weight heparin for investigator-initiated study) and received support for the development of educational presentations from Leo Pharma and Pfizer (honoraria for Continuing Medical Education projects). Dr. Meade is a mentor of the CIHR. Drs. Lauzier, Lamontagne, and Turgeon are recipients of a Research Career Award from the Fonds de la recherche du Québec-Santé. Dr. Zarychanski lectured for Bayer. His institution received grant support from Pfizer. Dr. Lamontagne is supported by the Mentee Award of the CIHR. Dr. Dodek’s institution received grant support from the CIHR. Dr. Hall’s institution received grant support from the CIHR, Heart and Stroke Foundation, Canadian Anesthesiologist’s Society, Public Health Agency of Canada, Cubist, Glaxo Smith Kline, Portola, and Asahi Kasei. Dr. Pai lectured for Bayer Canada and received royalties from UpToDate. Dr. Crowther consulted for Portola, Leo Pharma, Boerhinger-Ingelheim, Viropharm, and AKP America; provided expert testimony for Bayer and Merck; lectured for Leo Pharma, Bayer, Celgene, CSL Behring, and Shire; and received other support from Immucor GTI Diagnostics. His institution received grant support from Leo. Dr. Crowther holds a Career Investigator Award from the Heart and Stroke Foundation of Ontario and the Leo Pharma Chair in Thromboembolism Research at McMaster University. Dr. Warkentin provided expert witness testimony relating to heparin-induced thrombocytopenia; lectured for Pfizer Canada and Instrumentation Laboratory, IL (received lecture honoraria); and received royalties from Informa (edited books on heparin-induced thrombocytopenia). His institution received grant support from GlaxoSmithKline. Dr. Warkentin is supported by the Heart and Stroke Foundation of Ontario. Dr. Devereaux holds a Career Investigator Award from the Heart and Stroke Foundation of Ontario. Dr. Herridge’s institution received grant support from the CIHR, the Heart and Stroke Foundation of Canada, and Australian and New Zealand College of Anaesthetists Research Foundation. Dr. Geerts consulted for Bayer Healthcare, Leo Pharma, and Boehringer Ingelheim; lectured for Bayer Healthcare, Leo Pharma, Pfizer, and Sanofi; received support for the development of educational presentations from GlaxoSmithKline, Leo Pharma, and Bayer Healthcare; and received other support from Bayer Healthcare and Sanofi (program support provided to the hospital). His institution received provision of materials/support from Pfizer Canada (provided dalteparin for Canadian centers) and Eisai (provided dalteparin for centers in the United States). Dr. Finfer’s institution received grant support from Fresenius Kabi (grant to University of Sydney for conduct of Crystalloid vs Hydroxyethyl Starch Trial). Dr. Cook holds a Chair of the CIHR. The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: debcook@mcmaster.ca

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