Thromboembolism
Low-molecular-weight heparin thromboprophylaxis in medical-surgical critically ill patients: A systematic review

https://doi.org/10.1016/j.jcrc.2008.11.002Get rights and content

Abstract

Purpose

The study aimed to systematically review the effect of low-molecular-weight heparin (LMWH) thromboprophylaxis in medical-surgical critically ill patients in the intensive care unit.

Methods

In duplicate and independently, we searched for relevant articles using MEDLINE and EMBASE; we also contacted experts and reviewed reference lists. For included studies, we abstracted data on study and patient characteristics, LMWH use, clinical outcomes (venous thromboembolism [VTE], bleeding, and mortality), laboratory outcomes (anti-Xa levels and thrombocytopenia), and methodological quality.

Results

We included 8 prospective cohort studies and 1 randomized trial, with a total of 629 patients. Eight studies (n = 406 patients) reported anti-Xa levels and only 3 studies (n = 240 patients) reported on at least one clinical outcome. Low-molecular-weight heparin does not appear to bioaccumulate based on repeated measurements of trough anti-Xa levels. Thrombocytopenia occurred in 9.3% of patients receiving LMWH; heparin-induced thrombocytopenia was not reported. In studies reporting clinical outcomes, the frequency of VTE in patients receiving LMWH ranged from 5.1% to 15.5%, bleeding complications ranged from 7.2% to 23.1%, and mortality ranged from 1.4% to 7.4%.

Conclusions

Low-molecular-weight heparin may be effective for thromboprophylaxis in medical-surgical critically ill patients, but no trials have compared LMWH against an alternative active strategy; thus, LMWH cannot be recommended routinely. Trials testing LMWH thromboprophylaxis are required, which examine patient-important end points such as the incidence and clinical consequences of VTE, bleeding, heparin-induced thrombocytopenia, and mortality.

Introduction

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common cause of hospital-acquired morbidity and mortality in critically ill patients admitted to the medical-surgical intensive care unit (ICU). Risk factors such as prolonged immobilization, recent surgery, hypercoagulability from acute-phase reactants, and vascular injury caused by invasive procedures increase the risk of VTE in this setting [1]. Based on systematic screening, cross-sectional studies estimate the prevalence of DVT to be 2% to 10% on admission to the ICU, whereas longitudinal studies estimate the incidence of DVT developing over the ICU stay ranging from 9% to 40% [2], [3], [4], [5].

Anticoagulant thromboprophylaxis is the commonest approach to VTE prevention in medical-surgical critically ill patients. Surveys of stated practice, observational studies, and international registries indicate that unfractionated heparin (UFH) is most often prescribed [2], [3], [4], [6], [7], [8], [9]. Low-molecular-weight heparins (LMWHs) have also been examined in some recent observational studies in medical-surgical ICU patients [10], [11]. Low-molecular-weight heparins provide anticoagulation through antithrombin-mediated inhibition of factor Xa, and to a lesser extent, factor IIa (thrombin). The high bioavailability and predictable anticoagulant effect of LMWHs have led to their increasing use for thromboprophylaxis in medical and surgical patients, particularly because LMWHs do not require regular laboratory monitoring or dose adjustments [12].

Serum anti-Xa levels can be used to measure LMWH activity and are used as a surrogate marker to quantify bleeding risk. When LMWH is used for thromboprophylaxis in orthopedic and abdominal surgery, the optimal range that produces effective anticoagulation without excessive bleeding is thought to be achieved with doses of heparin that result in a peak plasma factor Xa activity between 0.25 an 0.29 IU/mL during the first 3 postoperative days and between 0.33 and 0.37 IU/mL from days 4 to 10 [13].

Outside of the ICU setting, meta-analyses of randomized trials have shown the efficacy and safety of UFH thromboprophylaxis, and of LMWH thromboprophylaxis, compared with no anticoagulant thromboprophylaxis in medical and surgical patients [14], [15]. However, no randomized trials have compared UFH vs LMWH in medical-surgical patients, and few studies have examined the efficacy of LMWH in the medical-surgical ICU. Although LMWH thromboprophylaxis has been shown to be more effective than UFH in trauma patients and in patients with spinal cord injuries, concerns remain about bioaccumulation, particularly among patients with renal impairment, potentially leading to hemorrhagic complications [16], [17], [18], [19]. The objective of this systematic review was to examine the effect of LMWH thromboprophylaxis on clinical and laboratory outcomes in medical-surgical critically ill patients in the ICU.

Section snippets

Study identification

We searched for relevant studies using a detailed electronic search of the MEDLINE (1950 to February 2008 week 3) database. We examined reference lists from studies identified through the electronic search and from eligible studies; we also consulted with content experts.

Eligibility criteria

We included prospective cohort and randomized controlled trials that used LMWH for thromboprophylaxis in critically ill patients in medical, surgical, trauma, or mixed ICU settings and evaluated clinically relevant outcomes

Study selection

Our search identified 111 published studies (Fig. 1). We excluded 92 studies after title and abstract screening and retrieved the remaining 19 studies for more detailed evaluation. Of these, 11 studies were excluded, one of which was a pilot trial reporting only feasibility data rather than clinical outcomes, 5 studies were excluded because they exclusively enrolled trauma or spinal cord injury patients, 2 were practice audits, and 3 were excluded because they were not published in English [20]

Discussion

We identified one randomized trial and 8 observational studies that examined the effect of LMWH thromboprophylaxis in medical-surgical critically ill patients. We documented that there is inadequate research upon which to recommend that LMWH be used for thromboprophylaxis or used in preference to UFH. First, in total, fewer than 1000 medical-surgical ICU patients have been studied. Second, all studies used anti-Xa levels as a surrogate marker for LMWH anticoagulant effectiveness. Third, the

Acknowledgments

This study was not funded. Dr Ribic has no conflicts of interest to declare. Dr Lim has received an unrestricted educational grant from Leo Pharma and is on the speaker's bureau and received honoraria from Leo Pharma and Pfizer. Dr Cook has received LMWH study drug from Pfizer for a thromboprophylaxis trial. Dr Crowther's conflicts of interest are pending.

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    Dr. Crowther has received research funding or honoraria, and/or has been an advisory board member of Bayer, Artisan, Pfizer, Sanofi Aventis, Leo Laboratories and Boehringher Ingelheim.

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