The Efficacy and Safety of Heparin in Patients With Sepsis

A Systematic Review and Metaanalysis

Ryan Zarychanski, MD, MSc; Ahmed M. Abou-Setta, MD, PhD; Salmaan Kanji, PharmD; Alexis F. Turgeon, MD, MSc; Anand Kumar, MD; Donald S. Houston, MD, PhD; Emily Rimmer, MD; Brett L. Houston, MD; Lauralyn McIntyre, MD, MSc; Alison E. Fox-Robichaud, MD, MSc; Paul Hébert, MD, MSc; Deborah J. Cook, MD, MSc; Dean A. Fergusson, PhD, MHA

Disclosures

Crit Care Med. 2015;43(3):511-518. 

In This Article

Abstract and Introduction

Abstract

Objective To evaluate the efficacy and safety of heparin in patients with sepsis, septic shock, or disseminated intravascular coagulation associated with infection.

Design Systematic review and metaanalysis.

Data Sources Randomized controlled trials from MEDLINE, EMBASE, CENTRAL, Global Health, Scopus, Web of Science, the International Clinical Trials Registry Platform (inception to April 2014), conference proceedings, and reference lists of relevant articles.

Study Selection and Data Extraction Two reviewers independently identified and extracted trial-level data from randomized trials investigating unfractionated or low molecular heparin administered to patients with sepsis, severe sepsis, septic shock, or disseminated intravascular coagulation associated with infection. Internal validity was assessed in duplicate using the Risk of Bias tool. The strength of evidence was assessed in duplicate using Grading of Recommendations Assessment, Development, and Evaluation methodology. Our primary outcome was mortality. Safety outcomes included hemorrhage, transfusion, and thrombocytopenia.

Measurements and Main Results We included nine trials enrolling 2,637 patients. Eight trials were of unclear risk of bias and one was classified as having low risk of bias. In trials comparing heparin to placebo or usual care, the risk ratio for death associated with heparin was 0.88 (95% CI, 0.77–1.00; I 2 = 0%; 2,477 patients; six trials; moderate strength of evidence). In trials comparing heparin to other anticoagulants, the risk ratio for death was 1.30 (95% CI, 0.78–2.18; I 2 = 0%; 160 patients; three trials; low strength of evidence). In trials comparing heparin to placebo or usual care, major hemorrhage was not statistically significantly increased (risk ratio, 0.79; 95% CI, 0.53–1.17; I 2 = 0%; 2,392 patients; three trials). In one small trial of heparin compared with other anticoagulants, the risk of major hemorrhage was significantly increased (2.14; 95% CI, 1.07–4.30; 48 patients). Important secondary and safety outcomes, including minor bleeding, were sparsely reported.

Conclusions Heparin in patients with sepsis, septic shock, and disseminated intravascular coagulation associated with infection may be associated with decreased mortality; however, the overall impact remains uncertain. Safety outcomes have been underreported and require further study. Increased major bleeding with heparin administration cannot be excluded. Large rigorous randomized trials are needed to evaluate more carefully the efficacy and safety of heparin in patients with sepsis, severe sepsis, and septic shock.

Introduction

Severe sepsis and septic shock are the second most common causes of mortality among critically ill patients, accounting for approximately 10% of admissions to the ICU and 1.3% of all hospital admissions.[1,2] Although the mortality rate associated with septic shock is improving over time (range, 24–50%), the incidence of septic shock is increasing.[3–5]

The pathogenesis of sepsis involves systemic inflammation, endothelial injury, and up-regulation of coagulation in response to an invading pathogen.[6,7] Given the pathobiologic relationship between coagulation and inflammation, anticoagulant agents have been evaluated in sepsis.[3,5,8] Heparin, a glycosaminoglycan of variable polymer length, inhibits blood coagulation and thrombin formation by potentiating the activity of antithrombin. A less recognized property of heparin is its ability to act as an anti-inflammatory agent. Since thrombin generation is inextricably linked to inflammation, thrombin inhibition serves to limit inflammation.[9,10] Heparin also possesses anti-inflammatory properties that appear to be independent of its role as an anticoagulant.[11–14]

Live animal models and meta-analyses of randomized trials in animals with sepsis have demonstrated lower mortality with heparin compared with placebo or no intervention.[15–17] Our group recently investigated this association in a retrospective propensity-matched analysis and found increased survival is associated with therapeutic doses of IV heparin in patients with septic shock.[18] Post hoc analyses from three phase III trials of commercial anticoagulant agents demonstrated increased survival in patients receiving low-dose heparin, either alone or in combination with the study drug.[19]

The purpose of this systematic review was to identify and critically appraise the efficacy and safety of heparin in randomized trials of patients with sepsis, septic shock, or disseminated intravascular coagulation (DIC) associated with infection.

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