Prevalence of Serious Bleeding Events and Intracranial Hemorrhage in Patients Receiving Activated Protein C: A Systematic Review and Meta-analysis

Abstract

BACKGROUND:

Activated protein C reduces 28-day mortality in patients with severe sepsis, but its anticoagulant properties entail a risk of bleeding.

OBJECTIVE:

The aim of this systematic review was to evaluate the prevalence of serious bleeding events in patients receiving activated protein C.

METHODS:

We searched the MEDLINE and EMBASE databases for studies that described the prevalence of serious bleeding events and intracranial hemorrhage in patients receiving activated protein C. We calculated the bleeding rates by calculating proportions and 95% CIs for each study, and then pooled the data to derive a pooled proportion and 95% CI.

RESULTS:

Our search yielded 17 studies, which included 10,679 patients. The occurrence of serious bleeding events in patients receiving activated protein C ranged from 0.5% to 9.6%, and the pooled prevalence was 3.3% (95% CI 2.4–4.4%) by the random effects model. The occurrence of intracranial hemorrhage ranged from 0% to 1.4%, and the pooled prevalence was 0.44% (95% CI 0.31–0.6%). Sensitivity analysis showed a higher prevalence of bleeding in the observational studies than in the randomized controlled trials. There was substantial clinical and statistical heterogeneity, but no evidence of publication bias.

CONCLUSIONS:

Activated protein C is associated with significant risk of bleeding, so strict inclusion and exclusion criteria should be set prior to administering activated protein C.

Keywords

drotrecogin alfa activated protein C serious bleeding event intracranial hemorrhage sepsis

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References

American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med, 1992; 20(6):864–874.

Bone

, Balk

, Cerra

, Dellinger

, Fein

, Knaus

, et al; American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest, 1992; 101(6):1644–1655.

Bernard

, Vincent

, Laterre

, LaRosa

, Dhainaut

, Lopez-Rodriguez

, et al. Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med, 2001; 344(10):699–709.

Abraham

, Laterre

, Garg

, Levy

, Talwar

, Trzaskoma

, et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med, 2005; 353(13):1332–1341.

Bernard

, Macias

, Joyce

, Williams

, Bailey

, Vincent

. Safety assessment of drotrecogin alfa (activated) in the treatment of adult patients with severe sepsis. Crit Care, 2003; 7(2):155–163.

Schein

, Kinasewitz

. Risk-benefit analysis for drotrecogin alfa (activated). Am J Surg, 2002; 184(6A Suppl):S25–S38.

Oppenheim-Eden

, Glantz

, Eidelman

, Sprung

. Spontaneous intracerebral hemorrhage in critically ill patients: incidence over six years and associated factors. Intensive Care Med, 1999; 25(1):63–67.

Fry

, Beilman

, Johnson

, Williams

, Rodman

, Booth

, et al. Safety of drotrecogin alfa (activated) in surgical patients with severe sepsis. Surg Infect (Larchmt), 2004; 5(3):253–259.

McCoy

. Safety of drotrecogin alfa (activated) in the treatment of patients with severe sepsis. Expert Opin Drug Saf, 2004; 3(6):625–637.

10.

Williams

, Macias

, Rustige

. Safety of drotrecogin alfa (activated): a fair comparison requires consistent definitions (letter). Intensive Care Med, 2007; 33(8):1487–1488.

11.

Fumagalli

, Mignini

. The safety profile of drotrecogin alfa (activated). Crit Care, 2007; 11(Suppl 5):S6.

12.

Freeman

, Tukey

. Transformations related to the angular and the square root. Ann Math Stat, 1950; 21(4):607–611.

13.

Miller

. The inverse of the Freeman-Tukey double arcsine transformation. Am Stat, 1978; 32(4):138–138.

14.

DerSimonian

, Laird

. Meta-analysis in clinical trials. Control Clin Trials, 1986; 7(3):177–188.

15.

Deeks

, Higgins

JPT

, Altman

. Analysing and presenting results. In: Alderson

, Green

, Higgins

JPT

, editors. Cochrane Reviewers' Handbook 422. Updated March 2004. Chichester, United Kingdom: John Wiley; 2004:68–139.

16.

Lau

, Ioannidis

, Schmid

. Quantitative synthesis in systematic reviews. Ann Intern Med, 1997; 127(9):820–826.

17.

Dear

, Begg

. An approach to assessing publication bias prior to performing a meta-analysis. Stat Sci, 1992; 7:237–245.

18.

Egger

, Smith

, Schneider

, Minder

. Bias in meta-analysis detected by a simple, graphical test. BMJ, 1997; 315(7109):629–634.

19.

Harbord

, Egger

, Sterne

. A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Stat Med, 2006; 25(20):3443–3457.

20.

Begg

, Mazumdar

. Operating characteristics of a rank correlation test for publication bias. Biometrics, 1994; 50(4):1088–1101.

21.

Bernard

, Ely

, Wright

, Fraiz

, Stasek

Jr , Russell

, et al. Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis. Crit Care Med, 2001; 29(11):2051–2059.

22.

Bernard

, Margolis

, Shanies

, Ely

, Wheeler

, Levy

, et al. Extended evaluation of recombinant human activated protein C United States Trial (ENHANCE US): a single-arm, phase 3B, multicenter study of drotrecogin alfa (activated) in severe sepsis. Chest, 2004; 125(6):2206–2216.

23.

Vincent

, Bernard

, Beale

, Doig

, Putensen

, Dhainaut

, et al. Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: further evidence for survival and safety and implications for early treatment. Crit Care Med, 2005; 33(10):2266–2277.

24.

Kubler

, Mayzner-Zawadzka

, Durek

, Gaszynski

, Karpel

, Mikaszewska-Sokolewicz

, et al. Results of severe sepsis treatment program using recombinant human activated protein C in Poland. Med Sci Monit, 2006; 12(3):CR107–CR112.

25.

Spriet

, Meersseman

, Wilmer

, Meyfroidt

, Casteels

, Willems

. Evaluation of drotrecogin alpha use in a Belgian university hospital. Pharm World Sci, 2006; 28(5):290–295.

26.

Bertolini

, Rossi

, Anghileri

, Livigni

, Addis

, Poole

. Use of Drotrecogin alfa (activated) in Italian intensive care units: the results of a nationwide survey. Intensive Care Med, 2007; 33(3):426–434.

27.

Kanji

, Perreault

, Chant

, Williamson

, Burry

. Evaluating the use of Drotrecogin alfa (activated) in adult severe sepsis: a Canadian multicenter observational study. Intensive Care Med, 2007; 33(3):517–523.

28.

Levi

, Levy

, Williams

, Douglas

, Artigas

, Antonelli

, et al. Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated). Am J Respir Crit Care Med, 2007; 176(5):483–490.

29.

Ridley

, Lwin

, Wyncoll

, Lippett

, Watson

, Gunning

, et al. Drotrecogin alfa (activated): diffusion from clinical trials to clinical practice. Eur J Anaesthesiol, 2008; 25(3):211–216.

30.

Rowan

, Welch

, North

, Harrison

. Drotrecogin alfa (activated): real-life use and outcomes for the UK. Crit Care, 2008; 12(2):R58.

31.

Taylor

, Lee

, Waxman

. Bleeding complications with Drotrecogin alfa activated (Xigris): a retrospective review of 31 operative and 68 non-operative patients with severe sepsis. Am Surg, 2008; 74(10):898–901.

32.

Wheeler

, Steingrub

, Schmidt

, Sanchez

, Jacobi

, Linde-Zwirble

, et al. A retrospective observational study of drotrecogin alfa (activated) in adults with severe sepsis: comparison with a controlled clinical trial. Crit Care Med, 2008; 36(1):14–23.

33.

Decruyenaere

, De Backer

, Spapen

, Laterre

, Raemaekers

, Rogiers

, et al. 90-day follow-up of patients treated with Drotrecogin Alfa (activated) for severe sepsis: a Belgian open label study. Acta Clin Belg, 2009; 64(1):16–22.

34.

Dhainaut

, Antonelli

, Wright

, Desachy

, Reignier

, Lavoue

, et al. Extended drotrecogin alfa (activated) treatment in patients with prolonged septic shock. Intensive Care Med, 2009; 35(7):1187–1195.

35.

Gentry

, Gross

, Sud

, Drevets

. Adverse outcomes associated with the use of drotrecogin alfa (activated) in patients with severe sepsis and baseline bleeding precautions. Crit Care Med, 2009; 37(1):19–25.

36.

Bearden

, Garvin

. Recombinant human activated protein C for use in severe sepsis. Ann Pharmacother, 2002; 36(9):1424–1429.