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Antithrobin III does not alter outcome in sepsis.

 

 

Antithrombin III does not improve survival in sepsis.
Increased risk of bleeding, for every 23 patients so treated there is 1 extra major bleed.
Level 1+ evidence.

 

Citation/s:   High-dose Antithrombin III in severe sepsis. JAMA 2001; 286: 1869-1878
 

Lead author's name and fax: SM Opal, Infectious Diseases Division, Brown University School of Medicine, Steven_Opal@brown.edu

 

Three-part Clinical Question: In patients with sepsis, do anticoagulants, lead to reduced mortality ?

 

Search Terms: 1. exp sepsis/ or severe sep$.tw or sept$.tw or sepsi$.tw (50301), 2. exp critical care/ or critical ca$.tw or intensive ca$.tw (22553), 3. exp anticoagulants or exp protein C (11865), 4. 1 and 2 and 3 (33), 5. therapy filter (652119), 6. 4 and 5 (25)

 

The Study: Double-blinded concealed randomised controlled trial with intention-to-treat.
 

The Study Patients: Multicentre study.   Hospitalized adults, > 18 yrs, clinical evidence of sepsis with suspected source of infection, temp > 38.5 °C or < 35.5 °C, wbc > 10 x 103.ml-1, or < 3.5 x 103.ml.-1. Plus 3 out of: HR > 100.min-1; tachypnoea (> 24.min-1) or ventilation; SBP < 90 mmHg despite fluids or on inotropes; elavted lactate or metabolic acidosis; oliguria < 20 ml.h-1. Exclusions: advance directive; expected fatal condition; pregnancy / breast feeding; history of hypersensitivity to study drug; other study in previous 30d; recent iv heparin, warfarin or NSAID; ongoing massive blood loss; thrombocytopaenia (< 30 x 103.ml-1; immunocompromised; acute MI; burns > 20%; malignancy; stroke; scheduled spinal surgery; liver or renal failure; bone marrow aplasia.

 

Control group (N = 1157; 1157 analysed): Identical placebo (1% albumin solution). Other ICU therapy at doctors’ discretion.
 

Experimental group (N = 1157; 1157 analysed): Antithrombin III 6000 IU over 30 min, then 6000 IU continuous infusion over 24 hours for 4 days (30 000 IU in total).

 

The Evidence:

Outcome

Time to Outcome

CER

EER

RRR

ARR

NNT

Mortality

28 day

0.387

0.389

-1%

-0.002

-500

95% Confidence Intervals:

-11% to 10%

-0.042 to 0.038

NNT = 27 to INF; NNH = 24 to INF

Bleeding (intracranial or required > 3 units blood)

28 day

0.057

0.100

-75%

-0.043

-23

95% Confidence Intervals:

-114% to -37%

-0.065 to -0.021

-47 to -15

 

Comments:


1.    Survival benefit if patient not receiving heparin (sub-group analyses).

2.    May be benefit at 90 days, but not a priori end-point of the study.    What is the best time point to summarise survival?

3.    Blood culture results: 45% gram positive, 46% gram negative, fungal 4%, other 5%.

4.    Negative NNT indicates increased risk of bleeding with antithrombin III.  Further increase if given heparin.

 

Appraised by: Malcolm Daniel, Department of Anaesthesia, Glasgow Royal Infirmary; Thursday, October 25, 2001    Email: md23s@udcf.gla.ac.uk

 

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