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Recombinant activated protein C reduces sepsis mortality.

 

 

For every 16 patients with sepsis given activated protein C, compared to placebo, one less patient dies.   (95% CI 9 to 44)
Risk of bleeding may be increased, but not certain.
Level 1+ evidence.

 

Citation/s:   Efficacy and safety of recombinant human activated Protein C for severe sepsis. NEJM 2001; 344: 699-709.
 

Lead author's name and fax: GR Bernard, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN. gordon.bernard@mcmail.vanderbilt.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: 164 centres in 11 countries. Eligible: known or suspected infection: 3 or more signs of systemic inflammation and sepsis induced dysfunction of at least one organ system lasting no longer than 24h. Entered study within 24h of fulfilling criteria. Exclusions: pregnancy or breast feeding, > 135 kg, platelets < 30,000, conditions that increased risk of bleeding (severe head trauma, AVM, cerebral aneurysm, gastro-intestinal bleeding within 6 weeks, trauma), known hypercoagulable condition (resistance to activated protein C, hereditary deficiencies, anticardiolipin Ab, antiphospholipid Ab, DVT, PE), lack of consent, advanced directive, not expected to survive 28d, HIV (CD4 < 50/mm3), prior transplant, CRF, portosystemic hypertension, pancreatitis, other study, or contra-indicated drug.   Followed up for 28 days. Primary end-point was death.
 

Control group (N = 857; 840 analysed): Placebo (0.9% saline with or without 0.1% albumin) at same rate as active drug.   Other ICU interventions fluids, ventilation, inotropes, antibiotics etc, were not standardized.
 

Experimental group (N = 871; 850 analysed): Drotrecogin alfa, 24 mg per kg per hour for 96 hours.

 

The Evidence:

Outcome

Time to Outcome

CER

EER

RRR

ARR

NNT

Death

within 28 days

0.313

0.248

21%

0.065

16

95% Confidence Intervals:

7% to 34%

0.023 to 0.107

9 to 44

Serious bleeding (intracranial,  or considered serious by investigator, or life threatening bleeding, or >3 units in 2 d)

within 28 days

0.020

0.034

-70%

-0.014

-71

95% Confidence Intervals:

-146% to 6%

-0.029 to 0.001

NNT = 797 to INF; NNH = 34 to INF

 

Comments:


1. Trial stopped after second interim analysis, big difference between the groups.
2. Primary end-point was death from any cause.
3. 75% of patients had ³ 2 organ systems dysfunction at enrolment.
4. Source of infection: 53.6% lungs, 19.9% abdomen.
5. Negative NNT for bleeding suggests greater risk of bleeding in activated Protein C group. 95% CI includes no effect, and reduced rate of bleeding, therefore uncertain about this.

6. See SICS guidelines on use.

 

 

Appraised by: Malcolm Daniel, Department of Anaesthesia, Glasgow Royal Infirmary; Thursday, October 04, 2001     Email: md23s@udcf.gla.ac.uk

 

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