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Meta-Analysis
. 2012 Dec 12;12(12):CD004388.
doi: 10.1002/14651858.CD004388.pub6.

Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients

Arturo J Martí-Carvajal  1 , Ivan Solà, Christian Gluud, Dimitrios Lathyris, Andrés Felipe Cardona
Affiliations
Meta-Analysis

Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients

Arturo J Martí-Carvajal et al. Cochrane Database Syst Rev. .

Abstract

Background: Sepsis is a common and frequently fatal condition. Human recombinant activated protein C (APC) has been introduced to reduce the high risk of death associated with severe sepsis or septic shock. This systematic review is an update of a Cochrane review originally published in 2007.

Objectives: We assessed the benefits and harms of APC for patients with severe sepsis or septic shock.

Search methods: We searched CENTRAL (The Cochrane Library 2012, Issue 6); MEDLINE (2010 to June 2012); EMBASE (2010 to June 2012); BIOSIS (1965 to June 2012); CINAHL (1982 to June 2012) and LILACS (1982 to June 2012). There was no language restriction.

Selection criteria: We included randomized clinical trials assessing the effects of APC for severe sepsis or septic shock in adults and children. We excluded studies on neonates. We considered all-cause mortality at day 28 and at the end of study follow up, and hospital mortality as the primary outcomes.

Data collection and analysis: We independently performed trial selection, risk of bias assessment, and data extraction in duplicate. We estimated relative risks (RR) for dichotomous outcomes. We measured statistical heterogeneity using the I(2) statistic. We used a random-effects model.

Main results: We identified one new randomized clinical trial in this update which includes six randomized clinical trials involving 6781 participants in total, five randomized clinical trials in adult (N = 6307) and one randomized clinical trial in paediatric (N = 474) participants. All trials had high risk of bias and were sponsored by the pharmaceutical industry. APC compared with placebo did not significantly affect all-cause mortality at day 28 compared with placebo (780/3435 (22.7%) versus 767/3346 (22.9%); RR 1.00, 95% confidence interval (CI) 0.86 to 1.16; I(2) = 56%). APC did not significantly affect in-hospital mortality (393/1767 (22.2%) versus 379/1710 (22.1%); RR 1.01, 95% CI 0.87 to 1.16; I(2) = 20%). APC was associated with an increased risk of serious bleeding (113/3424 (3.3%) versus 74/3343 (2.2%); RR 1.45, 95% CI 1.08 to 1.94; I(2) = 0%). APC did not significantly affect serious adverse events (463/3334 (13.9%) versus 439/3302 (13.2%); RR 1.04, 95% CI 0.92 to 1.18; I(2) = 0%). Trial sequential analyses showed that more trials do not seem to be needed for reliable conclusions regarding these outcomes.

Authors' conclusions: This updated review found no evidence suggesting that APC should be used for treating patients with severe sepsis or septic shock. APC seems to be associated with a higher risk of bleeding. The drug company behind APC, Eli Lilly, has announced the discontinuation of all ongoing clinical trials using this drug for treating patients with severe sepsis or septic shock. APC should not be used for sepsis or septic shock outside randomized clinical trials.

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Conflict of interest statement

In 2004, Arturo Martí‐Carvajal was employed by Eli Lilly to run a four‐hour workshop on 'How to critically appraise clinical trials on osteoporosis and how to teach this'. This activity was not related to his work with The Cochrane Collaboration or any Cochrane review.

In 2007, Arturo Martí‐Carvajal was employed by Merck to run a four‐hour workshop on 'How to critically appraise clinical trials and how to teach this'. This activity was not related to his work with The Cochrane Collaboration or any Cochrane review.

Ivan Solà: none known.

Christian Gluud: none known.

Dimitrios Lathyris: none known.

Andrés Felipe: none known

Cardona: none known.

Figures

1
1
Study flow diagram from June 2012 to May 2013.
2
2
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
3
3
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
4
4
Trial sequential analysis of human recombinant activated protein C (APC) versus placebo on all‐cause mortality at 28‐days based on the diversity‐adjusted required information size (DARIS) of 7230 patients. This DARIS was calculated based upon a proportion of patients dying within 28 days out of 23.3% in the control group; a RRR of 20% in the experimental intervention group; an alpha (α) of 5%; a beta (β) of 20%; and a diversity of 71%. The cumulative Z‐curve (blue line) crosses temporally the conventional alpha of 5%, but reverts to insignificant values. The cumulative Z‐curve never crosses the trial sequential alpha‐spending monitoring boundaries. After the third trial, the cumulative Z‐curve crosses the trial sequential beta‐spending monitoring boundary, showing that the area of futility has been reached. This suggests that no more trials may be needed for disproving an intervention effect of 20% relative risk reduction. Smaller risk reductions might still require further trials.
5
5
Trial sequential analysis of human recombinant activated protein C (APC) versus placebo in‐hospital mortality based on the diversity‐adjusted required information size (DARIS) of 6584 patients. This DARIS was calculated based upon a proportion of patients dying in‐hospital out of 27.2% in the control group; a RRR of 12% in the experimental intervention group; an alpha (α) of 5%; a beta (β) of 20%; and a diversity of 15%. The cumulative Z‐curve (blue line) crossed the trial sequential beta‐spending monitoring boundary, showing that the area of futility has been reached. This suggests that no more trials may be needed for disproving an intervention effect of 12% relative risk reduction. Smaller risk reductions might still require further trials.
6
6
Trial sequential analysis of human recombinant activated protein C (APC) versus placebo on adverse events based on the diversity‐adjusted required information size (DARIS) of 11480 patients. This DARIS was calculated based upon a proportion of patients developing adverse events out of 13.2% in the control group; a RRR of 13% in the experimental intervention group; an alpha an alpha (α) of 5%; a beta (β) of 20%; and a diversity of 0%. The cumulative Z‐curve (blue line) crossed the trials sequential beta‐spending monitoring boundary, showing that the area of futility has been reached. This suggest that no more trials are needed for disproving and intervention effect of 13% relative risk reduction.
7
7
Trial sequential analysis of human recombinant activated protein C (APC) versus placebo on serious bleeding based on the diversity‐adjusted required information size (DARIS) of 6665 patients. This DARIS was calculated based upon a proportion of patients with serious bleeding out of 2.2% in the control group; a RRR of 41% in the experimental intervention group; an alpha (α) of 5%; a beta (β) of 20%; and a diversity of 0%. The cumulative Z‐curve (blue line) crossed the lower conventional alpha of 5% and the lower trial sequential alpha‐spending monitoring boundaries, showing that we have robust data for significant harm.
1.1
1.1. Analysis
Comparison 1 APC versus placebo, Outcome 1 28‐Day all‐cause mortality (paediatric and adult patients).
1.2
1.2. Analysis
Comparison 1 APC versus placebo, Outcome 2 Any‐Day all cause mortality (paediatric and adults patients).
1.3
1.3. Analysis
Comparison 1 APC versus placebo, Outcome 3 28‐Day all‐cause mortality by age of the participants.
1.4
1.4. Analysis
Comparison 1 APC versus placebo, Outcome 4 28‐Day all‐cause mortality by treatment duration.
1.5
1.5. Analysis
Comparison 1 APC versus placebo, Outcome 5 28‐Day all‐cause mortality (according to PROWESS first and second protocol).
1.6
1.6. Analysis
Comparison 1 APC versus placebo, Outcome 6 28‐Day all‐cause mortality all trials compared to all trials excluding PROWESS first protocol).
1.7
1.7. Analysis
Comparison 1 APC versus placebo, Outcome 7 28‐Day all‐cause mortality by APACHE II score.
1.8
1.8. Analysis
Comparison 1 APC versus placebo, Outcome 8 28‐Day all‐cause mortality by protein C deficiency class.
1.9
1.9. Analysis
Comparison 1 APC versus placebo, Outcome 9 28‐Day all‐cause mortality, subgroup analysis by baseline organ dysfunction category.
1.10
1.10. Analysis
Comparison 1 APC versus placebo, Outcome 10 28‐Day all‐cause mortality, subgroup analysis by baseline organ dysfunction category.
1.11
1.11. Analysis
Comparison 1 APC versus placebo, Outcome 11 In‐hospital mortality.
1.12
1.12. Analysis
Comparison 1 APC versus placebo, Outcome 12 Serious adverse events.
1.13
1.13. Analysis
Comparison 1 APC versus placebo, Outcome 13 Serious bleeding events (days 0 to 90).
1.14
1.14. Analysis
Comparison 1 APC versus placebo, Outcome 14 Serious bleeding during infusion.
1.15
1.15. Analysis
Comparison 1 APC versus placebo, Outcome 15 Central nervous system bleeding events in pediatric and adult patients.
See this image and copyright information in PMC

Update of

References

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