Mayer, 2005

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Factor VII improves mortality and morbidity in intracerebral haemorrhage

In patients presenting with an intracerebral haemorrhage early treatment with recombinant activated factor VII decreases mortality (NNT 9) and improves neurological outcome (NNT 6).

Level of Evidence: 1⁺(RCT with a low risk of bias)

Citation/s: Mayer SA , et al. Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage.NEJM 2005: 352(8); 777 – 785

Lead author's name and email: Mayer SA, sam14@columbia.edu

Three-part Clinical Question: patients = suffering acute intracerebral haemorrhage; Treatment = Activated Factor VII; Outcomes = size of haematoma, favourable neurological outcomes & mortality

Search Terms: Medline: Activated factor VII (exp) AND Cerebral haemorrhage (exp)/ or intracerebral haemorrhage (mp), 21 references, limited to meta analysis or multicentrre trial or RCT

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

The Study Patients: Patients (18yr or older) suffering an intracerebral haemorrhage with CT evidence within 3 hours of onset. GCS of <6 were excluded. All four groups were similar at outset.

Control group (N = 96; 96 analysed): IV placebo within 1 hour of CT diagnosis.

Experimental group (3 groups) (N = 303; 303 analysed): Single IV bolus dose of recombinant activated Factor VII 40, 80 or 160microgram per Kg within 1 hour of CT diagnosis.

The Evidence:

Outcome	Time to Outcome	CER	EER	RRR	ARR	NNT
Mortality	90 days	0.292	0.185	37%	0.107	9
Mortality	95% Confidence Intervals:			2% to 71%	0.006 to 0.208	5 to 164
Unfavorable Modified Rankin Scale	90 days	0.688	0.528	23%	0.160	6
Unfavorable Modified Rankin Scale	95% Confidence Intervals:			8% to 39%	0.052 to 0.268	4 to 19
Thromboembolic events	90 days	0.021	0.069	-229%	-0.048	NS
Thromboembolic events	95% Confidence Intervals:			NS	NS	NS

Non-Event Outcomes	Time to outcome/s	Control group	Experimental group	P-value
Volume of ICH + IVH + Oedema	72 hours	69ml	53ml	0.003
Volume of ICH + IVH	24 hours	38ml	32ml	0.006
Increase in volume of ICH	24 hours	8.7ml	4.2ml	0.01

Comments:
Very early treatment with factor VII reduced the increase in size of CT lesions and overall size of CT lesions at 72 hours. It also improved the neurological outcomes in the survivors and improved the overall mortality rate. There was a trend to the best improvements being seen in the sub group treated with the higher doses of factor VII but the paper fails to present statistical evidence for this. The increase in thromboembolic events has to be put into context of this disease process for which we currently have no specific therapy for. By removing the late thromboembolic events which were deemed not to be due to the factor VII therapy and non 'disabling' episodes the rates of adverse events were similar between both groups (2%). Exclusion criteria were expanded during the trial, and the number of patients screened but excluded is not known.

SICS EBM questions

1) Do the methods allow accurate testing of the hypothesis? Yes

2) Do the statistical tests correctly test the results to allow differentiation of statistically significant results? Yes
3) Are conclusions valid in light of the results? Yes
4) Did results get omitted, and why? one patient removed consent therefore 399 out of 400 analysed
5) Did they suggest areas of further research? Yes – Need to identify patients at high risk of thromboembolic events, what the optimal therapeutic window is and to test for Factor VII mediated intracerebral haemorhage
6) Did they make any recommendations based on the results and were they appropriate? No - recommendations as such but state that ultra early therapy with factor VII improves mortality, size of CT lesions and functional outcomes.
7) Is the study relevant to my clinical practice? Yes – as ICU practitioners we are often called to give assistance in the emergency department for such patients, whether it be for accompanied transfer to the CT scanner or further management. Unfortunately many of the cases we get involved in have a GCS of less than 7, such patients were excluded from this trial.
8) What level of evidence does this study represent? Level 1+
9) What grade of recommendation can I make on this result alone? Grade B
10) What grade of recommendation can I make when this study is considered along with other available evidence? None – no similar trials found
11) Should I change my practice because of these results? Probably but note the adverse safety profile
12) Should I audit my current practice because of these results? Yes – with involvement of the stroke team for longer follow up

Appraised by: Ewan Jack Victoria Infirmary Glasgow; 22 June 2005
Email: ewanwendy@supanet.com

Kill or Update By: June 2009

Edited by CC & SJM

Citation: EBM Critical Appraisals. Scottish Intensive Care Society EBM Group. Jack E. 2004. : Mayer SA , et al. Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage.NEJM 2005: 352(8); 777 – 785.

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