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Three Part Question

In [adult patients with acute spontaneous intracerebral haemorrhage] is [rFVIIa] better than conservative treatment at improving [survival and functional outcome]

Clinical Scenario

A 50 year old gentleman attends the Emergency Department following a collapse. After initial resuscitation you obtain a CT scan of his brain, which shows a spontaneous intracerebral bleed. You want to know if rFVIIa will improve your patients survival rate / functional outcome.

Search Strategy

Medline, Embase Multifile searching using NHS Evidence date of searching 16 February 2013:
(((haemorrhage$.ti,ab) OR (haemorrhage$.ti,ab) OR (haematoma$.ti,ab) OR (hematoma$.ti,ab) OR (bleed$.ti,ab)) AND ((((Factor AND VII$).ti,ab) OR ((Factor AND 7).ti,ab) OR ((Factor AND 7a).ti,ab)) AND ((brain$.ti,ab) OR (cerebr$.ti,ab) OR (cerebell$.ti,ab) OR (intracerebral.ti,ab) OR (intracran$.ti,ab) OR (parenchymal.ti,ab) OR (intraventricular.ti,ab) OR (infratentorial.ti,ab) OR (supratentorial.ti,ab) OR ((basal AND ganli$).ti,ab) OR (putaminal.ti,ab) OR (putamen.ti,ab) OR ((posterior AND fossa).ti,ab)))) (Limit to: English Language and (Clinical Queries Therapy best balance of sensitivity and specificity OR Clinical Queries Review best balance of sensitivity and specificity (Year Published 2010-Current).

Cochrane Database of Systematic Reviews: Issue 1 of 12, January 2013: ‘Factor VII’ in title abstract keywords in Cochrane Reviews.

Search Outcome

Ninety-two papers found, of which seven were relevant. Only the latest meta-analyses are included in the table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Yuan et al, 2010, China	1305 patients with ICH receiving either placebo (377) or rFVIIa (928)	Meta-analysis of 5 RCTs	All cause mortality	18.7% (rFVIIa), 20.8% (placebo), OR=0.86, 95% CI 0.65-1.15	Methods of randomisation not always given, exclusion criteria changed halfway in one phase 2b trial, wide range of drug dosages prevented evaluation of dose-response relationship, baseline differences existed between treatment and control arms
			Death or dependence on Modified Rankin Scale (MRS) at day 90	OR 0.81, 95% CI 0.48-1.39
			Haematoma growth	Mean percentage growth in ICH volume from baseline to 24 hours. WWD= -11.68%, OR 1.56, 95% CI (-12.19% - 111.6%)
			Thromboembolic adverse events	9.1% (rFVIIa), 6.3% (placebo) OR=1.56, 95% CI 0.98-2.48
Al-Shahi Salman, 2009, Scotland	1398 Patients within 4 h of ICH onset receiving either placebo (423) or rFVIIa (975)	Meta-analysis of 6 RCTs	90 day case fatality	RR 0.85 (95% CI 0.58 to 1.25) No significant reduction with rFVIIa	Methods of randomisation and allocation concealment not always clear in some studies. Assessment of clinical outcome only blinded in 3/6 trials. Exclusion criteria for largest RCT were changed after 197/399 patients were enrolled due to concerns over danger of rFVIIa causing TAE in adults with history of thrombotic/vaso-occlusive disease. Data about the completeness of clinical follow-up provided in only one trial
			Death or dependence on MRS	RR 0.91 (95% CI 0.72 to 1.15) No significant improvement with rFVIIa
			Thromboembolic adverse events	RR 1.37 (CI 0.74 to 2.55) Possible increase in adverse events with rFVIIa

Comment(s)

Initial promising outcomes using rFVIIa appear to have been a result of abnormally poor outcomes in placebo groups. Further trials have shown a lack of efficacy for rFVIIa in intracranial haemorrhage coupled with an increase in thromboembolic adverse events. Unfortunately, the randomised controlled trials did not explore effects of rFVIIa in prespecified subgroups well known to predict mortality and functional outcome in intracranial haemorrhage. Due to the imprecise measurement of effect of treatment in these trials, much larger randomised controlled trials would be required to demonstrate a small overall benefit from haemostatic drugs.

Editor Comment

ICH, intracranial haemorrhage; MRS, modified Rankin scale; RCT, randomised controlled trial; rFVIIa, recombinant factor VIIa; TAE, thromboembolic adverse event.

Clinical Bottom Line

Current evidence does not support the use of rFVIIa in acute spontaneous intracranial haemorrhage.

References

1. Yuan ZH, Jiang JK, Huang WD et al. A meta-analysis of the efficacy and safety of recombinant activated factor VII for patients with acute intracerebral hemorrhage without hemophilia. J of Clin Neuroscience 2010:17; 685-693.
2. Al-Shahi Salman, R Haemostatic drug therapies for acute spontaneous intracerebral haemorrhage Cochrane Database of Systematic Reviews 2009, Issue 4. [Art. No.: CD005951. DOI: ]