Transcript Efficacy and Safety of Recombinant Activated Factor VII

Efficacy and Safety of
Recombinant Activated Factor VII
for Acute Intracerebral
Hemorrhage
Mayer et al NEJM May 15, 2008
Elianna Saidenberg
TM Resident Journal Club
June 2008
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Let’s start at the beginning…
Mayer et al NEJM Feb 24, 2005
• Double-blind, placebo controlled trial from Aug
2002-March 2004 at 73 hospitals in 20
countries
• Patients who suffered spontaneous ICH were
randomly assigned to receive one IV rFVIIa
dose of 40 mcg, 80 mcg or 160 mcg per kg or
placebo
• Primary endpoint was change in volume of ICH
from baseline to 24 hours
– The study was powered to detect a relative
reduction of 56% in growth of hematoma in any
one of the treatment groups compared to
placebo
– On the basis of a 2-sided Wilcoxon rank-sum
test, with beta=0.80 and alpha=0.0167, an
estimated standard deviation of 33% and a 20%
drop out rate
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Table 1
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Table 2
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Clinical outcomes
• Mortality at 3 months:
– 29% in placebo group
– 18% in rFVIIa groups combined
• Outcome scales:
– More favourable outcome in rFVIIa groups combined
versus placebo group
– Treatment with rFVIIa doubled the odds of improving
by one level in the modified Rankin Scale at 90 days
– Proportion of patients dead or severely disabled was
69% in placebo group and 53% in treatment groups
combined
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Table 3
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A little more on safety data
• The serious thromboembolic events in the rFVIIa groups:
– 7 myocardial ischemic events characterized by small elevations in
troponins, and “non-ST-segment elevation electrocardiographic
abnormalities”
– 2 massive fatal cerebral infarctions
– 5 moderately severe and disabling cerebral infarctions (2/5 occurred
>25 days after treatment)
– 2 asymptomatic cerebral infarctions
• “Arterial thromboembolic serious adverse events occurred
significantly more frequently with rFVIIa treatment than with placebo,
primarily in the form of myocardial ischemic events and cerebral
infarction within three days after the study drug was given. The
majority of patients recovered from these complications, and the
overall frequency of fatal or disabling thromboembolic serious
adverse events did not differ significantly between rFVIIa and the
placebo groups.”
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The authors conclude:
• “…ultra-early hemostatic therapy with
rFVIIa limits the growth of hemorrhage,
reduces mortality, and improves functional
outcomes after intracerebral hemorrhage.
Until additional data on safety are
available, however, rFVIIa should be
administered with caution to patients with
intracerebral hemorrhage who have risk
factors for thromboembolic disease.”
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What has happened since 2005?
• Assessment of the Registry of the
Canadian Stroke Network revealed that
only about 1/5 of Canadian ICH patients
would benefit from rFVIIa if it were
approved for this indication. The major
exclusion factor would be time to
diagnosis
•
Nadeau et al Cerebrovascular Diseases 22(4):271-5, 2006
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What has happened since 2005?-2
• 30-50% of patients with spontaneous ICH also
experience IVH. Mortality for patients with IVH
is ~5 times higher than for those with ICH alone.
• So Steiner and colleagues sought to identify
factors that influence the dynamics of IVH
growth during the acute stages of hemorrhage,
analyze the isolated effect of IVH growth on
overall mortality and morbidity and determine
the impact of treatment with rFVIIA on early IVH
growth.
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• This study represented “a planned secondary analysis of
data from a multicenter, randomized, placebo-controlled
trial on the effectiveness of rFVIIa in spontaneous ICH.”
• Analysis revealed that “the risk of further increases in
IVH volume was reduced when patients received rFVIIa.
A greater percentage of rFVIIa-treated patients had a
favourable functional outcome across all groups,
although these results did not reach statistical
significance…suggest that the clinical effect of rFVIIa on
functional outcome in patients with ICH may be, at least
in part, caused by its effects on both ICH and IVH
expansion.”
• No mention is made of safety concerns
• Neurosurgery 59:767-774, 2006
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What has happened since 2005? -3
• Earnshaw et al hypothesized that “if rFVIIa were
introduced as a treatment for ICH it would have a
substantial impact on drug costs, medical resource
costs, quality-adjusted life years and possibly costeffectiveness.”
• To test this hypothesis they developed a decisionanalytic model designed to calculate costs, life years,
QALYs, incremental cost per life year gained and
incremental cost per QALY gained
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The model
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The Results
• Lifetime medical costs:
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Treatment with placebo: $159,055
Treatment with 40 mcg rFVIIa: $167,160
Treatment with 80 mcg rFVIIa: $153, 264
Treatment with 160 mcg rFVIIa: $163, 730
• The authors conclude that “increases in cost
incurred because of the administration of rFVIIa
are offset by decreases in expected lifetime
medical costs associated with ICH.”
• Stroke, November 2006
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What has happened since 2005?-4
• Hallevi et al assess 46 patients treated with rFVIIa, 24 treated
within 3 hours of symptom onset and 22 treated 3-4 hours from
symptom onset to determine if the time window for use of
rFVIIa could be extended to 4 hours from symptom onset
• Study end points were hematoma growth at 24 hours, inhospital mortality and modified Rankin score on discharge
• They found that the clinical outcome was comparable in the 2
groups
• They report 7 thromboembolic events: 4 MIs, 2 DVTs and 1 PE
but give no further details
– Assuming a different person experienced each of the 7 events that
would give a rate of 15%
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Finally…The Study
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Phase 3 trial to confirm the previous study
Patients randomized to placebo, 20 mcg rFVIIa or 80 mcg rFVIIa
administered within 1 hour of CT scan and no more than 4 hours from
onset of symptoms
Inclusion criteria:
– ≥18 years of age
– Spontaneous ICH documented by CT scan within 3 hours of onset of symptoms
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Exclusion criteria:
– GCS ≤5
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Coma or death GCS 3
Severe, with GCS ≤ 8
Moderate, GCS 9 - 12
Minor, GCS ≥ 13
Planned surgical evacuation of hematoma
Secondary ICH
Use of anticoagulants
Known thrombocytopenia or coagulopathy
Sepsis
Crush injury
DIC
Pregnancy
Prestroke modified Rankin score >2
Thromboembolic disease <30 days before enrolment
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• Primary outcome: Severe disability or death as defined
by score on modified Rankin scale at 90 days
– Analyzed on an intention-to-treat basis
– Study was powered to detect an odds ratio of poor outcome of
≤0.53 with rFVIIa compared to placebo on the basis of a onesided chi-square test with a beta=0.10 and alpha=0.025 but
midway review revealed the need to increase target enrolment to
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– Is this 100% Kosher?
• Recall that the primary outcome in the phase 2 trial was ICH
growth not clinical outcomes
• Recall:
– Phase II trials are designed to assess how well the drug
works, as well as to continue Phase I safety
assessments in a larger group of volunteers and patients.
– Phase III studies are randomized controlled multicenter
trials on large patient groups and are aimed at being the
definitive assessment of how effective the drug is, in
comparison with current 'gold standard' treatment.
• Secondary outcomes: Barthel index, Extended Glasgow
Outcome Scale, NIHSS, EuroQol scale and the Revised
Hamilton Rating Scale for Depression all measured at 90
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days
Figure 1
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Table 1
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Table 2
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Table 3
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If ye seek….
• Exploratory post hoc analyses analysed the effect of 80
mcg/kg of rFVIIa in younger patients with smaller
hemorrhages treated in an earlier time frame
• These analyses found that in a subgroup of patients the
adjusted odds ration for poor outcomes at 90 days was
0.28 (P=0.03)
• The patients had to be:
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≤70 years of age
With a baseline volume of ICH of ≤60 mL,
With a baseline volume of IVH of ≤5 mL
Time from onset of symptoms to treatment of 2.5 hours
• Patients with these characteristics accounted for 19% of
the study population
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Author’s Conclusions
• rFVIIa “significantly reduced growth of the hematoma but
failed to improve survival or funtional outcome at 90
days…Possible explanations for these discrepant
findings include randomization imbalances, an increase
in arterial thromboembolic events with rFVIIa treatment,
the inclusion of very elderly patients at high risk for nonneurological causes of death, and substantially better
outcomes in the placebo group as compared with our
previous trial.”
• They summarize that “rFVIIa reduced hematoma growth
but did not reduce the rate of death or severe disability
after ICH. Whether this hemostatic effect can translate
to clinical benefit in a subgroup of patients at high risk for
active bleeding, either by treatment within an earlier time
window or by demonstration of intra-hematomal contrast
extravasation after CT angiography, deserves further 23
study.”
The Checklist
• Are the results valid?
– Were the patients randomized? 
– Was randomization concealed?  See 2005 study
– Were patients analyzed in the groups to which they
were randomized? 
– Were patients in the treatment and control groups
similar with respect to known prognostic variables? 
– Were patients aware of group allocation? 
– Were clinicians aware of group allocation? 
– Was follow up complete? 
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The Checklist-2
• What are the results?
– How large was the treatment effect?
• The primary outcome measure did not differ
significantly between the 2 groups
– How precise was the estimate of the
treatment effect?
• OR for poor outcome was 0.6-1.6 for rFVIIa 20
mcg/kg and 0.9-2.2 for 80 mcg/kg
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The Checklist-3
• How can I apply the results to patient
care?
– Were the study patients similar to patients in
my practice? 
– Were all clinically important outcomes
considered? 
• For more information about the scoring systems used in stroke research please see
http://www.strokecenter.org/
– Are the likely treatment benefits worth the
potential harms and costs?
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•
Costs and Harms vs Benefits
Lifetime medical costs:
– Treatment with placebo: $159,055
– Treatment with 40 mcg rFVIIa: $167,160
– Treatment with 80 mcg rFVIIa: $153, 264
– Treatment with 160 mcg rFVIIa: $163, 730
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Stroke, November 2006
No increase in the frequency of VTE
Increased troponin:
– Placebo group-15%
– 20 mcg rFVIIa-13%
– 80 mcg rFVIIa-22%
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STEMI
– Placebo group- 1.5%
– 20 mcg rFVIIa- 0.4%
– 80 mcg rFVIIa- 2.0%
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CT evidence of cerebral infarction
– Placebo group- 2.2%
– 20 mcg rFVIIa- 3.3%
– 80 mcg rFVIIa- 4.7
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Absolute increase of 5% in frequency of arterial events in the 80 mcg rFVIIa
group compared to placebo
No improvement in survival or functional outcome at 90 days
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