1 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

2 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

3 Table 1

4 Table 2

5 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

6 Table 3

7 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.”

8 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.”

9 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

10 What has happened since 2005? % 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.

11 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: , 2006

12 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 cost- effectiveness.” To test this hypothesis they developed a decision- analytic model designed to calculate costs, life years, QALYs, incremental cost per life year gained and incremental cost per QALY gained

13 The model

14 The Results 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 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

15 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, in- hospital 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%

16 Finally…The Study 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 Exclusion criteria: –GCS ≤5 Coma or death GCS 3 Severe, with GCS ≤ 8 Moderate, GCS 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

17 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 one- sided chi-square test with a beta=0.10 and alpha=0.025 but midway review revealed the need to increase target enrolment to 816 –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 days

18 Figure 1

19 Table 1

20 Table 2

21 Table 3

22 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: –≤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

23 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 non- neurological 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 study.”

24 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? 

25 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 for rFVIIa 20 mcg/kg and for 80 mcg/kg

26 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 –Are the likely treatment benefits worth the potential harms and costs?

27 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 Stroke, November 2006 No increase in the frequency of VTE Increased troponin: –Placebo group-15% –20 mcg rFVIIa-13% –80 mcg rFVIIa-22% STEMI –Placebo group- 1.5% –20 mcg rFVIIa- 0.4% –80 mcg rFVIIa- 2.0% CT evidence of cerebral infarction –Placebo group- 2.2% –20 mcg rFVIIa- 3.3% –80 mcg rFVIIa- 4.7 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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