Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

31st International Stroke Conference

Kissimmee, Florida / February 16-18, 2006

While there are now strategies for acute management of ischemic stroke, no therapy is currently available for management of acute intracranial hemorrhage other than supportive care. This represents a significant gap in stroke management because the prognosis for intracranial hemorrhage is worse than it is for ischemic stroke. Up to 50% of patients die within one month of an acute intracerebral hemorrhage and only about 20% of patients recover sufficiently to live independently. Previously, it was unclear whether therapy administered after an intracranial hemorrhage could prevent or modify disability. However, there is increasing evidence that the damage incurred progresses in the acute period. This has generated interest in identifying hemostatic agents or other therapies that can prevent or modify disability by rapidly asserting bleeding control.

Hematoma Expansion Adversely Affects Outcome

“Hematoma growth, together with initial hematoma volume, is a critical determinant of outcome in intracranial hemorrhage, validating hematoma growth as an important target for therapeutic interventions,” reported Dr. Stephen Davis, Royal Melbourne Hospital, University of Melbourne, Parkland, Australia. “Since hematoma growth resulted in worsened outcome, reduction or prevention of this growth is an important strategy for intracranial hemorrhage treatment.”

Strong evidence that intracerebral hemorrhages continue to progress in the acute period, increasing the risk for both morbidity and mortality, was produced by an analysis of pooled data from four studies. One of these studies was designed to evaluate the association between early hematoma growth and neurologic deterioration (103 patients), while the other three were early clinical trials with recombinant factor VIIa (rFVIIa), a hemostatic agent being developed for treatment of intracerebral hemorrhage (115 patients). These trials were primarily designed to determine a safe and effective dose of this therapy. In all studies, intracranial hemorrhages were documented with computed tomography (CT) within three hours of symptom onset. Based on follow-up CT scans, hematoma volumes were calculated by independent neuroradiologists using digital multi-slice planimetric techniques. Functional status was assessed using the modified Rankin score and the Barthel index in follow-up protocols that differed modestly among the trials included in this analysis. “A total of 72.9% of the patients in the pooled dataset showed some degree of hematoma growth. The overall increase in hematoma volume relative to the baseline CT scan was 41.3%,” Dr. Davis reported.

Pooled Analysis Findings

The mean absolute volume change was 6.9 mL, with relative change in volume providing a sensitive prognostic marker. Specifically, for every 1 mL increase in hematoma volume from baseline, there was a 1% increased risk of death, a 6% greater likelihood of a 1 category increase on the modified Rankin scale (ranging from 0 signifying no disability to 6 signifying death), and a 6% greater likelihood of decreasing level of independence on the Barthel index. Although baseline measures also predicted mortality and morbidity outcomes, the subsequent growth in the intracerebral hemorrhage volume contributed substantially to the final outcomes.

The need for therapy to reduce progression of intracerebral hemorrhage was underscored by the poor outcomes in this pooled analysis. Almost all patients had some degree of disability and 65.6% had a modified Rankin score of 4, signifying inability to walk without assistance or attend to bodily functions, or 5, signifying a bedridden state with incontinence.

According to Dr. Davis, the data from this pooled analysis suggest that both initial volume and evidence of hematoma growth should be used in clinical decision-making. The findings also contribute substantially to evidence that an expanding hematoma over the acute period after an intracerebral hemorrhage contributes independently to a poor clinical outcome. From a clinical perspective, he considered data generated from this pooled analysis to be important because it “provides evidence that intracerebral hemorrhage, like ischemic stroke, is an ongoing dynamic process for which early treatment limiting the volume of expansion would provide an improvement in clinical outcome.”

Complications Adversely Affect Outcome

In a Canadian study, the focus was the effect of in-hospital complications on outcome. The study evaluated data on all patients admitted for intracerebral hemorrhage at 12 acute care hospitals in Ontario. Retrospective analysis of hospital discharge data was conducted to identify all complications, defined as worsening of stroke, new stroke, transient ischemic attack, seizures and non-neurologic events, such as myocardial infarction. Preventable complications were defined as deep venous thromboembolism, embolism, falls, infection and skin ulcers.

Of the 678 patients with a diagnosis of intracerebral hemorrhage, neurological worsening was documented in 33.7%, non-neurological complications were recorded in 8.1% and preventable complications were observed in 22.1%. When patients with any of these complications were compared to those without complications, the difference in the median Canadian Neurological Score was found to be highly significant favouring the absence of complications (6.0 vs. 9.5; P<0.0001).

“Regression analysis showed complications increased length of stay by 11.3 days. Patients with complications had more severe neurologic deficits at discharge, were less likely to be discharged home and had a higher mortality,” reported Dr. Leanne Casaubon, University of Toronto, Ontario. Many of these differences were highly significant. For example, only 9.8% of patients with complications vs. 50.5% of patients without were discharged home (P<0.0001). The mortality rate of 52.8% in the group with complications was approximately three times greater than the 16.8% without complications (P<0.0001).

Preventing Neurologic Worsening

In addition to the complications identified as preventable in this study, Dr. Casaubon indicated that at least some of the neurological worsening might also have been preventable with an effective therapy to avert hemorrhage growth. Although it is not clear what proportion of those patients with neurologic worsening in this study would be candidates for a hemostatic agent such as rFVIIa, Dr. Casaubon specifically cited the current efforts to develop hemostatic agents as promising for control of stroke volume in these patients.

In fact, clinical studies with rFVIIa are progressing rapidly. Now that proof-of-concept and dose-ranging studies have been completed, a phase III study is underway. Approximately 675 patients are being entered in the multicentre FAST (Recombinant Factor VIIa in Acute Intracerebral Hemorrhage) trial. All participants must undergo a baseline CT scan to establish an intracerebral hemorrhage within three hours of symptom onset. Patients are then randomized to 20 µg/kg rFVIIa, 80 µg/kg rFVIIa or placebo. Treatment is to be administered within an hour of the CT scan and no more than four hours after symptom onset. The primary end point of this study, which includes males and females over the age of 18, is the modified Rankin score at day 90.

“We will also be evaluating several important secondary efficacy end points that should provide insight about the main clinical outcome. These include the absolute and per cent change in hematoma volume as measured by CT scans at baseline and at 24 hours and the absolute and per cent change in total lesion volumes,” explained Dr. Stephan Mayer, Columbia University College of Physicians and Surgeons, New York, New York. Additional secondary end points include the Barthel index at day 90 as well as mortality. Safety will be monitored until day 90 or hospital discharge, whichever comes first.

Corroborative Evidence from Initial Trials

The trials that preceded and supported a phase III investigation were highly encouraging. Summarizing these data, Dr. Mayer noted that the increase in intracerebral volume from baseline in patients receiving doses ranging from 40 µg/kg to 160 µg/kg was only 4.2 mL vs. 8.7 mL in the group receiving placebo (P=0.01). This relative protection against a growing hematoma volume was associated with an improvement in outcome over the 90-day follow-up. “At the end of 90 days, 69% of placebo patients died or were severely disabled, as defined by a modified Rankin score of 4 or above, vs. 53% of the patients who received rFVIIa [P=0.004]. Furthermore, patients who received 80 µg/kg had a 2.6 times higher likelihood of achieving a modified Rankin score of 1 or less than those treated with placebo [21% vs. 8%],” Dr. Mayer reported.

In these trials, active treatment was well tolerated, but a re-analysis of these data was recently conducted following several anecdotal reports of thromboembolism in patients treated off-label with rFVIIa. Due to their mode of action, hemostatic agents such as rFVIIa generally have the potential to increase the risk of thrombosis. However, in anecdotal reports, analysis of the relationship between the adverse event and rFVIIa is limited due to the lack of information on alternative etiologies, confounding factors and the number of individuals exposed to off-label rFVIIa for a particular indication. Upon re-analysis of data from the controlled trials, no increased risk of thromboembolism was observed at doses expected to be used clinically. For example, the rate of thromboembolic events was 5.2% in the placebo group, 7.3% at 5 µg/kg to 40 µg/kg and 5.7% at a dose of 80 µg/kg. Although the thromboembolic event rate climbed to 11.3% in the group that received 120 µg/kg to 160 µg/kg, suggesting some degree of dose dependence, this dosage range is not included in the phase III study. Moreover, the 90-day mortality in these trials was 27% for placebo, 18% for those receiving rFVIIa 5 µg/kg to 40 µg/kg, 16% at a dose of 80 µg/kg and 20% at a dose of 120 µg/kg to 160 µg/kg. When the rFVIIa data are pooled, the 18% mortality rate on the active treatment groups was significantly lower than placebo (P=0.0264).

According to Dr. Michael N. Diringer, Washington University School of Medicine, St. Louis, Missouri, “In the 160 µg/kg group, the frequency of arterial events was significantly greater than with placebo, suggesting that in elderly patients with atherosclerosis risk factors, higher doses, although reducing overall mortality, may increase the frequency of thromboembolic events. However, despite the theoretical risks, no significant differences in adverse events were observed in patients receiving lower doses of rFVIIa vs. those receiving placebo. There were no differences between any of the groups, including the highest dose of rFVIIa and placebo, for deep venous thrombosis or pulmonary embolism.”

Addressing Cost Savings

In a cost analysis conducted on the basis of a phase IIb study, active treatment was not only predicted to be cost-effective but also possibly to provide cost savings when assessed from a Medicare perspective. “Intracerebral hemorrhages are extremely costly due to the high proportion of patients who develop disability. Effective treatments that reduce the risk of disability have an enormous opportunity to reduce the consumption of health services,” reported Dr. Stephanie R. Earnshaw, RTI Health Solutions, Research Triangle Park, North Carolina. Dr. Earnshaw, the senior author of this cost analysis, evaluated the influence of 40 µg/kg and 80 µg/kg on patient management using medical costs related to pharmacotherapy, hospitalization, outpatient visits, durable medical equipment, home health care and rehabilitation nursing. She found that the cost per quality-adjusted life-year of treatment with 40 µg/kg of rFVIIa relative to placebo was $5,769 US, which is far below the $50,000 that is generally considered to be a benchmark of favourable cost efficacy. For the 80 µg/kg dose, there was a $5,866 saving. This latter outcome is notable, because savings from therapy are a relatively unusual phenomenon in cost-efficacy analyses.

“A worst-case sensitivity analysis results in an upper bound of $17,585 per quality-adjusted life-year for the 40 µg/kg dose and $3,094 per quality-adjusted life-year for the 80 µg/kg dose,” reported Dr. Earnshaw, emphasizing the potential long-term benefits of an effective therapy for intracerebral hemorrhage. While more data are needed to further explore the potential of rFVIIa as initial medical therapy for intracerebral hemorrhage, the risks of this type of stroke and the limited current therapeutic options have generated substantial interest in the phase III trial.

Summary

New data have confirmed that intracerebral hemorrhages progress after the initial event, increasing the risk of death and disability. As a result, an effective intervention has the potential to substantially improve outcome if administered early enough in the disease process. Currently, there is no therapy available for management of acute intracerebral hemorrhage other than supportive care. The promising results with rFVIIa, a hemostatic agent, in proof-of-concept and dose-ranging studies, have raised hope that an ongoing phase III study will confirm its clinical utility. Due to the enormous costs of the permanent disability associated with intracerebral hemorrhage, a therapy capable of limiting its consequences has the potential to be a major clinical advance.