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"spontaneous intracranial hemorrhage"

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Introduction to Recombinant Activated Factor VII (rFVIIa)
Recombinant activated factor VII (rFVIIa) is approved by the FDA for use in patients with hemophilia A or B with inhibitors, acquired hemophilia, and congenital factor VII deficiency. In the United States, prevalence of hemophilia A and hemophilia B are 1:10,000 and 1:25,000, respectively. Relatively few of these individuals will ever require rFVIIa for treatment as a result of developing antibody inhibitors to the exogenous replacement coagulation factors they are given to replace the deficient factor. In most cases, patients with inhibitors cannot be desensitized to their factor replacement regimen and require rFVIIa to bypass the inhibiting antibodies and to promote clotting during bleeding crises or for surgery and related procedures. The Stanford-UCSF Evidence-based Practice Center used the 2000–2008 data from the Perspective Comparative Database of Premier, Inc. (Charlotte, NC) to assess the in-hospital usage trends of rFVIIa. The Premier database includes information on 40 million annual hospitalizations occurring in 615 U.S. hospitals. Data from the Premier database indicated that in the past decade, off-label use of rFVIIa in the hospital has increased in many other nonhemophiliac bleeding situations that are unresponsive to conventional therapy to control excessive bleeding and reduce exposure to allogeneic blood.

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Introduction to Recombinant Activated Factor VII (rFVIIa)

Presentation: Comparative Effectiveness of In-Hospital Use of Recombinant Factor VIIa for Off-Label Indications vs. Usual Care

Keywords: comparative effectiveness | recombinant factor VIIa | off-label | FDA | hemophilia | spontaneous intracranial hemorrhage | trauma | adult cardiac surgery

Clinical Questions Addressed by the Comparative Effectiveness Review
The report titled, Comparative Effectiveness of In-Hospital Use of Recombinant Factor VIIa for Off-Label Indications vs. Usual Care, addressed the following clinical questions: (1) From an overview of real-world patterns of rFVIIa use and available comparative studies, which clinical populations are receiving off-label rFVIIa and which populations have been scientifically examined, and what are the characteristics of comparative studies evaluating off-label rFVIIa use?; and (2) What are the benefits and harms of using rFVIIa for selected off-label indications in patients with/undergoing: spontaneous intracranial hemorrhage, acquired coagulopathic massive bleeding from body trauma, bleeding from brain trauma, adult cardiac surgery, pediatric cardiac surgery, liver transplantation, or prostatectomy?

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Clinical Questions Addressed by the Comparative Effectiveness Review

Presentation: Comparative Effectiveness of In-Hospital Use of Recombinant Factor VIIa for Off-Label Indications vs. Usual Care

Keywords: comparative effectiveness | recombinant factor VIIa | off-label | clinical questions | benefits | harms

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Overview of In-Hospital, Off-Label vs. On-Label rFVIIa Use From the Premier Database (2000–2008)

Presentation: Comparative Effectiveness of In-Hospital Use of Recombinant Factor VIIa for Off-Label Indications vs. Usual Care

Keywords: comparative effectiveness | recombinant factor VIIa | off-label | Premier Database | adult cardiac surgery | body trauma | spontaneous intracranial hemorrhage

Evidence for rFVIIa Use for Spontaneous Intracranial Hemorrhage vs. Usual Care
Research on this topic identified four randomized controlled trials (RCTs) (two good quality, two fair quality) and one comparative observational study (fair quality) that examined treatment use of rFVIIa in 968 intervention patients. All four RCTs focused on patients who were not on oral anticoagulation therapy (OAT) and had intracerebral hemorrhage, rather than other forms of intracranial bleeding (e.g., subarachnoid or subdural hemorrhage). The observational study examined patients on OAT who could have experienced intracerebral hemorrhage or other forms of intracranial hemorrhage (e.g., subdural bleeding). Intracerebral hemorrhage is associated with high levels of mortality and functional disability. Over one third of patients die within one month, 50 percent have poor functional status at time of discharge, and 20 percent remain institutionalized at three months. Early hematoma growth occurs even in the absence of detectable systemic coagulopathy and is an important independent predictor of mortality and morbidity. There are no proven therapies for intracerebral hemorrhage. The purpose of this section is to describe the comparative studies of rFVIIa versus usual care for the treatment of intracranial hemorrhage, but the section necessarily focuses primarily on intracerebral hemorrhage because the majority of studies focused on this form of hemorrhage. The data for intracranial hemorrhage were analyzed according to low-, medium-, and high-dose rFVIIa groups, defined as less than or equal to 40 µg/kg, greater than 40 but less 120 µg/kg, and at least 120 µg/kg, respectively.

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Evidence for rFVIIa Use for Spontaneous Intracranial Hemorrhage vs. Usual Care

Presentation: Comparative Effectiveness of In-Hospital Use of Recombinant Factor VIIa for Off-Label Indications vs. Usual Care

Keywords: off-label | recombinant factor VIIa | spontaneous intracranial hemorrhage | usual care | comparative effectiveness

Overview of Comparative Effectiveness of rFVIIa for Spontaneous Intracranial Hemorrhage
These studies yielded moderate strength of evidence with good applicability for treatment use in the population targeted by the randomized controlled trials—those with spontaneous intracerebral hemorrhage who were not on anticoagulation therapy. Comparative analysis of patients with spontaneous intracerebral hemorrhage revealed that there was no effect of rFVIIa on mortality or rate of poor functional status; an increased rate of arterial thromboembolic events exists for medium- (41–119 ?g/kg) and high-dose (?120 ?g/kg) groups; however, the low-dose group (?40 ?g/kg) may not have been powered to detect a difference; rFVIIa was associated with a decrease in the percent hematoma expansion; therefore, the evidence suggests that neither benefits nor harms exceed each other for rFVIIa use in spontaneous intracranial hemorrhage.

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Overview of Comparative Effectiveness of rFVIIa for Spontaneous Intracranial Hemorrhage

Presentation: Comparative Effectiveness of In-Hospital Use of Recombinant Factor VIIa for Off-Label Indications vs. Usual Care

Keywords: hematoma expansion | mortality | off-label | poor functional status | recombinant factor VIIa | spontaneous intracranial hemorrhage | thromboembolic events | comparative effectiveness

Relative Hematoma Expansion Is Reduced After rFVIIa Use in Spontaneous Intracranial Hemorrhage
This table reports the relative change in hematoma volume as the standardized mean difference with a 95% confidence interval at three doses of rFVIIa used for spontaneous intracranial hemorrhage. Meta-analysis demonstrated significant reductions in the relative hematoma expansion for patients in the rFVIIa group when compared to the usual care group at all dosing levels. While the large Mayer 2005 study reported a significant dose-response effect of reduced hematoma growth with higher doses of rFVIIa, statistical tests for differences between dosing levels in our meta-analyses found no significant dose effect.

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Relative Hematoma Expansion Is Reduced After rFVIIa Use in Spontaneous Intracranial Hemorrhage

Presentation: Comparative Effectiveness of In-Hospital Use of Recombinant Factor VIIa for Off-Label Indications vs. Usual Care

Keywords: comparative effectiveness | recombinant factor VIIa | off-label | relative hematoma expansion | spontaneous intracranial hemorrhage

Increased Risk of Arterial Thromboembolic Events With rFVIIa for Spontaneous Intracranial Hemorrhage vs. Usual Care
Meta-analysis of arterial thromboembolic events identified, with a moderate level of evidence, significantly higher rates with rFVIIa use when compared to usual care for the medium- and high-dose groups. There was also low level evidence that a similar, but non-significant, finding for the low-dose group (risk difference: low dose 0.025 [95% CI -0.004 to 0.053], medium dose 0.035 [95% CI 0.008 to 0.062], high dose 0.063 [95% CI 0.011 to 0.063]. These results suggest that there is an increase in arterial thromboembolic events with rFVIIa use vs. usual care at medium and high doses; however, the low -dose group may not have been powered to detect a difference. There were no differences between groups in venous thromboembolic events.

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Increased Risk of Arterial Thromboembolic Events With rFVIIa for Spontaneous Intracranial Hemorrhage vs. Usual Care

Presentation: Comparative Effectiveness of In-Hospital Use of Recombinant Factor VIIa for Off-Label Indications vs. Usual Care

Keywords: arterial thromboembolic events | off-label | recombinant factor VIIa | spontaneous intracranial hemorrhage | comparative effectiveness

Conclusions From Available Evidence
For the uses examined, current evidence does not show that off-label use of rFVIIa reduces mortality or improves other direct outcomes. Thromboembolic events are increased by using rFVIIa to treat spontaneous intracranial hemorrhage and in adult cardiac surgery.

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Conclusions From Available Evidence

Presentation: Comparative Effectiveness of In-Hospital Use of Recombinant Factor VIIa for Off-Label Indications vs. Usual Care

Keywords: comparative effectiveness | recombinant factor VIIa | off-label | conclusions