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

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Rating the Strength of Evidence From the CERThe EPC GRADE approach, based on the standard GRADE approach, was used to assess the quality of the body of evidence for each outcome. The overall strength of evidence was graded as high (further research is very unlikely to change the confidence in the estimate of effect), moderate (further research may change the confidence in the estimate of effect and may change the estimate), low (further research is likely to change the confidence in the estimate of effect and is likely to change the estimate), or insufficient (evidence either is unavailable or does not permit estimation of an effect). The authors also independently evaluated the applicability to real-world practice of the total body of evidence within a given clinical indication using the PICOTS framework (population, intervention, comparator, outcome, timing, and setting).

Rating the Strength of Evidence From the CER

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

Comparative Studies on Off-Label rFVIIa Use
There were 24 randomized clinical trials (RCTs) and 31 comparative observational studies (COSs) available on rFVIIa use across a variety of clinical treatments. rFVIIa use in cardiac surgery (12 studies), trauma (9 studies), intracranial hemorrhage (8 studies), liver transplantation (8 studies), and other liver disease (5 studies) accounted for 57 percent of the 74 included studies. Thus, the focus of the review on rFVIIa use for intracranial hemorrhage, trauma, and cardiac surgery is justified by the prevalence of these uses.
Characteristics of Comparative Studies on Off-Label rFVIIa Use
With the exception of use in ICH, study sample sizes were small (median of 24 treated patients). The doses used in the studies that are the focus of this effectiveness review varied from 5 to 956 mcg/kg of patient weight, and only for intracranial hemorrhage was there a sufficient range of doses to assess the impact of rFVIIa dosing on outcomes. Most studies used indirect endpoints as their primary outcomes, particularly red blood cell (RBC) transfusion requirements. Direct outcomes, such as mortality, functional status, or thromboembolic events, were frequently reported, but most studies were individually underpowered to evaluate them. Most clinical research on rFVIIa has been directed and sponsored by Novo Nordisk, the product’s manufacturer. The strength of evidence available from existing studies was thereby compromised by small study size, use of indirect outcomes, and heterogeneity in dosage and indication. The applicability was diminished by less acutely ill patients and a mismatch between existing research and real-world patterns of indication and types of use.

Characteristics of Comparative Studies on Off-Label rFVIIa Use

Mean Differences in Mortality and Thromboembolic Event Rates by Study and rFVIIa Indication
This figure includes indications with two or more comparative studies: ICH, body trauma (Trauma), brain trauma (TBI), liver transplantation (LvrTx), and adult cardiac surgery (AdCS). Each circle represents a study; larger circles correspond to larger studies; shaded circles represent studies on treatment use of rFVIIa, and white circles represent studies on prophylactic use of rFVIIa. The mean differences in event rates for the direct (patient-centered) outcomes of total mortality and thromboembolic events are plotted for each comparative study and according to each rFVIIa indication using circle charts, with the area of each circle approximating the total sample size of its respective study. The figures show mean differences in mortality and thromboembolic event rates, respectively, for each comparative study and according to each rFVIIa indication. ICH = intracranial hemorrhage here—although in rest of report “ICH” indicates a subset of intracranial hemorrhage, namely intracerebral hemorrhage; Trauma = body trauma; TBI = brain trauma (traumatic brain injury); LvrTx = liver transplantation; AdCS = adult cardiac surgery

Mean Differences in Mortality and Thromboembolic Event Rates by Study and rFVIIa Indication

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.

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

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.

Overview of Comparative Effectiveness of rFVIIa for Spontaneous Intracranial Hemorrhage

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.

Relative Hematoma Expansion Is Reduced After rFVIIa Use in 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.

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

Evidence of rFVIIa Use for Bleeding Secondary to Body Trauma vs. Usual Care
Trauma is the leading cause of death in young men between the ages of 15 and 40. Hemorrhage is the leading cause of early death (within 24–48 hours) in trauma and second only to traumatic brain injury (TBI) as the overall cause of mortality. Hemorrhage after traumatic injury is associated with an acquired coagulopathy known as the “acute coagulopathy of trauma.” The coagulopathy develops when there is tissue injury in combination with hypotension. The severity of coagulopathy increases with increasing injury severity and is associated with worse outcomes. Resuscitation of these patients can worsen the coagulopathy. The dilution of blood due to rapid infusion of crystalloid, the development of hypothermia, and persistent acidosis occur during resuscitation and are known together as the “lethal triad,” which conspires to impede coagulation. Not surprisingly, the conditions which lead to the development of lethal triad are worse in cases of severe hemorrhage, particularly in those cases that require massive transfusions (most frequently defined as the use of 10 or more units of packed red blood cells [RBCs] within 24 hours of injury). This acquired coagulopathy potentiates further bleeding, which in turn leads to further physiologic derangements, increased morbidity, and increased mortality. Unfortunately, blood products that are used to replace lost blood and to treat coagulopathy can carry risks of their own. In particular, studies have highlighted increased risks of acute respiratory distress syndrome (ARDS), multiorgan failure (MOF), and sepsis with higher levels of blood product transfusions. rFVIIa has been investigated in trauma as an adjunct to control bleeding and thereby reduce the above risks.

Evidence of rFVIIa Use for Bleeding Secondary to Body Trauma vs. Usual Care

Overview of rFVIIa Use in Bleeding Secondary to Body Trauma
There were two randomized controlled trials (all fair quality) and three comparative observational studies (all fair quality) with 267 patients who received rFVIIa. This yielded low strength of evidence with fair applicability for treatment use in the population targeted—patients with blunt or penetrating trauma who were not censored for early in-hospital death (defined as 24 hours or 48 hours depending on the study). The findings suggest that there was no effect of rFVIIa on mortality or thromboembolism relative to usual care. There was conflicting evidence regarding RBC transfusion requirements. For acute respiratory distress syndrome, the blunt trauma RCT demonstrated a significant reduction with rFVIIa use vs. usual care, while the remaining two studies that evaluated this outcome (the penetrating trauma RCT and one observational study) showed a nonsignificant trend in the same direction. Overall, current evidence of low strength suggests the potential for benefit and little evidence of increased harm.

Overview of rFVIIa Use in Bleeding Secondary to Body Trauma

Evidence of rFVIIa Use for Bleeding Secondary to Brain Trauma vs. Usual Care
There was one RCT (fair quality) and one comparative observational study (fair quality) with a total of 79 patients who received rFVIIa.

Evidence of rFVIIa Use for Bleeding Secondary to Brain Trauma vs. Usual Care

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