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

Slides: 25–36 of 36
Overview of rFVIIa for Bleeding Secondary to Brain Trauma 
Research yielded low strength of evidence with fair applicability for treatment use in the population targeted—patients with intracranial hemorrhage secondary to TBI who were not on anticoagulation therapy. Regarding the benefits and harms of rFVIIa, our findings include:
There was no effect of rFVIIa on mortality or thromboembolic event rate.
rFVIIa use vs. usual care had no effect on hematoma growth but, in the one study that evaluated it, reduced the time to neurosurgical intervention (e.g., by normalizing the INR to an acceptable level). 
Current evidence of low strength is too limited to compare harms and benefits.
 Regarding subpopulations of patients, our findings include:
Patients with coagulopathy may have increased benefits. 
Patients experiencing blunt trauma to the cerebral vessels may have a greater risk of thromboembolic events when rFVIIa is used.

Overview of rFVIIa for Bleeding Secondary to Brain Trauma

Evidence of rFVIIa Use for Adult Cardiac Surgery vs. Usual Care
Despite advances in methods to control blood loss during and after cardiac surgery, perioperative blood transfusions are required in up to 80 percent of adult patients, and 3 to 5 percent of these patients require postoperative transfusions of over 10 RBC units. Postoperative bleeding that is refractory to surgical re-exploration or conventional hemostatic therapy is felt to be multifactorial, with contributions from the use of antiplatelet agents prior to surgery and various causes of coagulopathy triggered by the surgery itself. There were two RCTs (one good quality, one fair quality) and four comparative observational studies (two good quality, two fair quality) with 251 patients receiving rFVIIa. One of the RCTs assessed prophylactic rFVIIa use, whereas the rest of the studies evaluated treatment use.

Evidence of rFVIIa Use for Adult Cardiac Surgery vs. Usual Care

Overview of rFVIIa for Adult Cardiac Surgery: Clinical Outcomes
The strength of evidence was low for the findings of no effect of rFVIIa use on mortality, units of RBCs transfused, or ICU length of stay. Among the RCTs and higher quality cohort studies, there was a trend toward reduced transfusion requirements with therapy, but no difference in ICU length of stay. Study patients were similar in age to those in the Premier database. Compared to Premier patients, those in the cohort studies had comparable mortality rates, whereas those in the RCTs had somewhat lower mortality rates. The importance and nature of interactions between the timing of treatment use of rFVIIa and important clinical outcomes remain uncertain.

Overview of rFVIIa for Adult Cardiac Surgery: Clinical Outcomes

Increased Risk of Thromboembolic Events With rFVIIa Use for Adult Cardiac Surgery
There is evidence of moderate strength to suggest that the use of rFVIIa in adult cardiac surgery increases the rate of thromboembolic events when compared to usual care. Thus, current evidence of moderate strength (for thromboembolic events) or low strength (for all other outcomes) suggests that neither benefits nor harms substantially exceed each other for rFVIIa use in adult cardiac surgery.

Increased Risk of Thromboembolic Events With rFVIIa Use for Adult Cardiac Surgery

Evidence of rFVIIa Use for Pediatric Cardiac Surgery, Liver Transplantation, and Prostatectomy vs. Usual Care

Evidence of rFVIIa Use for Pediatric Cardiac Surgery, Liver Transplantation, and Prostatectomy vs. Usual Care

Overview of rFVIIa Use for Liver Transplantation
There were four RCTs (two of fair quality, two of poor quality) and one comparative observational study (fair quality) with 215 patients who received prophylactic rFVIIa at initiation of liver transplantation. This yielded low strength of evidence with fair applicability for prophylactic use in the population targeted—patients with cirrhosis of Child’s class B or C. There was no effect of rFVIIa use on mortality or thromboembolism relative to usual care. There was a trend across studies  toward reduced RBC transfusion requirements with rFVIIa use vs. usual care. Neither operating room time nor ICU length of stay  were reduced with rFVIIa use when compared to usual care. Current evidence of low strength is too limited to compare harms and benefits.

Overview of rFVIIa Use for Liver Transplantation

Overview of rFVIIa Use for Pediatric Cardiac Surgery
A total of 40 patients received rFVIIa prophylaxis in one poor-quality RCT (the only included study). This yielded an insufficient strength of evidence and fair applicability for the population targeted—infant patients with congenital heart defects requiring surgical repair. Current evidence is insufficient for comparing the harms and benefits of rFVIIa use in infant patients undergoing cardiac surgery for congenital heart defect repair. The importance and nature of interactions between rFVIIa administration, extracorporeal membrane oxygenation use, and the risk of thromboembolic events remain uncertain.

Overview of rFVIIa Use for Pediatric Cardiac Surgery

Overview of rFVIIa Use for Prostatectomy
The usual care of patients who require prostatectomy has changed considerably over the time period encompassing and since the performance of studies included in this analysis. These changes in practice likely account for the negligible use of rFVIIa noted in the Premier database. There were no deaths in either study group. One patient in the group that received the 20 µg/kg dose experienced a myocardial infarction at day 14, the only thromboembolic event identified in the study. The RBC transfusion requirements were significantly reduced in the rFVIIa group, as was the operating room time.
Overall applicability of the evidence is poor for prophylactic use in the populations targeted—patients undergoing retropubic prostatectomy for prostate cancer or benign hyperplasia but who are not on anticoagulation. In addition, the “usual care” approach to prostatectomy has evolved into something very different, in most cases, from the surgeries evaluated in the included RCT, thereby making the applicability of the comparator also poor. Current evidence is insufficient for comparing the harms and benefits of rFVIIa use in prostatectomy. In addition, the usual care for prostatectomy has likely evolved far beyond the standard of care employed in the RCT, making its relevance to current practice uncertain.

Overview of rFVIIa Use for Prostatectomy

Summary of Outcomes for Most Common Off-Label, In-Hospital Uses of rFVIIa
Overall study quality is fair to poor and the strength of evidence is low, with the exception of meta-analyses of intracranial hemorrhage that had moderate strength of evidence for all outcomes and of a meta-analysis of adult cardiac surgery studies that had moderate strength of evidence for the thromboembolic event outcome. Clinical efficacy is often defined via indirect/surrogate outcomes, such as transfusion requirements, change in hematoma volume, or ICU length of stay. Safety is defined via thromboembolic events and mortality, but individual studies often lack the statistical power to assess these outcomes. Evidence of rFVIIa benefit is suggested for several indications, but largely via the surrogate outcomes used in the included studies and with an uncertain relationship to improved patient survival or functional status. In addition, for some uses, rFVIIa produces an increased risk of thromboembolism. Current evidence of low strength suggests the potential for benefits to exceed harms for bleeding from body trauma. There are no indications where potential risks are likely to greatly exceed the benefits. Intracranial hemorrhage: There are four RCTs and one observational study involving 968 rFVIIa-treated patients. Treatment with rFVIIa reduced expansion of intracranial hematoma volume relative to usual care, but increased the risk of arterial thromboembolic events and did not reduce the rates of mortality or poor functional outcome. Current evidence of moderate strength suggests that neither benefits nor harms substantially exceed each other. Adult cardiac surgery: There are two RCTs and four included comparative observational studies with 251 patients receiving prophylactic or therapeutic rFVIIa. These studies showed that rFVIIa likely increased the risk of thrombembolic events, but failed to show an effect of rFVIIa on other outcomes, including mortality. rFVIIa use for this indication is increasing in the U.S. Body trauma: There are two RCTs and two comparative observational studies examining rFVIIa treatment in 257 patients experiencing massive blood loss from trauma. These suggested a possible reduced rate of ARDS, most likely to be present in cases of blunt trauma, but these findings are complicated by the exclusion of patients with early mortality from both of the RCTs and one of the cohort studies. There is no evidence of effect on mortality or of increased thromboembolic events with treatment. Current evidence of low strength suggests the potential for benefit and little evidence of increased harm.

Summary of Outcomes for Most Common Off-Label, In-Hospital Uses of rFVIIa

Additional Off-Label Uses of rFVIIa Requiring Future Research
Surgery-related uses include: management of abdominal aortic aneurysm (with and without surgical intervention), pediatric cardiac surgery, vascular  surgeries (not related to abdominal aortic aneurysm), and surgical procedures beyond cardiac and vascular surgery.

Additional Off-Label Uses of rFVIIa Requiring Future Research

Additional Off-Label Uses of rFVIIa Requiring Future Research
Medical conditions include: cancer-related conditions, gastrointestinal bleeding not related to liver disease, hematopoietic stem cell transplantation, liver disease (other than transplantation), neonatal conditions (beyond cardiac surgery), obstetrical conditions, primary clotting disorders (other than hemophilia), pulmonary conditions (e.g., pulmonary hemorrhage, pulmonary transplantation), and secondary clotting disorders (e.g., complications of warfarin anticoagulation).

Additional Off-Label Uses of rFVIIa Requiring Future Research

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.

Conclusions From Available Evidence

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