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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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Comparative Effectiveness of Recombinant Factor VIIa for Off-Label Uses vs. Usual Care in the Hospital Setting This slide set is based on the research presented in a comparative effectiveness review (CER) , Comparative Effectiveness of In-Hospital Use of Recombinant Factor VIIa for Off-Label Indications vs. Usual Care, that was developed by the Stanford-UCSF Evidence-based Practice Center for the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-02-0017) and is available online at effectivehealthcare.ahrq.gov. The findings and conclusions in this document are those of the author(s), who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. The information presented here is intended to help health care decisionmakers—clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of health care services. This information is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information, that is, in the context of available resources and circumstances presented by individual patients. CERs represent systematic reviews of the literature and usually compare two or more types of treatments, such as different drugs, devices, or procedures, for the same disease. The talk will cover data collected from the Perspective Comparative Database of Premier, Inc., in Charlotte, NC (2000 to 2008), as well as the current evidence from 10 electronic databases, grey literature, trial registries, and reference lists that were searched. Finally, the manufacturer’s web site and files supplied by the manufacturer of rFVIIa (Novo Nordisk) were reviewed, bibliographies of identified meta-analyses and systematic reviews were searched, and experts in the field were contacted to uncover studies not already identified by these searches. The methods used to develop this CER followed version 1.0 of the Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews published by AHRQ (draft available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf).
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Comparative Effectiveness of Recombinant Factor VIIa for Off-Label Uses vs. Usual Care in the Hospital Setting

Keywords: hospital setting | off-label | recombinant factor VIIa | systematic review | U.S. Department of Health and Human Services | comparative effectiveness
Outline of Study This slide set is based on a comparative effectiveness review (CER) titled, Comparative Effectiveness of In-Hospital Use of Recombinant Factor VIIa for Off-Label Indications vs. Usual Care, that was developed by the Stanford-UCSF Evidence-based Practice Center for the Agency for Healthcare Research and Quality (AHRQ) and is available online at effectivehealthcare.ahrq.gov (Contract No. 290-02-0017). CERs represent comprehensive systematic reviews of the literature and usually compare two or more types of treatments, such as different drugs, for the same disease. The methods used to develop this CER followed version 1.0 of the Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews published by AHRQ (draft available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf). The talk will cover the current evidence on the effectiveness and safety of using recombinant activated coagulation factor VII (rFVIIa) for in-hospital clinical indications beyond those approved by the U.S. Food and Drug Administration (FDA). We will briefly discuss the comparative effectiveness review process, including the specific questions addressed in this CER and the results from this research. Finally, the benefits and harms of rFVIIa are presented in such a way as to promote evidence-based decisionmaking.
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Outline of Study

Keywords: off-label | outline | recombinant factor VIIa | results | comparative effectiveness
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)

Keywords: comparative effectiveness | recombinant factor VIIa | off-label | FDA | hemophilia | spontaneous intracranial hemorrhage | trauma | adult cardiac surgery
The Coagulation Cascade: rFVIIa Mechanism of Action Recombinant activated factor VII is a form of human factor VII produced by recombinant technology. The molecule is 406 amino acids in length and has a molecular weight of 50 kDa. As a protein-based therapy, it must be given intravenously to facilitate coagulation at sites of bleeding and has a half-life of 2.5 hours. This intravenously delivered product works as a potent procoagulant by effectively bypassing parts of the clotting process normally required for clotting. rFVIIa helps to promote clotting in two ways: At physiologic levels and in association with tissue factor (e.g., on damaged tissue), it activates factors IX and X to initiate the clotting leading to formation of a thrombin plug, which allows for clot stability. This normal physiological mechanism suggests that rFVIIa activity is targeted to areas of tissue damage. In pharmacological doses, it also binds to activated platelets and drives the process of thrombin clot formation forward via factor X activation, even in the absence of tissue factor. This mechanism is relatively specific to areas of tissue damage. These mechanisms effectively bypass portions of the clotting process that are normally required for clotting to occur. Thus, clotting can occur despite factor deficiencies (in factors VII, VIII, IX, and XI) or when the number or function of platelets is reduced. It can facilitate control of bleeding in situations where standard human blood product transfusions have failed. While mainly used for hemophilia and related conditions, off-label use of rFVIIa has increased in the hospital setting. Practice patterns have outstripped available evidence as rFVIIa off-label use has transitioned from extraordinarily infrequent use to more common application.
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The Coagulation Cascade: rFVIIa Mechanism of Action

Keywords: coagulation cascade | mechanism of action | recombinant factor VIIa
FDA Approved Indications for rFVIIa Since 1999, the FDA has approved four separate applications that have gradually expanded the scope of rFVIIa use in hemophilia: Hemophilia A or B with inhibitors for bleeding episodes (March 25, 1999). Bleeding and surgery in congenital factor VII deficiency (July 11, 2005). Surgery and invasive procedures in hemophilia A or B with inhibitors (August 12, 2005). Bleeding and surgery in acquired hemophilia (October 13, 2006).
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FDA Approved Indications for rFVIIa

Keywords: acquired hemophilia | congenital factor VII deficiency | FDA-approved indications | hemophilia | inhibitors | recombinant factor VIIa
Off-Label Uses of rFVIIa The use of rFVIIa for off-label clinical indications originates in the ability of rFVIIa to “bypass” multiple defects in the coagulation pathway. These uses are listed by their relative proximity to the FDA approved uses. The following categories suggest increasing extension of rFVIIa use into clinical areas with diminishing similarity to the FDA approved uses. Chronic prophylactic use in hemophilia A and B in the absence of bleeding episodes or procedures. While not approved by the FDA, this form of use has been approved in Australia. Episodic use in other congenital and acquired clotting factor defects, including hemophilia C, von Willebrand’s disease, and factor VII deficiency, as well as in other rare coagulopathies. Episodic use for isolated congenital or acquired clotting defects that arise from deficiency or dysfunction of other components of the coagulation process. This includes platelet dysfunction, such as Glanzmann’s thrombasthenia, which has been approved by the EMEA but not the FDA. Episodic use in disease states where impaired coagulation is but one manifestation. Liver disease is a prominent example, but other conditions include leukemia, lymphoma, and other cancers. Episodic use where anticoagulant therapy contributes to bleeding problems beyond what would exist otherwise. This includes patients on warfarin and those undergoing cardiac surgery with cardiopulmonary bypass that requires heparin anticoagulation. Clinical circumstances where a consumptive coagulopathy has developed as the result of substantial and rapid blood loss. In practice, this often includes trauma patients and those with massive gastrointestinal bleeding. Situations where significant blood loss is anticipated in the absence of pre-existing coagulopathy, as with prophylactic use of rFVIIa in prostatectomy or vascular surgery. Clinical situations requiring prompt cessation of traumatic, surgical, or spontaneous bleeding in non-coagulopathic patients where hemorrhage extension is associated with significant adverse outcomes, as occurs with intracranial hemorrhage, brain surgery, and pulmonary hemorrhage.
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Off-Label Uses of rFVIIa

Keywords: bleeding | clotting factor defects | consumptive coagulopathy | hemophilia | off-label uses | recombinant factor VIIa | comparative effectiveness
The CER Development Process (1) The comparative effectiveness review (CER) topic, Comparative Effectiveness of Recombinant Factor VIIa for Off-Label Uses vs. Usual Care in the Hospital Setting, was nominated in a public process. The nominated topic was reviewed and selected based on need, importance, and feasibility. Sufficient research into the current literature by experts in the field and stakeholders determined that a CER on the off-label usage trends and benefits and harms for select patient populations was needed and would not duplicate existing work. Based on this research, key clinical questions that the report would address were developed and made available for public comment. The Agency for Healthcare Research and Quality (AHRQ) then commissioned the Stanford-UCSF Evidence-Based Practice Center to prepare the CER with input from a Technical Expert Panel. This advisory panel was comprised of experts in different specialties, including anesthesiology, pediatric hematology/oncology, transplantation, pathology, hematology, pharmacology, trauma surgery, and drug risk management. The panel identified important issues, reviewed proposed methods, defined parameters for the review of evidence, and helped develop the draft report.
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The CER Development Process (1)

Keywords: comparative effectiveness | recombinant factor VIIa | off-label | topic nomination | stakeholder | technical expert panel | research process
The CER Development Process (2) Utilization data for rFVIIa was taken from the Perspective Comparative Database of Premier, Inc., in Charlotte, NC (2000–2008). A comprehensive systematic review of the literature was conducted from 10 electronic databases, grey literature, trial registries, and reference lists. Studies on the spectrum of rFVIIa off-label use, effectiveness of rFVIIa for the five AHRQ-selected indications, and studies on the potential harms for the five indications were included. All methods used in the review followed version 1.0 of the Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews published by AHRQ (draft available at: http://effectivehealthcare.ahrq.gov/repFiles/2007_10DraftMethodsGuide.pdf). The draft CER was prepared and published online and was subject to public comment and peer review. Once finalized, the complete report was published on the Effective Health Care Program Web site (available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450).
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The CER Development Process (2)

Keywords: comparative effectiveness | recombinant factor VIIa | off-label | methods | peer review | research process
Framework for Analyzing Outcomes of Off-Label rFVIIa Use in the Hospital Setting This slide delineates the analytic framework for evaluating the off-label use of rFVIIa for the CER titled Comparative Effectiveness of Recombinant Factor VIIa for Off-Label Indications vs. Usual Care. The figure represents the trajectory of a patient who receives rFVIIa at some point during inpatient medical care. The first possible time of drug administration is in the case of prophylactic use (to limit blood loss) during a potentially bloody surgery, such as liver transplantation or cardiac surgery. The second possible time of drug administration is in the case of treatment use, which occurs as an attempt to arrest ongoing bleeding and is employed in numerous clinical scenarios, including intracranial hemorrhage and trauma. The final possible time of drug administration is in the case of end-stage use, as a last-ditch effort to salvage a patient who is dying from massive hemorrhage. Repeat doses of rFVIIa are possible during any of the above applications. Thick horizontal arrows near the top of the figure represent the overlap between the clinical questions addressed in the CER and the different types of rFVIIa use described above. For example, the bar representing the overall use of rFVIIa spans the entire range of potential uses—prophylaxis, treatment, and end-stage—whereas the bar representing the off-label indication of intracranial hemorrhage encompasses only treatment use.
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Framework for Analyzing Outcomes of Off-Label rFVIIa Use in the Hospital Setting

Keywords: comparative effectiveness | recombinant factor VIIa | off-label | framework | outcomes | research process
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

Keywords: comparative effectiveness | recombinant factor VIIa | off-label | clinical questions | benefits | harms
Outcomes of Interest for Off-Label rFVIIa Use in the Hospital Setting This slide lists examples of potential outcomes of rFVIIa use. These encompass a range, from indirect outcomes—of process/resource use or intermediate/surrogate outcomes (which are perhaps the easiest to measure but are not always closely connected to patient status)—to direct clinical endpoints such as death, adverse events, or functional status (which are the most relevant to patient well-being but are often more difficult to measure or occur less frequently than the other outcomes). Ideally, the CER would focus primarily on direct clinical outcomes for each of the clinical research questions, but this is not always possible given that the studies and other data sources may only report indirect outcome measures or have few events of this type.
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Outcomes of Interest for Off-Label rFVIIa Use in the Hospital Setting

Keywords: comparative effectiveness | recombinant factor VIIa | off-label | direct outcomes | indirect outcomes | endpoints | adverse effects
Four Domains Used To Assess Relevant Studies The following four major domains were examined: risk of bias (low, medium, high), consistency (no inconsistency, inconsistency present, unknown, or not applicable), directness (direct, indirect), and precision (precise, imprecise). Each key outcome on each comparison of interest was given an overall evidence grade based on the ratings for the individual domains.
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Four Domains Used To Assess Relevant Studies

Keywords: comparative effectiveness | recombinant factor VIIa | off-label | risk of bias | consistency | directness | precision
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