AHRQ Effective Health Care Program - Research Reviews

Effectiveness and Off-label Use of Recombinant Factor VIIa
Key questions published 28 Sep 2007

Draft Key Questions Comment Period from 28 Sep 2007 to 26 Oct 2007

Draft Research Review Comment Period open until 31 Jul 2009

Draft Complete

Final Key Questions
Draft key questions for this topic were posted for public comment. Key questions were finalized after review of the comments, assignment to an Evidence-based Practice Center and discussion with technical experts.

1. With respect to the spectrum of disease conditions and patient populations for which rFVIIa has been used or studied outside its current labeled indications:

1a. What are the different indications and populations for which recombinant Factor VIIa has been used and or studied?

1b. What is the clinical setting, dosage range of rfVIIa, study design/size, comparator, and outcomes measured (i.e., volume of red cell products, ICU and ventilator use, ARDS, Multi-organ system failure) in existing studies of rFVIIa?

2. Considering patients with intracranial bleeding;

2a. Does rFVIIa use reduce mortality and/or disability compared with usual care?

2b. Are there subpopulations of patients based on demographic (i.e., ethnicity, sex, age) or clinical factors (i.e., intraventricular hemorrhage, size of bleed, time from onset to treatment) who are more likely to benefit from rFVIIa use?

2c. Does rFVIIa use increase thrombosis-related events (i.e., DVT, PE, thrombotic stroke, MI, other thrombotic events) compared with usual care?

2d. Are there subpopulations of patients based on demographic (i.e., ethnicity, sex, age) or clinical factors who are more likely to experience harm from the use of rFVIIa?

2e. In whom do the benefits of rFVIIa use outweigh the harms (evidence of net benefit) and does net benefit vary by issues such as timing and dosage used?

3. Considering patients with (acquired) coagulopathic massive bleeding including trauma-related hemorrhagic shock:

3a. Does rFVIIa use reduce mortality and/or disability and treatment-related outcomes (volume of red cell and component products, ICU, dialysis and ventilator use, ARDS and multi-organ failure incidence) compared with usual care?

3b. Are there subpopulations of patients based on demographic (i.e., ethnicity, sex, age) or clinical factors (i.e., acidosis, levels, platelet count and fibrinogen level, nature of clinical disorder such as-blunt vs penetrating trauma) who are more likely to benefit from rFVIIa use?

3c. Does rFVIIa use increase thrombosis-related events (i.e., DVT, PE, thrombotic stroke, MI, other thrombotic events) compared with usual care?

3d. Are there subpopulations of patients based on demographic (i.e., ethnicity, sex, age) or clinical factors who are more likely to experience harm from the use of rFVIIa?

3e. In whom do the benefits of rFVIIa use outweigh the harms (evidence of net benefit) and does net benefit vary by issues such as timing and dosage used?

4. Considering patients with non-coagulopathic and acquired coagulopathic states undergoing surgeries including liver transplants, cardiac surgery or prostatectomy:

4a. Does salvage and/or prophylactic rFVIIa use reduce mortality and/or disability and treatment-related outcomes (volume of red cell products, requirement for return to operating room, ICU and ventilator use, ARDS and multi-organ failure) compared with usual care?

4b. Are there subpopulations of patients based on demographic (i.e., ethnicity, sex, age) or clinical factors who are more likely to benefit from rFVIIa use?

4c. Does rFVIIa use increase thrombosis-related events (i.e., DVT, PE, thrombotic stroke, MI, other thrombotic events) compared with usual care?

4d. Are there subpopulations of patients based on demographic (i.e., ethnicity, sex, age) or clinical factors who are more likely to experience harm from the use of rFVIIa?

4e. In whom do the benefits of rFVIIa use outweigh the harms (evidence of net benefit) and does net benefit vary by issues such as timing and dosage used?


BackgroundAcute blood loss and hemorrhage control are clearly concerns of great public health importance and as the therapeutic approach to acute blood loss has continued to evolve, the concept of pharmacological hemostasis has become a subject of much interest within the scientific and medical community.1 A brief survey of recent publications demonstrates a rapidly growing body of literature devoted to the use of therapeutic agents intended to limit or stop acute blood loss due to a wide range of causes. One such promising candidate agent is recombinant factor VIIa (rFVIIa). Initially intended for the treatment of congenital and acquired coagulopathies related to specific factor deficiencies,2 rFVIIa has been proposed as a potential therapeutic agent for use in a broad population of patients with severe bleeding3 including patients without hemophilia.4, 5.

An extensive clinical development effort for this agent provides some support for its potential use as a safe and effective therapeutic agent in patients outside the scope of its original indication.4 Consequently, an expert panel was recently convened by the Society for the Advancement of Blood Management (SABM) and the University HealthSystem Consortium (UHC) in order to review the current literature regarding off-label use of rFVIIa and to develop consensus recommendations for its appropriate off-label clinical use.6 A paucity of controlled prospective trials prevented the panel from conducting a formal systematic review or meta analysis and the authors noted that the resulting clinical recommendations are based largely on case reports and uncontrolled case series.

In addition to the paucity of well designed, controlled, prospective, randomized clinical trials demonstrating effectiveness, the risk of adverse events due the administration of rFVIIa also remains poorly characterized.7 Informed clinical decisions regarding the adoption of any therapeutic modality should optimally be based on a careful and deliberate evaluation of the clinical trials and a synthesis of the resulting data that support its use in relation to any potential harm.

This Comparative Effectiveness Review will examine and synthesize currently available data regarding the off-label use of rFVIIa.

ReferencesVoils S. Pharmacologic interventions for the management of critical bleeding. Pharmacotherapy. Sep 2007;27(9 Pt 2):69S-84S.
Hedner U. Factor VIIa in the treatment of haemophilia. Blood Coagul Fibrinolysis. Aug 1990;1(3):307-317.
Hedner U, Brun NC. Recombinant factor VIIa (rFVIIa): its potential role as a hemostatic agent. Neuroradiology. Oct 2007;49(10):789-793.
Weiskopf RB. Recombinant-activated coagulation factor VIIa (NovoSeven): current development. Vox Sang. May 2007;92(4):281-288.
Franchini M. Recombinant factor VIIa: a review on its clinical use. Int J Hematol. Feb 2006;83(2):126-138.
Shander A, Goodnough L, Ratko T, et al. Consensus Recommendations for the Off-Label Use of Recombinant Human Factor VIIa (NovoSeven®) Therapy. P&T. 2005;30(11):644-655.
Hoots WK. Challenges in the therapeutic use of a "so-called" universal hemostatic agent: recombinant factor VIIa. Hematology Am Soc Hematol Educ Program. 2006:426-431.
OutcomesPrimary outcomes

24-hour and 30-day mortality rates for patients with hemorrhagic shock and perioperative use of the drug
30-day and 6-month mortality rates for all other indications
Disability at one and six months
Amount of red blood cell products administered
Secondary outcomes

ICU-free days
Ventilator-free days
Reduced incidents of ARDS and multi-organ failure
Adverse events

Mortality
DVT, PE, thrombotic stroke, MI, and all thromboembolic events

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AHRQ Effective Health Care Program - Research Reviews