Evaluation of Off-Label Recombinant Activated Factor VII for Multiple Indications in Children

Abstract Abstract 4192 Background Most hospitals have clinical guidelines for the off-label use of recombinant activated Factor VII (rFVIIa, Novoseven), primarily as part of a massive transfusion protocol. Over the past years rFVIIa has increasingly been used outside the approved indications in haemophilia with inhibitors and Glanzmann's Thrombasthenia, particularly in trauma, cardiac surgery and other critical bleeding episodes. Use in these areas remains controversial. Methods Monash University established the Haemostasis Registry in 2005 (with an educational grant from NovoNordisk Pharmaceuticals) to monitor the use of rFVIIa throughout Australia and New Zealand. More than 95 hospitals are contributing data to the Registry including all major users of rFVIIa in Australia and New Zealand. As part of the process of joining the Registry project, participating hospitals are asked to supply copies of their protocols for use of rFVIIa. Results Approximately 3000 cases of rFVIIa use have been reported to the Register. Major areas of use are cardiac surgery (∼ 41%), other surgery (∼17%) and trauma (∼15%). The majority(77.3%) of hospitals have documented protocols for rFVIIa use. Many of these are similar and are centred around situations of massive transfusion. However, 64.5% of cases of rFVIIa use submitted to the Haemostasis Registry, from hospitals where protocols exist, do not conform with the numerical components of these protocols. Conclusions This is the largest dataset of rFVIIa cases published to date and can now provide greater insight into the actual rather than theoretical use of rFVIIa in Australia and New Zealand. Lack of compliance with hospital protocols for rFVIIa use indicates either that the protocols do not reflect actual and appropriate use or that clinicians need to be further educated regarding what is currently considered appropriate use. In the absence of sound clinical trial evidence, consensus regarding appropriate use has not been achieved. In these circumstances, data from the Haemostasis Registry continues to be important in elucidating the safety and efficacy of rFVIIa and providing important feedback to doctors and hospitals. The Haemostasis Registry is funded through an unrestricted Educational Grant from NovoNordisk Pharmaceuticals Pty Ltd. None of the authors have a financial interest in the outcomes of the study. Disclosures: Off Label Use: Recombinant activated Factor VII (rFVIIa, Novoseven). FVIIa is a naturally occurring initiator of haemostasis. Its recombinant form, rFVIIa, is approved for the treatment of spontaneous & surgical bleeding in patients with haemophilia A or B and with antibodies to either factor VIII or factor IX. It has been extensively used amongst haemophiliacs and appears to enhance clotting at the site of bleeding without systemic activation of the coagulation cascade At high doses rFVIIa binds to the surface of activated platelets and initiates the coagulation cascade at these sites Recently various case series and case reports have reported the efficacy of rFVIIa in patients with life-threatening bleeding in patients with coagulation disturbances but without coagulation inhibitors.

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Off-label use of recombinant activated factor VII in intractable haemorrhage after cardiovascular surgery: an observational study of practices in 23 French cardiac centres (2005–7)

European Journal of Cardio-Thoracic Surgery ◽

10.1016/j.ejcts.2011.03.032 ◽

2011 ◽

Cited By ~ 2

Author(s):

Marie Hacquard ◽

Marion Durand ◽

Thomas Lecompte ◽

Stéphanie Boini ◽

Serge Briançon ◽

...

Keyword(s):

Observational Study ◽

Cardiovascular Surgery ◽

Factor Vii ◽

Off Label Use ◽

Recombinant Activated Factor Vii ◽

Off Label ◽

Activated Factor Vii ◽

Label Use

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Off-label use of recombinant activated factor VII in surgical and non-surgical patients at 16 Canadian hospitals from 2007 to 2010 (Canadian Registry Report)

Canadian Journal of Anesthesia/Journal canadien d anesthésie ◽

10.1007/s12630-014-0184-z ◽

2014 ◽

Vol 61 (8) ◽

pp. 727-735 ◽

Cited By ~ 11

Author(s):

Keyvan Karkouti ◽

Ramiro Arellano ◽

Tim Aye ◽

Jean-Yves Dupuis ◽

Blaine Kent ◽

...

Keyword(s):

Surgical Patients ◽

Factor Vii ◽

Off Label Use ◽

Recombinant Activated Factor Vii ◽

Off Label ◽

Activated Factor Vii ◽

Registry Report ◽

Label Use

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The hemostatic profile of recombinant activated factor VII. Can low concentrations stop bleeding in off-label indications?

Thrombosis Journal ◽

10.1186/1477-9560-8-8 ◽

2010 ◽

Vol 8 (1) ◽

pp. 8 ◽

Cited By ~ 4

Author(s):

Raul Altman ◽

Alejandra Scazziota ◽

Maria de Lourdes Herrera ◽

Claudio D. Gonzalez

Keyword(s):

Factor Vii ◽

Recombinant Activated Factor Vii ◽

Off Label ◽

Activated Factor Vii ◽

Low Concentrations

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Recombinant Activated Factor VII (rFVIIa) in the Treatment of Non-Hemophilia Patients: Physician Underreporting of Thromboembolic Adverse Events.

Blood ◽

10.1182/blood.v110.11.3143.3143 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3143-3143

Author(s):

Cyrus C. Hsia ◽

Joanna H. Zurawska ◽

Michael Z.Y. Tong ◽

Kathleen Eckert ◽

Vivian C. McAlister ◽

...

Keyword(s):

Adverse Events ◽

Chart Review ◽

Tertiary Care ◽

Factor Vii ◽

High Risk Population ◽

Tertiary Care Centre ◽

Recombinant Activated Factor Vii ◽

Off Label ◽

Activated Factor Vii

Abstract Background: Recombinant activated factor VII (rFVIIa) is a potent hemostatic agent with a short half-life of 2.6 hours and is approved for various hereditary and acquired bleeding disorders. Its “off-label” utilization has increased and is the focus of a number of ongoing clinical trials. One concern is that its beneficial hemostatic effect may be offset by the potential for thromboembolic adverse events (TAEs). Despite its short half-life, rFVIIa likely produces a sustained hemostatic effect and the potential for thromboembolic events may also be prolonged. A recent review of adverse events reported to the FDA suggested that this risk was substantial. The duration that this risk may be present is unclear. Physicians may only consider adverse events to be causally related in the immediate few hours after administration of rFVIIa leading to underreporting TAEs. We conducted a retrospective review of all off-label uses of rFVIIa comparing physician reporting of TAEs to documented TAEs on chart review. Methods: Chart review of all non-hemophilia adult patients who had received rFVIIa at our tertiary care centre was completed. Following all off-label administration, questionnaires were routinely sent to all treating physicians to report outcomes and adverse reactions with the use of rFVIIa. We included all non-hemophilia adult patients at our tertiary care centre who have received rFVIIa. Exclusion criteria were age < 18 and patients with hemophilia or other bleeding disorders for which rFVIIa use is approved. TAEs identified during chart review were compared to physician reporting on questionnaires. Results: A total of 71 patients, 32 females and 39 males, satisfied study criteria during the period January 1, 2003 to June 30, 2007. Mean age was 54 (range 18–84). This was a high-risk population with 34 (47.9%) deaths. Mean duration of follow-up was 30 days (within 1 day to 312 days). Total doses of rFVIIa administered ranged from 2.4–19.2mg (mean 8.2mg) given in 1 to 4 divided doses. 11 arterial and 5 venous TAEs identified on chart review were deemed possibly or probably related. These occurred on average 25 days (within 2 day to 89 days) after exposure to rFVIIa. In total, 50 physician questionnaires (70%) were completed. There were no TAEs reported to the transfusion safety officer at our institution by the treating physician(s) in these questionnaires. Conclusions: Clinically important thromboembolic events due to recombinant activated factor VII are under-reported in this high-risk population. This review was not designed to determine if rFVIIa alters the rate of TAEs but emphasizes the need for careful follow-up, both immediate as well as longterm, of patients who have hemorrhage or are at risk of hemorrhage. Physicians treating patients with rFVIIa should be vigilant for potential TAEs beyond the immediate treatment period.

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Validation of the European Practice Guidelines for the Use of Recombinant Activated Factor VII In Patients with Massive Bleeding

Blood ◽

10.1182/blood.v116.21.4744.4744 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4744-4744

Author(s):

Prasad Pillai ◽

Raghuveer Ranganathan ◽

Rodina Vatanparast ◽

Ravindar Reddimallu ◽

Sarah Lantz ◽

...

Keyword(s):

Cardiac Surgery ◽

Hemophilia A ◽

Penetrating Trauma ◽

Massive Bleeding ◽

Factor Vii ◽

Recombinant Activated Factor Vii ◽

Off Label ◽

European Guidelines ◽

Activated Factor Vii ◽

Surgical Bleeding

Abstract Abstract 4744 Recombinant activated factor VII (rfVIIa) is approved for the treatment of bleeding in patients with hemophilia A or B with inhibitors, congenital factor VII deficiency and Glanzman's thrombasthenia. Since its approval there has been an increase in off-label use of rfVIIa in patients with massive bleeding. In 2006, a European consensus guideline was developed for the use of rfVIIa as an adjunctive therapy for massive bleeding1. The European guidelines recommend using rFVIIa in patients with massive bleeding from blunt trauma, post-partum hemorrhage and uncontrolled post surgical bleeding including cardiac surgery. The guidelines do not recommend use of rfVIIa for penetrating trauma, elective or liver surgery prophylaxis and bleeding in patients with cirrhosis. It is recommended that the efficacy of rfVIIa should be assessed visually and based on transfusion requirements. We conducted a retrospective study in 60 consecutive patient admissions to the Hahnemann University Hospital who were given rfVIIa over the past 2.5 years. The data was analyzed to assess the efficacy according to the clinical indications to validate the European practice guidelines. Details of the results are shown in the table below. In our analysis, use of rfVIIa in patients with inhibitors and uncontrolled post-surgical bleeding including cardiac surgery was effective in achieving hemostasis in an average of 6.4 hours. Conversely in blunt trauma we did not find significant hemostasis. We suspect that this was attributable to the presumed cirrhosis and active anticoagulation therapy in four of the eleven patients. Our study supports the consensus that rfVIIa therapy is not effective in bleeding patients with cirrhosis and penetrating trauma in achieving hemostasis. The average utilization of PRBC/Platelets/FFP in patients with penetrating trauma and cirrhosis were 4.3/0.9/4.2 in comparison with 1.1/0.3/1.0 in patients with inhibitors and uncontrolled peri-operative bleeding including cardiac surgery. The dosing and frequency of rfVIIa was inconsistent, ranging from 60–120 mcg/kg every 2–12 hours and over 1 to 45 days. We observed only one adverse event of venous-thromboembolism at a median follow up of 11 days in the entire group. We conclude that our study validates the efficacy of rfVIIa as an adjunctive therapy for massive bleeding in selected patient populations as recommended in the European guidelines. In addition, there is wide variation in the off-label usage of this product emphasizing the need for a clinical practice guideline for the use of recombinant activated factor VII in the USA. *Diffuse alveolar hemorrhage, Hemorrhage on anticoagulation, AML/MDS with thrombocytopenia, Congenital Hemophilia A, and Type I vWD. 1. Vincent JL, Rossaint R, Riou B, Ozier Y, Zideman D, Spahn DR: Recommendations on the use of recombinant activated factor VII as an adjunctive treatment for massive bleeding – a European perspective, Crit Care 2006, 10:R120. Disclosures: Off Label Use: Recombinant activated factor VIIa (rfVIIa) is approved for the treatment of bleeding in patients with hemophilia A or B with inhibitors, congenital factor VII deficiency and Glanzman's thrombasthenia.

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