TERAPÉUTICA CLÍNICA
Secondary prophylaxis with rFVIIa in hemophilia and inhibitors: Recommendations from an Experts Committee from Argentina
Raúl Pérez Bianco1,2, Daniela Neme2, Miguel Candela1,2, Miguel de Tezanos Pinto1,2
1Instituto de Investigaciones Hematológicas Mariano R. Castex, Academia Nacional de Medicina, Buenos Aires;
2Fundación de la Hemofilia, Buenos Aires, Argentina
Postal address: Dr. Raúl Pérez Bianco, Instituto de Investigaciones Hematológicas Mariano R. Castex, Academia Nacional de Medicina, J.A. Pacheco de Melo 3081 PB, 1425, Buenos Aires, Argentina Fax: (5411) 4805-0712 int: 29 e-mail: perezbianco@hematologia.anm.edu.ar
Abstract
Secondary prophylaxis with rFVIIa has been the subject of several publications in the past few years.
However, there is no general consensus on how this treatment should be put into practice, as publications
have been very heterogeneous in the dosing schedule they report. Furthermore, the mechanism of action
of rFVIIa and its short half life have been used as arguments against its role in prophylaxis. There have been a
series of recent publications that show that rFVIIa can traffic through the intact endothelium and be stored in
the subendothelium of several organs for a prolonged period of time. In order to consensuate the role of rFVIIa
in prophylaxis, a group of experts from Argentina, resumed available information regarding pharmacology and
clinical experience with this treatment, and developed a series of recommendations to use this drug in the prophylaxis
setting.
Key words: rFVIIa; Prophylaxis; Hemophilia; Inhibitors
Resumen
Profilaxis secundaria con rFVIIa en pacientes con hemofilia e inhibidores: Recomendaciones
de un comité de expertos de Argentina. La profilaxis secundaria con factor VII activado
recombinante (rFVIIa) ha sido objeto de varias publicaciones en los últimos años. Sin embargo, no existe un
consenso general sobre cómo este tratamiento debe ser puesto en práctica, dado que las publicaciones han
sido muy heterogéneas respecto del régimen de dosificación que publican. Además, el mecanismo de acción
del rFVIIa y su vida media corta se han utilizado como argumentos en contra de su papel en la profilaxis. Ha
habido una serie de publicaciones recientes que muestran que el rFVIIa puede atravesar el endotelio intacto y
almacenarse en el subendotelio de diversos órganos durante un período prolongado de tiempo. Con el fin de
consensuar el papel de rFVIIa en la profilaxis, un grupo de expertos de Argentina, ha recopilado la información
disponible sobre la farmacología y la experiencia clínica con este tratamiento, y desarrolló una serie de
recomendaciones para utilizar este fármaco en el ámbito de profilaxis.
Palabras clave: rFVIIa; Profilaxis; Hemofilia; Inhibidores
Prophylaxis therapy with Factor VIII and Factor IX has
been established as the best strategy to decrease the
bleeding frequency and prevent joint damage in people
with hemophilia A (HA) and B (HB) respectively1,2. However,
inhibitor patients, who can represent as much as
36% in severe HA and 8% in severe HB, can not benefit
from this treatment3. This situation leaves inhibitor patients
at a higher risk of developing recurrent joint bleeding
and severe haemophilic arthropathy4, 5.
In February 2010, secondary prophylaxis for patients
with hemophilia and inhibitors with recombinant activated
factor VII (rFVIIa) was approved to be included in the label
of NovoSeven® (Novo Nordisk, Bagsvaerd, Denmark)
by the "Administración Nacional de Medicamentos,
Alimentos y Tecnología Médica (ANMAT)". This new accepted
indication comes after new clinical and pharmacological
evidence supporting the use of rFVIIa in prophylaxis
emerged. All these publications proved prophylactic
use of rFVIIa to be effective6-14, but as they use different
dosing schedules they fail to provide physicians with
a guide on how to implement this treatment.
To address this issue, a group of experts from the
National Foundation of Hemophilia and the National Academy
of Medicine held a consensus meeting to agree on
recommendations for rFVIIa usage in secondary prophylaxis.
This article summarises the pharmacological and clinical
evidence supporting this indication and the recommendations
of the panel of experts on how to put into
practice secondary prophylaxis in hemophilia patients with
inhibitors.
Pharmacological evidence
Since the 1990s, pharmacokinetics and pharmacodynamics of rFVIIa have been thoroughly investigated, proving this drug to have a short half life and a differential behaviour in children than in adults15-19. Pharmacokinetic studies have also shown that rFVIIa has a steady state volume of distribution which can be 5-7 times larger than the plasmatic volume (Table 1). This finding suggests accumulation of rFVIIa. Although this information has been available for more than a decade, it was not until recently, that redistribution through the intact endothelium and accumulation in the subendothelium of rFVIIa could be demonstrated17, providing evidence that this drug can be useful as prophylactic therapy.
TABLE 1.- rFVIIa Pharmacokinetics: Differences in
children and adults*
*Adapted from reference 15
MRT: Mean Residence Time, Vss: Volume of Distribution at steady state
In order to prevent hemarthrosis, rFVIIa must be able
to reach the subendothelium after trafficking through the
intact endothelial layer. Endothelial Cell Protein C
Receptor (EPCR) has been postulated to aid rFVIIa in
this task. Ghosh et al. examined the binding of
radiolabeled FVIIa to endothelial cells and its subsequent
internalization20. They analyzed the behaviour of 125I-FVIIa
in non-stimulated and stimulated human umbilical vein
endothelial cells (HUVEC) in the presence of unlabelled
FVIIa and TF. They also examined the binding and internalization
of 125I-FVIIa to EPCR transfected CHO-K1 cells.
With this model, they were able to demonstrate that 125IFVIIa
bound to non-stimulated HUVEC cells. This binding
was independent of TF and was effectively blocked
by Protein C and monoclonal antibodies against EPCR.
Furthermore, they also demonstrated a marked increase
in 125I-FVIIa binding to EPCR transfected CHO-K1 cells
compared with the wild type. These results provide convincing
evidence that EPCR serves as the binding site
for FVII/FVIIa.
However, binding to endothelial cells does not imply
accumulation in the subendothelium. To address this issue,
Lopez-Vilchez et al., published a paper demonstrating
the traffic of rFVIIa through the endothelial cells and
its redistribution into the subendothelium21. Briefly, this
group exposed cultured endothelial cells and umbilical
veins to rFVIIa for 2 hours and combined immunocytochemical
techniques with confocal microscopy to localize
rFVIIa into the subendothelial compartments. The
exposed vessels were then de-endothelized and exposed
to flowing blood, determining platelet adhesion and fibrin
deposition. The immunocytochemical studies revealed an
enhanced presence of cytoplasmatic rFVIIa that relocate
into the nuclear and peripheral areas in the 24 hours
incubations. These studies also demonstrated that rFVIIa
localized in the endothelium and extended deeper into
the subendothelium of incubated umbilical veins.
Perfusion studies showed that the redistributed rFVIIa
improved fibrin generation and enhanced platelet thrombus
formation, rendering rFVIIa functional from this compartment
once the endothelium has been denudated.
Finally, Gopalakrishnan et al. examined in a murine
model, the extravascular distribution of rFVIIa administered
in a pharmacological dose (120 μg/kg)22. They were
able to demonstrate that rFVIIa associates with the vascular
endothelium, enters into the extravascular spaces
and binds to TF were it could be retained for prolonged
periods of time. Most noticeable, they were able to find
rFVIIa in the bone (in the zone of calcified cartilage) a
week after administration.
Altogether, the evidence provided by these studies
show that rFVIIa by binding with EPCR can traffic through
the intact endothelium, accumulates in the subendothelium
and remains functional for prolonged periods of time.
The slow release of rFVIIa from the storage sites may be
responsible for the prolonged effect of rFVIIa observed in
clinical studies20-22.
Clinical Evidence
Although until recently, rFVIIa was only approved for "on demand" treatment of bleeding episodes in inhibitor patients (both hemophilia A and B), there has been an increasing number of publications in the past few years where this drug was used for prophylaxis (Table 2)6-14.
TABLE 2.- Summary of the clinical experience with rFVIIa as prophylaxis
*Patients were in ITI treatment.
** Resume of congresses presentations on prophylaxis with rFVIIa
Five reports, including data from 9 patients were published
between the years 2000 and 20056-10. These represent
the first experience in the literature of prophylaxis
in inhibitor patients. The overall efficacy was satisfactory
with reduction of bleeding frequency in most patients.
After these preliminary reports, Konkle et al. published
in 2007 the first prospective, multicenter, randomized,
double blind study in inhibitor patients11. This study included
22 hemophilia A and B patients with inhibitors and
a history of heavy bleeding. After a three months observation
period, patients were randomized to receive rFVIIa
90 or 270 μg/kg once daily for three months. The prophylaxis
period was followed by an observation period of three months in which patients received "on demand" therapy.
Both arms showed a significant reduction in bleeding
episodes in the prophylaxis period compared with the
previous observation period (59% reduction for the 270
μg/kg arm and 45% for the 90 μg/kg arm - p<0.0001 for
both schedules). Most strikingly, these reductions persisted
in the 3 months follow up period with a 50% reduction
for the 270 μg/kg patients (p<0.0001) and 27% for
the 90 μg/kg ones (p<0.01). Although orthopaedic joint
scores did not change throughout the study, the reduction
in bleeding frequency was more pronounced in joint
bleeds, and a subsequent quality of life analysis publishes
by Hoots et al. showed a significant improvement in
school/work absenteeism, pain and EQ-5D and VAS
scores23. This trial is the first and only prospective evidence
of the efficacy of a bypassing agent as prophylaxis
therapy for hemophilia patients with inhibitors and
was the basis for the approval of prophylaxis in the
Argentinean label.
Following Konkle et al. publication, a retrospective
survey of 10 hemophilia centres was published by Morfini
et al12. This paper included data from 13 different inhibitor
patients who received completely different schedules
of prophylaxis with rFVIIa. The dosages varied not only
in the doses but also in the interval between doses (doses:
200-1540 μg/kg per week - interval: twice daily to twice a
week). Despite these differences, 12/13 patients experienced
a significant reduction in bleeding frequency.
Another interesting study was published by Jiménez-
Yuste et al13. The authors reported the outcome of 5 patients
with severe hemophilia A and inhibitors. Patients
received 90-100 μg/kg for 6-22 months. When bleeding
frequency was compared between the prophylaxis period
to the period of identical length prior to therapy, a
reduction from a median of 4 (3-10) bleeding episodes to
1(0-5) was reported. Only 1/5 patients developed a target
joint during prophylaxis, however, the total number of
bleeds were reduced in all 5 patients.
In a recent review of the literature, Auerswald et al.
identified 34 additional patients reported in several conference
abstracts who received different prophylaxis regimens24.
The overall results of these reports prove rFVIIa
to be an effective treatment in the prophylaxis setting regardless
the dosing scheduled chosen by the treating
physicians.
It is noteworthy to point out that none of the studies
described above reported thromboembolic events, making
rFVIIa safe as well as effective.
All these publications denote a growing interest in the
field, plus evidence an unmet need for standardization of
this treatment. Overall, there are more than 80 patients
reported in the literature that received rFVIIa as prophylaxis with good results, regardless of the scheduled used.
Congenital hemophilia is a rare disorder and inhibitor
patients represent a minority amongst them, so although
these numbers seem small, they represent a large amount
of inhibitor patients worldwide.
It is highly improbable that another prospective,
randomized trial can define which of the different dosing
schedules reported in the literature is the best for inhibitor
patients, so we decided to review all data and agreed
on a schedule that is effective, safe and feasible in an
outpatient setting, as we believe this are the three characteristics
that a prophylaxis regime should have.
Recommendations
The National Academy of Medicine and the Hemophilia Foundation have been working together in the interdisciplinary care of hemophilia patients for more than 60 years. Together they assist in the care of more than 2000 patients from all around the country and represent the institutions with more experience in the area. Given its position in hemophilia, the authors (who belong to these institutions) agreed to translate their experience and the available information into the recommendations that follow (Table 3).
TABLE 3.- Recommendations for the use of rFVIIa as prophylaxis
*Consider doses used as "on demand" therapy for the selection of initial dose
After reviewing all the clinical data, 5 categories of
patients were identified that would benefit from prophylaxis.
Patients who suffered a life threatening bleeding,
specifically a bleeding in the central nervous system
(CNS), those with recurrent bleeding episodes, those in
preparation for immune tolerance induction (ITI), those
who fail or are not suitable for ITI and those patient in
need for active and/or prolonged physiotherapy.
We based our recommendation for CNS bleeding in
the last consensus for this indication in non-inhibitor patients25.
According to this, all inhibitor patients with an intracranial
haemorrhage should receive treatment with a
bypassing agent for as long as 30 days. After completing
treatment, if the patient is stable, it should be put in a
prophylaxis schedule. For this indication we recommend
180-270 μg/kg every other day for at least six months.
This timeline was adopted in concordance with recommendations
for non-inhibitor patients, however the authors
believe the duration can be prolonged further. In
the case of a second episode, it was agreed that prophylaxis
should be maintained indefinitely, as the risk for a
new episode and sequels increases dramatically with
additional bleedings.
Most papers reporting prophylaxis with rFVIIa are
based on inhibitor patients who suffer recurrent bleeding
episodes. This indication although not life threatening,
carries a big concern for hemophilia caregivers, as frequent
joint bleedings are associated with increase morbidity,
decrease in the quality of life and increase in the
cost of care of these patients. However, there is no clear
definition on what should be considered recurrent bleeding.
Konkle et al., in their prospective evaluation, required
patients to suffered 4 bleedings per month as an inclusion
criteria and a total of ≥ 12 bleeds requiring haemostatic
treatment in the pre-prophylaxis observation period
to be randomized and receive prophylaxis therapy. Using
this work as background, we agreed that any patient
suffering ≥ 3 bleeds per month is a suitable candidate
for prophylaxis. It was also acknowledge by the authors
that some episodes can not be evaluated in this manner
if sequels want to be avoided. So, in the case of bleeding
into iliopsoas muscle, into other big volume muscles or
gastrointestinal bleedings which their natural history is to
recur, we agreed that ≥ 2 episodes in the same area
should be considered in the same way as a recurrent
bleeding and will make the patient suitable for prophylaxis. The dosing schedule we recommend for these patients
is 90-270 μg/kg every other day. Physicians should
take in consideration the dose used for each patient while
on "on-demand" treatment, as if they respond to that dose,
it will probably be wise to start with it and in the case of
lack of efficacy upscale the dosage or reduce the interval
between doses. The duration of treatment in these patients
is the more heterogeneous variable reported in the
literature, with reports of prophylaxis duration varying from
80 days to 50 months. Taking into consideration the results
reported by Konkle et al., we recommend treating
patients for at least 3 months. If after this first course of
prophylaxis, the patient presents again with criteria of
recurrent bleeding, physicians could opt for a new course
of prophylaxis but in this case, our recommendation is to
increase the duration of treatment.
With regards to patients who are candidates for ITI
and those who fail or are not suitable for this treatment,
we recommend evaluating them in accordance with their
bleeding frequency. Should they fulfil any of the criteria
described above, they should be put on prophylaxis; otherwise
it is our recommendation to continue "on demand" treatment with rFVIIa. Dosing and duration of treatment
should also be the same as for recurrent bleeders. In the
particular case of patients in preparation for ITI, prophylactic
treatment should continue until the initiation of immune
tolerance. At this moment, each patient should be
evaluated individually and determine the best course of
action according to prior history and ITI regimen chosen.
The last recommendation includes patients in need
for active or intense physiotherapy24, 25. This indication
can come after a surgery or in an attempt to recover mobility
of a moderate to severe arthropathy. We recommend
using 90-270 μg/kg three times a week coincidental
with the physiotherapy sessions. As for the previous
recommendations, our advice is to start with the usual
dose required for "on demand" therapy and upscale it if
necessary.
In conclusion; the introduction of prophylaxis with
factor VIII has proven to be a major advance in the treatment
of hemophilia patients without inhibitors. This strategy
allowed patients to live a nearly normal life with significant
fewer complications. However, the treatment of
hemophilia patients with inhibitors still remains as one of
the biggest challenges that physicians involved in this
field have to face. Prophylaxis with rFVIIa has emerged
as a viable option for these patients, specifically for patients
with life threatening bleeds and for recurrent bleeders.
There is still no consensus on the dosing schedule
to be used. However, based on the pharmacological evidence,
that supports the use of rFVIIa in daily or every
other day doses; and the clinical evidence that prove this
drug to be efficacious in almost all patients who received
prophylaxis, we develop these recommendations guideline
in an attempt to help physicians in the difficult task of
treating inhibitor patients. They are based on the experience
of the biggest institutions of Argentina dedicated to
the care of people with hemophilia. However, each patient
is different from the next one, so it is our advice to
use these recommendations as a guide and tailor the
prophylaxis therapy for each patient.
Conflicts of interest: Dr. Perez Bianco is member of the Advisory Board of Novo Nordisk Argentina. This study was supported by an unrestricted research grant from Novo Nordisk Argentina.
1. Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007; 357: 535-44.
2. Nilsson IM, Berntorp E, Löfqvist T, Pettersson H. Twenty-five years' experience of prophylactic treatment in severe hemophilia A and B. J Intern Med 1992: 232: 25-32.
3. Darby SC, Keeling DM, Spooner RJ, et al; UK Hemophilia Centre Doctors' Organisation. The incidence of factor VIII and factor IX inhibitors in the hemophilia population of the UK and their effect on a subsequent mortality, 1977-99. J Thromb Haemost 2004; 2: 1047-54.
4. Dobón M, Lucía JF, Aguilar C, Mayayo E, Roca M, Solano V, Peña A, Giralt M, Ferrández A. Value of magnetic resonance imaging for the diagnosis and follow-up of haemophilic arthropathy. Hemophilia 2003; 9: 76-85.
5. Morfini M, Haya S, Tagariello G, et al. European Study on Orthopaedic Status of hemophilia patients with inhibitors. Hemophilia 2007; 13: 606-12.
6. Brackmann HH, Effenberger E, Hess L. Schwaab R, Oldenburg J. NovoSeven in immune tolerance therapy. Blood Coagul Fibrinol 2000; 11(suppl 1): S39-44.
7. Cooper HA, Jones CP, Campion E, Roberts HR, Hedner U. Rationale for the use of high dose rFVIIa in a high-titre inhibitor patient with hemophilia B during major orthopaedic procedures. Hemophilia 2001; 7: 517-22.
8. Saxon BR, Shanks D, Jory CB, Williams V. Effective prophylaxis with daily recombinant factor VIIa (rFVIIa- Novoseven) in a child with high titre inhibitors and a target joint. Thromb Haemost 2001; 86: 1126-7.
9. Bryant PC, Carr ME, Martin EJ, Sutton JF. High dose recombinant activated factor VII in a pediatric patient with factor VIII deficiency and high titer inhibitor. Blood 2003; 102: Abstract 4128.
10. Young G, McDaniel M, Nugent DJ. Prophylactic recombinant factor VIIa in hemophilia patients with inhibitors. Hemophilia 2005; 11: 203-7.
11. Konkle BA, Ebbesen LS, Erhardtsen E, et al. Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors. J Thromb Haemost 2007; 5: 1904-13.
12. Morfini M, Auerswald G, Kobelt RA, et al. Prophylactic treatment of hemophilia patients with inhibitors: clinical experience with recombinant factor VIIa in European Hemophilia Centres. Hemophilia 2007;13: 502-7.
13. Jiménez-Yuste V, Alvarez MT, Martín-Salces M, et al. Prophylaxis in 10 patients with severe hemophilia A and inhibitor: different approaches for different clinical situations. Hemophilia 2009; 15: 203-9.
14. Jiménez-Yuste V, Quintana M, Alvarez MT, Martýín- Salces M, Hernandez-Navarro F. "Primary prophylaxis" with rFVIIa in a patient with severe hemophilia A and inhibitor. Blood Coagul Fibrinolysis 2008; 19: 719-20.
15. Villar A, Aronis S, Morfini M, et al. Pharmacokinetics of activated recombinant coagulation factor VII (NovoSeven) in children vs. adults with hemophilia A. Hemophilia 2004; 10: 352-9.
16. Erhardtsen E, Nony P, Dechavanne M, Ffrench P, Boissel JP, Hedner U. The effect of recombinant factor VIIa (NovoSeven) in healthy volunteers receiving acenocoumarol to an international normalized ratio above 2.0. Blood Coagul Fibrinolysis 1998; 9: 741-8.
17. Girard P, Nony P, Erhardtsen E, et al. Population pharmacokinetics of recombinant factor VIIa in volunteers anticoagulated with acenocoumarol. Thromb Haemost 1998; 80: 109-13.
18. Berrettini M, Mariani G, Schiavoni M, et al. Pharmacokinetic evaluation of recombinant, activated factor VII in patients with inherited factor VII deficiency. Haematologica 2001; 86: 640-5.
19. Klitgaard T, Nielsen T. Overview of the human pharmacokinetics of recombinant activated factor VII. Br J Clin Pharmacol 2008; 65: 3-11.
20. Ghosh S, Pendurthi UR, Steinoe A, Esmon CT, Rao LV. Endothelial cell protein C receptor acts as a cellular receptor for factor VIIa on endothelium. J Biol Chem 2007; 282: 11849-57.
21. López-Vilchez I, Tusell J, Hedner U, Altisent C, Escolar G, Galan AM. Traffic of rFVIIa through Endothelial Cells and Redistribution into Subendothelium: Implications for a Prolonged Hemostatic Effect. JCD 2009; 1: 1-6.
22. Gopalakrishnan R, Hedner U, Ghosh S, et al. Bio-distribution of pharmacologically administered recombinant factor VIIa (rFVIIa). J Thromb Haemost 2010; 8: 301-10.
23. Hoots KW, Ebbesen LS, Konkle BA, et al; NovoSeven (F7HAEM-1505) Investigators. Secondary prophylaxis with recombinant activated factor VII improves health-related quality of life (HRQoL) of hemophilia patients with inhibitors. Hemophilia 2008; 14: 466-75.
24. Auerswald G, Morfini M. Prophylaxis with Recombinant Activated Factor VII in Hemophilia Patients with Inhibitors. JCD 2010; 2: (1).
25. Teitel J, Berntorp E, Collins P, et al. A systematic approach to controlling problem bleeds in patients with severe congenital haemophilia A and high-titre inhibitors. Haemophilia 2007; 13: 256-63.