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Consensus perspectives on prophylactic therapy for haemophilia: summary statement.
Berntorp, Erik; Astermark, Jan; Björkman, S; Blanchette, V. S.; Fischer, K.; Giangrande, P. L.
F.; Gringeri, A.; Ljung, Rolf; Manco-Johnson, M. J.; Morfini, M.; Kilcoyne, R. F.; Petrini, P.;
Rodriguez-Merchan, E. C.; Schramm, W.; Shapiro, A.; M Van Den Berg, H.; Hart, C.
Published in:
Haemophilia
DOI:
10.1046/j.1365-2516.9.s1.17.x
2003
Link to publication
Citation for published version (APA):
Berntorp, E., Astermark, J., Björkman, S., Blanchette, V. S., Fischer, K., Giangrande, P. L. F., Gringeri, A., Ljung,
R., Manco-Johnson, M. J., Morfini, M., Kilcoyne, R. F., Petrini, P., Rodriguez-Merchan, E. C., Schramm, W.,
Shapiro, A., M Van Den Berg, H., & Hart, C. (2003). Consensus perspectives on prophylactic therapy for
haemophilia: summary statement.
Haemophilia
,
9
(Suppl 1), 41278. https://doi.org/10.1046/j.1365-2516.9.s1.17.x
Total number of authors:
17
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Consensus perspectives on prophylactic therapy for
haemophilia: summary statement
E. BERNTORP, J. ASTERMARK, S. BJO
¨
RKMAN,* V. S. BLANCHETTE, K. FISCHER,à
P. L. F. GIANGRANDE,§ A. GRINGERI,– R. C. LJUNG,** M. J. MANCO-JOHNSON,
M. MORFINI,àà R. F. KILCOYNE,§§ P. PETRINI,–– E. C. RODRIGUEZ-MERCHAN,***
W. SCHRAMM, A. SHAPIRO,ààà H. M. VAN DEN BERGà and C. HART§§§
Department of Coagulation Disorders, Malmo
¨
University Hospital, Malmo
¨
, Sweden, *Hospital Pharmacy, Malmo
¨
University Hospital, Malmo
¨
, Sweden, Division of Haematology/Oncology, The Hospital for Sick Children, Toronto,
Ontario Canada, àVan Creveldkliniek, University Medical Center Utrecht, Utrecht, The Netherlands, §Oxford
Haemophilia Centre, The Churchill Hospital, Headington, Oxford, UK, –Haemophilia and Thrombosis Centre,
Department of Internal Medicine, IRCCS Maggiore Hospital and University of Milan, Milan, Italy, **Departments
of Paediatrics and Coagulation Disorders, Malmo
¨
University Hospital, Malmo
¨
, Sweden, Mountain States Regional
Hemophilia and Thrombosis Center, Aurora, CO, USA, ààHemophilia Center, Azienda Ospedaliera Careggi, Florence,
Italy, §§University of Colorado Health Sciences Center, Denver, CO, USA, ––Department of Paediatric/Coagulation
Disorders, Karolinska Hospital, Stockholm, Sweden, ***Haemophilia Centre, and Service of Traumatology and
Orthopaedics, La Paz University Hospital, Madrid, Spain, Klinikum der Universitat Munchen, International
Hemophilia Centre, Munchen, Germany, àààIndiana Hemophilia and Thrombosis Center, Inc. Indianapolis, IN, USA,
§§§InforMEDical, Inc., Narberth, PA, USA
Summary. Participants in an international confer-
ence on prophylactic therapy for severe haemophilia
developed a consensus summary of the findings
and conclusions of the conference. In the consensus,
participants agreed upon revised definitions for
primary and secondary prophylaxis and also made
recommendations concerning the need for an inter-
national system of pharmacovigilance. Consider-
ations on starting prophylaxis, monitoring
outcomes, and individualizing treatment regimens
were discussed. Several research questions were
identified as needing further investigation, including
when to start and when to stop prophylaxis, optimal
dosing and dose interval, and methods for assessment
of long-term treatment effects. Such studies should
include carefully defined cohorts, validated ortho-
paedic and quality-of-life assessment instruments,
and cost-benefit analyses.
Keywords: haemophilia, diagnosis, treatment,
guidelines
Introduction
Consensus Perspectives on Prophylactic Therapy for
Hemophilia, held in London 20–21 September 2002,
was a small international conference convened to
review the field of haemophilia prophylaxis. Over the
2-day course of the conference, invited participants
from Sweden, the Netherlands, Germany, Italy,
Spain, the UK, the USA and Canada reviewed the
experience with prophylaxis in their own countries
as well as globally. The format of the conference
combined brief presentations with extended periods
of open discussion. The overall goal was to summar-
ize what is known regarding the indications, benefits,
costs, and optimal regimens for haemophilia pro-
phylaxis, as well as to identify issues in need of
further research.
Defining prophylaxis
Prophylaxis is defined as treatment by intravenous
injection of factor concentrate in anticipation of and
in order to prevent bleeding. Thus defined, prophy-
laxis may range from a single dose prior to surgery or
other anticipated bleeding, to long-term prophylaxis
Correspondence: Erik Berntorp, Department of Coagulation Dis-
orders, Malmo
¨
University Hospital, SE-205 02 Malmo
¨
, Sweden.
Tel.: +46 (0) 40 33 23 92; fax: +46 (0) 40 33 62 55;
e-mail: erik.berntorp@medforsk.mas.lu.se
Haemophilia (2003), 9, (Suppl. 1), 1–4
Ó 2003 Blackwell Publishing Ltd 1
begun in infancy and continued into adulthood.
Primary prophylaxis is started prior to the develop-
ment of joint damage, whereas secondary prophy-
laxis is started after the onset of joint damage or
other significant bleeding (e.g. intracranial bleeds).
Conference participants discussed the definitions
of primary and secondary prophylaxis developed by
the European Paediatric Network for the Manage-
ment of Haemophilia (Second Workshop of the
European Paediatric Network for Haemophilia
Management, 17–19 September 1998, Vitznau/
Switzerland). Several changes were proposed,
primarily to eliminate confusion over the proper
classification of some patients, for example, a child
who begins therapy at age 3 but before the first joint
bleed. It was felt that the revised definitions encom-
passed more clearly the differing treatment models
followed in Europe, where prophylaxis is usually
started by age 2 regardless of bleeding tendency, and
in North America, where prophylaxis is often initi-
ated after the first bleed. Conference participants felt
that there was no evidence to indicate how many
joint bleeds may be tolerated before irreversible
damage (i.e. arthropathy) occurs. Therefore, until
more data are available, they considered that pro-
phylaxis started after multiple joint bleeds should be
classified as secondary prophylaxis. The revised
definitions are shown in Table 1.
Conference participants emphasized the import-
ance of categorizing patients correctly in order to
provide meaningful data for analysing and compar-
ing outcomes. For example, if patients are not
receiving prophylaxis for 46–52 weeks a year, or if
treatment is initiated after more than one joint bleed,
then that cohort should be reported as managed by
secondary, not primary, prophylaxis.
Benefits and risks of prophylaxis
There are now over three decades of experience
with long-term prophylaxis. Observational studies
strongly suggest that continuous prophylaxis is
superior to on-demand treatment in delaying or
preventing the development of arthropathy and also
in controlling bleeding frequency. Despite the lack
of controlled studies, long-term prophylaxis should
be the standard for treating children with severe
haemophilia in developed countries with strong
economies and health care resources.
The primary goal of prophylaxis is the prevention
of arthropathy, and this is the major outcome
reported in long-term studies. Other long-term out-
comes such as school performance may also be
affected by the number of bleeding events experi-
enced. As important but less well studied is the
potential of prophylaxis to prevent intracranial and
other serious bleeds. This could clearly improve both
the child’s school performance and, later in life, the
adult’s contributions to society.
Frequent infusions of replacement therapy may
never be risk-free. While the modern record for
safety with recombinant products is excellent, con-
tinued vigilance is required as new pathogens con-
tinue to emerge, such as variant Creutzfeldt-Jakob
disease or West Nile virus. Based upon surveillance
data, there has been no increased incidence in the
development of inhibitors with the adoption of
recombinant products or with the more widespread
use of full prophylaxis. The incidence of inhibitors
does not appear to be influenced by product purity;
it seems more likely that a genetic predisposition is
responsible for the development of inhibitors.
However, under-reporting of complications and
adverse effects likely occurs throughout Europe and
North America. Clinicians, as well as patients,
caregivers and other healthcare personnel, must be
more involved in pharmacovigilance by documenting
all adverse effects, whether expected or unexpected.
Conference participants recommended the develop-
ment of a coherent international pharmacovigilance
system using cooperative national registries.
Prophylaxis in developing countries
Countries with low per capita income and many
competing health care issues are often unable to
Table 1. Revised definitions of primary and secondary prophylaxis.
Model Revised definition
Primary prophylaxis determined by age Long-term continuous* treatment started before the age of 2 years and prior to
any clinically evident joint bleeding.
Primary prophylaxis determined
by first bleed
Long-term continuous* treatment started prior to the onset of joint damage
(presumptively defined as having had no more than one joint bleed) irrespective of age.
Secondary prophylaxis Long-term continuous* treatment not fulfilling the criteria for primary prophylaxis.
Short-term prophylaxis Short-term treatment to prevent bleeding.
On demand therapy Treatment given when bleeding occurs.
*with the intent of treating 52 weeks/year up to adulthood and receiving treatment a minimum of 46 weeks/year.
2 E. BERNTORP et al.
Haemophilia (2003), 9, (Suppl. 1), 1–4 Ó 2003 Blackwell Publishing Ltd
provide adequate treatment for persons with
haemophilia. In these settings, care for persons
with haemophilia must be focused on saving lives
in the event of uncontrolled bleeding. The first
priority must thus be to develop capability to
provide adequate on-demand treatment of bleeding
episodes.
A review of the safety data suggests that plasma-
derived products meeting modern standards for
safety (including donor testing and documented viral
inactivation methods) may be used for both on-
demand and prophylactic treatment in countries in
which recombinant products are not readily avail-
able or affordable. However, a national system for
adverse event reporting should be instituted to allow
detection and recall of implicated products.
Access to prophylaxis in developing countries may
be improved by research that will define more clearly
the minimum effective prophylactic regimen as well
as analyse the cost-effectiveness of such a regimen
compared with on-demand treatment. These cost-
effectiveness studies should include the affected
individuals’ ability to participate as productive
members of society.
Starting prophylaxis
A majority of conference participants felt that
current evidence supports an early start for prophy-
laxis at 1–2 years of age in all children with severe
haemophilia A or B (factor levels <0.01 IU/mL or
1% of normal). Nonetheless, it is recognized that this
approach is not only costly, but may result in over-
treatment of a minority of children who are not
prone to haemarthroses despite low endogenous
levels of coagulant factor. An important research
issue therefore is the identification of markers that
might distinguish this population of persons with
severe haemophilia.
There are few data available to support guidelines
on the initial dosing interval. Conference participants
considered that starting with once-weekly dosing in
the youngest patients may be less stressful for
children and parents than starting full prophylaxis
at once. However, the goal should then be to increase
the dosing frequency gradually to full prophylaxis
(every other day for haemophilia A or every third day
for haemophilia B) by the time the child becomes
more active or begins to experience bleeding. The
long-term outcome of this approach needs to be
ascertained, optimally, by prospective studies or,
minimally, by ongoing follow-up.
Starting prophylaxis gradually with once-weekly
injections has the presumed advantage of avoiding
use of a central venous access device, such as a
Port-A-Cath, which is often necessary for frequent
injections in very young boys. The benefits and risks
of central venous access devices were extensively
discussed, as were the alternative benefits and risks
of once-weekly prophylaxis. The decision to insti-
tute early full prophylaxis by means of an injection
port must take into consideration the child’s bleed-
ing tendency, the family’s social situation, and the
experience of the specific haemophilia centre. The
reported complication rates for infection and
thrombosis have varied considerably from centre
to centre. Whether these differences are best
explained by surgical technique, by monitoring
and detection methods, or by other factors, is
currently unknown. For children with inhibitors
needing daily infusions for immune tolerance induc-
tion, a central venous line is often unavoidable, and
an increased incidence of infection is associated
with this regimen.
A number of straightforward measures may be
effective in reducing the risk of infection. These
include repeated education of patients and staff,
effective surveillance routines, and careful choice of
the individuals allowed to use the device. A cooper-
ative multicentre study might be of value for identi-
fying optimal techniques for placement, maintenance
and removal of the devices. In considering options
for early therapy, the currently understood risks and
benefits should be thoroughly discussed with the
parents.
Duration of prophylaxis
There are no data available for forming a consensus
on stopping prophylaxis in adult patients. The
mature joint would appear to be less vulnerable than
that of a growing child; nonetheless, adults with
haemophilia remain at risk for joint and other bleeds.
Research is needed to examine costs and outcomes of
more flexible lower-dose regimens in adults, partic-
ularly those who are less active and thus at reduced
risk of traumatic bleeding.
Individualizing the regimen: pharmacokinetic
considerations
The standard goal of maintaining factor levels above
1% of normal does not take variation in the clinical
severity of haemophilia into account. Moreover, the
use of standardized dosing disregards the approxi-
mately 3-fold variation in clearance and half-life of
the coagulation factors among patients. Conference
participants agreed that maintaining a specific trough
CONSENSUS SUMMARY STATEMENT 3
Ó 2003 Blackwell Publishing Ltd Haemophilia (2003), 9, (Suppl. 1), 1–4
level should not be an end in itself: the dosing regimen
should be based upon clinical outcome. The goal
should be to ascertain and use the minimum effective
dose for the individual patient. Pharmacokinetic dose
tailoring has been demonstrated to improve the cost-
effectiveness of prophylactic treatment. For this
purpose, the pharmacokinetics of the coagulation
factor in the patient needs to be determined, for
example, by means of a single-dose study at a suitable
time during prophylactic treatment or before elective
surgery. The plasma level of coagulation factor
activity should also be monitored as needed.
Monitoring, assessing, and reporting outcomes
Radiological assessment
Magnetic resonance imaging (MRI) is considered to
be more sensitive in the detection of early stage joint
disease than conventional radiography because it
allows an assessment of soft tissue and provides a
better visualization of erosions. It is now being
studied prospectively in the North American pro-
phylaxis trial as a research tool for assessing the
development and reversibility of cartilage damage,
joint space narrowing, and bony changes such as
cysts and erosions. In clinical practice, MRI would be
reserved for investigating difficult cases, for example,
diagnosing poor treatment response. Conference
participants concurred that it is not cost-effective
for routine monitoring. However, prior to invasive
surgical procedures such as synoviorthesis or syno-
vectomy, an MRI study is highly advisable as an
objective demonstration of synovitis; whenever feasi-
ble, these studies should be done by centres with
expertise in joint MRI studies. Standardization of
MR methods and grading systems is needed to allow
more valid comparisons of treatments and outcomes.
The WFH Paediatric Committee is currently working
to establish internationally accepted scoring systems
for both MRI and orthopaedic assessment.
Conference participants agreed that plain film
X-rays have no role in the early management of
children with haemophilia. Their proper use is for
more advanced disease, to detect the typical findings
of haemophilic arthropathy (narrowing of the joint
line, subchondral cysts, abnormalities in alignment,
etc.).
Clinical assessment
Validated and reliable instruments are important to
setting treatment goals and assessing patient satis-
faction and treatment outcome. Unfortunately, no
existing instrument avoids some level of subjectivity
in interpretation. Two instruments, one specific and
one general, are recommended for simultaneous use
in scoring and monitoring joint disease: a specific
haemophilia outcomes instrument, the Colorado
Physical Examination Instrument (Colorado PE-1
and Colorado PE-0.5 for children, reprinted in the
paper by E. C. Rodriguez-Merchan included in these
proceedings), which improves upon the World Fed-
eration of Haemophilia Physical Joint Examination
instrument; and a general health status assessment
such as the SF-36 Health Survey.
Health-related quality-of-life (HR-QoL) is a cru-
cial outcome for chronic diseases such as haemo-
philia for which there is no cure. Formal assessment
of HR-QoL for differing treatment strategies could
be very informative as a long-term outcome measure,
and a validated HR-QoL instrument should be
included in the design of clinical trials. Both generic
and specific indices should be used, and utility scores
should be included in economic analyses.
Cost-effectiveness of prophylaxis
The question as to whether the costs of long-term
prophylaxis will be offset by reduced hospital-
izations, improved quality of life, improved school
performance, and increased productivity in adult-
hood needs to be further investigated by well-
designed health economic studies. Cost comparisons
with other rare chronic diseases, using a variety of
perspectives and outcome measures, may aid in
clarifying issues of health care resource allocation.
Reductions in the cost of clotting factor concentrates
would certainly be important for increasing access to
prophylaxis amongst persons with severe haemophi-
lia worldwide. It is clear that prophylactic treatment
of severe haemophilia allows patients to lead func-
tionally normal and productive lives. Important steps
towards proving not only the humanitarian but also
the economic value of prophylactic treatment have
been taken, and as these proceedings will show, the
work goes on.
4 E. BERNTORP et al.
Haemophilia (2003), 9, (Suppl. 1), 1–4 Ó 2003 Blackwell Publishing Ltd
