Clotting factor concentrates given to prevent ble eding and
bleeding-related c om plications in people with hemophilia A
or B (Review)
Iorio A, Marchesini E, Marcucci M, Stobart K, Chan AKC
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2011, Issue 9
http://www.thecochranelibrary.com
Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people with hemophilia A or B (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
12DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Standard prophylaxis versus placebo (factor VIII concentrate (post-infusion level), Outcome 1
Bleed frequency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Analysis 1.2. Comparison 1 Standard prophylaxis versus placebo (factor VIII concentrate (post-infusion level), Outcome 2
Morbidity (length of stay). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Analysis 2.1. Comparison 2 Standard prophylaxis versus on-demand treatment (factor VIII concentrate), Outcome 1 Bleed
frequency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Analysis 2.2. Comparison 2 Standard prophylaxis versus on-demand treatment (factor VIII concentrate), Outcome 2 Joint
bleeding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Analysis 2.3. Comparison 2 Standard prophylaxis versus on-demand treatment (factor VIII concentrate), Outcome 3 Joint
function protection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Analysis 2.4. Comparison 2 Standard prophylaxis versus on-demand treatment (factor VIII concentrate), Outcome 4
Quality of Lif e. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Analysis 2.5. Comparison 2 Standard prophylaxis versus on-demand treatment (factor VIII concentrate), Outcome 5 Factor
concentrate usage [x1000 IU]. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Analysis 2.6. Comparison 2 Standard prophylaxis versus on-demand treatment (factor VIII concentrate), Outcome 6
Adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Analysis 3.1. Comparison 3 Standard pr ophy laxis versus alternative prophylaxis (factor VIII concentrate (post-infusion
level), Outcome 1 Bleed frequency. . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Analysis 4.1. Comparison 4 Standard prophylaxis versus alternative prophylaxis (factor V III concentrate), Outcome 1 Bleed
frequency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Analysis 4.2. Comparison 4 Standard prophylaxis versus alternative prophylaxis (factor VIII concentrate), Outcome 2
Clotting factor concentrate usage [x1000]. . . . . . . . . . . . . . . . . . . . . . . . . 34
Analysis 5.1. Comparison 5 Standard prophylaxis versus alternative prophylaxis (factor IX concentrate), Outcome 1 Bleed
frequency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
34ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
40APPENDICE S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
43WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
44HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
44CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
45INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iClotting factor concentrates given to prevent bleeding and bleeding-related complications in people with hemophilia A or B (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]
Clotting factor conce ntrates given to prevent bleeding and
bleeding-related c om plications in people with hemophilia A
or B
Alfonso Iorio
1
, Emanuela Marchesini
2
, Maura Marcucci
2
, Kent Stobart
3
, Anthony KC Chan
4
1
Clinical Epidemiology and Biostatistic Department, McMaster University, Hamilton, Canada.
2
Department of Internal Medicine,
University of Perugia, Perugia, Italy.
3
Northern Alberta Children’s Cancer Program, Department of Pediatrics, University of Alberta,
Edmonton, Canada.
4
Division of Pediatric Hematology/Oncology, Health S cie nces Centre, McMaster University, Hamilton, Canada
Contact address: A lfonso Iorio, Clinical Epidemiology and Biostatistic Department, McMaster University, 1280 Main Street West,
CRL - 140, Hamilton, ON, L8S 4K1, Canada.
iorioa@mcmaster. ca.
Editorial group: Cochrane Cystic Fibrosis and Genetic Disorders Group.
Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 9, 2011.
Review content assessed as up-to-date: 9 July 2011.
Citatio n: Iorio A, Marchesini E, Marcucci M, Stobart K, Chan AKC. Clotting factor concentrates given to prevent bleeding and
bleeding-related complications in people with hemophilia A or B. Cochrane Database of Systematic Reviews 2011, Issue 9. Art. No.:
CD003429. DOI: 10.1002/14651858.CD003429.pub4.
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
Background
The hallmark of severe hemophil ia is recurrent bleeding into joints and soft tissues with progressive joint damage, notwithstanding on-
demand treatment. Prophylaxis has long been used but not universally adopted because of medical, psychosocial, and cost controversies.
Objectives
To determine the effectiveness of clotting factor concentrate prophylaxis in the management of people with hemophilia A or B.
Search methods
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group’s Coagulopathies Trials Register. In addition, we searched
major electronic databases (MEDLINE, EMBASE, CENTRAL), handsearched relevant journals and abstract books and reference lists
of relevant articles.
Last search of Group’s Coagulopathies Trials Register: 07 April 2011.
Selection criteria
Randomised controlled trials and quasi-randomised controlled trials evaluating people with severe hemophil ia A or hemophilia B
receiving prophylactic cl otting factor concentrates.
Data coll ection and analysis
Two authors independently reviewed studies for eligibility, assessed risk of bias and extracted data.
1Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people w ith hemophilia A or B (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Main results
Six studies (including 142 participants) were eligible for inclusion. Two compared three-times-a-week prophylactic administration with
on-demand treatment in children with hemophilia. Pooled results from these two studies showed a rate ratio of 0.30 (95% confidence
interval; 0.12 to 0.76) for all bleedings and 0.22 (95% confidence interval 0.08 to 0.63) for joint bleedings favouring prophylaxis.
Results on the number of patients with preserved joints after three to seven years of follow-up were not pooled due to significant
heterogeneity. Three of the remaining four studies evaluated hemophilia A; one showed a statistically significant decrease in frequency
of joint bleeds with prophylaxis compared to placebo, with a rate diff erence of -10.73 (95% confidence interval -16.55 to -4.91) ble eds
per year. Two studies compared two prophylaxis regimens, failing to demonstrate an advantage of one regimen over the other in terms
of bleeding frequency. The fourth study evaluated hemophilia B and showed fewer joint bleeds with weekly (15 IU/kg) versus bi-weekly
(7.5 IU/kg) prophylaxis, rate difference -3.30 (95% confidence interval -5.50 to -1.10) bleeds per year. Non-significant increases in
both inhibitor and infectious complications were observed in patients on prophylaxis, which occurred more often when using long-
term venous access.
Authors’ conclusions
There is strong evidence from randomised controlled trials and observational trials that prophylaxis preserves joint function in children
with hemophilia as compared to on-demand treatment. There is insufficient evidence from randomised controlled trials to confirm
the observational evidence that prophylaxis decreases bleeding and related complications in patients with existing joint damage. Well-
designed randomised controlled trials and prospective observational controlled studies are needed to establish the best prophylactic
regimen and to assess th e effectiveness of prophylactic clotting factor concentrates in adult patients.
P L A I N L A N G U A G E S U M M A R Y
Regular clotting factor repl acement therapy to prevent joint disease in people with severe hemophilia A or B
Hemophilia A and B are X-linked inherited bleeding disorders, in which the major clinical problem is repeated bleeding into joints. As
this disorder progresses, joints become deformed and movement limited. Current therapy for treating and preventing bleeding includes
plasma-derived or recombinant clotting factor concentrates. This review includes six randomised controlled trials. Two compare the
regular use of clotting factor concentrates to prevent joint bleeds with their use ’on demand’. Four compare different regimens of
regular use in children and adults with hemophilia. It was clearl y evident that preventative therapy, as intravenous infusion of factor
concentrate repeated more times a week and star ted early in childhood was able to reduce joint deterioration as compared to treatment
administere d after bleeding occurred. This favourable effect is due to a consistent reduction in total bleeds and hemarthrosis (bleeding
into joints) and leads to a significant improvement in quality of life. Preventative ther apy is linked to an increased factor usage and cost
of treatment. We found weaker evidence (due to l ack of data) to show preventative therapy reduced joint deterioration whe n treatment
is started after joint damage has been established. Further studies are needed to establish the best preventative regimen, i.e. for example
starting time, dosage frequency, minimally effective dose.
B A C K G R O U N D
Hemophilia is an X-linked bleeding disorder due to a coagulation
factor deficiency (factor VIII for Hemophilia A and factor IX for
Hemophilia B) and is classified according to clotting factor level :
severe (with a basel ine coagulation factor level of less than 1% of
normal); moderate (with clotting factor levels of 1% to 5%); and
mild (with a clotting factor greater than 5%).
People with moderateand mild haemophilia bleed rarely, and often
only after trauma or in association with invasive procedures.
The frequency and se verity of bleeding is greatest in people with
severe hemophilia A or B, in which recurrent and often sponta-
neous bleeding into joints and soft tissues (since early childhood)
is the hallmark of severity. The consequence of recurrent joint
bleeding is the development of different degrees of haemophilic
arthropathy.
The availability of clotting factor concentrates has radically
changed the treatment of people with hemophilia, with a sig-
2Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people w ith hemophilia A or B (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
nificant improvement of morbidity, mortality and quality of life
(QoL) (
Lusher 1997). Since the introduction of clotting factor
concentrates, the early on-demand treatment for acute bleeding
episodes is now common practice. This has resulted in a decrease
in the number of joint deformities with respect to untreated or
minimally-treated patients (Ahlberg 1965; Hilgartner 1974).
However, observation of the natural history of haemophilic
arthropathy in people on long-term on-demand treatment shows
that this regimen is clearly sub-optimal. A milestone study in 1994
reported the resul ts of a longitudinal observation of 477 males
under 25 ye ars of age with severe hemophilia A without inhibitors
who were followed up for six years (
Aledort 1994). Patients treated
on demand showed a progressive deterioration of th eir joint func-
tion in some or all of the joints examined. Repeated bleeding in
the joints has been indicated as the mechanism which, through
abnormal proliferation of the synovial tissue, leads to joint disrup-
tion. At the time of this report’s publication, the preventive use of
clotting factor concentrates given at regular intervals had already
been adopted for several decades in Sweden (
Nilsson 1976). The n
in 1994, the Medical and Scientific Advisory Council (
MASAC),
of the United States of America’s National Hemophilia Founda-
tion reviewed the Swedish experience with prophylaxis and issued
guidelines stating that prophylaxis should be considered the opti-
mal therapy for children with severe hemophilia A and B (
NHF
1994
).
In the meanwhile, the focus of managing an individual with
hemophilia has changed from treating an acute bleeding episode to
the comprehensive care of the individual, including the adminis-
tration of clotting factor concentrate outside the hospital or treat-
ment centre, as subsequently theorized and better defined (Teitel
2004
).
In fact, the efficacy of prophylaxis is expected to be higher if started
early, i.e. before the establishment of any degree of joint deteri-
oration, and continued as much as possible, as only home care
treatment allows.
In this perspective, currently agreed definitions of prophylaxis
are those proposed by the European Paediatric Network for
Haemophilia Management (
Berntorp 2003; Ljiung 2000). In par-
ticular, prophylaxis was defined as:
• primary A (determined by age) if regular continuous
treatment is started after the first joint bleed and before the age
of two years;
• primary B (determined by first bleed) if regular continuous
treatment is started before the age of two years without previous
joint bleeds;
• secondary A if regul ar continuous (long-term) treatment is
started after two or more joint ble eds or at an age of over two
years;
• secondary B if inter mittent regular (short-term) treatment
is applied, based on frequent bleed events.
Primary prophylaxis (A or B) and secondary A regimens require
at least three doses per week for 42 weeks per year.
Despite the above recommendations, prophylaxis has not been
universally adopted because of medical, psychosocial, and cost
controversies (
Blanchette 2004). In fact, the use of cl otting fac-
tor concentrates is the single largest predictor of overall cost in
the care of people with hemophilia (
Miners 2004; Miners 2009),
and it prevents its extensive application worldwide. Furthermore,
there is no general agreement on the optimal prophylaxis regi-
men, and some schemes differ from that proposed by the Euro-
pean Paediatric Network which has been recently proven to be
feasible (
Feldman 2006; Collins 2009). In addition, evidence is
accumulating about the efficacy of secondary prophylaxis started
in adulthood to slow the progression of hemophilic arthropathy
in already damaged joints or to relieve symptoms, or both, and
improve QoL (
Fisher 2003; Hay 2007).
In order to help clarify the open issues and provide optimal treat-
ment recommendations for as many people with hemophilia as
possible, we aim to systematically appraise the available evidence
for th e effectiveness of prophylactic administration of factor con-
centrates
O B J E C T I V E S
The objective of this review is to evaluate whether the preventive
use of clotting factor concentrates in people with hemophilia A or
B improves short- and long-term outcomes as measure d by one or
more of the following:
Short-term
1. number of bleeding episodes per y ear or bleeding frequency
2. cl otting factor concentrate plasma levels
Long-term
1. cl inical joint function
2. orthopedic joint score
3. radiologic joint score
4. QoL measurements
M E T H O D S
3Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people w ith hemophilia A or B (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
