Journal of Thrombosis and Haemostasis, 8: 8389

DOI: 10.1111/j.1538-7836.2009.03650.x

IN FOCUS

Efficacy and safety of secondary prophylactic vs. on-demand

sucrose-formulated recombinant factor VIII treatment in adults
with severe hemophilia A: results from a 13-month crossover
study
P . C O L L I N S , * A . F A R A D J I , M . M O R F I N I , M . M . E N R I Q U E Z and L . S C H W A R T Z
*University Hospital of Wales, Cardiff, UK; Hautepierre Hospital, Strabourg, France; University Hospital, Firenze, Italy; Bayer HealthCare AG,
Wuppertal, Germany; and Bayer HealthCare Pharmaceuticals, Montville, NJ, USA

To cite this article: Collins P, Faradji A, Morfini M, Enriquez MM, Schwartz L. Efficacy and safety of secondary prophylactic vs. on-demand sucroseformulated recombinant factor VIII treatment in adults with severe hemophilia A: results from a 13-month crossover study. J Thromb Haemost
2010; 8: 839.
See also Aledort LM. To bleed or not to bleed is that a question. This issue, pp 812.

Summary. Background: Hemarthroses in severe hemophilia

precipitate physical, psychosocial and nancial diculties.
Objective: To compare the eects of secondary prophylaxis
with on-demand sucrose-formulated recombinant factor VIII
(rFVIII-FS) therapy in severe hemophilia A. Patients and
methods: This open-label study included patients aged 30
45 years with factor VIII (FVIII) coagulant activity
< 1 IU dL)1 who were using on-demand FVIII treatment.
Patients were treated with rFVIII-FS on demand for 6 months,
followed by 7 months prophylaxis (2040 IU kg)1, three times
per week, with the rst month considered a run-in). The primary
endpoint was the number of hemarthroses. Results: Twenty
patients were enrolled (n = 19 completed); the mean age was
36.4 years, and 16 had target joints. The median (2575%)
number of joint bleeds decreased signicantly with prophylaxis
[0 (03)] vs. on-demand [15 (1126); P < 0.001] therapy. The
number of all bleeds was 0 (03) vs. 20.5 (1437; P < 0.001),
respectively. Median (range) total Gilbert scores improved after
prophylaxis [18 (339)] compared with on-demand [25 (446)]
therapy, predominantly reecting the improved bleeding score.
Median time from last prophylactic infusion to bleed was
2 days; 82.5% of bleeds occurred 23 days after the last
infusion. Median 48-h and 72-h FVIII trough levels measured
during months 10 and 13 were consistently > 6 and
> 4 IU dL)1, respectively. Treatment was well tolerated, and
no inhibitor formation was observed. Conclusion: Secondary

Correspondence: Peter Collins, Arthur Bloom Haemophilia Centre,

University Hospital of Wales, School of Medicine, Cardi University,
Heath Park, Cardi CF14 4XW, UK.
Tel.: +44 2920742155; fax: +44 2920745442.
E-mail: peter.collins@cardiandvale.wales.nhs.uk
Received 2 July 2009, accepted 29 September 2009
 2009 International Society on Thrombosis and Haemostasis

prophylaxis with rFVIII-FS signicantly reduced the frequency

of hemarthroses compared with on-demand therapy in adult
patients with severe hemophilia A.
Keywords: factor VIII, hemophilia, on-demand therapy, secondary prophylaxis.
Introduction
Many of the physical, psychosocial and nancial difculties
associated with severe hemophilia are related to the effects of
recurrent joint bleeds and chronic arthropathy. The use of ondemand therapy has not been shown to effectively prevent
arthropathy, even when used at relatively high doses [1,2].
However, the observation that patients with moderate hemophilia (factor VIII [FVIII]/factor IX > 15 IU dL)1) rarely
develop chronic arthropathy provides a rationale for primary
prophylactic treatment of severe hemophilia [3].
The benets of initiating regular prophylaxis therapy at an
early age have been demonstrated in multiple studies [48].
These benets include fewer bleeds, reduced joint damage, and
improved quality of life (QoL) compared with on-demand
therapy [48]. Moreover, current guidelines recommend early
prophylaxis for patients with severe hemophilia A or B [911].
There is a paucity of evidence regarding the benets of
secondary prophylaxis (begun after development of some
degree of hemophilic arthropathy) in adult patients because
most data on long-term outcomes of prophylactic treatment
come from studies of pediatric patients [48,12]. Although the
World Health Organization recommends that prophylaxis
should be continued for the lifetime of the patient [11], the
optimal duration of prophylaxis has not been denitively
established, and hemophilic patients often discontinue prophylaxis as young adults [13] or switch their pattern of care to a
more targeted form of prophylaxis. The empirical use of
prophylaxis in adult patients with variable degrees of

84 P. Collins et al

hemophilic arthropathy has been introduced in many hemophilia centers, with anecdotal reports of success [1416].
However, the benet of secondary prophylaxis in adult patients
has not yet been demonstrated in prospective clinical trials.
The present study in adult patients with severe hemophilia A
and a history of frequent bleeding episodes was designed to
assess the effectiveness of secondary prophylaxis in preventing
bleeds with a full-length recombinant FVIII (rFVIII) product
formulated with sucrose (rFVIII-FS) as a stabilizer. The
primary objective was to compare the effects of prophylaxis vs.
on-demand therapy on the number of joint bleeds. Secondary
objectives were to compare the effects of the two treatment
strategies on all bleeds, joint function, health-related QoL,
health economics, and safety.

Study design

This was a multicenter, open-label, prospective trial conducted in the United States and Europe with one patient
group and two treatment schedules. After enrollment, all
patients received on-demand rFVIII-FS (Kogenate FS/
KOGENATE Bayer; Bayer HealthCare, Berkeley, CA,
USA) as their sole AHF treatment for 6 months (Fig. 1).
Patients were then switched to 7 months of rFVIII-FS
prophylaxis at a stable dose of 2040 IU kg)1 three times
per week. The rst month of prophylaxis (month 7) was a
run-in period to allow stabilization and was not included in
the primary outcome analysis. The prophylactic dose range
and frequency were based on historical clinical experience
from trials conducted predominantly in children [7,9]. An
individuals dose within the specied range was determined
by the investigator. Throughout the study, rFVIII-FS was
the only FVIII product used for treatment of bleeds.
Breakthrough bleeds were treated at a dose of 20
100 IU kg)1 according to bleed severity, and treatment
could be repeated every 1224 h until resolution according
to investigator routine practise. Prophylactic rFVIII-FS was
administered at home by slow intravenous infusion at a
maximum rate of 2 mL min)1. All FVIII administrations, as
well as all bleeds and their treatments (including reason for
treatment, severity of bleed as judged by the patient, and
treatment response), were documented by patients during
clinic or home treatment in patient diaries.
Approval was obtained from appropriate ethics committees and/or institutional review boards before the start
of the study, according to Good Clinical Practice,
and local laws, regulations and organizations. The study
was conducted in compliance with the Declaration of
Helsinki.

Methods
Patients

Male patients aged 3045 years with severe hemophilia A

(FVIII < 1 IU dL)1), an average of two relevant bleeds per
month and no additional bleeding disorders were eligible for
the trial. Patients were required to have a FVIII treatment
history of 100 exposure days and to be receiving on-demand
FVIII therapy at the time of study entry. All patients gave
written informed consent before study entry. Exclusion criteria
included: current or prior evidence of a FVIII inhibitor (dened
as inhibitor titer 0.6 Bethesda units mL)1); planned elective
orthopedic surgery during study duration; presence of any
medical or psychological condition that could potentially affect
treatment efcacy or QoL outcomes; history of anaphylactic or
other severe reaction to antihemophilic factor (AHF) treatment; and known hypersensitivity to active substance, mouse
or hamster protein, or any drug excipients.

Visit 4

FVIII infusions
AEs
Bleeds (joint and all)
Health economics
Physical activity
FVIII trough levels 48 h

Visit 2

FVIII infusions
AEs
Bleeds (joint and all)
Health economics
Physical activity
Month

Treatment

Visit 1

3
On-Demand
(n = 20)

Demographic data
Medical history
Bleeds (preceding 6 mo)
Lab assessments (FVIII level,
recovery, inhibitors)

Haemo-QoL-A
Gilbert score

and 72 h after last infusion

6

Prophylaxis
Run-In (n = 19)

10

13

Prophylaxis (20-40 IU kg1 3 times per wk)

(n = 19)

Visit 3

Visit 5

Gilbert score
Haemo-QoL-A
AEs
Lab assessments (inhibitors, FVII

Gilbert score
Haemo-QoL-A
AEs
Lab assessments (inhibitors,

FVIII infusions
Bleeds (joint and all)
Health economics
Physical activity

FVIII trough level 48 h and 72 h

after last infusion, recovery)
FVII infusions
Bleeds (joint and all)
Health economics
Physical activity

trough level 3 d after last infusion)

Fig. 1. Study design. AEs, adverse events; FVIII, factor VIII; Haemo-QoL-A, Haemophilia A Specific Quality of Life Questionnaire; IU, international
units.
 2009 International Society on Thrombosis and Haemostasis

Adult prophylaxis crossover study 85

Assessments and outcome measures

The primary outcome was the number of joint bleeds recorded

during 6 months of prophylaxis treatment (months 813)
compared with the previous 6 months of on-demand treatment
(months 16). Bleeds were assessed from information recorded
in patient diaries. Secondary endpoints included the number of
all bleeds, joint function, health-related QoL, health economics,
and safety. Joint function was assessed by the clinician (in the
absence of an acute bleeding episode) at baseline, month 6 and
month 13 using the physical examination score of the Gilbert
scale [17]. Patient QoL was assessed at baseline, month 6 and
month 13 using the Haemo-QoL-A questionnaire, a validated
hemophilia Aspecic instrument covering six areas (physical
functioning, role functioning, worry, consequences of bleeding,
positive affect, and treatment concerns) [18]. Health economic
data (e.g. days off work, visits to the general practitioner, and
hospitalization days due to hemophilia) were documented at
each clinic visit (months 3, 6, 10 and 13). Incidences of adverse
events (AEs), serious AEs (SAEs) and treatment-related
adverse reactions were documented throughout the study.
Laboratory assays

Assessment of FVIII inhibitor development was included in the

safety analyses and was performed at baseline (before rst
infusion) and at month 13. Measurements of FVIII levels were
performed at least 3 days after the last infusion during ondemand treatment and at 48 and 72 h after last infusion during
prophylaxis at months 10 or13. All laboratory tests were
performed locally.
Statistical analyses

A sample size of 30 patients was calculated to provide 94%

power to detect a mean treatment difference of four joint
bleeding episodes with two-sided a = 0.05, assuming a standard deviation (SD) of six joint bleeding episodes in 6 months.
Sample size was calculated using NQUERY, version 5.0, module
MOT 1-1 (Statistical Solutions, Saugus, MA, USA).
Differences in the number of bleeds (joint and all bleeds)
between the 6 months of prophylaxis (months 813) and
6 months of on-demand therapy (months 16) were analyzed
using a nonparametric Wilcoxon test. The rst month of
prophylaxis (month 7) was intended as a stabilization run-in
period between treatments and was not included in this
analysis. Median (2575%) annualized numbers of bleeds were
also calculated for both treatment periods and compared using
the Wilcoxon test to account for differences in the mean SD
length of each period (prophylaxis, 181.9 24.7 days; ondemand therapy, 193.3 25.9 days). A subgroup analysis
was further performed by bleeding type to determine numbers
of traumas and spontaneous bleeds. For joint function, healthrelated QoL and pharmacoeconomic endpoints, differences
between prophylaxis and on-demand treatment periods were
analyzed using a paired t-test. For both the Wilcoxon test and
 2009 International Society on Thrombosis and Haemostasis

paired t-test, P values 0.05 were considered statistically

signicant. All patients receiving the study drug were included
in the safety analyses.
Results
Patient disposition

Although a sample size of 30 patients was originally planned,

enrollment was stopped after 20 patients had been accrued to
the study owing to a low recruitment rate; the statistical power
was consequently reduced from 94% to 80%. Patients
participated in the study from February 2006 to March 2008.
There were no screening failures. Nineteen patients completed
the study; one patient withdrew consent during the on-demand
treatment period after receiving 30 infusions.
Patient baseline demographics and disease characteristics are
shown in Table 1. Patients had severe hemophilia A and were
3045 years of age, with a mean SD age of 36.4
3.5 years. At study entry, 16 (80%) patients had 1 target
joint (dened as three bleeds into the same joint within
6 months), the majority of which were elbows and ankles. The
total number of bleeds in patients during the 6-month period
before study entry was 342, of which 177 (51.8%) were
spontaneous and 54 (15.8%) were trauma related. The median
(2575%) number of bleeds occurring per patient during the
6 months before enrollment was 14.0 (12.018.5) and ranged
from 9 to 42. The most common bleeding sites were elbow
(29.2% of all bleeds), ankle (17.3%) and knee (12.3%). For the
217 bleeds with severity assessments, 52 (24.0%) were mild, 136
(62.7%) were moderate, and 29 (13.4%) were severe. The mean
total number of bleeds per patient during the 6 months before
study entry was 17.1. Fourteen patients used rFVIII product
only, four patients used plasma-derived FVIII product only,

Table 1 Baseline demographics and disease characteristics (n = 20)

Characteristic
Mean (SD) age, year
Race, n (%)
White
Hispanic
> 200 previous EDs, n (%)*
Patients with baseline
FVIII < 1 IU dL)1, n (%)
Patients with 1 target joint, n (%)
Positive serologic status, n (%)
HCV
HIV
Mean (SD) number of all
bleeds in previous 6 months
Mean (SD) FVIII consumption
in previous 6 months, IU

36.4 (3.5)
19
1
20
20

(95)
(5)
(100)
(100)

16 (80)
19 (95)
7 (35)
17.1 (9.0)
60 438 (44 078)

ED, exposure day; FVIII, factor VIII; HCV, hepatitis C virus; HIV,
human immunodeciency virus; IU, international unit. *Although the
study inclusion criterion was > 100 EDs, all enrolled patients had
> 200 EDs.

86 P. Collins et al

and two patients used both plasma-derived FVIII and rFVIII

products.
Recombinant factor VIII formulated with sucrose infusion and
consumption

In total, 2231 infusions were administered: 581 during the ondemand period and 1650 during the prophylaxis period. Nearly
3-fold more infusions per patient occurred during the prophylaxis period compared with the on-demand period
[mean SD (median) infusions per patient, 88.2 9.0
(88.0) vs. 29.1 14.1 (27.0), respectively]. The median (25
75%) number of infusions per week was 3.0 (2.53.0),
suggesting good compliance with the treatment schedule.
Although 89.8% of infusions were administered for treatment
of spontaneous or trauma bleeds during the on-demand period
(and 7.7% for preventive prophylaxis), only 3.2% of infusions
were for spontaneous or trauma bleeds during the prophylaxis
period (94.4% were for regular or preventive prophylaxis). The
mean SD weekly dose per patient was 31.3 18.1 IU kg)1
during the on-demand period and 87.3 16.5 IU kg)1 during
the prophylaxis period. Total consumption per patient during
the study was 70 421 43 057 and 211 933 54 725 IU,
respectively, and the calculated yearly dose was 1630 946
and 4552 861 IU kg)1.

demand therapy (P < 0.001; Table 2). The statistical signicance did not change after adjustment for the slightly different
length of observation periods. Most bleeds (97.8% during ondemand therapy, 92.8% during prophylaxis) were successfully
treated with one or two infusions. The mean SD number of
infusions for bleeds per patient was 26.1 13.8 and 2.8 4.7
during on-demand treatment and prophylaxis, respectively.
Severity assessments of bleeds by patients or investigators were
mild or moderate in 83% of occurrences for both treatment
strategies. Of the 40 bleeds occurring during prophylaxis, 28
were joint bleeds, 10 were other bleeds, and two had no
location recorded. All 28 joint bleeds were into target joints: 17
into the elbow, seven into the ankles, and four into the
shoulder.
Median and mean 48-h and 72-h trough FVIII levels at
months 10 and 13 are shown in Table 3. Despite the large
interindividual variability, both mean and median FVIII
trough levels were consistently > 4 IU dL)1 for up to 72 h
postinfusion in patients receiving prophylaxis. Postinfusion
trough levels were > 5 IU dL)1 at 48 h in 75% of patients and
2 IU dL)1 at 72 h for 57% of patients. Of the 40 bleeds
reported during prophylaxis, 22 (55%) occurred in patients
with 72-h FVIII trough levels < 2 IU dL)1. The median time
from last prophylactic infusion to bleed was 2 days, and 82.5%
of bleeds occurred 23 days after the last infusion (5%
occurred earlier than 2 days, 12.5% occurred later than

Efficacy

The median observed numbers of joint bleeds, all bleeds,

spontaneous bleeds and trauma bleeds are shown in Table 2.
Median numbers of actual joint bleeds (primary endpoint) were
signicantly lower during prophylaxis vs. on-demand treatment periods (P < 0.001). Although 80% of all reported
bleeds during both treatment strategies were joint bleeds, 10
(53%) of the 19 patients completing the prophylactic treatment
period did not experience any joint bleeds during the study.
These 10 patients had 12 target joints (mean, 1.2 per patient),
whereas there were 20 target joints in the nine patients
experiencing bleeds during prophylaxis (mean, 2.2 per patient).
All patients without target joints (n = 4) had zero bleeds
during prophylaxis.
Median numbers of all bleeds, spontaneous bleeds and
trauma bleeds were also signicantly lower during the
6 months of prophylaxis compared with the 6 months of on-

Table 3 Factor VIII (FVIII) trough levels*

After last prophylactic infusion
FVIII trough
level, IU dL)1

48 h
(n = 15)

72 h
(n = 14)

Mean SD
Median
Interquartile range
Range

7.3 6.6
6.0
1.011.0
0.324.6

4.1 3.8
4.0
0.56.0
0.312.0

IU, international unit. *FVIII levels below the detection limit were set
to 50% of the nominal value for calculation of means (i.e. values
< 1 IU dL)1 were set to 0.5 IU dL)1). One value was reported as
<0.6 IU dL)1, which was then converted to 0.3 IU dL)1 for analysis.

Protocol specications required a FVIIII measurement 72 h after

last on-demand infusion and before the start of prophylaxis; however,
two patients had a washout of < 72 h. Hours after last prophylactic
rFVIII-FS infusion at month 10 or 13.

Table 2 Actual number of bleeds

On-demand treatment*

Prophylactic treatment

Median (interquartile range)

number of bleeds per patient

Months 16
(n = 20)

Months 713
(n = 19)

P value

Joint bleeds
All bleeds
Spontaneous bleeds
Trauma bleeds

15.0
20.5
13.5
2.5

0
0
0
0

<
<
<
<

(1126)
(1437)
(729)
(09)

(03)
(03)
(01)
(0)

0.001
0.001
0.001
0.001

*Median observation period was 192 days. Median observation period was 177 days. Wilcoxon test.
 2009 International Society on Thrombosis and Haemostasis

Adult prophylaxis crossover study 87

3 days). At all time points, mean FVIII plasma levels increased

from < 10 IU dL)1 preinfusion to > 120 IU dL)1 postinfusion after administration of a mean dose of 4650 IU kg)1 as
determined by one-stage assays; this corresponded to a FVIII
recovery value of 2.4 (IU dL)1)/(IU kg)1).
Total and individual category Gilbert scores for both
treatment strategies are shown in Table 4. Mean total Gilbert
score was signicantly better after prophylaxis than on-demand
therapy (P < 0.001); this improvement was largely accounted
for by the decrease of 4.2 points in the bleeding score
(P < 0.001). Median (range) total Gilbert scores were also
improved after prophylaxis [18 (339)] compared with ondemand therapy [25 (446)]. When the pain and bleeding
categories were excluded, the difference in total Gilbert score
between prophylaxis and on-demand therapy was not statistically signicant (P = 0.067). Changes in scores for the
majority of individual categories were generally small and not
signicant.
There was no signicant improvement in QoL as measured
by the total transformed Haemo-QoL-A score (mean increase
from on-demand to prophylactic treatment, 2.6 points out of
100 possible; P = 0.314). Mean differences between treatment
strategies for the individual Haemo-QoL-A domains of
physical functioning, role functioning, worry, consequences
of bleeding, positive affect and treatment concerns were small
(< 0.5 points) and not signicant.
No signicant difference in health economic parameters
(days off work, general practitioner visits, or days hospitalized)
was noted between on-demand and prophylactic treatment
periods. The median number of days for each parameter and
each treatment strategy was zero. A small change in
mean SD number of days hospitalized from on-demand
(0.1 0.2 days) to prophylaxis (5.7 25.0 days) treatment
was noted; this was largely due to one patient who was
hospitalized for 109 days following a trafc accident, as
evidenced by the large SD to the mean. Additionally, no
signicant changes were observed in mean SD frequency
(2.3 3.2 vs. 2.7 3.5 times per week, respectively) or
duration (68 110 vs. 84 125 min, respectively) of physical activity following on-demand treatment vs. prophylaxis.

Safety

During the study, 51 AEs were reported in 13 patients (65%);

26 AEs occurred during the on-demand period and 25 during
prophylaxis. Nearly all (94%) AEs were mild or moderate in
intensity, and no AE led to study withdrawal. Two treatmentrelated AEs (dysgeusia and headache) occurred in separate
patients during on-demand treatment. Causal relationship for
one AE (hyperhydrosis) that occurred during prophylaxis was
missing; by denition, this AE was considered to be treatment
related. Six SAEs occurred in two patients during the study
(one patient during each treatment period). None of the SAEs
was considered by the investigator to be treatment related, and
no inhibitor formation was detected during either treatment
period.
Discussion
This study demonstrates that secondary prophylactic therapy
with rFVIII-FS decreases the number of joint and total bleeds
compared with on-demand therapy. Prophylaxis led to a
signicant reduction in joint bleeds, regardless of whether the
bleeds were spontaneous or trauma related. The best outcome
of prophylaxis treatment with a complete prevention of any
joint bleed during a 6 months observation period was observed
in patients with no or a low number of target joints. The
development of more than two target joints increased the risk
of bleeding even under prophylaxis treatment. The total Gilbert
score decreased during prophylaxis compared with on-demand
therapy; this effect was mainly due to the reduced number of
bleeds. The physical examination scores indicated a stabilization of joint function, although no control arm was included
and the follow-up was too short to draw denite conclusions on
long-term stabilization of joint pathology.
These ndings are important for assessing the role of
prophylaxis in adults. A recent study reported a tendency
toward increased bleeding symptoms with increasing age,
suggesting a benet from initiating prophylaxis in elderly
hemophilic patients [19]. Translating the results of pediatric
studies to adults is complicated by changes in treatment

Table 4 Joint function assessed by mean SD Gilbert score

Category (point range)
Total Gilbert score (0100)
Gilbert score excluding the
pain and bleeding subscales (064)
Pain (018)
Swelling (012)
Muscle atrophy (06)
Axial deformity (08)
Crepitus on motion (06)
Range of motion (012)
Flexion contracture (012)
Instability (08)
Bleeding (018)

Baseline
(n = 20)

Month 6
(n = 19)*

Month 13
(n = 19)

Mean dierence

P Value

24.8 15.1
16.0 10.9

25.3 11.7
17.2 9.3

19.8 11.7
15.9 10.0

)5.5
)1.3

< 0.001
0.07

)0.1
)0.3
)0.3
0.0
)0.2
)0.4
)0.3
0.2
)4.2

0.90
0.19
0.29
> 0.99
0.48
0.22
0.33
0.08
< 0.001

3.7
2.3
2.2
0.8
2.5
5.3
2.7
0.4
5.1

2.9
2.9
1.9
1.1
1.8
3.5
2.9
1.1
4.0

3.4
2.2
2.3
0.6
2.7
5.7
3.1
0.6
4.7

3.3
2.3
2.0
1.0
1.7
3.2
2.9
1.1
3.0

3.3
1.9
2.1
0.6
2.6
5.3
2.7
0.7
0.6

3.0
2.4
2.1
1.0
1.9
3.4
2.5
1.2
0.9

*Data missing for one patient at month 6. Dierence between month 6 and month 13 scores. Paired t-test.
 2009 International Society on Thrombosis and Haemostasis

88 P. Collins et al

patterns that tend to occur around puberty, including interruptions or temporary discontinuations of treatment [13].
However, data from the Orthopedic Outcome Study suggest
that reducing joint bleeds in young adults is likely to translate
into orthopedic benet [1]. Stabilization of arthropathy would
be of major benet to hemophilia A patients and may prevent
or delay the need for orthopedic intervention. Furthermore,
prevention of joint bleeds may improve mobility and allow
more intensive programs of physiotherapy [20].
Neither QoL nor pharmacoeconomic variables were significantly affected by the two treatment strategies. The relatively
short observation period may have limited the ability of these
endpoints to reect change. The fact that the patient population was relatively young and healthy may also have contributed to the lack of signicant health economic differences
observed. In general, patients had few lost days of work, visits
to the general practitioner and hospitalizations during both
treatment regimens. Thus, the ability to detect differences in
these parameters between the two treatment regimens may
have been affected by their low overall incidence.
Both treatment regimens were safe and well tolerated.
Despite the higher number of infusions required during the
prophylaxis period, roughly the same proportion of patients
(50%) reported AEs during each treatment period, and no
FVIII inhibitors were reported.
Total FVIII consumption was nearly three times higher
during the prophylactic period. The number of bleeds a patient
experiences on prophylaxis has been shown to be related to the
time per week spent with a FVIII < 1 IU dL)1 [21], and some
clinicians treat patients to maintain a trough level above this
threshold. Because most patients in the current study had 48-h
trough levels > 5 IU dL)1 and 75% of patients had trough
levels > 1 IU dL)1, it may have been possible to reduce the
overall FVIII usage in many patients while maintaining good
clinical outcomes. The higher than expected FVIII trough
levels observed in this study could be explained by the longer
half-life of rFVIII-FS in adults vs. young children [22]. Thus,
the ideal adult prophylactic regimen probably differs from the
one generally administered to children.
Limitations of this study include the lack of a control arm,
the low recruitment rate, and the relatively short follow-up
time. Patient enrollment was hindered somewhat by the fact
that most patients experiencing the number of relevant bleeds
required by the study design (n = 2 per month) were already
on prophylaxis, or were reluctant to be initiated on this
regimen. Although the feasibility of secondary prophylaxis in
adults with severe hemophilia A has been demonstrated by this
study, longer-term data from a larger study are necessary to
rmly establish this regimen.
In summary, secondary prophylaxis with rFVIII-FS was
well tolerated and effective at reducing the frequency of joint
and all bleeds compared with on-demand therapy in previously
treated adult patients with severe hemophilia A. The current
study shows that, even when initiated in adulthood, rFVIII-FS
prophylaxis markedly reduces hemarthroses and soft tissue
bleeds in patients with severe hemophilia A. Determining

whether a reduction in hemarthroses translates into other

benets, such as improved or stabilized joint function, would
require assessment in larger clinical trials with longer follow-up
times.
Acknowledgements
The authors would like to acknowledge all centers that
participated in the study, which was sponsored by Bayer
HealthCare (Berkeley, CA, USA). Additionally, the authors
acknowledge C. A. Kirk and T. Wetter for providing editorial
support funded by Bayer HealthCare.
Disclosure of Conflict of Interests
M.M. Enriquez and L. Schwartz are employees of Bayer
HealthCare. The other authors state that they have no conict
of interest.
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orthopaedic outcomes for severe factor-VIII-decient haemophiliacs.
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