重症血友病 A 男児を対象にした完全な定期補充療法達成の方法：各種

重症血友病 A 男児を対象にした完全な定期補充療法達成の方法：
各種レジメンならびに早期出血および静脈アクセスに及ぼす影響
How to achieve full prophylaxis in young boys with severe haemophilia A:
different regimens and their effect on early bleeding and venous access
A. Nijdam, K. Kurnik, R. Liesner, R. Ljung, B. Nolan, P. Petrini and K. Fischer on behalf of the PedNet Study
Group
Van Creveldkliniek, University Medical Center, Utrecht, The Netherlands; Dr. von Haunersches Children ’
s
Hospital, University of Munich, Munich, Germany; Haemophilia Center, Department of Haematology Great
Ormond Street Hospital for Children, London, UK; Department of Clinical Sciences Lund – Paediatrics and
Malmö Haemostasis & Thrombosis Centre, Lund University, Skåne University Hospital, Malmö, Sweden;
Department of Haematology Oncology, Our Lady ’
s Children ’
s Hospital, Crumlin, Dublin, Ireland; Paediatric
Department of Coagulation Disorders, Karolinska University Hospital, Stockholm, Sweden; and Julius Center
for Health Sciences and Primary Care University Medical Center, Utrecht, The Netherlands
要　約：早期の定期補充療法促進のため，定期補充
の 36%）。（iii）週 1 ～ 2 回から開始し，出血表現
療法を週 1 回の輸注により開始し，これを漸増させ
型（phenotype ）に応じて頻度を増加させ，3 歳以
るレジメンが導入された。初期レジメンの選択は，
降週 3 回以上に到達（施設の 38%，患者の 46%）。
転帰に影響を及ぼす可能性がある。本研究は，初期
定期補充療法開始年齢の中央値は，full および asap
の定期補充療法レジメンを分類し，その短期転帰に
レジメンでは 1.2 歳であったのに対し，phenotype
ついて比較することを目的とした。「European
レジメンでは 1.8 歳であった。関節内出血の完全予
Paediatric Network for Haemophilia Management」防に最も効果を示したのは full レジメンであった
（PedNet）レジストリから，インヒビターを保有し（full 32% に対して，asap 27%，phenotype 8%）。
ない重症血友病 A 患者で，2000 ～ 2012 年に出生
一方，full レジメンは CVAD の使用が最も多いと
した定期補充療法施行患者のデータを入手した。治
いう損失を生じた（full 88% に対して，asap 34%，
療施設は，初期の定期補充療法の輸注頻度および週
phenotype 22%）。今回確認された 3 種類の定期補
充療法レジメンは，早期の出血および CVAD の使
3 回以上の輸注に到達した年齢に基づいて分類され
た。出血および中心静脈アクセスデバイス（CVAD）用に及ぼす影響に違いがあった。今回の分類は，最
の使用状況について，4 歳の時点で比較を行った。適な定期補充療法レジメンの確立に向けた最初のス
患者 363 名・21 施設において，次の 3 種類のレジ
テップである。
メンが確認された。
（i）週 3 回以上の定期補充療法
の輸注を 3 歳になる前に開始〔完全（full ）：施設
Keywords： bleeding ， central venous catheters ，
患者の 18%〕。
（ii）
週 1 ～ 2 回から開始し， children ， haemophilia A ， prophylaxis ， step-up
の 19%，
可能な限り速やか（asap ）に頻度を増加させ，3 歳
regimen
になる前に週 3 回以上に到達（施設の 43%，患者
the asap regimen, the majority of patients started
patient on once weekly prophylaxis at 3.8 years of
prophylaxis before the onset of joint bleeding,
age who did not follow the regular protocol in a cenwhereas patients on the full and phenotype regimens
tre using
the asap regimen.
bleed prompted
STRATEGIES
FOR STARTING
EARLYThis
PROPHYLAXIS
5
FOR START
experienced a median of one joint bleed before startimmediate stepping up to infusions every otherSTRATEGIES
day.
ing
prophylaxis (P < 0.01). Starting prophylaxis
Overall, the proportion of intracranial bleeds and the
(a)
Discussion
Prophylaxis
≥3x/week
(a) at which they occurred were similar across the
before the
third joint
bleed was achieved in 89% of
age
Discussion
Prophylaxis ≥3x/week
Principal findings
Table 1. Patient and treatment characteristics according to prophylactic strategies.
Principal findings
*Due to clinical circumstances not all patients in a centre started prophylaxis according to the local regimen.
Three different regi
identified in Eu
≥39 week1 before
prophylaxis with
and stepping up t
3 years (as soon as
to patient’s bleeding
Full and asap reg
treatment intensity
regimen reached ≥3
much less CVADs
phenotype regimen
experienced two ad
but needed fewer C
Three different regimens for starting prophylaxis were
FULL
ASAP
PHENOTYPE centres:
identified
in European
starting with
Prophylactic strategy
Full prophylaxis
As soon as possible1
According to bleeding
P-value across strategies
≥39 week before the age of 3 years (full), starting
Number of centres (%)
4 (19)
9 (43)
8 (38)
prophylaxis with lower
frequencies (1–29– week1)
Number of patients on prophylaxis (%)
66 (18)
130 (36)
167 (46)
–
and
stepping
up
to
≥39
week1 before the
Age at 1st treatment
0.8 (0.3–1.1)
0.9 (0.6–1.1)
0.8 (0.5–1.1)
0.49age of
3
years
(as
soon
as
possible:
asap)
or
later
(according
At starting prophylaxis
Age
1.3 (0.9–1.8)
1.2to(0.9–1.5)
1.7phenotype).
(1.2–2.6)
<0.01
patient’s bleeding
Frequency 19 week1
9%*
49%
55%
<0.01
Full
and
asap
regimens
showed
similar
bleeding
and
Frequency 29 week1
8%*
35%
31%
<0.01
treatment
intensity. However,
patients on<0.01
the asap
Frequency ≥39 week1
83%
16%*
14%*
Infusion dose in IU kg1
52 (40–87)
46
(28–51) reached ≥39
41 (32–48)
and used
regimen
week1 6 months later<0.01
At reaching ≥39 week1
much less CVADs (88% vs. 34%). Patients on the
Age
1.3 (0.9–1.8)
1.8 (1.2–3.1)
3.9 (2.3–6.0)
<0.01
last and
regimen1.6 (0.2–3.8)
reached ≥39 week1 <0.01
Time to reach ≥39 week1 since starting
0.0 (0.0–0.0)
0.4phenotype
(0.1–1.9)
1
experienced
two additional
4 years,
51 (39–88)
34
(24–47)
29 (23–37) joint bleeds at age
<0.01
Infusion dose in IU kg
Values are numbers, proportions, medians (IQR) and P-values across strategies. but needed fewer CVADs (22%) and infusions.
STRATEGIES FOR STARTING EARLY PROPHYLAXIS
(b)
Haemophilia
(2014), 1--7
(a)
Internal and external validity
5
© 2014 John Wiley & Sons Ltd
(b)
Analyses
were based on the high-quality detailed dataDiscussion
base
from the repeatedly checked and monitored PedNet registry; data on EDs were missing in 4% only
Principal
[15].
Start findings
of prophylaxis was easy to assess, as it generally
thefor
firststarting
75 EDsprophylaxis
that were docuThree occurred
different within
regimens
were
mented
detail.
Follow-upcentres:
of outcome
datawith
on
identifiedin in
European
starting
1
bleeding,
of infusions
clotting
factor
conbefore
the age ofand
3 years
(full),
starting
≥39 weeknumber
1
sumption
waswith
limited
to age
4 years, as
it was
avail)
prophylaxis
lower
frequencies
(1–29
week
1 and by then most
able
for
the
majority
of
patients
before the age of
and stepping up to ≥39 week
1
.
patients
hadsoon
reached
prophylaxis
≥39
3 years (as
as possible:
asap)
or week
later (according
The
classification
of
regimens
at
centre
level is an
to patient’s bleeding phenotype).
essential
part
of regimens
this study.
Selection
biasbleeding
(confoundFull and
asap
showed
similar
and
ing
by indication)
wasHowever,
avoided by
analysing
treatment
intensity.
patients
on strategies
the asap
1 cohorts of patients with
at
centre reached
level, including
full
6 months later and used
regimen
≥39 week
different
phenotypes.
much less CVADs (88% vs. 34%). Patients on the
1
The classification
of prophylactic
regimens
last was
and
phenotype
regimen reached
≥39 week
based
on
published
data
showing
the
strong
experienced two additional joint bleeds at ageindepen4 years,
dent
effect of
age CVADs
at starting
prophylaxis
on outcome
but needed
fewer
(22%)
and infusions.
[4,19]. Differences between centres, other than prophylaxis start regimen, may affect outcome, but are
Internal to
and
Fig. 3. Cumulative incidence of (a) reaching ≥3 times week1 and (b) cenunlikely
beexternal
the mainvalidity
driver of differences between
(b)
Fig. 3. Cumulative incidence of (a) reaching ≥3 times week1 and (b) central venous access device (CVAD) use according to regimen. The Kaplan–
regimens.
Analyses
were device
based(CVAD)
on the
detailed
datatral venous access
usehigh-quality
according to regimen.
The Kaplan–
Meier one minus survival function estimates cumulative incidences,
Meier
one
minus
survival
estimates
cumulative
incidences,
Thefrom
classification
wasfunction
verified
with
treating
phyadjusted for inhibitor development and incomplete follow-up.
base
the repeatedly
checked
andthe
monitored
Ped6 A. NIJDAM et al.
adjusted for
development
and incomplete
follow-up. have forsicians
at inhibitor
the data
centres.
centres
Net
registry;
on Although
EDs
werefew
missing
in 4% only
three prophylactic regimens. No other potentially
mal
all treatingwas
physicians
agreed as
with
the
[15].protocols,
Start of prophylaxis
easy to assess,
it genTable 2. Bleeding and treatment up to age 4 years according to prophylactic strategy.
three occurred
prophylactic
regimens.
potentially
life-threatening bleeds were observed in the cohort.
classification
of within
their prophylactic
strategy.
erally
the first 75No
EDsother
that were
docuFULL
ASAP
PHENOTYPE
life-threatening
bleeds
were
observed
the cohort.
These
datadetail.
represent
treatment
inincountries
mented
in
Follow-up
of outcome
datawith
on
Prophylactic strategy
Full prophylaxis
As soon as possible
According to bleeding
good
access
to treatment
andand
medical
care
and
no
bleeding,
number
of
infusions
clotting
factor
conNumber
of
patients
66
130
167
P-value
across
strategies
Factor administrations and consumption
restrictions
in clotting
factor
consumption
It is
sumption
was
limited to
age consumption
4
years, as it only.
was availFactor administrations
and
Before starting prophylaxis
AtCumulative
the age number
of 4 years,
infulikely
thatthe
prophylactic
treatment
including
able0 (0–1)
for
majority1 of
patients strategies,
and by <0.01
then
most
of joint the
bleedscumulative number 1of
(0–1)
(1–3)
At65%
the age
4ofyears,
the cumulative
number
1
Without
joint bleeds
20%
<0.01
sions
received
was close to 400 for both the 42%
full and
the
introduction
prophylaxis,
are≥39
different
elsewhere.
. of infupatients
hadofreached
prophylaxis
week
sions
received
was
close
to
400
for
both
the
fullis and
Number
of
ICHs
(%
of
all
patients)
8
(10)
7
(5)
10
(5)
0.22
asap regimens, whereas significantly lower on the phenoThe classification of regimens at centre level
an
At 4 years of age
asap regimens,
whereas
significantly
lower
on(confoundthe phenotype
regimen
(223;
P
<
0.01).
Concurrently,
the
total
essential
part
of
this
study.
Selection
bias
Cumulative number of joint bleeds
1 (0–2)
1 (1–3)
3 (1–5)
<0.01
Other
studies
type
(223;was
P8%
<avoided
0.01). Concurrently,
the total
clotting
consumption at age 4 years was32%
around
Without factor
joint bleeds
27%
ing
byregimen
indication)
by analysing<0.01
strategies
clotting
factor
age 4 years
was
around
Cumulative
of infusions
360 (186–500)
402
(275–496)
(119–343)
<0.01
174
000 IUnumber
on the
full and asap regimens and
about
Most
information
on223
effective
prophylaxis
is
available
at
centre
level, consumption
including
fullatcohorts
of patients
with
Cumulative clotting factor consumption (in 1000 IU)
177 (72–340)
172 000
(109–238)
90 (53–149)
<0.01
174
IU
on
the
full
and
asap
regimens
and
about
half of that on the phenotype regimen (P < 0.01).
on
starting
prophylaxis before age 3 years or before
different
phenotypes.
Values are numbers, proportions, medians (IQR) and P-values across strategies. half of that on the phenotype regimen (P < 0.01).
The classification of prophylactic regimens was
ICHs, intracranial haemorrhages.
based on published data showingHaemophilia
the strong(2014),
indepen© 2014 John Wiley & Sons Ltd
1--7
© 2014
John of
Wiley
Ltd
dent
effect
age&atSons
starting
prophylaxis on outcome
Haemophilia (2014), 1–7 DOI: 10.1111/hae.12613
[4,19]. Differences
between centres, other than protheWiley
third&joint
to ≥39 week1 after implantation, avoiding CVAD
© 2014 John
Sons bleed
Ltd [4,19]. This is reflected in current
phylaxis start regimen, may affect outcome, but are
1
clinical
practice:
all three
regimens
generally
use was not the only reason to start at lower frequenhttp://onlinelibrary.wiley.com/doi/10.1111/hae.12613/abstract
Fig.
3. Cumulative
incidence
of (a) reaching
≥3 times
week andstarted
(b) cenunlikely to be the main driver of differences between
tral venous accessbefore
device (CVAD)
use of
according
to regimen.
The Kaplan–
prophylaxis
the age
3 years
and before
the
cies. Introducing prophylaxis at lower frequencies is
regimens.
Meier one
survival
function estimates
cumulative
incidences,
本誌の日本語訳は原著者の許可を得てワイリー・パブリッシング・ジャパンが作成しています。
third
jointminus
bleed.
However,
to improve
prophylactic
also thought to increase patients’ and parents’ accepThe classification was verified with the treating phyadjusted for inhibitor development and incomplete follow-up.
無断複製・転載・修正は著作権法により禁じられています。
treatment, it is important to study outcome of differtance of treatment [25].
sicians
at the centres. Although few centres have for詳しくは「ヘモフィリアステーション」
をご覧ください。
ent regimens beyond the initiation phase of prophythree
prophylactic
regimens.
No
other
potentially
mal
protocols,
all treating physicians agreed with the
http://www.hemophilia-st.jp/medical/
laxis.
life-threatening bleeds were observed in the cohort.
classification
of their prophylactic strategy.
Clinical
implications
The full regimen can be compared to the randomThese data represent treatment in countries with
To move towards more optimal treatment strategies,
ized trials of the Joint Outcome Study (n = 32) [20]
good access to treatment and medical care and no
Factor
it is important to assess regimens used in clinical pracand
theadministrations
ESPRIT study and
(n =consumption
21) [21] which started
restrictions in clotting factor consumption only. It is
tice. The data presented provide extensive experience
prophylaxis with 3–3.59 week1. However, as they
At the age of 4 years, the cumulative number of infulikely that prophylactic treatment strategies, including
started prophylaxis at older ages than those on the
in starting early prophylaxis for severe haemophilia A.
sions received was close to 400 for both the full and
the introduction of prophylaxis, are different elsewhere.
Comparing short-term benefits and burden across regifull regimen in this study, outcome cannot be comasap regimens, whereas significantly lower on the phenomens, the asap regimen seems to provide the best of
pared.
type regimen (223; P < 0.01). Concurrently, the total
Prophylaxis ≥3x/week
Internal and extern
Analyses were base
base from the repe
Net registry; data
[15]. Start of proph
erally occurred with
mented in detail.
bleeding, number o
sumption was limit
able for the major
patients had reache
The classification
essential part of th
ing by indication) w
at centre level, incl
different phenotype
The classificatio
based on published
dent effect of age a
[4,19]. Differences
phylaxis start regim
unlikely to be the
regimens.
The classification
sicians at the centr
mal protocols, all t
classification of the
These data repr
good access to tre
restrictions in clott
likely that prophyla
the introduction of
Other studies
Most information o
on starting prophy

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