Introduction
Glanzmann's thrombasthenia (GT) is a rare inherited bleeding disorder characterized
by quantitative or qualitative defects in the platelet membrane integrin α2bβ3 (also
known as glycoprotein IIb/IIIa), resulting in abnormal platelet function.[1] In addition to bleeding diathesis, loss of integrin α2bβ3 (from ITGA2B and/or ITGB3 mutations) and αvβ3 (from an ITGB3 mutation) may affect other biological processes in patients with GT.[2]
Patients with GT develop bleeding symptoms early in childhood.[3] In the Glanzmann's Thrombasthenia Registry (GTR), among the 187 patients with a
known age of onset of bleeding, 53% had bleeding symptoms by 1 year of age and 85%
by 14 years of age (median and mean ages of onset were 1 year and 5.6 years, respectively).[4]
Bleeding complications are typically mucocutaneous and may include epistaxis, purpura,
gingival hemorrhage, and menorrhagia. Patients with GT also experience bleeding following
trauma or surgical procedures, and during or after childbirth.[1]
[5] Women of reproductive age are particularly vulnerable to bleeding, with estimated
incidences of menorrhagia ranging from 74 to 98%.[1]
[4] In a systemic review by Siddiq et al, bleeding was reported in almost half of the
40 pregnancies in 35 women, although most bleeds were mucocutaneous and relatively
mild.[6] In addition, primary (within 24 hours of birth) and secondary (24 hours to 12 weeks
after birth) postpartum bleedings were observed in one-third and one-quarter of cases,
respectively.
Bleeding episodes can often be treated by local measures and antifibrinolytics.[5]
[7] Platelet transfusion is the standard of care if the bleeding is unresponsive to
these conservative means.[3]
[5] However, platelet transfusion has several limitations including potential for blood-borne
pathogen transmission, particularly bacterial infection.[8] Risk of residual viral infection with blood products is now very low,[9] but emergent pathogens are a concern.[8] Patients may develop antibodies to human leucocyte antigen (HLA) or integrin α2bβ3,
which can lead to platelet refractoriness, making future transfusions ineffective.[3]
[5] In addition, platelets may not be readily available in emergencies.[4] Importantly, antibodies against α2bβ3 can cross the placenta, resulting in thrombocytopenia
and bleeding in the fetus and neonates; among the 40 pregnancies reviewed by Siddiq
et al, maternal alloimmunization to platelet antigens (which may occur due to exposure
to α2bβ3 platelets in fetomaternal circulation as well as by platelet transfusion)
occurred in approximately three-quarters of pregnancies and was associated with four
neonatal deaths.[6] Therefore, there is an unmet need for a readily available alternative to platelet
transfusions to avoid the risk of alloimmunization against platelets.
Recombinant activated factor VII (rFVIIa; eptacog alfa activated, NovoSeven, Novo
Nordisk A/S, Bagsværd, Denmark) was approved by the European Medicines Agency (EMA)
in 2004 for the treatment of bleeding episodes and for the prevention of bleeding
during surgery or invasive procedures in patients with GT; but its use was limited
to those with antibodies to integrin α2bβ3 and/or HLA, and with past or present refractoriness
to platelet transfusions.[10]
The GTR was set up as a part of an EMA regulatory commitment to collect postmarketing
data on rFVIIa utilization in patients with GT. Data on the use of other therapeutic
options (platelets and antifibrinolytics) were also collected.[11]
[12] In addition to the GTR, other registries and surveys on the use of rFVIIa in GT
have been conducted over the past 20 years. An international survey evaluated the
efficacy and safety of rFVIIa in patients with GT, most of whom had platelet antibodies
or refractoriness.[13] The United States-based Hemophilia and Thrombosis Research Society registry also
collected data on the use of rFVIIa in patients with GT and other platelet disorders.[14]
Data from the registries and survey indicate that physicians use rFVIIa to prevent
bleeding cases irrespective of platelet antibodies and/or platelet refractoriness.[11]
[12]
[13] In the international survey, prevention of antiplatelet alloimmunization was cited
as one of the reasons to use rFVIIa in 43% of cases.[13] However, there is a need for data to support the efficacy and safety of rFVIIa in
patients without platelet antibodies, without refractoriness to platelets and in cases
when platelets are not readily available.
This article reports data from the GTR, a literature review, and the Novo Nordisk
safety surveillance database, and evaluates the efficacy and safety of rFVIIa in patients
with GT without antibodies or refractoriness to platelets using these three data sources.
These data were used to provide the required evidence to support the label extension
for the use of rFVIIa in cases where platelets are not readily available.
Methods
The Glanzmann's Thrombasthenia Registry
The GTR is a prospective, postmarketing, observational, multinational web-based registry
(NCT01476423) designed to allow the collection of data for the evaluation of efficacy
and safety of rFVIIa and other hemostatic agents used in patients with GT for the
treatment of severe bleeding episodes or the prevention of bleeding during surgery.[11]
[12]
Data entry into the GTR was from May 10, 2007 to December 16, 2011. Overall, data
collected from 218 patients with GT treated for 870 bleeding episodes and 204 surgical
procedures were used for primary effectiveness analysis. The secondary effectiveness
analysis was performed using data from 829 bleeding episodes and 206 surgical procedures.[11]
[12] Bleeding subtypes[12] and the most prevalent minor and major procedures[11] have been reported previously.
Full inclusion and exclusion criteria were listed previously.[11]
[12] In brief, patients (males and females of any age) with a diagnosis of congenital
GT were included in the GTR. Refractoriness to platelets or the presence of antibodies
was assessed initially and at specific intervals at the discretion of the investigator.
Dosing was according to local treatment practice and there were no set treatment protocols.
Full details on data handling are published elsewhere.[11]
[12]
Data from a subset of patients (N = 133) from the GTR who received rFVIIa, alone or in combination with other hemostatic
agents or platelets, were used to evaluate the efficacy and safety of rFVIIa in the
present analysis.
Definitions
Refractoriness to platelet transfusion was defined clinically as persistence of bleeding,
or rebleeding within 24 hours, or bleeding during surgery despite an adequate number
of platelet infusions (as determined by the clinician). A patient's refractoriness
and antibody status were both categorized as “positive” (indicates at least one positive
answer at any admission), “negative” (indicates no positive answers, but at least
one negative) or “unknown” (indicates only unknown or missing answers). As a result
of these categories, a nine-level classification was used on a per-patient basis in
relation to refractoriness and antibody status; refractoriness was categorized as
positive, negative, or unknown, with each category subclassified according to the
antibody status (positive, negative, or unknown).
Definitions used for treatment effectiveness during bleeding episodes and surgery
are shown in [Supplementary Table S1] (available in the online version).
Analysis of Efficacy and Safety
Analysis of efficacy was based on all treatment-allocated patients for whom information
on efficacy end points was available. Efficacy evaluations were summarized by age
(<12 years; 12–17 years; ≥18 years), refractoriness and antibodies to platelets status
(positive, negative, or unknown), and treatment group: rFVIIa alone (N7); rFVIIa with
platelets and other hemostatic treatment (N7POH, where P = platelets, OH = other hemostatic
treatment, mostly antifibrinolytics); rFVIIa with other hemostatic treatment (N7OH);
rFVIIa with platelets (N7P). All treatment episodes were included in the analysis
of safety. Due to the observational nature of data, descriptive statistics were used
to summarize the data and no formal statistical comparisons were performed.
Published Literature/Case Reports
A literature search for English language publications from January 01, 1999 to December
01, 2017 was performed by Novo Nordisk Global Information and Analysis using BIOSIS
Previews, Current Contents Search, Embase, and MEDLINE. Detailed search criteria and
number of hits identified using these criteria are shown in [Supplementary Table S2] (available in the online version). All GT cases of treatment and prevention of bleedings
(during delivery and surgery) in all ages and both sexes during the reported period
were included. Cases without antibodies to α2bβ3 and/or HLA and without past or present
refractoriness to platelet transfusions were described. Literature was selected avoiding
an overlap with the GTR and Novo Nordisk safety database. Data from published literature
and case reports were used to evaluate the efficacy of rFVIIa in patients with GT.
Novo Nordisk Safety Surveillance Database
Safety data from the use of rFVIIa in patients with GT were collected in the Novo
Nordisk safety database. Included safety data were obtained from spontaneous reports,
solicited reports from postauthorization studies and registries, and adverse events
(AEs) reported in the published literature. Data from the Novo Nordisk safety database
were used to evaluate the safety of rFVIIa in patients with GT.
Results
The Glanzmann's Thrombasthenia Registry
Patients and Demographic Characteristics
Overall, 133 patients (N7, n = 62; N7POH, n = 45; N7OH, n = 85; N7P, n = 11) were treated with rFVIIa in 492 admissions during the observational period
from May 10, 2007 to December 16, 2011. Among these, 94 patients were treated with
rFVIIa for 333 bleeding episodes and 77 patients received rFVIIa for the prevention
of bleeding during 159 surgical procedures. No noticeable differences in demographic
characteristics were observed between the four treatment groups ([Table 1]). In addition, no apparent differences were observed between patients treated for
bleeding and those undergoing surgery (data not shown) except for mean age, which
was slightly younger for patients treated for bleeding (21.0 years) than those undergoing
surgery (28.5 years).
Table 1
Summary of demography and patient history for patients treated with rFVIIa in the
GTR
|
Characteristics
|
|
N7 (N = 62)
|
N7POH (N = 45)
|
N7OH (N = 85)
|
N7P (N = 11)
|
All[a] (N = 133)
|
|
Age at first admission, y[b]
|
N
|
61
|
45
|
84
|
11
|
131
|
|
Mean (SD)
|
23.3 (16)
|
20.8 (19)
|
22.9 (17)
|
18.4 (17)
|
24.1 (18)
|
|
Range
|
1–64
|
0–80
|
1–80
|
2–64
|
0–80
|
|
Age at first admission, n (%)
|
<12 y
|
17 (27)
|
20 (44)
|
26 (31)
|
5 (45)
|
41 (31)
|
|
12–17 y
|
7 (11)
|
4 (9)
|
10 (12)
|
1 (9)
|
16 (12)
|
|
≥18 y
|
37 (60)
|
21 (47)
|
48 (56)
|
5 (45)
|
74 (56)
|
|
Not reported
|
1 (2)
|
0
|
1 (1)
|
0
|
2 (2)
|
|
Sex, n (%)
|
Female
|
36 (58)
|
24 (53)
|
48 (56)
|
8 (73)
|
75 (56)
|
|
Male
|
26 (42)
|
21 (47)
|
37 (44)
|
3 (27)
|
58 (44)
|
|
Ethnic origin, n (%)
|
African
|
4 (6)
|
1 (2)
|
3 (4)
|
0
|
6 (5)
|
|
Asian
|
4 (6)
|
5 (11)
|
9 (11)
|
1 (9)
|
14 (11)
|
|
Caucasian
|
30 (48)
|
29 (64)
|
45 (53)
|
9 (82)
|
72 (54)
|
|
Middle Eastern
|
1 (2)
|
1 (2)
|
1 (1)
|
0
|
1 (1)
|
|
Other
|
4 (6)
|
3 (7)
|
3 (4)
|
1 (9)
|
10 (8)
|
|
Unknown
|
19 (31)
|
6 (13)
|
24 (28)
|
0
|
30 (23)
|
|
Disease type,[c]
n (%)
|
Type I
|
30 (48)
|
18 (40)
|
49 (58)
|
3 (27)
|
62 (47)
|
|
Type II
|
7 (11)
|
4 (9)
|
7 (8)
|
2 (18)
|
13 (10)
|
|
Variant
|
2 (3)
|
1 (2)
|
2 (2)
|
0
|
3 (2)
|
|
Unknown
|
23 (37)
|
22 (49)
|
27 (32)
|
6 (55)
|
55 (41)
|
Abbreviations: GPIIb-IIIa, glycoprotein IIb-IIIa; GTR, Glanzmann's thrombasthenia
Registry; N7, rFVIIa alone; N7OH, rFVIIa + other hemostatic treatment; N7P, rFVIIa + platelets;
N7POH, rFVIIa + platelets + other hemostatic treatment; rFVIIa, recombinant activated
factor VII; SD, standard deviation.
a Patients who changed therapy during the study period or had both surgeries and bleedings,
have been counted in several groups; therefore, the number of patients in each group
does not sum up to the total.
b There were two patients (four admissions) ≥65 years of age; one was 80 and one was
73 years of age.
c The disease is classified based on the level of platelet α2bβ3 (GPIIb-IIIa) complexes
present: type I (less than 5% of normal GPIIb-IIIa levels), type II (5–20% of normal
GPIIb-IIIa levels), variant-type (the level of GPIIb-IIIa is above 20%; however, the
proteins are dysfunctional) or disease type not reported (unknown).
The pattern of refractoriness and antibody status was similar across the four treatment
groups ([Supplementary Table S3], available in the online version) and between age groups ([Supplementary Table S4], available in the online version). However, the number of patients in the N7P treatment
group was low (11 of the 133 patients) compared with the number of patients in the
other treatment groups. It should also be noted that the number of patients in the
12 to 17 years age group was low (19 patients) compared with the other age groups
(41 and 77 patients in the <12 years and ≥18 years age groups, respectively).
Dosing of rFVIIa
Although there was large variation, the median dose per infusion of rFVIIa in patients
with bleeding episodes was 90 μg/kg, which is in line with the recommended dose for
patients with GT (90 [range: 80–120] μg/kg). Median dose per infusion was similar
across all four treatment groups ([Table 2]). When assessed by refractoriness and antibody status, median dose per infusion
was 90 μg/kg in all but two patient categories ([Table 2]). The median dose per infusion was slightly lower (78 μg/kg) in patients with unknown
refractoriness/unknown antibody status than in other categories, but there were only
four admissions for patients with this status.
Table 2
Dosing of rFVIIa in bleeding episodes by treatment and by refractoriness and antibody
status in the GTR
|
Total number of admissions
|
Total number of doses[a]
|
No. of doses per admission,[a] median (range)
|
Dose per infusion (µg/kg), median (range)
|
Total dose per admission (µg/kg), median (range)
|
Interval between doses (h),[b] median (range)
|
Duration of treatment (h),[b] median (range)
|
|
All patients
|
327[c]
|
972
|
2.0 (1.0–10.0)
|
90 (28–450)
|
180 (28–6260)
|
3.0 (1.0–168.0)
|
8.0 (1.5–338.5)
|
|
Treatment group
|
|
N7
|
154
|
295
|
1.0 (1.0–10.0)
|
90 (48–272)
|
90 (48–1260)
|
3.0 (1.0–68.0)
|
4.0 (1.5–168.0)
|
|
N7POH
|
54
|
244
|
3.0 (1.0–10.0)
|
90 (36–450)
|
285 (40–6260)
|
3.0 (1.0–168.0)
|
26.0 (2.0–338.5)
|
|
N7OH
|
106
|
394
|
3.0 (1.0–10.0)
|
90 (28–300)
|
270 (28–6000)
|
3.0 (1.0–107.0)
|
12.5 (2.0–227.0)
|
|
N7P
|
13
|
39
|
2.0 (1.0–10.0)
|
90 (81–288)
|
243 (90–900)
|
3.0 (1.0–24.0)
|
4.0 (2.0–48.0)
|
|
Refractoriness and antibody status
|
|
Refr POS/AB POS
|
36
|
125
|
3.0 (1.0–10.0)
|
90 (40–450)
|
278 (40–4230)
|
3.0 (2.0–168.0)
|
9.0 (2.0–240.0)
|
|
Refr POS/AB NEG
|
31
|
177
|
5.0 (1.0–10.0)
|
90 (37–160)
|
574 (90–6260)
|
3.0 (1.0–114.0)
|
25.5 (2.0–338.5)
|
|
Refr POS/AB UNK
|
6
|
40
|
7.0 (3.0–10.0)
|
90 (90–90)
|
630 (270–1260)
|
3.0 (2.0–68.0)
|
27.0 (4.0–168.0)
|
|
|
Refr NEG/AB POS
|
43
|
172
|
3.0 (1.0–10.0)
|
96 (28–300)
|
270 (28–2760)
|
3.0 (2.0–25.0)
|
17.0 (2.0–72.0)
|
|
Refr NEG/AB NEG
|
157
|
257
|
1.0 (1.0–10.0)
|
90 (34–290)
|
90 (40–900)
|
3.0 (1.0–24.0)
|
4.0 (1.5–72.0)
|
|
Refr NEG/AB UNK
|
9
|
41
|
4.0 (2.0–9.0)
|
90 (26–111)
|
270 (72–810)
|
4.0 (2.0–57.0)
|
28.5 (3.0–136.0)
|
|
|
Refr UNK/AB POS
|
14
|
66
|
3.0 (1.0–10.0)
|
90 (62–360)
|
330 (90–1180)
|
4.0 (2.0–42.0)
|
52.0 (32.0–93.0)
|
|
Refr UNK/AB NEG
|
27
|
87
|
3.0 (1.0–10.0)
|
90 (70–170)
|
270 (80–1020)
|
3.0 (1.0–30.0)
|
4.8 (2.0–68.0)
|
|
Refr UNK/AB UNK
|
4
|
7
|
1.0 (1.0–4.0)
|
78 (78–128)
|
125 (96–312)
|
18.0 (3.0–19.0)
|
39.5 (39.5–39.5)
|
Abbreviations: AB, antibody; GTR, Glanzmann's Thrombasthenia Registry; N7, rFVIIa
alone; N7OH, rFVIIa + other hemostatic treatment; N7P, rFVIIa + platelets; N7POH,
rFVIIa + platelets + other hemostatic treatment; NEG, negative; POS, positive; Refr,
refractoriness; rFVIIa, recombinant activated factor VII; UNK, unknown.
a The doses of rFVIIa were reported as single dose per infusion, with date and time
for the first 10 records. In cases with more than 10 records, only the total amount
of the additional doses was collected. The number of additional doses was not recorded.
Therefore, the maximum number of doses per admission is 10.
b Only calculated for admissions with more than one dose and with date and time of
dose recorded.
c Six admissions had missing dose details and they are not included in this table.
Similar to the dosing in patients with bleeding episodes, there was a large variation
in the dose per infusion of rFVIIa among patients treated for prevention of bleeding
during surgery; however, the median dose per infusion (92 μg/kg) was similar in all
four treatment groups, ranging from 90 to 95 μg/kg ([Table 3]). Regardless of refractoriness or antibody status, the median dose per infusion
administered for the prevention of bleeding during surgical procedures was generally
similar across categories ([Table 3]); median doses were mostly close to or slightly higher than 90 μg/kg, except for
patients with refractoriness to platelets but without antibodies, for whom the median
dose per infusion was higher than those of other groups (142 μg/kg). A large variation
in total dose of rFVIIa and duration of treatment was seen across these categories.
Table 3
Dosing of rFVIIa in surgical cases by treatment and by refractoriness and antibody
status in the GTR
|
Total number of admissions
|
Total number of doses[a]
|
No. of doses per admission,[a] median (range)
|
Dose per infusion (µg/kg), median (range)
|
Total dose per admission (µg/kg), median (range)
|
Interval between doses (h),[b] median (range)
|
Duration of treatment (h),[b] median (range)
|
|
All patients
|
157[c]
|
720
|
3.0 (1.0–24.0)
|
92 (4–270)
|
270 (4–8544)
|
3.0 (1.0–749.0)
|
5.0 (1.5–749.0)
|
|
Treatment group
|
|
N7
|
62
|
210
|
2.5 (1.0–21.0)
|
90 (70–250)
|
270 (80–6336)
|
2.0 (2.0–264.0)
|
4.0 (1.5–264.0)
|
|
N7POH
|
21
|
134
|
3.0 (1.0–22.0)
|
90 (4–200)
|
270 (4–4617)
|
3.0 (1.0–18.0)
|
5.3 (2.0–139.0)
|
|
N7OH
|
70
|
331
|
3.0 (1.0–22.0)
|
95 (25–270)
|
305 (90–8544)
|
3.0 (1.0–749.0)
|
5.5 (1.5–749.0)
|
|
N7P
|
4
|
45
|
8.5 (4.0–24.0)
|
90 (90–90)
|
765 (360–2167)
|
3.0 (1.0–12.0)
|
25.0 (8.0–126.0)
|
|
Refractoriness and antibody status[d]
|
|
Refr POS/AB POS
|
40
|
120
|
3.0 (1.0–7.0)
|
102 (70–250)
|
300 (85–1250)
|
2.0 (2.0–26.0)
|
4.0 (1.5–68.0)
|
|
Refr POS/AB NEG
|
12
|
65
|
3.0 (1.0–20.0)
|
142 (85–200)
|
315 (90–4617)
|
2.0 (2.0–12.0)
|
6.0 (4.0–59.0)
|
|
Refr POS/AB UNK
|
1
|
11
|
11.0 (11.0–11.0)
|
90 (90–90)
|
990 (990–990)
|
3.0 (1.0–6.0)
|
28.0 (28.0–28.0)
|
|
|
Refr NEG/AB POS
|
24
|
140
|
3.0 (1.0–22.0)
|
93 (4–270)
|
418 (4–5954)
|
3.0 (1.0–13.0)
|
7.0 (1.5–102.0)
|
|
Refr NEG/AB NEG
|
36
|
178
|
3.0 (1.0–22.0)
|
90 (28–180)
|
270 (80–6336)
|
3.0 (1.0–749.0)
|
4.8 (2.0–749.0)
|
|
Refr NEG/AB UNK
|
1
|
24
|
24.0 (24.0–24.0)
|
90 (90–90)
|
2167 (2167–2167)
|
4.5 (1.0–12.0)
|
126 (126.0–126.0)
|
|
|
Refr UNK/AB POS
|
20
|
84
|
3.0 (1.0–21.0)
|
95 (25–240)
|
354 (90–1988)
|
4.0 (2.0–264.0)
|
6.5 (2.5–264.0)
|
|
Refr UNK/AB NEG
|
23
|
98
|
2.0 (1.0–20.0)
|
90 (90–180)
|
180 (90–8544)
|
2.0 (1.0–30.0)
|
5.0 (2.5–97.5)
|
Abbreviations: AB, antibody; GTR, Glanzmann's Thrombasthenia Registry; N7, rFVIIa
alone; N7OH, rFVIIa + other hemostatic treatment; N7P, rFVIIa + platelets; N7POH,
rFVIIa + platelets + other hemostatic treatment; NEG negative; POS, positive; Refr,
refractoriness; rFVIIa, recombinant activated factor VII; UNK, unknown.
a The doses of rFVIIa used prior, during, and after a surgery were reported as single
dose per infusion, with date and time for the first 20 records. In cases with more
than 20 records, only the total amount of the additional doses was collected. The
number of additional doses was not recorded. The maximum number of doses per admission
is three times 20 (prior, during, and after).
b Only calculated for surgeries with more than one dose, and with date and time of
dose recorded. The dose interval at 749.0 is probably an outlier most likely due to
an error in indication of timing of dosing.
c Two admissions had missing dose details, and they are not included in this table.
d There were no admissions in the UNK/UNK category.
Evaluation of rFVIIa Efficacy
Glanzmann's Thrombasthenia Registry
In all patients admitted for bleeding episodes, treatment with rFVIIa-based regimens
was evaluated as effective in 79% (262/333) of admissions. In each treatment group,
treatment was evaluated to be effective in most (65–86%) of the admissions ([Fig. 1A]). Regardless of refractoriness and antibody status, treatment was evaluated to be
effective in most of the admissions (range: 56 − 100%) across the categories ([Supplementary Table S5], available in the online version).
Fig. 1 Efficacy of rFVIIa alone or in combination with other hemostatic treatment or platelets
in patients with GT in the GTR. Efficacy of rFVIIa alone or in combination with other
treatment for the (A) treatment of bleeding episodes in patients with GT. (B) Prevention of bleeding during surgery in patients with GT. GT, Glanzmann's thrombasthenia;
GTR, Glanzmann's Thrombasthenia Registry; N7, rFVIIa alone; N7OH, rFVIIa + other hemostatic
treatment; N7P, rFVIIa + platelets; N7POH, rFVIIa + platelets + other hemostatic treatment;
rFVIIa, recombinant activated factor VII.
Overall, treatment with rFVIIa-based regimens during surgery was evaluated as effective
in 88% (140/159) of admissions. In each treatment group, treatment was effective in
most of the admissions (range: 68–100%; [Fig. 1B]). Regardless of refractoriness and antibody status, treatment was evaluated as effective
in most admissions (range: 67–100%) across the categories ([Supplementary Table S5], available in the online version).
Irrespective of age, most admissions were evaluated to be effective (data not shown).
Although not included as a predefined age group, only two patients (four admissions)
were aged ≥65 years (73 and 80 years of age); treatment was considered effective and
uneventful in these patients.
Published Literature
Overall, 143 references, including full articles and congress abstracts, met the search
criteria and were reviewed. After full-text assessment, 14 references that contained
sufficient predefined assessments of efficacy were included and evaluated.[6]
[13]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26] These references included 31 cases without antibodies to integrin or refractoriness
to platelets, or for which the status of antibodies/refractoriness was unknown ([Supplementary Table S6], available in the online version). Out of these, efficacy and safety of rFVIIa were
reported for 30 cases. These patients received treatment with rFVIIa or other hemostatic
agents for the treatment of bleeding episodes and to prevent bleeding during surgery.
In summary, published literature and case reports showed that a treatment regimen
of rFVIIa alone, or based mainly on rFVIIa, reduces platelet transfusions, was effective
for bleeding treatment or prophylaxis, and had an acceptable safety profile in patients
with GT without antibodies to platelets, or where platelets are not readily available.[13]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
Evaluation of rFVIIa Safety in Patients with GT
Glanzmann's Thrombasthenia Registry
In the GTR, a total of 15 AEs were reported in nine patients; of these, seven were
serious AEs. No deaths were reported in patients receiving rFVIIa ([Table 4]). Two patients treated with rFVIIa had AEs that were assessed by the investigator
as “possibly/probably” related to rFVIIa: “nausea,” “dyspnea,” and “headache” in one
patient (nonserious) and “deep vein thrombosis” (DVT) in one patient (serious). All
other AEs and serious AEs were considered unlikely to be related to rFVIIa. The DVT
occurred in a 25-year-old woman who received 19 doses of rFVIIa 142 μg/kg at 2- to
3-hour intervals (along with platelets 3 units and red blood cells 5 units) to prevent
bleeding during an emergency laparotomy; treatment was considered partially effective.
She presented with a DVT 5 days after the last dose of rFVIIa was administered and
remained in hospital 14 days postoperatively. The surgery and its associated immobilization
may have been confounding etiological factors for the DVT.
Table 4
Summary of adverse events in the GTR (treatments including rFVIIa)
|
Number of patients (N = 133)
|
Number of admissions (N = 492)
|
Number of adverse events
|
|
All adverse events, n
|
9
|
11
|
15
|
|
Serious, n
|
4
|
5
|
7[a]
|
|
Nonserious, n
|
6
|
6
|
8
|
Abbreviations: GTR, Glanzmann's Thrombasthenia Registry; N7, rFVIIa alone; N7OH, rFVIIa + other
hemostatic treatment; N7POH, rFVIIa + platelets + other hemostatic treatment; rFVIIa,
recombinant activated factor VII.
a Serious events (treatment group) were septicemia (N7POH), respiratory insufficiency
(N7POH), cardiac decompensation (N7POH), subarachnoideal bleeding (N7POH), rebleeding,
and hematoma due to a fall (N7), deep vein thrombosis (N7POH), and rectorrhagia (N7OH).
Analysis of the AEs reported in the GTR showed no new safety concerns. No differences
were observed in the type or severity of AEs between patients with or without refractoriness
or antibodies to platelets.
Novo Nordisk Safety Surveillance Database
Since the first approval of rFVIIa in the GT indication in 2004, 53 cases comprising
77 AEs (43 serious events) were cumulatively reported from postmarketing sources in
the Novo Nordisk safety database up to December 01, 2017. Based on the cumulative
experience with rFVIIa, the number of AEs for each of the important identified risks
relevant for treatment with rFVIIa in GT is shown in [Table 5]. In total, 42 AEs (24 serious) concerned important identified risks associated with
rFVIIa treatment. Analysis of these cases did not raise any safety concerns.
Table 5
Important identified risks and number of adverse events in GT (postmarketing, including
serious adverse events from the GTR)
|
Adverse events
|
Number of serious adverse events
|
Number of nonserious adverse events
|
Total
|
|
Arterial thromboembolic events
|
1
|
0
|
1
|
|
Venous thromboembolic events
|
9
|
0
|
9
|
|
Mixed thromboembolic events
|
4
|
1
|
5
|
|
Lack of efficacy
|
7
|
17
|
24
|
|
Allergic reactions[a]
|
3
|
0
|
3
|
|
Total
|
24
|
18
|
42
|
Abbreviations: GT, Glanzmann's thrombasthenia; GTR, Glanzmann's Thrombasthenia Registry;
N7POH, rFVIIa + platelets + other hemostatic treatment.
Note: There were two fatal outcomes associated with these adverse events. One patient
had a venous thromboembolic event (pulmonary embolism), co-reported with two mixed
thromboembolic events (“atrial thrombosis” and “intracardial thrombus”). The second
patient had mixed thromboembolic events (“disseminated intravascular coagulation”
and “thrombosis”). In the GTR, there was one serious adverse event of deep vein thrombosis,
which occurred in the N7POH treatment group.
a MedDRA narrow scope terms only.
Among the 53 cases, six case reports had a fatal outcome. Three patients had fatal
hemorrhagic events (vaginal [n = 1], site not defined [n = 1], cerebral [n = 1]). The patient with cerebral hemorrhage also had disseminated intravascular coagulation,
thrombocytopenia, postoperative renal failure, and thrombosis; a further patient had
atrial thrombosis. Intestinal ischemia was another fatal event, and no information
was available on the sixth case. Analysis of the fatal cases showed no new safety
concerns regarding the use of rFVIIa.
Only 11 cases had information on refractoriness and/or antibodies to platelets ([Supplementary Table S7], available in the online version). Due to the low number of cases with this information
(11/53 cases), a comparison between the patients with and without refractoriness and/or
antibodies to platelets was not possible. However, no difference was observed in the
type and severity of AEs between the patients with information on refractoriness and/or
antibodies to platelets and the group of patients without this information.
There were five cases with thromboembolic events reported; two of these were in patients
aged ≥65 years. One of these events was reported in the literature and involved a
72-year-old woman who underwent abdominal surgery for gastrointestinal bleeding and
received rFVIIa (30 μg/kg) at a high continuous rate over a prolonged period.[13]
[27] In addition, the surgery and its associated immobilization may have been confounding
factors for the thromboembolic event.
Discussion
Data collected from the GTR, published literature, and Novo Nordisk safety surveillance
database report the consistent efficacy and safety profile of rFVIIa in patients with
GT. Similar efficacy across patient categories regardless of refractoriness or antibody
status supports the label extension of use of rFVIIa in patients with GT where platelets
are not readily available. Dosing of rFVIIa in this analysis was close to the recommended
and approved dose regimen of rFVIIa in GT (90 μg/kg [range: 80 − 120 μg]) at intervals
of 2 hours (1.5–2.5 hours) for bleeding episodes and surgical cases.
When conservative means are ineffective, use of platelets is currently considered
the standard of care for the treatment or prevention of bleeding in patients with
GT. However, use of platelets is associated with several limitations, including risk
of pathogen transmission, development of antibodies, and refractoriness to platelets.
In addition, platelets may not be immediately or readily available in all clinics.[28]
The data presented here support the applicability of rFVIIa as a good alternative
treatment to platelet transfusions for severe bleeding episodes. Overall, treatment
effectiveness in N7 and N7OH groups was similar to that in N7P and N7POH groups; therefore,
the addition of platelets to rFVIIa given with or without other hemostatic agents
did not generally improve treatment effectiveness. Furthermore, in patients with a
“negative” refractoriness and antibody status, rFVIIa showed similar efficacy (% effective
admissions) to that observed in patients with a “positive” refractoriness and antibody
status in bleeding episodes (85% [negative category] vs. 72% [positive category])
and surgical cases (95% [negative category] vs. 95% [positive category]). Of note,
these efficacy data differ slightly to those included in the EMA Summary of Product
Characteristics[29] ([Supplementary Table S8], available in the online version) due to differences in patient categorization.
Previous analyses of GTR data suggest that the effectiveness of rFVIIa is similar
to that of platelet-based treatment in patients without refractoriness or antibodies.[11]
[12] This indicates the validity of rFVIIa use in all patients with GT, irrespective
of refractoriness/antibodies to platelets status. There were also no relevant differences
between the effectiveness and safety of rFVIIa in adults and children.[30] Only two patients in the GTR were ≥65 years of age; treatments including rFVIIa
were considered effective in 4/4 admissions in these patients, with no AEs reported.
However, given the limited patient numbers, we are unable to make any conclusions
regarding response in patients ≥65 years of age compared with younger age groups.
Use of rFVIIa offers several benefits over platelet transfusion. There is no need
for time-consuming and difficult assessments of antibody or refractoriness status
in emergency situations. rFVIIa is not associated with the risk of blood-borne pathogen
transmission. Furthermore, rFVIIa prevents the risk of alloimmunization and refractoriness
associated with platelet transfusions. This is particularly important in women of
reproductive age with GT, where there is a substantial risk of transfer of alloantibodies
to the fetus via the placenta following platelet transfusions, resulting in potentially
fatal neonatal bleeding.
As a hemostatic agent, rFVIIa is associated with some potential risks that include
thromboembolic events, lack of efficacy, and allergic reactions. In patients treated
with rFVIIa in the GTR, there was a low rate of thrombosis (1/133 patients) and allergic
reactions (1/133 patients). Reported lack of effectiveness of rFVIIa in patients in
the GTR was very low (∼1.4%). Thromboembolic events, lack of efficacy, and allergic
reactions were, however, identified in the postmarketing database. In patients with
hemostatic deficiency and presence of thromboembolic risk factors, thromboembolic
events may occur when a hemostatic agent such as rFVIIa is used to normalize hemostasis.
The overall incidence of thromboembolic events with rFVIIa was low and in line with
what has been reported previously in patients with GT.[31] Importantly, data from all the available sources included in the present study did
not raise any new safety concerns or suggest a difference in thromboembolic risk between
patients with and without refractoriness or antibodies to platelets.
Limitations
Owing to the observational design of the GTR, it is difficult to compare efficacy
and safety outcomes between groups. The data (dosage and treatment parameters) from
the literature and postmarketing database are heterogeneous in nature; dosing in all
cases was according to local practice. However, it is challenging to collect data
from large randomized controlled trials due to the rarity of GT. Therefore, data from
the sources included in the present study provide valuable evidence on efficacy and
safety of rFVIIa in GT.
In the GTR, coding of refractoriness/antibody status was performed at first admission
or at the discretion of the investigator. In the other data sources used in the present
analysis, antibody or refractoriness status was not always reported. Lack of documentation
of antibody/refractoriness status at the time of each episode limits the analysis.
The number of AEs reported in the GTR was low, limiting analysis between patients
with or without refractoriness or antibodies to platelets. In addition, there were
only a few cases from the Novo Nordisk safety database with available information
on refractoriness and/or antibodies to platelets, limiting comparisons between categories.
