Keywords
anticoagulation - idarucizumab - dabigatran etexilate - real-world utilization - reversal
agent
Introduction
Anticoagulant reversal is central to the management of uncontrolled bleeding in anticoagulated
patients and, where possible, in those on anticoagulants who require emergency surgery
or other invasive procedures.[1] The strategy undertaken to attempt reversal will vary according to the type of anticoagulant
in use and availability of reversal agents. Nonvitamin K antagonist oral anticoagulants
(NOACs), including the direct thrombin inhibitor dabigatran and the factor Xa (FXa)
antagonists (rivaroxaban, apixaban, edoxaban, and betrixaban), are now recommended
in guideline statements as the preferred agents in most clinical settings due to their
similar efficacy and lower bleeding risk compared with vitamin K antagonists.[2]
[3]
[4] Reversal of NOACs was not possible until 2015, when idarucizumab became commercially
available in the United States and European Union (EU) for the specific reversal of
dabigatran.[5]
[6] Andexanet alfa was approved in 2018 in the United States for the treatment of rivaroxaban-
and apixaban-associated bleeding in patients, but is not yet available elsewhere,
nor is it approved for use in surgical patients.[7] Prior to this, treatment was limited to nonspecific empiric approaches (e.g., administration
of blood or blood derivatives, or waiting until anticoagulant activity had waned).
Nonspecific approaches are still used in countries that have no approved specific
reversal agents, and in bleeding associated with oral anticoagulants (OACs) for which
there are no specific reversal agents available.
Idarucizumab is a humanized mouse monoclonal antibody fragment that binds directly
to dabigatran with high affinity, reversing its anticoagulant effects within minutes.[8]
[9] In the phase III RE-VERSE AD (NCT02104947) trial, idarucizumab rapidly and completely
reversed dabigatran's anticoagulant effect in almost all patients with life-threatening
or uncontrolled bleeding or those requiring emergency surgery or procedures. In addition,
no safety concerns, specifically anaphylaxis or prothrombotic effects, were reported.[10] Dabigatran is indicated to reduce the risk of stroke and systemic embolism in nonvalvular
atrial fibrillation, to treat deep venous thrombosis (DVT) and pulmonary embolism
(PE), to prevent recurrent DVT and PE in adults (DVT/PE), and for primary prevention
of venous thromboembolism in orthopedic surgery.[11]
[12] Idarucizumab (5 g initially; two 50 mL vials each containing 2.5 g idarucizumab
constitute one complete 5 g dose [a second 5 g dose may be considered under specific
clinical circumstances]) is indicated in adult patients when rapid reversal of dabigatran
is required for life-threatening or uncontrolled bleeding or emergency surgery/urgent
procedures.[5]
[6]
To characterize the utilization of idarucizumab and provide data on usage patterns
in a real-world setting, RE-VECTO, a global drug administration surveillance program,
was initiated.
Methods and Analysis
Program Design and Participants
RE-VECTO, an international, multicenter, cross-sectional surveillance program, was
a postapproval study commitment for the European regulatory authorities. RE-VECTO
involved hospital pharmacies or departments in North America, the EU, and the Asia-Pacific
region, where idarucizumab was dispensed between August 2016 and June 2018, depending
on marketing authorization, country regulations and requirements, and availability
of the protocol.
In countries where idarucizumab was approved, potential sites where idarucizumab was
dispensed were identified and invited to register; after which data were collected
via a retrospective chart review. Initially, all centers who ordered idarucizumab
were sent a welcome pack and invited to register on the Web site. The response rate
was low and the process was redefined to include only those centers that ordered and
then restocked idarucizumab. However, this was not necessarily indicative of use of
idarucizumab as reorders could be for multiple reasons (i.e., supplying satellite
locations within the hospital or toward the end of the trial—replacing expired product).
In total, over 2,000 invitations were sent, and other methods were used to narrow
site selection to those with known patients receiving the product (i.e., claims data
or medical science liaison conversations). All centers that registered, completed
required training, and finalized the required trial documents were activated, regardless
if they had an identified patient or not.
Idarucizumab was prescribed at the discretion of the treating physician and not influenced
by participation in the program. Prescription of idarucizumab other than indicated
by the label was considered as off-label use, such as an unapproved indication (e.g.,
elective surgery), an unapproved dose (e.g., 2.5 g), or treatment of a patient who
did not receive dabigatran. Patients aged ≥ 18 years receiving idarucizumab as part
of their clinical care were eligible, regardless of prior OAC use. Any patients participating
in a dabigatran or idarucizumab clinical trial were excluded.
Informed consent was not required because the program was based on anonymized data.
The protocol was approved by an independent ethics committee where necessary, based
on country-specific regulations.
Data Collection
In patients treated with idarucizumab, anonymized patient data were entered into an
electronic data capture system via an Internet portal. A prespecified data-management
plan and prespecified rules generated autoqueries for missing fields, and data listing
reviews were conducted prior to database lock. Patient demographics such as age categories
and previous anticoagulant use (e.g., last intake of dabigatran etexilate or other
OACs) were collected. Previous antiplatelet treatment, safety, and efficacy data were
not collected.
Idarucizumab utilization, including the reason for idarucizumab use (life-threatening
or uncontrolled bleeding requiring medical intervention, or emergency surgery or other
urgent medical procedure necessitating rapid reversal of the anticoagulant effect
of dabigatran), was recorded. Information regarding the location of the bleeding event
(gastrointestinal [GI] tract, intracranial, postprocedural, skin, urogenital tract,
undefined location, other defined location) was also collected. In addition, the dosage
and timing of idarucizumab administration (total dose administered and the time interval
between administration of the first and second vials [the standard approved dosage
is 2 × 2.5 g vials]), whether idarucizumab administration was discontinued prematurely,
and the care setting (e.g., emergency department, intensive care unit, or operating
room) were recorded.
The characteristics of the hospital pharmacy were collected for each participating
site to evaluate the diversity of sites, including: country, whether the pharmacy
was central or decentralized, the number of pharmacy units within the hospital if
there is no central pharmacy (e.g., the emergency department, intensive care unit,
or operating room), idarucizumab stocks, storage location, distribution channels within
the hospital, type of practice (academic, nonacademic, private, or public), and availability
of electronic prescription records at the pharmacy.
Statistical Analysis
The program sample size was driven by regulatory requirements, and idarucizumab usage
and provider participation. A minimum of 300 patients was requested by the European
Medicines Agency.
Data from all enrolled patients who received idarucizumab were analyzed using descriptive
statistics (generated using SAS version 9.2 or higher [SAS Institute, Cary, North
Carolina, United States]). Categorical variables were summarized as numbers and proportions.
Continuous variables are reported as mean (standard deviation [SD]) or median (interquartile
ranges [IQRs]). Subgroups analyzed included region, indication for use of idarucizumab,
age, prior administration of idarucizumab, department where idarucizumab was administered,
bleeding event location and type, and whether the bleeding was life-threatening. Missing
data were not imputed.
Results
Characteristics of Sites Prescribing Idarucizumab
Of the 132 registered hospitals, 61 sites enrolled 359 patients (8 sites in the Asia-Pacific
region, 42 sites in the EU, and 29 sites in North America). Just over half (52.5%)
were nonacademic institutions, and the majority were public hospitals (67.2%) ([Table 1]).
Table 1
Hospitals treating patients with idarucizumab by region
|
Asia Pacific
N = 8
|
Europe
N = 24
|
North America
N = 29
|
Total
N = 61
|
|
Hospital type 1,[a] n (%)
|
|
|
|
|
|
Academic
|
6 (75.0)
|
15 (62.5)
|
7 (24.1)
|
28 (45.9)
|
|
Nonacademic
|
2 (25.0)
|
9 (37.5)
|
21 (72.4)
|
32 (52.5)
|
|
Other
|
0 (0.0)
|
0 (0.0)
|
1 (3.4)
|
1 (1.6)
|
|
Hospital type 2,[a] n (%)
|
|
|
|
|
|
Private
|
0 (0.0)
|
1 (4.2)
|
18 (62.1)
|
19 (31.1)
|
|
Public
|
8 (100.0)
|
23 (95.8)
|
10 (34.5)
|
41 (67.2)
|
|
Other
|
0 (0.0)
|
0 (0.0)
|
1 (3.4)
|
1 (1.6)
|
|
Type of pharmacy, n (%)
|
|
|
|
|
|
Central pharmacy
|
7 (87.5)
|
23 (95.8)
|
22 (75.9)
|
52 (85.2)
|
|
Decentralized pharmacy
|
1 (12.5)
|
1 (4.2)
|
7 (24.1)
|
9 (14.8)
|
|
Availability of electronic prescription records at the pharmacy, n (%)
|
|
|
|
|
|
Yes
|
4 (50.0)
|
16 (66.7)
|
28 (96.6)
|
48 (78.7)
|
|
No
|
4 (50.0)
|
8 (33.3)
|
1 (3.4)
|
13 (21.3)
|
|
Availability of electronic medical records at the pharmacy, n (%)
|
|
|
|
|
|
Yes
|
5 (62.5)
|
16 (66.7)
|
27 (93.1)
|
48 (78.7)
|
|
No
|
3 (37.5)
|
8 (33.3)
|
2 (6.9)
|
13 (21.3)
|
|
Number of pharmacy units per hospital,[b] n (%)
|
1
|
1
|
7
|
9
|
|
Median (IQR)
|
9.0 (9.0–9.0)
|
3.0 (3.0–3.0)
|
8.0 (1.0–10.0)
|
8.0 (2.0–9.0)
|
|
Total number of idarucizumab units (2 × 2.5 g) stocked per hospital pharmacy in all
storage locations,[c] n (%)
|
8
|
24
|
28
|
60
|
|
Median (IQR)
|
2.0 (1.0–3.0)
|
2.0 (2.0–3.5)
|
2.0 (1.0–2.0)
|
2.0 (1.0–3.0)
|
|
Storage location of idarucizumab stocks,[c]
[d] n (%)
|
|
|
|
|
|
Primary pharmacy
|
5 (62.5)
|
11 (45.8)
|
25 (86.2)
|
41 (67.2)
|
|
Satellite pharmacy
|
0 (0.0)
|
0 (0.0)
|
0 (0.0)
|
0 (0.0)
|
|
Emergency room
|
2 (25.0)
|
9 (37.5)
|
7 (24.1)
|
18 (29.5)
|
|
Other
|
3 (37.5)
|
12 (50.0)
|
0 (0.0)
|
15 (24.6)
|
Abbreviation: IQR, interquartile range.
a Type 1: academic sector type; Type 2: practice hospital type.
b Only available when type of pharmacy is decentralized pharmacy.
c Data for 1 hospital pharmacy missing for North America.
d Multiple answers possible.
Most pharmacies (85.2%) were centralized. In sites with decentralized pharmacies,
the median number of pharmacy units per hospital was 8.0 (IQR 2.0–9.0) ([Table 1]). The majority of hospitals (78.7%) had electronic prescription and electronic medical
records available, and stored idarucizumab in the primary pharmacy (67.2%). Other
storage locations include satellite pharmacies, emergency department, intensive care
unit or operating room, and other specialist departments (cardiology and neurology).
The median total idarucizumab units (one unit = 2 × 2.5 g vials) stocked per hospital
pharmacy in all storage locations was 2.0 (IQR 1.0–3.0).
Characteristics of Patients Treated with Idarucizumab
Of the 359 enrolled patients, most were either in the EU (152/359 [42.3%]) or North
America (157/359 [43.7%], of whom 140 were enrolled in the United States) ([Table 2]). The majority of patients were treated in hospitals that were academic (208/359
[57.9%]) and public (238/359 [66.3%]).
Table 2
Characteristics of patients treated with idarucizumab by region
|
Asia Pacific
N = 50
|
Europe
N = 152
|
North America
N = 157
|
Total
N = 359
|
|
Age group (y), n (%)
|
|
|
|
|
|
18–50
|
2 (4.0)
|
4 (2.6)
|
5 (3.2)
|
11 (3.1)
|
|
51–70
|
11 (22.0)
|
28 (18.4)
|
40 (25.5)
|
79 (22.0)
|
|
> 70
|
37 (74.0)
|
120 (78.9)
|
112 (71.3)
|
269 (74.9)
|
|
Prior administration of idarucizumab, n (%)
|
|
|
|
|
|
Yes
|
0 (0.0)
|
1 (0.7)
|
3 (1.9)
|
4 (1.1)
|
|
No
|
48 (96.0)
|
129 (84.9)
|
128 (81.5)
|
305 (85.0)
|
|
Unknown
|
2 (4.0)
|
22 (14.5)
|
26 (16.6)
|
50 (13.9)
|
|
Hospital type 1,[a] n (%)
|
|
|
|
|
|
Academic
|
41 (82.0)
|
108 (71.1)
|
59 (37.6)
|
208 (57.9)
|
|
Nonacademic
|
9 (18.0)
|
44 (28.9)
|
93 (59.2)
|
146 (40.7)
|
|
Other
|
0 (0.0)
|
0 (0.0)
|
5 (3.2)
|
5 (1.4)
|
|
Hospital type 2,[a] n (%)
|
|
|
|
|
|
Private
|
0 (0.0)
|
10 (6.6)
|
87 (55.4)
|
97 (27.0)
|
|
Public
|
50 (100.0)
|
142 (93.4)
|
46 (29.3)
|
238 (66.3)
|
|
Other
|
0 (0.0)
|
0 (0.0)
|
24 (15.3)
|
24 (6.7)
|
a Type 1: academic sector type; Type 2: practice hospital type.
Four (1.1%) patients had received idarucizumab previously, and this information was
missing for 50 (13.9%) patients. Most patients were aged > 70 years (74.9%) and 85.0%
had not received idarucizumab before (98.7% if excluding the 50 patients with unknown
prior use). The dose and last intake of previous anticoagulant medications (dabigatran
and/or other) is shown in [Table 3]. All patients had received an anticoagulant before recruitment. Dabigatran was the
last anticoagulant used by most patients (97.5%), and of these, only two (0.6%) patients
were taking dabigatran and another oral or parenteral anticoagulant (both had life-threatening
or uncontrolled bleeding). Of the nine patients without dabigatran documented as their
last anticoagulant medication, four had received rivaroxaban or an unknown anticoagulant,
and one had received apixaban. Dabigatran dosage regimens (eight types were recorded)
were known for 332 patients, with the most frequent being 150 mg twice daily (52.4%)
and 110 mg twice daily (35.8%). Of those patients receiving dabigatran 110 mg or 150 mg
twice daily, 89.9 and 60.3% were aged > 70 years. The dose of dabigatran was not recorded
for 18 (5.0%) patients.
Table 3
Last anticoagulant medication taken prior to recruitment, according to the reason
for idarucizumab administration
|
Life-threatening or uncontrolled bleeding
N = 207
|
Emergency surgery or other urgent medical procedure
N = 129
|
Scheduled or planned surgery/procedure
N = 12
|
Other
N = 11
|
Total
N = 359
|
|
Anticoagulant medication, n (%)
|
|
|
|
|
|
|
Dabigatran any dose[a]
|
203 (98.1)
|
124 (96.1)
|
12 (100.0)
|
11 (100.0)
|
350 (97.5)[a]
|
|
Rivaroxaban any dose
|
3 (1.4)
|
1 (0.8)
|
0 (0.0)
|
0 (0.0)
|
4 (1.1)
|
|
Apixaban any dose
|
0 (0.0)
|
1 (0.8)
|
0 (0.0)
|
0 (0.0)
|
1 (0.3)
|
|
Edoxaban any dose
|
0 (0.0)
|
0 (0.0)
|
0 (0.0)
|
0 (0.0)
|
0 (0.0)
|
|
Vitamin K antagonist
|
0 (0.0)
|
0 (0.0)
|
0 (0.0)
|
0 (0.0)
|
0 (0.0)
|
|
Other anticoagulant
|
2 (1.0)
|
0 (0.0)
|
0 (0.0)
|
0 (0.0)
|
2 (0.6)
|
|
Unknown
|
2 (1.0)
|
4 (3.1)
|
0 (0.0)
|
0 (0.0)
|
6 (1.7)[b]
|
a Includes two patients who received ≥ 1 dose dabigatran plus other anticoagulant.
b Includes two patients who were receiving another known anticoagulant medication.
Utilization of Idarucizumab
Most patients (341/359 [95.0%]) received the full dose (2 × 2.5 g) of idarucizumab,
with the mean (SD) time between vials being 15.3 (8.6) minutes ([Table 4]); time between two vials was missing for 123/341 (36.1%) patients. Of the 18 patients
who were documented as not receiving the full dose of idarucizumab initially, 12 received
one vial (2.5 g) and the dose was unknown for the other 6. A second treatment with
5 g of idarucizumab, based on clinical signs in combination with coagulation tests,
was administered to six patients (1.7%), either in the emergency department (n = 2) or intensive care unit (n = 4). The mean (SD) time between vials for the second treatment was 14.0 (7.1) minutes,
with the time between two vials missing in 2/6 (33.0%) patients. Of the six patients
requiring a second full dose of idarucizumab, five given idarucizumab for initial
life-threatening or uncontrolled bleeding required the second treatment for additional
urgent intervention (n = 1) or for rebleeding/prolonged coagulation test (n = 4); one patient given idarucizumab initially for emergency surgery/urgent medical
procedures required the second treatment for prolonged rebleeding/prolonged coagulation
test. No adverse events were reported in any patient.
Table 4
Idarucizumab utilization according to the reason for idarucizumab administration
|
Life-threatening or uncontrolled bleeding[a]
N = 207
|
Emergency surgery or other urgent medical procedure[b]
N = 129
|
Scheduled or planned surgery/procedure
N = 12
|
Other
N = 11
|
Total
N = 359
|
|
Idarucizumab total dose, n (%)
|
|
|
|
|
|
|
2.5 g (1 vial)
|
7 (3.4)
|
5 (3.9)
|
0 (0.0)
|
0 (0.0)
|
12 (3.3)
|
|
5 g (2 vials)
|
195 (94.2)
|
123 (95.3)
|
12 (100.0)
|
11 (100.0)
|
341 (95.0)
|
|
Other
|
5 (2.4)
|
1 (0.8)
|
0 (0.0)
|
0 (0.0)
|
6 (1.7)
|
|
Time between 2 vials (min)[c]
[d]
|
|
|
|
|
|
|
N
|
127
|
83
|
7
|
1
|
218
|
|
Mean (SD)
|
15.80 (8.72)
|
14.20 (8.59)
|
16.14 (5.70)
|
25.00 (–)
|
15.25 (8.60)
|
|
Second round of idarucizumab 5 g, n (%)
|
|
|
|
|
|
|
No
|
198 (95.7)
|
125 (96.9)
|
12 (100.0)
|
11 (100.0)
|
346 (96.4)
|
|
Yes
|
5 (2.4)
|
1 (0.8)
|
0 (0.0)
|
0 (0.0)
|
6 (1.7)
|
|
Unknown
|
4 (1.9)
|
3 (2.3)
|
0 (0.0)
|
0 (0.0)
|
7 (1.9)
|
|
Reason for second round,[e] n (%)
|
|
|
|
|
|
|
Additional urgent intervention
|
1 (20.0)
|
0 (0.0%)
|
0 (0.0)
|
0 (0.0)
|
1 (16.7)
|
|
Rebleeding/coagulation test prolongation
|
4 (80.0)
|
1 (100.0)
|
0 (0.0)
|
0 (0.0)
|
5 (83.3)
|
|
Time between 2 vials for second round (min)[c]
[e]
[f]
|
|
|
|
|
|
|
N
|
4
|
0
|
0
|
0
|
4
|
|
Mean (SD)
|
14.00 (7.12)
|
–
|
–
|
–
|
14.00 (7.12)
|
Abbreviations: ICU, intensive care unit; SD, standard deviation.
a Life-threatening or uncontrolled bleeding requiring urgent medical intervention.
b Emergency surgery or other urgent medical procedure necessitating rapid reversal
of dabigatran prior to surgery or procedure (emergency defined as within the next
8 hours).
c Calculated only for those patients administered total dose of 5 g (2 vials), and
defined as the end time of second vial minus the start time of the first vial. If
the start or end time of dosing was unknown, the estimated time of total infusion
was used; if this estimate was not known, then time was set to missing.
d Missing data for 68 patients in the emergency setting, 40 in the operating setting,
5 in the intensive care setting, and 10 in the other setting.
e Among patients who had second round of dosing with 5 g of idarucizumab.
f Missing data for 1 patient in the emergency and ICU settings.
Idarucizumab was primarily administered in the emergency department (209/359 [58.2%]).
Bleeding was the most frequent indication for the administration of idarucizumab (207/359
[57.7%] patients), followed by emergency surgery/urgent procedure (129/359 [35.9%]
patients). This pattern was consistent in most departments, except for the surgical
department.
The most frequent bleeding events were GI tract (92/207 [44.4%] of patients) and intracranial
(80/207 [38.6%]) ([Figs. 1] and [2]). Most patients with GI bleeding (88/92 [95.7%]) received the full dose (2 × 2.5 g)
of idarucizumab, with the mean (SD) time between vials being 15.2 (9.8) minutes. Similarly,
the majority of patients with intracranial bleeding (76/80 [95.0%]) received the full
dose of idarucizumab, with the mean (SD) time between vials being 16.3 (7.1) minutes.
Of the 194/207 (93.7%) patients who received the full dose (2 × 2.5 g) of idarucizumab
for a bleeding event, the time between two vials was not available for 68/194 (35.1%)
patients. For those patients who received the full dose (2 × 2.5 g) of idarucizumab
for GI or intracranial bleeding events, the time between two vials was not available
for 28/88 (31.8%) and 25/76 (32.9%) patients, respectively. Four patients (1.1%) were
reported to have prematurely discontinued idarucizumab, with none due to adverse events.
Fig. 1 Location of bleedinga events (N = 207) leading to idarucizumab use, and idarucizumab use by bleeding location. aLife-threatening or uncontrolled bleeding requiring medical intervention. bCalculated only for those patients administered total dose of 5 g (2 vials), and defined
as the end time of second vial minus the start time of the first vial. If the start
or end time of dosing was unknown, the estimated time of total infusion was used;
if this estimate was not known, then time was set to missing. cMissing data for 28 patients with gastrointestinal tract bleeding, 25 with intracranial
bleeding, 3 with skin bleeding, 3 with urogenital tract bleeding, 1 with intramuscular
bleeding, 2 with retroperitoneal bleeding, and 6 with other bleeding locations. GI,
gastrointestinal; NE, not evaluable; SD, standard deviation.
Of the 141 (39.3%) patients who were administered idarucizumab for emergency or for
scheduled or planned surgery/procedure ([Figs. 2] and [3]), GI and/or abdominal surgery or procedures were most frequently performed (in 36
[25.5%] of patients), followed by orthopedic procedures (in 31 [22.0%] patients),
thoracic surgery including cardiac surgery (23 [16.3%] patients), and vascular operations
(in 20 [14.2%] patients). Of the 23 patients who received idarucizumab for thoracic
surgery including cardiac surgery, 6 patients underwent cardiac catheterization, 3
patients had a cardiac pacemaker insertion or removal, 1 patient had a central venous
catheterization, and 5 patients had a pericardial excision and pericardial drainage.
No intraprocedural bleeds were reported. The study also included patients who required
rapid reversal of the anticoagulant effect of dabigatran prior to thrombolysis (n = 12) and thrombectomy (n = 2). On average, data were missing for 6.4% of patients with regard to the type
of surgery/procedure; 8/129 (6.2%) patients underwent emergency surgery or other urgent
medical procedures, and 1/12 (8.3%) patients who underwent scheduled or planned surgery/procedures.
Fig. 2 RE-VECTO surveillance program. GI, gastrointestinal.
Fig. 3 Type of surgery or procedure by indication for idarucizumab use. aMissing data for 8 patients undergoing emergency surgery or other urgent medical procedures.
bMissing data for 1 patient undergoing scheduled or planned surgery/procedures.
Discussion
The RE-VECTO postapproval surveillance study has shown that sites prescribing idarucizumab
were mainly nonacademic institutions and public hospitals, with approximately two
doses of idarucizumab stored onsite. Most of the patients were European or North American.
More than half of the registered hospitals either registered proactively prior to
identification of a patient treated with idarucizumab or had historical cases of patients
treated with idarucizumab but did not enter patients into the registry. Of those sites
that entered patient data, as expected, dabigatran was the anticoagulant used by most
patients. Nearly all patients received the full dose (2 × 2.5 g) of idarucizumab,
with only one full dose required in almost all patients. There was minimal off-label
dosing (e.g., use of 2.5 g in 12 patients), and administration of idarucizumab to
7 patients using FXa inhibitors (without dabigatran) was reported. As expected, idarucizumab
was most frequently given in the emergency department, and bleeding (the most common
locations being GI tract and intracranial) was the most frequent reason for administering
idarucizumab.
The findings from RE-VECTO describing idarucizumab uptake, dabigatran prescribing
patterns, and patient characteristics in the real-world setting add to the idarucizumab
clinical trial data and few case collections available to date.[10]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20] While the patients in RE-VECTO were less well characterized due to the limitations
of data collection, outcomes were largely consistent with those observed in the clinical
trial setting with regard to indications, rates of bleeding, and emergent surgery
events. In addition, RE-VECTO demonstrates that the real-world usage of idarucizumab
was mostly as recommended in the label. Moreover, the reversal of dabigatran in RE-VECTO
rarely required a second round of idarucizumab dosing (< 2% of patients), supporting
the findings from the RE-VERSE-AD study in which a second round of dosing was required
in 1.6% of patients.[10] In addition, the reversal of dabigatran in the real-world setting involved a mainly
elderly population treated with several different dabigatran dosage regimens. In RE-VERSE-AD,
the median age was 78 (range, 21–96) years, and > 97% of patients received one of
three approved dosage regimens of dabigatran (150/110/75 mg twice daily).
Aside from idarucizumab, one other reversal agent, andexanet alfa, is available commercially
in the United States for the reversal of rivaroxaban- and apixaban-related bleeding
only, following positive results from clinical trials.[21]
[22] Another potential FXa inhibitor reversal agent, ciraparantag, has yet to begin phase
II or III evaluation in patient settings; phase II data in healthy volunteers administered
rivaroxaban (NCT03172910) or apixaban (NCT03288454) are expected in 2019.
The RE-VECTO surveillance program was designed to collect data on drug use in a simple
and effective way, although the voluntary registration design and/or resource limitations
may have reduced participation and resulted in some incomplete data sets. Some recruited
sites known to be prescribing idarucizumab did not enter patient data in the registry
during the specified time period for data collection, and were not actively surveyed.
Data listing reviews conducted prior to database lock did not involve an independent
data review committee, and onsite source data verification was not conducted. Administration
of idarucizumab is rare, and without patient data being entered into the registry,
we are unable to ascertain whether these sites were restocking idarucizumab, supplying
satellite locations within the hospital, replacing expired idarucizumab, or administering
idarucizumab to patients. Nevertheless, drug surveillance programs are one source
of real-world data[23] that are particularly useful for identifying improper use. By identifying potential
risks, action can be taken to help minimize the risk of adverse drug reactions resulting
from medication errors. This study assessed idarucizumab utilization in a predefined
sample of prescriptions in the clinical practice setting, based on medical and pharmacy
record review. This approach was in line with postmarketing surveillance requested
by the European Medicines Agency.
Conclusion
Real-world information from the RE-VECTO surveillance program adds to the data obtained
from idarucizumab clinical trials and provides valuable insights into the current
strategies employed to reverse the anticoagulation effects of dabigatran in emergency
situations. Usage patterns of idarucizumab were aligned with idarucizumab prescribing
information, with minimal off-label use (see [Fig. 2]).
What is known about this topic?
-
Limited data are available that describe idarucizumab utilization in routine clinical
practice.
-
Postmarketing observational studies can provide insight into the use of medications
in the real world where there is a broad patient population with various comorbidities
and concomitant therapies.
What does this paper add?
-
It provides the first insight into how a NOAC reversal agent is used in the real-world
setting, examining where idarucizumab is prescribed (across regions and within hospitals),
the patients who receive idarucizumab, and why they received it.
-
The RE-VECTO study confirmed that 5 g of idarucizumab was used appropriately in > 98%
of dabigatran-treated patients with life-threatening bleeding or in need of emergency
surgery.
-
Idarucizumab use was generally consistent with the data collected in the clinical
trial setting with minimal off-label prescribing.
