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Home > About Argatroban > Clinical Efficacy
Heparin-induced thrombocytopenia (HIT) is a serious,
immune-mediated complication of heparin therapy that is strongly associated
with subsequent venous and arterial thrombosis. Initial treatment of HIT
is to discontinue administration of all heparins, including unfractionated
and low-molecular-weight heparins (LMWH).
Heparin-Induced Thrombocytopenia:
Study 1 (ARG-911) and Study 2 (ARG-915)
The conclusion that Argatroban is an effective treatment for HIT and heparin-induced
thrombocytopenia and thrombosis syndrome (HITTS) is based upon the data
from two clinical studies that were comparable with regard to study design,
study objectives, dosing regimens, study outline, conduct, and monitoring[1,2,3]:
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Study 1 (ARG-911): a
prospective, historically controlled efficacy and safety study (because
no other therapy of HIT with or without
thromboses was available in the US during patient enrollment, and
a placebo-controlled trial was considered unethical, therapy with
Argatroban was compared with historical controls) |
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Study 2 (ARG-915): a
follow-on efficacy and safety study that used the same historical
control group from ARG-911 as the comparator |
Entry criteria and patient characteristics
In the two studies, 568 adult patients were treated with Argatroban and
193 adult patients made up the historical control group.[2]
Patients were required to have a clinical diagnosis of HIT, either without
thrombosis (HIT) or with thrombosis (HITTS) and be males or nonpregnant
females between the ages of 18 and 80 years.
HIT/HITTS was defined by a fall in platelet count to less than 100,000/mcL
or a 50% decrease in platelets after the initiation of heparin therapy with
no apparent explanation other than HIT. Patients with HITTS also had presence
of an arterial or venous thrombosis documented by appropriate imaging techniques
or supported by clinical evidence, such as acute myocardial infarction,
stroke, pulmonary embolism, or other clinical indications of vascular occlusion.
Patients who required anticoagulation with documented histories of positive
HIT antibody test were also eligible in the absence of thrombocytopenia
or heparin challenge (e.g., patients with latent disease).[2]
Patients with documented unexplained aPTT >200% of control at baseline,
documented coagulation disorder or bleeding diathesis unrelated to HITTS,
a lumbar puncture within the past 7 days or a history of previous aneurysm,
hemorrhagic stroke, or recent thrombotic stroke within the past 6 months
unrelated to HITTS, were excluded from these studies.
Treatment
The treatment group for Argatroban received an initial dose of 2 mcg/kg/min
via continuous intravenous infusion.[2]
The first aPTT was measured at least 2 hours after the start of the infusion
of Argatroban and subsequent dose adjustments were made (up to a maximum
of 10 mcg/kg/min) to achieve a steady-state aPTT that was 1.5 to 3.0 times
the baseline value (not to exceed 100 seconds).[2]
Patients remained on Argatroban for up to 14 days, until the underlying
condition resolved or appropriate anticoagulation was provided with other
agents.[1] The historical control
group consisted of patients at the participating centers who met the inclusion/exclusion
criteria for the study, and who presented prior to the initiation of the
study and did not receive Argatroban.
Efficacy analysis
The primary efficacy analysis was based on a comparison of event rates for
a composite endpoint that included death (all causes), amputation (all causes),
or new thrombosis during the treatment and follow-up period (study days
0 to 37).[2]
Secondary analyses included evaluation of the event rates for the components
of the composite endpoint, as well as time-to-event analyses. In Study 1,
304 patients were enrolled having active HIT (129/304, 42%), active HITTS
(144/304, 47%), or latent disease (31/304, 10%). Among the 193 historical
controls, 139 (72%) had active HIT, 46 (24%) had active HITTS, and 8 (4%)
had latent disease. Within each group, those with active HIT and those with
latent disease were analyzed together. Positive laboratory confirmation
of HIT/HITTS by the heparin-induced platelet aggregation test or serotonin
release assay was demonstrated in 174 of 304 (57%) Argatroban-treated patients
(i.e., in 80 with HIT or latent disease and 94 with HITTS) and in 149 of
193 (77%) historical controls (i.e., in 119 with HIT or latent disease and
30 with HITTS). The test results for the remainder of the patients and controls
were either negative or not determined.
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Summary of results from Study 1 and 2
| In Study 1, Argatroban improved
the composite endpoint (death, amputation, or new thrombosis) among
patients with HIT and HITTS compared with historical controls.[1,2] |
Study 1 (ARG-911) endpoint results:
A categorical analysis showed a significant improvement in the composite
outcome (death, amputation, or new thrombosis) in patients with HIT and
HITTS treated with Argatroban compared with those in the historical control
group (see Table 1). The components of the composite
endpoint are shown in Table 2.
Table 1. Efficacy Results of Study 1 (ARG-911):
Composite Endpoint*
|
HIT |
HITTS |
HIT/HITTS |
Parameter,
N (%) |
Control
n=147 |
Argatroban
n=160 |
Control
n=46 |
Argatroban
n=144 |
Control
n=193 |
Argatroban
n=304 |
| Composite Endpoint |
57 (38.8) |
41 (25.6) |
26 (56.5) |
63 (43.8) |
83 (43.0) |
104 (34.2) |
Table 2. Efficacy Results of Study 1 (ARG-911):
Components of the Composite Endpoint, Ranked by Severity*
|
HIT |
HITTS |
HIT/HITTS |
Parameter,
N (%) |
Control
n=147 |
Argatroban
n=160 |
Control
n=46 |
Argatroban
n=144 |
Control
n=193 |
Argatroban
n=304 |
| Death |
32 (21.8) |
27 (16.9) |
13 (28.3) |
26 (18.1) |
45 (23.3) |
53 (17.4) |
| Amputation |
3 (2.0) |
3 (1.9) |
4 (8.7) |
16 (11.1) |
7 (3.6) |
19 (6.2) |
| New Thrombosis |
22 (15.0) |
11 (6.9) |
9 (19.6) |
21 (14.6) |
31 (16.1) |
32 (10.5) |
| In Study 1, Argatroban significantly
increased the time-to-first-event in patients with HIT or HITTS compared
with historical controls.[1,2] |
Time-to-event analyses showed significant improvements in the time-to-first-event
in patients with HIT or HITTS treated with Argatroban versus those in the
historical control group. The between-group differences in the proportion
of patients who remained free of death, amputation, or new thrombosis were
statistically significant in favor of Argatroban by these analyses (P=0.007
in patients with HIT and P=0.018 in patients with HITTS, according
to log-rank test). A time-to-event analysis for the composite endpoint is
shown in Figure 1 for patients with HIT and Figure
2 for patients with HITTS.
Figure 1. Time-to-First-Event for the Composite
Efficacy Endpoint:
HIT Patients (Study 1 ARG-911)
Figure 2. Time-to-First-Event for the Composite
Efficacy Endpoint:
HITTS Patients (Study 1 ARG-911)
Study 2 (ARG-915) endpoint results: In
Study 2, 264 patients were enrolled, having either HIT (125/264, 47.3%)
or HITTS (139/264, 52.7%), and then treated with Argatroban. Categorical
analysis demonstrated significant improvement in the composite efficacy
outcome for Argatroban-treated patients, versus the same historical control
group from Study 1, among patients having HIT (25.6% vs 38.8%), patients
having HITTS (41.0% vs 56.5%), and patients having either HIT or HITTS (33.7%
vs 43.0%). Time-to-event analyses showed significant improvements in the
time-to-first-event in patients with HIT or HITTS treated with Argatroban
versus those in the historical control group. The between-group differences
in the proportion of patients who remained free of death, amputation, or
new thrombosis were statistically significant in favor of Argatroban.
Anticoagulant effect: In Study 1 (ARG-911),
the mean (±SE) dose of Argatroban administered was 2.0 ± 0.1
mcg/kg/min in the HIT arm and 1.9 ± 0.1 mcg/kg/min in the HITTS arm.
Moreover, 76% of patients with HIT and 81% of patients with HITTS achieved
a target aPTT at least 1.5-fold greater than the baseline aPTT at the first
assessment occurring on average at 4.6 hours (HIT) and 3.9 hours (HITTS)
following initiation of therapy with Argatroban. No enhancement of aPTT
response was observed in subjects receiving repeated administration of Argatroban.
Platelet count recovery: In Study 1 (ARG-911),
the majority of patients, 53% of those with HIT and 58% of those with HITTS,
had a recovery of platelet count by day 3. Platelet count recovery was defined
as an increase in platelet count to >100,000/mcL or to at least 1.5-fold
greater than the baseline count (platelet count at study initiation) by
day 3 of the study.
Percutaneous Coronary Intervention (PCI) in HIT/HITTS Patients:
Studies ARG-216, ARG-310, and ARG-311
In 3 similarly designed trials, Argatroban was administered to 91 patients
with current or previous clinical diagnosis of HIT/HITTS or heparin-dependent
antibodies, who underwent a total of 112 percutaneous coronary interventions
(PCIs) including percutaneous transluminal coronary angioplasty (PTCA),
coronary stent placement, or atherectomy.[2]
Entry criteria and patient characteristics
Among the 91 patients treated with Argatroban who had a current or previous
clinical diagnosis of HIT/HITTS or heparin-dependent antibodies, notable
ongoing or recent medical history included myocardial infarction (n=35),
unstable angina (n=23), and chronic angina (n=34). There were 33 females
and 58 males. The average age was 67.6 years (median 70.7, range 44-86),
and the average weight was 82.5 kg (median 81.0 kg, range 49-141). Due to
the history or presence of the heparin-dependent antibody or HIT/HITTS,
these patients required alternative anticoagulation. Seven of 91 patients
received glycoprotein IIb/IIIa inhibitors. Safety and efficacy were compared
with historical control populations. Per protocol, all patients received
oral aspirin (325 mg) 2 to 24 hours prior to the interventional procedure.
Treatment
After venous or arterial sheaths were in place, anticoagulation was initiated
with a bolus of Argatroban of 350 mcg/kg via a large-bore IV line or through
the venous sheath over 3 to 5 minutes. Simultaneously, a maintenance infusion
of 25 mcg/kg/min was initiated to achieve a therapeutic ACT of 300 to 450
seconds. If necessary to achieve this therapeutic range, the maintenance
infusion was titrated (15 to 40 mcg/kg/min) and/or an additional bolus dose
of 150 mcg/kg could be given. Each patient's ACT was checked 5 to 10 minutes
following the bolus dose. The ACT was checked as clinically indicated thereafter.
Arterial and venous sheaths were removed no sooner than 2 hours after discontinuation
of Argatroban and when the ACT was less than 160 seconds.
| In clinical trials of patients
with HIT undergoing PCI, the ACT was used for monitoring anticoagulant
activity of Argatroban during the procedure. |
If a patient required anticoagulation after the procedure, Argatroban could
be continued, but at a lower infusion dose between 2.5 and 5 mcg/kg/min.
An aPTT was drawn 2 hours after this dose reduction and the dose of Argatroban
then adjusted as clinically indicated (not to exceed 10 mcg/kg/min), to
reach between 1.5 and 3 times baseline value (not to exceed 100 seconds).
Results
| Argatroban provided rapid (usually
within 10 minutes) and effective anticoagulation effects in patients
at risk for and with HIT undergoing percutaneous coronary intervention
(PCI)— without an increased risk of bleeding compared with historical
control group. |
Ninety-one patients were treated with Argatroban on their first PCI, and
21 patients were re-exposed to Argatroban on subsequent percutaneous coronary
interventions (PCIs). In 92 of the 112 interventions (82%), the patient
received the initial bolus of 350 mcg/kg and an initial infusion dose of
25 mcg/kg/min. The majority of patients did not require additional bolus
dosing during the PCI procedure. The mean value for the initial ACT measurement
after the start of dosing for all interventions was 379 sec (median 338
sec; 5th percentile-95th percentile 238 to 675 sec). The mean ACT value
per intervention over all measurements taken during the procedure was 416
sec (median 390 sec; 5th percentile-95th percentile 261 to 698 sec). About
65% of patients had ACTs within the recommended range of 300 to 450 seconds
throughout the procedure. The investigators did not achieve anticoagulation
within the recommended range in about 23% of patients. However, in this
small sample, patients with ACTs below 300 seconds did not have more coronary
thrombotic events, and patients with ACTs over 450 seconds did not have
higher bleeding rates.
Figure 3. ACTs Before and During PCI With
Anticoagulation With Argatroban in Three Clinical Trials*
Figure 4. Acute Procedural Success in HIT
Patients Undergoing Percutaneous Coronary Intervention (PCI)
| These data support the ability
of anticoagulation with Argatroban to enable acute procedural success.[2,4] |
Acute procedural success was defined as lack of death, emergent coronary
artery bypass graft (CABG), or Q-wave myocardial infarction. As shown in
Figure 4, acute procedural success was reported in 98.2% of patients who
underwent PCIs with anticoagulation with Argatroban compared with 94.3%
of historical control patients anticoagulated with heparin (P=NS).
Safety Profile
Among the 112 interventions, 2 patients underwent emergency CABG, 3 required
repeat PTCA, 4 had non-Q-wave myocardial infarctions, 3 had myocardial ischemia,
1 had an abrupt closure, and 1 had an impending closure (some patients may
have experienced more than one event). No patients died. Two patients had
protocol-defined major bleeding, one of which was retroperitoneal and the
other gastrointestinal. Minor bleeding occured in 4.5% of interventions.
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Additional information
Cardiac therapy
Except for PCI in patients with heparin-induced thrombocytopenia (HIT),
safety and effectiveness of Argatroban for other cardiovascular interventions
have not yet been established.
Re-exposure and lack of antibody formation
Plasma from 12 healthy volunteers treated with Argatroban over 6 days showed
no evidence of antibodies that either neutralize or increase the effects
of Argatroban.[2] Repeated administration
of Argatroban to more than 40 patients was tolerated with no loss of anticoagulant
activity. No change in the dose was required.[2,5]
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