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Study Finds Idarucizumab Can
Reverse the Anticoagulant
Effects of Dabigatran
he experimental drug idarucizumab quickly and effectively
reversed the anticoagulant
effect of dabigatran within
minutes, according to results
from a n interim analysis presented at the
20th Congress of the International Society
on Thrombosis and Haemostasis (ISTH) by
Charles Pollack Jr., MD, from the Hospital of the University of Pennsylvania in
Philadelphia. The findings were simultaneously published in The New England Journal
of Medicine. According to these findings,
idarucizumab, a monoclonal antibody that
binds to dabigatran to reverse its effects, can
be considered the first “antidote” to one of
the novel oral anticoagulants (NOACs).
Dabigatran is approved by the U.S.
Food and Drug Administration (FDA) to
prevent the risk of stroke in patients with
nonvalvular atrial fibrillation and for the
prevention and treatment of venous thromboembolism (VTE). These non-vitamin
K antagonists are “generally safer than
warfarin and provide similar or improved
efficacy,” Dr. Pollack said in his presentation, “nonetheless, serious bleeding events
may occur with NOAC use, and patients
taking one of these agents occasionally require urgent surgery or other interventions
for which normal hemostasis is required.”
In this event, dabigatran can increase the
risk of perioperative bleeding, and, therefore, a dabigatran-reversal agent would be
beneficial to this patient population.
Idarucizumab is an experimental drug
not currently approved by the U.S. FDA,
though it is currently under review through
the Accelerated Approval Pathway, according to Dr. Pollack.
RE-VERSE AD, an ongoing phase III,
multicenter, prospective, cohort trial for
which Dr. Pollack and colleagues are investigators, seeks to determine the safety of 5 g of
idarucizumab (administered intravenously)
and its efficacy in reversing the anticoagulant effects of dabigatran in 90 patients who
either experienced serious, overt, life-threatening bleeding that was judged by a treating
physician to require a reversal agent (group
A; n=51), or who required an urgent invasive procedure that could not be delayed for
at least the eight hours required for normal
hemostasis (group B; n=39). Patients are eligible for study inclusion if they are 18 years
of age or older and taking dabigatran.
The study’s primary endpoint is the
38
ASH Clinical News
maximum percentage reversal of the anticoagulant effect of dabigatran within four
hours after administration of idarucizumab.
Dr. Pollack presented data from 90 patients
in the interim analysis, though he noted that
the researchers plan to enroll 300 patients by
the end of the trial.
In both groups A and B, idarucizumab
provided a median maximum reversal of
100 percent within four hours of its administration (95% CI 100-100).
After four hours, laboratory tests
showed that idarucizumab also normalized
clotting assay results for the majority of
patients who had elevated dilute thrombin
time (98% in group A; 93% in group B) or
elevated ecarin clotting time (89% in group
A; 88% in group B) at baseline.
In most cases, Dr. Pollack said, the
reversal effect was evident within minutes,
and the effect was durable, as well, with concentrations of unbound dabigatran staying
below 20 ng/mL in 79 percent of patients
after 24 hours.
“Clinical outcomes were quite good in
this multi-morbid patient population,” Dr.
Binder reported. Among the 35 patients in
group A who could be assessed for restoration of hemostasis (the study’s secondary
endpoint), hemostasis was restored at a
median of 11.4 hours; for the 36 patients in
group B who underwent a procedure, normal intraoperative hemostasis was reported
in 33 patients, and mildly or moderately
abnormal hemostasis was reported in two
and one patient, respectively.
The experimental drug was generally
well-tolerated. Twenty-one patients (13 in
group A; 8 in group B) experienced serious
adverse events, including gastrointestinal
hemorrhage (n=2), postoperative wound
infection, delirium, right ventricular failure,
and pulmonary edema (n=1 for all).
Thrombotic events occurred in five patients, and 18 deaths occurred in the entire
study population. Five of these deaths were
attributed to bleeding events.
While idarucizumab appears to ameliorate dabigatran-induced bleeding disorders
from the list of concerns with the NOAC,
Dr. Pollack cautioned that idarucizumab is
not truly an “antidote.” “In fact, most such
cases can already be successfully and safely
managed with general support and ‘tincture
of time’ because the half-life of dabigatran is
much shorter than that of warfarin,” he said.
“But having a specific ‘go-to’ option could
streamline the care of the most significantly compromised patients.”
The researchers noted a major
limitation of the study was the lack
of a control group, though they
commented it was deemed unethical to randomly assign patients to
receive placebo in this patient
population.
Although this is only an interim
analysis, Dr. Pollack told ASH Clinical News, “The interim analysis is
important, as it provides the first
insights into the effect of a specific
reversal agent to a non-vitamin K
antagonist oral anticoagulant during
real-world emergency situations.
Availability of such an agent might
improve the perception of safety
among providers prescribing anticoagulation therapy for their patients
with nonvalvular atrial fibrillation
and venous thromboembolism.” ●
REFERENCES
Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for
dabigatran reversal. N Engl J Med. 2015 Jun 22 [Epub ahead
of print]
Paul E. Monahan, MD
Early Trial of Gene Therapy
Option for Patients with
Hemophilia B
Early results from an open-label
phase I/II study of a new gene
therapy product, named BAX335,
offer promise of a long-term alternative to Factor IX (FIX) infusions
for patients with hemophilia B. The
first-in-human study was presented at the International Society
on Thrombosis and Haemostasis
(ISTH) meeting by Paul E. Monahan, MD, of the University of North
Carolina School of Medicine Gene
Therapy Center and Lineberger
Comprehensive Cancer Center in
Chapel Hill, North Carolina.
“BAX335 appears to be well-tolerated in the subjects dosed to date,”
the researchers concluded, “and
hemostatically effective plasma FIX
level s were achieved in two dosing
cohorts.” Approximately 40 percent
of patients with hemophilia B (an
X-linked recessive disease associat-
ed with a deficiency of coagulation
Factor IX) have less than 1 percent
of normal plasma Factor IX levels
and experience recurrent bleeding episodes, Dr. Monahan noted.
Gene therapy may provide longterm benefit by enabling persistent
endogenous production of Factor
IX with a single administration.
BAX335 is a non-integrating
adeno-associated viral (AAV) vector
carrying a Factor IX gene. BAX335
was developed based on previous research that has established that AAV
induces stable transgene expression
with a sound safety profile. However, in previous efforts to use gene
therapy to deliver DNA carrying the
genetic sequence encoding Factor
IX have been thwarted by the immune response that these therapies
provoked.
In the current ongoing trial, Dr.
August 2015