ASH News Daily 2016 - Issue 2 - A-3

Sunday, December 4, 2016

ASH News Daily

Page A-3
®

A N T I C OA G U L A N T S

I-DARE-you-scis-ooh-mab: Show Me the Evidence
By Leslie Skeith, MD

hat anticoagulant carries the lowest bleeding
risk? How do I reverse a
patient's anticoagulant if he or she
bleeds? How and when should I
restart anticoagulants after a bleed,
if ever? Anticoagulants are highly
effective for treatment of venous
thromboembolism and prevention
of stroke in patients with atrial fibrillation. However, the most feared
complication is a life-threatening
bleed such as an intracranial hemorrhage. Having an approach to
anticoagulant reversal in a patient
who is bleeding or needs an urgent
procedure is necessary in this fastpaced and ever-changing area of
thrombosis. Yesterday, Drs. Sabine
Eichinger, Mark Crowther, and Daniel Witt helped answer these questions and provided guidance in the
education program session "Reversing Old and New Anticoagulants"
(a repeat of the session takes place
today at 7:30 a.m. in Room 6CDEF,
San Diego Convention Center).
Dr. Eichinger opened the session by discussing reversal of vita-

FDA

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combinations that will keep us busy
for many years to come." One important consideration is use of these
agents when considering potential
allogeneic stem cell transplantation
(alloSCT), which can be a curative
treatment in patients with relapsed
HL. From a group of 17 patients receiving checkpoint inhibitor therapy as a bridge to alloSCT, there were
six early deaths. This has resulted in
increased caution prior to using this
approach for bridging due to concern for immune system activation
post-alloSCT and increased risk of
death.
Dr. Joan Gill discussed the recent
FDA approval of a recombinant von
Willebrand factor (rvWF). As a fellow
at the Medical College of Wisconsin,
I recall being awestruck by Dr. Gill's
vast knowledge of von Willebrand
disease (vWD), the most common inherited bleeding disorder, affecting 1
percent of the population. The agent
is approved for the management
of bleeding episodes in patients 18
years and older with vWD. It was
designated orphan product status to
promote the development of drugs
intended to treat rare diseases. The
efficacy of rvWF was studied in type
I (partial quantitative deficiency)
and type II (qualitative deficiency)
vWD, but was predominantly evalu-

min K antagonists (VKA), such as
warfarin, that are frequently used
worldwide due to economic considerations and contraindications to
direct oral anticoagulants (DOACs).
According to Dr. Eichinger, "The
group of patients with contraindications to direct oral anticoagulants
are at particular risk of bleeding,
and knowing strategies to reverse
vitamin K antagonists and manage
bleeding will remain important."
Dr. Crowther then reviewed
what to do if a patient on a DOAC is
bleeding or requires an urgent procedure: "The direct oral anticoagulants have really changed the way
we 'do' anticoagulation," he says.
"However, clinicians and patients
have identified the lack of a reversal agent as a real limitation in their
use. Development of reversal agents
and strategies will both help us to
treat bleeding patients and provide
reassurance that using DOACs is
both safe and effective."
Dr. Crowther reviewed the evidence for the use of nonspecific
agents such as prothrombin complex concentrate (PCC), activated
prothrombin complex concentrate

(aPCC), such as FEIBA, and other
strategies like antifibrinolytics or
hemodialysis. He introduced the
targeted reversal agents: idarucizumab, andexanet alfa, and ciraparatag. Idarucizumab (i-DAREyou-scis-ooh-mab) is a U.S. Food
and Drug Administration (FDA)-
approved targeted antidote to the
direct thrombin inhibitor dabigatran. Idarucizumab is a humanized
mouse monoclonal antibody fragment that binds free and thrombinbound dabigatran. Andexanet alfa
is an inactive recombinant factor
Xa that acts as a decoy to bind factor Xa inhibitors such as apixaban,
edoxaban, and rivaroxaban. Andexanet alfa also has reported activity
against the low-molecular-weight
heparin enoxaparin. Ciraparatag
is a small synthetic molecule that
binds to direct factor Xa inhibitors,
direct thrombin inhibitors, and heparins. Andexanet alfa and ciraparatag are still under investigation and
are not yet FDA approved. In this
session, Dr. Crowther reviewed the
latest evidence for all three reversal
agents, including interim results of
RE-VERSE AD (idarucizumab) and

ANNEXA-4 (andexanet alfa), and
the real-world data available on idarucizumab.
What happens if a patient has a
major bleed on an anticoagulant?
In the last presentation, Dr. Witt reviewed the evidence for when and
how to restart anticoagulation after
a patient has an intracranial hemorrhage or gastrointestinal bleed, and
highlighted remaining questions in
this area. "For patients suffering anticoagulation-related bleeding who
require interruption of therapy," he
advises, "the default plan should
be resumption of anticoagulation
therapy once bleeding has been successfully managed. Patient-specific
and bleeding-specific factors may
alter this default plan in certain circumstances, but the benefit in terms
of reduction in thromboembolism
and overall mortality appears to
outweigh risk of recurrent bleeding in most cases." For more specific
recommendations from Dr. Witt, be
sure to attend the second education
session offered this morning.

ated in type III (severe quantitative
deficiency leading to factor VIII deficiency mimicking hemophilia A). Dr.
Gill reviewed the landmark study
(Gill JC et al. Blood. 2015;126:20382046) leading to FDA approval of 22
patients with 192 bleeding episodes
in which hemostasis was achieved
after a single infusion of rvWF in
81.1 percent of cases. The efficacy of
hemostasis was rated as excellent or
good in 100 percent of cases. It was
interesting to learn that hemostasis cannot be achieved unless factor
VIII coagulation activity (FVIII:C) is
at least 40 percent normal activity.
Therefore, in patients with FVIII:C of
less than 40 percent or unknown, it is
necessary to administer recombinant
factor VIII (rFVIII) at a ratio of 1.3:1
(i.e., 30 percent more rvWF than rFVIII). Per Dr. Gill "I really appreciate
that you can titrate the rvWF and rFVII to achieve the goals of hemostasis that you want." The rFVIII should
be administered within 10 minutes
of giving rvWF. Comparatively, intermediate purity (plasma-derived)
FVIII concentrates also contain vWF
measured in ristocetin cofactor activity units, with which co-administration of two separate products is not
necessary. While not occurring in
the study, patients receiving rvWF
should be monitored for severe allergic reactions, thrombotic events and
VWF or FVIII inhibitor development.
In the studies of rvWF there were no
thrombotic events and no severe al-

lergic reactions. To learn more about
FVIII inhibitors, tune into oral abstract #322 at 9:30 a.m. today where
Dr. Frits Rosendaal will discuss risk
stratification strategies to minimize
FVIII inhibitor development.
Continuing the theme of recently
approved hemostatic agents, Dr. Steven Pipe reviewed the first coagulation factor-albumin fusion protein to
treat patients with hemophilia B. Approved both for adults and children,
a newly approved recombinant factor IX (rFIX) albumin fusion protein
offers another therapeutic option for
this disorder. The advantages of being albumin bound include a longer
duration of action and biological
half-life (19 days) with the potential
for less frequent dose administrations. Dr. Pipe reviewed the pivotal
phase III study (Santagostino et al.
Blood. 2016;127:1761-1769) of adolescents and adults with moderate to severe hemophilia B and another study
in previously treated children (Kenet
et al. Thromb Haemost. 2016;116:659668). In patients 12 years and older, it
was incredible to learn that the prophylaxis dosing interval, which starts
at every seven days, can be titrated
up to every 14 days. This compares
favorably to twice- to three-timesweekly administration with rFIX as
the historical standard of care due
to shorter biological half-life. This is
truly a remarkable achievement and
per Dr. Pipe "Previously, we have
been treating patients with prophy-

laxis based on the pharmacokinetics of the molecule and accepting a
trough level that is good but maybe
not optimal in how we manage patients overall, and there is evidence
that the amount of time spent below
desired levels increases the risk of
bleeding. Now, we have an opportunity to push the trough levels up to
areas believed to be associated with
nearly no risk of breakthrough joint
bleeding." The agent was also highly
effective at controlling on-demand
bleeding episodes, with an impressive 94 percent controlled after just
one infusion. Due to the longer halflife this compound may also lead
to fewer on-demand uses of factor
replacement therapy. When studied
in the pediatric population the incidence of annualized spontaneous
bleeding rate was near zero, which is
phenomenal.
Another drug approved in 2016
was venetoclax, which was not covered in this session. It was approved
for chronic lymphocytic leukemia
with 17p deletion. To learn more
about this topic, plan to attend oral
presentation session #642 titled
"Venetoclax Monotherapy for Patient with CLL Who Relapsed after
or Were Refractory to Ibritinib or
Idelalisib" Monday at 7:00 a.m. in
Room 5AB of the San Diego Convention Center.

Dr. Skeith has no relevant conflicts
of interest.

Dr. Cornell has no relevant conflicts
of interest.

Table of Contents for the Digital Edition of ASH News Daily 2016 - Issue 2