CLINICAL
NEWS
American College of Cardiology Extended Learning
Slipping into Reverse
New agents under study for reversing target-specific oral anticoagulants
T
he direct thrombin inhibitor dabigatran as
well as the anti-factor Xa (fXa) agents rivaroxaban, apixaban, and edoxaban (listed in
order of U.S. approval for stroke prevention in nonvalvular atrial fibrillation [AF] patients), are a new
generation of oral anticoagulants that are transforming clinical practice. While these target-specific
oral anticoagulants (TSOAs) overcome some of the
difficulties associated with anticoagulation with
vitamin K antagonists, one reason for a slower
than-expected uptake in clinical practice may be the
absence of specific reversal agents.
Serious bleeding events are low and the need for
reversal of any anticoagulant is relatively rare: over
a 12-month period ending in June 2013, there were
about 6.8 million patients taking anticoagulants in
the United States, of whom approximately 345,000
(5.1%) presented to the emergency room with a
bleeding event.1 Approximately 228,000 of those
patients warranted hospital admission.
Also, the rapid offset of the TSOAs (half-life of
rivaroxaban is 4 to 9 hours and 12 to 17 hours
for dabigatran and apixaban) obviates the need for
reversal in most situations, although antidotes for
these agents would be beneficial to manage patients
who require urgent surgery or interventions and to
treat individuals with life-threatening bleeds.
In the summer of 2015, Mark Crowther, FRCP,
MD, a professor of medicine at McMaster University, Canada, published a review of the anticoagulants, their current use, and future potential.2
Unlike the anti-fXa agents, the absorption of
dabigatran can be reduced by activated charcoal if
administered shortly after ingestion and it can be
removed from the blood with hemodialysis.
Prothrombin complex concentrate, activated prothrombin complex concentrate, and recombinant
factor VIIa all show some activity in reversing the
anticoagulant effect of these drugs but this is largely
based on ex vivo, animal, and volunteer studies. It
is unclear, which, if any, of these approaches is the
most suitable for emergency reversal.
Three novel molecules (idarucizumab, andexanet,
and PER977) may provide the most effective and
safest way of reversal. These agents are currently in
premarketing studies.
UNIVERSAL ANTIDOTE FOR FACTOR XA
INHIBITORS
Recently, Dr. Crowther presented the results
of a phase III clinical trial of Andexanet alfa
(PRT064445), a universal antidote for fXa inhibitors. An FDA-designated breakthrough therapy, this
protein acts as a decoy for direct fXa inhibitors,
binding to anti-fXa agents in a dose-dependent
manner, preventing them from acting on the coagulation cascade. The new agent is being studied with
all of the direct fXa inhibitors: apixaban, rivaroxa-
28 CardioSource WorldNews
ban, and edoxaban. It is also being studied as an antidote for patients on enoxaparin, a low-molecularweight heparin (LMWH) and indirect fXa inhibitor.
The drug does not seem to be effective against the
factor IIa inhibitor dabigatran.
The trial is known as ANNEXA (Andexanet Alfa
a Novel Antidote to the Anticoagulant Effects of
fXA Inhibitors) with ANNEXA–A referring to the
specific apixaban study (presented at AHA.14) and
ANNEXA–R referring to the rivaroxaban study
(data presented at ACC.15).
In ANNEXA–A, 33 healthy volunteers were
given apixaban 5 mg twice daily for 4 days and
then randomized in a 3:1 ratio to andexanet alfa
administered as a 400 mg intravenous (IV) bolus
(n = 24) or to placebo (n = 9). The new agent was
well-tolerated and met all pre-specified primary
and secondary efficacy endpoints with p < 0.0001.
Fully 100% of andexanet-treated participants had ≥
90% reversal of anti-fXa activity and restoration of
thrombin generation to baseline (pre-anticoagulant)
levels. Andexanet produced near complete normalization of all coagulation parameters measured
within 2 minutes of infusion completion and the
effect lasted 1-2 hours with bolus dose.
A second part of ANNEXA was presented at the
June 2015 International Society on Thrombosis
and Haemostasis Congress in Toronto, Canada. This
analysis included 31 healthy volunteers also given
apixaban 5 mg twice daily for 4 days and both the
original 400 mg IV bolus followed by a continuous
infusion of 4 mg/min for 120 minutes (n = 23) or
to placebo (n = 8). The agent has a very short halflife, so in order t