by andexanet compared with placebo
(p < 0.0001).
• Endogenous thrombin potential significantly
increased from baseline to peak in andexanet
subjects compared with the placebo volunteers
(p < 0.0001).
• Finally, 26 of 27 andexanet alfa subjects returned
to the normal range of thrombin generation
within 10 minutes of the end of the bolus administration.
The second part of the ANNEXA-R study is expected to be presented soon in these healthy volunteers
who, after receiving an 800 mg IV bolus, received a
continuous infusion of 8 mg/min for 120 minutes
or placebo.
IDARUCIZUMAB FOR DABIGATRAN
REVERSAL
Also in June of 2015, investigators published an
interim analysis of a prospective cohort study to
determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant
effects of dabigatran in 90 patients who had serious
bleeding (group A) or required an urgent procedure
(group B).3
Significantly more
andexanet alfa subjects
(26 of 27) than placebo
subjects (0) had a 90%
or greater reduction in
anti-Factor Xa activity
from baseline to nadir
(p < 0.0001).
Idarucizumab is a humanized MoAb fragment
with high affinity for the oral direct thrombin
inhibitor dabigatran that selectively and immediately neutralizes its anticoagulant activity.4 The data
ACC.org/CSWN
is a small, synthetic, water-soluble, cationic moleindicate that the antidote effectively and within
cule that is a nonspecific reversal agent which binds
minutes of administration neutralized the activto several of the direct oral anticoagulants by means
ity of dabigatran with a satisfactory safety profile.
of electrostatic interactions. In vitro and in vivo
Normal hemostasis was reported in more than 90%
studies indicate that PER977 reverses anticoagulaof the patients who underwent procedures after the
tion with each of the new oral agents mentioned
administration of idarucizumab. Concentrations of
above. This reversal effect is due to direct binding
unbound dabigatran remained below 20 ng/ml at
24 hours in 79% of the patients. Among 35 patients to the anticoagulant molecule but no binding to
blood coagulation factors or to other proteins in the
in group A who could be assessed, hemostasis, as
blood.
determined by local investigators, was restored at a
On April 2, 2015, the FDA granted Fast Track
median of 11.4 hours. Among 36 patients in group
designation for PER977 and phase III trials are in
B who underwent a procedure, normal intraoperathe final planning stages. ■
tive hemostasis was reported in 33, and mildly or
moderately abnormal hemostasis was reported in
REFERENCES:
two patients and one patient, respectively.
1. Truven Marketscan® Commercial, Medicare Supplemental,
In an accompanying editorial, Kenneth A. Bauer,
and Medicaid Databases. Time period: January 1, 2012, to
MD, chief of the hematology section, VA Boston
June 30, 2013. Extracted April 2014. Unpublished results.
Health Care System, and director, Thrombosis
2. Crowther M, Crowther MA. Arterioscler Thromb Vasc Biol.
2015 Jun 18. [Epub ahead of print]
Clinical Research, Beth Israel Deaconess Medical
3. Pollack CV Jr, Reilly PA, Eikelboom J, et al. N Engl J Med.
Center in Boston, MA, noted that, without a control
2015 Jun 22 [Epub ahead of print]
4. Glund S, Stangier J, Schmohl M, et al. Lancet. 2015 Jun 15.
group, it is difficult to assess the clinical benefit of
[Epub ahead of print]
idarucizumab in patients with dabigatran-related
5. Bauer KA. N Engl J Med. 2015;37