US Pharm. 2014;39(1):HS2-HS.
ABSTRACT: Cerebral vascular disease is the
fourth leading cause of death in the United States. Hemorrhagic stroke
accounts for 13% of all stroke cases per year. The use of oral
anticoagulants leads to a 7- to 10-fold higher risk of spontaneous
intracranial hemorrhage. With the introduction of the oral direct
thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban
and apixaban come questions about emergent reversal in the presence of
hemorrhagic stroke. There are no currently available antidotes to any of
the newer oral anticoagulants. The use of blood products and other
therapies for acute management and reversal is explored.
Cerebral vascular disease is currently the fourth leading cause of death in the United States.1
It has been reported that a cerebral vascular accident (CVA) occurs
every 40 seconds in the U.S. at an estimated rate of 795,000 new or
recurrent cases each year. Of these cases, 13% are classified as being
hemorrhagic in nature, with bleeding occurring in either the
intracerebral or subarachnoid space.2
Intracerebral hemorrhage (ICH) is defined as a focal
collection of blood within the brain parenchyma or ventricular system
that is not caused by trauma.3 It is the most common cause of hemorrhagic stroke in the U.S., accounting for 10% of all stroke cases per year.4
A subarachnoid hemorrhage (SAH) is defined as bleeding into the
subarachnoid space, the space between the arachnoid membrane and the pia
mater of the brain or spinal cord.3 It is estimated that SAH
accounts for 3% of all stroke cases in the U.S.; however, this may be
inaccurate due to SAH often being classified as simply intracranial
hemorrhage that encompasses any bleeding within the skull.4
There are many risk factors that may increase a person’s
likelihood of experiencing a hemorrhagic stroke. Age, ethnicity, gender,
and genetics are nonmodifiable factors correlated to increased risk of
hemorrhage. It has been well documented that with each decade of life
after age 55 years, the risk of intracerebral hemorrhage doubles.5
When comparing ethnicities, African Americans and Hispanics have been
shown to have a higher risk of intracerebral hemorrhage in relation to
non-Hispanic whites.6 Stroke, including those hemorrhagic in
nature, is more common among men than women. The exception to this
appears to be during the fourth and fifth decades of life (ages 35-44
years) in which women have been shown to have a greater risk. Genetics,
specifically familial history of stroke, increases a person’s risk of
CVA by approximately 30%.5
There are a number of modifiable risk factors for
intracranial hemorrhage, with hypertension likely being the most
important. Other risk factors include alcohol intake (in which risk
increases as intake increases), low levels of serum cholesterol (an
inverse association has been noted), drug abuse (specifically
sympathomimetics such as cocaine), cigarette smoking (which increases
SAH risk 2- to 4-fold), and anticoagulation.7
Persons who use oral anticoagulants (OACs) have a 7- to
10-fold higher risk of spontaneous ICH compared with those not receiving
treatment.4 It is estimated that nearly 12% of all ICHs may
be related to the use of OACs, with mortality occurring in 50% of
patients with anticoagulation-related ICH.4,8,9 The vitamin K
antagonist warfarin has been the most widely used oral anticoagulant
since its introduction in 1954. Warfarin is indicated for both treatment
and prophylaxis of thromboembolic disorders, including the prevention
of cardioembolic stroke secondary to atrial fibrillation. The risk of
hemorrhagic stroke with warfarin is directly related to the intensity of
anticoagulation; however, most warfarin-associated ICHs occur while
international normalized ratios (INRs) are within the generally accepted
therapeutic range of 2.0 to 3.5.8
Warfarin reversal in acute hemorrhagic stroke is
docu-mented in numerous case series and centers around the
administration of vitamin K and fresh frozen plasma (FFP). Neither of
these methods is ideal for emergency reversal, as they both take several
hours to normalize INR. They are, however, useful in restoring the
body’s ability to produce clotting factors and reverse the coagulation
defect, respectively, providing a sustained effect on the coagulation
With the introduction of newer OACs come many questions
about emergent reversal. The oral direct thrombin inhibitor dabigatran
and the factor Xa inhibitors rivaroxaban and apixaban have yet to be on
the market for 5 years (TABLE 1).11-13 Though data are
far from robust, we present currently proposed options for acute
management of newer OACs in acute hemorrhagic stroke, including the
reversal agents prothrombin complex concentrates (PCCs), FFP, and
recombinant factor VIIa (rFVIIa) (TABLE 2).14-17
Prothrombin Complex Concentrates: PCCs
are derived from concentrated pooled plasma products that contain
either 3 or 4 vitamin K–dependent clotting factors. Three-factor PCCs
contain factors II, IX, and X, while 4-factor PCCs also contain factor
VII. In addition to clotting factors, both formulations may include
small quantities of protein C and S, heparin, and antithrombin to aid in
the reduction of thrombo-genicity. Currently, the only 3-factor PCCs
available in the U.S. are Profilnine SD and Bebulin VH. Unfortunately,
evidence for their use as reversal agents has not been established.18,19
Kcentra (prothrombin complex concentrate [human]) and
FEIBA (factor eight inhibitor bypassing activity) are the two 4-factor
PCCs currently available in the U.S. (TABLE 2).14,15 FEIBA is the only commercially available activated 4-factor PCC, as it contains factor VII primarily in the activated form.20 Kcentra was approved by the FDA in April 2013.14 The primary concern with using activated PCC is the subsequent increased thrombotic risk.20
The safety and efficacy of 4-factor PCCs in hemorrhagic patients has
not been assessed in large systematic studies. The small body of
evidence that does exist is limited to animal models, healthy
volunteers, and case reports.
Several animal models have been developed to investigate
4-factor PCCs as viable reversal agents, but it is difficult to
extrapolate animal data for human use. Both activated and nonactivated
PCCs were tested in a rat-tail bleeding model in which supratherapeutic
doses of dabigatran were administered. Bleeding time was corrected to
baseline within 5 minutes of PCC administration. Conversely, thrombin
time (TT), activated partial thromboplastin time (aPTT), and ecarin
clotting time (ECT) did not correct after treatment.21
The efficacy of nonactivated PCC was assessed in a model
where mice received dabigatran at a dose that provided systemic
anti-coagulation. Following successful anticoagulation, induction of
intracranial hemorrhage was performed. PCC was administered at 100 U/kg
30 minutes after the initiation of the hemorrhage, which led to reduced
hematoma expansion and tail-vein bleeding time.22
To date, only one small study involving nonactivated PCC
has been performed in humans. A randomized, placebo-controlled,
crossover study involving 12 healthy men not actively bleeding evaluated
the use of nonactivated PCC as a reversal agent in patients taking
either rivaroxaban 20 mg twice daily or dabigatran 150 mg twice daily.23
After 2 days of anticoagulation therapy, patients were treated with
4-factor PCC at 50 U/kg or a saline placebo. The prothrombin time was
immediately reversed in the rivaroxaban-treated patients. In the
dabigatran group, PCC had no effect on aPTT, TT, or ECT. The authors
concluded that nonactivated PCC at 50 U/kg immediately and completely
reverses the anticoagulant effect of rivaroxaban in healthy individuals
but has no effect on the anticoagulant effects of dabigatran.23
There are several published case reports involving the use
of PCC in patients with active bleeds. In most cases a
multi-intervention/drug approach was taken, yielding conflicting results
and making it difficult to determine if PCC alone is a viable option.
In one such case report, FFP, PCC, and rFVIIa failed to correct
life-threatening bleeding secondary to dabigatran in elderly patients.24
In another fatal case report, a dabigatran-treated patient presented
with a traumatic subdural hematoma. The patient was unsuccessfully
treated with PCC and other procoagulant factors.25
Conversely, one case reported that postsurgical bleeding was managed
successfully with 4-factor PCC and other procoagulants in a patient
An ex-vivo crossover study was done in blood samples of 10
healthy white men who took a single dose of rivaroxaban 20 mg and
dabigatran 150 mg. The samples were treated with nonactivated PCC,
rFVIIa, or FEIBA. The results concluded that only FEIBA reversed all of
the thrombin generation tests in the rivaroxaban samples and that both
the nonactivated PCC and FEIBA increased thrombin generation in the
rFVIIa and FFP: rFVIIa is a prohemostatic agent that can be used for patients with complicated coagulation disorders.16,17 FFP is a blood product that contains all coagulation factors.28
It is kept frozen during storage and therefore must be thawed for 15 to
20 minutes before it can be used. ABO blood compatibility testing is
also required before admin-istration. Due to these obstacles, immediate
administration in an emergent situation may not be possible.29
A case of life-threatening gastrointestinal (GI) and
incisional bleeding secondary to accumulation of dabigatran was reported
by Harinstein et al.30 FFP, rFVIIa, and cryoprecipitate were
administered without benefit. Furthermore, a 92-year-old man developed
profuse rectal bleeding secondary to an unidentified gastric ulcer after
taking one dose of dabigatran. He died 7 days later despite treatment
with packed red blood cells (PRBCs), FFP, platelets, and vitamin K.31
In two other cases (a lower GI bleed and a pericardial effusion),
bleeding was controlled after administration of PRBCs, platelets, and
FFP.32 The use of FFP and rFVIIa as reversal agents for factor Xa inhibitors has not been evaluated in humans.29
Hemodialysis or hemoperfusion is considered an option for
removal of dabigatran. Thirty-five percent of dabigatran is
protein-bound; therefore, the remaining unbound portion can be removed
via dialysis. One open-label study found that dialysis removes 60% of
serum dabigatran in 2 or 3 hours.33 Although an option, it
may not be possible to place an unstable patient on dialysis.
Rivaroxaban and apixaban are highly protein-bound, 92% to 95% and 87%,
respectively.12,13 Therefore, dialysis is not an option with their use.
There are new drug entities currently under investigation
to reverse the effects of the new OACs. One such entity is a modified,
inactive form of factor Xa that retains an affinity to factor Xa
inhibitors.34 Monoclonal antibodies to direct thrombin inhibitors are also being investigated.35
Though the approval of these agents for human use may be years away, if
found effective they may ease concerns many practitioners have with the
use of newer OACs.
Appropriate management of acute hemorrhagic stroke in the
presence of onboard OACs remains a mystery. Unlike with warfarin, there
are no definitive reversal agents for direct thrombin inhibitors or
factor Xa inhibitors. Despite the lack of definitive data, a few things
are certain. First, discontinuation of the OAC is paramount. The use of
hemodialysis in patients receiving dabigatran is also an option.
Four-factor PPCs, such as Kcentra, seem to be the most promising
emergent treatment. Though efficacy in the reversal of dabigatran is
still uncertain, its use in patients receiving factor Xa inhibitors
seems promising. The use of FFP and rFVIIa alone or in combination
appears to be ineffective in the reversal of dabigatran. Their use will
likely be either institution or practitioner-specific.
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