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The Industry
Direct Oral Anticoagulants:
A Cost-Effective Approach
to Thromboembolism
By Amy Cully, Pharm.D.
Thromboembolism is a common cause of
morbidity and mortality in adults due to the
large number of people affected and major
challenges with prevention.
1
Prevention and
treatment often involve anticoagulants. For
years, the only oral anticoagulant available
was warfarin, a vitamin K antagonist. It
was approved for stroke prevention in cases
of atrial fibrillation, deep vein thrombosis
and pulmonary embolism. Warfarin is also
used to treat deep vein thrombosis and
pulmonary embolism directly.
While warfarin has been effective for these
disorders, it also has drawbacks. It has
multiple drug-drug and food interactions.
It also requires ongoing blood draws to
maintain narrow therapeutic drug levels. One
benefit of warfarin therapy includes a known
antidote, vitamin K.
2
In the late 1990s, subcutaneous injectable
anticoagulants (e.g., enoxaparin, dalteparin
and fondaparinux) became available.
These injectable forms provided a more
predictable anticoagulation effect without
the monitoring requirement. However, they
have their own issues: higher cost, large size
(making them less portable for patients), a
daily injection requirement (limiting them to
short-term use) and no available antidote.
1
In 2010, the FDA approved the first
of a group of drugs called novel oral
anticoagulants. Recent recommendations
from the International Society on
Thrombosis and Haemostasis have changed
the nomenclature of this class of drugs to
direct oral anticoagulants (DOACs).
3
This
class consists of five drugs. Four DOACs are
currently on the market: a direct thrombin
inhibitor, dabigatran (Pradaxa); and three
factor Xa inhibitors, apixaban (Eliquis),
rivaroxaban (Xarelto) and edoxaban
(Savaysa). The fifth drug, betrixaban, is a
factor Xa inhibitor currently being studied
for approval.
DOACs were developed to overcome
some of the limitations associated with
conventional anticoagulants.
4
They provide
predictable oral anticoagulation while
demonstrating similar or superior efficacy
to existing anticoagulants. They are safer
(e.g., lower risk of bleeding) and have minor
drug interactions and no food interactions.
In addition, they do not require blood level
monitoring and are convenient to use.
2, 5
The biggest advantage of DOACs over the
vitamin K antagonist is the short onset and
offset of action. The rapid onset eliminates
the need for overlapping patients with
parental anticoagulation while the rapid
offset is important in patients requiring
surgical treatment.
4
The onset and offset of action can also
be a disadvantage of DOACs in patients
with poor medication compliance. The
risk of thromboembolic events increases
with non-compliant patients. Another
potential disadvantage is the limited
clinical experience with DOACs compared to
warfarin. Limited data is available on using
DOACs in special populations. There is also
the cost: the average cost per month for
warfarin is $20 while DOACs average $300.
4
Until recently, a DOAC antidote was not
available. This has been a concern with
providers as recent clinical trial results
showed that annually between 1 percent to
4 percent of patients treated with factor Xa
inhibitors may experience major bleeding
and an additional 1 percent may require
emergency surgery.
6
However, several
antidotes are either now entering the market
or in the final stages of FDA approval.
The first, idarucizumab (Praxbind),
was approved in October 2015. It is a
monoclonal antibody administered via
IV infusion as a one-time five gram dose.
It is indicated for dabigatran (Pradaxa)
reversal during emergency surgery,
urgent procedures or for life-threatening
uncontrolled bleeding.
7
Idarucizumab
provides specific and immediate reversal of
dabigatran anticoagulant effects without
interfering with the coagulation cascade.
8,9
Potential disadvantages include a risk of a
thromboembolic event associated with the
underlying disease. It is recommended to
start anticoagulation therapy as soon as
medically appropriate.
7
Praxbind’s estimated
cost is around $3,500 for the one-time dose.
Andexanet alfa is a potential first-in-class
recombinant modified factor Xa molecule.
It is being developed as an antidote for
patients receiving a direct or indirect factor
Xa inhibitor who suffer a major bleeding
episode or may require emergency surgery.
Andexanet alfa has the potential to address
numerous clinical scenarios by allowing for
flexible and controlled reversal.
10
Studies
were conducted for use of andexanet alfa as
a reversal agent for the factor Xa inhibitors
apixaban and rivaroxaban. The results
showed that andexanet rapidly (within
2–5 minutes) restored factor Xa activity
and thrombin generation in addition to
reducing the unbound factor Xa inhibitor
concentrations in patients treated with
apixaban and rivaroxaban.
11
A Phase II
study is being done with andexanet alfa
effectiveness at reversing edoxaban,
enoxaparin, fondaparinux and betrixaban.
