NOACs
NOACs at a Glance
Dabigatran
• FDA approvals: prevention of stroke in
patients with AF, treatment of deep-vein
thrombosis (DVT) and pulmonary embolism
(PE) in patients who have been treated with
a parenteral anticoagulant for 5 to 10 days;
prevention of recurrent DVT and PE
• Dosage forms and strengths: 75 mg and 150
mg, twice daily
• Mechanism of action: Direct thrombin inhibitor, Factor IIa inhibitor
• Half-life: 12 to 17 hours
Rivaroxaban
• FDA approvals: prevention of stroke in patients with AF; treatment of DVT and PE; prevention of recurrent DVT and PE; prophylaxis
of DVT after knee or hip replacement surgery
• Dosage forms and strengths: 10 mg, 15 mg,
or 20 mg, once daily
• Mechanism of action: Factor Xa inhibitor
• Half-life: 5 to 9 hours in younger, healthy
patients; 11 to 13 hours in older patients
Apixaban
• FDA approvals: prevention of stroke in AF;
treatment of DVT and PE; prevention of recurrent DVT and PE; prophylaxis of DVT after
knee or hip replacement surgery
• Dosage forms and strengths: 2.5 mg, 5 mg,
or 10 mg, twice daily
• Mechanism of action: Factor Xa inhibitor
• Half-life: 12 hours
Edoxaban
• FDA approvals: prevention of stroke and
systemic embolism in AF; treatment of DVT
and PE; treatment of DVT and PE in patients
who have been treated with a parenteral
anticoagulant for 5 to 10 days
• Dosage forms and strengths: 15 mg, 30 mg,
and 60 mg, once daily
• Mechanism of action: Factor Xa inhibitor
• Half-life: 10 to 14 hours
example, patients given concurrent
antiplatelet treatment are at increased
risk for major bleeding ev ents and will
require close monitoring.
For example, the ATLAS ACS 2
TIMI 51 trial, which tested 2.5-mg
and 5-mg rivaroxaban against placebo in 15,526 patients with recent
acute coronary syndrome receiving
standard antiplatelet therapy, found
that the NOAC significantly reduced
the risk of the composite endpoint
of death from cardiovascular causes,
myocardial infarction, or stroke.6
On the other hand, rivaroxaban also
increased the risk for major bleeding
and intracranial hemorrhage, though
there was no increased risk for fatal
bleeding.
Body Mass Index
Clinicians may also want to take
a patient’s weight into consideration. According to Dr. Crowther,
the clinical studies examining
the efficacy of these drugs rarely
included patients at the extremes
of weight. When treating a patient
who weighs 250 to 300 pounds, for
instance, warfarin may be a better option because it is unknown
how efficacious an unmonitored
dose of the new agent would be.
Similarly, when treating a patient
who is underweight, a full dose
of the oral anticoagulants may be
“over-anticoagulation” and could
be associated with a higher risk for
bleeding.
“With anybody who falls outside
of the norm I would lean toward
warfarin because of our ability to
monitor it,” Dr. Crowther said.
Working Without the
Safety Net of Reversal
Some clinicians may shy away from
using these NOACs because of the
perceived lack of reversal agents in
the event of bleeding. According to
Dr. Ansell, though, this may in fact be
“ ven the most die-hard warfarin
E
aficionado will acknowledge that
these newer agents have a lower risk
for intracerebral hemorrhage than
warfarin, and hemorrhage is very
expensive to manage.”
—MARK A. CROWTHER, MD
44
ASH Clinical News
more of a perception than a reality.
“Among the major atrial fibrillation trials and journal articles published recently, the outcomes of major
bleeding episodes between these new
agents and those patients on warfarin
were the same – if not better – even
without a specific reversal agent
available,” Dr. Ansell said. “Rates of
hospitalization and all-cause mortality
as a result of bleeding were about the
same or less.”
This perception may be, in part,
aided by the plethora of commercials from lawyers advertising
class-action lawsuits against the
manufacturers of some of these
drugs, Dr. Crowther added.
“Everybody knows that anticoagulants cause bleeding. To not
use one of these agents because of a
perceived inability to reverse them
makes no sense,” Dr. Crowther said.
“If you look at the research published
regarding bleeding risk and mortality
risk in patients with a major or lifethreatening bleed, the risk of dying
was substantially less with the newer
drugs than with warfarin – despite
the fact that we have a reversal agent
for warfarin.”
Even without specific reversal
agents, the newer oral anticoagulants
all have much shorter half-lives than
warfarin, which provide patients and
clinicians with other advantages,
Dr. Zakai said, particularly when a
patient requires a medical procedure.
He offered the following example:
“If I had a patient on warfarin who
needed to undergo a colonoscopy, I
would have to hold warfarin for five
days, debate whether to use another
anticoagulant during that time, and
then debate whether to use an injectable heparin to get the patient back
on warfarin. The shorter half-lives
of the newer agents mean I can stop
medication for a shorter period of
time and start back up just after the
colonoscopy, making it easier to
manage the risks of these patients.”
newer drugs all seem to be priced at
a point where they are competitive
with the approximate cost of warfarin, plus the associated monitoring
fees. However, in the real-world
setting, the prices do not necessarily
work out to be equal. Patients’ outof-pocket expenses can be affected by
their insurance plans, prescriptions
plans, and co-pays.
Many factors complicate the ability to calculate overall cost-effectiveness of these drugs – for example, the
cost of treating adverse effects of the
drugs, or the cost of treating bleeding
events that may occur.
“Even the most die-hard warfarin aficionado will acknowledge
that these newer agents have a
lower risk for intracerebral hemorrhage than warfarin, and hemorrhage is very expensive to manage,”
Dr. Crowther said.
Cost-Benefit
Considerations
2. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban
versus warfarin in nonvalvular atrial fibrillation. N Engl J
Med. 2011;365:883–91.
One of the remaining reasons clinicians may choose to continue using
warfarin is cost.
“Warfarin [itself] is inexpensive,
but what makes it expensive is the
monitoring it requires,” Dr. Zakai
said. “Monitoring may be as often
as once a month – and there are fees
associated with phlebotomy and
laboratory work.”
According to Dr. Zakai, the
Where Does that Leave Us?
Even considering all of this information, the choice of which oral anticoagulant to use will almost always
come down to individual patient
characteristics, patient preference,
and a patient’s likelihood of adhering
to the prescribed medication regimen – especially in the case of the
new drugs with shorter half-lives.
“Most of us would look at these
medications, just like any medication, and say that they have some
favorable characteristics and some
unfavorable characteristics,” Dr.
Crowther said. “Clinicians should
take patients’ comorbidities, bleeding
risk, renal function, and, perhaps,
age into account. It’s also important to pay attention to the package
inserts, and make sure that you are
complying with the recommendations issued around each drug.” ●
—By Leah Lawrence
References
1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus
warfarin in patients with atrial fibrillation. N Engl J Med.
2009;361:1139-51.
3. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban
versus warfarin in patients with atrial fibrillation. N Engl J
Med. 2011;365:981–92.
4. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus
warfarin in patients with atrial fibrillation. N Engl J Med.
2013;369:2093-104.
5. Hijazi Z, Hohnloser SH, Oldgren J, et al. Efficacy and safety
of dabigatran compared with warfarin in relation to
baseline renal function in patients with atrial fibrillation: a
RE-LY trialanalysis. Circulation. 2014;129:961-70.
6. Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in
patients with a recent acute coronary syndrome. N Engl J
Med. 2012;366:9-19.
March 2015