EFFICACY, SAFETY AND SECURITY:

A New Data For Dabigatran Etexilate in Primary SPAF Anticoagulation Care

Erika Maharani
Department of Cardiology and Vascular Medicine
Faculty of Medicine Universitas Gadjah Mada
Dr. Sardjito General Hospital Yogyakarta, Indonesia

Abstract

Atrial fibrillation is the most common cardiac arrhythmia. Thirty-three million

people have atrial fibrillation, more common in elderly. This arrhythmia occurred
caused by interplay between ectopic electrical activity, genetic predisposition and
abnormal atrial tissue substrate that could propagates itself. Atrial fibrillation causes
the trembling of atrium and produces static of blood that could initiate thrombus
appearance, especially in left atrial appendage. Embolic event could happen anytime
if thrombus became fragile, and this condition could initiate ischemic stroke. Atrial
fibrillation confers a 5-10 times fold higher risk of ischemic stroke and accounts for
>20% of all ischemic strokes (Aggarwal et al., 2015; Saliba, 2015).

Prevention of thromboembolic event using anticoagulant agent must be given

in patient with atrial fibrillation. CHA2DS2-VASc score has been using to stratify
anticoagulant’s requirement. Vitamin K antagonist, such as warfarin, in the
therapeutic range (international normalized ratio of 2-3) was proven to reduce the
risks of ischemic stroke and death in atrial fibrillation with CHA2DS2-VASc score
≥2 compare to control. But this agent has 3-fold increase in bleeding risk if
international normalized ratio >3 compare to control therapy. Vitamin K antagonists
are cumbersome to used, because of their interactions with food and other drugs,
requirement frequent laboratory monitoring, and difference in dose effect among
people (Graham et al., 2015).
 Recently, non-vitamin K oral anticoagulants (NOACs) was believed could
prevent thromboembolic event in non-valvular atrial fibrillation patient which do not
need a laboratory monitoring and dose adjustment, unlike vitamin K antagonist.
Dabigatran etexilate, direct thrombin inhibitor, has been using to prevent
thromboembolic event in patient with atrial fibrillation. This drug has fix dose and do
not need laboratory monitoring and dose titration. Dabigatran etexilate is simpler to
dose than warfarin and do not require therapeutic monitoring. Dabigatran etexilate
was also associated with a reduced risk of ischemic stroke, intracranial hemorrhage,
and mortality compared with warfarin (Connolly et al., 2009; Graham et al., 2016).

Keywords: atrial fibrillation, anticoagulant, dabigatran

 Atrial fibrillation (AF) is a supraventricular tachycardia characterized
electrically by a chaotic atrial activation and a resultant mechanically ineffective
atrial contraction. AF is the most common cardiac arrhythmia that could happen in a
normal heart or structural heart disease. Thirty-three million people have atrial
fibrillation, more common in elderly. We have learned that this arrhythmia happen
caused by interplay between ectopic electrical activity, genetic predisposition and
abnormal atrial tissue substrate that could propagates itself. AF is independently
associated with a two-fold increased risk of all-cause mortality in women and a 1.5-
fold increase in men (Aggarwal et al., 2015; Kirchhof et al., 2016; Nabar and Pathan,
2016).

Detection and Management of Atrial Fibrillation

According the European Society Cardiology (ESC), AF can be divided in the

five types: 1. First diagnosed AF is AF that has not been diagnosed before,
irrespective of the duration of the arrhythmia or the presence and severity of AF-
related sympstoms. 2. Paroxysmal AF is self terminating, in most cases within 48
hours but may continue for up to seven days. 3. Persistent AF is AF that lasts longer
than seven days, including episodes that are terminated by cardioversion. 4. Long
standing AF is a continuous AF lasting for > 1 year when it is decided to adopt a
rhythm control strategy. 5. Permanent AF is arrhythmia accepted by patient and
physician or therapy failure (Kirchhof et al., 2016)

Atrial fibrillation causes the trembling of atrium and produces static of blood
that could initiate thrombus appearance, especially in left atrial appendage. Embolic
event could happen anytime if thrombus became fragile, and this condition could
initiate ischemic stroke. Atrial fibrillation confers a 5-fold higher risk of ischemic
stroke and accounts for >20% of all ischemic strokes (Saliba, 2015). AF responsible
for nearly a third of all strokes and the leading cause of embolic stroke that has worse
prognostic for patient. An integrated, structured approach to AF care, as applied
successfully to other domains of medicine will facilitate consistent, guideline-
adherent AF management for all, with the potential to improve outcomes (Kirchhof et
al., 2016).

Figure 1. Acute and chronic management of atrial fibrillation patients (Kirchoff et al.,
2016)

Stroke Prevention in Atrial Fibrillation

The prevention of embolic event is important to prevent the stroke in patient

with AF. Anticoagulant agent could prevent the thromboembolic event in AF, but
only patient with high risk of thromboembolic event given with anticoagulant agent.
The CHA2DS2-VASc score, contained with Congestive Heart Failure, Hypertension,
Age, Diabetes Mellitus, prior thromboembolic event, vascular disease, sex, was
proven to be score that sorting out which the patient with non-valvular heart disease
and AF who need anticoagulant to prevent thromboembolic event, include ischemic
stroke. The patient must be given with anticoagulant if CHA2DS2-VASc score is
more or equal than 2 (Tarkowski et al., 2015).
Figure 2. Stroke Prevention in Atrial Fibrillation (Kirchhof et al., 2016)

Vitamin K antagonist, such as warfarin, is the anticoagulant agent that

depletes functional vitamin K reserves, which in turn reduces synthesis of active
clotting factors by competitively inhibiting subunit 1 of the multi-unit vitamin K
epoxide reductase complex 1. Warfarin in the therapeutic range, international
normalized ratio of 2-3, was proven to reduce the risks of ischemic stroke and death
in atrial fibrillation with CHA2DS2-VASc score ≥2 (Katritsis et al., 2015). Vitamin K
antagonists are cumbersome to use, because of their interactions with food and other
drugs, requirement frequent laboratory monitoring, and difference in dose effect
among people (Connoly et al., 2009). This agent has 3-fold increase in bleeding risk
if international normalized ratio >3 compare to control therapy, including intracranial
bleeding, upper and lower gastrointestinal bleeding. The HASBLED score is often
used to predict the bleeding risk in atrial fibrillation patient who plans to received the
anticoagulant agent. This is a friendly score to assess 1-year risk of major bleeding in
atrial fibrillation patient. The higher HASBLED score, the higher risk of bleeding that
could occur and the caution of anticoagulant choices is important to prevent bleeding
event in this patient (Saliba, 2015).

Non vitamin-K oral anticoagulants are the new grup of anticoagulants

that at least as effective as vitamin K antagonist for prevention of stroke in non-
valvular atrial fibrillation patient and are associated with significantly decreased risks
of intracranial bleeding. There are several drug in non vitamin-K oral anticoagulants
that approved to used in this setting, as dabigatran, rivaroxaban, apixaban, edoxaban
(Saliba, 2015). The use non vitamin-K oral anticoagulant is more comfortable than
vitamin-K antagonist because don’t need to improve a patient’s compliance with
dosing, drug-food and drug-drug interaction and the need for routinely International
Normalize Ratio checking (Graham et al., 2016).

Dabigatran for Stroke Perevntion in Atrial Fibrillation

Dabigatran etexilate is an oral prodrug that is rapidly converted to potent

direct thrombin inhibitor. It has an absolute bioavailability of 6.5% and 80% of the
given dose is excreted by the kidneys. Dabigatran etexilate has a serum half-life is 12
to 17 hours. Is does not require regular monitoring of International Normalize Ratio.
In the Randomized Evaluation of Long-TermAnticoagulationTherapy (RE-LY) trial,
dabigatran treatment was superior to warfarin treatment for reduction of stroke and
intracranial hemorrhage (ICH) in patients with nonvalvular AF but was inferior for
major gastrointestinal bleeding, in which risk was increased (Graham et al., 2016). In
a study comparing dabigatran versus warfarinin Asians versus non-Asians,
hemorrhagic stroke rates were higher on warfarin in Asians versus non-Asians,
despite similar blood pressure, younger age, and lower international normalized ratio
values. Hemorrhagic strokes were significantly reduced by dabigatran in both Asians
and non-Asians (Hori et al., 2013).
In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared
with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial
Fibrillation (ROCKET-AF), rivaroxaban treatment was noninferior to warfarin
treatment for prevention of stroke or systemic embolization. Intracranial and fatal
bleeding events were reduced while major gastrointestinal bleeding was increased in
the rivaroxaban arm (Graham et al., 2016).
An observational study of 8.754 Chinese patients with atrial fibrillation to
know the impact of quality of anticoagulation control, as reflected by time in
therapeutic range (TTR), on the effectiveness and safety of warfarin therapy in
Chinese patients with atrial fibrillation. In Chinese patients with atrial fibrillation, the
benefits of warfarin therapy for stroke prevention and ICH risk are closely dependent
on the quality of anticoagulation, as reflected by TTR. Even at the top TTR quartile,
warfarin was associated with a higher stroke and ICH risk than dabigatran (Ho et al.,
2015).
A restrospective cohort study of 118.891 patients with nonvalvular AF who
were 65 years or older, comparing Dabigatran 150 mg twice daily versus
Rivaroxaban 20 mg once daily. Treatment with rivaroxaban 20 mg once daily was
associated with statistically significant increases in ICH and major extracranial
bleeding, including major gastrointestinal bleeding, compared with dabigatran 150
mg twice daily (Graham et al., 2016).

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