Novel Pharmacotherapies for the Preventi
HEART RHYTHM
|
ORIGINAL RESEARCH
Novel Pharmacotherapies for the Prevention of Stroke or
Systemic Embolism in Adults with Non-valvular Atrial Fibrillation - Part 1
Christos Dresios , MD & Gregory Y H Lip, MD
University of Birmingham Centre for Cardiovascular Sciences
Received: 28/8/13, Reviewed: 28/2/14, Accepted: 28/3/14
Key words: atrial fibrillation, stroke prevention, apixaban
DOI: 10.5083/ejcm.20424884.116
ABSTRACT
CORRESPONDENCE
Over the last decade, a paradigm shift is apparent in the field of stroke prevention in atrial fibrillation
(AF). For more than 6 decades, warfarin has represented the mainstay of anticoagulation therapy
when used in AF patients. However, warfarin has important disadvantages, which limit its use in
clinical practice. The recent emergence of novel oral anticoagulant drugs (NOACs) that overcome
many of limitations of warfarin has allowed the provision of effective stroke prevention for many
more patients with AF, as these drugs have a favorable efficacy–safety profile but also certain
pharmacokinetic and pharmacodynamic properties that render periodic anticoagulant monitoring
and dose adjustments unnecessary.
Prof Gregory Y H Lip,
University of Birmingham Centre
for Cardiovascular Sciences,
City Hospital, Birmingham,
United Kingdom
The NOACs fall into 2 broad categories, the oral direct thrombin inhibitors (dabigatran) and the
oral factor Xa inhibitors (rivaroxaban, apixaban).The scope of this manuscript is to review currently
available data regarding NOACs and to address practical issues relating to the safe and effective use
of NOACs in clinical practice.
g.y.h.lip@bham.ac.uk
Sponsored by Bristol-Myers
Squibb. The author(s)
maintained full control of the
content and writing of the
manuscript
INTRODUCTION
Atrial fibrillation (AF) is the most common abnormality of the cardiac rhythm and represents
a growing global health issue of epidemic proportions [1, 2]. There is strong evidence that AF
confers a high thromboembolic risk, and the
use or oral anticoagulants (OAC) such as warfarin is associated with considerable reduction of
the risk of stroke and thromboembolic events,
as well as mortality, when compared to control
[3-6].
Despite its demonstrated efficacy, the use of
warfarin in clinical practice is rendered inconvenient by several inherent pharmacological characteristics. The slow onset and offset of action,
the narrow therapeutic range, the necessity of
periodic anticoagulant monitoring, the high
inter- and intra- individual variability with dayto-day variations in the anticoagulant response
as well as the multiple food and drug have led
not only to the underuse of warfarin, but also to
high rates of its discontinuation[7,8].
There is also a close correlation between the
benefits conferred by warfarin and the time in
which INR falls within the intended therapeutic
range and taking in consideration the difficulties in achieving optimal time in therapeutic
range (TTR, ideally >70% of the time within INR
2-3) in real world, it is inferred that many AF patients on warfarin are suboptimally protected
against thromboembolic complications [9].
The NOACs fall into two broad categories: (i) the
oral direct thrombin inhibitors (dabigatran) and
(ii) the oral direct factor Xa inhibitors (e.g. rivaroxaban, apixaban, etc).In general, NOACs deliver
predictable and consistent antithrombotic response allowing for a fixed-dose regimen without the need for routine coagulation monitoring. This represents an important asset because
simplification and convenience help improve
management of patients in clinical practice. In
addition, the NOACs are generally well tolerated, have a rapid onset of action, short half life
and have few known drug-drug interactions.
ISSN 2042-4884
318
EUROPEAN JOURNAL OF CARDIOVASCULAR MEDICINE
VOL III ISSUE I
NOVEL PHARMACOTHERAPIES FOR THE PREVENTION OF STROKE OR SYSTEMIC EMBOLISM IN ADULTS....PART 1
Currently NOACs are based on the impressive results of well designed large randomised controlled trials in which were compared
to warfarin. The new drugs have features in major international
guidelines and represent a reliable alternative to warfarin for the
management of patients with non-valvular, paroxysmal or permanent AF with ≥1 risk factors for stroke or systemic embolism. However, despite the promising results and the great expectations that
were created in the scientific community, NOAC are not 100% free
of constraints and drawbacks.
The scope of this article is to review currently available data regarding NOACs and to address practical issues relating to the safe and
effective use of NOACs in everyday clinical practice.
METHODS
We performed a search using English-language in regard to clinical studies, abstracts, references of detected articles and review articles. Google scholar and, PubMed databases up to January 2013
third week were searched. The search strategies were based on the
terms “atrial fibrillation”, “apixaban in atrial fibrillation’’, “dabigatran
in atrial fibrillation”, “rivaroxaban in atrial fibrillation” and “novel oral
anticoagulants”.
Pharmacokinetic and Pharmacodynamic characteristics
of three new oral anticoagulants
The NOACs are low molecular weight synthetic molecules that inhibit the activity of specific pathways in the coagulation process.
NOACS have various favorable pharmacokinetic and pharmacodynamic properties that render its use in clinical practice very convenient.
Dabigatran exitilate does not interact with the cytochrome P450
system and thus the risk of drug – drug interaction is significantly
reduced. On the other hand, dabigatran exitilate is a substrate of
P-glycoprotein which is an efflux pump that exports its substrates
out of the cell, and thus the concomitant use with potent P-glycoprotein inhibitors or P- glycoprotein inducers may lead to increased
risk of significant variation of its plasma concentrations. In patients
who receive potent P-glycoprotein inhibitors (azole-antimycotics,
immunosuppressants, and human immunodeficiency virus protease inhibitors must be avoided), or P-glycoprotein inducers (potent
P-gp inducers such as rifampin), the use of dabigatran is contraindicated (Table 2)
Which drugs matter in cardiology? Verapamil is a P-glycoprotein
inhibitor and its concomitant use in patients receiving dabigatran may lead to increased plasma concentrations of dabigatran.
With regard to amiodarone and quinidine, no dose adjustment is
required. On the other hand, dronedarone is a potent inhibitor of
P-gp efflux transporter should be avoided in patients receiving
dabigatran because it may leads to increased dabigatran plasma
levels.
Particular care should be taken in case of concomitant use of antiplatelet agents. In addition, concurrent treatment with non-steroidal anti-inflammatory drugs (NSAIDs) significantly increases the risk
of major bleeding and requires a careful benefit-risk assessment.
Concomitant treatment with any other anticoagulants is contraindicated except in case of switching therapy to or from dabigatran
or when unfractionated heparin (UFH) is administrated at doses
necessary to maintain the patency of central venous or arterial
catheters.
The recommended dose of dabigatran is usually 150 mg twice daily.
Treatment with dabigatran 110 mg b.i.d. dose is recommended for:
Dabigatran etexilate
Dabigatran etexilate is a prodrug which is rapidly and completely
converted into the main active compound, dabigatran. The generation of dabigatran is carried out by esterase-catalyzed hydrolysis in
the plasma and liver. Dabigatran is also further metabolized into
active glucuronide products. Specifically, dabigatran exitilate is a
non peptidic synthetic molecule that has been proven to be a direct competitive and reversible thrombin inhibitor of both free and
clot-bound thrombin [10-12]. After oral administration, dabigatran
etexilate is quickly absorbed and the peak plasma concentrations
are achieved within 0.5–4 hours. However, its bioavailability is low
(6.5%), and this is unrelated to food intake nor drug administration
[13]
Additionally, dabigatran is characterized by low plasma protein
binding and thus exhibit low likelihood of drug-drug interactions
[14].Indeed only 35% of dabigatran is protein binded. After the
rapid distribution phase, follows a relatively protracted elimination
phase that results in a half-life of 17 hours after multiple doses [15].
Renal excretion of dabigatran accounts for approximately 80% of
total clearance [15]. Due to the fact that in patients with impaired renal function dabigatran may exhibit prolonged elimination, its use
in this setting requires particular caution. According to European
guidelines, dabigatran is contraindicated in patients with severe
renal dysfunction (CrCl 80 years),
- In patients with moderate renal impairment (CrCl 30-50 ml/min)
who are at high risk of bleeding, including age 75-80 years,
- Simultaneous use of P- glycoprotein inducers or inhibitors.
- In patients at high bleeding risk (eg. HAS-BLED >3)
In the USA, the FDA approved the 150 mg b.i.d. dose but also approved a 75 mg bid dose regimen, for patients with severe renal
impairment (CrCl 15–30 ml/min), even though this does has never
been tested for stroke prevention in AF. In addition to the dose of
75mg twice should be also considered in patients with moderate
renal impairment who receive concomitantly dronedarone or systemic ketoconazole.
Rivaroxaban
Rivaroxaban is competitive reversible inhibitor of activated factor
X (Xa), which is generated at the confluence of the extrinsic and
intrinsic pathways, plays an important role at several steps of the
coagulation cascade. Notably, rivaroxaban represents the only
FDA-approved anticoagulant agent that has the advantage of being administrated once-daily.
319
HEALTHCARE BULLETIN
|
HEART RHYTHM
Rivaroxaban is a small-synthetic molecule and has a high bioavailability (80%) with rapid, absorption after oral administration. The
bioavailability of rivaroxaban is dose dependent [16, 17],ranging
from 80% to 100% when administrated in the dose of 10-mg dose,
while at a dose of 20mg the bioavailability is about 66%. Peak concentrations in plasma are achieved at2.5 to 4 hours. Of note, absorption rates and bioavailability are influenced by food intake, and
both are reduced in fasted patients. Thus, rivaroxaban should be
administrated after food intake. The half life of rivaroxaban is 5-13
hours, but this is shorter in elderly patients [16].
In contrast to dabigatran, rivaroxaban demonstrate high plasma
protein binding (92%-95%), and consequently it is not dialyzable.
Approximately>50% of rivaroxaban is metabolized by liver enzymes, principally by cytochrome P450 3A4 whereas the remainder
is eliminated unchanged via kidneys [17, 18].
Rivaroxaban (similar to dabigatran exitilate and apixaban) is a substrate of P-glycoprotein. Concurrent use of drugs which are strong
inhibitors of CYP-3A4 or P-glycoprotein efflux transporter (eg, systemic ketoconazole, intrakonazole) lead to increased rivaroxaban
anticoagulant effect and thus, the concomitant use of these drugs
should be avoided [19] Additionally, potent inducers of CYP-3A4
and/or P-glycoprotein efflux transporter should be avoided due to
the significant decrease in rivaroxaban plasma concentration.
Again, concomitant use of NSAIDs and platelet aggregation inhibitors should be undertaken with caution due to increased the bleeding risk by concomitant therapy. Due to the increased hemorrhagic
risk, concomitant treatment with other anticoagulant drugs is contraindicated. Notwithstanding, UFH may be administered at doses
necessary to maintain an open central venous or arterial catheters,
or in case of switching therapy to or from rivaroxaban.
Most of the administered dose of rivaroxaban (>66%) appears in
urine and the remainder is eliminated by the faecal-biliary route. In
patients with nonvalvular AF, the recommended dose of rivaroxaban is 20 mg once daily with the evening meal. However, taking
into consideration that rivaroxaban is eliminated by the kidneys,
in patients with moderate renal impairment (CrCl 30-49 mL/min),
rivaroxaban should be administrated at a dose of 15mg o.d. Due to
lack of evidence in relation to the efficacy-safety profile of rivaroxaban in patients with severe renal impairment (CrCl
|
ORIGINAL RESEARCH
Novel Pharmacotherapies for the Prevention of Stroke or
Systemic Embolism in Adults with Non-valvular Atrial Fibrillation - Part 1
Christos Dresios , MD & Gregory Y H Lip, MD
University of Birmingham Centre for Cardiovascular Sciences
Received: 28/8/13, Reviewed: 28/2/14, Accepted: 28/3/14
Key words: atrial fibrillation, stroke prevention, apixaban
DOI: 10.5083/ejcm.20424884.116
ABSTRACT
CORRESPONDENCE
Over the last decade, a paradigm shift is apparent in the field of stroke prevention in atrial fibrillation
(AF). For more than 6 decades, warfarin has represented the mainstay of anticoagulation therapy
when used in AF patients. However, warfarin has important disadvantages, which limit its use in
clinical practice. The recent emergence of novel oral anticoagulant drugs (NOACs) that overcome
many of limitations of warfarin has allowed the provision of effective stroke prevention for many
more patients with AF, as these drugs have a favorable efficacy–safety profile but also certain
pharmacokinetic and pharmacodynamic properties that render periodic anticoagulant monitoring
and dose adjustments unnecessary.
Prof Gregory Y H Lip,
University of Birmingham Centre
for Cardiovascular Sciences,
City Hospital, Birmingham,
United Kingdom
The NOACs fall into 2 broad categories, the oral direct thrombin inhibitors (dabigatran) and the
oral factor Xa inhibitors (rivaroxaban, apixaban).The scope of this manuscript is to review currently
available data regarding NOACs and to address practical issues relating to the safe and effective use
of NOACs in clinical practice.
g.y.h.lip@bham.ac.uk
Sponsored by Bristol-Myers
Squibb. The author(s)
maintained full control of the
content and writing of the
manuscript
INTRODUCTION
Atrial fibrillation (AF) is the most common abnormality of the cardiac rhythm and represents
a growing global health issue of epidemic proportions [1, 2]. There is strong evidence that AF
confers a high thromboembolic risk, and the
use or oral anticoagulants (OAC) such as warfarin is associated with considerable reduction of
the risk of stroke and thromboembolic events,
as well as mortality, when compared to control
[3-6].
Despite its demonstrated efficacy, the use of
warfarin in clinical practice is rendered inconvenient by several inherent pharmacological characteristics. The slow onset and offset of action,
the narrow therapeutic range, the necessity of
periodic anticoagulant monitoring, the high
inter- and intra- individual variability with dayto-day variations in the anticoagulant response
as well as the multiple food and drug have led
not only to the underuse of warfarin, but also to
high rates of its discontinuation[7,8].
There is also a close correlation between the
benefits conferred by warfarin and the time in
which INR falls within the intended therapeutic
range and taking in consideration the difficulties in achieving optimal time in therapeutic
range (TTR, ideally >70% of the time within INR
2-3) in real world, it is inferred that many AF patients on warfarin are suboptimally protected
against thromboembolic complications [9].
The NOACs fall into two broad categories: (i) the
oral direct thrombin inhibitors (dabigatran) and
(ii) the oral direct factor Xa inhibitors (e.g. rivaroxaban, apixaban, etc).In general, NOACs deliver
predictable and consistent antithrombotic response allowing for a fixed-dose regimen without the need for routine coagulation monitoring. This represents an important asset because
simplification and convenience help improve
management of patients in clinical practice. In
addition, the NOACs are generally well tolerated, have a rapid onset of action, short half life
and have few known drug-drug interactions.
ISSN 2042-4884
318
EUROPEAN JOURNAL OF CARDIOVASCULAR MEDICINE
VOL III ISSUE I
NOVEL PHARMACOTHERAPIES FOR THE PREVENTION OF STROKE OR SYSTEMIC EMBOLISM IN ADULTS....PART 1
Currently NOACs are based on the impressive results of well designed large randomised controlled trials in which were compared
to warfarin. The new drugs have features in major international
guidelines and represent a reliable alternative to warfarin for the
management of patients with non-valvular, paroxysmal or permanent AF with ≥1 risk factors for stroke or systemic embolism. However, despite the promising results and the great expectations that
were created in the scientific community, NOAC are not 100% free
of constraints and drawbacks.
The scope of this article is to review currently available data regarding NOACs and to address practical issues relating to the safe and
effective use of NOACs in everyday clinical practice.
METHODS
We performed a search using English-language in regard to clinical studies, abstracts, references of detected articles and review articles. Google scholar and, PubMed databases up to January 2013
third week were searched. The search strategies were based on the
terms “atrial fibrillation”, “apixaban in atrial fibrillation’’, “dabigatran
in atrial fibrillation”, “rivaroxaban in atrial fibrillation” and “novel oral
anticoagulants”.
Pharmacokinetic and Pharmacodynamic characteristics
of three new oral anticoagulants
The NOACs are low molecular weight synthetic molecules that inhibit the activity of specific pathways in the coagulation process.
NOACS have various favorable pharmacokinetic and pharmacodynamic properties that render its use in clinical practice very convenient.
Dabigatran exitilate does not interact with the cytochrome P450
system and thus the risk of drug – drug interaction is significantly
reduced. On the other hand, dabigatran exitilate is a substrate of
P-glycoprotein which is an efflux pump that exports its substrates
out of the cell, and thus the concomitant use with potent P-glycoprotein inhibitors or P- glycoprotein inducers may lead to increased
risk of significant variation of its plasma concentrations. In patients
who receive potent P-glycoprotein inhibitors (azole-antimycotics,
immunosuppressants, and human immunodeficiency virus protease inhibitors must be avoided), or P-glycoprotein inducers (potent
P-gp inducers such as rifampin), the use of dabigatran is contraindicated (Table 2)
Which drugs matter in cardiology? Verapamil is a P-glycoprotein
inhibitor and its concomitant use in patients receiving dabigatran may lead to increased plasma concentrations of dabigatran.
With regard to amiodarone and quinidine, no dose adjustment is
required. On the other hand, dronedarone is a potent inhibitor of
P-gp efflux transporter should be avoided in patients receiving
dabigatran because it may leads to increased dabigatran plasma
levels.
Particular care should be taken in case of concomitant use of antiplatelet agents. In addition, concurrent treatment with non-steroidal anti-inflammatory drugs (NSAIDs) significantly increases the risk
of major bleeding and requires a careful benefit-risk assessment.
Concomitant treatment with any other anticoagulants is contraindicated except in case of switching therapy to or from dabigatran
or when unfractionated heparin (UFH) is administrated at doses
necessary to maintain the patency of central venous or arterial
catheters.
The recommended dose of dabigatran is usually 150 mg twice daily.
Treatment with dabigatran 110 mg b.i.d. dose is recommended for:
Dabigatran etexilate
Dabigatran etexilate is a prodrug which is rapidly and completely
converted into the main active compound, dabigatran. The generation of dabigatran is carried out by esterase-catalyzed hydrolysis in
the plasma and liver. Dabigatran is also further metabolized into
active glucuronide products. Specifically, dabigatran exitilate is a
non peptidic synthetic molecule that has been proven to be a direct competitive and reversible thrombin inhibitor of both free and
clot-bound thrombin [10-12]. After oral administration, dabigatran
etexilate is quickly absorbed and the peak plasma concentrations
are achieved within 0.5–4 hours. However, its bioavailability is low
(6.5%), and this is unrelated to food intake nor drug administration
[13]
Additionally, dabigatran is characterized by low plasma protein
binding and thus exhibit low likelihood of drug-drug interactions
[14].Indeed only 35% of dabigatran is protein binded. After the
rapid distribution phase, follows a relatively protracted elimination
phase that results in a half-life of 17 hours after multiple doses [15].
Renal excretion of dabigatran accounts for approximately 80% of
total clearance [15]. Due to the fact that in patients with impaired renal function dabigatran may exhibit prolonged elimination, its use
in this setting requires particular caution. According to European
guidelines, dabigatran is contraindicated in patients with severe
renal dysfunction (CrCl 80 years),
- In patients with moderate renal impairment (CrCl 30-50 ml/min)
who are at high risk of bleeding, including age 75-80 years,
- Simultaneous use of P- glycoprotein inducers or inhibitors.
- In patients at high bleeding risk (eg. HAS-BLED >3)
In the USA, the FDA approved the 150 mg b.i.d. dose but also approved a 75 mg bid dose regimen, for patients with severe renal
impairment (CrCl 15–30 ml/min), even though this does has never
been tested for stroke prevention in AF. In addition to the dose of
75mg twice should be also considered in patients with moderate
renal impairment who receive concomitantly dronedarone or systemic ketoconazole.
Rivaroxaban
Rivaroxaban is competitive reversible inhibitor of activated factor
X (Xa), which is generated at the confluence of the extrinsic and
intrinsic pathways, plays an important role at several steps of the
coagulation cascade. Notably, rivaroxaban represents the only
FDA-approved anticoagulant agent that has the advantage of being administrated once-daily.
319
HEALTHCARE BULLETIN
|
HEART RHYTHM
Rivaroxaban is a small-synthetic molecule and has a high bioavailability (80%) with rapid, absorption after oral administration. The
bioavailability of rivaroxaban is dose dependent [16, 17],ranging
from 80% to 100% when administrated in the dose of 10-mg dose,
while at a dose of 20mg the bioavailability is about 66%. Peak concentrations in plasma are achieved at2.5 to 4 hours. Of note, absorption rates and bioavailability are influenced by food intake, and
both are reduced in fasted patients. Thus, rivaroxaban should be
administrated after food intake. The half life of rivaroxaban is 5-13
hours, but this is shorter in elderly patients [16].
In contrast to dabigatran, rivaroxaban demonstrate high plasma
protein binding (92%-95%), and consequently it is not dialyzable.
Approximately>50% of rivaroxaban is metabolized by liver enzymes, principally by cytochrome P450 3A4 whereas the remainder
is eliminated unchanged via kidneys [17, 18].
Rivaroxaban (similar to dabigatran exitilate and apixaban) is a substrate of P-glycoprotein. Concurrent use of drugs which are strong
inhibitors of CYP-3A4 or P-glycoprotein efflux transporter (eg, systemic ketoconazole, intrakonazole) lead to increased rivaroxaban
anticoagulant effect and thus, the concomitant use of these drugs
should be avoided [19] Additionally, potent inducers of CYP-3A4
and/or P-glycoprotein efflux transporter should be avoided due to
the significant decrease in rivaroxaban plasma concentration.
Again, concomitant use of NSAIDs and platelet aggregation inhibitors should be undertaken with caution due to increased the bleeding risk by concomitant therapy. Due to the increased hemorrhagic
risk, concomitant treatment with other anticoagulant drugs is contraindicated. Notwithstanding, UFH may be administered at doses
necessary to maintain an open central venous or arterial catheters,
or in case of switching therapy to or from rivaroxaban.
Most of the administered dose of rivaroxaban (>66%) appears in
urine and the remainder is eliminated by the faecal-biliary route. In
patients with nonvalvular AF, the recommended dose of rivaroxaban is 20 mg once daily with the evening meal. However, taking
into consideration that rivaroxaban is eliminated by the kidneys,
in patients with moderate renal impairment (CrCl 30-49 mL/min),
rivaroxaban should be administrated at a dose of 15mg o.d. Due to
lack of evidence in relation to the efficacy-safety profile of rivaroxaban in patients with severe renal impairment (CrCl