Novel Pharmacotherapies for the Preventi (1)
HEART RHYTHM
|
ORIGINAL RESEARCH
Novel Pharmacotherapies for the Prevention of Stroke or
Systemic Embolism in Adults with Non-valvular Atrial Fibrillation - Part 2
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
CORRESPONDENCE
This article is a continuation of Novel Pharmacotherapies for the Prevention of Stroke or
Systemic Embolism in Adults with Non-valvular Atrial Fibrillation - Part 1.
EUROPEAN JOURNAL OF CARDIOVASCULAR MEDICINE 2014;3(1):318-327
Prof Gregory Y H Lip,
University of Birmingham Centre
for Cardiovascular Sciences,
City Hospital, Birmingham,
United Kingdom
Clinical implications and issues in everyday management
[email protected]
NOACs offer efficacy, safety and convenience as thromboprophylaxis in AF patients. Moreover the lack
of laboratory monitoring or dose adjustments, as well as the few food and drug- drug interactions,
render NOACs attractive alternatives to warfarin in clinical practice especially in patients with
unstable INR (TTR >70%).In elderly people NOACs are associated with lower rates of major bleeding,
including intracranial hemorrhage, compared with warfarin, which represents an important
advantage of NOACs since 45% of the patients diagnosed with AF are older than 75 years [40].
Sponsored by Bristol-Myers
Squibb. The author(s)
maintained full control of the
content and writing of the
manuscript
An algorithm illustrating the choice of antithrombotic therapy in patients with AF is shown
in Figure 1.
Despite the fact that NOACs have gain clinical
approval and are currently increasingly available
for the prevention of stroke or systemic embolism in patients with non valvular AF, there are
important clinical considerations in relation to
their use in certain clinical circumstances.
NOACs in the elderly
The risk of stroke and bleeding complications
increases with age. Despite the fact that NOACs
have a favourable risk-benefit profile in all age
groups, some caution is required in order to
reduce not only the thromboembolic risk but
also the bleeding risk. Indeed, in elderly patients receiving NOACs close monitoring of renal function is of great importance, particularly
relevant for dabigatran which is mainly renally
excreted. Thus, in patients receiving dabigatran
renal function should be evaluated at least once
every 6 months. Also, renal function should be
closely monitored during pathological condition that could potentially have impact on creatinine clearance.
Elderly patients have higher plasma concentrations of dabigatran compared to younger patients, in patients aged 80 years and above treated with dabigatran, dosing should be reduced
to 110mg twice daily. Although dose adjustment is not routinely recommended in elderly
patients treated with rivaroxaban, age related
changes in renal function should be evaluated
and consequently a dose adjustment should be
considered. The benefits of apixaban compared
to warfarin in prevention of stroke with lower
rates of major bleeding are consistent across
major subgroups, including the elderly. In patients receiving apixaban dosing adjustment is
not required unless the criteria for dose reduction previously discussed are met.
Missed dose
Due to the fact that NOACs have relatively short
half-lives adherence to the therapeutic scheme
is of crucial importance. Indeed, the omission of
a single dose could be associated with increased
thromboembolic risk.
ISSN 2042-4884
328
EUROPEAN JOURNAL OF CARDIOVASCULAR MEDICINE
VOL III ISSUE I
NOVEL PHARMACOTHERAPIES FOR THE PREVENTION OF STROKE OR SYSTEMIC EMBOLISM IN ADULTS....PART 2
Figure 1: Choice of antithrombotic therapy based on the ESC guidelines 2012
Dabigatran and apixaban should be taken regularly twice a day,
at approximately 12 hour intervals. When the prescribed dose of
the anticoagulant drug is not received at the scheduled time, the
dose should be taken as soon as possible on the same day. A missed
dose of dabigatran or apixaban may be administered till 6 h after
the scheduled intake. If that is not possible, the missed dose should
be skipped and the next scheduled dose should be received as recommended. In any case, the dose should not be doubled within the
same day to make up for a missed dose.
Due to the short half life of NOACs the interruption of anticoagulant
treatment and supportive treatment is the initial approach. Administration of activated charcoal to reduce absorption between 2 and
6 hours after ingestion of NOACs could be useful in the management of overdose. Where bleeding is evident, non-specific reversal
agents (eg prothrombin complex concentrates, rFVIIa etc) and (for
dabigatran) haemodialysis should be considered.
On the other hand, patients who miss a dose of rivaroxaban should
receive the missed dose till 12 h after the scheduled intake and continue on the following day with the once daily administration as
recommended. Similarly to other NOACs, the dose should not be
doubled within the same day to make up for a missed dose.
Chronic kidney disease (CKD) is associated with increased risk of
both thrombo-embolic and bleeding complication in patients with
AF [41,42]. Although NOACs represent a reasonable option for anticoagulant treatment in AF patients with mild or moderate renal
impairment, their use in severe renal impairment (CrCl36hours
Last dose: >48hours
Not indicated
No official indication for use
Last dose >48 hours
Last dose: >72hours
Last dose: >96hours
Not indicated
No official indication for use
RIVAROXABAN
CrCl >80mL/minute
CrCl 50‐80mL/minute
CrCl:30-50mL/minute
CrCl: 15-30 mL/minute
CrCl24 hours
Last dose: >24hours
Last dose: >24hours
Last dose: >36hours
No official indication for use
Last dose: >48 hours
Last dose: >48 hours
Last dose: >48 hours
Last dose: >48 hours s
No official indication for use
APIXABAN
CrCl >80mL/minute
CrCl 50‐80mL/minute
CrCl:30-50mL/minute
CrCl: 15-30 mL/minute
CrCl24 hours
Last dose: >24hours
Last dose: >24hours
Last dose: >36hours
No official indication for use
Last dose: >48 hours
Last dose: >48 hours
Last dose: >48 hours
Last dose: >48 hours s
No official indication for use
Given that the risk for major bleeding complications after some
types of surgery may outweigh the risk for thromboembolism, caution may be required [68]. Thus, NOACs should be restarted postoperatively when adequate hemostasis has been achieved. NOACs
should be restarted 6–8 h after the procedure if immediate and
adequate hemostasis has been achieved and the clinical situation
allows [57]. On the other hand in high bleeding risk surgical interventions full dose anticoagulation should be deferred 48–72 h after the invasive procedure. Prophylactic doses of LMWH 6-8 hours
after the procedure should be considered before resuming NOACs
in immobilized patients at high thrombo-embolic risk if adequate
hemostasis has been established [57].
Patients who present with an acute coronary syndrome
Patients receiving NOACs may also present withacute coronary syndrome (ACS). Treating AF patients presenting with an ACS represent a challenging task in clinical practice. Taking into consideration
not only that the DAPT does not eliminate completely the risk of
late stent thrombosis (the rate is about 0.6% per year in patients
on DAPT) but also the limitations of VKAs per se to protect patients
from stent thrombosis, management of AF patients after stent implantation is complicated [69].
EUROPEAN JOURNAL OF CARDIOVASCULAR MEDICINE
VOL III ISSUE I
Management should be decided on an individual basis, taking into
consideration that the individual bleeding risk should be balanced
with the individual ischemic risk. Despite the fact that triple therapy
(TT) increases significantly the risk of hemorrhagic complications,
this represents the most efficient antithrombotic strategy to protect against both stent thrombosis and thromboembolic complications in AF patients undergoing PCI [70].
Evidence data on TT with a NOAC are limited. The only trial where
clopidogrel use was not contraindicated was RE-LY. Interestingly in
the Phase 2 RE-DEEM study which evaluated the role of dabigatran
on the top of DAPT in patients with a recent non-ST or ST-elevation myocardial infarction, dabigatran demonstrated a favorable
efficacy-safety profile. On the other hand, the APPRAISE and ATLAS
studies have assessed the safety and efficacy of the oral factors Xa
inhibitors rivaroxaban and apixaban in combination with DAPT, in
patients with acute coronary syndrome [71,72].
333
HEALTHCARE BULLETIN
|
HEART RHYTHM
In ATLAS ACS 2–TIMI 51 study, low dose rivaroxaban (2.5mg bid)
reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke at the cost of
increased major bleeding and intracranial hemorrhage compared
to DAPT. Nevertheless there is lack of evidence on ACS in regard
to the dose of rivaroxaban used for anticoagulation in AF patients
per se, using the stroke prevention dose and treatment regime. In
the APPRAISE-2 study, patients were assigned to receive apixaban,
in the stroke prevention dose (5 mg b.i.d.), or placebo, in addition
to mono or dual antiplatelet therapy. This study showed that the
use of apixaban on top of DAPT was associated with higher rate of
major bleeding events without a significant reduction in recurrent
ischemic events.
Patients who present with an ischaemic stroke
Patients receiving NOACs may also present with an acute ischaemic
stroke. In these clinical circumstances it is of crucial importance to
estimate the impact of NOACs on the coagulation system and rule
out the presence of residual anticoagulant effects before administrating thrombolysis. Thus, thrombolysis should not be administered regardless of level of prothrombin time, INR, or PTT. Indeed
if the aPTT or the PT is prolonged in a patient taking dabigatran
or rivaroxaban respectively, as fibrinolytic therapy is potentially of
greater risk and thus should not be undertaken [73].
In the RE-LY study, dabigatran 150 mg b.i.d. resulted in a significant reduction in both ischaemic and haemorrhagic stroke, whilst
neither rivaroxaban nor apixaban significantly reduced ischaemic
stroke, compared with warfarin in the ROCKET-AF and ARISTOTLE
trials, respectively.
The timing of initiation of NOACs after stroke has not been established. The concerns about the use of NOACs in the setting of a new
ischaemic stroke are based on the potential risk of causing hemorrhagic transformation of a new ischemic stroke. In the RE-LY study,
patients with a new ischaemic stroke had to wait 2 weeks before
initiation of dabigatran. In the ROCKET AF and ARISTOTLE trials,
patients could not be treated with rivaroxaban and apixaban within
14 days and 7 days respectively of a new ischemic stroke. In these
studies, there was no evidence of increased hemorrhagic transformation with NOACs.
Changing NOACs to (or from) VKAs
It is recommended that dabigatran should be started immediately
as soon as the INR falls below 2.0 [74,75]. In the case of transition to
rivaroxaban it is recommended that warfarin should be discontinued and rivaroxaban initiate when INR falls to
|
ORIGINAL RESEARCH
Novel Pharmacotherapies for the Prevention of Stroke or
Systemic Embolism in Adults with Non-valvular Atrial Fibrillation - Part 2
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
CORRESPONDENCE
This article is a continuation of Novel Pharmacotherapies for the Prevention of Stroke or
Systemic Embolism in Adults with Non-valvular Atrial Fibrillation - Part 1.
EUROPEAN JOURNAL OF CARDIOVASCULAR MEDICINE 2014;3(1):318-327
Prof Gregory Y H Lip,
University of Birmingham Centre
for Cardiovascular Sciences,
City Hospital, Birmingham,
United Kingdom
Clinical implications and issues in everyday management
[email protected]
NOACs offer efficacy, safety and convenience as thromboprophylaxis in AF patients. Moreover the lack
of laboratory monitoring or dose adjustments, as well as the few food and drug- drug interactions,
render NOACs attractive alternatives to warfarin in clinical practice especially in patients with
unstable INR (TTR >70%).In elderly people NOACs are associated with lower rates of major bleeding,
including intracranial hemorrhage, compared with warfarin, which represents an important
advantage of NOACs since 45% of the patients diagnosed with AF are older than 75 years [40].
Sponsored by Bristol-Myers
Squibb. The author(s)
maintained full control of the
content and writing of the
manuscript
An algorithm illustrating the choice of antithrombotic therapy in patients with AF is shown
in Figure 1.
Despite the fact that NOACs have gain clinical
approval and are currently increasingly available
for the prevention of stroke or systemic embolism in patients with non valvular AF, there are
important clinical considerations in relation to
their use in certain clinical circumstances.
NOACs in the elderly
The risk of stroke and bleeding complications
increases with age. Despite the fact that NOACs
have a favourable risk-benefit profile in all age
groups, some caution is required in order to
reduce not only the thromboembolic risk but
also the bleeding risk. Indeed, in elderly patients receiving NOACs close monitoring of renal function is of great importance, particularly
relevant for dabigatran which is mainly renally
excreted. Thus, in patients receiving dabigatran
renal function should be evaluated at least once
every 6 months. Also, renal function should be
closely monitored during pathological condition that could potentially have impact on creatinine clearance.
Elderly patients have higher plasma concentrations of dabigatran compared to younger patients, in patients aged 80 years and above treated with dabigatran, dosing should be reduced
to 110mg twice daily. Although dose adjustment is not routinely recommended in elderly
patients treated with rivaroxaban, age related
changes in renal function should be evaluated
and consequently a dose adjustment should be
considered. The benefits of apixaban compared
to warfarin in prevention of stroke with lower
rates of major bleeding are consistent across
major subgroups, including the elderly. In patients receiving apixaban dosing adjustment is
not required unless the criteria for dose reduction previously discussed are met.
Missed dose
Due to the fact that NOACs have relatively short
half-lives adherence to the therapeutic scheme
is of crucial importance. Indeed, the omission of
a single dose could be associated with increased
thromboembolic risk.
ISSN 2042-4884
328
EUROPEAN JOURNAL OF CARDIOVASCULAR MEDICINE
VOL III ISSUE I
NOVEL PHARMACOTHERAPIES FOR THE PREVENTION OF STROKE OR SYSTEMIC EMBOLISM IN ADULTS....PART 2
Figure 1: Choice of antithrombotic therapy based on the ESC guidelines 2012
Dabigatran and apixaban should be taken regularly twice a day,
at approximately 12 hour intervals. When the prescribed dose of
the anticoagulant drug is not received at the scheduled time, the
dose should be taken as soon as possible on the same day. A missed
dose of dabigatran or apixaban may be administered till 6 h after
the scheduled intake. If that is not possible, the missed dose should
be skipped and the next scheduled dose should be received as recommended. In any case, the dose should not be doubled within the
same day to make up for a missed dose.
Due to the short half life of NOACs the interruption of anticoagulant
treatment and supportive treatment is the initial approach. Administration of activated charcoal to reduce absorption between 2 and
6 hours after ingestion of NOACs could be useful in the management of overdose. Where bleeding is evident, non-specific reversal
agents (eg prothrombin complex concentrates, rFVIIa etc) and (for
dabigatran) haemodialysis should be considered.
On the other hand, patients who miss a dose of rivaroxaban should
receive the missed dose till 12 h after the scheduled intake and continue on the following day with the once daily administration as
recommended. Similarly to other NOACs, the dose should not be
doubled within the same day to make up for a missed dose.
Chronic kidney disease (CKD) is associated with increased risk of
both thrombo-embolic and bleeding complication in patients with
AF [41,42]. Although NOACs represent a reasonable option for anticoagulant treatment in AF patients with mild or moderate renal
impairment, their use in severe renal impairment (CrCl36hours
Last dose: >48hours
Not indicated
No official indication for use
Last dose >48 hours
Last dose: >72hours
Last dose: >96hours
Not indicated
No official indication for use
RIVAROXABAN
CrCl >80mL/minute
CrCl 50‐80mL/minute
CrCl:30-50mL/minute
CrCl: 15-30 mL/minute
CrCl24 hours
Last dose: >24hours
Last dose: >24hours
Last dose: >36hours
No official indication for use
Last dose: >48 hours
Last dose: >48 hours
Last dose: >48 hours
Last dose: >48 hours s
No official indication for use
APIXABAN
CrCl >80mL/minute
CrCl 50‐80mL/minute
CrCl:30-50mL/minute
CrCl: 15-30 mL/minute
CrCl24 hours
Last dose: >24hours
Last dose: >24hours
Last dose: >36hours
No official indication for use
Last dose: >48 hours
Last dose: >48 hours
Last dose: >48 hours
Last dose: >48 hours s
No official indication for use
Given that the risk for major bleeding complications after some
types of surgery may outweigh the risk for thromboembolism, caution may be required [68]. Thus, NOACs should be restarted postoperatively when adequate hemostasis has been achieved. NOACs
should be restarted 6–8 h after the procedure if immediate and
adequate hemostasis has been achieved and the clinical situation
allows [57]. On the other hand in high bleeding risk surgical interventions full dose anticoagulation should be deferred 48–72 h after the invasive procedure. Prophylactic doses of LMWH 6-8 hours
after the procedure should be considered before resuming NOACs
in immobilized patients at high thrombo-embolic risk if adequate
hemostasis has been established [57].
Patients who present with an acute coronary syndrome
Patients receiving NOACs may also present withacute coronary syndrome (ACS). Treating AF patients presenting with an ACS represent a challenging task in clinical practice. Taking into consideration
not only that the DAPT does not eliminate completely the risk of
late stent thrombosis (the rate is about 0.6% per year in patients
on DAPT) but also the limitations of VKAs per se to protect patients
from stent thrombosis, management of AF patients after stent implantation is complicated [69].
EUROPEAN JOURNAL OF CARDIOVASCULAR MEDICINE
VOL III ISSUE I
Management should be decided on an individual basis, taking into
consideration that the individual bleeding risk should be balanced
with the individual ischemic risk. Despite the fact that triple therapy
(TT) increases significantly the risk of hemorrhagic complications,
this represents the most efficient antithrombotic strategy to protect against both stent thrombosis and thromboembolic complications in AF patients undergoing PCI [70].
Evidence data on TT with a NOAC are limited. The only trial where
clopidogrel use was not contraindicated was RE-LY. Interestingly in
the Phase 2 RE-DEEM study which evaluated the role of dabigatran
on the top of DAPT in patients with a recent non-ST or ST-elevation myocardial infarction, dabigatran demonstrated a favorable
efficacy-safety profile. On the other hand, the APPRAISE and ATLAS
studies have assessed the safety and efficacy of the oral factors Xa
inhibitors rivaroxaban and apixaban in combination with DAPT, in
patients with acute coronary syndrome [71,72].
333
HEALTHCARE BULLETIN
|
HEART RHYTHM
In ATLAS ACS 2–TIMI 51 study, low dose rivaroxaban (2.5mg bid)
reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke at the cost of
increased major bleeding and intracranial hemorrhage compared
to DAPT. Nevertheless there is lack of evidence on ACS in regard
to the dose of rivaroxaban used for anticoagulation in AF patients
per se, using the stroke prevention dose and treatment regime. In
the APPRAISE-2 study, patients were assigned to receive apixaban,
in the stroke prevention dose (5 mg b.i.d.), or placebo, in addition
to mono or dual antiplatelet therapy. This study showed that the
use of apixaban on top of DAPT was associated with higher rate of
major bleeding events without a significant reduction in recurrent
ischemic events.
Patients who present with an ischaemic stroke
Patients receiving NOACs may also present with an acute ischaemic
stroke. In these clinical circumstances it is of crucial importance to
estimate the impact of NOACs on the coagulation system and rule
out the presence of residual anticoagulant effects before administrating thrombolysis. Thus, thrombolysis should not be administered regardless of level of prothrombin time, INR, or PTT. Indeed
if the aPTT or the PT is prolonged in a patient taking dabigatran
or rivaroxaban respectively, as fibrinolytic therapy is potentially of
greater risk and thus should not be undertaken [73].
In the RE-LY study, dabigatran 150 mg b.i.d. resulted in a significant reduction in both ischaemic and haemorrhagic stroke, whilst
neither rivaroxaban nor apixaban significantly reduced ischaemic
stroke, compared with warfarin in the ROCKET-AF and ARISTOTLE
trials, respectively.
The timing of initiation of NOACs after stroke has not been established. The concerns about the use of NOACs in the setting of a new
ischaemic stroke are based on the potential risk of causing hemorrhagic transformation of a new ischemic stroke. In the RE-LY study,
patients with a new ischaemic stroke had to wait 2 weeks before
initiation of dabigatran. In the ROCKET AF and ARISTOTLE trials,
patients could not be treated with rivaroxaban and apixaban within
14 days and 7 days respectively of a new ischemic stroke. In these
studies, there was no evidence of increased hemorrhagic transformation with NOACs.
Changing NOACs to (or from) VKAs
It is recommended that dabigatran should be started immediately
as soon as the INR falls below 2.0 [74,75]. In the case of transition to
rivaroxaban it is recommended that warfarin should be discontinued and rivaroxaban initiate when INR falls to