1. health and fitness
2. therapy

Chapter
123
Stroke Prevention in Atrial Fibrillation:
What is New?
Prafulla G Kerkar, Srivallabh Karlekar, Vinay Jaiswal
INTRODUCTION
NEED FOR A NOVEL ORAL ANTICOAGULANT
Atrial fibrillation (AF) is the most common cardiac arrhythmia
observed in the elderly population. Stroke is the most common and
devastating complication of AF, even in the absence of rheumatic
valvular disease. The incidence of all-cause stroke in patients with
AF is 5% per year. Stroke risk persists even in asymptomatic AF and
the mortality in AF is primarily due to stroke.
Warfarin is a vitamin K antagonist and has a half-life of 36 hours and
predominantly circulates bound to albumin. The dose-response
of warfarin is impacted on by environmental and genetic factors.
Polymorphisms of genes that encode for the vitamin-K epoxide
reductase enzyme and CYP2C9 enzyme have been identified as the
most important contributors to the wide interindividual variations in
dose requirements.
RISK STRATIFICATION AND BLEEDING RISK
ASSESSMENT: WHAT IS NEW?
For stroke prevention in atrial fibrillation (SPAF), most of the stroke
risk assessment schemes categorize patients into “high”, “moderate”,
and “low” risk categories for stroke. The simplest of the strokeassessment scheme is the CHADS2 score. For patients with a CHADS2
score 0−1 or where a more detailed stroke risk assessment is indicated,
a more thorough and comprehensive risk factor-based approach, the
CHA2DS2-VASc scoring system (Table 1) has been recommended.
While the CHADS2 score is easy to remember, CHA2DS2-VASc score
is more accurate in identifying the patients who are actually at low
risk of stroke and has been approved as Class I recommendation for
risk assessment in stroke prevention in patients of nonvalvular AF.
Bleeding complications with oral anticoagulants (OAC) is
the major concern with the use of these drugs, which needs to be
balanced against the risk of ischemic stroke. Individual bleeding risk
in real-world patients with AF can be assessed using hypertension,
abnormal renal/liver function, stroke, bleeding history or
predisposition, Labile international normalized ratio, elderly, drugs/
alcohol concomitantly (HAS-BLED) risk score (Table 2). This risk
score potentially supports clinical decision-making regarding
antithrombotic therapy in patients with AF. A HAS-BLED score more
than or equal to 3 indicates that caution should be exercised while
prescribing oral anticoagulant therapy and the patient should be
available for regular review. Importantly, a high HAS-BLED score
does not contraindicate OAC therapy and for a given HAS-BLED
score, the risk of intracranial hemorrhage (ICH) and major bleeding
in patients on aspirin is similar to that for those taking warfarin.
The 2010 European Society of Cardiology (ESC) Guidelines on AF,
Canadian Cardiovascular Society Guidelines (recently updated)
and the consensus document on bleeding in AF, prepared by the
European Heart Rhythm Association (EHRA) and the ESC Working
Group on thrombosis, all recommended use of the simple bleeding
risk assessment score, HAS-BLED, rather than the more complicated
HEMORR2HAGES score, or the less practical ATRIA score. The HASBLED score has better predictive value than that of ATRIA and,
importantly, highlights risk factors that can be actively managed to
reduce the bleeding risk.
Ideal Anticoagulant
Efficacy of warfarin as prophylaxis against stroke is established and
unequivocal. Unfortunately, there are many limitations associated
with warfarin (Table 3). Due to these factors, warfarin requires
close laboratory monitoring of coagulation via the international
normalized ratio (INR) and subsequent dose adjustments. These
TABLE 1 │ The CHA2DS2-VASc score for risk of stroke in
nonvalvular atrial fibrillation (AF)
Risk factors
Score
Congestive cardiac failure
Hypertension
Age > 75 years
Diabetes mellitus
Stroke/TIA/thromboembolism
Vascular disease
Age 65–74 years
Female sex
Maximum score
1
1
2
1
1
1
1
1
9
Source: Lip GY, Nieuwlaat R, Pisters R, et al. Chest. 2010;137:2630-72.
TABLE 2 │ The HAS-BLED score for bleeding risk
Risk factor
Score
Hypertension
Abnormal renal/liver function
Stroke
Bleeding tendency
Labile INR
Age (e.g. > 65 years)
Drugs (e.g. concomitant aspirin, NSAIDs, etc.) or alcohol
Maximum score
1
1 or 2
1
1
1
1
1
9
Notes: A score of 0–2 indicates low risk of bleeding; a score of more than 3
indicates high risk of bleeding. Hypertension is defined as a systolic blood
pressure: 160 mm Hg. 1 point is awarded for each of abnormal renal or liver
function, and drugs or alcohol.
Source: Pisters R, Lip GY, Nieuwlaat R, et al. Chest. 2010;138:1093-100.
Section 16
Chapter 123 Stroke Prevention in Atrial Fibrillation: What is New?
TABLE 3 │ Limitations of warfarin
• Frequent monitoring necessitating regular clinic attendance
• Narrow therapeutic window
• Slow onset and offset of action, requiring 3–6 days to reach
therapeutic levels
• Long half-life
• Numerous drug and dietary interactions
• Genetic polymorphisms exist which confer increased sensitivity or
resistance to warfarin
• Unpredictable pharmacodynamics and pharmacokinetics leading to
inter- and intraindividual variability in dose and metabolism
TABLE 4 │ Characteristics of the ideal anticoagulant
• • • • • • • • • Equivalent efficacy to warfarin at least
Predictable response
Wide therapeutic window
Low inter- and intrapatient variability
Fixed oral dosing
Low potential for drug and dietary interactions
No need for regular coagulation monitoring
Fast onset and offset of action
Low incidence and severity of adverse effects
Source: Ahmad Y, Lip GY. Clinical insights in cardiology. 2012;6: 65-78.
regular clinics attendances bring an increased financial burden and
inconvenience to patients. Thus, many patients who are eligible
for warfarin choose not to use it. A clinically viable alternative to
warfarin will need to possess several key characteristics (Table 4).
New therapies would of course need to be safe and well tolerated,
with low frequency and severity of adverse effects. They should also
obviate the need for regular coagulation monitoring.
SO WHAT IS NEW ON THE HORIZON?
Direct Thrombin Inhibitors
The final step of the coagulation pathway requires thrombin to
convert fibrinogen to fibrin. Direct thrombin inhibitors bind to
thrombin and prevent its interaction with substrates; this inhibits
fibrin production. Ximelegatran was the first available oral direct
thrombin inhibitor, was withdrawn from the market in 2004 due
to its potential to cause raised liver enzymes and reported cases of
fulminant hepatic failure.
Dabigatran etexilate is an oral pro-drug which is converted in the
liver to its active compound; dabigatran. Dabigatran exerts an effect
on both clot-bound and free thrombin. Dabigatran has a fast onset of
action (peak 0.5–4 hours), a half-life of 17 hours with multiple doses
(7–9 hours with single dose) and reaches clinical steady state within
2.5 days of initiation. Dabigatran is predominantly (80%) cleared by
the kidneys. Absorption of dabigatran may be delayed by food and
there is an age effect on pharmacokinetic parameters although no
reported gender effect.
Factor Xa Inhibitors
Fondaparinux inhibits factor Xa indirectly, utilizing antithrombin as
a cofactor and producing a conformational change similar to heparin
to inhibit factor Xa—but it can only inhibit factor Xa in its free form.
The emerging direct factor Xa inhibitors do not require antithrombin
as a cofactor and bind directly to the active site of factor Xa. Factor Xa
has fewer effects outside of the clotting cascade, so may cause fewer
side-effects than direct thrombin inhibitors.
Apixaban is an oral, selective, reversible direct factor Xa inhibitor.
It has high oral bioavailability and onset of action is within 3 hours.
The drug has a half-life of 12 hours and is cleared via multiple
pathways: 25% renal, 75% in feces. Data indicate that apixaban does
not inhibit or induce CYP enzymes. Its absorption is not impacted by
food.
Rivaroxaban is an oral, reversible, direct factor Xa inhibitor. It
inhibits prothrombinase activity, as well as free and clot-associated
Fax activity in plasma. It has high oral bioavailability and is rapidly
absorbed with a half-life of 9 hours in healthy subjects and 12
hours in those aged over 75 years. It has a rapid onset of action with
maximal concentrations reached between 2 and 4 hours.
Rivaroxaban has a dual mode of elimination with no identified
active circulating metabolite: one-third of the dose is renal cleared,
the remainder being metabolized by the liver. The pharmacokinetics
of rivaroxaban are dose proportional and generally unaffected by
gender, body weight or extremes of age. Although rivaroxaban can
theoretically be affected by drugs that interact with CYP3A4, a low
potential for clinically significant drug or food interactions has been
reported (Table 5).
Left Atrial Appendage Closure
Although clinically applied for decades, there is no conclusive
evidence that surgical left atrial appendage (LAA) excision or
occlusion reduces stroke risk in AF patients, due to a lack of large
controlled trials with systematic follow-up. Furthermore, there are
data to suggest that not all strokes in AF patients are cardioembolic or
due to AF, and the LAA is probably not the only left atrial region where
thrombi can potentially originate. This suggests that there may be a
need for antithrombotic therapy in AF patients, even after removal or
closure of the LAA (Table 6). At present, interventional LAA closure
is not indicated simply as an alternative to OAC therapy to reduce
stroke risk. ESC guidelines recommend transcatheter closure of LA
appendage should be considered in patients with a high stroke risk
and contraindication for long-term anticoagulation.
Clinical Studies of the Old and New OACs:
Efficacy and Safety
Warfarin
Oral vitamin K antagonists (VKAs) are the gold standard over the last
5 decades in the prevention of thromboembolism in patients with
nonvalvular AF as demonstrated in several trials, with relative risk
reduction ranging from 52–86%. Also, multiple primary prevention
trials evaluated the efficacy of aspirin at various doses (50–325 mg/
day) compared to VKAs (AFASAK-1, SPAF-II, SPAF-III, AFASAK-2).
These trials concluded that in comparison with aspirin, warfarin
showed a 52% relative risk reduction for stroke.
The SPAF III study comparing the efficacy of a combination
of low-intensity, fixed-dose VKAs plus aspirin with conventional
adjusted-dose VKA, in 1,044 patients had to be stopped prematurely
after a mean follow-up of 1.1 years due to the occurrence of higher
rates of ischemic stroke and systemic embolism in patients who were
on combination therapy compared to those on adjusted-dose VKAs
(7.9% per year vs 1.9% per year; p < 0.0001).
The ACTIVE-W study showed clearly that warfarin was superior
dual antiplatelet therapy (DAPT) with aspirin and clopidogrel, and
was stopped early due to the clear benefit of oral anticoagulation. In
ACTIVE-A trial patients deemed unsuitable for warfarin were given
either aspirin alone or a combination of aspirin and clopidogrel.
Aspirin plus clopidogrel reduced the rate of ischemic stroke by
28% compared with aspirin alone. Therefore, DAPT would not
be a suitable alternative to warfarin in patients deemed high-risk
for hemorrhage. However, DAPT may be a therapeutic option for
patients truly ineligible for warfarin for other reasons.
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Neurology
Section 16
TABLE 5 │ Pharmacokinetic and pharmacodynamics properties of the novel anticoagulants
Dabigatran
Rivaroxaban
Apixaban
Mechanism of action
Direct thrombin inhibitor
Direct factor Xa inhibitor
Direct factor Xa inhibitor
Prodrug
Double prodrug
No
No
Dosing frequency
Twice daily
Once daily
Twice daily
Bioavailability %
6.5
50
80
Tmax
2 hours
2–4 hours
3 hours
Half-life
17 hours with multiple doses
7–9 hours with single dose
9 hours in healthy subjects
12 hours in elderly subjects
12 hours
Mode of excretion
80% cleared renally
One-third cleared renally, two-thirds
metabolized by the liver
70% cleared in feces
25% cleared renally
Age effect
Age effect affects pharmacokinetic
parameter
No
No
Drug interactions
Interaction with aspirin at high doses
None reported
None reported
Source: Ahmad Y, Lip GY. Clinical Medicine Insights: Cardiology. 2012;6:65-78.
TABLE 6 │Recommendations for prevention of thromboembolism in nonvalvular atrial fibrillation (AF)
Recommendations for prevention of thromboembolism in nonvalvular AF—general
Antithrombotic therapy to prevent thromboembolism is recommended for all patients (both male and female) who are at a risk (aged
< 65 years and lone factor AF) or with contraindications.
I
A
The choice of antithrombotic therapy should be based upon the absolute risks of strokes/thromboembolism and bleeding and the net
clinical benefit of a given patient.
I
A
The CHA2DS2-VASc score is recommended as a means of assessing stroke risk in nonvalvular AF.
I
A
In patients with a CHA2DS2-VASc score of 0 (i.e. aged < 65 years with lone AF) who are at low risk, with none of the risk factors, no
antithrombotic therapy is recommended.
I
B
In patients with a CHA2DS2-VASc score ≥ 2, OAC therapy with:
• Adjusted-dose VKA (INR 2–3); or
• A direct thrombin inhibitor (dabigatran); or
• An oral factor Xa inhibitor (e.g. rivaroxaban, apixaban)d is recommended, unless contraindicated.
I
A
In patients with a CHA2DS2-VASc score of 1, OAC therapy with:
• Adjusted-dose VKA (INR 2–3); or
• A direct thrombin inhibitor (dabigatran); or
• An oral factor Xa inhibitor (e.g. rivaroxaban, apixaban)d should be considered, based upon an assessment of the risk of bleeding
complications and patient preferences.
IIa
A
Female patients who are aged < 65 years and have lone AF (but still have a CHA2DS2-VASc score of 1 by virtue of their gender) are
low risk and no antithrombotic therapy should be considered.
IIa
B
When patients refuse the use of any OAC (whether VKAs or NOACs), antiplatelet therapy should be considered, using combination
therapy with aspirin 75–100 mg plus clopidogrel 75 mg daily (where there is a low risk of bleeding) or—less effectively—aspirin
75–325 mg daily.
IIa
B
Source: 2012 Focused Update of the ESC Guidelines of the management of atrial fibrillation.
Dabigatran
The RE-LY trial was a phase III, blinded, noninferiority trial in 18,113
patients with nonvalvular AF with a CHADS2 score of 1 or higher or
who were older than 65 years with coronary artery disease. Patients
were randomized to either dabigatran, at a dosage of 110 or 150 mg
twice daily or warfarin titrated to a goal INR of 2–3. Major bleeding
was less with 110 mg of dabigatran when compared to warfarin,
and rates of major hemorrhage are similar with 150 mg dabigatran
and warfarin. Low-dose dabigatran was shown to be noninferior
to warfarin and high-dose dabigatran was shown to be superior
to warfarin. Dabigatran 150 mg was found to have a trend towards
increased rate of myocardial infarction (0.74%) when compared
with warfarin (0.53%/year) which was revised in a subsequent
publication12 to 0.81 versus 0.64%/year, p = 0.12).
Rivaroxaban
564
ROCKET-AF study was a phase III, randomized, double-blind, eventdriven noninferiority trial with over 14,000 patients comparing
rivaroxaban with warfarin in nonvalvular AF and a history of stroke,
TIA, or non-CNS embolism or at least two independent risk factors
for future stroke. Patients were randomized to rivaroxaban 20 mg
once daily (or 15 mg once daily in patients with moderate renal
impairment), or dose-adjusted warfarin titrated to a target INR of
2.5. Rivaroxaban was similar to warfarin for the primary efficacy
endpoint of prevention of stroke and systemic embolism. Major and
nonmajor clinically relevant bleeding was similar with rivaroxaban
and warfarin. The rivaroxaban group demonstrated significantly less
fatal bleeding, intracranial hemorrhage.
Apixaban
The AVERROES study enrolled 5,600 patients with AF who were either
intolerant of or unsuitable for warfarin and compared apixaban 5 mg
twice daily with aspirin 81–324 mg/day. The study was prematurely
terminated because of an acceptable safety profile and benefit in
favor of apixaban.
The ARISTOTLE trial was randomized phase III, double-blind,
international trial comparing apixaban 5 mg twice/day versus
Section 16
Chapter 123 Stroke Prevention in Atrial Fibrillation: What is New?
warfarin titrated to an INR between 2 and 3 in over 18,000 patients.
Apixaban was found to be safer than warfarin in regard to major
bleeding: 2.13% per year in the apixaban group versus 3.09% per year
in the warfarin group.
PATIENT VALUES AND PREFERENCES
Patients will, generally speaking, be taking the prescribed therapies
for the duration of their lives so it is crucial that they are adequately
informed. The predominant concern of patients is that of stroke,
and many are willing to accept slightly increased bleeding risks to
avoid a stroke. Physicians tend to be more concerned with hospital
admissions, whereas patients are ultimately worried about death. The
AF-AWARE study also found that physicians tended to overestimate
the burden of anticoagulant treatment. By and large, patients are
willing to accept the inconveniences of anticoagulation to avoid
serious adverse outcomes.
The advent of novel anticoagulant therapies is changing the
landscape of stroke prevention in AF, and will significantly impact
on patient preference. In comparison to the VKAs, these new
alternatives have therapeutic advantages, given their superior or
similar reduction in stroke risk, a lower risk of ICH, and similar or
lower major bleeding. The new agents circumvent many of the
inconveniences of warfarin: regular INR checks, dietary restrictions,
drug interactions. Therefore, these novel OACs will be preferred
alternatives to VKAs in many patients for SPAF, although the high
cost of the drugs may be a major hurdle in a developing country like
India. They also bring with them other considerations and caveats.
There are no known antidotes currently available for dabigatran,
rivaroxaban or apixaban.
The benefit of not requiring regular INR monitoring is offset by
the fact that there is no validated way to assess the anticoagulant
effect or level of the drug. We are also yet to establish how successful
anticoagulant bridging prior to surgery can be achieved with the
new agents. Dabigatran and rivaroxaban must be used with caution
in patients with renal insufficiency, and the dose of dabigatran
recommended by the FDA for renal impairment was not studied in the
RE-LY trial.
PLACE IN THERAPY
Warfarin has a clearly defined place in therapy, as the established gold
standard antithrombotic for SPAF. The optimal INR for AF patients is
in the range 2.0–3.0, with increased risk of thromboembolism and
hemorrhage outside this range at either end. The benefit of warfarin
is strongly linked to the proportion of time spent in the therapeutic
range (TTR). Even modest TTR improvements of 5%–10% have
profound beneficial effects on clinical outcomes. TTR in clinical
trials is typically 60%–65%, but this exceeds that routinely achieved
in clinical practice. Very low TTR may completely obliterate the
potential benefit of warfarin. It has been demonstrated that selfmonitoring improves the quality of INR control and therefore
outcome measures. Despite its efficacy, the limitations of warfarin
mean that a large group of patients with AF are not receiving effective
prophylaxis against stroke.
The US guidelines recommend dabigatran 150 mg BD as an
alternative to warfarin (or 75 mg for patients with renal impairment).
The European guidelines currently recommend 150 mg dabigatran
twice a day for a patient at low bleeding risk (HAS-BLED score 0–2)
and 110 mg dabigatran twice a day for those at high risk of bleeding
(HAS-BLED score 3 or greater). Rivaroxaban has been approved
for stroke prevention in nonvalvular AF by both the FDA and the
EMA, and in many countries worldwide. European commission has
approved apixaban for stroke prevention in adults with nonvalvular
AF with 1 or more risk factors. These two factorial inhibitors have not
been shown to cause significant upset, so may represent an appealing
treatment option for those patients unsuited to warfarin and unable
to tolerate dabigatran due to dyspepsia. Conclusive comparisons
between the new and emerging agents cannot be made until they
have been evaluated against each other in trials.
CONCLUSION
For six decades, warfarin has been the only available therapeutic
strategy for prophylaxis against stroke inpatients with AF. Its
limitations have led to its underutilization and wide variability in
AF management. Major progress has been made in AF research,
providing clinicians with improved management strategies.
Better risk stratification schemes permits accurate identification
of truly low-risk patients who do not require anticoagulation, and
those patients who ought to be receiving antithrombotic therapy.
We are also able to simply and practically evaluate a patient’s risk in
relation to bleeding, enabling risk-benefit decisions to be made in a
more straightforward manner. The advent of novel OACs means that
warfarin is no longer the only choice for effective stroke prophylaxis.
The recent aggressive propaganda for novel OACs in medical
literature, on the internet and in medical conferences could also
mean a justifiable attention to SPAF and a rational prescription of
OACs both old and new.
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