Atrial Fibrillation and Stroke

Hendro Susilo

Abstract
Atrial fibrillation (AF) is associated with an increased risk of thromboembolic
complications, a risk that can be reduced with antithrombotic therapy. The world faces an
epidemic AF and AF related stroke. The most common cardiac source of cerebral embolism
is the left atrium and its appendage, with the most common underlying disorder is non-
valvular AF. AF is associated with a five-fold increased risk of stroke, two-fold increased in
mortality and an increase in vascular cognitive impairment compared with age-matched
control. Vitamin K antagonists such as warfarin are underused and poorly managed. The
direct thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban and apixaban are
new oral anticoagulants that are at least as efficacious and safe as warfarin. Their advantages
are predictable anticoagulant effects, low propensity for drug interaction and lower rates of
intracranial haemorrhage than warfarin. These were all might affect the prophylactic
antithrombotic management of patients with atrial fibrillation who are at risk of stroke.

Introduction
Atrial fibrillation (AF) is a common cardiac arrhythmia seen in our daily practice
with the prevalence of AF increases more than 10 times from less than 1% in patients with
the age younger than 60 years to almost 10% in patients over the age of 80 years (Go AS et
al. 2001). The incidence of AF showed similar increase from 0.2% per year in men under
the age of 40 to more than 2% per year in men aged 80-89 years, with a lower age-adjusted
incidence in women (Psaty BM et al. 1997; Heeringa J et al. 2006). Hence AF is
predominantly a problem of the older population, and the prevalence of AF is projected to
rise as the population ages and the prevalence of cardiovascular risk factors increases
(Miyasaka Y et al. 2006). From several studies and reports during the last 2 decades give a
trend of increasing incidence and prevalence of AF in the community. Analysis data
estimates that the number of people with AF in the USA will be around 12.1 million by 2050.
AF accounts for more than 1% of health-care expenditure in the UK (Stewart S et al.
2004) and treatment of thromboembolic stroke incurs a significant share of the health-care
costs associated with AF (Wolf PA et al. 1998). AF also associated with a four to fivefold
increase in the risk of stroke, and an estimated 15% of all strokes are caused by AF,
importantly, this proportion increases substantially with age (Wolf PA et al. 1991). In a
selected population of patients with ischaemic stroke, AF was highly prevalent (almost 25%)
and associated with longer hospital stay, greater disability, higher rates of stroke recurrence,
and higher rates of mortality compared with stroke patients without AF (Marini C et al.
2005). The risk of stroke in patients with paroxysmal or persistent AF is comparable to the
risk in patients with permanent AF and the absence of symptoms does not imply lower risk of
thromboembolism (Flaker GC et al. 2000).
Atrial Fibrillation and ischaemic stroke pathophysiology
Virchow triad demonstrated strong relation between vessel wall abnormalities,
abnormal blood stasis, and abnormal blood constituents required for thrombus formation
(thrombogenesis). The criterias for Virchows triad are fulfilled in patients with AF:
structural heart disease (vessel wall abnormalities and endothelial or endocardial damage or
dysfunction), blood stasis within the left atrium and its appendage, and coagulation of
platelets and fibrinolysis abnormalities all are associated with AF and thrombogenesis
(Choudhury A et al., 2003).
The data imply that abnormalities of the atrial wall and endocardium in AF contribute
to thrombogenesis and the increased propensity for thromboembolism eg, in mitral valve
disease or left ventricular dysfunction are present (Choudhury A et al. 2003-2004). Abnormal
stasis in AF is most evident through spontaneous echocontrast in the left atrium and reduced
blood flow velocities in the left atrial appendage, which have been linked to
thromboembolism in patients with AF (Goldman ME et al. 1999). Clinical risk factors for
stroke in patients with AF were also related to increased stasis in the left atrial appendage.
For example, older age and hypertension are the most prevalent risk factors associated with
decreased left atrial appendage contractility and reduced flow velocity . Abnormalities of
coagulation or platelets and fibrinolysis have been reported in AF, which might be associated
with indices of endothelial damage or dysfunction, inflammation, growth factors, and
turnover of the extracellular matrix (Lip GY et al. 2003), all of which are consistent with a
prothrombotic state in AF.

Stroke risk assessment in patients with AF

The use of antithrombotic therapy must be balanced with the anticipated benefit of
reduced thromboembolic complications and the potential risk of bleeding in patients with AF.
The absolute benefit of anticoagulation therapy is directly related to the absolute risk of
thromboembolic complications. The absolute benefits of anticoagulation and antiplatelet
therapy are smaller in the context of primary prevention, where the absolute risk of stroke is
low. Therefore, the use of anticoagulation or antiplatelet therapy should be guided by an
assessment of the risks of thromboembolism and bleeding.
Assesment of thromboembolic risk is helped by several risk-stratification models,
which are derived from pooled analysis of the data from the original antithrombotic
treatment trials
(Stroke Risk in Atrial Fibrillation Working Group, 2007). In a recent systematic review of
risk factors for stroke in patients with AF, four clinical features prior stroke or TIA, older
age, hypertension, or diabetes mellitus were consistent independent risk factors for stroke and
thromboembolism. Of these, prior stroke or TIA was the most powerful risk factor (>5% per
year [averaging 10% per year]), whereas absolute stroke rates associated with other
individual risk factors are difficult to estimate (Lip GY, 2007).
Some differences among the different published risk stratification schemes are
evident, although most identify previous stroke or TIA, being older than 75 years,
hypertension, and diabetes mellitus as high-risk factors. Female sex is a risk factor in the
Stroke Prevention in Atrial Fibrillation; however, women were generally underrepresented in
the trials, although some data suggest that female sex might increase stroke risk. Other
possible risk factors, such as coronary, carotid, or peripheral artery disease, were not
systematically studied. Patients with AF and peripheral artery disease are a high risk group
for vascular events (Conway et al. 2004), and a complex aortic plaque on the descending
aorta, seen by transoesophageal echocardiography, is an independent risk factor for ischaemic
stroke .
 CHADS2 (Gage BF et al. 2001) is a well validated scheme for predicting stroke risk
in patients with AF: one point is given for each of congestive heart failure, hypertension, age
older than 75 years, and diabetes mellitus, whereas stroke or TIA are given two points.
Notwithstanding that the CHADS2 scheme is simple; it does not include echocardiographic
left ventricular impairment nor the associated vascular disease as high-risk factors or criteria.
Also, if stroke or TIA is the only risk factor for a patient with AF, they have a CHADS2
score of two, which classifies them as moderate risk, although such patients are clearly at
high risk. From the Cohort trial (Baruch L et al. 2007), the CHADS2 scheme classified the
largest cohort of participants as moderate risk (60%) compared with most participants being
classified as high risk by most other stroke stratification schemes.

Risk of Bleeding
After more than sixty years using vitamin K antagonist warfarin several major risk
factors for bleeding have been identified, including uncontrolled anticoagulation, recent
haemorrhage, binge drinking, liver and kidney disease, the concomitant use of aspirin and
non-steroidal anti-inflammatory agents, uncontrolled hypertension, concomitant bleeding
tendency (Fihn SD et al. 1993). The higher rates of major bleeding in older patients treated
with vitamin K antagonist warfarin have also been reported.
A novel user friendly HAS-BLED score was derived from 3456 patients with AF who
had 53 major bleeds during 1 year follow up (Pisters R et al.,2010) . It is scored by allocation
of one point each for uncontrolled hypertension, abnormal renal function,stroke, bleeding
history, labile INR, elderly age (>65 years), drugs ( antiplatelet or NSAID) and excessive
intake of alcohol. HAS-BLED score of more than 3 identifies patients with AF at high
bleeding risk, warranting special caution and control of modifiable risk factors for bleeding
and close monitoring (Camm AJ, 2010, Lip GY,2011). It does not necessarily mean that oral
anticoagulation should be stopped. This is because the risk of ischaemic stroke without
anticoagulation is often higher than the risk of intracranial bleeding with anticoagulation
(Friberg L, 2012).

Prevention of a First Stroke in AF

Adjusted dose Warfarin with the target INR 2.0 to 3.0 is recommended according to
American Heart Association and American Stroke Association for patients with NVAF
deemed to be at high risk and many deemed to be at moderate risk for stroke who can receive
it safely (Goldstein LB et al. 2011) and aspirin recommended for low risk and some
moderate risk patients with AF on the basis of patient preference , estimated bleeding risk if
anticoagulated , and access to high quality anticoagulation monitoring. For high risk patients
with AF deemed unsuitable for anticoagulation, dual-antiplatelet therapy with clopidogrel
and aspirin offers more protection against stroke than aspirin alone but with an increased risk
of major bleeding and might be reasonable ( Furie LK, 2012 )

Prevention of Stroke in Patients With a History of Stroke or TIA

For patients with ischemic stroke or TIA with paroxysmal (intermittent) or permanent
AF, anticoagulation with vitamin K antagonist (target INR, 2.5; range, 2.0-3.0) is
recommended For patients unable to take oral anticoagulants, aspirin alone is recommended.
The combination of clopidogrel plus aspirin carries a risk of bleeding similar to that of
warfarin and therefore is not recommended for patients with a hemorrhagic contra indication
to warfarin (Furie LK, 2012)
The existing AHA recommendations the use of dabigatran reported that Dabigatran is useful
as an alternative to warfarin for the prevention of stroke and systemic thromboembolism in
patients with paroxysmal to permanent AF and risk factors for stroke or systemic
embolization who do not have a prosthetic heart valve or haemodynamically significant valve
disease, severe renal failure (CrCl < 15 mL/min), or advanced liver disease (impaired
baseline clotting function) .

New oral anticoagulants

Warfarin has a slow onset of action with variable dose requirements that are due in
part to genetic variability which are involved in the metabolism of warfarin ( Ansell JH,2008
) . Fluctuations in dietary intake of vitamin K, alcohol and several drug-drug interactions
further contribute to the anticoagulant effect of warfarin. Consequently despite close
monitoring of INR, this ratio is frequently outside the therapeutic range. This limitation has
prompted the development and assessment of several new oral anticoagulants (Alberts MJ
2012).

Dabigatran
Dabigatran is a new oral direct thrombin inhibitor with two doses (110 mg twice daily
or 150 mg twice daily) was compared with warfarin (target INR 2.0-3.0) in the RE-LY
(Randomized Evaluation of Long term anticoagulant therapy) trial. Exclude patients with
poor renal function (creatinine clearance of <30 ml/min), active liver disease or a stroke
within 14 days or were considered at high risk for bleeding ( Connolly,2009 ). The lower
dose of dabigatran was non inferior to warfarin in reducing the stroke rate or systemic
embolism (p<0.001 for non inferiority) and the higher dose was superior (p<0.001 for
superiority). The higher dose also significantly reduced the rate of ischaemic stroke compared
with warfarin. Both doses of dabigatran significantly reduce major bleeding compared with
warfarin in patients younger than 75 years, however in elderly the lower dose was associated
with a similar rate and the higher dose with an increased rate of major bleeding. Both doses
of dabigatran significantly reduce haemorrhagic stroke and intracerebral haemorrhage
compared with warfarin. Dabigatran has a higher rates of dyspepsia than did warfarin
presumably related to tartaric acid content of the dabigatran etexilate capsule.

Rivaroxaban
The oral direct acting factor Xa inhibitor was compared with warfarin in the
ROCKET-AF (Rivaroxaban Once Daily oral direct factor Xa inhibition compared with
vitamin K antagonist [target INR 2.0-3.0] for prevention of Stroke and Embolism Trial in
Atrial Fibrillation) ( Patel MR et al,2011). The population study here were at high risk of
stroke, 55% patients had a previous stroke or TIA, and 90% had either a previous stroke/TIA,
or three or more risk factors for stroke. Rivaroxaban was non inferior to warfarin for the
prevention of stroke or systemic embolism in the primary per protocol, on treatment analysis
(p<0.001 for non inferiority), but was not better than warfarin according to the intention to
treat analysis (p=0.117 for superiority). The rates of major and clinically relevant non major
bleeding were similar with rivaroxaban and warfarin, however rivaroxaban was associated
with lower rates of intracranial haemorrhage and fatal bleeding but higher rates of major
gastrointestinal bleeding .
Apixaban
The ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic
Events in Atrial Fibrillation) trial compared apixaban with warfarin (INR 2.0-3.0). Patients
with impaired renal function ( serum creatinine >2.5 mg/dl or creatinin clearance <25
mL/min ) were excluded . Patients who were already 80 years or older , had low body weight
(60 kg or lighter) or a serum creatinin of 1.5 mg/dl or greater received a lower dose of
apixaban (2.5 mg twice a day) than did other patients (5 mg twice a day). Apixaban was
better than warfarin in reducing the rate of stroke or systemic embolism (p=0.01 for
superiority) (Granger CB, 2011). Apixaban was also associated with significantly less major
bleeding (p<0.001), less intracranial hemorrhage (p<0.001) and lower mortality.The
occurence of gastrointestinal haemorrhage and myocardial infarction was similar in both
groups.

New Recommendations
Warfarin, dabigatran ,apixaban and rivaroxaban with different level of evidence are all
indicated for the prevention of first and recurrent stroke in patients with nonvalvular AF.Still
there are no published data directly comparing dabigatran, rivaroxaban, and apixaban to one
another, only comparisons to warfarin with the limited follow-up duration of the trials.
Because of their short half-lives, patients who are noncompliant and miss medication doses
might be at risk for thrombembolism. Treatment decisions should account for differences in
costs to patients, which could also affect compliance. The transition from warfarin must be
managed carefully and may constitute a period of increased risk. It is not known whether
patients receiving these agents but otherwise eligible for thrombolysis can be treated safely
with a thrombolytic agent (ie, iv r-tPA) for an acute ischemic stroke. There are no antidotes to
emergently reverse dabigatran, apixaban or rivaroxaban in the setting of hemorrhage.
The selection of an antithrombotic agent should be individualized on the basis of risk
factors, cost, tolerability, patient preference, potential for drug interactions, and other clinical
characteristics, including time in INR therapeutic range if the patients has been taking
warfarin. Dabigatran 150 mg twice daily is an efficacious alternative to warfarin for the
prevention of first and recurrent stroke in patients with nonvalvular AF and at least 1
additional risk factor who have CrCl > 30 mL/min. On the basis of pharmacokinetic data, the
use of dabigatran 75 mg twice daily in patients with AF and at least 1 additional risk factor
who have a low CrCl (15-30 mL/min) may be considered, but its safety and efficacy have not
been established . Because there are no data to support the use of dabigatran in patients with
more severe renal failure, dabigatran is not recommended in patients with a CrCl < 15
mL/min.
Apixaban 5 mg twice daily is an efficacious alternative to aspirin in patients with
nonvalvular AF deemed unsuitable for vitamin K antagonist therapy who have at least 1
additional risk factor and no more than 1 of the following characteristics: age 80 years,
weight 60 kg, or serum creatinine 1.5 mg/dL. Although its safety and efficacy have not
been established, apixaban 2.5 mg twice daily may be considered as an alternative to aspirin
in patients with nonvalvular AF deemed unsuitable for vitamin K antagonist therapy who
have at least 1 additional risk factor and 2 of the following criteria: age 80 years, weight
60 kg, or serum creatinine 1.5 mg/dL .
In patients with nonvalvular AF who are at moderate to high risk of stroke (prior
history of TIA, stroke, or systemic embolization or 2 additional risk factors), rivaroxaban
20 mg/d is reasonable as an alternative to warfarin. In patients with renal impairment and
nonvalvular AF who are at moderate to high risk of stroke (prior history of TIA, stroke, or
systemic embolization or 2 additional risk factors), with a CrCl of 15 to 50 mL/min, 15 mg
of rivaroxaban daily may be considered; however, its safety and efficacy have not been
established and rivaroxaban should not be used if the CrCl is < 15mL/min. The safety and
efficacy of combining dabigatran, rivaroxaban, or apixaban with an antiplatelet agent have
not been established (Furie KL, 2012).

References

Alberts MJ. Antithrombotic therapy for stroke prevention in non-valvular atrial fibrillation.
Lancet Neurol 2012;11:1066-81
Ansell J et al. for the American College of Chest Physicians. Pharmacology and management
of the vitamin K antagonists: American College of Chest Physicians evidence-based
clinical practice guideline (8th edn). Chest 2008;133 (suppl):1605-985
Baruch L, Gage BF, Harrow J, et al. C. Can patients at elevated risk of stroke treated with
anticoagulants be further risk stratified? Stroke 2007; 38: 2459-63.
Camm AJ et al, for the European Heart Rhythm Association and European Association for
Cardiothoracic Surgery, Guidelines for the management of atrial fibrillation: the Task
Force for the Management of Atrial Fibrillation of the European Society of
Cardiology (ESC). Eur Heart J 2010;31:2369-29
Choudhury A, Lip GY. Atrial fibrillation and the hypercoagulable state: from basic science to
clinical practice. Pathophysiol Haemost Thromb 2003-2004; 33: 282-89.
Connolly SJ et al. for the RE-LY Steering Committee and Investigators. Dabigatran versus
warfarin in patient with atrial fibrillation. N Engl J Med 2009;361:1139-51
Conway DS, Lip GY. Comparison of outcomes of patients with symptomatic peripheral
artery disease with and without atrial fibrillation (the West Birmingham Atrial
Fibrillation Project). Am J Cardiol 2004; 93: 1422-25.
Fihn SD, McDonell M, Martin D, et al. risk factors for complications of chronic
anticoagulation. A multicenter study. Warfarin Optimised Outpatient Follow-up Study
Group. Ann Intern Med 1993; 118: 511-20.
Flaker GC, Belew K, Beckman K, et al, for the AFFIRM Investigators, Asymtomatic atrial
fibrillation: demographic features and prognostic information from the atrial
fibrillation follow-up investigation of rhythm management (AFFIRM) study. Am
Heart J 2005; 149: 657-63.
Friberg. Net clinical benefit of warfarin in patients with atrial fibrillation: a report from the
Swedish atrial fibrillation cohort study. Circulation 2012;125:2298-307
Furie KL et al. Oral antithrombotic agents for the prevention of stroke in nonvalvular atrial
fibrillation. Stroke 2012;43:00-00.
Gage BF, Walraven CV, Pearce L, et al. Selecting patients with atrial fibrillation for
anticoagulation. Stroke risk stratification in patients taking aspirin. Circulation 2004;
110: 2287-92.
Go AS, Hylek EM, Philips KA, Henault LE, Selby JV, Singer DE, Prevalence of diagnosed
atrial fibrillation in adults. National implications for rhythm management and stroke
prevention: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA)
Study. JAMA 2001; 285: 2370-75.
Goldman ME, Pearce LA, Hart RG et al. Pathophysiologic correlates of thromboembolism in
non-valvular atrial fibrillation: reduced flow velocity in the left atrial appendage. J
Am Coll Cardiol 1998; 31: 1622-26.
Granger CB,et al, for the ARISTOTLE Committees and Investigators. Apixaban versus
warfarin in patients with atrial fibrillation. N Eng J Med 2011;365:981-92.
Heeringa J, van der Kuip DAM, Hofman A, et al. Prevalence, incidence and lifetime risk of
atrial fibrillation: the Rotterdam Study. Eur Heart J 2006; 27: 949-53.
Lip GY. The prothrombotic state in atrial fibrillation: the atrium, the endothelium and tissue
factor? Thromb Res 2003; 111: 133-5.
Lip GY. Coronary artery disease and ischemic stroke in atrial fibrillation. Chest 2007; 132:
8-10
Lip GY, Andreotti F, Fauchier L et al. Bleeding risk assessment and management in atrial
fibrillation patients: a position document from the European Heart Rhythm
association endorsed by the European Society of Cardiology Working Group on
Thrombosis . Europace 2011;13:723-46
Marini C, De Santis F. Sacco S, et al. Contribution of atrial fibrillation to incidence and
outcome of ischaemic stroke. Results from a population study. Stroke 2005; 36: 1115-
19.
Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in
Olmsted County Minnesota, 1980 to 2000, and implications on the projections for
future prevalence. Circulation 2006; 114: 119-25.
Pasty BM, Manolio TA, Kuller LH, et al. Incidence of and risk factors for atrial fibrillation in
older adults. Circulation 1997; 96: 2455-61.
Patel MR et al, for the ROCKET AF investigators. Rivaroxaban versus warfarin in
nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91.
Pisters R et al. A novel user friendly score (HAS-BLED) to assess one-year risk of major
bleeding in atrial fibrillation patients: the Euro Heart Survey. Chest 2010;138:1093-
100
Stewart S., Murphy N, Walker A, McGuire A, McMurray JJV, Cost of an emerging epidemic
and economic analysis of atrial fibrillation in the UK, Heart 2004; 90: 286-92.
Stroke Risk in Atrial Fibrillation Working Group. Independent predictors of stroke in patients
with atrial fibrillation: a systematic review. Neurology 2007; 69: 546-54.
Wolf PA, Abbott RD, Kannel WB, Atrial fibrillation as an independent risk factor for stroke
the Framingham Study. Stroke 1991; 22: 983-88.
Wolf PA, Mitchell JB, Baker CS, Kannel WB, dAgostino RB, Impact of Atrial fibrillation
on mortality, stroke, and medical costs. Arch Intern Med 1998; 158: 229-34.