Download Backgrounder: The Risk of Stroke in Atrial Fibrillation

Backgrounder: The Risk of Stroke in Atrial Fibrillation (AF)
What is Atrial Fibrillation (AF)?
Atrial fibrillation, or AF, is the most common type of arrhythmia, a problem with the rate
or rhythm of the heartbeat. During an arrhythmia, the heart can beat too fast, too slow,
or with an irregular rhythm. AF occurs if rapid, disorganised electrical signals cause the
heart's two upper chambers, the atria, to fibrillate.1
In atrial fibrillation, the heart does not contract as strongly as it should. This can cause
blood to pool in the heart and form clots. When the blood clots dislodge, they may
move to the brain, where they can become trapped in a narrow brain artery, blocking
the blood flow and causing a stroke. Research suggests that over 90 percent of blood
clots responsible for stroke in patients with AF originate in a pouch on the left side of
the heart called left atrial appendage (LAA).2
Atrial fibrillation may be brief, with symptoms that come and go and it is possible to
have an AF episode that resolves on its own. However, AF may be persistent and
require treatment. Sometimes AF is permanent, and medications or other treatments
cannot restore a normal heart rhythm.
Risk factors for AF include3:
 Hemodynamic stress (i.e. heart
failure or hypertension)
 Atrial ischemia
 Inflammation
 Non-cardiovascular respiratory
causes




Alcohol and drug use
Endocrine disorders (i.e.
diabetes)
Neurologic disorders
Genetic factors/Advancing age
Prevalence and death rates
Atrial Fibrillation affects approximately one to two percent of the general population
worldwide4. Over six million Europeans suffer from this arrhythmia, and its prevalence
is estimated to at least double in the next 50 years as the population ages. AF affects
around 800,000 people a year in the UK5.
AF is strongly age-dependent, affecting four percent of individuals older than 60 years
and eight percent of persons older than 80 years. The Framingham study, a long-term,
ongoing cardiovascular trial showed that approximately 25 percent of male and female
individuals aged 40 years and older will develop AF during their lifetime.6
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AF in itself is an independent contributor to mortality, morbidity and impaired quality of
life.7, 8 The disease is associated with a 1.5- to 1.9-fold higher risk of death, which is in
part due to the strong association between AF and thromboembolic events, according
to data from the Framingham heart study.9
The global burden of Atrial Fibrillation (AF)
Atrial fibrillation is an increasing burden on the global healthcare system because of the
numbers of patients affected, the impact of stroke, and the cost of both inpatient and
outpatient therapy.10
Atrial fibrillation is associated with significant economic costs from the perspective of
statutory health insurance, with the largest part of costs attributable to inpatient stays
and drug usage.11 Several studies that have estimated the economic burden of AF
have identified direct costs and hospitalisations as major cost drivers. In the UK and in
Germany, hospital admissions have been found to represent 44 to 50 percent of direct
costs and in France hospitalisations have been found to represent 60 percent of direct
costs among patients with AF.12, 13, 14, 15
What is stroke?
A stroke is a vascular event in the brain that causes abnormal neurological function
lasting for more than 24 hours. The World Health Organisation (WHO) defines stroke
as a clinical syndrome which consists of rapidly developing clinical signs of focal (or at
some times global) disturbances of cerebral function. Symptoms last 24 hours or longer
and can lead to death with no apparent cause other than of vascular origin.16 The most
common symptom of a stroke is sudden weakness or numbness of the face, arm or
leg, most often on one side of the body. Other symptoms include confusion, difficulty
speaking or understanding speech, difficulty seeing with one or both eyes, difficulty
walking, dizziness, loss of balance or coordination, severe headache with no known
cause, fainting or unconsciousness.
Stroke can be caused either by a clot obstructing the flow of blood to the brain, an
ischemic stroke, or by a blood vessel rupturing and preventing blood flow to the brain, a
haemorrhagic stroke. A transient ischemic attack (TIA) is caused by a temporary clot
and related symptoms will go away completely within 24 hours. People who have a TIA
are very likely to have a stroke in the near future.
Prevalence of stroke and death rates
According to the WHO, stroke is the most common cardiovascular disorder after heart
disease and affects 15 million people worldwide each year. The WHO estimates that
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stroke is the number two cause of death worldwide; of the 15 million people who suffer
a stroke annually, five million die and another five million are permanently disabled.
About one million first strokes occur each year in the European Union (EU) and
approximately 25 percent of men and 20 percent of women can expect to suffer a
stroke if they live to be 85 years old.17 The total number of stroke deaths in 48 European
countries is currently estimated at 1,239,000 per year.18
AF-related stroke risk
AF is a major risk factor for stroke, making a person with AF five times more likely to
suffer from it in comparison to the general population.19, 20 Overall, AF is estimated to be
responsible for approximately 15 percent of all strokes21, 22, 23 and for 20 percent of all
ischemic strokes.24 As the population ages, the global burden of AF-related stroke will
continue to increase.
The prevalence of stroke in AF patients older than 70 years doubles with each decade.25
Furthermore, AF-related strokes are associated with poorer outcomes than non-AFrelated strokes. This increased severity of strokes in patients with AF is thought to be
related to the large size of the clots that will block a larger-sized intracranial artery
depriving a larger territory of the brain of blood flow. 26 They are generally linked to
higher levels of morbidity and cause higher inpatient costs than other forms of stroke.27, 28
The global burden of stroke
Stroke presents a major public health challenge, with a high case fatality and a large
proportion of survivors dependent on nursing and other types of care.29 The financial
burden of stroke in the European Union was €38 billion in 2006, accounting for two to
three percent of total healthcare expenditure in the EU.30 The average medical cost
alone of stroke per patient with AF has been calculated to approximately €12.000.31
This cost is set to increase dramatically as the size of the aging population continues to
rise.
Reducing the risk of stroke in Atrial Fibrillation (AF)
Management of AF patients is aimed at reducing symptoms and the risk of severe
complications associated with AF such as stroke. The cornerstone stroke risk reduction
in AF patients is oral anticoagulation therapy, with warfarin as a gold standard. In
addition, non-pharmacological approaches such as closing off the left atrial appendage
(LAA) offer treatment alternatives, e.g. for patients with non-valvular AF who require
treatment for potential thrombus formation in the LAA and LAA and have a contraindication to anticoagulant therapy. These one-time procedures offer a permanent
solution for AF patients and eliminate the need for lifelong oral anticoagulation therapy.
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Treatment Guidelines
To assess the right course of treatment in AF-related stroke prophylaxis, there are
several sets of international, European and country-specific guidelines, and various
methods exist to categorise stroke risk. The simplest risk assessment scheme is the
CHADS2 score, which is based on a point system where two points are assigned for a
history of stroke or TIA and one point each is assigned for age, >75 years, a history of
hypertension, diabetes, or recent cardiac failure. Treatment recommendations are
based on a patient’s CHADS2 score.
In addition, the 2010 European Society of Cardiology (ESC) guidelines for the
management of AF also refer to the CHA2DS2-VASc score.32 It includes additional, nonmajor stroke risk factors such as age (65 to 74 years), female gender and vascular
disease and complements the previous scoring system.33 It also puts extra weight on
age “>75 years” as a major risk factor.
In order to reduce risk of AF-related strokes, the European Society of Cardiology (ESC)
recommends the initiation of anticoagulation therapy. When this therapy is appropriately
used and monitored, it is highly effective, lowering stroke risk by about two thirds.34
However, current data indicates that the management of AF is still sub-optimal, with
many of those receiving anticoagulation not consistently in the optimal therapeutic
range.35 Also, a large percentage are not at all prescribed OACs, with most of them
being over 80 years old36. In August 2012, the European Society of Cardiology (ESC)
announced the inclusion of LAA closure devices like WATCHMAN™ in the revised
“Guidelines for Management of Patients with Atrial Fibrillation”. The new Guidelines
recommend LAA closure as a class IIb, level of evidence b, for patients with a high
stroke risk and contraindications for long-term oral anticoagulation, based on existing
clinical evidence such as the PROTECT AF trial. 37 Previous versions of the guidelines
had already suggested that occlusion of the LAA may reduce stroke in AF patients.38
Anticoagulation therapy
The goal of anticoagulant therapy is to administer the lowest possible dose of
anticoagulant to reduce the risk of clot formation or expansion. Anticoagulation therapy
with warfarin (Coumadin™) is widely considered the standard of care for stroke
prophylaxis in patients with AF who are at high risk of stroke.39
However, the therapeutic effect of warfarin is highly unpredictable and can change due
to a variety of factors, such as changes in diet or concomitant medications. As a result,
safe and effective utilisation of chronic warfarin therapy requires frequent monitoring.40
The International Normalised Ratio (INR) measures the time it takes for blood to clot
and compares it to an average, an important step for ensuring optimised anticoagulation
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therapy. Warfarin has a narrow therapeutic window, making it easy to over- or underdose patients, which can lead to complications, mainly bleeding.41 The FDA’s Adverse
Event Reporting System indicated that warfarin is among the top 10 drugs with the
largest number of serious adverse event reports submitted during the 1990 and 2000
decades42.
Recent developments in the area of oral anticoagulants
During the last years, new oral anticoagulants have entered the market. Such
anticoagulants can be used as an alternative to warfarin to aim at stroke prevention in
AF patients:
 Dabigatran – In the RE-LY trial, this first-to-market new oral anticoagulant
showed the higher 150-mg twice-daily dose to be superior to warfarin, reducing
stroke/peripheral embolic events by 34 percent and the risk of haemorrhagic
stroke by 74 percent, with comparable major bleeding rates. The lower 110-mg
dabigatran dose was non-inferior to warfarin in terms of efficacy, with a 20
percent reduction in major bleeding.43
 Rivaroxaban – The ROCKET AF trial, reported at the 2010 American Heart
Association (AHA) Scientific Sessions, rivaroxaban 20 mg once daily was
shown non-inferior to warfarin in reducing all-cause stroke and non-central
nervous system (CNS) embolism in AF patients, with a similar rate of major
bleeding.44
 Apixaban – The ARISTOTLE study showed that in patients with atrial fibrillation,
apixaban was superior to warfarin in preventing stroke or systemic embolism,
caused less bleeding, and resulted in lower mortality.45
While oral anticoagulants that are on the market, awaiting approval or under research
offer benefits over warfarin, additional data are necessary before conclusions can be
drawn on the potential for these new anticoagulant drugs to replace warfarin in patients
with AF.46 In particular, patient treatment adherence and bleeding risk continue to
remain major challenges of stroke risk reduction in AF patients.
LAA Closure for AF-related stroke risk reduction
Research shows that in over 90 percent of patients with non-valvular atrial fibrillation
the stroke-causing blood clots are developed in the left atrial appendage (LAA).
Currently, these patients, being at high risk of stroke, are treated with warfarin or other
anticoagulant drugs. However, by closing off the source of blood clot formation, the risk
of stroke may be reduced and could eliminate the need for long-term OAC therapy.47, 48
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LAA closure is a minimally-invasive procedure that usually only lasts about an hour and
presents a permanent therapy option for stroke prophylaxis in patients with non-valvular
AF, who require treatment for potential thrombus.
In the first large-scale randomised trial, PROTECT AF, LAA closure with the WATCHMAN™
device was proven to be an alternative to warfarin. The trial demonstrated the therapeutic
non-inferiority of LAA closure as an alternative to long-term warfarin in reducing the risk
of stroke in non-valvular AF patients with a CHADS2 score ≥1.49 A second landmark
study – the ASAP (Aspirin And Plavix®) registry – a non-randomised, prospective,
multi-centre feasibility study showed a 77 percent reduction of ischemic stroke risk in
high risk patients with AF who are contraindicated to warfarin. This wealth of existing
data for WATCHMAN™ led to approval of expanded use of the device in Europe in
August 2012, offering a treatment alternative to patients with AF, both indicated and
contraindicated to anticoagulation therapy. This expands the benefits of the therapy to
a wider population and especially those at higher risk than others.50, 51, 52
Currently, only two LAA closure devices have CE mark, including WATCHMAN™, with
others currently still being in clinical trials.
Additional Information
European Society of Cardiology, www.escardio.org
American Heart Association, www.heart.org
American College of Cardiology, www.cardiosource.org
Media Contact
Mark McIntyre
Public Affairs
Boston Scientific
Mobile: + 44 77 17300167
[email protected]
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