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58
CHAPTER 4 Cerebrovascular Disease
a 3.5 percent absolute risk reduction in cardiovascular events over 5 years in
patients with a recent TIA or stroke.
53
There are data showing that statins
reduce infl ammation (independent of LDL levels), which may be a factor in
stabilizing atherosclerotic plaques.
54
Aggressive treatment of diabetes mellitus
with tight control of blood sugar has generally not shown striking reductions in
stroke and other large-vessel ischemic events.
46,47
A variety of antiplatelet agents (aspirin, clopidogrel, aspirin combined with
extended-release dipyridamole) have all shown benefi t for the secondary pre-
vention of stroke and other vascular events.
55,56
The benefi t of these agents
is likely related to reducing the formation of a thrombus on an atheroscle-
rotic plaque. Compared to placebo, most antiplatelet agents show relative risk
reductions in the 15 to 37 percent range for the prevention of recurrent stroke.
When these agents are compared to aspirin, the risk reductions are more mod-
est, in the 9 to 15 percent range.
55
In the setting of cerebrovascular disease, the use of monotherapy antiplate-
let regimens appears to be as effi cacious as dual antiplatelet therapies. Studies
such as MATCH, CHARISMA, and PRoFESS (among others) showed that the
effi cacy of monotherapy with clopidogrel or ASA was equal to the benefi ts
of combination therapy (see Table 4.6 for details).
57–59
The recent SPS3 study
showed the same pattern for patients with lacunar strokes: patients treated
with ASA alone had outcomes equal to those treated with ASA and clopi-
dogrel.
60
A new antiplatelet agent, vorapaxar, showed a similar pattern of lack
of benefi t with combination therapy in a stroke population.
61
All of these studies showed lower rates of cerebral and systemic hemor-
rhage with monotherapy compared with dual antiplatelet therapy. Overall, dual
antiplatelet therapy (for patients with symptomatic cerebrovascular disease)
increases the relative risk of serious cerebral and systemic hemorrhage by
40 percent or more.
52
There are several ongoing studies that are evaluating the
use of short term (typically 3 months) dual antiplatelet theapy for secondary
stroke prevention, in an attempt to achieve greater effi cacy and safety. The use
of anticoagulants for secondary prevention of atherothrombotic strokes has
Table 4.5 Benefi ts of Risk Factor Control for Secondary
Stroke Prevention
Risk Factor Relative Risk
Reduction
Comment
Hypertension 24–25% Applies to a variety of medications
Hyperlipidemia 16–21% Mostly based on statin therapy
Diabetes
(type 1 and 2)
0–47% Most studies showed no major treatment
effect.
Smoking No data Most studies were for primary prevention.
Alcohol abuse No data Most studies were for primary prevention.
Obesity No data
Exercise 27% Unclear how many patients had initial strokes
Relative risk reduction based on recurrent stroke
Data based on references 6 and 52.
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CHAPTER 4 Cerebrovascular Disease
been evaluated in several studies such as ESPRIT and WARSS. These studies
did not fi nd any benefi t for anticoagulation compared to antiplatelet therapy,
although anticoagulation was associated with a higher rate of hemorrhages.
Antiplatelet therapy should be continued for many years, since studies have
shown that cessation of such therapy is associated with an increased risk of isch-
emic cardiovascular events.
62,63
It is common for such therapy to be discontinued
around the time of an invasive procedure, but there is no clear scientifi c rationale
for holding therapy for more than 5 days (for anticoagulants) before surgery. For
antiplatelet therapy, new recommendations suggest continuing such therapy up to
the time of surgery in most cases.
64
Often, however, the therapy is not restarted
for many weeks or not at all, leading to a high risk of a recurrent ischemic event.
Anticoagulants are very effective for the primary or secondary prevention of
cardioembolic strokes, particularly in the setting of atrial fi brillation. There are
several novel anticoagulant classes, such as direct thrombin inhibitors and anti-
Factor Xa agents, that are as effective as—if not more effective than—warfarin
for primary or secondary stroke prevention in the setting of atrial fi brillation.
These agents generally do not require dose adjustments, have few food and
drug interactions, and do not require routine monitoring of their anticoagulant
effects. They all appear to be safer than warfarin in terms of producing fewer
cerebral hemorrhages, although the rate of gastrointestinal bleeds (particularly
among the elderly) may be higher than with warfarin.
65
While there is inter-
est in testing these new agents for secondary prevention of atherothrombotic
stroke, there are no large studies with data to guide or support such therapy.
Table 4.6 Major Studies of Dual Antiplatelet Therapy for
Ischemic Cerebrovascular Disease
Study Name Medications Year Outcomes Comment
MATCH Clopidogrel
vs. ASA +
Clopidogrel
2004 Equal effi cacy;
2x more major
bleeds with dual Rx
Included high-risk
TIA, stroke
patients
PRoFESS Clopidogrel
vs. ASA +
ER-dipyridamole
2008 Equal effi cacy; 15%
increase in major
bleeds with dual Rx
No difference
in composite of
stroke/MI/vascular
death
SPS3 ASA vs. ASA +
clopidogrel
2012 Equal effi cacy; 2x
more bleeds with
dual Rx
Focused on
lacunar strokes
CHARISMA* ASA vs. ASA +
clopidogrel
2006 Slight benefi t
in secondary
prevention group;
more moderate
bleeding with
dual Rx
Symptomatic
stroke subgroup
showed benefi t
with dual Rx.
TIMI-50* Standard therapy
+ placebo or
Vorapaxar
2012 No benefi t in
stroke patients;
66% increase in
bleeds with dual Rx
Most of bleeding
seen in stroke
group
* Study enrolled patients with a variety of ischemic atherothrombotic diseases, including stroke.
Data derived from references 56–60.
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CHAPTER 4 Cerebrovascular Disease
The benefi ts of carotid endarterectomy (CEA) and carotid artery stenting
(CAS) are roughly equivalent in patients with symptomatic carotid athero-
thrombotic disease, especially if the degree of stenosis exceeds 70 percent.
CEA has the advantage of physically removing the plaque, and recurrence is
quite rare (less than 7 percent) over the next 7 to 10 years. CAS is associ-
ated with slightly higher rates of periprocedural stroke than is CEA (4.1 versus
2.3 percent) and over the next 4 years (10 versus 8 percent).
66
The rate of recurrent stenosis was about 6 percent for either CEA or CAS
at 2 years for patients in the CREST study.
67
However, the European EVA-3S
study reported rates of restenosis (of at least 50 percent) of 12.5 percent after
CAS versus 5 percent after CEA 2 years after the procedure.
68
Patients in the
CAVAATAS study who had endovascular therapy (mainly angioplasty) also had
higher rates of restenosis compared to those treated with CEA.
69
Long-term
studies after CEA found rates of restenosis of only 5 percent in the operated
artery.
70
A global registry found the 2-year outcomes (stroke or death) to be
equal between CEA and CAS.
71
CAS appears to be a safe and durable treat-
ment for patients with restenosis after CEA, especially since some surgeons are
reluctant to re-operate on a carotid artery due to scarring
72
Acute therapies for ischemic stroke are generally limited to reperfusion
strategies, general supportive measures, and prevention of peri-stroke compli-
cations. The most commonly used and successful is intravenous recombinant
tissue plasminogen activator (IV-rtPA), which was approved by the U.S. Food
and Drug Administration (FDA) in 1996 after the landmark 1995 NINDS TPA
study.
73
This therapy, when used within 3 hours of symptom onset, is associated
with a 12 to 13 percent absolute increase in the number of patients who are
neurologically normal at 3 months compared to placebo. Higher percentages of
patients have a reduction in neurological defi cits, although they did not return
to normal. The main risk of this therapy is cerebral hemorrhage, which occurs
in 4 to 6 percent of treated patients. A large European study, ECASS III, showed
evidence of benefi t up to 4.5 hours after symptom onset.
74
Although the FDA
did not approve IV-rtPA up to 4.5 hours, it is still commonly used in the United
States and in other parts of the world up to that time limit.
Summary
Atherothrombosis is the most common disease process causing ischemic
stroke. While there are many well-described risk factors for atherothrombosis
and stroke, we still do not fully understand all of the factors that underlie its
pathogenesis and progression. Aggressive risk factor control has the potential
to reduce the burden of stroke, although this potential remains largely unful-
fi lled. The safety and effi cacy of medical, surgical, and endovascular approaches
for the primary prevention of ischemic strokes is more challenging to prove
compared to secondary prevention, which is unfortunate since the majority
of ischemic strokes are fi rst-time events. While it is encouraging that several
approaches to secondary stroke prevention appear effi cacious, such therapies
are often under-utilized in many cases and populations. Nonetheless, it is clear
that the best way to treat stroke is to prevent the stroke.
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CHAPTER 4 Cerebrovascular Disease
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Chapter 5
Atrial Fibrillation
Yousif Ahmad and Gregory Y. H. Lip
Introduction
The global burden of atrial fi brillation (AF) is growing: it is already the most
common arrhythmia encountered worldwide,
1
and estimates suggest that
16 million people in the United States will be affected by 2050.
2
This trend is
unlikely to be reversed, especially with the ongoing advances in the treatment
of other chronic cardiac disorders that predispose to AF. AF leads to a hyper-
coagulable state; coupled with stasis in the left atrium, this places patients at a
substantial risk of thromboembolic disease. The most severe manifestation of
this is stroke: AF-related strokes are associated with higher mortality, greater
levels of dependence, and longer stays in the hospital.
3
The majority of throm-
botic complications of AF could be avoided with effective anticoagulation.
Traditionally the only therapeutic option in this context has been vitamin K
antagonists (i.e., warfarin); despite its effi cacy, there has been global underuse
of warfarin.
4
This situation can probably be attributed to the multiple pharma-
cological limitations of warfarin, making it an inconvenient therapy for both
clinicians and patients. A combination of these factors has stimulated a period
of intensive research and unparalleled advances in the sphere of stroke preven-
tion in AF. This has produced information that provides clinicians with a deeper
understanding of the risk of stroke in AF; a clutch of new anticoagulant agents
proven to be safe and effective thromboprophylaxis in AF; and the potential for
the role of upstream therapies in this disorder.
AF and thrombotic risk
It is well established that AF is a risk factor for stroke and thromboembolism,
increasing the risk of stroke fi vefold.
5
Stasis of blood in the dilated left atrium
is an important contributory cause, but evidence now suggests that throm-
bogenesis in AF is multifactorial and that these factors combine to cause a
hypercoagulable state.
6
Similarly, the pathogenesis of atherothrombosis is also
multifactorial,
7
and there are shared mechanisms of thrombogenesis in AF and
atherothrombosis. Commonalities in the pathogenesis of thrombus in AF and
atherothrombosis include infl ammation, endothelial dysfunction, and activation
of the renin-angiotensin-aldosterone system.
8
Furthermore, there is also sig-
nifi cant overlap in comorbid risk factors for both AF and atherothrombosis—
including advancing age and hypertension.
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CHAPTER 5 Atrial Fibrillation
The risk of stroke in AF is not homogenous and is dependent on the cumula-
tive risk associated with the presence of various stroke risk factors.
9
The CHADS
2
risk stratifi cation scheme
10
incorporated some common stroke risk factors into a
simple scoring system that classifi ed patients at “high,” “intermediate,” or “low”
risk for stroke. Guidelines recommended anticoagulation for high-risk patients,
aspirin for low-risk patients, and a choice of either for those at intermediate risk.
This method of risk scoring had several limitations: evidence suggests aspirin is not
effective in low-risk patients
11
; a large grouping of patients were in the gray area
of “intermediate risk”
12
; and warfarin has been shown to be superior for patients
identifi ed by CHADS
2
as being at intermediate risk.
13
An interplay of these factors
means that sole use of CHADS
2
as a tool to inform the prescription of thrombo-
prophylaxis could potentially see a large proportion of AF patients undertreated
with aspirin.
14
This resulted in the development of the CHA
2
DS
2
VASc score,
15
which includes common stroke risk factors omitted from CHADS
2
. This score
has been included in international guidelines
16
following validation that has con-
fi rmed it is superior to CHADS
2
,
17
particularly for identifying the truly low-risk
patients who do not require any antithrombotic therapy.
To complement this CHA
2
DS
2
VASc score, the HAS-BLED score
18
is a simple
tool to facilitate assessment of bleeding risk. This risk score can be periodically
reassessed and prompts clinicians to consider correctable risk factors such as
poorly controlled hypertension and concomitant drugs. Following validation in
a large real-world cohort
19
and demonstration of its good performance against
other more cumbersome bleeding risk scores,
20
HAS-BLED has been incor-
porated into international guidelines.
16
It is important for clinicians to remem-
ber that a high HAS-BLED score is not a contraindication to anticoagulation;
indeed, bleeding risk tracks stroke risk owing to the many common risk factors
they share. The net clinical benefi t of warfarin is therefore actually greater
21
at
higher HAS-BLED scores and is only negative at a CHA
2
DS
2
VASc score of 0.
Antithrombotic therapy
Having established risk factors that identify the small number of truly low-risk
patients who do not require antithrombotic therapy, clinicians’ next priority
should be to provide their patients with appropriate thromboprophylaxis to
protect against stroke.
Compared with placebo, warfarin reduces ischemic stroke by 64 percent
and mortality by 26 percent.
22
Warfarin was also proved to reduce stroke when
compared to aspirin,
23
and the results of these trials led to an increase in the
use of warfarin and a decrease in the number of strokes.
24
Despite its proven
effi cacy, there has been reluctance on the part of both clinicians and patients
to fully adopt this therapy.
4
Furthermore, the effi cacy of warfarin is dependent
on a high time in therapeutic range (TTR).
25
Patients are at risk of both bleeding
and thrombotic complications when they are outside of therapeutic range, and
a low TTR can obviate the benefi ts of warfarin.
26
Self-monitoring can improve
TTR toward the values achieved in clinical trials.
Renewed efforts to establish antiplatelet therapy as a viable alternative to
warfarin culminated in the ACTIVE-W trial, which compared dual antiplatelet
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67
CHAPTER 5 Atrial Fibrillation
therapy with aspirin and clopidogrel to warfarin for the prevention of stroke
and systemic embolism in AF.
27
The trial was stopped early due to warfarin’s
signifi cant superiority in the prevention of thromboembolic complications and
the equivalent rates of bleeding in the two groups. Antiplatelet therapy is,
therefore, an inferior option for thromboprophylaxis in AF and carries its own
substantial hemorrhagic risk. A further arm of this study, ACTIVE-A, compared
dual antiplatelet therapy with aspirin and clopidogrel to treatment with aspirin
alone
28
in patients considered unsuitable for VKAs. This trial demonstrated that
the addition of clopidogrel was associated with a reduction in stroke (RR 0.72;
95 percent CI 0.6–0.83; p < 0.001) but also an increased risk of major bleeding
(RR 1.57; 95 percent CI 1.29–1.92; p < 0.001).
New oral anticoagulants
The well-documented limitations of warfarin
29
have spurred the search for new
alternative therapies, resulting in the development of a group of new oral anti-
coagulants.
30
The two major classes are direct thrombin inhibitors (dabigatran)
and Factor Xa inhibitors (rivaroxaban and apixaban) (Table 5.1).
Dabigatran
Following the withdrawal of ximelegatran due to issues with hepatotoxicity,
dabigatran was the fi rst available direct thrombin inhibitor. It was compared to
warfarin in the landmark RE-LY trial,
31
which demonstrated the safety and effi -
cacy of two different dosages of dabigatran (110 mg and 150 mg, twice daily)
(Table 5.2). High-dose dabigatran was found to be superior to warfarin for
Table 5.1 Pharmacological Properties of the New Anticoagulants
Mechanism
of action
Direct thrombin
inhibitor
Direct Factor Xa
inhibitor
Direct Factor
Xa inhibitor
Pro-drug Double pro-drug No No
Dosing
frequency
Twice daily Once daily Twice daily
Bioavailability
(%)
6.5 50 80
T
max
2 hours 2–4 hours 3 hours
Half-life 17 hours with multiple
doses, 7–9 hours with
single doses
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 Affects pharmacokinetic
parameters
No No
Drug
interactions
Interactions with
dronedarone and
ketoconazole; increased
bleeding with aspirin at
high doses (300 mg)
None reported None reported
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