Download Stroke: Effective Strategies for Secondary Prevention

Stroke: Effective Strategies for Secondary
Prevention
Louis Caplan, MD and Howard Kirshner, MD
Louis Caplan, MD, is Chief of the Division of Cerebrovascular Diseases at Beth Israel Deaconess
Medical Center, and Professor of Neurology at Harvard Medical School, Boston.
Howard Kirshner, MD, is Professor and Vice Chair of Neurology at Vanderbilt University Medical Center,
Nashville.
Stroke remains the third leading cause of death in the United States, and evidence
suggests that available and proven effective methods for its diagnosis, prevention, and
treatment are underused. Most strokes are preventable and primary prevention
strategies aimed at reducing modifiable risk factors and identifying treatable
conditions, such as atrial fibrillation, remain paramount. Education of high-risk patients
with respect to stroke warning signs is also essential. Urgency is the focus in acute
ischemic stroke and adequate treatment of the first ischemic insult may have a
significant impact on reducing recurrence risk. Nevertheless, patients who have
experienced an ischemic stroke or transient ischemic attack remain at the highest risk
of stroke. Recent studies have revealed that the incidence of short-term stroke
recurrence is substantially higher than previously realized in these patients. Thus,
secondary prevention measures should be implemented as early and aggressively as
possible after the index event. In-hospital initiation of secondary prevention strategies
should be considered. Drugs such as statins, antihypertensives, antithrombotic agents,
and methods such as endarterectomy or stenting, can prevent a second stroke. In
particular, all patients who have experienced noncardioembolic stroke should be
placed on a regimen of antiplatelet agents, such as aspirin plus extended-release
dipyridamole.
INTRODUCTION
Stroke is the third leading cause of death in the United States and a major cause of disability. 1,2 Over
700,000 strokes occur each year, or slightly more than one per minute, and 70% of these are first
strokes.1,3,4 The financial burden created by stroke is high; direct (eg, hospital and physician care) and
indirect costs (eg, lost productivity) are estimated at $57 billion in 2005. 1
Enormous progress has been made in diagnostic technology and new therapeutic options for prevention
and treatment of stroke over the past 20 years, such as newer magnetic resonance imaging (MRI)
techniques, helical computed tomography (CT), duplex extracranial ultrasound, and newer and more
effective antiplatelet agents and antihypertensives. Despite this progress, recent evidence suggests that
mortality from stroke is no longer on the decline and the incidence of stroke is again on the rise. 3,5
These data suggest shortcomings in present methods for preventing and treating stroke or suboptimal
application of available treatments.6 Stroke prevention is not like a cure for cancer, awaiting a scientific
breakthrough but rather a matter of applying readily available, proven therapies to patients at risk.
Updating knowledge about recent diagnostic/therapeutic advances and appropriate use of these
advances may facilitate a more favorable prognosis for the future. While the main focus of this review is
on secondary stroke prevention, key considerations pertaining to primary stroke prevention will also be
addressed.
PRIMARY PREVENTION
Most strokes are preventable. The essence of primary prevention is reduction of as many modifiable risk
factors as possible and evaluation of potentially treatable lesions/conditions, such as carotid artery
disease and atrial fibrillation (AF).
Table 1 presents risk factors for ischemic stroke, stratified by strength of evidence and modifiability.
Patients who have had a prior transient ischemic attack (TIA) or ischemic stroke are at the highest risk
for stroke. In a relatively large cohort study, Johnston et al 7 reported that 180 of 1,707 patients (10.5%)
diagnosed with TIA in an emergency department returned with a stroke within a 90-day period. Stroke
occurred in 91 of these patients (5%) within 48 hours of the index TIA. For this reason, TIA should be
considered a medical emergency and immediate testing for preventable causes of stroke is advised.
PRIMARY PREVENTION GUIDELINES
A menu for risk factor modification in primary prevention is:
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Treat hypertension.
Correct dyslipidemia (diet, drug therapy).
Eliminate smoking.
Eliminate heavy alcohol use (moderate alcohol use may be protective against total and
ischemic stroke).8
Engage in an exercise program.
Detect and treat cardiac disease, including AF, which accounts for 15% of all strokes in the US. 9
Detect and treat asymptomatic carotid artery stenosis (consider endarterectomy). 3
Control diabetes mellitus.
Use aspirin to prevent a first MI in men10 and stroke in women.11
Recommendations of the American Heart Association (AHA) for primary prevention are available. 3
Effective management of hypertension alone can reduce stroke incidence by as much as 70%. 12 No
specific antihypertensive agent of choice has emerged, however, and ensuring control of blood pressure
may be more important than the specific class of antihypertensive agent used.
Table 1
Stroke Risk Factors and Their Modifiability*1-3,7,12
Nonmodifiable
Age: Advancing; doubles in each decade after age 55
Gender: More prevalent in men; however, rate of stroke-related case fatality higher in
women
Race/Ethnicity: African-Americans/Hispanics have higher risk/mortality rates than do whites
Heredity: Maternal and paternal history may increase risk; fivefold increase in stroke
prevalence in monozygotic vs dizygotic twins
Modifiable, well-documented
Prior TIA/stroke
Cardiac disease
Hypertension
Atrial fibrillation
Diabetes mellitus
Asymptomatic carotid stenosis
Cigarette smoking
Sickle cell disease
Dyslipidemia
Potentially modifiable/Less well-documented
Alcohol abuse
Hypercoagulability
Drug abuse
HRT/Oral contraceptives
Obesity
Inflammatory processes
Poor nutrition
Stress (?)
Physical inactivity
Sleep apnea (?)
Hyperhomocysteinemia
TIA, transient ischemic attack; HRT, hormone replacement therapy.
* Well-documented and modifiable risk factors are supported by good epidemiologic data and modifiability
in randomized clinical trials. Modifiable and/or less well-documented risk factors likely increase stroke risk
but usually apply to small groups in the population; in some cases, modifiability has not been clearly
demonstrated.
Recent studies have demonstrated reduction in ischemic stroke/TIA risk in survivors of MI with HMGCoA reductase inhibitors (statins).3,13,14
Pravastatin and simvastatin are approved for stroke reduction after MI. In general, statins are indicated
for primary stroke prevention in selected patients with high low-density lipoprotein cholesterol (LDL-C)
levels following MI and in patients in whom vascular studies identify atherosclerotic plaques within large
arteries.2,15,16 New guidelines proposed by the National Cholesterol Education Program (NCEP) are that
LDL-C levels be reduced to less than 100 mg/dL (2.6 mmol/L) in high-risk patients; in very high-risk
patients less than 70 mg/dL (1.8 mmol/L) should be considered. 15,16 Aggressive LDL-C reduction has
been shown to decrease atherosclerosis progression in both carotid and coronary arteries.16
In patients with asymptomatic carotid artery stenosis, carotid endarterectomy is generally
recommended if there is greater than 60% and less than 100% carotid stenosis. The Asymptomatic
Carotid Atherosclerosis Study (ACAS) compared carotid endarterectomy plus medical therapy with
medical therapy alone in patients with high-grade stenosis (> 60% diameter reduction). The study was
stopped after median follow-up of 2.7 years because of the benefit of surgery. The estimated five-year
aggregate risk for ipsilateral stroke, any perioperative stroke, or death was 5% in surgical patients and
11% in medical patients (53% relative risk reduction [RRR]). 17 This amounts to an absolute risk reduction
of approximately one case per 100 cases operated per year, and the operative morbidity and mortality of
2.4% should be taken into account before recommending surgery to asymptomatic patients.
Carotid artery stenting with an embolus protection device has recently been used effectively as a less
invasive approach for patients with asymptomatic or symptomatic carotid artery stenosis (see Secondary
Prevention of Ischemic Stroke).
Ischemic stroke in patients with AF is mainly due to cardiac (cardiogenic) embolism, and patients with AF
have at least a four- to fivefold higher risk of stroke.9,18,19 Nonvalvular AF is the most common cause of
cardiac emboli.19 AF is one of the few indications for warfarin in stroke patients. Five placebo-controlled
primary prevention trials have evaluated the efficacy of warfarin to prevent acute ischemic stroke (AIS) in
AF.3,9 Collectively, these trials showed that warfarin reduced annual ischemic stroke rates from 3.0% to
7.4% (control) to 0.4% to 3.4%; the relative risk of thromboembolic stroke was reduced by 68%.
Although either aspirin or warfarin is recommended in AF by the AHA, based on risk factors and age,
warfarin is more effective and preferred. Studies comparing aspirin with control groups indicated an RRR
of 21% with aspirin. Comparisons of aspirin and warfarin demonstrated a significantly greater RRR with
warfarin.9
CHADS2 risk scores represent an alternative to AHA recommendations for evaluating AF patients. 20-22 An
acronym derived from the risk factors of Congestive heart failure, Hypertension, Age greater than 75,
Diabetes mellitus, and prior Stroke or transient ischemic attack, CHADS2 can reliably estimate the risk of
stroke at the bedside and may assist in the selection of antithrombotic therapy. Two points are assigned
for prior stroke or TIA, with one point given to the other risk factors (Figure 1). Patients with no points can
be managed with aspirin, those with more than three points should receive warfarin, and those with one
to two points can be managed at the clinician’s discretion. The CHADS 2 scheme has been validated in
1,733 Medicare beneficiaries with nonvalvular AF who were not receiving warfarin upon hospital
discharge.20 These guidelines bear similarity to those provided in AHA guidelines. 3 For secondary
prevention, warfarin is indicated over aspirin in AF patients. 23
Figure 1: CHADS2 Score Risk Stratification Scheme for AF 20,21
Relationship between CHADS2 score and annual risk of stroke.
ASA, aspirin.
Post-MI: Aspirin is recommended to prevent a second MI but is not routinely recommended for primary
stroke prevention following MI.2 Warfarin is recommended after MI if other conditions are also present,
such as AF, left ventricular thrombi, or significant left ventricular dysfunction. 2
STROKE WARNING SIGNS—AN OVERLOOKED PROBLEM
Most patients who are having a stroke, and most bystanders witnessing the event, are unaware of initial
stroke symptoms.24 Studies have also shown that those at highest risk of stroke, including AfricanAmericans, the elderly (older than 75), and men, have the least knowledge about stroke warning signs
and risk factors.1 Time is paramount for stroke victims, and lack of awareness of warning signs can delay
potentially life-saving treatment. Greater education of the general public is needed; most importantly,
clinicians must inform high-risk patients and their families of warning signs and risk factors. A warning
sign refresher is found in the sidebar.25
URGENCY
In the setting of AIS, catchphrases “time is brain” and “stroke is a brain attack” should be on the minds of
all clinicians and should be conveyed to patients. Patients at high risk or who have had prior TIA or
stroke and their immediate family members should be urged to call 911 and not their doctor or HMO.
Reminders for clinicians in the emergency setting of AIS include: triage to hospital with stroke team;
ABCs (airway, breathing, circulation); early consultation with a neurologist or stroke team; emergency CT
or MRI of the brain; and thrombolytic therapy.23,24,26 The only thrombolytic currently approved by the FDA
for acute stroke is rt-PA (alteplase). Early and effective treatment of an acute stroke may significantly
reduce the risk of recurrence.
Standard management of the AIS patient should incorporate:
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For IV fluids, use of normal saline, not dextrose 5% in water.
Avoidance of hyperthermia; treatment of fever.
Swallowing assessment.
Oxygen saturation (pulse oximetry).
Electrolytes, renal and liver function tests, coagulation tests, blood glucose, complete blood
count.
Additional diagnostic imaging.
Secondary stroke prevention.
Deep vein thrombosis prophylaxis.
SECONDARY PREVENTION OF ISCHEMIC STROKE
Many essential ingredients of secondary prevention are similar to those of primary prevention. A
therapeutic checklist for secondary prevention is:
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Treat hypertension.
Treat dyslipidemia with HMG-CoA reductase inhibitors (statins).
Antithrombotic agents (Table 2).
Endarterectomy or stenting for symptomatic carotid artery stenosis.
Modify all other known risk factors (eg, screen for diabetes mellitus).
Encourage smoking cessation.
In the study by Johnston et al mentioned earlier, 5% of patients diagnosed with TIA in an emergency
department returned within 48 hours with a stroke.7 Data from this study and another study in patients
with minor stroke27 suggest that the early risk of a subsequent stroke is much higher than previously
thought. Patients who have already had stroke or TIA also represent the group that is at highest risk of a
recurrent cerebrovascular event. These combined data emphasize the need for early and aggressive
secondary prevention strategies. The stroke Preventing Recurrence of Thromboembolic Events through
Coordinated Treatment (PROTECT) program implements eight evidence-based drug/behavioral
secondary prevention measures during the hospitalization of patients who have had an ischemic stroke
or TIA. High adherence rates have been observed post–hospital discharge for all measures, including
therapy with statins, antithrombotics, and antihypertensives. 25
The inpatient setting is ideal for initiation of secondary prevention and should be considered. Not taking
advantage of this opportunity may significantly delay implementation of secondary prevention measures
during the early postevent period, where they are needed most. In-hospital immediate secondary
prevention appears safe and at least potentially capable of improving 90-day adherence rates. It might
also enhance compliance with national guidelines for treating patients at high-risk for vascular events.25
Stroke warning-sign education or re-education should be an important component of a secondary
prevention program (sidebar).
Patient Education Refresher: Early Warning Signs of Stroke25
Sudden numbness/weakness of face or extremities
Sudden confusion or trouble speaking
Sudden trouble seeing
Sudden trouble walking or dizziness
Sudden severe headache
ANTIHYPERTENSIVES
Data on the use of antihypertensives in patients following stroke or TIA are limited compared with
primary prevention, in part because potential deleterious effects of acute blood pressure lowering in
ischemic stroke have raised concerns about the use of antihypertensive agents at all in these
patients.28,29
However, results of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) assured
that reducing blood pressure in ischemic-stroke patients is beneficial and that benefits were actually
greater with more aggressive blood pressure lowering. 29,30 PROGRESS (N = 6,105) evaluated the
angiotensin-converting enzyme (ACE) inhibitor perindopril 4 mg per day with or without indapamide
versus placebo in hypertensive and nonhypertensive patients with a history of recent stroke or TIA.
Stroke occurred in 10% and 14% of those given active treatment and placebo, respectively, a significant
difference (RRR 28%). The risk of total major vascular events was also significantly reduced by active
treatment (26%). Patients receiving the combination of perindopril plus indapamide experienced greater
risk reductions for stroke and major vascular events than those given perindopril alone.30
Table 2
Recommendations for Use of Antithrombotic Agents in the Secondary
Prevention of Stroke. From the Seventh American College of Chest
Physicians (ACCP) Conference on Antithrombotic and Thrombolytic
Therapy23*
Prevention of:
Recommendations/Evidence-Based Guideline Rating:†
Cerebral ischemic events in
patients with
noncardioembolic
stroke or TIA
(atherothrombotic,
lacunar, or cryptogenic):
antiplatelet agents
1. Antiplatelet therapy recommended for all patients (1A)
2. Aspirin 50–325 mg/day, clopidogrel 75 mg/day, or the
combination of aspirin 25
mg and ER dipyridamole 200 mg bid are all acceptable
options for initial therapy
3. Aspirin plus ER dipyridamole 25–200 mg bid suggested
over aspirin alone (2A);
clopidogrel suggested over aspirin (2B)
4. Low-dose aspirin (50–100 mg/day) suggested in patients
at moderate to high risk of
bleeding (1C+)
5. Clopidogrel recommended in patients allergic to aspirin
(1C+)
Cerebral ischemic events in
patients with
noncardioembolic
stroke or TIA: oral
anticoagulants
1. Antiplatelet agents recommended over oral anticoagulation
for most patients (1A)
2. For well-documented prothrombotic disorders, oral
anticoagulation recommended
over antiplatelet agents (2C)
Cerebral ischemic events in
patients undergoing carotid
endarterectomy: antiplatelet
agents
Aspirin 81–325 mg/day recommended before and following
the procedure (1A)
Cardioembolic cerebral
ischemic events in patients
with
prior stroke or TIA and
underlying atrial fibrillation
1. Long-term anticoagulation recommended (target INR 2.5)
(1A)
Aspirin 81–325 mg/day recommended before and following
the procedure (1A)
2. Aspirin is recommended in patients with contraindications
to oral anticoagulants
(1A)
Cardioembolic cerebral
ischemic events in patients
with stroke associated with
aortic atherosclerotic lesions
Antiplatelet therapy is recommended over no therapy (1C+)
Cardioembolic cerebral
ischemic events
Either oral anticoagulants or antiplatelet agents
recommended (2C)
Cardioembolic cerebral
ischemic events in patients
with cryptogenic ischemic
stroke
and a patent foramen ovale
Antiplatelet therapy recommended over no therapy (1C+) and
antiplatelet agents
suggested over anticoagulation (2A)
Cardioembolic cerebral
ischemic
events in patients with mitral
valve strands or prolapse
who
have history of TIA or stroke
Antiplatelet therapy recommended (1C+)
* Copyright Lippincott Williams & Wilkins 2001. Used with permission.
† For a review of this specific grading system, see Guyatt G, Schunemann HJ, Cook D, et al. Applying the
grades of recommendation for antithrombotic and thrombolytic therapy: the Seventh ACCP Conference on
Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 suppl):179S-187S.
The Morbidity and Mortality After Stroke— Eprosartan Versus Nitrendipine for Secondary Prevention
(MOSES) study recently announced initial results in patients with a history of ischemic stroke and
hypertension (N = 1,400). Anti-hypertensive efficacy was similar with the calcium-channel blocking agent
and the angiotensin receptor blocker (ARB) eprosartan. However, eprosartan protected against
cerebrovascular and cardiovascular events, suggesting benefits above protection via blood pressure
control.31
In evaluation of Acute Candesartan Cilexetil Evaluation in Stroke Survivors (ACCESS), a phase II study,
patients with ischemic stroke were randomized to the ARB candesartan or placebo as soon as possible
after recognition of symptoms (average 30 hours). Blood pressure was similar in the two groups
throughout one year of follow-up. There was also no difference in outcome at three months of treatment,
but a significant benefit of candesartan was seen at one year, as evidenced by reduced mortality (2.9%
vs 7.2%) and vascular events (9.8% vs 18.7%), including recurrent stroke. 32 These benefits were not
seen when candesartan was initiated seven days after stroke onset, underscoring the need for early and
aggressive secondary prevention.
Findings similar to the above studies were observed in some primary prevention trials, such as the
Losartan Intervention For Endpoint (LIFE) reduction study33 and the Heart Outcomes Prevention
Evaluation (HOPE) trial.34 Although mainly a primary prevention study, the HOPE trial (N = 9,297)
included a broad range of high-risk patients; about 11% had had a prior TIA or stroke. The ACE inhibitor
ramipril reduced the rates of MI, stroke, and vascular death; stroke was reduced from 4.9% to 3.4%.
Other studies and clinical data also suggest that beneficial effects of ACE inhibitors or ARBs in
secondary and primary stroke prevention are independent of blood pressure reduction; ie, effects on the
renin-angiotensin-aldosterone system.28,31,35 Evidence is somewhat stronger for ARBs.31 The specific
efficacy of these agents in secondary prevention remains to be confirmed by ongoing clinical trials, such
as the Prevention Regimen For Effectively avoiding Second Strokes (PRoFESS) trial. 31 In the meantime,
use of an ACE inhibitor or ARB, with or without a diuretic, would seem to be a rational choice in the
secondary prevention setting. However, effective blood pressure control should be the primary goal for
all patients with prior cerebrovascular events,29 regardless of the specific class of antihypertensive agent
used.
STATINS
Statins have not been evaluated extensively for secondary prevention and specific guidelines are
unavailable. However, statins are justified and indicated in patients with atherosclerotic ischemic
stroke.36,37 The NCEP Adult Treatment Panel III (ATP III) recommends optimal LDL-C lowering in
coronary heart disease risk equivalents (< 100 mg/dL or 2.6 mmol/L) and atherosclerotic symptomatic
carotid artery disease is considered a coronary heart disease risk equivalent by ATP III.15 Aggressive
LDL-C reduction has been shown to decrease atherosclerosis progression in both carotid and coronary
arteries.16
In the Heart Protection Study,38 simvastatin 40 mg per day was compared with placebo in high-risk
patients, which included those with coronary disease, other occlusive arterial disease, or diabetes
mellitus (N = 20,536). Approximately 9% of the initial population had suffered TIA or stroke. Simvastatin
was shown to reduce the occurrence of first stroke (fatal, nonfatal), from 5.7% to 4.3% (RRR 25%),
regardless of initial LDL-C level. The subgroup of patients with prior TIA or stroke also benefited from
simvastatin therapy. The FDA has approved simvastatin 40 mg per day for secondary stroke prevention.
More definitive guidelines regarding statins for secondary stroke prevention will emerge from the Stroke
Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study, which is assessing the
efficacy of atorvastatin versus placebo in patients with prior stroke or TIA. The primary endpoint is fatal
or nonfatal stroke.36
ANTITHROMBOTIC AGENTS
Refresher: Vascular Pathology39,40
The goals of antithrombotic therapy are to prevent formation of new thrombi and to prevent propagation
and embolization of thrombi already present. Thrombus formation is dependent upon the interplay of
many factors, including the number of circulating platelets and their activation and local vascular injury or
roughening. White clots (platelets and fibrin) can form on abnormal or roughened surface areas of
systemic arteries, characteristically in fast-moving bloodstreams, whereas red clots (erythrocyte-fibrin
thrombi) tend to form in areas of low flow or stagnation.
Antithrombotic agents for secondary prevention may be classified as antiplatelet agents and
anticoagulants. In general terms, antiplatelet agents prevent adhesion, activation, and/or aggregation of
white platelet clots. Anticoagulant agents, such as warfarin, heparin, and heparinoids, and direct
thrombin inhibitors (eg, hirudin, ximelagatran) prevent formation of red clots.
ACCP guidelines for the use of antithrombotic agents for secondary prevention are found in Table 2.
Antiplatelet Agents
Aspirin inhibits platelet aggregation via irreversible inhibition of platelet cyclooxygenase; however, it has
minimal effect on other pathways of platelet activation. 26
Noncardioembolic stroke prevention: Aspirin is moderately effective for preventing stroke after
noncardioembolic ischemic stroke or TIA (RRR 20% to 25%). 23,41,42 In large controlled studies such as the
Dutch TIA Trial, the UK-TIA trial, and Swedish Aspirin Low-dose Trial (SALT), low doses (30–325
mg/day) were about as effective as high doses (up to 1,300 mg/day).23 The UK-TIA trial, for example,
found similar efficacy with 325 mg and 1,300 mg.
Cardioembolic stroke prevention: In stroke or TIA patients with high-risk sources of cardiac embolism
(mainly AF), aspirin has been evaluated in only one secondary prevention trial, European Atrial
Fibrillation Trial (EAFT).43 In this study, 1,007 nonvalvular AF patients with recent TIA or stroke were
assigned to either open oral anticoagulation (international normalized ratio [INR] 2.5–4.0) or double-blind
treatment with aspirin 300 mg per day or placebo. With a mean follow-up of 2.3 years, the RRR was 16%
for stroke with aspirin 300 mg per day relative to placebo but this difference failed to reach statistical
significance. In contrast, oral anticoagulation was highly effective and more effective than aspirin,
reducing stroke incidence from 12% to 4% per year. Based on aspirin data from primary prevention trials
(RRR 21%), the ACCP recommends aspirin in patients with contraindications to warfarin.23
Cilostazol: This quinoline derivative is somewhat unique in that it has putative platelet anti-adhesion,
vasodilator, antimitogenic, and cardiotonic activity; beneficial effects on serum lipids have been
observed.26 In a secondary prevention trial in patients with stroke within the prior one to six months (N =
1,052), cilostazol 100 mg bid was significantly more effective than placebo in reducing the risk of
recurrent stroke (RRR 41.7%). Similar results were achieved on intention-to-treat analysis (RRR 42.3%).
No significant adverse effects were reported.44 Cilostazol is not generally recognized for its antiplatelet
activity in the US but it is used for symptomatic relief of peripheral vascular disease.
Clopidogrel: This thienopyridine derivative inhibits adenosine diphosphate-induced binding of fibrinogen
to platelets.26 It has been slightly but significantly more effective than aspirin for secondary prevention.
Clopidogrel versus aspirin: In the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events
(CAPRIE) study (N = 19,185),45 patients with prior ischemic stroke, MI, or peripheral arterial disease were
randomized to clopidogrel 75 mg per day or aspirin 325 mg per day for one to three years. The endpoint
was stroke, MI, or vascular death, and the annual endpoint risk was 5.32% in the clopidogrel group and
5.83% in the aspirin group (RRR 8.7% for clopidogrel). Safety was similar.
Clopidogrel plus aspirin: In the Management of Atherothrombosis with Clopidogrel in High-risk patients
(MATCH) study (N = 7,599),46 aspirin 75 mg per day or placebo was added to clopidogrel 75 mg per day
for 1.5 years in high-risk patients with recent ischemic stroke or TIA plus one additional vascular risk
factor (Table 3). The primary endpoint was a composite of ischemic stroke, MI, vascular death, or
rehospitalization for an ischemic event, and analysis was by intention to treat. The endpoint was reached
in 16.7% on clopidogrel alone and 15.7% on clopidogrel plus aspirin (nonsignificant). Lifethreatening/major bleeding was greater with the combination (3% vs 1%). Mortality did not differ between
groups.
Clopidogrel plus aspirin versus warfarin: The large Atrial fibrillation Clopidogrel Trials with Irbesartan for
prevention of Vascular Events (ACTIVE) are designed to compare aspirin plus clopidogrel versus
warfarin, clopidogrel plus aspirin versus aspirin, and irbesartan versus placebo for prevention of stroke,
MI, or vascular death in high-risk AF patients.47 However, the aspirin plus clopidogrel versus warfarin
portion of this trial was recently halted due to the high incidence of stroke in the clopidogrel/aspirin group.
The other studies are ongoing.
Dipyridamole: This coronary vasodilator inhibits platelet aggregation and also has effects on the
vascular endothelium. In placebo-controlled studies, the combination of dipyridamole plus aspirin
reduced composite stroke, MI, or vascular death by about 30%; extended-release (ER) dipyridamole plus
aspirin reduced recurrent stroke by about 37%.23,42
The second European Stroke Prevention Study (ESPS-2) (N = 6,602),42
involving patients with prior stroke or TIA, found that the combination of aspirin and ER dipyridamole was
superior to either agent given singly. Stroke was reduced by 37% with aspirin 25 mg plus ER
dipyridamole 200 mg bid, 18% with aspirin alone 25 mg bid, and 16% with ER dipyridamole alone 200
mg bid (Figure 2). The comparison between ER dipyridamole plus aspirin versus aspirin alone showed a
RRR of 23%.
Ticlopidine: The mechanism of action of ticlopi-dine is similar to that of clopidogrel. In secondary
prevention studies, such as the Ticlopidine Aspirin Stroke Study (TASS), the drug has shown efficacy in
reducing the risk of stroke and other vascular outcomes.23,26 However, adverse effects of ticlopidine,
including severe neutropenia and thrombotic thrombocytopenic purpura, have limited its use.
Table 3
MATCH Outcomes
Number (%) With Event
Aspirin +
Placebo +
Clopidogrel Clopidogrel
(N = 3,797) (N = 3,802)
Risk Reduction
Absolute
(95% CI)
Relative
(95% CI)
P
(Log-Rank
Test)
Primary Outcome
596 (16%)
636 (17%)
1.0%
6.4%
(-0.6 – 2.7) (-4.6 – 16.3)
0.244
Ischemic Stroke (All)
309 (8%)
333 (9%)
0.62%
7.1%
(-0.6 – 1.9) (-8.5 – 20.4)
0.353
Life-Threatening
Bleeding
96 (3%)
49 (1%)
All-Cause Mortality
201 (5%)
201 (5%)
Difference between groups = 1.26 (CI
0.64 – 1.88); Pearson’s ?2 test: P <.001
-0.01%
0.1%
(-1.0 – 1.0) (-21.5 – 17.8)
0.992
Summary of antiplatelet efficacy and recommendations: According to ACCP guidelines, aspirin,
clopidogrel, or aspirin plus ER dipyridamole are all acceptable options for initial therapy of
noncardioembolic stroke or TIA. Aspirin/ER dipyridamole and clopidogrel are more efficacious than
aspirin alone. The use of aspirin with clopidogrel offers no benefit over clopidogrel alone and causes
more bleeding. For secondary prevention of stroke in patients with AF, warfarin is indicated (below), with
aspirin reserved for patients with contraindications to anticoagulant therapy.
Anticoagulants
Warfarin has limited application in stroke. It is highly effective for both primary and secondary prevention
in patients with AF.23,43 Warfarin is also favored in patients with prosthetic heart valves, low ejection
fraction cardiomyopathy, and hypercoagulable states, though most of these indications have not been
confirmed by randomized clinical trials. Warfarin is indicated for three to six months in cerebral venous
sinus thrombosis following initial heparin therapy.23 Warfarin may also be indicated in patients with
dissections of the vertebral or carotid arteries, though no randomized trials have been carried out.
In the Warfarin-Aspirin Recurrent Stroke Study (WARSS) (N = 2,206), patients with previous
noncardioembolic stroke were randomized to warfarin (INR 1.4–2.8) or aspirin 325 mg per day. No
significant difference in the incidence of recurrent ischemic stroke was observed over a two-year period,
although there was a slight trend favoring aspirin (Figure 3). Overall, the primary combined endpoint of
death from any cause or recurrent stroke occurred in 16% and 17.8% of patients in the aspirin and
warfarin groups, respectively. The incidence of major hemorrhage was similar in each group; however,
minor hemorrhages were significantly more frequent in those receiving warfarin. 48 Warfarin is not
indicated for patients with ischemic stroke, without the above mechanisms.
Figure 2: ESPS-2: Effects on Stroke
ESPS-2: second European Stroke Prevention Study; RRR, relative risk reduction;
ASA, aspirin; ER-DP, extended-release dipyridamole.
The Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial included patients with TIA or stroke
caused by 50% to 99% intracranial artery stenosis. There was no benefit of warfarin (INR 2.0–3.0) over
aspirin 1.3 g per day. A significantly higher rate of adverse events was seen with warfarin. 49 Aspirin is
preferred in this setting, although combination antiplatelet regimens have not been evaluated.
Figure 3: Warfarin-Aspirin Recurrent Stroke Study (WARSS)
Direct thrombin inhibitors include parenteral hirudin and argatroban (indicated for heparin-induced
thrombocytopenia) and parenteral bivalirudin (indicated as a heparin substitute during coronary
angioplasty).26 Ximelagatran is an orally administered direct thrombin inhibitor that gained attention for
stroke prevention because of the simplicity of its use. Unfortunately, the drug has not been approved
because of hepatotoxicity. Other direct thrombin inhibitors are under development.
CAROTID ENDARTERECTOMY/STENTING
Results of the North American Symptomatic Carotid Endarterectomy Trial (NASCET)50,51 showed that
carotid endarterectomy significantly reduced stroke in patients with symptomatic carotid stenosis of
greater than 70%, whereas lesser benefit was seen in patients with moderate stenosis of 50% to 69%;
there was no benefit in those with stenosis of less than 50%. The European Carotid Surgery Trial
(ECST)52 showed similar benefit with greater than 70% stenosis but no benefit in moderate stenosis. In
patients with prior TIA or nondisabling stroke, endarterectomy is generally recommended only for those
with high-grade stenosis (70% to 99%).12
In NASCET, cumulative risks of ipsilateral stroke after two years in patients with high-grade stenosis
were 9% in patients who underwent endarterectomy and 26% in those receiving medical care only. The
absolute risk reduction with endarterectomy was 17%.50 Patients 75 or older in NASCET with 70% to
99% stenosis benefited more from carotid endarterectomy than did younger patients (risk reduction 29%
vs 15% in those 65 to 74 and 10% in youngest group).53
Carotid-artery stenting using an embolus-protection device is an effective alternative in patients with
either asymptomatic or symptomatic carotid artery stenosis who are deemed unsafe for endarterectomy
due to coexistent cardiac or cerebrovascular “high risk” conditions. The Stenting and Angioplasty with
Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial found that stenting (nitinol
stents) with an embolus-protection device (AngioGuard™) in such patients was not inferior to carotid
endarterectomy. The study included patients with asymptomatic stenosis of 80% or greater and those
with symptomatic stenosis of at least 50%. The primary composite endpoint of death, stroke, or MI within
one month postintervention was 39% less frequent in the stenting group.54 Protected stenting should be
considered over endarterectomy in symptomatic, high-risk surgical patients.
The ongoing Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) is comparing
carotid endarterectomy and carotid artery stenting in patients with symptomatic stenosis of 50% or
greater.55
CONCLUSION
Prevention still trumps treatment and modification of risk factors remains paramount in the prevention of
a first stroke, including control of hypertension, dyslipidemia, AF, and asymptomatic carotid artery
stenosis, and cessation of smoking. In hypertension, control of blood pressure may be more important
than the class of agent used. Secondary prevention after stroke or TIA has occurred should be initiated
as early as possible and should incorporate the use of statins, antihypertensives, anticoagulants or
antiplatelet therapy, carotid endarterectomy/stenting in selected patients, and continued modification of
other known risk factors. All noncardioembolic stroke patients should be placed on antiplatelet agents,
such as aspirin, aspirin plus ER dipyridamole, or clopidogrel. There is no benefit from adding aspirin to
clopidogrel in high-risk patients post-TIA or ischemic stroke. Warfarin is indicated for both primary and
secondary prevention in patients with AF. TS
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