You are on page 1of 9

Journal of the American College of Cardiology Vol. 56, No.

9, 2010
© 2010 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00
Published by Elsevier Inc. doi:10.1016/j.jacc.2009.12.072

STATE-OF-THE-ART PAPER

Stroke Prevention and Treatment


James D. Marsh, MD,* Salah G. Keyrouz, MD†
Little Rock, Arkansas

The decline in stroke incidence and mortality in the U.S. over the past 20 years is reaching a plateau, and the
number of strokes may actually start to increase as the population ages. However, recent clinical trials have
demonstrated that there are numerous opportunities to improve stroke prevention strategies and also opportuni-
ties to effectively intervene in and treat acute strokes. For patients with diabetes and for those with prior strokes
or transient ischemic attacks, it has become evident that aggressive low-density lipoprotein lowering with statin
medications will decrease the risk for total and fatal strokes. Optimal anticoagulation and antiplatelet therapy
for primary and secondary stroke prevention in atrial fibrillation is being carefully defined. With numerous novel
factor Xa and direct thrombin inhibitor drugs completing phase III clinical trials, it is likely that additional oral
anticoagulant drugs will be clinically available for stroke prevention soon. Additionally, a major clinical trial is
nearing completion that may resolve the role of carotid stenting and carotid endarterectomy in primary and sec-
ondary stroke prevention. There are recent notable advances in the acute treatment of stroke. It is likely that the
time window for thrombolysis for appropriate patients with strokes will be increased from 3 to 4.5 h, permitting
the inclusion of more patients in this treatment approach. There is ongoing investigation of intra-arterial throm-
bolysis and of acute intra-arterial thrombus extraction for treatment of selected patients with strokes. Unlike the
progress in treatment of ischemic strokes, treatment of hemorrhagic stroke is progressing more slowly. (J Am
Coll Cardiol 2010;56:683–91) © 2010 by the American College of Cardiology Foundation

Stroke Prevention disease, and about 36% remained cryptogenic (no definite
cause identified) (Fig. 2). Stroke subtype is somewhat
Cerebrovascular disease is the third leading cause of death in
the U.S. and the number 1 cause of long-term major dependent on ethnicity (3).
disability. It is estimated that there are 795,000 incident Atherosclerosis and stroke prevention. Atherosclerosis is
strokes in the U.S. each year, resulting in 1 of every 17 a systemic disease affecting the large and medium-sized
deaths in the U.S. due to stroke. There are more than 4.8 arteries of the entire systemic arterial tree. Therefore,
million stroke survivors alive today (1). Although there was measures to prevent atherosclerosis systemically will affect
a 60% decline in stroke mortality over the 29-year period risk for both ischemic stroke and ischemic heart disease.
between 1968 and 1996, the rate of decline began to slow in Risk factors for atherosclerosis and ischemic stroke include
the 1990s and has plateaued in several regions of the smoking, hypertension, diabetes, and elevated cholesterol.
country. There are major regional differences in stroke There is very compelling evidence from clinical trials of
incidence across the U.S. (Fig. 1) (1), with the persistence cholesterol lowering for ischemic heart disease indicating
over many decades of a high-incidence “stroke belt” cen- that risk for the first stroke is markedly diminished with
tered on southeastern and south central states. pharmacological lowering of low-density lipoprotein (LDL)
In considering stroke prevention, one must be aware that and total cholesterol (4). Statin therapy reduces LDL
the mechanisms of disease underlying the clinical stroke cholesterol level, with each 10% reduction in LDL choles-
syndrome are quite varied, and thus preventive measures terol estimated to decrease the risk for stroke by 15% (4).
must be tailored to the disease mechanism. Overall, 87% of For patients with established coronary artery disease, there
strokes are ischemic, 9% are due to intracerebral hemor- is now compelling evidence that statins reduce the risk for
rhage (ICH), and 4% are due to subarachnoid hemorrhage stroke compared with placebo (5,6). Reviewed elsewhere are
(2). Among all strokes in 1 series (3), about 19% were a host of additional trials of statin therapy for patients with
cardioembolic, 26% were lacunar, 15% were due to carotid established ischemic heart disease that demonstrated a
substantial decrease in stroke risk (7).
From the *Department of Internal Medicine, University of Arkansas for Medical
Diabetes is a major risk factor for stroke. An important
Sciences, Little Rock, Arkansas; and the †Department of Neurology, University of study, the CARDS (Collaborative Atorvastatin Diabetes
Arkansas for Medical Sciences, Little Rock, Arkansas. The authors have reported that Study), randomized patients with diabetes and 1 additional
they have no relationships to disclose.
Manuscript received September 24, 2009; revised manuscript received December 1, risk factor to placebo or atorvastatin. In this study of 2,838
2009, accepted December 7, 2009. patients, there was a dramatic 48% reduction in the relative
684 Marsh and Keyrouz JACC Vol. 56, No. 9, 2010
Stroke Prevention and Treatment August 24, 2010:683–91

Abbreviations risk for stroke for those on the


and Acronyms statin compared with placebo (8).
The benefit of statins for stroke
AF ⴝ atrial fibrillation
prevention in patients with dia-
CAS ⴝ carotid artery
stenting
betes is very clear. In 2006, the
American Heart Association rec-
CEA ⴝ carotid
endarterectomy
ommended that adults with dia-
CI ⴝ confidence interval
betes, particularly those with
other atherosclerosis risk factors,
FDA ⴝ Food and Drug
Administration
be treated with statins (9). The
optimal aggressiveness for glyce-
IA ⴝ intra-arterial
mic control remains controver-
ICH ⴝ intracerebral
hemorrhage
sial. Some recent evidence sug-
gests tight glycemic control in
INR ⴝ international
normalized ratio
patients with ischemic cardiovas-
IV ⴝ intravenous
cular disease actually worsens
outcomes (10), and other evi- Figure 2 Stroke Subtypes
LDL ⴝ low-density
lipoprotein
dence favors moderately aggres-
sive glycemic control. for fatal or nonfatal stroke (p ⫽ 0.03) and a 23% reduction
OR ⴝ odds ratio
The prevention of recurrent in risk for TIA or stroke (p ⫽ 0.001). There was also a
PFO ⴝ patent foramen
ovale
strokes has focused on the use of reduction in coronary events (hazard ratio: 0.58; p ⬍ 0.001)
antiplatelet therapy and blood in this population with no known ischemic heart disease at
TIA ⴝ transient ischemic
attack
pressure control; the role of LDL time of enrollment in the study. Thus, the evidence is
t-PA ⴝ tissue plasminogen
lowering for secondary stroke compelling that for secondary stroke prevention, high-dose
activator prevention had been unclear un- statin therapy with atorvastatin reduces the risk for recurrent
WRICH ⴝ warfarin-related
til recently. To address the im- stroke and TIA and also markedly decreases the risk for
intracerebral hemorrhage portant question of the potential acute coronary events. Low high-density lipoprotein is an
role of LDL lowering with statin independent risk factor for stroke, and recent evidence
therapy for secondary prevention indicates that adding a high-density lipoprotein–raising
after a stroke or transient ischemic attack (TIA), the drug (niacin) to a statin improves a surrogate measure
SPARCL (Stroke Prevention by Aggressive Reduction in (carotid intima-media thickness) for atherosclerotic disease
Cholesterol Levels) study was undertaken (11). In this (12).
study, 4,731 patients with prior strokes or TIAs, but no Carotid endarterectomy (CEA) and carotid artery stenting
evident ischemic heart disease and no atrial fibrillation (CAS). CEA. Two seminal studies, NASCET (North
(AF), were randomized to placebo or atorvastatin 80 mg/ American Symptomatic Carotid Endarterectomy Trial) and
day. During the median follow-up period of nearly 5 years, ECST (European Carotid Surgery Trial), examined the
there was a 16% risk reduction with atorvastatin treatment potential benefit of CEA in patients with symptomatic

Figure 1 Stroke Age-Adjusted Death Rates by State, 2005

Reprinted, with permission, from Lloyd-Jones et al. (1).


JACC Vol. 56, No. 9, 2010 Marsh and Keyrouz 685
August 24, 2010:683–91 Stroke Prevention and Treatment

carotid stenosis. For symptomatic subjects, CEA benefitted women and 4.2% for men (p ⫽ NS) (20). Until the results
those with 50% to 99% stenoses, reviewed by Chaturvedi et of CREST are available, there are insufficient data to make
al. (13). The landmark ACAS (Asymptomatic Carotid a firm judgment on the superiority of CEA compared with
Atherosclerosis Study) established that for patients with CAS, particularly which patient groups may benefit from 1
60% to 99% stenosis who could be operated on with very approach or the other.
low perioperative risk for stroke or death, CEA produced Cardioembolic strokes. AF. In patients with paroxysmal,
more favorable outcomes than best medical therapy (relative persistent, or permanent AF, anticoagulant and antiplatelet
risk reduction: 53%, p ⫽ 0.004). (14). Thus, the current therapy unequivocally decreases stroke risk. The SPAF
recommendation is that for symptomatic patients with a (Stroke Prevention in Atrial Fibrillation) study (21,22) and
⬎5-year life expectancy and 50% to 99% stenoses, CEA additional landmark studies have clearly established the
should be considered. Additionally, for asymptomatic pa- roles of warfarin and aspirin for stroke prevention (9). Over
tients with a ⬎5-year life expectancy and 60% to 99% 25 years of intense investigation, it has become evident that
stenosis, it is reasonable to consider CEA (13,15). Of note, there are low-, intermediate-, and high-risk groups for
there is good evidence that patients with more severe stroke in AF that can be categorized by the CHADS2 score
stenoses (but not subtotal or total occlusions) are more likely (23); antithrombotic therapy can be tailored to the risk
to benefit from CEA than those with less severe stenoses category, as reviewed by Fuster et al. (24). If there are no
(13,15). risk factors, the recommended therapy is aspirin 81 to 325
mg/day. Moderate-risk factors include age ⱖ75 years,
CAS. Recently completed and ongoing clinical trials are diabetes, hypertension, heart failure, and ejection fraction
comparing CAS with CEA for patients with symptomatic ⱕ35%. For 1 moderate-risk factor, the recommendation is
and asymptomatic carotid artery stenosis. At this time, there aspirin 81 to 325 mg/day or warfarin (target international
are major unanswered questions regarding the potential normalized ratio [INR] 2.0 to 3.0). For any high-risk factor
superiority of CAS compared with CEA for various patient (prior stroke or TIA) or more than 1 moderate-risk factor,
groups with regard to safety, efficacy, rate of recurrent warfarin (target INR 2.0 to 3.0) is recommended.
stenosis, and durability of clinical benefit. A recent trial The actual prevalence of paroxysmal AF in the U.S. is
studied high-risk patients (16). The investigators concluded unknown, but because of the aging population and higher
that CAS was not inferior to CEA. However, it has become incidence of AF in older patients, it is very likely that the
evident that the relative safety of CEA compared with CAS prevalence of paroxysmal AF is increasing. Moreover, con-
is critically dependent on the skill and qualifications of the temporary pacemakers and intracardiac defibrillators usually
operator (17). In 1 European study in which there was not have the capacity to record high-rate episodes that are AF or
rigorous prequalification of CAS operators, the 30-day atrial tachycardia, and interrogation of devices is demon-
stroke or death rate was high (9.6%) and inferior to that strating considerably more paroxysmal AF than anticipated.
with CEA (17). The 30-day ipsilateral stroke or death rates Indexes of AF and atrial tachycardia are being developed,
for CEA and CAS were also compared in the SPACE and the AF or atrial tachycardia burden (h/day) is being
(Stent-Protected Angioplasty Versus Carotid Endarterec- investigated as a risk factor for thromboembolism and
tomy) trial. With a CEA end point rate of 6.34% and a stroke.
CAS end point rate of 6.84%, noninferiority of CAS was Warfarin has numerous well-known limitations in its use.
not established (18). Longer-term follow-up data are There are currently at least 9 drugs in phase II and III
awaited. A recent subgroup analysis from the trial suggests clinical trials as possible substitutes for warfarin. A pivotal
that CAS may be safer in younger patients, while a trial comparing warfarin with dabigatran, a direct thrombin
difference in outcomes for CEA and CAS was not evident inhibitor for stroke prevention, was recently reported (25).
in older patients (19). The exciting findings established that dabigatran is more
A major U.S. and Canadian trial comparing the safety, efficacious at a dose of 150 mg twice daily, has similar safety
efficacy, and durability of CAS with those of CEA in to warfarin, and is much easier to administer. No monitor-
symptomatic and asymptomatic patients is nearing conclu- ing of INR is needed, and there appear to be fewer drug and
sion. The CREST (Carotid Revascularization Endarterec- food interactions. It is likely that this trial with dabigatran,
tomy vs. Stenting Trial) enrolled 2,522 patients with symp- if approved by the U.S. Food and Drug Administration
tomatic and asymptomatic carotid stenoses. The primary (FDA), will lead to the use of dabigatran rather than
end points are death, stroke, and myocardial infarction warfarin for a large number of patients with AF.
during the first 30 days after the procedure and then Novel antiplatelet strategies for stroke prevention have
ipsilateral stroke during the year after the procedure. The been investigated in patients who are not candidates for
CREST investigators undertook a rigorous credentialing warfarin therapy, often because of perceived risk for bleed-
process for both the CEA surgeons and CAS operators. A ing or falls. The ACTIVE A (Atrial Fibrillation Clopi-
large lead-in study for CAS was performed, and initial dogrel Trial With Irbesartan for Prevention of Vascular
results show that the process of careful qualification of the Events) evaluated the role of clopidogrel plus aspirin for the
operators results in 30-day death or stroke rates of 4.5% for prevention of stroke and other vascular events in AF (26).
686 Marsh and Keyrouz JACC Vol. 56, No. 9, 2010
Stroke Prevention and Treatment August 24, 2010:683–91

Clopidogrel 75 mg/day plus aspirin 75 to 100 mg/day the general population has been unclear. In 1 population-
decreased the risk for stroke (2.4% per year) compared based study (31), after adjustment for risk factors, large
with aspirin alone (3.3% per year) (p ⬍ 0.001). Major aortic arch plaques were not associated with combined
bleeding increased in the clopidogrel-plus-aspirin group vascular events. Associated cofactors, notably hyperlipid-
(2.0% per year) compared with aspirin alone (1.3% per emia, may be the underlying cause for the previously
year) (p ⬍ 0.001). described association between plaque and stroke.
In another arm of ACTIVE, the ACTIVE W, patients Patent foramen ovale (PFO) and stroke prevention. Ap-
with AF and at least 1 risk factor who were candidates for proximately 25% to 40% of strokes are cryptogenic (32).
warfarin therapy were randomized to either warfarin (target The association between a PFO and cryptogenic stroke is
INR 2.0 to 3.0) or clopidogrel 75 mg/day plus aspirin 75 well established (33). Numerous studies reviewed elsewhere
to 100 mg/day. The trial was stopped early because of indicate that associated factors, including the size of the
clear superiority of oral anticoagulation therapy (27). PFO, the size of the interatrial shunt, and the presence of an
Thus, for warfarin-eligible patients, the regimen of aspi- atrial septal aneurysm, may all contribute to the relative risk
rin plus clopidogrel produces inferior outcome and can- for a stroke (32,34,35). The optimal management of pa-
not be recommended. tients with PFOs and TIAs or strokes remains controversial.
It appears that for medical management, aspirin is as
LEFT VENTRICULAR THROMBI AS A SOURCE OF CARDIO-
effective as warfarin in secondary prevention (36).
EMBOLIC STROKE. There is little doubt that after acute Surgical closure of PFOs has been undertaken in the past
myocardial infarction and in chronic left heart failure, mural (32), but the surgical approach is no longer widely used
thrombi may form and produce an embolic stroke. How- because of the growth of catheter-based minimally invasive
ever, for patients in sinus rhythm, the optimal strategy to approaches. There have been numerous studies, some ran-
prevent left ventricular thrombi from forming and emboli- domized and some observational, using catheter-delivered
zing is uncertain. To determine whether warfarin, clopi- devices to close PFOs. Indeed, there are currently 16 active
dogrel, or aspirin would have an optimal effect on outcome trials of strategies for PFO management, mostly for isch-
in chronic heart failure, including an effect on stroke emic stroke indications.
prevention, Massie et al. (28) launched the WATCH The American Heart Association/American Stroke As-
(Warfarin and Antiplatelet Therapy in Chronic Heart sociation guidelines recommend antiplatelet therapy for
Failure) trial. Unfortunately, because of slow enrollment, patients with TIAs or strokes, unless there are additional
the trial was terminated early, with only 1,587 patients indications for warfarin therapy (9). The guidelines for
instead of the planned 4,500. The study was underpowered, secondary stroke prevention state that “insufficient data exist
but the investigators concluded that for the primary com- to make a recommendation about PFO closure in patients
posite end point and all-cause mortality, major differences with a first stroke and PFO. However, PFO closure may be
between outcomes with warfarin and antiplatelet therapy are considered for patients with recurrent cryptogenic stroke
unlikely. It cannot be considered a definitive trial. despite optimal medical therapy. There is a major need for
A major trial, WARCEF (Warfarin Versus Aspirin in definitive resolution of the optimal management of patients
Patients With Reduced Cardiac Ejection Fraction), is under with a documented PFO and who have had an initial stroke
way to compare aspirin and warfarin to prevent stroke and or TIA.” Physicians are urged to enroll suitable patients in
death for patients with left ventricular ejection fractions the ongoing randomized trials to resolve this question (34).
ⱕ35% (29). This study will provide definitive evidence for Hypertension and stroke. For more than 30 years, the
the relative efficacy of warfarin or aspirin for patients with evidence has been compelling that there is a strong associ-
low ejection fractions who are in sinus rhythm. The ation between elevated blood pressure and stroke, both
WARCEF trial was projected to successfully complete ischemic stroke and ICH. The relationship between blood
recruiting in February 2010, with publication of the primary pressure and stroke is a continuous variable and independent
findings in 2012. Until the results of the trial are published, of other risk factors (15). The relationship between hyper-
there are no definitive data from which to draw conclusions tension and lacunar stroke is particularly strong and may
regarding optimal antithrombotic therapy for stroke preven- occur in individuals with no other stroke risk factors. It
tion in patients with low ejection fractions. has become abundantly clear that screening for hyperten-
Atherosclerotic disease of the ascending aorta and aortic sion and treatment of hypertension are important and
arch and risk for ischemic stroke. It has been long effective in stroke prevention. Numerous classes of anti-
suspected that atherosclerotic plaques in the aortic arch are hypertensive medications, including thiazide diuretic
associated with ischemic strokes (30). Plaques ⬎4 mm in agents, angiotensin-converting enzyme inhibitors, angio-
thickness as determined by transesophageal echocardiogra- tensin receptor blockers, beta-blockers, and calcium-
phy appear to be particularly strongly associated with brain channel blockers, have all been shown to decrease the risk
infarct in patients who present with strokes (30). Causality for cardiovascular events including stroke. There may be a
has been more difficult to establish. Furthermore, the particular advantage to the use of angiotensin-converting
association between proximal aortic plaques and stroke in enzyme inhibitors and angiotensin receptor blockers for
JACC Vol. 56, No. 9, 2010 Marsh and Keyrouz 687
August 24, 2010:683–91 Stroke Prevention and Treatment

stroke prevention (37,38). It is a Class IA recommendation thrombolysis is used only in a small fraction of these patients
of the AHA and American Stroke Association Stroke (46). A recent study, the ECASS III (European Coopera-
Council that hypertension be diagnosed and treated to tive Acute Stroke Study) showed that the window for
prevent stroke. intervention could be extended up to 4.5 h (47). This trial
Prevention of ICH. Prospective, community-based stud- excluded patients with severe stroke (National Institutes of
ies have clearly established that hypertension is the leading Health Stroke Scale score ⬎25) and those with diabetes
controllable risk factor for hemorrhagic stroke in the U.S. who had previous strokes. More patients had favorable
population (39 – 41). Age and African American ancestry outcomes, as assessed by a modified Rankin Scale score of 0
were associated with ICH and affected both sexes equally or 1, with IV t-PA than with placebo (52.4% vs. 45.2%;
(2). Smoking is also a substantial risk factor for both sexes OR: 1.34; 95% CI: 1.02 to 1.76; p ⫽ 0.04). The incidence
(42,43). of symptomatic ICH was higher in the IV t-PA group than
Lifestyle and stroke prevention. For many years, it has the placebo group (2.4% vs. 0.2%, p ⫽ 0.008). The death
been well established that lifestyle contributes to the risk for rate did not differ between the 2 groups.
myocardial infarction. However, only recently has the major Currently in Europe, IV thrombolysis is performed up to
effect of lifestyle on stroke risk been established. Chiuve et 4.5 h from the time of symptom onset. The FDA has not
al. (44) conducted a major cohort study of over 114,000 men yet approved the use of IV t-PA between 3 and 4.5 h in the
and women and identified diet and lifestyle factors with an U.S. Nonetheless, many stroke centers have updated their
important bearing on lowering stroke risk. The 5 factors are treatment algorithms with the new time frame, a practice
body mass index ⬍25 kg/m2, ⬎30 min/day of moderate that has been recently recommended by the American Heart
activity, not smoking, modest alcohol intake, and scoring in Association (48). The earlier IV thrombolysis is performed,
the top 40% on a healthy diet score. For women, 54% of the more likely it is to be efficacious; therefore, practitioners
ischemic stroke risk is attributable to lack of adherence to should make every effort to administer t-PA soon after
low-risk lifestyle. For men, 52% of ischemic strokes may symptom onset within the window of opportunity (45).
have been prevented. Thus, for both men and women, a Many investigators have sought augmentation of throm-
healthy lifestyle has an immense impact on stroke risk. It bolytic effect by combining other therapeutic modalities to
clearly must be the cornerstone of all physician recommen- thrombolysis; however, thus far, no such combination ther-
dations for stroke prevention. apy has affected overall outcomes (49).
INTRA-ARTERIAL (IA) THROMBOLYSIS. Two landmark
Stroke Treatment
studies investigated IA thrombolysis in patients with middle
Hyperacute and acute therapy for ischemic stroke. The cerebral artery territory strokes and M1 or M2 occlusion
progress in the past 15 years in the treatment of ischemic within 6 h of symptom onset. The PROACT (Prolyse in
stroke exceeds anything seen in other neurological con- Acute Cerebral Thromboembolism) and PROACT II trials
ditions. We have also witnessed the establishment of appeared promising but were not definitive, and the therapy
certified stroke centers, in which a systematic and orga- (IA prourokinase) did not receive FDA approval (50,51).
nized approach with standard-of-care measures is at the However, many stroke centers are currently offering IA
core of investigations and treatment of stroke patients. thrombolysis to patients, either alone or in combination
Despite these efforts, stroke victims are still missing out with IV t-PA. The IMS (Interventional Management of
on timely therapy, in part because they are poorly informed Stroke) study explored this latter approach because investi-
but also because of the small window of opportunity for gators noted the relative lack of efficacy of IV t-PA on large
intervention. strokes and patients with major arterial occlusions; there are
several ongoing investigations (52,53).
INTRAVENOUS (IV) THROMBOLYSIS. IV thrombolysis with
tissue plasminogen activator (t-PA) remains the only FDA- MECHANICAL THROMBECTOMY. Several devices for embo-
approved acute therapy for ischemic stroke. This major lectomy are being studied, including the FDA-approved
breakthrough occurred in 1996, when t-PA was approved Merci device (Concentric Medical, Inc, Mountain View,
for ischemic stroke within 3 h of symptom onset (45). IV California) in the MERCI (Mechanical Embolus Removal
t-PA significantly improved outcomes after ischemic stroke in Cerebral Ischemia) trial (54). The Multi MERCI trial
at 3 months; the odds ratio (OR) for a favorable outcome further investigated the role of the Merci device in patients
was 1.7 (95% confidence interval [CI]: 1.2 to 2.6; p ⫽ with acute ischemic strokes within 8 h of symptom onset
0.008). Mortality at 3 months was similar in the 2 groups. (55). It is important to note, however, that the efficacy of the
The incidence of symptomatic ICH within 36 h after the Merci device was evaluated against historical controls of IV
onset of symptoms was significantly higher in the IV t-PA and IA t-PA and not evaluated in a randomized controlled
group (6.4 vs. 0.6, p ⬍ 0.001). This explains in part the trial. Unlike its sister trial, the Multi MERCI trial allowed
reluctance of some physicians to administer IV t-PA. mechanical embolectomy to be performed on patients who
Twenty percent to 25% of patients with strokes arrive at the had already received IV t-PA and had persistent large vessel
hospital within 3 h of symptom onset, but currently, occlusion. Moreover, IA thrombolysis was permitted in
688 Marsh and Keyrouz JACC Vol. 56, No. 9, 2010
Stroke Prevention and Treatment August 24, 2010:683–91

Figure 3 A Left Hypertensive Thalamic Hemorrhage

A left hypertensive thalamic hemorrhage (4 ml) 3 h after symptom onset (left) and 1 h later (16 ml) (right).
Hematoma expansion in this case, ultimately lethal, was accompanied by clear neurological deterioration.

patients in whom mechanical intervention failed to achieve LOWERING OF ACUTELY ELEVATED BLOOD PRESSURE.
arterial patency (at least Thrombolysis In Myocardial In- Chronic hypertension is a major risk factor for developing
farction flow grade 2). Recanalization was achieved in ICH, and aggressive antihypertensive therapy unequivocally
55% of 164 patients in whom the device was deployed lowers the risk for ICH (62). In the acute phase of ICH,
and in 68% of the same cohort when adjuvant IA elevated blood pressure is commonly encountered, with
thrombolysis was used. Symptomatic ICH occurred in evidence linking acute hypertension to increased mortality,
9.8% of patients. When recanalization occurred, good disability, and risk for hematoma growth (63). One argu-
neurological outcomes at 90 days were observed in 49% of ment against aggressive treatment of acute hypertension in
patients compared with 9.6% of patients who did not ICH was altering autoregulation and potentially reducing
recanalize (p ⬍ 0.001). Similarly, in the same groups, perfusion around the hematoma. However, several investi-
90-day mortality was observed in 25% and 52%, respectively gations suggest that more aggressive lowering of blood
pressure may be safe (64 – 66); nonetheless, definitive data
(p ⬍ 0.001). Mechanical thrombectomy remains an area of
are still awaited to shed more light on this most important
active clinical investigation.
clinical dilemma.
Hyperacute and acute therapy for ICH. The mortality
and morbidity of ICH is staggeringly high. ICHs account HEMOSTATIC THERAPY. Although bleeding into brain pa-
for 9% to 15% of all strokes, affecting 70,000 Americans renchyma is apoplectic, with hematoma reaching its maxi-
yearly (56), yet they are responsible for a disproportionate mum volume within minutes, this process is far from being
static. Early hematoma growth or expansion (defined as a
death rate approaching 50% (57). Determinants of outcome
ⱖ33% or 12.5-ml increase in the size of the clot during the
include age, baseline hematoma volume, admission Glasgow
first 24 h) has been shown to occur (Fig. 3). In 1 study of
Coma Scale score, presence and amount of intraventricular
head computed tomography in 204 patients with ICH who
blood, and early hematoma growth (57–59). One-half of
had repeat computed tomography within 48 and 120 h from
deaths from ICH occur in the first 48 h after bleeding, as a the onset of bleeding, 20% of patients developed hematoma
result of mass effect and brain tissue shifts. The latter are expansion. Those were more likely to deteriorate clinically
intimately related to hematoma volume (57). Perihemato- than patients who did not experience expansion (OR: 11.7;
mal edema and inflammation linked to thrombin and iron 95% CI: 5.0 to 27.8). Furthermore, 29% of patients with
toxicity add to the acute, cataclysmic neurological injury in expansion died early after bleeding, in contrast to 3% of
patients with ICHs (60). Most of the remaining deaths patients who did not have expansion (67). Other investiga-
occur later, within the first 30 days, as a consequence of tors have reported concordant findings (68).
medical complications made more likely due largely to the In light of these observations, and especially after the
functional disability (61). Unlike the breakthrough achieved failure of surgical evacuation to improve outcomes of pa-
in the treatment of ischemic stroke during the past 2 tients with ICH (see the following discussion), an interest in
decades, progress has been limited in the treatment of ICH. an early, aggressive medical therapy that would limit the
JACC Vol. 56, No. 9, 2010 Marsh and Keyrouz 689
August 24, 2010:683–91 Stroke Prevention and Treatment

incidence of hematoma expansion and therefore clinical WRICH is 0.6% to 2% (77). WRICH has a worse
deterioration emerged (69). Given its characteristics as a prognosis compared with non-WRICH (78), partly because
hemostatic agent (enhancing coagulation and stopping it afflicts older patients and has larger initial hematoma
bleeding), recombinant factor VIIa, the activated form of volumes (79), which are not only more likely to expand but
the naturally occurring factor VII, was studied in patients could do so beyond the 24-h period during which expansion
with ICH. In pharmacological doses and through a cascade is expected (78).
of molecular activation, recombinant factor VIIa results in a There are no available clinical trials gauging the effec-
“thrombin burst” generated by activated platelets. Despite tiveness of different acute therapies for WRICH. It is
initial encouraging results, a pivotal trial of this strategy did common practice to discontinue warfarin and correct the
not show improvement in outcomes (70 –72). There is INR with the quick administration of vitamin K (IV or
potential for recombinant factor VIIa use in warfarin- parenteral) and fresh-frozen plasma. There is much current
related ICH and less devastated patients with smaller
interest in prothrombin complex concentrate, given how
hemorrhages and more favorable baseline examination
quickly it normalizes the INR, and the small administration
results.
volume compared with fresh-frozen plasma.
SURGICAL EVACUATION. The rationale for the evacuation
of cerebral parenchymal hemorrhages is to rid neurons and
glial cells from the source of thrombin and iron, both toxic Likely Developments in the Next 5 Years
compounds implicated in edema formation and secondary
damage to brain tissue not yet damaged by the initial It is very likely that alternatives to warfarin for oral antico-
physical insult that occurs when bleeding takes place. In agulation in AF will be introduced into clinical practice
addition, the surgical removal of blood clots may alleviate soon. Dabigatran appears to be a promising orally effective
pressure gradients inside the skull and restore normal direct thrombin inhibitor that may achieve FDA approval
anatomy. This would then lessen or abolish altogether soon (25). No doubt, newer antithrombotic agents will
pressure on, and injury to, vital midline diencephalic struc- present some clinical challenges to use, including bleeding.
tures that could subsequently lead to brain death. The role of CAS relative to CEA will become clearer as
McKissock et al. (73) conducted an early trial of hema- the CREST trial results are published in 2010. Also as the
toma evacuation in spontaneous ICH. It demonstrated a WARCEF trial is concluded and published in 2011 and
trend toward worse outcomes with surgical intervention. 2012, the role of aspirin compared with warfarin for stroke
Subsequently, many studies using different techniques of prevention in patients with low left ventricular ejection
clot evacuation were published. Most are very small, failing fractions will become clear.
to show any statistically significant and consistent benefit of Mechanical embolectomy is undergoing further investi-
surgery over conservative medical management (74,75). gations in 2 ongoing studies: the IMS III trial and the MR
One trial, the STICH (International Surgical Trial in RESCUE (Magnetic Resonance and Recanalization of
Intracerebral Haemorrhage), is notable (76). It is the largest Stroke Clots Using Embolectomy) trial. Imaging (magnetic
to date and most recent completed randomized trial of the resonance imaging and angiography) is being used to better
surgical evacuation of spontaneous ICH. It is a multicenter identify eligible patients. In expert hands, mechanical clot
trial of different surgical techniques for early (within 24 h of
retrieval alone or in combination with other therapeutic
randomization) hematoma evacuation versus conservative
modalities is appealing because it extends the window of
medical management. Using the extended Glasgow Coma
opportunity for treatment, a major hurdle for effective acute
Scale at 6 months as an end point, favorable outcomes were
stroke treatment delivery. The results of IMS III and MR
observed in 26% of patients allocated to the early surgery
arm, compared with 24% of patients allocated to conserva- RESCUE are eagerly awaited.
tive treatment (OR: 0.89; 95% CI: 0.66 to 1.19). Further- Finally, the FDA will likely endorse extension of the time
more, the mortality rate in the early surgery group was 36% window for IV t-PA administration to 4.5 h for selected
compared with 37% for the conservative treatment group patients in the U.S.
(OR: 0.95; 95% CI: 0.73 to 1.23; p ⫽ 0.707). Subgroup Demographic factors (age and obesity, with resultant
analyses showed a potential benefit for surgery in patients comorbidities) will tend to increase stroke risk over the next
with superficial hematoma. This latter finding served as the 10 years in the U.S. However, there is reason for a cautious
basis for the ongoing STICH II trial, which is comparing optimism that relatively new and specific strategies for
early surgery with conservative treatment in patients with stroke prevention and treatment will be countervailing and
lobar hematoma. In current clinical practice, ICHs are decrease stroke incidence and morbidity.
rarely evacuated unless they are lobar.
WARFARIN-RELATED INTRACEREBRAL HEMORRHAGE Acknowledgment
(WRICH). This dreaded complication of warfarin therapy is The authors thank GibAnn Berryhill, MA, for her editorial
relatively common in clinical practice. The annual risk for assistance.
690 Marsh and Keyrouz JACC Vol. 56, No. 9, 2010
Stroke Prevention and Treatment August 24, 2010:683–91

18. SPACE Collaborative Group, Ringleb PA, Allenberg J, et al. 30 day


Reprint requests and correspondence: Dr. James D. Marsh, results from the SPACE trial of stent-protected angioplasty versus
University of Arkansas for Medical Sciences, 4301 West Markham carotid endarterectomy in symptomatic patients: a randomised non-
Street, #832, Little Rock, Arkansas 72205. E-mail: jdmarsh@ inferiority trial. Lancet 2006;368:1239-47.
19. Stingele R, Berger J, Alfke K, et al. Clinical and angiographic risk
uams.edu. factors for stroke and death within 30 days after carotid endarterec-
tomy and stent-protected angioplasty: a subanalysis of the SPACE
study. Lancet Neurol 2008;7:216 –22.
REFERENCES
20. Howard VJ, Voeks JH, Lutsep HL, et al. Does sex matter? Thirty-day
stroke and death rates after carotid artery stenting in women versus
1. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and men: results from the Carotid Revascularization Endarterectomy
stroke statistics—2009 update: a report from the American Heart Versus Stenting Trial (CREST) lead-in phase. Stroke 2009;40:
Association Statistics Committee and Stroke Statistics Subcommittee. 1140 –7.
Circulation 2009;119:e21–181. 21. Stroke Prevention in Atrial Fibrillation Investigators. Stroke Pre-
2. Petrea RE, Beiser AS, Seshadri S, Kelly-Hayes M, Kase CS, Wolf vention in Atrial Fibrillation study: final results. Circulation 1991;
PA. Gender differences in stroke incidence and poststroke disability in 84:527–39.
the Framingham Heart Study. Stroke 2009;40:1032–7. 22. Stroke Prevention in Atrial Fibrillation Investigators. Warfarin versus
3. White H, Boden-Albala B, Wang C, et al. Ischemic stroke subtype aspirin for prevention of thromboembolism in atrial fibrillation: Stroke
incidence among whites, blacks, and Hispanics: the Northern Man- Prevention in Atrial Fibrillation II study. Lancet 1994;343:687–91.
hattan Study. Circulation 2005;111:1327–31. 23. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW,
4. Amarenco P, Labreuche J, Lavallee P, Touboul PJ. Statins in stroke Radford MJ. Validation of clinical classification schemes for predicting
prevention and carotid atherosclerosis: systematic review and up-to- stroke: results from the National Registry of Atrial Fibrillation. JAMA
date meta-analysis. Stroke 2004;35:2902–9. 2001;285:2864 –70.
5. Collins R, Armitage J, Parish S, Sleight P, Peto R; Heart Protection 24. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006
Study Collaborative Group. Effects of cholesterol-lowering with sim- guidelines for the management of patients with atrial fibrillation—
vastatin on stroke and other major vascular events in 20536 people executive summary: a report of the American College of Cardiology/
with cerebrovascular disease or other high-risk conditions. Lancet American Heart Association Task Force on Practice Guidelines and
2004;363:757– 67. the European Society of Cardiology Committee for Practice Guide-
6. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and lines (Writing Committee to Revise the 2001 Guidelines for the
stroke events with atorvastatin in hypertensive patients who have Management of Patients With Atrial Fibrillation). J Am Coll Cardiol
average or lower-than-average cholesterol concentrations, in the 2006;48:854 –906.
Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm 25. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus
(ASCOT-LLA): a multicentre randomised controlled trial. Drugs warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:
2004;64:43– 60. 1139 –51.
7. Nassief A, Marsh JD. Statin therapy for stroke prevention. Stroke 26. ACTIVE Investigators. Effect of clopidogrel added to aspirin in
2008;39:1042– 8. patients with atrial fibrillation. N Engl J Med 2009;360:2066 –78.
8. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary preven- 27. ACTIVE Writing Group on behalf of the ACTIVE Investigators.
tion of cardiovascular disease with atorvastatin in type 2 diabetes in the Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrilla-
Collaborative Atorvastatin Diabetes Study (CARDS): multicentre tion in the Atrial Fibrillation Clopidogrel Trial With Irbesartan for
randomised placebo-controlled trial. Lancet 2004;364:685–96. Prevention of Vascular Events (ACTIVE W): a randomised controlled
9. Adams RJ, Albers G, Alberts MJ, et al. Update to the AHA/ASA trial. Lancet 2006;367:1903–12.
recommendations for the prevention of stroke in patients with stroke 28. Massie BM, Collins JF, Ammon SE, et al. Randomized trial of
and transient ischemic attack. Stroke 2008;39:1647–52. warfarin, aspirin, and clopidogrel in patients with chronic heart failure:
10. The Action to Control Cardiovascular Risk in Diabetes Study Group. the Warfarin and Antiplatelet Therapy in Chronic Heart Failure
Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med (WATCH) trial. Circulation 2009;119:1616 –24.
2008;358:2545–59. 29. Pullicino P, Thompson JLP, Barton B, Levin B, Graham S, Freuden-
11. Amarenco P, Benavente O, Goldstein LB, et al. Results of the Stroke berger RS. Warfarin Versus Aspirin in Patients With Reduced
Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Cardiac Ejection Fraction (WARCEF): rationale, objectives, and
trial by stroke subtypes. Stroke 2009;40:1405–9. design. J Card Fail 2006;12:39 – 46.
12. Taylor A, Villines T, Stanek E, et al. Extended-release niacin or 30. Amarenco P, Cohen A, Tzourio C, et al. Atherosclerotic disease of the
ezetimibe and carotid intima-media thickness. N Engl J Med 2009; aortic arch and the risk of ischemic stroke. N Engl J Med 1994;331:
361:1–10. 1474 –9.
13. Chaturvedi S, Bruno A, Feasby T, et al. Carotid endarterectomy—an 31. Russo C, Jin Z, Rundek T, Homma S, Sacco RL, Di Tullio MR.
evidence-based review: report of the Therapeutics and Technology Atherosclerotic disease of the proximal aorta and the risk of vascular
Assessment Subcommittee of the American Academy of Neurology. events in a population-based cohort: the Aortic Plaques and Risk of
Neurology 2005;65:794 – 801. Ischemic Stroke (APRIS) study. Stroke 2009;40:2313– 8.
14. Executive Committee for the Asymptomatic Carotid Atherosclerosis 32. Homma S, Sacco RL. Patent foramen ovale and stroke. Circulation
Study. Endarterectomy for asymptomatic carotid artery stenosis. 2005;112:1063–72.
JAMA 1995;273:1421– 8. 33. Handke M, Harloff A, Olschewski M, Hetzel A, Geibel A. Patent
15. Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of foramen ovale and cryptogenic stroke in older patients. N Engl J Med
ischemic stroke: a guideline from the American Heart Association/ 2007;357:2262– 8.
American Stroke Association Stroke Council: cosponsored by the 34. O’Gara PT, Messe SR, Tuzcu EM, Catha G, Ring JC. Percutaneous
Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working device closure of patent foramen ovale for secondary stroke prevention.
Group; Cardiovascular Nursing Council; Clinical Cardiology Council; A call for completion of randomized clinical trials. A science advisory
Nutrition, Physical Activity, and Metabolism Council; and the Quality from the American Heart Association/American Stroke Association
of Care and Outcomes Research Interdisciplinary Working Group: the and the American College of Cardiology Foundation. J Am Coll
American Academy of Neurology affirms the value of this guideline. Cardiol 2009;53:2014 – 8.
Stroke 2006;37:1583– 633. 35. Wohrle J. Closure of patent foramen ovale after cryptogenic stroke.
16. Yadav JS, Wholey MH, Kuntz RE, et al. Protected carotid-artery Lancet 2006;368:350 –2.
stenting versus endarterectomy in high-risk patients. N Engl J Med 36. Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP, for the
2004;351:1493–501. PFO in Cryptogenic Stroke Study (PICSS) Investigators. Effect of
17. Mas JL, Chatellier G, Beyssen B, et al. Endarterectomy versus stenting medical treatment in stroke patients with patent foramen ovale: Patent
in patients with symptomatic severe carotid stenosis. N Engl J Med Foramen Ovale in Cryptogenic Stroke Study. Circulation 2002;105:
2006;355:1660 –71. 2625–31.
JACC Vol. 56, No. 9, 2010 Marsh and Keyrouz 691
August 24, 2010:683–91 Stroke Prevention and Treatment

37. Neal B, MacMahon S, Chapman N. Blood Pressure Lowering 57. Broderick JP, Brott TG, Duldner JE, Tomsick T, Huster G. Volume
Treatment Trialists’ Collaboration. Effects of ACE inhibitors, calcium of intracerebral hemorrhage. A powerful and easy-to-use predictor of
antagonists, and other blood-pressure-lowering drugs: results of pro- 30-day mortality. Stroke 1993;24:987–93.
spectively designed overviews of randomised trials. Lancet 2000;356: 58. Davis SM, Broderick J, Hennerici M, et al. Hematoma growth is a
1955– 64. determinant of mortality and poor outcome after intracerebral hem-
38. ALLHAT Officers and Coordinators for the ALLHAT Collaborative orrhage. Neurology 2006;66:1175– 81.
Research Group. Major outcomes in high-risk hypertensive patients 59. Tuhrim SM, Horowitz DRM, Sacher MM, Godbold JHP. Volume of
randomized to angiotensin-converting enzyme inhibitor or calcium ventricular blood is an important determinant of outcome in supra-
channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering tentorial intracerebral hemorrhage. Crit Care Med 1999;27:617–21.
Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 60. Hua Y, Keep RF, Hoff JT, Xi G. Brain injury after intracerebral
288:2981–97. hemorrhage: the role of thrombin and iron. Stroke 2007;38:759 – 62.
39. Rosamond WD, Folsom AR, Chambless LE, et al. Stroke incidence 61. Daverat P, Castel JP, Dartigues JF, Orgogozo JM. Death and
and survival among middle-aged adults: 9-year follow-up of the functional outcome after spontaneous intracerebral hemorrhage. A
Atherosclerosis Risk in Communities (ARIC) cohort. Stroke 1999;30: prospective study of 166 cases using multivariate analysis. Stroke
736 – 43. 1991;22:1– 6.
40. Longstreth WT Jr., Bernick C, Fitzpatrick A, et al. Frequency and 62. PROGRESS Collaborative Group. Randomised trial of a
predictors of stroke death in 5,888 participants in the Cardiovascular perindopril-based blood-pressure-lowering regimen among 6105
Health Study. Neurology 2001;56:368 –75. individuals with previous stroke or transient ischaemic attack.
41. Sturgeon JD, Folsom AR, Longstreth WT Jr., Shahar E, Rosamond Lancet 2001;358:1033– 41.
WD, Cushman M. Risk factors for intracerebral hemorrhage in a 63. Zhang Y, Reilly KH, Tong W, et al. Blood pressure and clinical
pooled prospective study. Stroke 2007;38:2718 –25. outcome among patients with acute stroke in Inner Mongolia, China.
42. Kurth T, Kase CS, Berger K, Schaeffner ES, Buring JE, Gaziano JM. J Hypertens 2008;26:1446 –52.
Smoking and the risk of hemorrhagic stroke in men. Stroke 2003;34: 64. Powers WJ, Zazulia AR, Videen TO, et al. Autoregulation of cerebral
1151–5. blood flow surrounding acute (6 to 22 hours) intracerebral hemor-
43. Kurth T, Kase CS, Berger K, Gaziano JM, Cook NR, Buring JE. rhage. Neurology 2001;57:18 –24.
Smoking and risk of hemorrhagic stroke in women. Stroke 2003;34: 65. Zazulia AR, Diringer MN, Videen TO, et al. Hypoperfusion without
2792–5. ischemia surrounding acute intracerebral hemorrhage. J Cereb Blood
44. Chiuve SE, Rexrode KM, Spiegelman D, Logroscino G, Manson JE, Flow Metab 2001;21:804 –10.
Rimm EB. Primary prevention of stroke by healthy lifestyle. Circula- 66. Anderson CS, Huang Y, Wang JG, et al. Intensive Blood Pressure
tion 2008;118:947–54. Reduction in Acute Cerebral Haemorrhage Trial (INTERACT): a
45. Marler JR, Tilley BC, Lu M, et al. Early stroke treatment associated randomised pilot trial. Lancet Neurol 2008;7:391–9.
with better outcome: the NINDS rt-PA Stroke Study. Neurology 67. Kazui S, Naritomi H, Yamamoto H, Sawada T, Yamaguchi T.
2000;55:1649 –55. Enlargement of spontaneous intracerebral hemorrhage: incidence and
46. Demaerschalk BM, Yip TR. Economic benefit of increasing utiliza- time course. Stroke 1996;27:1783–7.
tion of intravenous tissue plasminogen activator for acute ischemic 68. Brott T, Broderick J, Kothari R, et al. Early hemorrhage growth in
stroke in the United States. Stroke 2005;36:2500 –3. patients with intracerebral hemorrhage. Stroke 1997;28:1–5.
47. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 69. Mayer SA. Intracerebral hemorrhage: natural history and rationale of
to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359: ultra-early hemostatic therapy. Intensive Care Med 2002;28 Suppl 2:
1317–29. S235– 40.
48. del Zoppo GJ, Saver JL, Jauch EC, Adams HP Jr, on behalf of the 70. Mayer SA, Brun NC, Broderick J, et al. Safety and feasibility of
AHA Stroke Council. Expansion of the time window for treatment of recombinant factor VIIa for acute intracerebral hemorrhage. Stroke
acute ischemic stroke with intravenous tissue plasminogen activator. A 2005;36:74 –9.
science advisory from the American Heart Association/American 71. Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated
Stroke Association. Stroke 2009;40:2945– 8. factor VII for acute intracerebral hemorrhage. N Engl J Med
49. Alexandrov AV, Molina CA, Grotta JC, et al. Ultrasound-enhanced 2005;352:777– 85.
systemic thrombolysis for acute ischemic stroke. N Engl J Med 72. Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of
2004;351:2170 – 8. recombinant activated factor VII for acute intracerebral hemorrhage.
50. del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA,
N Engl J Med 2008;358:2127–37.
Gent M. PROACT: a phase II randomized trial of recombinant
73. McKissock W, Richardson A, Taylor J. Primary intracerebral
pro-urokinase by direct arterial delivery in acute middle cerebral artery
hemmorrhage: a controlled trial of conservative and surgical treatment
stroke. Stroke 1998;29:4 –11.
in 180 unselected cases. Lancet 1961;2:221– 6.
51. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase
74. Fernandes HM, Gregson B, Siddique S, Mendelow AD. Surgery in
for acute ischemic stroke: the PROACT II study: a randomized
intracerebral hemorrhage: the uncertainty continues. Stroke 2000;31:
controlled trial. JAMA 1999;282:2003–11.
2511– 6.
52. The IMS I Trial Investigators. Combined intravenous and intra-
75. Prasad K, Mendelow AD, Gregson B. Surgery for primary supraten-
arterial recanalization for acute ischemic stroke: the Interventional
torial intracerebral haemorrhage. Cochrane Database Syst Rev 2008;
Management of Stroke study. Stroke 2004;35:904 –11.
8:CD000200.
53. The IMS II Trial Investigators. The Interventional Management of
76. Mendelow AD, Gregson BA, Fernandes HM, et al. Early surgery
Stroke (IMS) II study. Stroke 2007;38:2127–35.
versus initial conservative treatment in patients with spontaneous
54. Smith WS, Sung G, Starkman S, et al. Safety and efficacy of
supratentorial intracerebral haematomas in the International Surgical
mechanical embolectomy in acute ischemic stroke: results of the
MERCI trial. Stroke 2005;36:1432– 8. Trial in Intracerebral Haemorrhage (STICH): a randomised trial.
55. Smith WS, Sung G, Saver J, et al. Mechanical thrombectomy for acute Lancet 2005;365:387–97.
ischemic stroke: final results of the Multi MERCI trial. Stroke 77. Hart RG, Tonarelli SB, Pearce LA. Avoiding central nervous system
2008;39:1205–12. bleeding during antithrombotic therapy: recent data and ideas. Stroke
56. Broderick J, Connolly S, Feldmann E, et al. Guidelines for the 2005;36:1588 –93.
management of spontaneous intracerebral hemorrhage in adults: 2007 78. Cucchiara B, Messe S, Sansing L, Kasner S, Lyden P, for the
update: a guideline from the American Heart Association/American CHANT Investigators. Hematoma growth in oral anticoagulant
Stroke Association Stroke Council, High Blood Pressure Research related intracerebral hemorrhage. Stroke 2008;39:2993– 6.
Council, and the Quality of Care and Outcomes in Research Inter- 79. Flaherty ML, Tao H, Haverbusch M, et al. Warfarin use leads to
disciplinary Working Group: the American Academy of Neurology larger intracerebral hematomas. Neurology 2008;71:1084 –9.
affirms the value of this guideline as an educational tool for neurolo-
gists. Stroke 2007;38:2001–23. Key Words: stroke y prevention y treatment.

You might also like