Stroke Update

Galen V. Henderson, M.D.Brigham and Women’s Hospital

Assistant Professor of NeurologyHarvard Medical School

I have no Industry Relationships

Outline and Learning Objectives

•Review epidemiology•Review polyvascular disease•Discuss new definitions of TIA•Review medical interventions–Antihypertensives–Statin therapy–Anticoagulants–Antiplatelet therapy

•Review barriers to improve outcomes•Discuss promotion of stroke centers•Review stroke workup

Stroke. 2011;42:849-877

Stroke in the US• 795 000 people experience a new or

recurrent stroke.

– Approximately 610 000 of these are first attacks, and 185 000 are recurrent attacks.

• 137 000 stroke deaths annually in the United States.

• Leading cause of serious, long-term disability

• Third leading cause of death in the U.S.; second leading cause worldwide

• Second-leading cause of hospital admission among older adults

0

5

10

15

20

25

Healthy CV disease MI Stroke

Yea

rs

Analysis of data from the Framingham Heart Study.Peeters A et al. Eur Heart J. 2002;23:458-466.

Average remaining life expectancy at age 60 (men)

10.8 yrs12.3 yrs

8 yrs

Atherothrombosis Significantly Shortens Life Expectancy

20 yrs

Atherothrombotic Conditions

0%

10%

20%

30%

40%

50%

60%

70%

Pe

rce

nta

ge

Wit

h O

utc

om

e

Low High

Estimated Outcomes After Ischemic Stroke

Adapted with permission from Sacco RL. Neurology. 1997;49(5 suppl 4):S39.

Dementia at 52 mo

Functional disability (complete

or partial dependence)

5-yr strokemortality

5-yr strokerecurrence

25%

40% 40%

60%

24%

34%

53%

Estimated Outcomes

Estimated %

Prevalence of Ischemic Stroke

88%of all strokes

are ischemic

Ischemic Stroke88% Intracerebral

Hemorrhage9%

3%

SubarachnoidHemorrhage

American Heart Association. Heart Disease and Stroke Statistics—2005 Update. 2005.

Ischemic Stroke: Common Causes

•Atherothrombosis– Large-vessel

• Extracranial• Aortic• Cervical ICA• Cervical CCA

• Intracranial• ICA• MCA• Vertebral artery• Basilar artery

– Small vessel• Lacunar

•Cardiac source– Atrial fibrillation– Dilated cardiomyopathy

•Nonatherosclerotic arteriopathies, eg:– Vasculitis– Migraine

•Prothrombotic disorders

Helgason CM et al. Circulation. 1997;96:701-707.

Overlap of Serious Vascular Disease in the Stroke Patient

• REduction of Atherothrombosis for Continued Health (REACH) Registry – www.reachregistry.org

• CVD population: N=18,957– TIA: N=8741 (48%)– Stroke: N=13,650 (73%)

• 40.2% of the total CVD population has more than 1 disease location– 34.3% have 2 disease

locations– 5.9% have 3 disease locations

Multiple Risk Factors Only

Cardiac

CerebralN=5704

Peripheral

N=1120

N=794

N=11,339

Bhatt DL, et al. JAMA. 2006;295:180-189.Stegg PG , et al. Presented at: American College of Cardiology 55th Annual Scientific Session; March 12, 2006; Atlanta, Ga. Alberts M, et al. Submitted to European Stroke Conference 2006. Poster.

REACH Registry

Modifiable

•Hypertension•Diabetes•Cardiac disease•Atrial fibrillation•TIA/prior stroke•Metabolic syndrome•Dyslipidemia•Cigarette smoking•Alcohol abuse•Obesity•Physical inactivity•Carotid stenosis

Nonmodifiable

•Age•Gender•Race/ethnicity•Heredity

Goldstein L et al. Circulation. 2001;103:163-182.Broderick J et al. Stroke. 1998;29:415-421.Brown WV. Clin Cornerstone. 2004;6 Suppl 3:S30-S34.

Risk Factors for Stroke

*For the protective factor of physical activity, the population-attributable risks are provided for individuals who do not participate in regular physical activity.

Risk factor Population-attributable risk, % (99% CI)

Hypertension 34.6 (30.4–39.1)Smoking 18.9 (15.3–23.1)Waist-to-hip ratio (tertile 2 vs tertile 1) 26.5 (18.8–36.0)Dietary risk score (tertile 2 vs tertile 1) 18.8 (11.2–29.7)Regular physical activity 28.5 (14.5–48.5)Diabetes 5.0 (2.6–9.5)Alcohol intake 3.8 (0.9–14.4)Cardiac causes 6.7 (4.8–9.1)Ratio of apolipoprotein B to A1(tertile 2 vs tertile 1)

24.9 (15.7–37.1)

Psychological factors•Stress 4.6 (2.1–9.6)•Depression 5.2 (2.7–9.8)

INTERSTROKE: Population-attributable risk for common risk factors

O'Donnell MJ et al. Lancet 2010; available at: http://www.thelancet.com.

0

2

4

6

8

10

12

14

20–24 25–34 35–44 45–54 55–64 65–74 75+Age range (years)

% o

f p

op

ula

tio

n

Men

Women

AHA. Heart Disease and Stroke Statistics—2004 Update.

Prevalence of Stroke by Age

Note: data for the years 2000 to 2050 are middle-series projections of the population.Reference population: these data refer to the resident population.US Census Bureau. Decennial Census Data and Population Projections, 2003.

Millions80

60

40

20

01900 1950 2000 2050

65 or older

85 or older

Projected

Total Number of Elderly by Age Group: 1900 to 2050

Age-adjustedrate per 100,000

40-57

58-61

62-6768-83

*Strokes are classified by ICD-10 codes: I60-I69. Source: National Vital Statistics Surveillance System, National Center for Health Statistics, CDC.

Geographical VariationStroke mortality, 2010

Estimated Cost of Stroke in the US

$26.5

$2.7 $1.1 $2.7

$6.1

$14.5

Hospital/nursing home Physician/other professionals

Medications Home health care

Lost productivity/morbidity Lost productivity/mortality

Direct costs: $33 billion

Indirect costs: $20.6 billion

Total 2006 cost: $57.9 billion: now 2010 cost 74 Billion

AHA Heart Disease and Stroke Statistics—2006 Update. Dallas, Texas.: American Heart Association; 2006.AHA Heart Disease and Stroke Statistics—2010 Update. Dallas, Texas.: American Heart Association; 2010.

Transient Ischemic Attacks (TIAs)

Historic DefinitionTemporary focal brain or retinal deficits caused by vascular disease that resolve within 24 hours

New Definition of TIA

TIA is a brief episode of neurologic dysfunction caused by focal brain or retinal ischemia, with clinical symptoms typically lasting less than one hour, and without evidence of acute infarction

N Engl J Med, Vol. 337, Nov 21, 2002, 1713-1717.

Stroke, Vol 37, 2006, 577-617.

Stroke. 2009;40:2276.

Short-term Prognosis after Emergency Department Diagnosis of TIA

Johnston SC. et al. JAMA 2000;284: 2901-2906

25.1%

10.5%

12.7%

2.6% 2.6%

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%

Total Stroke RecurrentTIA

CV event Death

Outcome events

Inclusion criteria:

Objective:

Outcome Measures:

TIA by ED physicians

Short-term risk of strokeafter ED diagnosis

Risk of stroke and otherevents during the 90 daysafter index TIA

ABCD2 of TIA• Patients with TIA score points for each of the following factors:

• Age 60 years (1 point)

• Blood pressure 140/90 mm Hg on first evaluation (1 point)

• Clinical symptoms of focal weakness with the spell (2 points) or speech impairment without weakness (1point)

• Duration 60 minutes (2 points) or 10 to 59 minutes (1 point)

• Diabetes (1 point).

• 2-day risk of stroke: • 0% for scores of 0 -1• 1.3% for 2 -3• 3, 4.1% for 4-5• 8.1% for 6-7 Stroke. 2009;40:2276.

Working up TIA

• Neuroimaging evaluation within 24 hours of symptom onset.• MRI, including DWI, is the preferred brain diagnostic

imaging modality.

• Noninvasive imaging of the cervicocephalic vessels shouldbe performed routinely as part of the evaluation

• Noninvasive testing of the intracranial vasculature reliablyexcludes the presence of intracranial stenosis

• Patients with suspected TIA should be evaluated as soon as possible after an event

• ECG/ECHO

Stroke. 2009;40:2276

Admit to the Hospital?

• Reasonable to hospitalize patients with TIA if they present within 72 hours of the event and any of the following criteria are present:

– ABCD2 score of 3 or greater

– ABCD2 score of 0-2 and uncertainty that diagnostic workup can be completed within 2 days as anoutpatient

Stroke. 2009;40:2276.

Evaluation of Tissue Status: Noncontrast Head CT

Advantages

• Almost universally available

• Rapid

• High sensitivity for detection of hemorrhage (100% ICH, 90% SAH)

Disadvantages

•Often normal in hyperacute phase

•Insensitive to lacunar and posterior fossa strokes

Evaluation of Tissue Status: Multimodal MRI (including DWI)

Advantages– More sensitive to

acute ischemia

– More sensitive to posterior fossa lesions

– More sensitive to small vessel, lacunar lesions

•Disadvantages– Not universally

available

– Longer scanning time

– Patient contraindications (e.g. pacemaker)

CT

DWI

MRI - Tissue Status: Ischemia

Evaluation of Vessel Status

1. CT Angiography

2. MR Angiography

3. Ultrasound Techniques

4. Catheter Angiography

CT Angiography

•Requires injection of intravenous contrast agent

•New generation helical scanners allow rapid evaluation of aortic arch, neck, and intracranial vessels with 1 injection

•80-100% accuracy compared with catheter angiography

•Disadvantages: iodinated contrast agent, radiation exposure

CTA: Carotid Stenosis CTA: MCA Stenosis

MR Angiography

•Noninvasive means to evaluate neck and intracranial vessels

•Time of flight technique may overestimate stenoses

•Not reliable in identifying distal or branch intracranial occlusions

•Sensitivity and specificity 70-100% compared to catheter angiography

•Power-injector, contrast-enhanced techniques –increased sensitivity

•Subject to limitations of standard MRI

MR Angiography

Neck MRA: Right Carotid Stenosis

Intracranial MRA: Left ICA Occlusion

AHA Guidelines for the Use of Imaging in Acute Stroke•Brain imaging is required to guide the selection of acute interventions to treat patients with stroke

•CT remains the most important brain imaging test

•New studies suggest that MRI could be an alternative to CT–May be used to detect acute ICH

Adams H et al. Stroke. 2005;36:916-923

Evidence-based guideline: The role of diffusion and perfusion MRI for the diagnosis of acute ischemic stroke

• DWI should be considered superior to noncontrast CT scan for the diagnosis of acute ischemic stroke in patients presenting within 12 hours of symptom onset (Level A).

• There is insufficient evidence to support or refute the value of PWI in diagnosing acute ischemic stroke (Level U).

• Baseline DWI volume should be considered useful in predicting baseline clinical stroke severity and final lesion volume in anterior-circulation stroke syndromes (Level B).

• Baseline DWI volume may be considered not useful in predicting baseline NIHSS score in posterior-circulation stroke syndromes (Level C).

• Baseline DWI volume may be considered useful in predicting clinical outcome as measured by the NIHSS and Barthel Index (Level C).

• Baseline PWI volume may be considered useful in predicting baseline clinical stroke severity (Level C). NEUROLOGY 2010;75:177-185

rtPA for Acute Stroke

•Only FDA-approved therapy•Can reverse effects of stroke•Only used in about 4% of cases–Time limit: must be administered within 3 hours

of stroke onset–Rapid identification and treatment

•Utility of rt-PA is limited due to:– Three hours time window– Associated with a significant risk of ICH

Overall Benefits and Risks of IV tPA for Stroke

•Benefit: Neurologically normal at 3 months1

–55% relative increase; 12% absolute increase

•Robust effect2:–NNT to cure=7

•Risk of symptomatic ICH: 6.4%1

•Overall benefits in spite of the ICHs•Risk of ICH can be reduced by closely following tPA protocol

1. NINDS rt-PA Stroke Study Group. N Engl J Med. 1995;333:1581-1587.2. Ringleb PA et al. Stroke. 2002;33:1437-1441.

Empirical Characteristics of Litigation Involving TissuePlasminogen Activator and Ischemic Stroke

Study objective:• The use of tissue plasminogen activator (tPA) in potential

stroke victims by emergency physicians is controversial. One factor that may represent a barrier to use is medicolegal concerns resulting from adverse outcomes.

Results:• Thirty-three cases were found involving tPA ischemic

stroke therapy. In 29 (88%) of these cases, patient injury was claimed to have resulted from failure to treat with tPA.

• Emergency physicians were the most common physician defendants. Defendants prevailed in 21 (64%) cases, and among the 12 with results favorable to the plaintiff, 10 (83%) involved failure to treat and 2 (17%) claimed injury from treatment with tPA.

Ann Emerg Med. 2008;52:160-164.

Acute Ischemic Stroke: ASA/AAN/ACCP Guidelines

• Pharmacotherapies– tPA (tissue plasminogen activator) within 3 hours of stroke

onset

– Aspirin for acute stroke (within 48 hours of symptom onset): 160 to 325 mg/day) to reduce stroke mortality and decrease morbidity; ONLY if no contraindications or if patient will not be given rtPA1

– Heparin and low molecular weight heparin (LMWH): not indicated and may increase bleeding complications;

– LMWH and heparinoids may be considered for DVT prophylaxis in at-risk patients1

• Early consultation by neurologist or stroke team critical2

1. Coull BM et al. Stroke. 2002;33:1934-1942.

2. Adams HP et al. Stroke. 2003;34:1056-1083.

An Advisory Statement from the Stroke Council, American Heart Association and American Stroke Association

EXPANSION OF THE TIME WINDOW FOR TREATMENT OF ACUTE ISCHEMIC STROKE WITH INTRAVENOUS

TISSUE PLASMINOGEN ACTIVATOR

Gregory J. del Zoppo, MD, MS, FAHA; Jeffrey L. Saver, MD, FAHA; Edward C. Jauch, M.D, MS, FAHA; Harold P. Adams, Jr., MD, FAHA

This science advisory reflects a consensus of expert opinion following thorough literature review that consisted of a look at clinical trials and other evidence related to the management of acute ischemic stroke.

ECASS - 3

DESIGN AND METHODS• Multicenter, prospective, placebo-controlled RCT

• Usual criteria for rt-PA eligibility within 3 hrs, exclusion criteria included:

– older than 80 years; baseline NIH Stroke Scale score >25; on oral anticoagulants; combo of a previous stroke & DM

• rt-PA (n = 418) or placebo (n = 403) given at 3.0 - 4.5 hrs from stroke symptom onset

• Dose = 0.9 mg/kg (max 90 mg); 10% as initial bolus & remainder infused over 1 hr.

• Primary outcome: modified Rankin Scale Score 0-1 (minimal or no disability) at 90 days after Tx.

•

ECASS - 3

RESULTS

Primary Outcome:• mRS 0-1: rt-PA (52.4%) vs placebo (45.2%)

(OR 1.34, 95% CI = 1.02-1.76; p = 0.04)

Secondary Outcome: Global Favorable Outcome

(mRS of 0-1, Barthel Index score >95, an NIHSS score of 0-1& Glascow Outcome Score of 1)

• ECASS – 3 = OR 1.28, 95% CI = 1.00-1.65) vsNINDS pool pts (enrolled 0-3hrs) = OR1.9, 95% CI 1.2-2.9

ECASS - 3

RESULTS• Symptomatic ICH (ECASS-3 definition) occurred in

rt-PA n = 10 (2.4%) vs placebo n = 1 (0.2%) (OR 9.85, 95% CI 1.26-77.32, p = 0.008)

• Symptomatic ICH (NINDS study definition) occurred inrt-PA n = 33 (7.9%) vs placebo n = 14 (3.5%)

(OR 2.38, 95% CI = 1.25-4.52, p = 0.006)

• Increased incidence of symptomatic ICH is consistent with the experience with rt-PA in other clinical trials with rt-PA

• Mortality in the two treatment groups did not differ significantly, although it was nominally higher among the subjects treated with placebo (7.7% vs. 8.4%, p=0.68)

Recommendations

• rt-PA should be administered to eligible pts within 3.0-4.5 hours after stroke (Class I Recommendation, LOE B)

• Eligibility criteria in this time period are similar to those for persons treated at earlier time periods with the following additional exclusion criteria:

– Age > 80 years; Oral anticoagulant use with INR ≤ 1.7*; baseline NIH Stroke Scale score > 25; a history of stroke and diabetes (*For the 3.0 –4.5 hr window all pts receiving oral anticoagulant are excluded whatever their INR).

• The efficacy of IV rt-PA within 3.0 – 4.5 hours after stroke in pts with these exclusion criteria is not well-established & requires further study. (Class IIb Recommendation, LOE C)

Physician Resistance to rtPA • Skill set for correct diagnosis

• Establishment of onset time necessary/difficult

• Alteplase protocol vs lack of existing protocols

• Lack of communication/understanding between EDs, neurologists, PCPs

• Difficulty in implementing standing orders in hospital setting

Morgenstern LB et al. Arch Intern Med. 2003;163:2198-2202.

INTRA-ARTERIAL ADMINISTRATION OF THROMBOLYTIC AGENTS

• Potential advantages–Higher concentration of medication at site–Lower systemic doses might improve

safety

• Potential disadvantages–Facilities not widely available–Time required to mobilize resources

• No head-to-head comparisons with IV therapy

Times for thrombolysis

• < 3 hours for IV TPA - FDA approved

• >3 – 4.5 hours for IV TPA – Not FDA approved

• Time of onset to 6 hours – Not FDA approved with device or IA thrombolytics

Lowering Blood Pressure

*Treatment determined by highest category.†Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mm Hg.‡May consider ACEI, ARB, BB, CCB, or combination.

Adapted from Chobanian AV, et al. JAMA. 2003;289:2560-2572.

7th Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

HYPERTENSION

BPClassification

SBP*(mm Hg)

DBP*(mm Hg)

LifestyleModification Initial Drug Therapy

Normal <120 and <80 EncourageWithout

Compelling Indications

With Compelling Indications

Pre-hypertension 120-139 or 80-89 Yes

No antihypertensive drug indicated

Drug(s) for compelling indications†

Stage 1 Hypertension 140-159 or 90-99 Yes

Thiazide-type diuretics‡

Drug(s) for compelling indications†

Other antihyper-tensives

Stage 2 Hypertension >160 or >100 Yes

2-drug combination therapy

ASA Treatment Guidelines for 2007: Ischemic Stroke Not Eligible for Thrombolytic Therapy

BP Level(mm Hg)

Treatment

SBP <220 OR

DBP <120No treatment unless end-organ involvement

SBP >220 OR

DBP <121-140Nicardipine or labetalol to 10% -15% ↓ in BP

DBP >140 Nitroprusside to 10% -15% ↓ in BP

ASA = American Stroke Association; IS = ischemic stroke; SBP = systolic blood pressure; DBP = diastolic blood pressure.

Adams HP, et al. Stroke. 2007;38:1655-1711.

ASA Treatment Guidelines for 2007: Ischemic Stroke Eligible for Thrombolytic Therapy

BP Level (mm Hg) Treatment

PretreatmentSBP >185 or

DBP >110

Labetalol (may repeat once), nitropaste, or nicardipineIf BP not reduced and maintained, do not administer rt-PA

During and afterrt-PA

SBP 180-230OR

DBP 105-120Labetalol

SBP >230OR

DBP 121-140

Nicardipine or labetalolIf BP not controlled, consider nitroprusside

rt-PA = recombinant tissue plasminogen activator.

Adams HP, et al. Stroke. 2007;38:1655-1711.

Blood Pressure and StrokeWhat to Conclude

• All studies support detection and aggressive treatment of blood pressure for both primary and secondary prevention

• Reduction of stroke by 35%-40% possible1

• Thiazide-type diuretic recommended as first therapeutic agent1

• ACEI and ARBs are more effective in reducing progression of renal disease and are recommended as first-choice medications for patients with diabetes

1. Chobanian AV et al, and the National High Blood Pressure Education Program Coordinating Committee. JAMA. 2003;289:2560-2572.2. Stroke, Vol 37, 2006, 577-617.3. Schrader J. Stroke. 2003;34:1199-1703.

Antiplatelets

0 0.5 1.0 1.5 2.0

500 mg–1500 mg 34 19

160 mg–325 mg 19 26

75 mg–150 mg 12 32

<75 mg 3 13

Any aspirin 65 23

Antiplatelet Better

Antiplatelet Worse

Aspirin Dose No. of Trials OR (%) Odds Ratio

*Vascular events included nonfatal MI, nonfatal stroke, and death from vascular causes.Treatment effect P<0.0001.Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71-86. Reproduced with permission from BMJ Publishing Group.

Efficacy of Aspirin at Various Doses in Reducing Vascular Events in High-risk Patients*

ATCEuropean Stroke Prevention Study (ESPS-2)

TIA or stroke < 3 months6,602 patients R

DP-XR 200 mg BID1,654 patients

ASA 25 mg BID1,649 patients

DP-XR 200 mg+ ASA 25 mg BID

1,650 patients

Placebo1,649 patients

Design• 2 x 2 factorial design• Stroke (76%) or TIA (24%)Endpoints• Primary: Stroke, death, stroke and death• Secondary: TIA, MI• Follow-up: 2 years Diener HC. et al. J Neurol Sciences. 1996;143:1-13.

Risk Reduction for Stroke or Death

StrokeP

value

Stroke or

Death

Pvalue

Death P value

ASA vs placebo 18.1 0.013 13.2 0.016 10.9 NS

DP vs placebo 16.3 0.039 15.4 0.015 7.3 NS

DP + ASA vs placebo

37.0 <0.001 24.4 <0.001 8.5 NS

DP + ASA vs ASA 23.1 0.006 12.9 NS -2.7 NS

DP + ASA vs DP 24.7 0.002 10.7 NS 1.3 NS

PairwiseComparisons Relative Risk Reduction (%)

ASA = aspirin 25 mg bid; DP = modified-release dipyridamole 200 mg bid.Adapted from Diener HC et al. J Neurol Sci. 1996;143:1-13.

Clopidogrel vs Aspirin in Patients at Risk for Ischemic Events

ObjectiveTo test the relative efficacy of clopidogrel and aspirin for prevention of stroke, MI, or vascular death

Study Design

Randomized, blinded, prospective, international trials at 304 study centers in 16 countries

Patient Population

19,185 patients with• Recent MI• Recent ischemic stroke• Established PAD

Treatment

Patients were randomized to • Clopidogrel bisulfate: 75 mg/d• Aspirin: 325 mg/d

Treatment duration lasted up to 3 years (mean 1.6 y)

CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.

CAPRIE

Months of Follow-Up

Cu

mu

lati

ve

Eve

nt

Rat

e (%

)

0

4

8

12

16

Clopidogrel

Aspirin Overall Relative RiskReduction2

8.7%*

0 3 6 9 12 15 18 21 24 27 30 33 36

Aspirin

5.83%1

5.32%1

Clopidogrel

P = 0.0452

* ITT analysis.1. CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.2. PLAVIX Prescribing Information.

CAPRIE

Median Follow-up = 1.91 years

Efficacy of Clopidogrel vs Aspirin in MI, Ischemic Stroke, or Vascular Death (N=19,185)

Study subjects had either recent MI, recent ischemic stroke, or symptomatic peripheral arterial disease.

2008 AHA/ASA Guidline Recommendations for Antiplatelet Therapy in Stroke and TIA

“For patients with noncardioembolic ischemic stroke or TIA, antiplatelet agents rather than oral anticoagulation are recommended to reduce the risk of recurrent stroke and other cardiovascular events (Class I, Level of Evidence A).”

“Aspirin (50 to 325 mg/d) monotherapy, the combination of aspirin and extended-release dipyridamole, and clopidogrel monotherapy are all acceptable options for initial therapy (Class I, Level of Evidence A).”

Stroke. 2008;39:1647

2008 AHA/ASA Guidline Recommendations for Antiplatelet Therapy in Stroke and TIA

“The combination of aspirin and extended-release dipyridamole is recommended over aspirin alone (Class I, Level of Evidence B)”

“Clopidogrel may be considered over aspirin alone on the basis of direct-comparison trials (Class IIb, Level of Evidence B).”

Stroke. 2008;39:1647

PRoFESS® Results Announced at XVII European Stroke Conference

DP + ASA clopidogrel

Recurrent stroke event rates

9.0% 8.8%HR 1.01, 95% CI 0.92-1.11

•The study did not meet its primary endpoint of non-inferiority for DP + ASA versus clopidogrel

Secondary endpoint of the composite of stroke, MI or vascular death

13.1% 13.1%

Hemorrhagic strokes 0.8% 0.4%

Benefit-risk ratio expressed as the combination of recurrent stroke and major hemorrhage

11.7% 11.4% HR 1.03, 95% CI 0.95-1.11).

ASA = aspirin 25 mg bid; DP = modified-release dipyridamole 200 mg bid N Engl J Med 359:1238, September 18, 2008

PRoFESS® Adverse Events

DP + ASA clopidogrel

Number of randomized pts

10,181 10,151

Headache with permanent discontinuation

600 (5.95%) 88 (0.9%)

Dizziness or lightheadedness

1365 (13.6%) 908 (9.1%)

Fainting 149 (1.5%) 76 (0.8%)

Migraine during first 6 months of study

562 (5.9%) 314 (3.3%)

ASA = aspirin 25 mg bid; DP = modified-release dipyridamole 200 mg bid N Engl J Med 359:1238, September 18, 2008 Adapted from Mohr J, et al, for the WARSS Group. N Engl J Med. 2001;345:1444-1451.

Number at Risk:Warfarin 1103 1047 1013 998 972 956 939 924 885Aspirin 1103 1057 1032 1004 984 974 951 932 900

0 90 180 270 360 450 540 630 720Days After Randomization

Aspirin

Warfarin

Pro

babi

lity

of E

ven

t (%

)

No significantdifference

10

Primary Endpoint: Time to Recurrent Ischemic Stroke or Death

WARSS

20

30

Newer treatments for nonvavular Afib

• Warfarin–Inhibits synthesis of vitamin K dependent clotting factors

• Dabigatran–Direct thrombin inhibitor

• Rivaroxaban–Direct factor Xa inhibitor

Reversal of Treatments• Warfarin– Vitamin K– Fresh frozen plasma– Protein complex concentrates

• Dabigatran– No antidote– Hemodialysis

• Rivaroxaban– Hemostatics PCC, rFVIIa may be considered but not been

evaluated– NOT dialyzable

Studies Relative risk reduction

All stroke (total) 0.82 (0.77–0.87)•All stroke (primary-prevention studies) 0.81 (0.75–0.87)•All stroke (secondary prevention: SPARCL, HPS, LIPID, and CARE)

0.88 (0.78-0.99)

Fatal stroke (total) 0.87 (0.73–1.03)•Fatal stroke (primary-prevention studies) 0.90 (0.76–1.05)•Fatal stroke (secondary prevention: SPARCL) 0.59 (0.36–0.97)Hemorrhagic stroke (total) 1.03 (0.75–1.41)•Hemorrhagic stroke (primary-prevention studies) 0.81 (0.60–1.08)•Hemorrhagic stroke (secondary prevention: SPARCL and HPS)

1.73 (1.19–2.50)

Effect of statins on all strokes, fatal stroke, and hemorrhagic stroke

Amarenco P, Labreuche J. Lancet Neurol 2009; 8:453-463.

Effects of High-dose Atorvastatin After Stroke or TIA

SPARCL Investigators. N Engl J Med. 2006;355:549-559.

SPARCL

SPARCL=Stroke Prevention by Aggressive Reduction in Cholesterol Levels.

No. at RiskAtorvastatin 2365 2148 2023 1933 1837 871 119Placebo 2366 2132 1998 1871 1780 803 126

HR, 0.77 (95% CI, 0.67–0.88); P<0.001

Atorvastatin 80 mg qd

Placebo

Years Since Randomization

Stro

ke o

r TI

A (

%)

2008 AHA/ASA Recommendations for Lipid Management

•Ischemic stroke or TIA patients with elevated cholesterol, comorbid coronary artery disease, or evidence of an atherosclerotic origin should be managed according to NCEP III guidelines, which include lifestyle modification, dietary guidelines, and medication recommendations. Class I, Level A

•Statin agents are recommended, and the target goal for cholesterol lowering for those with CHD or symptomatic atherosclerotic disease is an LDL-C level of 100 mg/dL. An LDL-C 70 mg/dL is recommended for very high-risk persons with multiple risk factors. Class I, Level AStroke. 2008;39:1-6.

2008 AHA/ASA Recommendations for Lipid Management

•Ischemic stroke or TIA patients with low HDL cholesterol may be considered for treatment with niacin or gemfibrozil. Class IIb, Level B

Stroke. 2008;39:1-6.

Blanco M et al. Neurology 2007; 69:904-910.

Adjusted risk for death or dependence associated with statin withdrawal

Statin-withdrawal group, n (%)

Odds ratio

95% CI

27 (60) 4.66 1.46–14.91

Individuals who stop statin treatment after hospitalization for ischemic stroke have nearly a fivefold increased risk for death or dependence within three months poststroke

Awareness Is Not Enough!

NCEP, National Cholesterol Education Program.Pearson TA, et al. Arch Intern Med. 2000;160:459-467.

95%

38%

0

20

40

60

80

100

Physician Awareness ofNCEP Guideline

Patient Treated to Goal

Sam

ple

(%

)

Impact of PROTECT pilot phase on Treatment Rates at Discharge

0

20

40

60

80

100

Antithrombotic Statin ACEI/ARB Thiazide

Percent

Pre PROTECT

--Ovbiagele et al, Stroke 2003

Work-up of TIA and Ischemic Stroke

All Patients•Brain Imaging•Neurovascular imaging•Blood glucose•Serum electrolytes•CBC w/ Platelets•PT/PTT/INR•12 lead EKG/ROMI•Holter monitoring•TTE/TEE•Supplemental O2

•Fever reduction

•Lipids

Selected Patients–Hepatic functions–Toxicology–Blood alcohol level–Pregnancy–Hypercoagulable

w/u–EEG–LP

Discharged with:

•Blood pressure control–Diabetics ACEI/ARBs

•Antiplatelets

•Statins

•Lifestyle changes

Review of Learning Objectives

•Review Epidemiology•Review polyvascular disease•Discuss new definitions of TIA•Review medical interventions–Antihypertensives–Statin therapy–Anticoagulants–Antiplatelet therapy

•Review barriers to improve outcomes•Discuss promotion of stroke centers•Review stroke workup

• All who drink of this treatment recover within a short time, except in those who do not.

Therefore, it fails only in incurable cases

-Galen

Thank you for your Attention