Update in NeurologyUpdate in Neurology

29 August, 200829 August, 2008

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http://epilepsy.kku.ac.th

E-mail : somtia@kku.ac.th

TopicsTopics

��Status epilepticus : Status epilepticus :

European clinical practiceEuropean clinical practice

��Stroke prevention :Stroke prevention :

PROFESS trialPROFESS trial

SPARCL trialSPARCL trial

Status Epilepticus in EuropeStatus Epilepticus in Europe

�� Status epilepticus classificationStatus epilepticus classification

�� Drug available in Europe Drug available in Europe

�� Efficacy of new AED iv in status epilepticusEfficacy of new AED iv in status epilepticus

�� New standard practice in EuropeNew standard practice in Europe

General concern in SE 1. VPA are sufficient for inclusion in protocol

2. Continuous EEG monitoring (20%)

3. Protocol at AE

4. PB is still justified

Survey of Adult GCSE �45 physicians from 26 countries

�41/45 were neurologist

�79% from university hospital

�16% from private, public hospital

�5% from research institute

�64% have protocol for SE at AE

PrePre--hospital managementhospital management

�� Prognosis of SE related with time to controlPrognosis of SE related with time to control

�� Success rate to control seizure related early treatmentSuccess rate to control seizure related early treatment

�� Mortality rate related success rate of seizure controlMortality rate related success rate of seizure control

�� PrePre--hospital treatment is very importanthospital treatment is very important

�� IV or rectal benzodiazepineIV or rectal benzodiazepine

�� BuccalBuccal or intranasal or intranasal midazolammidazolam

Treatment are used in 9out-of hospital=

�Rectal diazepam 57/34/9%

�Buccal miadzolam -/33/67%

(most/some/never)

Annex 1. Availability and licensing of drugs for SE in European Annex 1. Availability and licensing of drugs for SE in European countries.countries.

ValproateValproate Phenytoin Phenytoin LorazepamLorazepam Diazepam Diazepam MidazolamMidazolam ClonazepamClonazepam

AvailableAvailable Reg.f.SEReg.f.SE AvailableAvailable Reg.f.SEReg.f.SE AvailableAvailable Reg.f.SEReg.f.SE AvailableAvailable Reg.f.SEReg.f.SE AvailableAvailable Reg.f.SEReg.f.SE AvailableAvailable Reg.f.SEReg.f.SE

Australia Australia yesyes nono yes yes yes yes yesyes nono yesyes yesyes yesyes nono yesyes yesyes

Austria Austria yesyes nono yes yes yes yes yesyes yesyes yesyes yesyes yesyes nono yesyes nono

Belgium Belgium yesyes nono yes yes yes yes yesyes nono yesyes yesyes yesyes nono yesyes nono

Canada Canada nono nono yes yes yes yes yesyes nono yesyes yesyes yesyes nono yesyes nono

Czech Republic Czech Republic nonoaa nono yes yes yes yes nono nono yesyes yesyes yesyes nono yesyes yesyes

Denmark Denmark yesyes nono yes yes yes yes —— —— —— —— —— —— —— ——

Finland Finland yesyes nono yes yes yes yes yesyes nono yesyes yesyes yesyes nono yesyes nono

France France yesyes nono yes yes yes yes yesyes nono yesyes yesyes yesyes nono yesyes yesyes

GermanyGermany yesyes nono yes yes yes yes yesyes yesyes yesyes yesyes yesyes nono yesyes yesyes

Greece Greece yesyes nono yes yes yes yes —— —— —— —— —— —— —— ——

Hungary Hungary yesyes yesyes yes yes yes yes nono nono yesyes yesyes yesyes nono yesyes nono

Ireland Ireland yesyes nono yes yes yes yes yesyes nono yesyes nono nono nono yesyes yesyes

ItalyItaly yesyes nono yes yes nono yesyes yesyes yesyes yesyes yesyes nono yesyes yesyes

JapanJapan nono nono yes yes yes yes yesyes nono yesyes yesyes yesyes nono yesyes nono

Reg.f.SEReg.f.SE, registered for use in SE., registered for use in SE.aaValproateValproate intravenous (IV) is licensed but not marketed.intravenous (IV) is licensed but not marketed.

Annex 1. Availability and licensing of drugs for SE in European Annex 1. Availability and licensing of drugs for SE in European countries.countries.

ValproateValproate Phenytoin Phenytoin LorazepamLorazepam Diazepam Diazepam MidazolamMidazolam ClonazepamClonazepam

AvailableAvailable Reg.f.SEReg.f.SE AvailableAvailable Reg.f.SEReg.f.SE AvailableAvailable Reg.f.SEReg.f.SE AvailableAvailable Reg.f.SEReg.f.SE AvailableAvailable Reg.f.SEReg.f.SE AvailableAvailable Reg.f.SEReg.f.SE

Korea Korea yesyes nono yes yes yes yes yesyes yesyes yesyes yesyes yesyes yesyes yesyes yesyes

The NetherlandsThe Netherlands yesyes nono yes yes yes yes yesyes nono yesyes nono yesyes nono yesyes yesyes

Norway Norway yesyes yesyes yes yes yes yes nono nono yesyes yesyes yesyes nono yesyes nono

Poland Poland yesyes nono yes yes yes yes yesyes yesyes yesyes nono yesyes yesyes yesyes nono

Portugal Portugal yesyes nono yes yes yes yes yesyes nono yesyes nono yesyes nono yesyes nono

Russia Russia yesyes nono nono nono —— —— —— —— —— —— —— ——

South Africa South Africa yesyes nono yes yes yes yes yesyes nono yesyes yesyes yesyes nono yesyes yesyes

Spain Spain yesyes nono yes yes yes yes yesyes nono yesyes yesyes yesyes nono yesyes yesyes

Sweden Sweden yesyes nono yes yes yes yes yesyes nono yesyes yesyes yesyes nono yesyes yesyes

Switzerland Switzerland yesyes nono yes yes yes yes yesyes nono yesyes yesyes yesyes nono yesyes yesyes

Turkey Turkey —— nono yes yes yes yes —— —— —— —— —— —— —— ——

United Kingdom United Kingdom yesyes nono yes yes yes yes yesyes yesyes yesyes yesyes yesyes nono yesyes yesyes

United States of United States of

America America yesyes nono yes yes yes yes yesyes nono yesyes yesyes yesyes nono yesyes nono

Reg.f.SEReg.f.SE, registered for use in SE., registered for use in SE.aaValproateValproate intravenous (IV) is licensed but not marketed.intravenous (IV) is licensed but not marketed.

Survey of licensed drug for SE : 25 countries in Europe

�Sodium valproate 2:22 (registered: available)

�Phenytoin 24:24(registered: available)

�Sodium valproate : Hungary, Norway

�No Phenytoin : Russia

Intravenous benzodiazepine �First line

�DZP 66%

�LOR 29.5%

�MID 4.5%

�Second line

�DZP 26%

�LOR 18%

�MID 56%

Intravenous AED after BZP

43.516VPA

2818PB

2.523FOS

2643PHT

Second line(%)First line (%)

Anesthetic agent in RSE

1428Midazolam

3023.5Propofol

148.5Phenobarb

4240Thiopental

Second line (%)First line (%)

New generation of anticonvulsant �Non-GABAergic mechanisms

�Topiramate

�Levetiracetam

�Blockade of NMDA receptor

�MK-801

Newer therapy � IV VPA is another choice for treatment in elderly

�Loading dose 15 mg/kg @ 70 mg/kg

�Safety and tolerability of rapid infusion rate

�Low risk of hypotension,

respiratory depression sedative

VPA for SE in Srinagarind hospitalVPA for SE in Srinagarind hospital

�� First line drug 41%First line drug 41%

�� Second line drug 54.5%Second line drug 54.5%

��Third line drug 4.5%Third line drug 4.5%

��Dosage 15Dosage 15--25 mg/kg/dose, mean 16.8225 mg/kg/dose, mean 16.82

��Total dose/day 750Total dose/day 750--2700 mg, mean 10252700 mg, mean 1025Somsak Tiamkao,et al 2007

Outcome of seizure controlOutcome of seizure control

��Complete seizure controlled 56.8%Complete seizure controlled 56.8%

��Stop, then recurrent seizure 15.9%Stop, then recurrent seizure 15.9%

��Partially seizure controlled 11.4%Partially seizure controlled 11.4%

�No seizure controlled 13.6%Somsak Tiamkao,et al 2007

Outcome of treatmentOutcome of treatment

��Complete recovery 27.9 %Complete recovery 27.9 %

��Death recovery 41.9%Death recovery 41.9%

��Partial recovery 16.3%Partial recovery 16.3%

��Recovery to sameRecovery to same previous previous

neurological deficit 14%neurological deficit 14%Somsak Tiamkao,et al 2007

Newer therapy �IV levetiracetam, July 2006 available

�1000 @ 6000 mg

�23% respond (3/13)

�38% undetermine

�31% no respond

Newer therapy in RSE �Topiramate nasogastric

�Ettectvie dose 300 @ 1600 mg/day

�Most of cases : CPSE

Table 1. Classification of SETable 1. Classification of SE

1. NCSE occurring in the neonatal and infantile epilepsy syndrom1. NCSE occurring in the neonatal and infantile epilepsy syndromeses

1a. 1a. OhtaharaOhtahara syndromesyndrome

1b. West syndrome1b. West syndrome

1c. Severe 1c. Severe myoclonicmyoclonic encephalopathy of infancy (SMEI; encephalopathy of infancy (SMEI; DravetDravet syndrome)syndrome)

1d. NCSE in other forms of neonatal or infantile epilepsy1d. NCSE in other forms of neonatal or infantile epilepsy

2. NCSE occurring only in childhood2. NCSE occurring only in childhood

2a. NCSE in early2a. NCSE in early--onset benign childhood occipital epilepsy (Panayiotopoulos syndronset benign childhood occipital epilepsy (Panayiotopoulos syndrome)ome)

2b. NCSE in other forms of childhood epileptic 2b. NCSE in other forms of childhood epileptic encephalopathiesencephalopathies, syndromes, and etiologies , syndromes, and etiologies

(e.g., Ring chromosome 20, (e.g., Ring chromosome 20, AngelmanAngelman syndrome, syndrome, RettRett syndrome, syndrome, myoclonicmyoclonic--astaticastatic epilepsy, epilepsy,

other childhood other childhood myoclonicmyoclonic encephalopathiesencephalopathies))

2c. Electrical status epilepticus in slow wave sleep (ESES)2c. Electrical status epilepticus in slow wave sleep (ESES)

2d. Landau2d. Landau--KleffnerKleffner syndromesyndrome

3. Convulsive SE occurring only in childhood3. Convulsive SE occurring only in childhood

3a. Febrile SE3a. Febrile SE

4. NCSE occurring in both childhood and adult life with epilepti4. NCSE occurring in both childhood and adult life with epileptic encephalopathyc encephalopathy

4a. NCSE in the Lennox4a. NCSE in the Lennox--GastautGastaut syndromesyndrome

i. Atypical absence SEi. Atypical absence SE

ii. Tonic SEii. Tonic SE

4b. Other forms of NCSE in patients with learning disability or 4b. Other forms of NCSE in patients with learning disability or disturbed cerebral development disturbed cerebral development

(cryptogenic or symptomatic) without epileptic encephalopathy(cryptogenic or symptomatic) without epileptic encephalopathy

4c. Typical absence SE in idiopathic generalized epilepsy4c. Typical absence SE in idiopathic generalized epilepsy

Table 1. Classification of SETable 1. Classification of SE

4d. Complex partial SE:4d. Complex partial SE:

i. Limbici. Limbic

ii. ii. NonlimbicNonlimbic

4e. NCSE in the 4e. NCSE in the postictalpostictal phase of tonicphase of tonic––clonic seizuresclonic seizures

4f. Subtle SE (4f. Subtle SE (myoclonicmyoclonic SE occurring in the late stage of convulsive SE)SE occurring in the late stage of convulsive SE)

4g. Aura continua [with: (i) sensory, (ii) special sensory, (iii4g. Aura continua [with: (i) sensory, (ii) special sensory, (iii) autonomic, (iv) cognitive ) autonomic, (iv) cognitive

symptoms]symptoms]

5. Convulsive forms of SE occurring in childhood and adult life5. Convulsive forms of SE occurring in childhood and adult life

5a. Tonic5a. Tonic––clonic status epilepticusclonic status epilepticus

5b. Epilepsia partialis continua (EPC; simple partial motor SE)5b. Epilepsia partialis continua (EPC; simple partial motor SE)

5c. 5c. MyoclonicMyoclonic SESE

6. NCSE occurring in late adult life6. NCSE occurring in late adult life

6a. De novo absence SE of late onset6a. De novo absence SE of late onset

7. Boundary 7. Boundary syndromessyndromesaa

7a. Some cases of epileptic encephalopathy7a. Some cases of epileptic encephalopathy

7b. Some cases of coma due to acute brain injury with 7b. Some cases of coma due to acute brain injury with epileptiformepileptiform EEG changesEEG changes

7c. Some cases of epileptic behavioral disturbance or psychosis7c. Some cases of epileptic behavioral disturbance or psychosis

7d. Some cases of drug induced or metabolic confusional state wi7d. Some cases of drug induced or metabolic confusional state with th epileptiformepileptiform EEG changesEEG changes

aaBoundaryBoundary syndromes are defined as cases in which it is not clear to whatsyndromes are defined as cases in which it is not clear to what extent the extent the

continuous continuous epileptiformepileptiform electrographic abnormalities are contributing to the clinical ielectrographic abnormalities are contributing to the clinical impairment.mpairment.

Status epilepticus : SEStatus epilepticus : SE

• Non-convulsive SE : NCSE

- NCSE in neonatal, childhood, adult

- NCSE : absence, CPS, subtle

••Convulsive SE : CSEConvulsive SE : CSE

- CSE in childhood, adult

- CSE : tonic-clonic, myoclonic, EPC

PrePre--hospital managementhospital management

�� Prognosis of SE related with time to controlPrognosis of SE related with time to control

�� Success rate to control seizure related early treatmentSuccess rate to control seizure related early treatment

�� Mortality rate related success rate of seizure controlMortality rate related success rate of seizure control

�� PrePre--hospital treatment is very importanthospital treatment is very important

�� IV or rectal benzodiazepineIV or rectal benzodiazepine

�� BuccalBuccal or intranasal or intranasal midazolammidazolam

Protocol for in-hospital treatment of tonic-clonic SE

Stage 1 : stage of early status (0 - 10/30 min)

Stage 2 : stage of established status (10/30 – 60/90 min)

Stage 3 : stage of refractory status (> 60/90 min)

Stage 1 : early status (0 - 10/30 min)

- Lorazepam : 4 mg IV bolus

(can be replaced once 5-10 min)

- If seizures continue after 30 min

Drug used in the stage early tonicDrug used in the stage early tonic--clonic SEclonic SE

Route of administrationRoute of administration Adult doseAdult dose

DiazepamDiazepam IV bolus (not exceed 2IV bolus (not exceed 2--5 mg/min)5 mg/min) 1010--30 mg30 mg

Rectal administrationRectal administration 1010--30 mg30 mg

ClonazepamClonazepam IV bolus (not exceed 2 mg/min)IV bolus (not exceed 2 mg/min) 11--2 mg at 2 mg/min2 mg at 2 mg/min

LorazepamLorazepam IV bolusIV bolus 4 mg (0.07 mg/kg)4 mg (0.07 mg/kg)

MidazolamMidazolam BuccalBuccal, intranasal, intranasal 55--10 mg10 mg

Stage 2 : established status(10/30 – 60/90 min)

- Phenobarbital : IV infusion 10 mg/kg at a maximum

rate of 100 mg/min

- Phenytoin : IV infusion 15 mg/kg at a maximum rate

50 mg/min

- Fosphenytoin : IV infusion 15 mg/kg at a maximum

rate 50 mg/min

- Valproate : IV infusion 25 mg/kg at 3-6 mg/kg/min

- Levetiracetam : IV bolus 2000 – 4000 mg

New PracticeNew Practice

34

Stroke in ThailandStroke in Thailand

� Bangkok metropolis (1983) = 690 : 100,000 age over 20

(Viriyavejakul A, et al. 6th Excerpta Medical No.22; 1983: 10)

� Stroke in the elderly (1998); overall 1.12%

Central 1.99 North 0.6

South 1.5 Northeast 0.6

(Viriyavejakul A, et al. J Med Assoc Thai 1998; 81: 497-505)

�Thai Epidemiology Stroke Study (TES Study 2004): Stroke in age 45-80 years = 2.46%

Prevalence

CINP Asia pacific Regional Meetng March 14-17, 2006, Pattaya, Thailand Abstracts P54-55

35

Secondary

Prevention:

Antiplatelets

therapy

ASA for Secondary Prevention

Dipyridamole plus ASA and ASA alone: ESPS 2

38

CClopidogrellopidogrel versus versus AASA in SA in PPatients at atients at RRisk of isk of IIschemic schemic EEventsventsObjectiveObjectiveObjectiveObjective

- To assess the relative efficacy of Clopidogrel and ASA in

reducing the incidence of ischemic stroke, MI, Vascular death

among patients who had survived a recent ischemic stroke,

recent MI, or had symptomatic atherosclerotic peripheral arterial

disease

- To assess the relative safety and tolerability of Clopidogrel

and ASA

CAPRIE

39

Primary End Point

▪ First occurrence of ischemic

stroke, MI, or vascular death

Primary End Point

▪ First occurrence of ischemic

stroke, MI, or vascular death

FollowFollow--up 1 to 3 yearsup 1 to 3 years

N=19,185

n=9,586Aspirin 325 mgAspirin 325 mg

n=9,599Clopidogrel 75 mgClopidogrel 75 mg

384 centers

16 countries

384 centers

16 countries

Patient Population

▪ Patients with recent

MI, recent ischemic

stroke,

or established PAD

Patient Population

▪ Patients with recent

MI, recent ischemic

stroke,

or established PAD

Study DesignStudy Design

CAPRIE

CAPRIE Steering Committee. Lancet. 1996;348:1329-1339. 40

Efficacy of Clopidogrel vs Aspirin in MI, Efficacy of Clopidogrel vs Aspirin in MI, Ischemic Stroke, or Vascular Death Ischemic Stroke, or Vascular Death (N=19,185)(N=19,185)11

Months of Follow-Up

Cu

mu

lati

ve

E

ve

nt

Ra

te (

%)

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

Clopidogrel

P=0.0452

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

Median Follow-up=1.91 years

Study subjects had either recent MI, recent ischemic

stroke, or established peripheral arterial

disease.

CAPRIE

41

Study Drug Permanently DiscontinuedStudy Drug Permanently Discontinued

CAPRIE Safety/Tolerability*CAPRIE Safety/Tolerability*

0.93%†0.52%Gastrointestinal hemorrhage

1.37%1.20%Any bleeding disorder

0.29%0.23%Abnormal liver function

0.33%0.21%Intracranial hemorrhage

2.41%†1.90%Indigestion/nausea/vomiting

0.27%0.42%Diarrhea

0.41%†0.90%Rash

Aspirin 325 mgn=9,586

Clopidogrel 75 mgn=9,599Adverse Experiences

* Aspirin-intolerant patients excluded.† Statistically significant p<0.05

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

CAPRIE

42

MATCH

Rationale

- Patients with a recent TIA or Ischemic Stroke remain at high risk of

subsequent major vascular events

- Prevention of major ischemic events in high-risk patients requires aggressive

antiplatelet therapy

- Synergy between clopidogrel and ASA is supported by pre-clinical and

clinical data

- Benefit of clopidogrel is amplified in high-risk patients

Objectives

- Evaluate clopidogrel plus ASA versus monotherapy in patients with a recent

TIA or ischemic stroke and at high risk of recurrent ischemic events

- Evaluate safety of long-term administration of combined clopidogrel and ASA

treatment in patients with cerebrovascular disease

Management of ATherothrombosis with Clopidogrel

In High-risk patients with recent TIA or IS

43

28 countries28 countries

clopidogrel 75 mg + placeboclopidogrel 75 mg + placebo

clopidogrel 75 mg + ASA 75 mgclopidogrel 75 mg + ASA 75 mg

N=7,599

18 months

n=3,797

n=3,802

Diener H-C et al for the MATCH Investigators. Lancet. 2004;364:331-337.

Patient Population

▪ Patients with recent TIA

or IS, and at high risk for

recurrent events

� Previous IS, MI,

angina, DM, or

symptomatic PAD

Patient Population

▪ Patients with recent TIA

or IS, and at high risk for

recurrent events

� Previous IS, MI,

angina, DM, or

symptomatic PAD

Primary End Point

▪ First occurrence of MI, IS, vascular

death, or rehospitalization for acute

ischemic event

Primary End Point

▪ First occurrence of MI, IS, vascular

death, or rehospitalization for acute

ischemic event

MATCH

Study DesignStudy Design

44† ITT analysis.

MI=myocardial infarction; IS=ischemic stroke.

Diener H-C et al for the MATCH Investigators. Lancet. 2004;364:331-337.

6.4%†

Overall

Relative Risk

Reduction

P=0.244

Months of Follow-Up

Cu

mu

lati

ve

Ev

en

t R

ate

(%

)

Clopidogrel+ ASA

Clopidogrel+ Placebo

0

4

8

12

16

20

0 3 6 9 12 15 18

N=7,599

Primary End Point: MI, IS, Vascular Death, Primary End Point: MI, IS, Vascular Death, or Rehospitalization for an Acute Ischemic or Rehospitalization for an Acute Ischemic Event Event

MATCH

45

22 (1%)

38 (1%)

11 (<1%)

49 (1%)

Placebo +Placebo +

ClopidogrelClopidogrel

(n=3,781)(n=3,781)

<0.00011.26 (0.64, 1.88) 96 (3%)Life-Threatening* Events (%)

Major Bleeding† Events (%)

Nonfatal

Fatal

Type of Bleeding Events (%)Type of Bleeding Events (%)

73 (2%)

81 (2%)

16 (<1%)

ASA + ASA +

ClopidogrelClopidogrel

(n=3,759)(n=3,759)

1.36 (0.86,1.86)

1.15 (0.59, 1.71)

0.13 (-0.14, 0.40)

% Absolute % Absolute

DifferenceDifference

(95% CI)(95% CI)

<0.0001

PP--valuevalue

Main Safety OutcomesMain Safety Outcomes

* Defined as “Life threatening”: any fatal bleeding event, or a drop in hemoglobin of ≥5g/dL, or significant hypotension with the need for inotropes (hemorrhagic shock), or symptomatic intracranial hemorrhage, or requiring transfusion of ≥4 units of RBC or equivalent amount of whole blood.

† Defined as “Major bleeding”: significantly disabling (with persistent sequelae), or intraocular bleeding leading to significant loss of vision, or requiring transfusion of ≤3 units of RBC or equivalent amount of whole blood.ASA=aspirin; CI=confidence interval.

1. Diener H-C et al for the MATCH Investigators. Cerebrovasc Dis. 2004;17:253-261.2. Diener H-C et al for the MATCH Investigators. Lancet. 2004;364:331-337.

MATCH

Stroke Mortality Rate by Age1

Blood Pressure and Stroke Mortality

Stroke mort al ity rate in each decade o f age vs. usual b lood pressure at the star t of the decade.

A meta-analysis involving 1 mill ion parti cipants in 61 cohort studies to determine the relevance of

blood pressure to risk of disease in patients of di fferent ages.1. Prospective Studies Collaboration. Lancet 2002; 360:1903-1913.

6

Treatment HT and Stroke

PERINDOPRIL PROTECTION AGAINST RECURRENT STROKE STUDY

The firs t randomized trial of ACE

inhibitor-bas e d tre atment in patients

with a his tory of c ere brovas cular

dis e as e

Nea l B, Ma cMa hon S. J Hype rtens . 19 95 ;13:18 69 -1 87 3.

The Losartan I ntervention For Endpoint Reductionin Hypertension Study

An invest igator init iated community-based study in 945

sites in 7 countries enrolling 9,193 patients

Steering Committee Chair/ Vice-Chair B. Dahl?f, D. Devereux

European/ US Coordinators S.E. Kje ldsen, S. Julius

Data and Safety Monitoring Committee Chair J. Kjekshus

Clinical Endpoint Classif ication Committee D. Levy, K. Thygesen

LIFE

Reduction in the Risk of Stroke1

No significant difference in CV death and MI vs. ateno lol. Risk reduction = relative risk vs. atenolol.

Losartan (n) 4605 4528 4469 4408 4332 4273 4224 4166 4117 3974 1928 925

Atenolol (n) 4588 4490 4424 4372 4317 4245 4180 4119 4055 3894 1901 897

Number at risk

161. Dahl?f B et al. Lancet 2002;359: 995-1003.

Atenolo

l

Pro

por

tio

n o

f p

atie

nts

wit

h f

irst

eve

nt(%

)

6

7

0

2

3

4

5

0 6 423012 18 24 36 48 54 60 66

Time (months)

Losartan

1Adjusted risk reduction 24.9%, p = 0.0010Unadjusted risk reduction 25.8%, p = 0.0006

Fatal and nonfatal stroke

8

53

Stroke prevention ?

▪ASA

▪Clopidogrel

▪ASA + Dypiridamole

▪Antiplatelet + ACE I/ ARB

Ischemic Stroke Risk Increases Ischemic Stroke Risk Increases With Serum CholesterolWith Serum Cholesterol

• Estimate adjusted for age, sex, race, hypertension, index year, time to cholesterol measurement, SBP and DBP, coronary heart disease, atrialfibrillation, diabetes, tobacco use, and use of statins

CI=confidence interval; SBP=systolic blood pressure; DBP=diastolic blood pressure.

Adapted from Tirschwell DL et al. Neurology. 2004;63:1868-1875.

Total Ischemic Stroke (95% CI)

Total Cholesterol (mmol/L)

Total Cholesterol (mg/dL)

4 5 6 7 8

4

3

2

1

0.5

Od

ds R

ati

o (

95

% C

l)

Mea

n v

alu

e o

f lo

west q

uin

tile

150 175 200 225 250 275 300 325

(n=1242)

Statin Therapy Is Statin Therapy Is NotNot Associated With Associated With Increased Risk for Hemorrhagic StrokeIncreased Risk for Hemorrhagic Stroke

Adapted from Amarenco P. et al. Stroke. 2004;35:2902-2909; Yano K et al. Stroke. 1989;20:1460-1465;

Iso H et al. N Engl J Med. 1989;320:904-910.

Favors Statin Favors Control

Trials Odds Ratios (95% Cl)

HPS*

GREACE†

MIRACL‡

KLIS§

LIPIDıı

CAREıı

SSSS*

AFCAPS¶

OVERALL (95% Cl)Heterogeneity

0.90 (0.65–1.22)P=.15

1.00.50.20.05 3.0 10.0

* Simvastatin vs placebo.† Atorvastatin vs usual care.‡ Atorvastatin vs placebo.§ Pravastatin vs conventional treatment.ııPravastatin vs placebo.¶ Lovastatin vs placebo.

Primary PreventionPrimary Prevention

–11*–9*

–27†

–48‡–50

–45

–40

–35

–30

–25

–20

–15

–10

–5

0WOSCOPS ALLHAT-LLT ASCOT-LLA CARDS

Rela

tiv

e R

isk R

ed

ucti

on

fo

r S

tro

ke (

%)

Adapted from Sever PS et al. Lancet. 2003;361:1149-1158; Shepherd J et al. N Engl J Med. 1995;333:1301-1307; ALLHAT

Officers. JAMA. 2002;288:2998-3007; Colhoun HM et al. Lancet. 2004; 364:685-696.

WOSCOPS=West of Scotland Coronary Prevention Study; ALLHAT-LLT=Antihypertensive and Lipd-Lowering Treatment to

Prevent Heart Attack Trial–Lipid-Lowering Treatment; ASCOT-LLA=Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-

Lowering Arm; CARDS=Collaborative Atorvastatin Diabetes Study.

*P=NS (pravastatin vs placebo or usual care).†P=.024 (atorvastatin vs placebo).‡P=not reported (atorvastatin vs placebo).

(n=6595)(n=10,355)

(n=10,305)

(n=2841)

Prevention of Stroke in Patients Without Prevention of Stroke in Patients Without Documented Cardiovascular DiseaseDocumented Cardiovascular Disease

.016

.024

.31

.57

P Value

–48*46 (40)28413.9Atorvastatin 10 CARDS

–2437 (35)10,3053.3Atorvastatin 10 ASCOT-LLA

–924 (17)10,3554.8Pravastatin 40 ALLHAT-LLT

–1150 (26)65954.9Pravastatin 40 WOSCOPS

Relative Risk

Reduction

Between-Group Difference in LDL-C

Reduction, mg/dL (%)

Number of Patients

Follow-up, y

Statin Dose, mgTrial

Adapted from Sever PS et al. Lancet. 2003;361:1149-1158; Shepherd J et al. N Engl J Med. 1995;333:1301-1307;ALLHAT Officers. JAMA. 2002;288:2998-3007; Colhoun HM et al. Lancet. 2004;364:685-696; Newman C et al.

Accepted for presentation at the American Heart Asssociation Scientific Sessions 2005; Dallas, TX. November 13-16, 2005.

* 95% CI for the HR = 0.31–0.89.

ASCOTASCOT--LLA: Atorvastatin Lowers Stroke Risk LLA: Atorvastatin Lowers Stroke Risk in Patients With Good Blood Pressure Controlin Patients With Good Blood Pressure Control

ASCOT-LLA = Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm; HR = hazard ratio.Adapted from Sever PS et al. Lancet. 2003;361:1149-1158.

0

1

2

3

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Years

Pro

po

rtio

n o

f P

ati

en

ts (

%)

HR=0.73 (0.56–0.96)

P=.0236

27%

reduction

Atorvastatin 10 mg Number of events 89

Placebo Number of events 121

(n=10,305)

CARDS: Stroke Prevention CARDS: Stroke Prevention in Diabetic Patients Without CHDin Diabetic Patients Without CHD

–48% (–69, –11)21 (1.5)39 (2.8)Stroke

–1% (–59, +16)24 (1.7)34 (2.4)Coronary revascularization

–36% (–55, –9)51 (3.6)77 (5.5)Acute coronary events

–37% (–52, –17)

P=.001

83 (5.8)127 (9.0)Primary end point

Relative Risk (CI)Hazard RatioAtorva*Placebo*Event

.2 .4 .6 .8 1 1.2

Favors Atorvastatin

Favors Placebo

CARDS=Collaborative Atorvastatin Diabetes Study.

* Number of patients with an event (%).

Adapted from Colhoun HM et al. Lancet. 2004;364:685-696; Newman C et al. Accepted for presentation at

the American Heart Association Scientific Sessions 2005; Dallas, TX. November 13–16, 2005.

(n=2841)

Prevention of Stroke in Patients With Prevention of Stroke in Patients With Documented Cardiovascular DiseaseDocumented Cardiovascular Disease

–30*– 31†

– 19‡

– 25§

+3ıı

– 22ıı

– 47¶

– 13#

– 25**

–50

–45

–40

–35

–30

–25

–20

–15

–10

–5

04S CARE LIPID HPS

PROSPER

KLIS GREACE ALLIANCE TNT

Rela

tiv

e R

isk R

ed

ucti

on

fo

r S

tro

ke (

%)

Adapted from LaRosa JC et al. N Engl J Med. 2005;352:1425-1435; Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389; Sacks FM et al. N Engl J Med. 1996;336:1001-1009; LIPID Study Group. N Engl J Med. 1998;339:1349-1357; HPS Collaborative Group. Lancet. 2002;360:7-22; Shepherd J et al. Lancet. 2002;360:1623-1630; KLIS Study Group. J AtherosclerThromb. 2000;7:110-121; Athyros VG et al. Curr Med Res Opin. 2002;18:220-228; Koren MJ et al. J Am Coll Cardiol. 2004;44:1772-1779.

* P=.024 (simvastatin vs placebo).† P=.03 (pravastatin vs placebo).‡ P=.048 (pravastatin vs placebo).§ P<.0001 (simvastatin vs placebo).ıı P=NS (pravastatin vs placebo or conventional treatment).¶ P=.034 (atorvastatin vs usual care).# P=NS (atorvastatin vs usual care).

**P=.02 (80 mg vs 10 mg atorvastatin).

(n=4444) (n=4159) (n=9014) (n=20,536)

(n=5804)

(n=3853) (n=1600) (n=2442) (n=10,001)

Atorvastatin is not indicated for secondary prevention of CVD.

Stroke Reduction in TNTStroke Reduction in TNT

0 1 2 3 4 5 6

Time (years)

0

0.01

0.02

0.04

0.03

HR = 0.75 (95% CI 0.59, 0.96)P=.02

RRR 25%

Atorvastatin 10 mg (n=5006)

Atorvastatin 80 mg (n=4995)

Pro

po

rtio

n o

f P

ati

en

ts W

ith

Even

t

TNT = Treating to New Targets; RRR = relative risk reduction.

Atorvastatin is not indicated for secondary prevention of CVD.

Adapted from LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.

Statin Therapy for Stroke Prevention Statin Therapy for Stroke Prevention in ACS: MIRACLin ACS: MIRACL

Adapted from Waters DD et al. Circulation. 2002;106:1690-1695.

0

0.5

1

1.5

2

0 4 8 12 16

Time Since Randomization (weeks)

Cu

mu

lati

ve I

ncid

en

ce (

%)

Relative risk = 0.49P=.04

95% CI 0.24–0.98

Atorvastatin (n=1538)

Placebo (n=1548)

Placebo

540 Planned Primary End Points

4732

Patients

• ~200 sites worldwide

• Previously documented stroke or TIA

• No history of CHD

• LDL-C levels ≥100 mg/dL and ≤190 mg/dL

Atorvastatin 80 mg/d

Double-Blind PeriodPopulation

Primary End Point

Time to First Occurrence of a Fatal or Nonfatal Stroke

SPARCL: Study DesignSPARCL: Study Design

TIA= transient ischemic attack.

The SPARCL Investigators. Cerebrovasc Dis. 2003;16:389-395.

SPARCL: SPARCL: Secondary End PointsSecondary End Points

• Time to occurrence of

– Cerebrovascular event (includes TIA)

– Major coronary event, consisting of cardiac death, nonfatal MI, or resuscitated cardiac arrest

– Major cardiovascular event, defined as a major coronary event or fatal or nonfatal stroke

– Any CHD event, defined as an acute coronary event, coronary revascularization procedure, or angina/ischemia requiring emergent hospitalization

– Any revascularization procedure (coronary, carotid, or peripheral)

– Any cardiovascular event (any event except noncardiovascular death)

– All-cause mortality (death from any cause)

The SPARCL Investigators. Cerebrovasc Dis. 2003;16:389-395.

• MI, resuscitated cardiac arrest, or unstable angina

• Absolute and percent changes in serum lipids/lipoproteins

• Stroke impact as measured by

– Modified Rankin Scale (MRS) (handicap)

– Barthel Index (BI) (disability)

– NIH Stroke Scale (NIHSS) (impairment)

NIH=National Institutes of Health.

The SPARCL Investigators. Cerebrovasc Dis. 2003;16:389-395.

SPARCL: SPARCL: Secondary End Points (contSecondary End Points (cont’’d)d)

Thank you for your attention