Cerebral Blood Flow

And
Ischemic Brain Disease

BERNARDO L. CONDE, M.D.

Professor of Neurology & Psychiatry
Faculty of Medicine & Surgery
University of Santo Tomas
Normal Metabolism
 All tissues require constant sources of
oxygen and oxidizable substrates
 The brain requires –
 Oxygen 3.5 ml/100 grams
 Glucose 5.5 mg/100 grams
 Blood Flow 50 ml of blood/100 grams
The BRAIN extracts
 10% (30 umol/100 gram per ml) of
glucose from the blood.
 50% (156 umol/100 gram per minute) of
the oxygen delivered to the brain.
Regulation of Cerebral Metabolic Rate

 Brain consumes about 1/5 of the total

body oxygen consumption.
 Continuous cerebral circulation is
absolutely required to provide sufficient
oxygen.
1. Anaerobic Glycolysis

Glucose
Pyruvic
acid

2. Krebs (citric acid) Cycle

Pyruvic Acetyl
acid CoA

C
O

3. Respiratory (electron-transport)
chain

10 NADH → 10 NAD +
2 FADH3 → 2 FAD +
H2O
Five Levels of Vaso-regulation of the
Cerebro-Vascular System

 Autoregulation
 Regulation by intrinsic neural pathways
 Regulation by extrinsic neural pathways
 Metabolic coupling
 Regulation by the endothelium
 Factors Increased CBF Decreased CBF
Extrinsic
Systemic blood pressure MAP <50 to 70 mmHg
Cardiovascular function Cardiac arrhythmias; orthostatic
hypotension; loss of carotid
sinus and aortic arch reflexes
Blood viscosity Anemia Polycythemia
Intrinsic
State of the cerebral Arteriovenous malformation Atherosclerosis
vasculature
Intracranial CSF pressure Increased intracranial pressure
Cerebral autoregulatory
mechanism
Myogenic factors Decreased intraluminal pressure Increased intraluminal pressure
(vasodilation) (vasoconstriction)
Neurogenic factors Parasympathetic stimulation Sympathetic stimulation
(vasodilation) (vasoconstriction)
Biochemical-metabolic Increased CO2 (vasodilation) Decreased CO2
factors Decreased O2 (vasodilation) (vasoconstriction)
Decreased pH (acidosis) Increased O2 (vasoconstriction)
(vasodilation) Increased pH (alkalosis)
Lactic acidosis (vasodilation) (vasoconstriction)
Pathogenesis of the PLAQUE
 “RESPONSE TO INJURY” Hypothesis:
 The plaque is initiated by endothelial damage,
and the development of the plaque is the
result of proliferation of smooth muscle cells
in response to mitogenic agents, LDL, and
platelet-derived growth factors.
ENDOTHELIAL INJURY
 Includes actual desquamation of
endothelial cells as well as functional
disturbances that result in alterations in
thrombo-resistance or inability of the
endothelium to act as effective barrier for
the transfer of macromolecules into the
vessel wall.
Systemic Factors affecting the
CEREBRO-VASCULAR SYSTEM
 Hypertension
 Diabetes mellitus
 Hypercholesterolemia
 Cigarette smoking
 Obesity
Probable Mechanism of Action of
Risk Factors at the Cellular Level
 HYPERTENSION
 Increased endothelial permeability to LDL due
to:
 Increased artery tension
 “Trap door effect”of angiotensin

 Platelet sticking (NE induced?) with release of

vasoactive amines
 Especially bad when added to

hypercholesterolemia
Probable Mechanism of Action of
Risk Factors at the Cellular Level
 HYPERCHOLESTEROLEMIA
 Increased level of circulating LDL damage
endothelium and carry cholesterol into artery
wall;
 Lipid (cholesterol) is “trapped”, accumulates
in smooth muscle cells or is bound to their
extracellular product;
 Lead to cell proliferation and/or necrosis,
increased collagen formation, etc.
Cell Membrane Cholesterol
Ischemic Stroke Risk Increases
With Serum Cholesterol
Total Cholesterol (mmol/L)
4 5 6 7 8

4
Mean value of lowest quintile

3
Odds Ratio (95% Cl)

(n=1242) • Estimate adjusted for age,

2
sex, race, hypertension, index
year, time to cholesterol
measurement, SBP and DBP,
coronary heart disease, atrial
1 fibrillation, diabetes, tobacco
use, and use of statins
Total Ischemic Stroke (95% CI)

0.5
150 175 200 225 250 275 300 325

Total Cholesterol (mg/dL)

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

Adapted from Tirschwell DL et al. Neurology. 2004;63:1868-1875.
Probable Mechanism of Action of
Risk Factors at the Cellular Level
 DIABETES
 CHO induced hyperlipidemia (VLDL) along
with unknown factors stimulating arterial
media cell proliferation.
Probable Mechanism of Action of
Risk Factors at the Cellular Level
 CIGARETTE SMOKING
 Damage to cells of artery wall due to:
 Circulating CO;
 Platelet agglutination (NE induced?);

 Lipid mobilization (NE induced?) leading to

hyperlipidemia and;
 Increased lipid in artery wall
Probable Mechanism of Action of
Risk Factors at the Cellular Level
 OBESITY
 Elevated blood lipids;
 Increased incidence of diabetes and
hypertension;
 Poor cardiac reserve and increased work of
the heart.
Local Factors affecting the
CEREBRO-VASCULAR SYSTEM
 Geometry of the vessel
 Shear stress of flowing blood
Local Risk Factors for Stroke Among Filipinos

Hypertension 6.01 ( 4.48 – R

8.05) I
Diabetes 1.60 F
(1.10 – 2.32) A
Atrial Fibrillation 1.91 ( 0.51 – S
7.19) A
MI 4.67 F
(1.18 - 18.52)
RHD 3.69 (1.05
-12.99 )
Smoking 1.36
A. Roxas for PNA-DOH Risk factors for stroke (1.00
among Filipinos -
(RIFASAF).
1.86)
Phil J Neur 2002; 6:1-7.
 Risk Factors for Stroke: Philippines

Risk Factors Risk (OR) Prevalence(%)

Data source PNA-DOH RIFASAF 2003 NNHeS
Hypertension 6.01X 17.4
Diabetes 1.6X 4.6
Smoking 1.36X 56.3/12.1
CAD 4.67X 12.1
Atrial Fibrillation 1.91X ?
Hypercholesterolemia ? 8.5
Snoring 3.37X ?
Stress 1.69X -
Previous Stroke ? 1.4%

PNA-DOH. Risk factors for stroke among Filipinos. Phil J Neur 2002; 6:1-7. Phil. J of Intern Med May-June 2005,Vol.43.
 RISK FACTORS FOR
ATHEROTHROMBOSIS
Hypercoagulable Lifestyle Hyperlipidemi
states (smoking, diet, a
Homocysteinemi Hypertensio
lack of exercise)
a n
Diabetes Infection ?
Obesity Age
Genetics Gender

ATHEROSCLEROS
Atherothrombotic Manifestations
IS Vascular Death)
(MI, Ischemic STROKE,
Schematic Time Course of Human
Atherogenesis Ischemic Heart
Disease

Cerebrovascular
Disease

Peripheral
Vascular
Lesion initiation
Disease

No symptoms ± Symptoms Symptoms

Time (y)
 Atherogenesis & Atherothrombosis:
A Progressive Process

INCREASING AGE MYOCARDIAL

INFARCTION

ISCHEMIC STROKE
ANGINA, TIA,
CLAUDICATIONS, CRITICAL LEG
CLINICALLY
PAD ISCHEMIA
SILENT
CARDIOVASCULAR
DEATH
Atheromas are not filled merely with lipids, but
also contain cells whose functions critically
influence atherogenesis:

Intrinsic Vascular Wall Cells:

 Endothelium
 Smooth Muscle Cells
Inflammatory Cells:
 Macrophages
 T Lymphocytes
 Mast Cells
Cell Types in the Human Atheroma
Monocyte/
Macrophage

Endothelium
Intima

Tunica T-lymphocytes
Media
Smooth muscle
cells
Leukocyte–Endothelial Adhesion Molecules
Mono
T PMN
B
Macrophage Functions in
Atherogenesis
Attachment
Macrophage Functions in
Atherogenesis

Penetration
Macrophage Functions in
Atherogenesis

Activation
Molecular Mediators of
Atherogenesis

VCAM-1

MCP-1 M-CSF
Macrophage Functions in
Atherogenesis

Division
Anatomy of the Atherosclerotic Plaque

Fibrous cap

Lumen
Lipid Shoulder
Core
Intima
Elastic Internal
Media laminæ
External
Platelet Adhesion
 When blood vessels are injured, their
endothelial lining is disrupted exposing the
subendothelial matrix to the blood.
Platelets make contact with and spread
upon this matrix in a process known as
adhesion.
Thrombotic Reactions to
Vascular Injury
 Endothelial disruption rapidly leads to
platelet adhesion, degranulation and
recruitment to form an enlarging
thrombotic mass.
Thrombotic Reactions to
Vascular Injury
 The collagen causes platelets to adhere,
aggregate and form a nidus from which a
thrombus can evolve
 Recruitment of platelets into forming
thrombus requires that GPIIb/GPIIIa
complex undergoes conformational
change to become expressed as
fibrinogen receptor.
 ADP: A Key Mediator of PLATELET
Platelet Activation AGGREGATION

FIBRINOGEN FIBRINOGEN BINDING

SITE

EXTERNA PLATELET
L ADP RECRUITMENT

AD
OTHER AD P
AGONIST
S
P

AD INTERNA
PLATELET L ADP
ADHESION P
FIBRINOGEN BINDING FIBRINOGEN
SITE
PLATELET AGGREGATION
 Signal Response Coupling in
Platelets IIb
FIB AGGREGATION

IIIa
A A
ACTIVATION
R R G
PHOSPHOLIPASE
PHOSPHOLIPASE C
A2
Ca 2+ DENSE
IP3
ARACHIDONI PIP2
C ACID DIACYLGLYCEROL
TUBULE
Ca 2+
TXA2 C-
GRANU KINASE

LE
SECRETION
Physiologic Antithrombotic
Mechanisms
 Endothelial cells products
 Heparan sulfate
 Stimulates activity of antithrombin III
 AT III inhibits coagulation factors II; IX; X; XI; XII
Physiologic Antithrombotic
Mechanisms
 Thrombomodulin bind thrombin
 Tm+Th+factor V stimulates activation of
protein C
 Protein C inactivates factor V; VII; and
neutralizes the inhibitor of tPA
Thrombin Inactivation
 Vasodilatation-Thrombin increases
production of nitric oxide (endothelial
derived relaxing factor which induces
vasodilatation locally and inhibits platelet
function directly and synergistically with
prostacyclin)
Thrombin Inactivation
 Anti-thrombin III inhibits thrombin and
coagulation factors IXa; VIIa; and Xa
Normal Control of THROMBOSIS
TFPI
PROTEIN Ca
VIIa-IXa
S
ATIII HEPARIN
PROTEIN C
THROMB0-
MODULIN V
Xa
LYSIS

PLATELETS THROMBIN
PLASMIN
ACTIVATED
TXA2/NO
tPA
PLASMINOGE
N
FIBRIN
CLOT
GLUCOSE METABOLISM
 During hypoxia, the brain decreases
glucose transport against the BBB
 A way of adaptation to prevent accumulation
of lactate since the brain has poor lactate
transport capacity
 Neonates
 THANK YOU VERY MUCH
Thrombosis of a Disrupted Atheroma, the Cause
of Most Acute Coronary Syndromes, Results
from:

 Weakening of
the fibrous cap

 Thrombogenicity
of the lipid core

Illustration courtesy of Michael J. Davies, MD

 Plaque Rupture with Thrombosis
Thrombus Fibrous cap

1 mm
Lipid core
Illustration courtesy of Frederick J. Schoen, MD, PhD
Matrix Metabolism and Integrity of the
Plaque’s Fibrous Cap

e sis Brea
Sy nt h k down

Collagen-degrading Fibrous
IFN-γ – Proteinases
cap

+ + + + IL-1
CD-40L TNF-α
+ MCP-1
+ M-CSF
Tissue
Lipid core Factor
Procoagulant

Libby P. Circulation. 1995;91:2844-2850.

CD40 ligand on activated platelets
triggers an inflammatory reaction of
endothelial cells

Henn V, et al. Nature. 1998;391:591-594.

Inflammation Can Promote Thrombosis
Fibrinogen
via gp
Tissue llb/llla
Factor
Platelet
Platelet-
CD40L Fibrin Fibrin
Thrombus

Platelet

Fibrinopeptides
Stroke Risk Factors
Statin Therapy Is Not Associated With
Increased Risk for Hemorrhagic Stroke
Trials Odds Ratios (95% Cl)

HPS*
GREACE†
MIRACL‡
KLIS§
LIPIDıı
CAREıı
SSSS*
AFCAPS¶

OVERALL (95% Cl) 0.90 (0.65–1.22)

Heterogeneity P=.15

0.05 0.2 0.5 1.0 3.0 10.0

Favors Statin Favors Control

* Simvastatin vs placebo.
†
Atorvastatin vs usual care.
‡
Atorvastatin vs placebo.
§
Pravastatin vs conventional treatment.
ıı
Pravastatin vs placebo.
¶
Lovastatin vs placebo.
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.
Statins and
Cholesterol
Epidemiology of Stroke
Worldwide Stroke Prevalence:
Strokes per 1000 People

<5 16-19
10-14
<5 <5
10-14
<5 5-9 5-9
10-14
5-9 <5
10-14
10-14
<5
5-9

Adapted from World Health Organization. Global Burden of Stroke. 2005. Available at:
www.cvd_atlas_15_burden_stroke.pdf.
10% of All Deaths Worldwide
Are Due to Stroke
Tuberculosis Malaria
Diarrheal disease
Perinatal causes
2%
3% 3%
Chronic obstructive 4%
pulmonary disease 5%
Other 27%
HIV/AIDS 5%
Respiratory tract
infection 7%
Coronary heart
Injury disease
9% 13%
Stroke Cancer
12%
10%

HIV/AIDS=human immunodeficiency virus/acquired immunodeficiency syndrome.

Adapted from World Health Organization. Global Burden of Stroke. 2005. Available at:
www.cvd_atlas_16_death_from_stroke.pdf.
 2003 Phil. Prevalence Data :
Atherosclerosis Disease-Risk Factors

PREVALENCE (%)
Stroke 1.4
HPN Q (BP or History) 17.4
Diabetes(FBS or History) 4.6
Hypercholesterolemia(TC≥ 240) 8.5
Current Smoking 56.3/12.1
Obesity (BMI≥30) 4.8
WHR M/F 12.1/54.8
Angina 12.1
PAD 8.9

Antonio L. Dans, M.D., Dante D. Morales, M.D., Felicidad Velandria, Teresa B. Abola, M.D., Artemio Roxas Jr., M.D.,
Felix Eduardo R. Punzalan, M.D., Rosa Allyn G. Sy, M.D., Elizabeth Paz Pacheco :National Nutrition and Health Survey (NNHeS):
Atherosclerosis - Related Diseases and Risk Factors: Phil. J of Intern Med May-June 2005,Vol.43.Impress
Burden of Stroke
Stroke-Associated Costs
Are High Worldwide
3,000,000
†
120,000
Lifetime Cost ($US)*

100,000

80,000

60,000

40,000

20,000

0
Australia Netherlands United United United Industrialized
Kingdom Kingdom States Countries
*All values were converted to US dollars using 14 Aug 2005 exchange rates from Trustnet.
Available at: http://www.trustnet.com/general/rates.asp.
†
Maximum reported value.
Adapted from Dewey HM et al. Stroke. 2003;34:2502-2507; Taylor TN et al. Stroke. 1996;27:1459-1466; Youman P et al.
Pharmacoeconomics. 2003;21(suppl 1):43-50; Bergman L et al. Stroke. 1995;26:1830-1836; Caro JJ et al. Stroke. 1999;30:2574-2579;
Palmer AJ et al. Curr Med Res Opin. 2005;21:19-26.
 Spiraling Effects of Stroke
Stroke is a leading cause Why Stroke Prevention Is Important
of adult disability in North
America, Europe and Asia1
The risk of stroke
recurrence over 5 years is
15% to 40%3

The risk of disability and

Recurrent stroke is a One in three stroke survivors dependence and the
chief contributor to is functionally dependent a high cost of stroke
disability and death2 treatment underscore
year after suffering a stroke3
the need for stroke
prevention5

1st Nearly 66% of people

who suffer a stroke die
Stroke or become permanently
disabled4 2nd
Risk of severe disability Stroke
or death increases with
each stroke recurrence2

References: 1. Higashida RT and Furlan AJ for the Technology Assessment Committees of the American Society of Interventional and Therapeutic Neuroradiology and the Society of Interventional
Radiology. Trial Design and Reporting Standards for Intra-Arterial Cerebral Thrombolysis for Acute Ischemic Stroke. Stroke. 2003;34:1923-1924. 2. National Institute of Neurological Disorders and
Stroke. Stroke: Hope through Research. Available at: http://www.ninds.nih.gov/disorders/stroke/detail_stroke.htm. Accessed May 04, 2006. 3. Wolfe CD. The Impact of Stroke. Brit Med Bull.
2000;56: 275-286. 4. Mackay J, Mensah G. The Atlas of Heart Disease and Stroke, World Health Organization, 2004. Global Burden of Stroke, 50-51. Available at:
http://www.who.int/cardiovascular_diseases/en/cvd_atlas_15_burden_stroke.pdf. Accessed May 04, 2006. 5. Mackay J, Mensah G. The Atlas of Heart Disease and Stroke, World Health
Organization, 2004. Deaths from Stroke, 52-53. Available at: http://www.who.int/cardiovascular_diseases/en/cvd_atlas_16_death_from_stroke.pdf. Accessed May 04, 2006.
Risk of Recurrent Cardiovascular
Events Is High
20 Recurrent stroke

MI or fatal cardiac event

Patients With Event (%)

15
(n=655)

10

0
30 Days 1 Year 5 Years
Follow-up Timepoint
MI = myocardial infarction.

Adapted from Dhamoon MS et al. Presented at the 57th Annual Meeting of the American Academy of Neurology;
Miami Beach, FL. April 9-16, 2005. S38.005.
Statins in Stroke Prevention
Cholesterol Lowering and Stroke Risk:
All Approaches Are Not Equally Effective
No. of
RR P Subject
Other s
0.998 .995 3421

Diet
0.603 .11 1741

Nonstatins
0.926 .32 32,550

Statins
0.756 <.001 32,684

Total
0.828 <.001 70,396

0.3 0.5 0.7 1.0 1.4

RR=relative risk.
Adapted from Corvol J-C et al. Arch Intern Med. 2003;163:669-676.
 Role of Statins in Stroke
Prevention
STATIN
Pleiotropic effects

LDL-C Reduction Plaque Stabilization

35-80% of benefit  Macrophages

 Smooth muscle cells

 Immunologic response

 Lipid core

 Oxidized LDL

 Improved endothelial function


Reduced hemorheologic stress
 Reduced platelet aggregation
 Reduced thrombotic and
 Enhanced fibrinolytic state
 Blood pressure reduction

Decreased incidence of MI and of left
ventricular mural thrombus
Ref: Amarenco P. Effect of statins in stroke prevention. Current Opinion in Lipidology, 2005.
Statins: Mechanism of Action

Cholesterol VLDL
synthesis LDL receptor–
LDL receptor Apo B mediated hepatic
(B–E receptor) VLDL R
uptake of LDL and
synthesis Apo E
VLDL remnants
Intracellular Apo B Serum LDL-C
Cholesterol
LDL Serum VLDL remnants
Serum IDL

Hepatocyte Systemic Circulation

Reduce hepatic cholesterol synthesis, lowering intracellular
cholesterol, which stimulates upregulation of LDL receptor and
increases the uptake of non-HDL particles from the systemic
circulation.
The LDL-C–Lowering Efficacy of the
Currently Available Statins
Daily
Dose Atorva Fluva Lova Prava Simva

10 mg –39% –22% –30%

20 mg –43% –22% –27% –32% –38%

40 mg –50% –25% –32% –34% –41%

80 mg –60% –36% –42% –47%

Physician’s Desk Reference. 55th ed. Montvale, NJ: Medical

Economics, 2001.
Treatment of Hyperlipidemia
High LDL-C

Therapeutic Lifestyle Change

Drug Therapy
Therapy of Choice: Statin

Alternative: Resin or niacin

Expert Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
 Treatment Categories, LDL-C Goals and
Cutpoints
Consider Drug
Risk Category LDL-C Goal Therapy

CHD or
CHD risk equivalent <100 mg/dL ≥130 mg/dL*

≥2 Risk Factors
10-yr risk 10–20% <130 mg/dL ≥130 mg/dL
10-yr risk <10% <130 mg/dL ≥160 mg/dL

<2 Risk Factors <160 mg/dL ≥190 mg/dL

* 100–129 mg/dL = after TLC, consider statin, niacin, or fibrate therapy

Expert Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
Targets for Therapy after LDL-C Goal in
Patients with TG ≥200 mg/dL

LDL-C target Non-HDL-C

Patient Category (mg/dL) target (mg/dL)
No CHD, <2 RF <160 <190

No CHD, 2+ RF <130 <160

CHD or CHD risk
<100 <130
equivalent

Expert Panel on Detection, Evaluation, and Treatment of High Blood

Cholesterol in Adults. JAMA 2001;285:2486-2497.
Treatment of Mixed Hyperlipidemia
High LDL-C and TGs

Therapeutic Lifestyle Change

Drug Therapy

STEP 1 Achieve the LDL-C goal

Achieve the non-HDL-C goal

STEP 2 Increase LDL-C lowering or
Add a fibrate, niacin or fish oils
Expert Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
Progression of Drug Therapy for

LDL-C
Visit 1 Lowering
Visit 2 Visit 3
q
F/U Visits
6 6 4–6
Initiate If LDL goal If LDL goal Monitor
wks wks mo
LDL- not achieved, not achieved, response
lowering intensify LDL- drug therapy and
drug lowering or refer to a adherence
therapy therapy lipid specialist to therapy

Start Consider higher If LDL goal

statin or dose of the has been
bile acid statin or add a achieved,
resin or bile acid resin treat other
nicotinic or nicotinic acid lipid risk
acid factors

Expert Panel on Detection, Evaluation, and Treatment of High

Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
Potential Time Course of Statin Effects
Vulnerable
LDL-C Inflammation plaques
lowered* reduced stabilized

Endothelial Ischemic Cardiac

function episodes events
reduced*
restored reduced

Days Years
* Time course established
Statins in Primary Stroke Prevention
Primary Prevention
WOSCOPS ALLHAT-LLT ASCOT-LLA CARDS
Relative Risk Reduction for Stroke (%)

0
Pravastatin Pravastatin Atorvastatin Atorvastatin
–5
(n=10,355)
–10 (n=6595)
–9*
–15 –11*
–20

–25 (n=10,305)
–30 –27†
–35
–40
*P=NS (pravastatin vs placebo or usual care). (n=2841)
–45 †
P=.024 (atorvastatin vs placebo).

–50
‡
P=not reported (atorvastatin vs placebo). –48‡
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.
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.
 ASCOT-LLA
Study Design
 N = 10,305 hypertensive patients with additional 3 or
more risk factors; no history of CHD
 Randomized to atorvastatin 10 mg/d or placebo for 5
years (stopped after 3.3 years)
 Primary outcome: time to first nonfatal MI and fatal
CAD
 Risk Reduction by 36%

Sever et al. Lancet. 2003;361:1149.

ASCOT-LLA: Atorvastatin Lowers Stroke Risk
in Patients With Good Blood Pressure Control
3
Proportion of Patients (%)

27%
(n=10,305) reduction
2

1
HR=0.73 (0.56–0.96)
P=.0236

0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Years
Atorvastatin 10 mg Number of events 89
Placebo Number of events 121

ASCOT-LLA = Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm; HR = hazard ratio.

Adapted from Sever PS et al. Lancet. 2003;361:1149-1158.
The Collaborative AtoRvastatin
Diabetes Study (CARDS)
Atorvastatin 10 mg/day
Placebo 2838
patients
Placebo
6-week placebo lead-in
prerandomization 304 primary end points

Patient population:
 Enrolled at 132 sites in the UK and Ireland
 Type 2 diabetes with no previous MI or CHD
 ≥1 other CHD risk factor plus LDL-C 4.14 mmol/L
(160 mg/dL) and TG 6.78 mmol/L ( 600 mg/dL)
 Aged 40-75 years

Colhoun HM, Thomason MJ, Mackness MI, et al. Diabet Med. 2002;19:201-211.
CARDS: Stroke Prevention
in Diabetic Patients Without CHD
Relative Risk
Event Atorva* Hazard (CI)
Placebo* Ratio

Primary end 127 (9.0) 83 (5.8) –37% (–52, –

point 17)
P=.001
Acute coronary 77 (5.5) 51 (3.6) –36% (–55, –9)
events

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

revascularization
Stroke 39 (2.8) 21 (1.5) .2 .4 .6 .8 1 1.2 –48% (–69, –
(n=2841) Favors Favors 11)
Atorvastatin 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.
Stroke Prevention in Patients
With Cardiovascular Disease
 Prevention of Stroke in Patients With
Documented Cardiovascular Disease
+3ıı
4S CARE LIPID HPS (n=5804)
KLIS GREACE ALLIANCE TNT
Relative Risk Reduction for Stroke (%)

0
(n=4444) (n=4159) (n=9014) (n=20,536) PROSPER (n=3853) (n=1600) (n=2442) (n=10,001)
–5

–10

–15 – 13#

–20 – 19‡
–25 – 22ıı
– 25§ – 25**
–30
–30*
– 31†
–35

–40 * P=.024 (simvastatin vs placebo).

†
P=.03 (pravastatin vs placebo).
‡
P=.048 (pravastatin vs placebo).
–45 §
P<.0001 (simvastatin vs placebo).
ıı
–50
P=NS (pravastatin vs placebo or conventional treatment). – 47¶
¶
P=.034 (atorvastatin vs usual care).
#
P=NS (atorvastatin vs usual care).
** P=.02 (80 mg vs 10 mg atorvastatin).
Atorvastatin is not indicated for secondary prevention of CVD.
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 Atheroscler
Thromb. 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.
Treating to New Targets (TNT):
Study Design
Double-blind
Patient Population LDL-C <130 mg/dL (<3.4 mmol/L)
 CHD
LIPITOR 10 mg
LDL-C target: 100mg/dL (2.6mmol/L)
N = 10,001

LIPITOR 80 mg
LDL-C target: 75mg/dL (1.9mmol/L)

Median follow-up = 4.9 years

Primary Efficacy Outcome Measure

 Time to occurrence of a major CV event
 CHD death
 Nonfatal, non-procedure-related MI
 Resuscitated cardiac arrest
 Fatal or nonfatal stroke

LaRosa JC, et al. N Engl J Med. 2005; 352

 TNT Main
Results
Primary End Point* First Stroke
15
% Major Cardiovascular Events

4
RRR

% Fatal Or Nonfatal Stroke

LIPITOR 10 mg = LIPITOR 10 mg
LIPITOR 80 mg 22% LIPITOR 80 mg RRR
3 =
10
25%
P=0.0002
2
P=0.02
5
1

0 0
0 1 2 3 4 5 6 0 1 2 3 4 5 6
Time Time
(Years) (Years)
*CHD death, nonfatal non-procedure-related MI, Lipitor 80 mg mean LDL= 77 mg/dL
resuscitated cardiac arrest, fatal or nonfatal stroke Lipitor 10 mg mean LDL= 101 mg/dL
TNT Confirms High Dose Safety

% of Patients
LIPITOR 10 mg LIPITOR 80 mg
(n=5006) (n=4995)
Treatment-Related
5.8 8.1
AEs
Treatment-Related
4.7 4.8
Myalgia
AST / ALT Elevation
0.2 1.2
>3 x ULN
Stroke Prevention
in Patients With ACS
MIRACL: study design

Placebo + diet
Hospitalization
n=3086
for Randomized
unstable angina
or non-Q MI 24–96 hours
after admission Atorvastatin 80 mg + diet

16 weeks

Assessments conducted at
weeks 0, 2, 6 and 16

Schwartz GG et al. Am J Cardiol 1998;81:578–581.

Statin Therapy for Stroke Prevention
in ACS: MIRACL
2
Cumulative Incidence (%)

Placebo (n=1548)
1.5

1
Atorvastatin (n=1538)

0.5
Relative risk = 0.49
P=.04
95% CI 0.24–0.98
0
0 4 8 12 16
Time Since Randomization (weeks)

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

Secondary Stroke Prevention
HPS Subanalysis: Statin Therapy
Failed to Demonstrate Efficacy in Secondary
Prevention of Stroke
Percentage of Patients

12
10.3 10.4
10
With Stroke

2
(n=3280)
0

Simvastatin Placebo

HPS = Heart Protection Study.

Adapted from HPS Collaborative Group. Lancet. 2004;363:757-767.
 STROKE
Statins in the Prevention
Of Cerebrovascular Disease:
Implications of
Recent Evidence
BERNARDO L. CONDE, M.D.
Professor of Neurology & Psychiatry
Faculty of Medicine & Surgery
University of Santo Tomas