Cerebral Blood Flow; Stroke

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 Glucose Blood Flow

3.5 ml/100 grams 5.5 mg/100 grams 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 acid

Acetyl 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

Arteriovenous malformation

Atherosclerosis

Intrinsic State of the cerebral vasculature Intracranial CSF pressure

Increased intracranial pressure

Cerebral autoregulatory mechanism Myogenic factors

Decreased intraluminal pressure (vasodilation)

Increased intraluminal pressure (vasoconstriction)

Neurogenic factors

Parasympathetic stimulation (vasodilation)

Sympathetic stimulation (vasoconstriction)

Biochemical-metabolic factors

Increased CO2 (vasodilation) Decreased O2 (vasodilation) Decreased pH (acidosis) (vasodilation) Lactic acidosis (vasodilation)

Decreased CO2 (vasoconstriction) Increased O2 (vasoconstriction) Increased pH (alkalosis) (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 Mean value of lowest quintile

Odds Ratio (95% Cl)

4

5

3

2

6

7

8

• Estimate adjusted for age,

(n=1242)

sex, race, hypertension, index year, time to cholesterol measurement, SBP and DBP, coronary heart disease, atrial fibrillation, diabetes, tobacco use, and use of statins

1

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 F MI 4.67 (1.18 - 18.52) RHD 3.69 (1.05 -12.99 ) Smoking 1.36 (1.00 A. Roxas for PNA-DOH Risk factors for stroke among Filipinos (RIFASAF). Phil J Neur 2002; 6:1-7. 1.86)

Risk Factors for Stroke: Philippines Risk Factors

Risk (OR)

Data source

PNA-DOH RIFASAF

Prevalence(%) 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

?

?

8.5

Snoring

3.37X

?

Stress

1.69X

-

?

1.4%

Hypercholesterolemia

Previous Stroke

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 states Homocysteinemi a Diabetes

Lifestyle (smoking, diet, lack of exercise)

Hyperlipidemi a Hypertensio n 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 Disease

Lesion initiation

No symptoms

± Symptoms

Time (y)

Symptoms

Atherogenesis & Atherothrombosis: A Progressive Process

INCREASING AGE

CLINICALLY SILENT

ANGINA, TIA, CLAUDICATIONS, PAD

MYOCARDIAL INFARCTION ISCHEMIC STROKE CRITICAL LEG ISCHEMIA 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

Intima Tunica Media

Endothelium

T-lymphocytes

Smooth muscle cells

Leukocyte–Endothelial Adhesion Molecules Mono

T

B

PMN

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 Core

Shoulder

Intima Media

Elastic laminæ

Internal 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 Activation

FIBRINOGEN BINDING SITE

FIBRINOGEN

PLATELET RECRUITMENT

EXTERNA L ADP

OTHER AGONIST S

PLATELET ADHESION

PLATELET AGGREGATION

AD P AD P

FIBRINOGEN BINDING SITE

PLATELET AGGREGATION

AD P

INTERNA L ADP

FIBRINOGEN

Signal Response Coupling in FIB AGGREGATION Platelets IIb IIIa

A

ACTIVATION

R

PHOSPHOLIPASE A2

Ca

2+

A R

G PHOSPHOLIPASE C

DENSE IP3 PIP2

ARACHIDONI C ACID

TXA2

TUBULE Ca 2+

GRANU LE SECRETION

DIACYLGLYCEROL

CKINASE

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

THROMB0MODULIN

V Xa LYSIS

PLATELETS

THROMBIN PLASMIN

ACTIVATED TXA2/NO

tPA FIBRIN CLOT

PLASMINOGE N

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

1 mm Illustration courtesy of Frederick J. Schoen, MD, PhD

Fibrous cap

Lipid core

Matrix Metabolism and Integrity of the Plaque’s Fibrous Cap Brea k

sis e h t n Sy

IFN-γ

down

Collagen-degrading Proteinases

– CD-40L +

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

+ + + + +

Fibrous cap

IL-1 TNF-α MCP-1 M-CSF

Tissue

Factor Procoagulant

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 llb/llla

Tissue Factor

Platelet

CD40L

Fibrin

Platelet

Fibrinopeptides

PlateletFibrin Thrombus

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¶ 0.90 (0.65–1.22) P=.15

OVERALL (95% Cl) Heterogeneity 0.05 * Simvastatin vs placebo. † Atorvastatin vs usual care. ‡ Atorvastatin vs placebo. § Pravastatin vs conventional treatment. ıı Pravastatin vs placebo. ¶ Lovastatin vs placebo.

0.2

Favors Statin

0.5

1.0

3.0

10.0

Favors Control

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 <5

<5

<5

5-9 5-9

10-14

10-14

5-9 <5

16-19 10-14 10-14

10-14 5-9 Adapted from World Health Organization. Global Burden of Stroke. 2005. Available at: www.cvd_atlas_15_burden_stroke.pdf.

<5

10% of All Deaths Worldwide Are Due to Stroke Tuberculosis Diarrheal disease Perinatal causes Chronic obstructive pulmonary disease HIV/AIDS Respiratory tract infection

4%

3%

3%

5%

Malaria

2%

Other 27%

5% 7% Injury 9%

Coronary heart disease 13%

Stroke 10%

Cancer 12%

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

†

Lifetime Cost ($US)*

120,000 100,000 80,000 60,000 40,000 20,000 0 Australia

Netherlands

United Kingdom

United Kingdom

United States

Industrialized 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 of adult disability in North America, Europe and Asia1

Why Stroke Prevention Is Important The risk of stroke recurrence over 5 years is 15% to 40%3

Recurrent stroke is a chief contributor to disability and death2

1st Stroke Risk of severe disability or death increases with each stroke recurrence2

One in three stroke survivors is functionally dependent a year after suffering a stroke3 Nearly 66% of people who suffer a stroke die or become permanently disabled4

The risk of disability and dependence and the high cost of stroke treatment underscore the need for stroke prevention5

2nd Stroke

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 Patients With Event (%)

20

Recurrent stroke MI or fatal cardiac event

15

(n=655) 10

5

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 RR

P

No. of Subject s

0.998

.995

3421

0.603

.11

1741

0.926

.32

32,550

0.756

<.001

32,684

0.828

<.001

70,396

Other

Diet

Nonstatins

Statins

Total

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 35-80% of benefit

Plaque Stabilization  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 synthesis

VLDL LDL receptor Apo B VLDL R (B–E receptor) Apo E synthesis

Intracellular Cholesterol

Apo B LDL

LDL receptor– mediated hepatic uptake of LDL and VLDL remnants Serum LDL-C 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

10 mg

–39%

20 mg

–43%

–22%

40 mg

–50%

80 mg

–60%

Fluva

Lova

Prava

Simva

–22%

–30%

–27%

–32%

–38%

–25%

–32%

–34%

–41%

–36%

–42%

Physician’s Desk Reference. 55th ed. Montvale, NJ: Medical Economics, 2001.

–47%

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 Risk Category

LDL-C Goal

Consider Drug Therapy

CHD or CHD risk equivalent

<100 mg/dL

≥130 mg/dL*

≥2 Risk Factors 10-yr risk 10–20% 10-yr risk <10%

<130 mg/dL <130 mg/dL

≥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 Patient Category

LDL-C target (mg/dL)

Non-HDL-C target (mg/dL)

No CHD, <2 RF

<160

<190

No CHD, 2+ RF CHD or CHD risk

<130

<160

<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 Visit 1 Lowering Visit 2 LDL-C Initiate LDLlowering drug therapy

Start statin or bile acid resin or nicotinic acid

Visit 3

6 6 If LDL goal If LDL goal wks wks not achieved, not achieved, intensify LDLdrug therapy lowering or refer to a therapy lipid specialist

Consider higher dose of the statin or add a bile acid resin or nicotinic acid

q 4–6 mo

If LDL goal has been achieved, treat other lipid risk factors

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

F/U Visits Monitor response and adherence to therapy

Potential Time Course of Statin Effects LDL-C lowered*

Vulnerable Inflammation plaques reduced stabilized

Endothelial function restored

Days * Time course established

Ischemic episodes reduced

Cardiac events reduced*

Years

Statins in Primary Stroke Prevention

Relative Risk Reduction for Stroke (%)

Primary Prevention 0

WOSCOPS Pravastatin

–5 –10 –15

(n=6595)

–11*

ALLHAT-LLT Pravastatin

ASCOT-LLA

CARDS

Atorvastatin

Atorvastatin

(n=10,355)

–9*

–20 –25

(n=10,305)

–30

–27†

–35 –40 –45 –50

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

(n=2841)

–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–LipidLowering 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 Proportion of Patients (%)

3

27% reduction

(n=10,305) 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 Event

Atorva* Placebo*

Primary end point

Relative Risk (CI)

Hazard Ratio

127 (9.0)

83 (5.8)

–37% (–52, – 17) P=.001

Acute coronary events

77 (5.5)

51 (3.6)

–36% (–55, –9)

Coronary revascularization

34 (2.4)

24 (1.7)

–1% (–59, +16)

Stroke

39 (2.8)

21 (1.5) .2 .4 .6 .8 1 1.2

(n=2841)

Favors Atorvastatin

–48% (–69, – Favors 11) 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 Relative Risk Reduction for Stroke (%)

+3ıı

0 –5

4S

CARE

LIPID

HPS

(n=5804)

KLIS

(n=4444)

(n=4159)

(n=9014)

(n=20,536)

PROSPER

(n=3853)

GREACE ALLIANCE (n=1600)

(n=2442)

TNT (n=10,001)

–10 –15

– 13#

–20

– 19‡ – 22ıı

–25 –30

– 25§ –30*

– 31†

–35 –40 –45 –50

– 25**

* 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). †

– 47¶

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;339:13491357; 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 LDL-C <130 mg/dL (<3.4 mmol/L)

Patient Population 

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 First Stroke

15 RRR = 22%

LIPITOR 10 mg LIPITOR 80 mg 10

P=0.0002 5

0 0

1

2

3

4

5

6

Time (Years) *CHD death, nonfatal non-procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke

% Fatal Or Nonfatal Stroke

% Major Cardiovascular Events

Primary End Point* 4

3

LIPITOR 10 mg LIPITOR 80 mg

RRR = 25%

2

P=0.02 1

0 0

1

2

3

4

5

6

Time (Years)

Lipitor 80 mg mean LDL= 77 mg/dL Lipitor 10 mg mean LDL= 101 mg/dL

TNT Confirms High Dose Safety % of Patients

Treatment-Related AEs Treatment-Related Myalgia AST / ALT Elevation >3 x ULN

LIPITOR 10 mg (n=5006)

LIPITOR 80 mg (n=4995)

5.8

8.1

4.7

4.8

0.2

1.2

Stroke Prevention in Patients With ACS

MIRACL: study design Hospitalization for unstable angina or non-Q MI

Placebo + diet

n=3086 Randomized 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 Cumulative Incidence (%)

2

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

Time Since Randomization (weeks) Adapted from Waters DD et al. Circulation. 2002;106:1690-1695.

16

Secondary Stroke Prevention

Percentage of Patients With Stroke

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

12

10.4

10.3

10 8 6 4 2

(n=3280)

0

Simvastatin

HPS = Heart Protection Study. Adapted from HPS Collaborative Group. Lancet. 2004;363:757-767.

Placebo

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