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MedSlides.com 1

50% Coronary Heart Disease

1%

Congenit
al
Heart
Defects

1%

Rheumatic
Fever/
Rheumatic
Heart
Disease

4%

Congestive
Heart
Failure

2%
Atheroscleros
is

4% High Blood
Pressure

22% Other

Coronary Heart Disease:

Despite Advances, Still the #1 Killer

Percentage Breakdown of Deaths From Cardiovascular

Diseases

United States: 1995 Mortality, Final Data

16%
Stroke

American Heart Association

1998 Heart and Stroke Facts:

Statistical Update

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MedSlides.com 2

Epidemiology

• Coronary artery disease remains the

single leading killer in the Western
world

• In the United States

–

13.5 million individuals with CAD

–

1.5 million myocardial infarctions / year

–

500,000 fatal MIs

–

estimated economic toll of $ 90 billion in
1997

Am J Cardio 1998; 1U-2U

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MedSlides.com 3

Risk Factors in Primary

Prevention

National Cholesterol Education Program

Adult Treatment Panel Guidelines

Positive Risk Factors
• Age: 45 yr in men; 55 yr, or premature menopause without ERT, in

women

• Family history of premature CAD: MI or sudden death before age 55 yr

in father or other male first-degree relative, or before age 65 yr in
mother or other female first-degree relative

• Current cigarette smoking
• Hypertension: 140/90 mm Hg, or on antihypertensive medication
• Low HDL-C <35 mg/dL
• Diabetes mellitus

Negative Risk Factor
• High HDL-C: 60 mg/dL

NHLBI; September 1993

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MedSlides.com 4

Castelli WP. Am J Med. 1984;76:4-12

Gotto AM Jr, et al. Circulation.

1990;81:1721-1733

1

0

-y

e

a

r

C

H

D

d

e

a

th

ra

te

(D

e

a

th

s

/1

0

0

0

)

Serum cholesterol (mg/dL)

1% reduction in total cholesterol
resulted in a 2% decrease in CHD
risk

(MRFIT) (n=361,662)

150

200

250

300

0

50

40

30

20

10

0

25

50

75

100

125

150

C

H

D

i

n

d

ic

a

ti

o

n

s

p

e

r

1

0

0

0

Each 1% increase in total cholesterol
level is associated with a 2% increase
in CHD risk

Serum cholesterol (mg/100 mL)

Framingham Study (n=5209)

20

4

205-

234

235-264

265-

294

29

5

Relationship Between Cholesterol and CHD

Risk Epidemiologic Trials

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MedSlides.com 5

Relationship Between Cholesterol and CHD

Risk Epidemiologic Trials

Wakugami K, Iscki R, Kimura Y, et al. Japanese Circulation
Journal. 1998;62:7-14.
Verschuren WMM, Jacobs DR, Bloemberg BPM, et al. JAMA.
1995;274:131-136

C

u

m

u

la

ti

v

e

i

n

c

id

e

n

c

e

o

f

A

M

I

p

e

r

1

0

0

,0

0

0

s

c

re

e

n

e

d

s

u

b

je

c

ts

i

n

2

y

e

a

rs

0

100

200

300

400

500

Men
Women

Cumulative incidence of acute myocardial
infarction (AMI) increased with the level of
serum cholesterol

Serum cholesterol (mg/dL)

Range 167

168-191

192-217

218

Mean

149.3

179.8

203.7

245.3

Okinawa, Japan



C

H

D

m

o

rt

a

li

ty

r

a

te

s

(

%

)

Using linear approximation, a 20-
mg/dL increase in total cholesterol
corresponded to a 17% increase in
mortality risk

Serum cholesterol (mg/dL)

Seven Countries Study

†

125

175

225

275

325

0

10

20

30

40

Northern Europe
Southern Europe, Mediterranean
United States
Serbia
Southern Europe, Inland
Japan

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MedSlides.com 6

Coronary Artery Disease

Risk Reduction

• For every

1%

reduction in total cholesterol, there is

a

2%

decrease in coronary artery disease

incidence

• meta-analysis by Law & coworkers (500,000 men

and 18,000 ischemic events)

age 40

1 : 5 %

age 50

1 : 4 %

age 60

1 : 3 %

age > 70

1 : 2 %

BMJ 1994:308:367-372

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MedSlides.com

alkohol a miażdżyca

• umiarkowane spożycie - spadek ryzyka sercowo-naczyniowego

w porównaniu z abstynentami lub pijącymi dużo

• „francuski paradoks” - Francuzi jedzą dość dużo tłuszczów

nasyconych, ale piją też dużo wina - ryzyko sercowo-
naczyniowe podobne jak w krajach śródziemnomorskich,
mniejsze niż w USA

• wino, piwo czy alkohole wysokoprocentowe?
• czerwone wino: działanie przeciwutleniające,

naczyniorozszerzające, przeciwzakrzepowe (m. in.
rezweratrol, kwercytyna)

• być może chodzi nie o samo spożycie alkoholu, ale o styl życia

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MedSlides.com

HRT a miażdżyca

•

badania epidemiologiczne i obserwacyjne - korzyść z
HRT

•

brak potwierdzenia korzyści z HRT w randomizowanych
próbach klinicznych

- badanie HERS (Heart and Estrogen-Progestin
Replacement Study) - brak wpływu HRT na
występowanie incydentów sercowo-naczyniowych

- badanie ERA (Estrogen Replacement and
Atherosclerosis Trial) - brak korzyści z HRT w ocenie
angiograficznej (MLD)

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Chlamydia pneumoniae a miażdżyca

• podwyższone miano przeciwciał we krwi pacjentów z

miażdżycą i w próbkach uzyskanych podczas
aterektomii wieńcowej

• brak potwierdzenia związku przyczynowo-skutkowego

pomiędzy zakażeniem chlamydiami a niestabilnymi
zespołami wieńcowymi

• badanie ROXIS - stosowanie roksytromycyny w

niestabilnych zespołach wieńcowych (po 8 miesiącach
- zmniejszenie częstości występowania incydentów
klinicznych)

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Mechanisms of plaque

rupture

• Vulnerable plaque

– a thin fibrous cap
– large lipid-rich core
– high concentration of

inflammatory cells

• Culprit lesion (FATS)

– a small group of all

plaques (1 in 8) have
substantial lipid core,
causing majority (8 of
9) of cardiac events

Lipid core

Fibrous cap

plaque

rupture

thrombus

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MedSlides.com11

Culprit Lesions

severity of coronary stenoses at initial

angiogram 30.2 months before myocardial

infarction in 329 patients

0

5

10

15

20

25

30

35

40

45

50

<50

50-75

>75

Diameter Stenosis (%)

P

a

ti

e

n

ts

(

%

)

Am J Cardio 1997;80(9A):2I-10I

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MedSlides.com12

Lipid Lowering Therapy

• reduce the risk of

– total mortality
– non-fatal myocardial infarction
– myocardial revascularization procedures
– stroke or transient ischemic attack

• slow CAD progression
• regression of atherosclerotic lesions

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MedSlides.com13

Primary Prevention

Secondary Prevention

Statin Mega Trials

1994 - 4S (Scandinavian Simvastatin)

1995 - WOSCOP (West of Scotland)

1996 - CARE (Chol and Recurrent Event)
1997 - Post-CABG Trial
1998 - LIPID Trial (long-term intervention)

1998 - AFCAPS / TexCAPS

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Statin Prevention Studies

Primary prevention

WOSCOPS

Men only with no documented MI

H

(n = 6,595)
AFCAPS/TexCAPS Men and women with no clinical CAD

NM

(n = 6,605)

Secondary prevention

4S

Men and women with previous CAD

H

(n = 4,444)

CARE

Men and women with a history of MI

NM

(n = 4,159)

LIPID

Men and women with a history of MI

NH

(n = 9,014)

and/or unstable angina pectoris

(Total cholesterol:

H

=high,

NM

=normal to mild,

NH

=normal to high)

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MedSlides.com15

Statin Prevention Trials

-20

-25

-20

-18

-26

-35

-28

-25

5

8

5 6

-31

-34

-24

-24

-33

-42

-19

-24 -22

-30

-8

-22

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

5

10

WOSCOPS

4S

CARE

LIPID

TC

LDL-C

HDL-C

Nonfatal

MI/CAD

Death

CAD

Death

All-Cause

Mortality

*

*

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Statin Prevention Trials

decrease in clinical events with

lower LDL-C

LDL-C Achieved (mg/dL)

100 110 120

90

130 140 150 160 170 180 190 200

0

5

10

15

20

25

30

E

v

e

n

t

R

a

te

(

%

)

AFCAPS

CARE

AFCAPS

WOSCOPS

WOSCOPS

CARE

LIPID

LIPID

4S

4S

Treatment

Placebo

1

0

prevention

2

0

prevention

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Angiographic Statin Trials

treatment predictive of MLD change

100

90

110

120

130

140

150

160

170

LDL-C Achieved (mg/dL)

0.01

0.02

0.03

0.04

0.05

0.06

0.00

Pr

o

g

re

ss

io

n

(

M

LD

d

e

cr

e

a

se

)

(m

m

/y

)

Treatment

Placebo

MARS

LCAS

MAAS

REGRESS

CCAIT

PLAC I

MARS

MAAS

LCAS

PLAC I

CCAIT

REGRESS

Curr Opin Lipidol 1997;8:354-361

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MedSlides.com18

Primary Prevention Trials

Effect on Nonfatal MI or CAD Death

LDL-C 5 year Event Rate

Trial

Base / Rx / % statin / placebo / RRR

ARR /

NNT

WOSCOPS

192 159

26%

5.3% 7.5%

29%

2.2%

46

(N=6,595)
Pravastatin 40

AFCAP/

150 115

25%

3.5% 5.5%

37%

2.0%

50

TexCAPS

(N=6,605)
Lovastatin 20-40

RRR = relative risk reduction
ARR = Absolute risk reduction
NNT = 1/ARR = # need to treat to prevent 1 event

Arch Intern Med 1998

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WOSCOPS

West of Scotland Prevention Study

Determine whether long-term therapy with pravastatin to
decrease LDL-C would decrease the incidence of first
acute major event

NEJM 1995;333:1301-1307

• Design: double-blind,

pravastatin (40 mg/day)

• Patients: 6,595 men, age 45-64, no history of MI. Baseline

lipids: TC 221 mg/dL, LDL-C 150 mg/dL, triglyceride 158 mg/dL

• Results: At 4.9-year follow-up, total cholesterol reduction was

20% greater than placebo, LDL by 26%, triglycerides by 12%,
HDL increased by 5%.

Major coronary event (nonfatal MI

and CAD death) was reduced by 31%

(p<.001). Risk for

overall mortality was reduced by 22% (p=0.051).

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AFCAPS / TexCAPS

Air Force / Texas Coronary Atherosclerosis

Prevention Study

Determine whether long-term therapy with lovastatin to decrease
LDL-C would decrease the incidence of first acute major event
(unstable angina, fatal and nonfatal MI, sudden cardiac death)

JAMA 1998;279:1615-1622

• Design: double-blind,

lovastatin (20-40 mg/day), LDL-C goal <110

mg/dL

• Patients: 6,605 adults age 73 (5,608 , 997), baseline lipids: TC 221

mg/dL, LDL-C 150 mg/dL, triglyceride 158 mg/dL

• Results: At 5.2-year follow-up, total cholesterol reduction was 18.4%

greater than placebo, LDL by 25%, triglycerides by 15%, HDL increased
by 6%.

First acute coronary event was reduced by 37%

(p<.001).

Significant reduction also seen in secondary endpoints:
revascularization, 33%; unstable angina, 32%; fatal and nonfatal MI,
40%; fatal and nonfatal coronary events, 25%.

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Secondary Prevention Trials

Effect on Nonfatal MI or CAD Death

LDL-C 5 year Event Rate

Trial

Base / Rx / % statin / placebo / RRR

ARR /

NNT

4S (1994)

188 122

35%

19.4% 27.9%

34%

8.5%

12

simvastatin

CARE (1996)

139 98

32%

10.2% 13.2%

24%

3.0%

34

pravastatin

LIPID (1998)

150 112

25%

12.3% 15.7%

23%

3.4%

30

pravastatin

Arch Intern Med 1998

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4S

Scandinavian Simvastatin Survival Study

To determine whether long-term cholesterol reduction with
simvastatin will reduce overall mortality in post-myocardial
infarction (MI) and angina patients with hypercholesterolemia

• Design:

simvastatin (20-40 mg/day)

• Patients: 4,444 pts with CAD (MI or angina), baseline TC 212-310

mg/dL

• Results: Average 5.4-year follow-up. Simvastatin reduced TC by 25%,

LDL-C by 35%, triglyceride by 10%; HDL increased by 8%.

Risk of

total mortality was reduced by 30%

(p<0.00001). Other benefits

of treatment included the reduction of coronary mortality by 42%,
major coronary events by 34%, CABG/PTCA by 37%, LDL-C by 38%.

Lancet 1994; 344:1383-1389

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CARE

Scandinavian Simvastatin Survival Study

To determine whether long-term cholesterol reduction with
pravastatin will reduce overall mortality in post-myocardial
infarction (MI) patients with “average” cholesterol level.

• Design:

pravastatin (40 mg/day)

• Patients: 4,159 pts (3,583 , 576 ) with prior MI; baseline TC

<240 mg/dL (mean 209), LDL 115-174 mg/dL (mean 139)

• Results: Average 5-year follow-up. Therapy reduced TC by 20%,

LDL-C 28%, triglyceride 14%; HDL increased 5%.

Risk of major

coronary event (nonfatal MI and fatal coronary event) was
reduced by 24%

(p=0.003). There was no significant change in

overall mortality or mortality from noncardiovascular causes.

N Engl J Med 1996;335:10001-1009

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LIPID

Long-term Intervention with

Pravastatin in Ischemic Disease

Assess efficacy of treatment with pravastatin (Pravachol, Bristol
Myers Squibb) on reduction of coronary mortality and morbidity in
patients with history of myocardial infarction or unstable angina
and average or below average total and LDL cholesterol levels.

• Design: double-blind,

pravastatin (40 mg/day)

vs placebo

• Patients: 9,014 (83% ), age 31-75, baseline cholesterol 219

mg/dL (155-271), LDL-C 150 mg/dL, triglyceride 161 mg/dL

• Results: At 6.1-year follow-up, total cholesterol reduction was

18% greater than placebo (p=.001), LDL by 25%, triglycerides
by 12%, HDL increased by 6% (p=.001).

Coronary mortality

was reduced by 24%

(6.4% vs 8.3%, p<0.001). Total mortality

was reduced by 22% ( 11.0% vs 14.1%, p<0.001).

N Engl J Med 1998;339:1349-1357

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MedSlides.com

populacje o dużym i małym ryzyku

liczebność populacji

10000 10000

liczba incydentów rocznie

100

10

zmniejszenie ryzyka względnego

30%

30%

korzyść z leczenia (ile incydentów mniej?)

30

3

poważne objawy uboczne

0,1% 0,1%

szkodliwość leczenia (ile powikłań?)

10

10

koszt leczenia 1 pacjenta rocznie

1

1

koszt uniknięcia jednego incydentu

333

3333