ACUTE CORONARY SYNDROME

ACUTE CORONARY SYNDROMESPATHOPHYSIOLOGY

• PLAQUE RUPTURE & SUPERIMPOSED NONOCCLUSIVE THROMBUS

• DYNAMIC OBSTRUCTION

• PROGRESSIVE MECHANICAL OBSTRUCTION

• INFLAMMATION AND/OR INFECTION

• SECONDARY UNSTABLE ANGINA INCREASED O2 DEMAND

FRISC - IIPROTOCOL

2457 PATIENTS

JUNE 17, 1996 TO MAY 6, 1998 (2 YEARS)

58 SCANDINAVIAN CENTERS

1.76 PATIENTS PER MONTH PER CENTER

FRISC - II ELIGIBILITY

• ST DEPRESSION MORE THAN 0.1 MV

• T WAVE INVERSION MORE THAN 0.1 MV

• RAISED BIOCHEMICAL MARKERS CPK - MB

• MORE THAN 6 G/L, TROPORIN T MORE THAN 0.1 G/L

• MB ISOENZYME ABOVE LIMIT FOR DIAGNOSIS OF MI

• MAJORITY ABOVE 65 YEARS AND WITH MULTIPLE RISK FACTORS

• HIGHLY SELECTIVE GROUP OF ACS (IN BLOCKS & CAPS - DIFFERENT COLUR)

THE TIMI RISK SCORE FOR UA/NSTEMI

Characteristics PointsHistorical

Age 65 years 1 3 Risk factors for CAD 1 Known CAD (stenosis 50%) 1 Aspirin use in past 7 days 1

Presentation

Recent ( 24 h) severe angina 1

ST-segment deviation 0.5 mm 1

Cardiac markers 1

Risk Score = Total Points 0-7

Antman et al JAMA 2000, 784 835

RITA-3

• 1810 PATIENTS WITH ACS• 915 CONSERVATIVE STRATEGY• 895 INTERVENTION STRATEGY• INTERVENTION : ASPIRIN, ENOX, GP II B / III A,

TICLO / CLOPIDOGREL• CONSERVATIVE ASPIRIN, ENOX

? GPIIB/IIIA

? TICLO / CLOPIDOGREL

LANCET 2002, 360, 743

TROPONIN T LEVELS IN ACS & CARDIAC DEATH

1506 Patients

FRISC – Circ. 1996, 93 : 1651FRISC – Circ. 1996, 93 : 1651

TACTICS – TIMI 18

12.816.1

19.5

11.8

20.3

30.6

0

5

10

15

20

25

30

35

Low (0-2) Intermed (3-4) High (5-7)

TIMI Risk Score for UA/NSTEMI

D/M

I/A

CS

by

6 m

on

ths

INV CONS

New Eng. J. Med, 2001, 344 : 1879New Eng. J. Med, 2001, 344 : 1879

21 % risk reduction (p=0.048)

36 % risk reduction (p=0.018)

TACTCS - TIMI 18

• 2220 PATIENTS WITH ACS

• INVASIVE 1114

• CONSERVATIVE 1106

• CHARACTERISED ACCORDING TO TIMI RISK SCORE

RITA - 3

Intervention Conservative(n =895) (n=915)

Deaths 4 months 26 231 year 41 36All follow-up 60 72Myocardial infarctions (MIS)4 months 30 34 1 year 34 44All follow – up 45 56

Lancet 2002,360,743

RITA - 3

Intervention Conservative(n =895) (n=915)

Refractory angina 4 months 39 851 year 58 106Primary endpointsDeath, MI, or 86 (9.6%) 133 (14.5 %)Refractory angina 4 months Death or MI 68(7.6%) 76 (8.3 %)1 year

Lancet 2002,360,743

ACS – Report Incidence & D/MI CONS. V/s INV.

Number of deaths or MIS within 1 year

Intervention Conservative

RITA 68/895(7.6%) 68/895(7.6%)

VINO 4/64(6.36%) 15/(22.4%)

TACTICS-TIMI 18 81/1114(7.3%) 105/1106(9.5%)

TRUCS 6/76(7.6%) 12/72(16.7%)

FRISC II 127/1219(10.4%) 68/895(7.6%)

MATE 11/111(9.9%) 6/90(6.7%)

VANQWISH 111/462(24.0%) 85/458(18.6%)

TIMI IIIB 52/484(10.8%) 62/509(12.2%)

Risk Ratio (95 % CI)

ASSESSMENT OF THE CLINICAL UTILITY OF NOVEL MARKERS OF CARDIOVASCULAR RISK

ADDITIVE TO

TOTAL AND

ASSAY PROSPECTIVE HIGH-DENSITY

CONDITIONS STUDIES LIPOPROTEIN

MARKER STANDARDIZED ? CONSISTENT ? CHOLESTEROL ?

Lipoprotein (a) No Yes/no Yes /no

Total homocysteine Yes Yes/no Yes /no

Tissue-type plasminogen activator Yes/no Yes Yes/no

And plasminogen activator inhibitor

Fibrinogen Yes/no Yes Yes

High-sensitiviety-C-reactive protein Yes Yes Yes

From Ridker PM: Evaluating novel cardiovascular risk factors : Can we better predict heart attacks

?Ann Intern Med 130:933-937,1999

100

80

60

40

20

0(n=895) (n=915) (n=856) (n=873) (n=799) (n=814)

Intervention

Intervention

Conservative

Conservative

Intervention

Intervention

Conservative

Conservative

Intervention Intervention

ConservativeConservative

Pro

po

rtio

n o

f p

ati

ents

(%

)

Baseline 4 months 1 year

Prevalence of angina over time treatment

Lancet 2002,360,743

Grade 1

Grade 2

Grade 3/4

Nitricoxide (NO) ThrombomodulinTM

Protects Endothelium

Endothelium

Damages Endothelium

Depletion of NO and TM

Reactive Oxygen Species

Oxidation

Homocysteine

Mechanism of Homocysteine Induced Vascular Damage

RITA - 3

Intervention Conservative (n =895) (n=915)

Deaths 4 months 26 231 year 41 36All follow-up 60 72Myocardial infarctions (MIs)4 months 30 34 1 year 34 44All follow – up 45 56

Lancet 2002,360,743

RITA - 3

Intervention Conservative(n =895) (n=915)

Refractory angina 4 months 39 851 year 58 106Primary endpointsDeath, MI, or 86 (9.6%) 133 (14.5 %)Refractory angina 4 months Death or MI 68(7.6%) 76 (8.3 %)1 year

Lancet 2002,360,743

ACS – Report Incidence & D/MI CONS. V/s INV.

Number of deaths or MIS within 1 year

Intervention Conservative

RITA 68/895(7.6%) 68/895(7.6%)

VINO 4/64(6.36%) 15/(22.4%)

TACTICS-TIMI 18 81/1114(7.3%) 105/1106(9.5%)

TRUCS 6/76(7.6%) 12/72(16.7%)

FRISC II 127/1219(10.4%) 68/895(7.6%)

MATE 11/111(9.9%) 6/90(6.7%)

VANQWISH 111/462(24.0%) 85/458(18.6%)

TIMI IIIB 52/484(10.8%) 62/509(12.2%)

Risk Ratio (95 % CI)

ASSESSMENT OF THE CLINICAL UTILITY OF NOVEL MARKERS OF CARDIOVASCULAR RISK

ADDITIVE TO

TOTAL AND

ASSAY PROSPECTIVE HIGH-DENSITY

CONDITIONS STUDIES LIPOPROTEIN

MARKER STANDARDIZED ? CONSISTENT ? CHOLESTEROL ?

Lipoprotein (a) No Yes/no Yes /no

Total homocysteine Yes Yes/no Yes /no

Tissue-type plasminogen activator Yes/no Yes Yes/no

And plasminogen activator inhibitor

Fibrinogen Yes/no Yes Yes

High-sensitiviety-C-reactive protein Yes Yes Yes

From Ridker PM: Evaluating novel cardiovascular risk factors : Can we better predict heart attacks

?Ann Intern Med 130:933-937,1999

100

80

60

40

20

0(n=895) (n=915) (n=856) (n=873) (n=799) (n=814)

Intervention

Intervention

Conservative

Conservative

Intervention

Intervention

Conservative

Conservative

Intervention Intervention

ConservativeConservative

Pro

po

rtio

n o

f p

ati

ents

(%

)

Baseline 4 months 1 year

Prevalence of angina over time treatment

Lancet 2002,360,743

Grade 1

Grade 2

Grade 3/4

Conventional Fisk Factors for CAD

1. DysIipidaemia : elevated LDL-C and low HDL-C

2. Smoking

3. Diabetes

4. Hypertension

5. Obesity

6. Sedentary lifestyle

7. Positive family history of premature vascular disease

8. Advancing age

9. Male gender and postmenopausal state in women

ACUTE CORONARY SYNDROMESPATHOPHYSIOLOGY

• PLAQUE RUPTURE & SUPERIMPOSED NONOCCLUSIVE THROMBUS

• DYNAMIC OBSTRUCTION

• PROGRESSIVE MECHANICAL OBSTRUCTION

• INFLAMMATION AND/OR INFECTION

• SECONDARY UNSTABLE ANGINA INCREASED O2 DEMAND

Factors influencing homocysteine metabolism

Inherited Enzyme deficiencies in the metabolic pathway (cysthionine B synthase, 5, 10 – methylene

tetrahydrofolate reductase, methionine synthase)

Age and sex Advancing age, male sex, menopause

Nutritional Folic acid, vitamins B6 and B12

deficiencies

Disease Status Renal failure, malignancies, psoriasis,Rheumatoid arthritis, systemic lupuseythematosus, hypothyroidismDiabetes mellitus

Medications Metformin, methotrexate, Anticonvulsants, Niacin and theophylline, decreased levels of

betaine.

Conventional Fisk Factors for CAD1. DysIipidaemia : elevated LDL-C and low HDL-C

2. Smoking

3. Diabetes

4. Hypertension

5. Obesity

6. Sedentary lifestyle

7. Positive family history of premature vascular disease

8. Advancing age

9. Male gender and postmenopausal state in women

New and Emerging Risk Factors for CAD1. Inflammation and infectious agents

2. Hyperhomocysteinemia

3. Elevated lipoprotein (a) Lpa

4. Insulin resistance

5. Hypertriglyceridemia and increased IDE

6 Hyperfibrinogenemia

7. Small dense LDL phenotype

8. Psychosocial factors

9. Non-lipid related gene polymorphisms

10. Miscellaneous : oxidation susceptibility and antioxidant intake WBC count and Hemostatic / Fibrinolytic abnormalities, iron overload

Association between angiotensin-converting enzyme (ACE) genotypes and incidence of myocardial infarction in men with

primary hypercholesteolemia100

90

80

70

60

50

40

30

20

10

0 40 45 50 55 60 65

Inci

denc

e of

Myo

card

ial I

nfar

ctio

n (%

)

Age (years)

DI + II

DD

CAD – INFECTION Circ. 2002, 105, 1555

Patients randomized (n=152)

Patients commencing treatment (n = 148)

Placebo (n=74) Clarithromycin (n=74)

Urgent revascularization (n=2)Pancreatitis (n = 1)Renal failure (n=1)

Kaplan-Meier plot of cumulative survival during follow-up

Circ. 2002, 105, 1555Circ. 2002, 105, 1555

LEVELS OF HOMOCYSTEINE

Normal

• Male 8.0 - 14.0 mol/L

• Female 6.0 - 12.0 mol/L

Homocysteinemia

• Moderate 16-30 mol/L

• Intermediate 31-100 mol/L

• Severe > 100 mol/L

Hyperhomocysteinemia and risk of atherosclerotic vascular disease

1 1 11.7

2.5

6.8

0

2

4

6

8

Coronary arterydisease 15(n=5,047)

Cerebrovasculardisease 9(n=2,411)

Peripheral vasculardisease 5(n=1,391)

Studies for OR

Od

ds

Ra

tio

(O

R)

Hyperhomocysteinemia

Normal homocysteine levels

Meta analysis of 27 studies

* P < 0.05 v/s normal

(Boushey et al)

**

*

Homocysteine levels in CAD patients and controls

10.8

12

10

10.5

11

11.5

12

Healthy Men n=518 Patients with CHD n=257

Fa

sti

ng

pla

sm

a le

ve

ls (

mic

rom

mo

l/L)

A Higher plasma homocysteine levels

in Indian patients with CAD

B Increased risk in CAD in Indian Asians

due to hyperhomocysteinemia

1.5

1.4

1.3

1.2

1.1

1.011-12 12-1 113-1 14-15 >=15

Od

ds

rat

io f

or

CH

D

Homocysteine conc. (micrommol/L)

*p<0.05

n=775*

1.07

1.15

1.24

1.33

1.43

ONGOING STUDIES ON HOMOCYSTEINEMIA

• VISP

• NORVIT

• WENBIT

• SEARCH

• PACIFIC

HOMOCYSTEINE LEVELS IN DIFFERENT DIETS

Vegetarian Vegan Omnivore

Hcy level 13.2mmol/L 15.8mmol/L 10.2mmol/L

Vitamin B12 214.8pmol/L 140pmol/L 344.7pmol/L

Deficiency of vitamin B12 26 % 78 % 0 %

Joint effects of antimicrobial antibodies, smoking and CRP on the risk of coronary events

HOMOCYSTEINE METABOLISM

RELATION OF tHcy LEVELS WITH MORTALITY RATES

Homocysteine (micromol/L) Mortality (%)

< 9 3.8

9-14.9 8.6

>15 24.7

EMERGING / NOVEL RISK FACTORS FOR CADSERUM FIBRINOGEN

• MAJOR DETERMINANT OF PLASMA VISCOSITY

• PLAYS ROLE IN THROMBOSIS

• 1.8 FOLD INCREASE IN INCIDENCE FOR CAD

• GENETIC POLYMORPHISM – GENE IDENTIFIED

• FREQUENT BLOOD DONATIONS OFFERPROTECTION AGAINST CAD ? VISCOSITY

NOVEL RISK FACTORS FOR CAD

• ANXIETY

• DEPRESSION

• HOSTILITY

• RAGE

• SOCIAL ISOLATION

• DEPRESSION

4.78.3

13.2

19.9

26.2

40.9

0

10

20

30

40

50

60

0/1 2 3 4 5

TIMI Risk Score for UA/NSTEMI

D/M

I/U

R b

y 1

4 D

ays (

%)

Antman RM et al JAMA 2000, 284, 835Antman RM et al JAMA 2000, 284, 835

% Population 4.3 17.3 32.0 29.3 13.0 3.4

6-7

SABATINE AND ANTMAN SABATINE AND ANTMAN TIMI RISK SCORE FOR UA/NSTEMITIMI RISK SCORE FOR UA/NSTEMI

SABATINE AND ANTMAN SABATINE AND ANTMAN TIMI RISK SCORE FOR UA/NSTEMITIMI RISK SCORE FOR UA/NSTEMI