Upload
cardiositeindia
View
695
Download
6
Tags:
Embed Size (px)
DESCRIPTION
Citation preview
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