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Acs ppt

  1. 1. ACUTE CORONARY SYNDROME
  2. 2. ACUTE CORONARY SYNDROMES PATHOPHYSIOLOGY <ul><li>PLAQUE RUPTURE & SUPERIMPOSED NONOCCLUSIVE THROMBUS </li></ul><ul><li>DYNAMIC OBSTRUCTION </li></ul><ul><li>PROGRESSIVE MECHANICAL OBSTRUCTION </li></ul><ul><li>INFLAMMATION AND/OR INFECTION </li></ul><ul><li>SECONDARY UNSTABLE ANGINA INCREASED O 2 DEMAND </li></ul>
  3. 3. FRISC - II PROTOCOL <ul><li>2457 PATIENTS </li></ul><ul><li>JUNE 17, 1996 TO MAY 6, 1998 (2 YEARS) </li></ul><ul><li>58 SCANDINAVIAN CENTERS </li></ul><ul><li>1.76 PATIENTS PER MONTH PER CENTER </li></ul>
  4. 4. FRISC - II ELIGIBILITY <ul><li>ST DEPRESSION MORE THAN 0.1 MV </li></ul><ul><li>T WAVE INVERSION MORE THAN 0.1 MV </li></ul><ul><li>RAISED BIOCHEMICAL MARKERS CPK - MB </li></ul><ul><li>MORE THAN 6  G/L, TROPORIN T MORE THAN 0.1  G/L </li></ul><ul><li>MB ISOENZYME ABOVE LIMIT FOR DIAGNOSIS OF MI </li></ul><ul><li>MAJORITY ABOVE 65 YEARS AND WITH MULTIPLE RISK </li></ul><ul><li>FACTORS </li></ul><ul><li>HIGHLY SELECTIVE GROUP OF ACS (IN BLOCKS </li></ul><ul><li>& CAPS - DIFFERENT COLUR) </li></ul>
  5. 5. THE TIMI RISK SCORE FOR UA/NSTEMI <ul><li>Characteristics Points </li></ul><ul><li>Historical </li></ul><ul><li> Age  65 years 1  3 Risk factors for CAD 1 Known CAD (stenosis  50%) 1 Aspirin use in past 7 days 1 </li></ul><ul><li>Presentation </li></ul><ul><li>Recent (  24 h) severe angina 1 </li></ul><ul><li>ST-segment deviation  0.5 mm 1 </li></ul><ul><li> Cardiac markers 1 </li></ul><ul><li>Risk Score = Total Points 0-7 </li></ul>Antman et al JAMA 2000, 784 835
  6. 6. RITA-3 <ul><li>1810 PATIENTS WITH ACS </li></ul><ul><li>915 CONSERVATIVE STRATEGY </li></ul><ul><li>895 INTERVENTION STRATEGY </li></ul><ul><li>INTERVENTION : ASPIRIN, ENOX, GP II B / III A, TICLO / CLOPIDOGREL </li></ul><ul><li>CONSERVATIVE ASPIRIN, ENOX </li></ul><ul><li>? GPIIB/IIIA </li></ul><ul><li>? TICLO / CLOPIDOGREL </li></ul><ul><li>LANCET 2002, 360, 743 </li></ul>
  7. 7. TROPONIN T LEVELS IN ACS & CARDIAC DEATH 1506 Patients FRISC – Circ. 1996, 93 : 1651
  8. 8. TACTICS – TIMI 18 New Eng. J. Med, 2001, 344 : 1879 21 % risk reduction (p=0.048) 36 % risk reduction (p=0.018)
  9. 9. TACTCS - TIMI 18 <ul><li>2220 PATIENTS WITH ACS </li></ul><ul><li>INVASIVE 1114 </li></ul><ul><li>CONSERVATIVE 1106 </li></ul><ul><li>CHARACTERISED ACCORDING TO TIMI RISK SCORE </li></ul>
  10. 10. RITA - 3 <ul><li>Intervention Conservative </li></ul><ul><li>(n =895) (n=915) </li></ul><ul><li>Deaths </li></ul><ul><li>4 months 26 23 </li></ul><ul><li>1 year 41 36 </li></ul><ul><li>All follow-up 60 72 </li></ul><ul><li>Myocardial infarctions (MIS) </li></ul><ul><li>4 months 30 34 </li></ul><ul><li>1 year 34 44 </li></ul><ul><li>All follow – up 45 56 </li></ul>Lancet 2002,360,743
  11. 11. RITA - 3 <ul><li>Intervention Conservative </li></ul><ul><li>(n =895) (n=915) </li></ul><ul><li>Refractory angina </li></ul><ul><li>4 months 39 85 </li></ul><ul><li>1 year 58 106 </li></ul><ul><li>Primary endpoints </li></ul><ul><li>Death, MI, or 86 (9.6%) 133 (14.5 %) </li></ul><ul><li>Refractory angina </li></ul><ul><li>4 months </li></ul><ul><li>Death or MI 68(7.6%) 76 (8.3 %) </li></ul><ul><li>1 year </li></ul>Lancet 2002,360,743
  12. 12. ACS – Report Incidence & D/MI CONS. V/s INV. <ul><li>Number of deaths or MIS within 1 year </li></ul><ul><li>Intervention Conservative </li></ul><ul><li>RITA 68/895(7.6%) 68/895(7.6%) </li></ul><ul><li>VINO 4/64(6.36%) 15/(22.4%) </li></ul><ul><li>TACTICS-TIMI 18 81/1114(7.3%) 105/1106(9.5%) </li></ul><ul><li>TRUCS 6/76(7.6%) 12/72(16.7%) </li></ul><ul><li>FRISC II 127/1219(10.4%) 68/895(7.6%) </li></ul><ul><li>MATE 11/111(9.9%) 6/90(6.7%) </li></ul><ul><li>VANQWISH 111/462(24.0%) 85/458(18.6%) </li></ul><ul><li>TIMI IIIB 52/484(10.8%) 62/509(12.2%) </li></ul>Risk Ratio (95 % CI)
  13. 13. ASSESSMENT OF THE CLINICAL UTILITY OF NOVEL MARKERS OF CARDIOVASCULAR RISK <ul><li>ADDITIVE TO </li></ul><ul><li> TOTAL AND </li></ul><ul><li>ASSAY PROSPECTIVE HIGH-DENSITY </li></ul><ul><li>CONDITIONS STUDIES LIPOPROTEIN </li></ul><ul><li>MARKER STANDARDIZED ? CONSISTENT ? CHOLESTEROL ? </li></ul><ul><li>Lipoprotein (a) No Yes/no Yes /no </li></ul><ul><li>Total homocysteine Yes Yes/no Yes /no </li></ul><ul><li>Tissue-type plasminogen activator Yes/no Yes Yes/no </li></ul><ul><li>And plasminogen activator inhibitor </li></ul><ul><li>Fibrinogen Yes/no Yes Yes </li></ul><ul><li>High-sensitiviety-C-reactive protein Yes Yes Yes </li></ul><ul><li>From Ridker PM: Evaluating novel cardiovascular risk factors : Can we better predict heart attacks </li></ul><ul><li>?Ann Intern Med 130:933-937,1999 </li></ul>
  14. 14. 100 80 60 40 20 0 (n=895) (n=915) (n=856) (n=873) (n=799) (n=814) Intervention Conservative Intervention Conservative Intervention Conservative Proportion of patients (%) Baseline 4 months 1 year Prevalence of angina over time treatment Lancet 2002,360,743 Grade 1 Grade 2 Grade 3/4
  15. 15. Nitricoxide (NO) Thrombomodulin TM Protects Endothelium Endothelium Damages Endothelium Depletion of NO and TM Reactive Oxygen Species Oxidation Homocysteine Mechanism of Homocysteine Induced Vascular Damage
  16. 16. RITA - 3 <ul><li> Intervention Conservative </li></ul><ul><li> (n =895) (n=915) </li></ul><ul><li>Deaths </li></ul><ul><li>4 months 26 23 </li></ul><ul><li>1 year 41 36 </li></ul><ul><li>All follow-up 60 72 </li></ul><ul><li>Myocardial infarctions (MIs) </li></ul><ul><li>4 months 30 34 </li></ul><ul><li>1 year 34 44 </li></ul><ul><li>All follow – up 45 56 </li></ul>Lancet 2002,360,743
  17. 17. RITA - 3 <ul><li>Intervention Conservative </li></ul><ul><li>(n =895) (n=915) </li></ul><ul><li>Refractory angina </li></ul><ul><li>4 months 39 85 </li></ul><ul><li>1 year 58 106 </li></ul><ul><li>Primary endpoints </li></ul><ul><li>Death, MI, or 86 (9.6%) 133 (14.5 %) </li></ul><ul><li>Refractory angina </li></ul><ul><li>4 months </li></ul><ul><li>Death or MI 68(7.6%) 76 (8.3 %) </li></ul><ul><li>1 year </li></ul>Lancet 2002,360,743
  18. 18. ACS – Report Incidence & D/MI CONS. V/s INV. <ul><li>Number of deaths or MIS within 1 year </li></ul><ul><li>Intervention Conservative </li></ul><ul><li>RITA 68/895(7.6%) 68/895(7.6%) </li></ul><ul><li>VINO 4/64(6.36%) 15/(22.4%) </li></ul><ul><li>TACTICS-TIMI 18 81/1114(7.3%) 105/1106(9.5%) </li></ul><ul><li>TRUCS 6/76(7.6%) 12/72(16.7%) </li></ul><ul><li>FRISC II 127/1219(10.4%) 68/895(7.6%) </li></ul><ul><li>MATE 11/111(9.9%) 6/90(6.7%) </li></ul><ul><li>VANQWISH 111/462(24.0%) 85/458(18.6%) </li></ul><ul><li>TIMI IIIB 52/484(10.8%) 62/509(12.2%) </li></ul>Risk Ratio (95 % CI)
  19. 19. 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
  20. 20. 100 80 60 40 20 0 (n=895) (n=915) (n=856) (n=873) (n=799) (n=814) Intervention Conservative Intervention Conservative Intervention Conservative Proportion of patients (%) Baseline 4 months 1 year Prevalence of angina over time treatment Lancet 2002,360,743 Grade 1 Grade 2 Grade 3/4
  21. 21. Conventional Fisk Factors for CAD <ul><li>1. DysIipidaemia : elevated LDL-C and low HDL-C </li></ul><ul><li>2. Smoking </li></ul><ul><li>3. Diabetes </li></ul><ul><li>4. Hypertension </li></ul><ul><li>5. Obesity </li></ul><ul><li>6. Sedentary lifestyle </li></ul><ul><li>7. Positive family history of premature vascular disease </li></ul><ul><li>8. Advancing age </li></ul><ul><li>9. Male gender and postmenopausal state in women </li></ul>
  22. 22. ACUTE CORONARY SYNDROMES PATHOPHYSIOLOGY <ul><li>PLAQUE RUPTURE & SUPERIMPOSED NONOCCLUSIVE THROMBUS </li></ul><ul><li>DYNAMIC OBSTRUCTION </li></ul><ul><li>PROGRESSIVE MECHANICAL OBSTRUCTION </li></ul><ul><li>INFLAMMATION AND/OR INFECTION </li></ul><ul><li>SECONDARY UNSTABLE ANGINA INCREASED O 2 DEMAND </li></ul>
  23. 23. Factors influencing homocysteine metabolism <ul><li>Inherited Enzyme deficiencies in the metabolic pathway (cysthionine B synthase, 5, 10 – methylene tetrahydrofolate reductase, methionine synthase) </li></ul><ul><li>Age and sex Advancing age, male sex, menopause </li></ul><ul><li>Nutritional Folic acid, vitamins B 6 and B 12 </li></ul><ul><li>deficiencies </li></ul><ul><li>Disease Status Renal failure, malignancies, psoriasis, Rheumatoid arthritis, systemic lupus eythematosus, hypothyroidism Diabetes mellitus </li></ul><ul><li>Medications Metformin, methotrexate, Anticonvulsants, Niacin and theophylline, decreased levels of betaine. </li></ul>
  24. 24. Conventional Fisk Factors for CAD <ul><li>1. DysIipidaemia : elevated LDL-C and low HDL-C </li></ul><ul><li>2. Smoking </li></ul><ul><li>3. Diabetes </li></ul><ul><li>4. Hypertension </li></ul><ul><li>5. Obesity </li></ul><ul><li>6. Sedentary lifestyle </li></ul><ul><li>7. Positive family history of premature vascular disease </li></ul><ul><li>8. Advancing age </li></ul><ul><li>9. Male gender and postmenopausal state in women </li></ul>
  25. 25. New and Emerging Risk Factors for CAD <ul><li>1. Inflammation and infectious agents </li></ul><ul><li>2. Hyperhomocysteinemia </li></ul><ul><li>3. Elevated lipoprotein (a) Lpa </li></ul><ul><li>4. Insulin resistance </li></ul><ul><li>5. Hypertriglyceridemia and increased IDE </li></ul><ul><li>6 Hyperfibrinogenemia </li></ul><ul><li>7. Small dense LDL phenotype </li></ul><ul><li>Psychosocial factors </li></ul><ul><li>9. Non-lipid related gene polymorphisms </li></ul><ul><li>10. Miscellaneous : oxidation susceptibility and antioxidant intake WBC count and Hemostatic / Fibrinolytic abnormalities, iron overload </li></ul>
  26. 26. Association between angiotensin-converting enzyme (ACE) genotypes and incidence of myocardial infarction in men with primary hypercholesteolemia 100 90 80 70 60 50 40 30 20 10 0 40 45 50 55 60 65 Incidence of Myocardial Infarction (%) Age (years) DI + II DD
  27. 27. 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)
  28. 28. Kaplan-Meier plot of cumulative survival during follow-up Circ. 2002, 105, 1555
  29. 29. LEVELS OF HOMOCYSTEINE <ul><li>Normal </li></ul><ul><li>Male 8.0 - 14.0  mol/L </li></ul><ul><li>Female 6.0 - 12.0  mol/L </li></ul><ul><li>Homocysteinemia </li></ul><ul><li>Moderate 16-30  mol/L </li></ul><ul><li> Intermediate 31-100  mol/L </li></ul><ul><li>Severe > 100  mol/L </li></ul>
  30. 30. Hyperhomocysteinemia and risk of atherosclerotic vascular disease Meta analysis of 27 studies * P < 0.05 v/s normal (Boushey et al) * * *
  31. 31. Homocysteine levels in CAD patients and controls 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 1.0 11-12 12-1 113-1 14-15 >=15 Odds ratio for CHD Homocysteine conc. (micrommol/L) *p<0.05 n=775 * 1.07 1.15 1.24 1.33 1.43
  32. 32. ONGOING STUDIES ON HOMOCYSTEINEMIA <ul><li>VISP </li></ul><ul><li>NORVIT </li></ul><ul><li>WENBIT </li></ul><ul><li>SEARCH </li></ul><ul><li>PACIFIC </li></ul>
  33. 33. HOMOCYSTEINE LEVELS IN DIFFERENT DIETS <ul><li> Vegetarian Vegan Omnivore </li></ul><ul><li>Hcy level 13.2mmol/L 15.8mmol/L 10.2mmol/L </li></ul><ul><li>Vitamin B 12 214.8pmol/L 140pmol/L 344.7pmol/L </li></ul><ul><li>Deficiency of vitamin B 12 26 % 78 % 0 % </li></ul>
  34. 34. Joint effects of antimicrobial antibodies, smoking and CRP on the risk of coronary events
  35. 35. HOMOCYSTEINE METABOLISM
  36. 36. RELATION OF tHcy LEVELS WITH MORTALITY RATES <ul><li>Homocysteine (micromol/L) Mortality (%) </li></ul><ul><li>< 9 3.8 </li></ul><ul><li>9-14.9 8.6 </li></ul><ul><li>>15 24.7 </li></ul>
  37. 37. EMERGING / NOVEL RISK FACTORS FOR CAD SERUM FIBRINOGEN <ul><li>MAJOR DETERMINANT OF PLASMA VISCOSITY </li></ul><ul><li>PLAYS ROLE IN THROMBOSIS </li></ul><ul><li>1.8 FOLD INCREASE IN INCIDENCE FOR CAD </li></ul><ul><li>GENETIC POLYMORPHISM – GENE IDENTIFIED </li></ul><ul><li>FREQUENT BLOOD DONATIONS OFFER </li></ul><ul><li>PROTECTION AGAINST CAD ?  VISCOSITY </li></ul>
  38. 38. NOVEL RISK FACTORS FOR CAD <ul><li>ANXIETY </li></ul><ul><li>DEPRESSION </li></ul><ul><li>HOSTILITY </li></ul><ul><li>RAGE </li></ul><ul><li>SOCIAL ISOLATION </li></ul><ul><li>DEPRESSION </li></ul>
  39. 39. Antman 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 TIMI RISK SCORE FOR UA/NSTEMI

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