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TREATMENT

TREATMENT. The Present Survival with CAD. Time 0. Hospital Mortality Post MI. 25%. 11%. 8%. Follow-up 132 Grafts at 10 Years. Is This the Best We Can Do?. 10 Years Later. Treatment Goals in CAD Patients Identify and Treat Unstable Life-Threatening Coronary Lesions

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TREATMENT

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  1. TREATMENT

  2. The Present Survival with CAD Time 0

  3. Hospital Mortality Post MI 25% 11% 8%

  4. Follow-up 132 Grafts at 10 Years

  5. Is This the Best We Can Do? 10 Years Later

  6. Treatment Goals • in CAD Patients • Identify and Treat • Unstable Life-Threatening • Coronary Lesions • Antithrombotic Rx • Prevent Ventricular • Dilation with ACE Rx • Lower LDL • the More the Better • After Lifestyle • smoking • obesity

  7. Factors affecting therapy of hyperlipidemia Modifiable risk factors Hypertension Cigarette smoking Diabetes mellitus Obesity Alcohol intake Other factors Family history of coronary heart disease or peripheral vascular disease Personal history of early onset coronary heart disease Male sex  Dietary, Exercise & Lifestyle Modifications

  8. Passive smoking The incidence of heart disease among women with smoking husbands was 14.9 times higher than that of women with non smoking husbands.

  9. Nutritional Management of Hypercholesterolemia

  10. Obesity • Not an independent factor • Strong association with other • risk factors: • increased blood pressure • diabetes • hypercholesterolemia

  11. Body weight deserves a deliberate attention in any effort to reduce cardiovascular risk.

  12. Relation of Body Mass Index, (BMI) to Relative Mortality Risk

  13. Body Weight • Restoration of normal body weight is most • important. • Several studies have shown that decreasing body • weight decreases the plasma lipids regardless of • the design of the diet: • decreases LDL Chol • decreases TG • Increases HDL Chol

  14. Dietary Fats and Cholesterol AHA Recommendations

  15. CCCC recommendations: • Intervention by dietary modification plus exercise • Goals for dietary intervention: • Dietary component% of caloric intake • fat < 30% • saturated fatty acids < 10% • polyunsaturates < 10% • protein 10-15% • In Addition: • <30% fat; alcohol, sugar, sodium restrictions • Balance: carbohydrates, esp polysaccharides, and fibre • sources • Physical activity for CV fitness • For children, adjust for healthy weight

  16. Strategies • Most families have 10-15 recipes that • constitute their daily diet • It is often more efficient to modify or • replace individual meals, taking into • account: • preparation time • cost • taste

  17. Cholesterol • Cholesterol intake should be • less than 300 mg per day

  18. Strategies • Reduction of the major and obvious • sources of saturated fatty acid and • cholesterol. • Substitute rather than delete.

  19. FAT • Saturated fat: Increases total Chol and LDL C • Monounsaturated fat: neutral • Polyunsaturated fat: decreases total Chol • and LDL C • Subtracting a certain amount of • saturated fat has the same effect as • adding twice that amount of • polyunsaturated fat. • Animal and vegetable fats do not make • a complete distinction: • butter, coconut oil: Increase Chol • corn oil, whale oil: decrease Chol

  20. Replace fat in the diet by carbohydrate. • Carbohydrate has less calories than fat. • Increase fiber gradually

  21. Increase fish intake to two to three • 90 g servings per week. • Avoid fish oil supplements.

  22. Maximum Potential of Dietary Changes to Reduce Serum Cholesterol Average effect of dietary changes: 1.1 – 1.4 mmol/L decrease in serum cholesterol level

  23. Dietary Modification Hepatic over production is a major cause of increased plasma lipids Reduce excess dietary fat & excess caloric load & this will reduce hepatic production & reduce obesity   hypertension  diabetes Chylomicron Intestine LPL VLDL Liver Remnant LPL HDL3 Remnant (IDL) LCAT HPL HPL HDL2 LDL

  24. Diet modification remains a principal therapy for people with elevated blood lipid levels.

  25. Lower LDL – the More the Better

  26. + DRUGS

  27. Lipid-lowering agents • HMG-CoA reductase inhibitors: Inhibit hepatic cholesterol production • Bile acid resins: Bind cholesterol in gut • Fibric acid derivatives: ↑ cholesterol excretion in bile • Probucol: ↑ LDL-C breakdown and may inhibit LDL-C oxidation • Nicotinic acid: ↓ production of VLDL-C

  28. Mechanism of action of Bile Acid Sequestrants LDL LDL LDL IIMG CoA IIMG CoA Cholesterol Bile Acids Cholesterol Bile Acids Resins

  29. Bile acid Sequestrants in Primary Hypercholesterolaemia 8.9 Diet only Diet + Cholestyramine (16g/day) 7.2 6.8 Total Cholesterol LDL-Cholesterol HDL-Cholesterol Triglyceride 5.0 Serum Concentration (mmol/l) 1.5 1.4 1.2 1.1 % Change - 23 - 30.5 + 9.1 + 7.0

  30. HMG CoA Reductase Inhibitors Prevastatin CS 514, SQ 31000 Mevastatin (compactin) Lovastatin (mevinolin) Simvastatin (Synvinolin) HMG COA Rate limiting control of cholesterol synthesis (secreted in lipoproteins) Fluvastatin (Fluindostatin, SRI 62320) (Lactone form) (Lactone form) (Lactone form) Statins are pharmacologic targets to  Reduce hepatic production  Peripheral catabolism

  31. Treatment of hypercholesterolemia 8 6 4 2 Cholesterol (mmol/l) 0 4 8 12 16 20 24 Weeks on treatment Total LDL HDL Effect of statin treatment (20 mg/day) on total, LDL and HDL cholesterol concentrations (means +- s.e.m., n=10) in patients with high plasma cholesterol.

  32. HMG-CoA Reductase Inhibitors • Contraindications • Active liver disease • Pregnancy and lactation • Hypersensitivity • Relative Contraindications • Childhood • Concurrent use of cyclosporine, erythromycin, (fibrates, niacin) • Side effects • ↑ Serum transaminases • ↑ CK • Myopathies • Abdominal pain, diarrhea, constipation • Headaches

  33. Primary Prevention Trials • Trials of Diet • LA Veterans Study • Oslo Primary Prevention Study • Multiple Risk Factor Intervention Trial (MRFIT) • Trials of Drugs • WHO Cooperative Trial of Clofibrate • Lipid Research Clinics • Coronary Primary Prevention Trial (LRC-CPPT) • Helsinki Heart Study

  34. OSLO Primary Prevention Trial 325 300 275 TC (mg/dl) 0 1 2 3 4 5 Years Treatment Group N = 604 Controls N = 628

  35. OSLO Primary Prevention Trial Number of episodes Change Relative to Controls Coronary 19 - 47.2% Heart Disease 36* All Cardiovascular 22 - 43.6% Disease 39* Sudden 3 - 72.7% Death 11 Total CVD Death 8 - 46.7% (inc. Stroke) 15 Total 16 - 33.3% Deaths 24 Treatment Group N = 604 Controls N = 628 * P < 0.05

  36. Conclusions from Primary Prevention Studies • Elevated blood cholesterol is a major risk factor for CHD • Primary preventative measures can greatly reduce CHD risk • A 1% reduction of blood cholesterol reduces CHD risk by 2%

  37. Atherosclerosis CAN be Reversed Regression only Progression only Lipid effects  athero LDL HDL TG 25 P = 0.005 -32% 43% -29% 39 Niacin + Colestipol -46% 15% -9% 32 Lovastatin + Colestipol 21 46 -7% 5% 15% 11 Conventional -40 -20 0 20 40 Global change score Definite lesion changes in the FATS trial according to the three treatment groups. The numbers in the horizontal bars on the graph represent percentage of patients. The numbers in the squares on the right represent the lipid and lipoprotein changes in each of the corresponding treatment groups.

  38. Examples of regression - FATS LAD OMB RCA OMB LCx Mean % Stemosis 100% 39% 48% 69% 44% Mean % Stemosis28% 18% 30% 37% 30% Baseline After 2.5 years

  39. OBJECTIVES Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Study (4S) Lancet 344, 1994 To investigate whether long-term simvastatin therapy reduces total mortality and coronary events in post-MI and angina patients with serum total cholesterol levels of 5.5 to 8.0 mmol/L (212-309 mg/dl)

  40. Simvastatin and Platelet Dysfunction TAC ADP pM PLATELET TXB2 ng/108 pits 8 6 4 2 0 70 60 50 40 30 20 10 0 mean + SD * P < 0.01 * * * * * * * B 1 4 8 12 B 1 4 8 12 B 1 4 8 12 B 1 4 8 12

  41. Decrease in Ischemia With Decrease in LDL 24 17 15 10 5 0 Placebo (n = 20) Treatment (n = 20) 24 17 15 10 5 0 Episodes of ischemia / 48 hours Baseline 6 months Baseline 6 months

  42. MAJOR CORONARY EVENTS Coronary death and nonfatal MI 100 90 80 70 0 Simvastatin Placebo Proportion (%) of patients without events P < 0.00001 34% Risk reduction 1 2 3 4 5 6 Years since randomization

  43. Women and older patients BACKGROUND • CHD is the chief cause of death in women • More than 75 percent of deaths from CHD occur in individuals older than age 65 • Few clinical trials have focused on therapeutic intervention in women and the elderly • Subgroups of both women and the elderly (> 60 years) were included in the Scandinavian Simvastatin Survival Study

  44. Women MAJOR CORONARY EVENTS Coronary death and nonfatal MI 35% Risk reduction 100 75 50 25 0 91 Number of patients 59 P = 0.01 Placebo Simvastatin

  45. CAD: Therapeutic • Strategies for the 2000’s • Antiatherogenic • Antithrombogenic • Angiogenic • Obesity and Diet

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