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המלצות 2004

המלצות 2004. למניעת מחלות לב וכלי דם. של ההסתדרות הרפואית בישראל. מבט על כולסטרול. פרופ' ארדון רובינשטין כנס אביב 2005 החברה ליתר לחץ דם בישראל. Evolution of the NCEP Guidelines. המלצות הר"י. המלצות 1 (3/88). המלצות 2 (5/95). המלצות 3 (1/00). ATP I. ATP II. ATP III. 1970s.

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המלצות 2004

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  1. המלצות 2004 למניעת מחלות לב וכלי דם של ההסתדרות הרפואית בישראל מבט על כולסטרול פרופ' ארדון רובינשטין כנס אביב 2005 החברה ליתר לחץ דם בישראל

  2. Evolution of the NCEP Guidelines המלצות הר"י המלצות 1 (3/88) המלצות 2 (5/95) המלצות 3 (1/00) ATP I ATP II ATP III 1970s 1988 1993 2001 • Framingham • MRFIT • LRC-CPPT • Coronary Drug Project • Helsinki Heart Study • CLAS (angio) • Angiographic Trials • (FATS, POSCH, SCOR, STARS, Ornish, MARS) • Meta-Analyses • (Holme, Rossouw) • 4S, WOSCOPS, CARE, LIPID, AFCAPS/TexCAPS, VA-HIT, others

  3. המלצות מספר 3 לחולים עם סיכון גבוה LDL-C 130 LDL-LoweringDrug Diet Rx LDL-C 100–129 TherapeuticOptions Fibrates/nicotinic acid Statins LDL-C <100 No LDL-LoweringTherapy LDL-C goal

  4. המלצות מספר 3 – קטגורית סיכון High Risk Moderately High Risk • CHD, PAD, carotid disease, diabetes, 2+ RF (10-year risk >20%) • LDL-C goal • <100 mg/dL • 2+ RF (10-yr risk 10–20%) • - LDL-C goal <130 mg/dL Moderate Risk Lower Risk • 2+ RF (10-yr risk <10%) • - LDL-C goal <130 mg/dL • 0–1 RF • - LDL-C goal <160 mg/dL

  5. Evolution of the NCEP Guidelines המלצות הר"י המלצות 1 (3/88) המלצות 2 (5/95) המלצות 3 (1/00) המלצות 4 (2004) ATP I ATP II ATP III 2004 1993 2001 1970s 1988 • Framingham • MRFIT • LRC-CPPT • Coronary Drug Project • Helsinki Heart Study • CLAS (angio) • 4S, WOSCOPS, CARE, LIPID, AFCAPS/TexCAPS, VA-HIT, others • H.P.S • ASCOT • PROVE-IT • REVERSAL • PROSPER • CARDS • Angiographic Trials • (FATS, POSCH, SCOR, STARS, Ornish, MARS) • Meta-Analyses • (Holme, Rossouw)

  6. והמחקריםעליהם מבוססות ההמלצות החדשות Heart Protection Study (HPS) Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Prospectivestudy of Pravastatinin the Elderlyat Risk (PROSPER) Reversing Atherosclerosis with Aggressive Lipid Lowering PRavastatin Or atorVastatin Evaluation and Infection Therapy (PROVE IT) מחקרי סוכרת : Collabrative AtoRvastatin Diabetes Study (CARDS)

  7. Heart Protection Study: Design • 20,536 UK adults (40–80 years) • High-risk patients: CHD, PVD, diabetes, high BP • Variable LDL-C at baseline • Rx: simvastatin 40 mg vs. placebo (also vitamin arm) • 5-yr study

  8. Prior Disease at Baseline * Overlap between categories within “No CHD” group

  9. Total and LDL Cholesterol at Baseline

  10. 0.4 0.6 0.8 1.0 1.2 1.4 Simvastatin: Major Vascular Events Risk ratio and 95% CI STATIN Better PLACEBOBetter 24% SE 3reduction(2P<0.00001)

  11. Heart Protection Study: Results • 13% reduction in all-cause mortality • 24% reduction in major vascular events • 27% reduction in major coronary events • 25% reduction in stroke • 24% reduction in revascularization

  12. Simvastatin: Average LDL Cholesterol Difference by Baseline LDL Cholesterol

  13. HPS: Reduction in Major Vascular Events According to Baseline LDL-C (mg/dL) LDL-C>130 LDL-C100–130 LDL-C<100 % Relative Risk Reduction -22% -22% -30%

  14. Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Design  Multicenter trial with 2 treatment comparisons  A prospective, randomized, open, blinded endpoint (PROBE) design comparing 2 antihypertensive regimens in hypertensive men and women without known CHD who had 3 other CV risk factors (n=19,342)  A double-blind, placebo-controlled trial of atorvastatin 10 mg/d in the subsample of patients with total cholesterol 250 mg/dL (n=10,305)  Primary endpoint: nonfatal MI (including silent MI) or CHD death  Planned follow-up average of 5 yr; lipid-lowering arm stopped early at median follow-up of 3.3 yr

  15. ASCOT Lipid-Lowering Arm • 10,305 subjects with hypertension (40–79 yrs) • Primary prevention in higher-risk subjects • Mean LDL-C 132 mg/dL • Rx: atorvastatin 10 mg vs. placebo • Study stopped at 3.3 yr (positive outcome) • 29% reduction in total coronary events • 27% reduction in stroke

  16. ASCOT: Lipid Changes with Atorvastatin Baseline 1 Year 3 Years mg/dl TC LDL-C HDL-C TG

  17. Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) • 5804 subjects (70–82 yrs) at high risk • Rx: pravastatin 40 mg vs. placebo • 19% reduction in major coronary events • 24% reduction in CHD mortality • 25% reduction in TIAs (no stroke reduction) • Conclusion:elderly patients benefit from LDL-C–lowering therapy

  18. REVERSAL Trial Reversing Atherosclerosis with Aggressive Lipid Lowering

  19. REVERSAL Trial 502 symptomatic coronary artery disease patients with elevated LDL Randomized, double-blind, multicenter • Aggressive lipid lowering strategy • Atorvastatin (80 mg) • n=253 • Moderate lipid-lowering strategy • Pravastatin (40 mg) • n=249 • Endpoints (follow-up 18 months): • Primary – Percent change in atheroma volume on IVUS between baseline and 18 month follow-up • Secondary – Absolute change in atheroma volume; change in the percent obstructive volume

  20. THE STUDY Patients were randomized to treatment with either LIPITOR 80 mg/day or pravastatin 40 mg/day. The effects of treatment were measured with Intravascular Ultrasound (IVUS), a novel technology that uses high-frequency sound waves to provide an accurate assessment of plaque build-up within the artery walls.

  21. Coronary Remodeling Progression Expansion overcome: lumen narrows Compensatory expansion maintains constant lumen Normal vessel Minimal CAD Moderate CAD Severe CAD

  22. Angiography Cannot Account forCoronary Remodeling 3.1 mm

  23. REVERSAL Trial HDL at follow-up p=0.06 LDL at follow-up p<0.001 mg/dL Total-cholesterol at follow-up p<0.001 mg/dL mg/dL

  24. RESULTS • The primary endpoint of percent change in atheroma volume as assessed with IVUS showed that while pravastatin patients experienced progression of more than 2.5% from baseline, atorvastatin had little percent change decrease(<0.5%) in atheroma volume (p=0.02). • Pravastatin treatment resulted in a final mean LDL of 110 for a -25.2% change from baseline, while atorvastatin resulted in a final LDL of 79 for a 46.3% change (p<0.0001).

  25. PRavastatin Or atorVastatin Evaluation and Infection Therapy (TIMI 22)

  26. PROVE IT • 4162 patients post acute coronary syndrome • Rx: pravastatin 40 mg vs. atorvastatin 80 mg • On-Rx LDL-C levels: pravastatin 95 mg/dL, atorvastatin 62 mg/dL • 2-yr mean follow-up • 16% reduction in composite CVD endpoint on atorvastatin compared with pravastatin

  27. PROVE-IT Conclusion Patients recently hospitalized for an ACS benefit from early and continued lowering of LDL-C to levels substantially below current target levels.

  28. Aim of CARDS To evaluate the effectiveness and safety of atorvastatin 10mg daily versus placebo in the primary prevention of cardiovascular disease (CAD and stroke) in patients with type 2 diabetes without raised cholesterol levels

  29. CARDS Design Placebo 2838 patients Placebo Atorvastatin 10mg 6 week pre-randomisation placebo run in phase then visits at month 1, 3, 6 and 6 monthly

  30. PlaceboMean (SD) or N (%) AtorvastatinMean (SD) or N (%) Diabetes duration (years) 7.8 (6.3) 7.9 (6.4) Diabetes treatment Diet only 228 (16.2%) 214 (15.0%) Oral hypoglycaemic only 916 (65.0%) 932 (65.3%) Insulin only 207 (14.7%) 210 (14.7%) Insulin+oral hypoglycaemic 59 (4.2%) 72 (5.0%) HbA1c % 7.8 (1.4) 7.9 (1.4) Plasma glucose mmol/L 9.8 (3.2) 10.0 (3.3) CARDS Diabetes Related Characteristics

  31. Lipid Levels by Treatment Total cholesterol (mmol/L) LDL cholesterol (mmol/L) Average difference 26% 1.4 mmol/L (54mg/dL) p<0.0001 Average difference 40% 1.2 mmol/L (46mg/dL) p<0.0001 6 3 4 2 2 1 0 0 0 1 2 3 4 4.5 0 1 2 3 4 4.5 Years of Study Years of Study Placebo Atorvastatin

  32. Summary • 37% reduction in major CVD events • 48% reduction in stroke • 27% reduction in all cause mortality of borderline statistical significance • Consistent effect regardless of baseline lipids, sex or age • Atorvastatin 10mg was well tolerated with no cases of rhabdomyolysis and no differences in muscle and liver adverse effects

  33. מה הקשר בין LDL-C לסיכון של מחלת לב איסכמית ?

  34. Study Hypothesis: Lower Is Better 4S-PBO 25 Secondary prevention Primary prevention 20 LIPID-PBO 4S-Rx 15 With CHD event (%) CARE-Rx CARE-PBO 10 WOS-PBO LIPID-Rx WOS-Rx ? 5 AFCAPS-Rx AFCAPS-PBO 0 50 70 90 110 130 150 170 190 210 LDL-C (mg/dL)

  35. Heart Protection Study(5-Year Trial) Simvastatin40 mg LogCHDRisk 26% Reduction in CVD Simvastatin40 mg 22% Reduction in CVD LDL-C (mg/dL) 60 100

  36. PROVE IT–TIMI 22(2-Year Trial) Pravastatin40 mg LogCHDRisk Atorvastatin80 mg 16% Reduction in CVD 60 100 LDL-C Level

  37. T.N.T Atorva 10 mg LogCHDRisk Atorva80 mg 22% Reduction in CVD 100 LDL-C Level 77 130

  38. Rationale for New Therapeutic Option: Very Low LDL-C Goal <70 mg/dL • HPS results • PROVE IT results • Not final word on very low LDL-C goals • TNT • IDEAL • SEARCH

  39. Candidates for Very Low LDL-C Goal of <70 mg/dL • Very high risk patients • Established atherosclerotic CVD • + multiple risk factors (esp. diabetes) • + severe and poorly controlled risk factors (e.g., cigarette smoking) • + metabolic syndrome (high TG, low HDL-C) • + acute coronary syndromes (PROVE IT)

  40. Implications of Recent LDL-Lowering Trials • High-risk patients with various LDL-C levels • Patients with diabetes • Older patients • Acute coronary syndromes • Moderately high risk patients

  41. Implications of Recent LDL-Lowering Trials • High-risk patients with various LDL-C levels • LDL-C 130 mg/dL: drug + diet • LDL-C 100–129: LDL-lowering drug preferred (over other options) • LDL-C <100 mg/dL • Very high risk patients: LDL-C goal <70 • Other high-risk patients: optional therapies including statins, fibrates, nicotinic acid

  42. What’s New for High-Risk Patients? • ATP III LDL-C goal: <100 mg/dL • For very high risk: optional goal <70 mg/dL • For LDL-C 100 mg/dL, start LDL-lowering drug simultaneously with lifestyle changes • For LDL-C <100 mg/dL, LDL-lowering drug is a therapeutic option • For high TG/low HDL-C, consider fibrate or nicotinic acid in combination with LDL- lowering drug

  43. LDL-C 132 LDL-C <132 ASCOT Results for Patients at Moderately High Risk Atorvastatin10 mgReduces CHDRisk by 1/3 ATP IIILDL-CGoal

  44. What’s New for Moderately High Risk Patients? • ATP III LDL-C goal: <130 mg/dL • LDL-C level 130 mg/dL: start drug with diet Rx • New therapeutic option: LDL-C goal <100 mg/dL (based on ASCOT) • LDL-C level 100–129 mg/dL: drug therapy optional (based on ASCOT)

  45. Lifestyle-Related Risk Factors(High or Moderately High Risk) • Treat lifestyle-related risk factors, regardless of LDL-C level • Obesity • Physical inactivity • Elevated triglyceride • Low HDL-C • Metabolic syndrome

  46. When LDL-lowering drug therapy is employed in high-risk or moderately high risk patients, intensity of therapy should be sufficient to achieve a 30–40% reduction in LDL-C levels.

  47. RISK ASSESSMENT • Use of the European SCORE (Systematic Coronary Risk Evaluation) • Integrated risk factors: gender, age, smoking, systolic blood pressure and either total cholesterol or the cholesterol/HDL ratio. • Predicts any kind of fatal atherosclerotic end-point i.e. fatal CVD events over a ten-year period. • Tailored for individual countries provided reliable national mortality information is available – Israel a low-risk region.

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