1. TREATING LIPIDS FOR PREVENTION OF CAD : HOW AGGRESSIVE SHOULD WE BE? Robert B. Baron MD MS Professor and Associate Dean UCSF School of Medicine Declaration of full disclosure: No conflict of interest

2. IN CLINICAL TRIALS WE TRUST

3. Risk reduction $$ Harm The magnitude of benefit from any given intervention is a function of: 1) The relative risk reduction conferred by the intervention, and 2) The native risk of the patient A RISK-BASED APPROACH

4. Primary Prevention Secondary Prevention STATIN MEGA TRIALS: PRE-ATP III 1994 - 4S (Scandinavian Simvastatin) 1995 - WOSCOP (West of Scotland) 1996 - CARE 1998 - LIPID Trial 1998 - AFCAPS / TexCAPS

5. Primary Prevention Secondary Prevention NEWER STATIN TRIALS: POST-ATP III 2002 - Heart Protection Study (simva 40) 2002 - PROSPER (prava 40) 2003 - ALLHAT (prava 40) 2003 - ASCOT (atorva 10) 2004 - PROVE IT (prava 40 vs atorva 80) 2004 - CARDS (atorva 10 in DM) 2005 - TNT (atorva 10 vs atorva 80)

6. 63 yo woman; s/p MI LDL 115 HDL 45 TG 160

7. LDL Goal and Cutpoints in Patients with CHD and CHD Risk Equivalents (10-Year Risk >20%) 2001 130 mg/dL (100–129 mg/dL: drug optional) 100 mg/dL <100 mg/dL LDL Level at Which to Consider Drug Therapy LDL Level at Which to Initiate Diet LDL Goal

8. LDL Goal and Cutpoints in Patients with CHD and CHD Risk Equivalents (10-Year Risk >20%) 2004 100 mg/dL (<100mg/dL: drug optional) 100 mg/dL <100 mg/dL Optional : <70 LDL Level at Which to Consider Drug Therapy LDL Level at Which to Initiate Diet LDL Goal

9. HEART PROTECTION STUDY RCT of 20,536 high-risk individuals; 40-80 yr Total cholesterol >135 mg/dl (>3.5 mmol/L) Confirms efficacy of statin in secondary prevention: All-cause mortality: 12.9% vs 14.7% CAD mortality: 5.7% vs 6.9% Benefit seen in subgroups poorly represented in other trials

10. Baseline Feature LDL (mg/dL) <100 100 <130 130 ALL PATIENTS Statin Placebo (10,269) (10,267) 285 360 670 881 10871365 20422606 (19.9%) (25.4%) 0.40.60.8 1.01.21.4 24% reduction (p<0.00001) HPS: Vascular Events by Baseline LDL-C Risk Ratio and 95% Cl Statin better Statin worse No. Events

11. LaRosa, NEJM 2005 TREATING TO NEW TARGETS (TNT) RCT of 10,001 patients with stable CHD; 35-75 yr LDL <130 mg/dl Atorvastatin 10 vs atorvastain 80 Followed for 4.9 years Research question: safety and efficacy of lowering LDL below 100 mg/dl

12. LaRosa, NEJM 2005 TREATING TO NEW TARGETS (TNT) LDL Event % Death % LFTs % Atorv 10101 10.9 2.5 0.2 Atorv 80 77 8.7 2.0 1.2 p value <0.001 0.09

13. The Lower, the Better Relative Risk for CHD (Log Scale) 3.7 2.9 2.2 1.7 1.3 1.0 LDL-C (mg/dL) 4070100130160190 0 1 Grundy SM et al. Circulation 2004;110:227–239.

14. 63 yo woman; diabetes LDL 115 HDL 45 TG 160

15. Baseline Feature Previous MI Other CHD No prior CHD CVD PVD Diabetes ALL PATIENTS Statin Placebo (10,269) (10,267) 10071255 452 597 182 215 332 427 279 369 20422606 (19.9%) (25.4%) Risk Ratio and 95% Cl Statin better Statin worse 0.40.60.8 1.01.21.4 24% reduction (p<0.00001) HPS: Vascular Events by Prior Disease No. Events

16. Colhoun, Lancet, 2004 COLLABORATIVE ATORVASTATIN DIABETES STUDY (CARDS) RCT of 2838 patients, 40-70, with DM2 + HTN, cigs, or diabetic complication LDL 117 mg/dl Atorvastatin 10 vs placebo Followed for 4 years Research question: is statin better than placebo for primary prevention in patients with diabetes?

17. Colhoun, Lancet, 2004 COLLABORATIVE ATORVASTATIN DIABETES STUDY (CARDS) Trial terminated two years early Placebo 127 events vs. atorvastain 83 Reduction 37% all events Reduction in CHD (36%), revascularisations (31%), stroke (48%), death (27%)

18. Lancet, 2005 FENOFIBRATE INTERVENTION AND EVENT LOWERING IN DIABETES (FIELD) STUDY RCT of 9795 patients, 50-75, with DM2 Fenofibrate 200 vs placebo Followed for 5 years Outcome: coronary events

19. Lancet, 2005 FENOFIBRATE INTERVENTION AND EVENT LOWERING IN DIABETES (FIELD) STUDY Coronary events: –5.9% on placebo vs. 5.2% on fenofibrate 11% reduction, not statistically significant HR 0.89 (95% CI 0.75 - 1.05) p=0.16

20. CHD Risk Equivalents Risk for major coronary events equal to that in established CHD e.g. >20%risk of MI or CHD death in 10 years Peripheral artery disease Abdominal aortic aneurysm Symptomatic CVD Diabetes Multiple risk factors with >20% risk in 10 years

21. Other Potential CHD Risk Equivalents Risk for major coronary events equal to that in established CHD e.g. >20%risk of MI or CHD death in 10 years Renal insufficiency: yes Congestive heart failure: yes Metabolic syndrome: probably not (calculate Framingham risk)

22. LDL Goal and Cutpoints in Patients with CHD and CHD Risk Equivalents (10-Year Risk >20%) 2004 100 mg/dL (<100mg/dL: drug optional) 100 mg/dL <100 mg/dL Optional : <70 LDL Level at Which to Consider Drug Therapy LDL Level at Which to Initiate Diet LDL Goal

23. 63 yo man; s/p MI LDL 70 HDL 25 TG 400

24. 63 yo man; s/p MI {LDL 70, HDL 25, TG 400, Total 175} Total - HDL = Non-HDL 175 - 25 = 150 NCEP non-HDL goal: LDL goal + 30 = 100

25. 100160220 Risk of CHD Low HDL-C is an Independent Predictor of CHD Risk Even When LDL-C is Low HDL-C (mg/dL) LDL-C (mg/dL) 25 Gordon T et al. Am J Med 1977;62:707-714. 45 65 85

26. Therapeutic lifestyle changes –Smoking cessation –Regular aerobic exercise –Weight loss –Alcohol use? Management of Low HDL-C

27. VA-HIT: Major Coronary Events in Gemfibrozil vs. Placebo Groups Cumulative Incidence (%) 0 Rubins HB et al. N Engl J Med 1999;341:410-418. 123456 Year Placebo Gemfibrozil –22% reduction P = 0.006

28. Combination Drug Therapy Adding Niacin or a Fibrate to a Statin Pros Better TG and HDL-C May LDL-C more (niacin or fenofibrate) Lp(a) (niacin) LDL particle size Fibrinogen (fibrates) Angiographic data Cons Increased cost and complexity Increased myositis risk Increased hepatitis risk (niacin) Potential for other drug interactions Lack of outcome data

29. Lifestyle changes and secondary causes Pharmacologic therapy –If LDL-C elevated: statin –If TG elevated: fibrate or fish oil –If isolated low HDL-C: niacin Combination therapy Management of Low HDL-C

30. 63 yo woman, no risk factors LDL 175 HDL 45 TG 160

31. POSITIVE RISK FACTORS Age: Men >45: women >55 Family history premature CHD Cigarette smoking Hypertension Low HDL-cholesterol (<40 mg/dl)

32. NEGATIVE RISK FACTOR High HDL-cholesterol > 60 mg/dl

33. LDL Goal and Cutpoints Patients with 0–1 Risk Factor 2001 and 2004 190 mg/dL (160–189 mg/dL: LDL-lowering drug optional) 160 mg/dL <160 mg/dL LDL Level at Which to Consider Drug Therapy LDL Level at Which to Initiate Diet LDL Goal

34. 63 year old woman, HTN LDL 175 HDL 45 TG 160 SBP 120 on RX Nonsmoker

35. POSITIVE RISK FACTORS Age: Men >45: women >55 Family history premature CHD Cigarette smoking Hypertension Low HDL-cholesterol (<40 mg/dl)

36. LDL Goal and Cutpoints Patients with Multiple Risk Factors (10-Year Risk 20%) 2001 10-year risk 10–20%: 130 mg/dL 10-year risk <10%: 160 mg/dL 130 mg/dL <130 mg/dL LDL Level at Which to Consider Drug Therapy LDL Level at Which to Initiate Diet LDL Goal

37. LDL Goal and Cutpoints Patients with Multiple Risk Factors (10-Year Risk 20%) 2004 10-year risk 10–20%: 130 Optional 100-129 10-year risk <10%: 160 130 mg/dL <130 mg/dL LDL Level at Which to Consider Drug Therapy LDL Level at Which to Initiate Diet LDL Goal

38. www.nhlbi.nih.gov/guidelines/cholesterol www.statcoder.com www.med-decisions.com On-line and PDA tools

39. 63 yo woman, HTN LDL 175 HDL 45 TG 160 SBP 120 on RX Nonsmoker NCEP: yes 10 yr risk: 6%…maybe not

40. 63 yo man, HTN LDL 175 HDL 45 TG 160 SBP 120 on RX Nonsmoker NCEP: yes 10 yr risk: 18%…yes

41. 63 yo woman, no risks LDL 175 HDL 45 TG 160 SBP 120 Nonsmoker NCEP: no treat 10 yr risk: 3%…no

42. 63 yo man, no risk factors LDL 175 HDL 45 TG 160 SBP 120 Nonsmoker NCEP: no treat 10 yr risk: 13%…yes

43. EMERGING RISK FACTORS Lipoprotein (a) Small Dense LDL Homocysteine Fibrinogen Inflammatory factors Subclinical atherosclerosis

44. EMERGING RISK FACTORS Evidence review of CRP, Lp(a), fibrinogen, homocysteine All independently associated with CVD Little evidence of additional yield over Framingham risk factors Less evidence on use in guiding treatment Explanatory power of established risk factors underestimated

45. Coronary Artery Calcium Heartscan Does it just reflect what we already know? Adjusted RR estimates from meta-analysis CAC scoreRR adj (95% CI) 01 (ref) 1-1002.1 (1.6-2.9) 101-4005.4 (2.2-13) > 40010 (3.1-34) Pletcher et al; Arch Int Med 2004; 164:1285-68

46. C-reactive protein (CRP) Meta-analysis of cohort studies RR 1.7 for top third vs. bottom third Mean CRP levels 2.4 in top third, 1.0 in bottom

47. C-reactive protein (CRP) Hard to directly integrate into the Framingham risk…. Rough calculations: CRP in top third increases risk by factor of 1.2-1.3 Average risk = x Risk in top tertile = 1.3x Risk in middle tertile = x Risk in middle tertile = 0.7x

48. CONCLUSIONS Patients with CHD or CHD equivalent: Treat aggressively with statin independent of LDL level (to LDL <70 in most cases) Treat other risk factors aggressively as well, especially easy ones (HTN, Aspirin use) Treat elevated non-HDL cholesterol and low HDL Patients at high risk are undertreated

49. CONCLUSIONS Patients without CHD: Assess overall risk with Framingham risk score LDL goal LDL treatment threshold High Risk (>20%) <100 (<70 optional)100 (<100 optional) Mod high risk (10-20%)<130 130 (100-129 optional) Moderate risk (5-10%)<130 160 Lower risk (<5%)<160190 (160-189 optional) Engage patient in shared decision making, especially if risk <10%