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

IN CLINICAL TRIALS WE TRUST

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

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

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

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

LDL Goal and Cutpoints in Patients with CHD and CHD Risk Equivalents (10-Year Risk >20%) 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

LDL Goal and Cutpoints in Patients with CHD and CHD Risk Equivalents (10-Year Risk >20%) 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

HEART PROTECTION STUDY RCT of 20,536 high-risk individuals; 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

Baseline Feature LDL (mg/dL) < < ALL PATIENTS Statin Placebo (10,269) (10,267) (19.9%) (25.4%) % reduction (p< ) HPS: Vascular Events by Baseline LDL-C Risk Ratio and 95% Cl Statin better Statin worse No. Events

LaRosa, NEJM 2005 TREATING TO NEW TARGETS (TNT) RCT of 10,001 patients with stable CHD; 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

LaRosa, NEJM 2005 TREATING TO NEW TARGETS (TNT) LDL Event % Death % LFTs % Atorv Atorv p value <

The Lower, the Better Relative Risk for CHD (Log Scale) LDL-C (mg/dL) Grundy SM et al. Circulation 2004;110:227–239.

63 yo woman; diabetes LDL 115 HDL 45 TG 160

Baseline Feature Previous MI Other CHD No prior CHD CVD PVD Diabetes ALL PATIENTS Statin Placebo (10,269) (10,267) (19.9%) (25.4%) Risk Ratio and 95% Cl Statin better Statin worse % reduction (p< ) HPS: Vascular Events by Prior Disease No. Events

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?

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%)

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

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 ) p=0.16

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

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)

LDL Goal and Cutpoints in Patients with CHD and CHD Risk Equivalents (10-Year Risk >20%) 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

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

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

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:

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

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

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

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

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

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

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

LDL Goal and Cutpoints Patients with 0–1 Risk Factor 2001 and 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

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

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

LDL Goal and Cutpoints Patients with Multiple Risk Factors (10-Year Risk 20%) 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

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

On-line and PDA tools

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

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

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

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

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

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

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) ( ) (2.2-13) > (3.1-34) Pletcher et al; Arch Int Med 2004; 164:

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

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

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

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%)< ( optional) Moderate risk (5-10%)< Lower risk (<5%)< ( optional) Engage patient in shared decision making, especially if risk <10%