TREATING LIPIDS FOR PREVENTION TREATING LIPIDS FOR PREVENTION OF CAD : OF CAD :

HOW AGGRESSIVE SHOULD WE BE?HOW AGGRESSIVE SHOULD WE BE?

Robert B. Baron MD MSRobert B. Baron MD MSProfessor and Associate DeanProfessor and Associate Dean

UCSF School of MedicineUCSF School of Medicine

Declaration of full disclosure: No conflict of interest

IN CLINICAL TRIALS IN CLINICAL TRIALS

WE TRUSTWE TRUST

Riskreduction

$$ 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: STATIN MEGA TRIALS: PRE-ATP IIIPRE-ATP III

1994 - 4S (Scandinavian Simvastatin)

1995 - WOSCOP (West of Scotland)

1996 - CARE

1998 - LIPID Trial

1998 - AFCAPS / TexCAPS

Primary Prevention Secondary Prevention

NEWER STATIN TRIALS:NEWER STATIN TRIALS:POST-ATP IIIPOST-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)

63 yo woman; s/p MI

LDL 115

HDL 45

TG 160

LDL Goal and Cutpoints in Patients with CHD and LDL Goal and Cutpoints in Patients with CHD and CHD CHD

Risk Equivalents (10-Year Risk >20%)Risk Equivalents (10-Year Risk >20%)20012001

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 DietLDL Goal

LDL Goal and Cutpoints in Patients with CHD and LDL Goal and Cutpoints in Patients with CHD and CHD CHD

Risk Equivalents (10-Year Risk >20%)Risk Equivalents (10-Year Risk >20%)20042004

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 DietLDL Goal

HEART PROTECTION STUDYHEART 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

BaselineFeature

LDL (mg/dL)

<100

≥100 <130

≥130

ALL PATIENTS

Statin Placebo(10,269) (10,267)

285 360

670 881

1087 1365

2042 2606(19.9%) (25.4%)

0.4 0.6 0.8 1.0 1.2 1.4

24% reduction(p<0.00001)

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)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

LaRosa, NEJM 2005

TREATING TO NEW TARGETS (TNT)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

“The Lower, the Better”

RelativeRisk

for CHD (Log Scale)

3.7

2.9

2.2

1.7

1.3

1.0

LDL-C (mg/dL)40 70 100 130 160 190

0

1

Grundy SM et al. Grundy SM et al. CirculationCirculation 2004;110:227 2004;110:227––239.239.

63 yo woman; diabetes

LDL 115

HDL 45

TG 160

BaselineFeature

Previous MI

Other CHD

No prior CHD

CVD

PVD

Diabetes

ALL PATIENTS

Statin Placebo (10,269) (10,267)

1007 1255

452 597

182 215

332 427

279 369

2042 2606 (19.9%) (25.4%)

Risk Ratio and 95% Cl

Statin better Statin worse

0.4 0.6 0.8 1.0 1.2 1.4

24% reduction

(p<0.00001)

HPS: Vascular Events by Prior Disease

No. Events

Colhoun, Lancet, 2004

COLLABORATIVE ATORVASTATIN COLLABORATIVE ATORVASTATIN DIABETES STUDY (CARDS)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 COLLABORATIVE ATORVASTATIN DIABETES STUDY (CARDS)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 FENOFIBRATE INTERVENTION AND EVENT LOWERING IN DIABETES EVENT LOWERING IN DIABETES

(FIELD) STUDY(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 FENOFIBRATE INTERVENTION AND EVENT LOWERING IN DIABETES EVENT LOWERING IN DIABETES

(FIELD) STUDY(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

CHD Risk EquivalentsCHD 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 Other Potential CHD Risk EquivalentsEquivalents

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 LDL Goal and Cutpoints in Patients with CHD and CHD CHD

Risk Equivalents (10-Year Risk >20%)Risk Equivalents (10-Year Risk >20%)20042004

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 DietLDL 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

175 - 25 = 150

NCEP non-HDL goal:

LDL goal + 30 = 100

100 160 2200.0

1.0

2.0

3.0

Ris

k of

CH

DLow 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.

4565

85

Therapeutic lifestyle changes

– Smoking cessation

– Regular aerobic exercise

– Weight loss

– Alcohol use?

Management of Low HDL-C

VA-HIT: Major Coronary Events in VA-HIT: Major Coronary Events in Gemfibrozil vs. Placebo GroupsGemfibrozil vs. Placebo Groups

Cu

mu

lati

ve In

cid

en

ce

(%)

0

Rubins HB et al. N Engl J Med 1999;341:410-418.

1 2 3 4 5 6Year

Placebo

Gemfibrozil

–22% reductionP = 0.006

Combination Drug TherapyAdding 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 175HDL 45TG 160

POSITIVE RISK FACTORSPOSITIVE RISK FACTORS

• Age: Men >45: women >55

• Family history premature CHD

• Cigarette smoking

• Hypertension

• Low HDL-cholesterol (<40 mg/dl)

NEGATIVE RISK FACTORNEGATIVE RISK FACTOR

High HDL-cholesterol > 60 mg/dl

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

2001 2001 andand 2004 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 DietLDL Goal

63 year old woman, HTN

LDL 175HDL 45TG 160SBP 120 on RXNonsmoker

POSITIVE RISK FACTORSPOSITIVE RISK FACTORS

• Age: Men >45: women >55

• Family history premature CHD

• Cigarette smoking

• Hypertension

• Low HDL-cholesterol (<40 mg/dl)

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

Risk Risk 20%) 20%)20012001

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 DietLDL Goal

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

Risk Risk 20%) 20%)20042004

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 DietLDL Goal

www.nhlbi.nih.gov/guidelines/cholesterol

www.statcoder.com

www.med-decisions.com

On-line and PDA toolsOn-line and PDA tools

63 yo woman, HTN

LDL 175HDL 45TG 160SBP 120 on RXNonsmoker

NCEP: yes10 yr risk: 6%…maybe not

63 yo man, HTN

LDL 175HDL 45TG 160SBP 120 on RXNonsmoker

NCEP: yes10 yr risk: 18%…yes

63 yo woman, no risks

LDL 175HDL 45TG 160SBP 120Nonsmoker

NCEP: no treat10 yr risk: 3%…no

63 yo man, no risk factors

LDL 175HDL 45TG 160SBP 120Nonsmoker

NCEP: no treat10 yr risk: 13%…yes

EMERGING RISK FACTORSEMERGING RISK FACTORS

• Lipoprotein (a)

• Small Dense LDL

• Homocysteine

• Fibrinogen

• Inflammatory factors

• Subclinical atherosclerosis

EMERGING RISK FACTORSEMERGING 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 score RRadj (95% CI)0 1 (ref)1-100 2.1 (1.6-2.9)101-400 5.4 (2.2-13)

> 400 10 (3.1-34)

Pletcher et al; Arch Int Med 2004; 164:1285-68

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 byfactor 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

CONCLUSIONSCONCLUSIONS

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

CONCLUSIONSCONCLUSIONS

Patients without CHD: • Assess overall risk with Framingham risk score

LDL goal LDL treatment thresholdHigh Risk (>20%) <100 (<70 optional) ≥100 (<100 optional)Mod high risk (10-20%) <130 ≥130 (100-129 optional)Moderate risk (5-10%) <130 ≥160Lower risk (<5%) <160 ≥190 (160-189 optional)

• Engage patient in shared decision making, especially if risk <10%