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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%