TREATING LIPIDS FOR PREVENTION OF CAD : HOW AGGRESSIVE SHOULD WE BE

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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

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• IN CLINICAL TRIALS
• WE TRUST

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A RISK-BASED APPROACH

Harm
Risk reduction
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
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STATIN MEGA TRIALS PRE-ATP III
Primary Prevention Secondary Prevention

• 1994 - 4S (Scandinavian Simvastatin)
• 1995 - WOSCOP (West of Scotland)
• 1996 - CARE
• 1998 - LIPID Trial
• 1998 - AFCAPS / TexCAPS

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NEWER STATIN TRIALSPOST-ATP III
Primary Prevention Secondary Prevention

• 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)

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

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LDL Goal and Cutpoints in Patients with CHD and
CHD Risk Equivalents (10-Year Risk gt20)2001
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LDL Goal and Cutpoints in Patients with CHD and
CHD Risk Equivalents (10-Year Risk gt20)2004
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HEART PROTECTION STUDY

• RCT of 20,536 high-risk individuals 40-80 yr
• Total cholesterol gt135 mg/dl (gt3.5 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

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HPS Vascular Events by Baseline LDL-C
No. Events
Risk Ratio and 95 Cl Statin better
Statin worse
BaselineFeature LDL (mg/dL) lt100 100
lt130 130 ALL PATIENTS
Statin Placebo (10,269)
(10,267) 285 360 670
881 1087 1365 2042 2606 (19.9) (25.4)
24 reduction(plt0.00001)
1.0
1.2
1.4
0.4
0.6
0.8
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TREATING TO NEW TARGETS (TNT)

• RCT of 10,001 patients with stable CHD 35-75 yr
• LDL lt130 mg/dl
• Atorvastatin 10 vs atorvastain 80
• Followed for 4.9 years
• Research question safety and efficacy of
  lowering LDL below 100 mg/dl

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TREATING TO NEW TARGETS (TNT)

• LDL Event Death
  ? LFTs
• Atorv 10 101 10.9 2.5 0.2
• Atorv 80 77 8.7 2.0
  1.2
• p value lt0.001 0.09

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The Lower, the Better
3.7
1
2.9
RelativeRiskfor CHD (Log Scale)
2.2
1.7
1.3
1.0
0
40
70
100
130
160
190
LDL-C (mg/dL)
Grundy SM et al. Circulation 2004110227239.
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• 63 yo woman diabetes
• LDL 115
• HDL 45
• TG 160

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HPS Vascular Events by Prior Disease
No. Events
Risk Ratio and 95 Cl Statin better
Statin worse
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)
24 reduction(plt0.00001)
1.0
1.2
1.4
0.4
0.6
0.8
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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?

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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)

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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

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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) p0.16

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CHD Risk Equivalents

• Risk for major coronary events equal to that in
  established CHD e.g. gt20risk of MI or CHD death
  in 10 years
• Peripheral artery disease
• Abdominal aortic aneurysm
• Symptomatic CVD
• Diabetes
• Multiple risk factors with gt20 risk in 10 years

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Other Potential CHD Risk Equivalents

• Risk for major coronary events equal to that in
  established CHD e.g. gt20risk of MI or CHD death
  in 10 years
• Renal insufficiency yes
• Congestive heart failure yes
• Metabolic syndrome probably not (calculate
  Framingham risk)

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LDL Goal and Cutpoints in Patients with CHD and
CHD Risk Equivalents (10-Year Risk gt20)2004
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• 63 yo man s/p MI
• LDL 70
• HDL 25
• TG 400

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• 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

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Low HDL-C is an Independent Predictor of CHD Risk
Even When LDL-C is Low
Risk of CHD
25
45
HDL-C(mg/dL)
65
85
100
160
220
LDL-C (mg/dL)
Gordon T et al. Am J Med 197762707-714.
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Management of Low HDL-C

• Therapeutic lifestyle changes
• Smoking cessation
• Regular aerobic exercise
• Weight loss
• Alcohol use?

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VA-HIT Major Coronary Events in Gemfibrozil vs.
Placebo Groups
Placebo
22 reduction P 0.006
Cumulative Incidence ()
Gemfibrozil
0
1
2
3
4
5
6
Year
Rubins HB et al. N Engl J Med 1999341410-418.
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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

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Management of Low HDL-C

• 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

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

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POSITIVE RISK FACTORS

• Age Men gt45 women gt55
• Family history premature CHD
• Cigarette smoking
• Hypertension
• Low HDL-cholesterol (lt40 mg/dl)

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NEGATIVE RISK FACTOR

• High HDL-cholesterol gt 60 mg/dl

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LDL Goal and Cutpoints Patients with 01 Risk
Factor2001 and 2004
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• 63 year old woman, HTN
• LDL 175
• HDL 45
• TG 160
• SBP 120 on RX
• Nonsmoker

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POSITIVE RISK FACTORS

• Age Men gt45 women gt55
• Family history premature CHD
• Cigarette smoking
• Hypertension
• Low HDL-cholesterol (lt40 mg/dl)

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LDL Goal and Cutpoints Patients with Multiple
Risk Factors (10-Year Risk ? 20)2001
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LDL Goal and Cutpoints Patients with Multiple
Risk Factors (10-Year Risk ? 20)2004
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On-line and PDA tools

• www.nhlbi.nih.gov/guidelines/cholesterol
• www.statcoder.com
• www.med-decisions.com

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

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

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

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

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EMERGING RISK FACTORS

• Lipoprotein (a)
• Small Dense LDL
• Homocysteine
• Fibrinogen
• Inflammatory factors
• Subclinical atherosclerosis

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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

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Coronary Artery CalciumHeartscan

• 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)
• gt 400 10 (3.1-34)

Pletcher et al Arch Int Med 2004 1641285-68
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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

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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

Risk in top tertile 1.3x
Average risk x
Risk in middle tertile x
Risk in middle tertile 0.7x
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CONCLUSIONS

• Patients with CHD or CHD equivalent
• Treat aggressively with statin independent of
  LDL level (to LDL lt70 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

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CONCLUSIONS

• Patients without CHD
• Assess overall risk with Framingham risk score
  
• LDL goal LDL treatment threshold
• High Risk (gt20) lt100 (lt70
  optional) 100 (lt100 optional)
• Mod high risk (10-20) lt130 130
  (100-129 optional)
• Moderate risk (5-10) lt130 160
• Lower risk (lt5) lt160 190 (160-189 optional)
• Engage patient in shared decision making,
  especially
• if risk lt10