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-9
-20
-28-24
5
-20
-35
-30
-25
-20
-15
-10
-5
0
5
10
TCLDL-
C
HDL-C
Nonfatal MI/CHD death
CHD death
All-cause
mortality
*As compared to placebo.†P=0.003.
CARE: Effect of Lipid Lowering on Lipid Values and Coronary Events in
CHD Patients With Average Cholesterol
%+
**
**
**
††
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0
5
10
15
1 2 3 4 5
Pravastatin
Placebo
Yr
n=269
n=206
CARE: Fatal CHD or Nonfatal MI(Primary End Point)
% with
events
Sacks FM et al. N Engl J Med. 1996;335:1001-1009.
-24% reductionP=0.002
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CARE: Secondary End PointsReductions observed in: % P
Confirmed nonfatal MI 23 0.02
MI, fatal and nonfatal 25 0.006
CABG 26 0.005
PTCA 23 0.01
Sacks FM et al. N Engl J Med. 1996;335:1001-1009.
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CARE: Impact of Drug Therapy on Lipids and Lipoproteins in Older
Patients With MI
Data from Lewis SJ et al. Ann Intern Med. 1998;129:681-689.
-19
-27
5
-14
-20
-29
4
-12
-30
-20
-10
0
10
<65yr
65yr
TC LDL-C TG
HDL-C
P<0.001 for all comparisons with placebo
%
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CARE: Reduction in Coronary Events, Revascularizations, and Stroke in Older Adults
With MI and Average Cholesterol Levels
-32
-45
-32
-40
-20-25
11
-19
-50
-40
-30
-20
-10
0
10
20 Major coronary
events
CHD death
Revascular-izations Stroke
*P=0.005; †P=0.001; ‡P>0.2; §P=0.004; ||P=0.01; ¶P=0.03. All P values represent within-group differences (treatment vs placebo).
*
†
‡
†
||
¶
‡
§
RR(%)
<65 yr (n=2,876)
65-75 yr (n=1,283)
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CARE: Incidence of Coronary Events in Younger Versus Older Patients
5
10
15
20
30
25
0
5
10
15
20
30
25
010 2 3 4 5 10 2 3 4 5
Yr YrPatients at risk, n
Placebo 1,435 1,341 1,273 1,194 1,119 265
Pravastatin 1,441 1,357 1,285 1,228 1,177 294
<65 yr 65 yr
Placebo
Pravastatin
Placebo
Pravastatin-19%P=0.005
-32%P=0.001
%patients
643 595 559 515 477 119640 590 563 534 505 125
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AFCAPS/TexCAPS: Effects of LDL-C Lowering in Patients With Average
Cholesterol Levels
-18
-25
6
-37-40
-32 -33
-45-40-35-30-25-20-15-10
-505
10
%
TC LDL-C
HDL-C
MIC UA RV
P<0.001P=0.002
P=0.02 P=0.001
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Statin Trials: Therapy Reduces Major Coronary Events in Women
4S (n=827) CARE (n=576)AFCAPS/TexCAPS
(n=997)2 Prevention 1 Prevention
-50-45-40-35-30-25-20-15-10-505
10
Major coronary events*
-34 -46 -46
%
P=0.012P=0.001
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Overall Risk Reduction for Major Coronary Events by Age: A Meta-analysisNo. of Events RRR, % ARR/1000 NNT
P
65 y 740 539 32 (23 to 39) 44 (30 to 58)<0.001
4S 168 122 38 (19 to 53) 98 (43 to 154) 23<0.001
CARE 111 69 42 (20 to 57) 65 (27 to 103) (17-33)<0.001
LIPID 349 270 25 (11 to 37) 42 (17 to 67)0.001
AFCAPS 112 78 32 (8 to 49) 21 (5 to 38)0.01
PI Statin (95% CI) (95% CI) (95% CI) Value
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Overall Risk Reduction for Major Coronary Events by Age: A Meta-analysis (Cont.)
No. of Events RRR, % ARR/1000 NNTP
<65 y 1302 951 31 (24 to 36) 32 (24 to 40)
<0.001
4S 454 309 38 (27 to 47) 83 (55 to 110)<0.001
CARE 163 143 14 (-9 to 32) 14 (-8 to 37) 310.21
LIPID 366 287 25 (12 to 37) 31 (13 to 48) (25-41)<0.001
WOSCOPS 248 174 31 (16 to 44) 23 (11 to 34)<0.001
AFCAPS 71 38 47 (22 to 63) 19 (8 to 31)0.001
PI Statin (95% CI) (95% CI) (95% CI) Value
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Overall Risk Reduction for Major Coronary Events by Sex: A Meta-analysis
No. of Events RRR, % ARR/1000 NNTP
Women 247 180 29 (13 to 42) 33 (13 to 52)
<0.001 4S 91 60 37 (10 to 56) 69 (17 to 122) 31
0.01
CARE 39 23 43 (3 to 66) 54 (4 to 104) (19-75)0.04
LIPID 104 90 15 (-15 to 37) 18 (-16 to 51)0.30
AFCAPS 13 7 46 (-31 to 78) 12 (-5 to 29)0.17
PI Statin (95% CI) (95% CI) (95% CI)
Value
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Overall Risk Reduction for Major Coronary Events by Sex: A Meta-analysis (Cont)
No. of Events RRR, % ARR/1000 NNTP
PI Statin (95% CI) (95% CI) (95% CI)
ValueMen 1795 1310 31 (26 to 35) 37 (29 to 44)
<0.0014S 531 371 38 (28 to 47) 90 (62 to 118)
<0.001
CARE 235 189 22 (5 to 36) 26 (5 to 47) 270.02
LIPID 611 467 27 (17 to 36) 39 (23 to 55) (23-34)
<0.001
WOSCOPS 248 174 31 (16 to 44) 23 (11 to 34)
<0.001
AFCAPS <0.001(710) 109 37 (20 to 50) 22 (10 to 33)
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-80-70
-89
-33 -33
-7,7 -2.0-0.3
-2.8-3.0
-100
-75
-50
-25
0
25
FATS FATS STARS HARP LCAS(nicotinic acid (lovastatin (diet + resin) (diet + + colestipol) + colestipol) fluvastatin)
Event Reduction in Angiographic Plaque Regression Trials
+% stenosis*
Event reduction
(%)
%%
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Post-CABG: Impact of Aggressive vs Moderate Lowering of LDL-C on Atherosclerosis
Study group characteristics• Sample size: 1,351 (M/F)• 1 to 11 yr post-CABG• 2 patent SVGs (1 in females)• LDL-C 130-174 mg/dL after dietTreatment• Randomized, blinded to
– lovastatin 40-80 mg/day + cholestyramine 8 g/day (if needed)– lovastatin 2.5-5 mg/day + cholestyramine 8 g/day (if needed)– aggressive LDL-C target: 85 mg/dL– moderate LDL-C target: 130-140 mg/dL
Monitoring• Quantitative coronary angiography
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80
90
100
110
120
130
140
150
160
0 12 24 36 48
Follow-up (mo)
Aggressive Tx (93-96)*
Moderate Tx (134-136)*
Post-CABG Study:Aggressive vs Moderate Treatment
6
Post-CABG Trial Investigators. N Engl J Med. 1997;336:153-162.
LDL-C(mg/dL)
* Mean achieved.
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Post-CABG: End Points, Results, Conclusions• Primary end point: Mean per-patient percentage of grafts
with significant progression in SVG (0.6 mm change)
• Secondary end point: New occlusions, new lesions, lumen narrowing
• Results:
– aggressive treatment group: significantly less (P<0.001) progression, fewer new occlusions and lesions, and mean lumen diameter
– revascularization rate 29% (P=0.03)
• Conclusions: Mean LDL-C levels of 95 mg/dL associated with greater benefit than mean LDL-C of 135 mg/dL
Post-CABG Trial Investigators. N Engl J Med. 1997;336:153-162.
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P value
Post-CABG Angiographic OutcomesMRE Difference
ModerateAggressive %
Progression 39 28 28 <0.001
New occlusions 16 10 40 <0.001
New lesions 21 10 52 <0.001
Mean lumen changein mm
Minimum diameter -0.38 -0.20 48 <0.001
Mean diameter -0.34 -0.16 52 <0.001
MRE=Mean per-patient percentage of grafts.
Post-CABG Trial Investigators. N Engl J Med. 1997;336:153-162.
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0
5
10
15
%
Yr after enrollment
Aggressive
Moderate
Event=PTCA or bypass surgery
P=0.03.
Post-CABG: Event Rates by Cholesterol Group
0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5
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-15
-32*-27*
-40
-30
-20
-10
0
*P=0.001.†95% confidence interval of percentage of relative reduction.
Effects of Statins on Stroke Events: A Meta-analysis of Primary- and Secondary-Prevention Trials
Relative
reduction
in rates (%)
1° Prevention (-42 to -27)†
2° Prevention (13-45)†
Combined (11-40)†
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-30 -33-29 -28
-22
-40
-30
-20
-10
0
LDL-C StrokeTotal
mortality
%
* *† ‡
§
*Confidence interval (CI) not reported.†95% CI, 14%-41%.‡95% CI, 16%-37%.§95% CI, 12%-31%.
Hebert PR et al. JAMA. 1997;278:313-321.
Impact of Lowering LDL-C on CVD Events and Total Mortality
Nonfatal/fatal CHD
CVDmortality
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Clinical Trial Findings: The Statins• Statins LDL-C by 25%-35% (achieved in clinical
event trials and regression studies)• Benefits at various LDL-C levels; evident soon after
therapy in some studies• in LDL-C required for in CHD morbidity/mortality• in all-cause mortality in 2° prevention and in
cardiovascular mortality in 1° prevention• Studies support treatment in various patient groups
– women– elderly– diabetics
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Recent Landmark Coronary Prevention StudiesRecent Landmark Coronary Prevention Studies
Study Drug N Duration(Years)
Main Findings
4S† simvastatin 4,444 5 30% total mortality 34% coronary events*
WOS‡ pravastatin 6,595 5 31% coronary events 22% total mortality
CARE† **
pravastatin 4,159 5 24% coronary events 31% stroke
AFCAPS/TexCAPS‡ **
lovastatin 6,605 5 37% coronary events/unstable angina
Low HDL population
LIPID† pravastatin 9,014 6 22% total mortality 24% death from CHD
angina
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VA-HIT Results
0%
6%
-31%
-22% -22%
-29%-35
-30-25
-20
-15
-10-5
0
5
10
LDL HDL TG NonfatalMI orCHD
Death
CHDDeath
Stroke
*p0.05 **p=0.07 † Investigator designated
†
% C
han
ge
*
*
* ** *
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LDL Particle Size Subclass
IDLIDL L3L3 L2L2 L1L1
large, large, buoyantbuoyant
small, densesmall, dense
AA BBABAB
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Significance of Small, Dense LDL• Low cholesterol content of LDL particles
particle number for given LDL-C level
• Associated with levels of TG and LDL-C, and levels of HDL2
• Marker for common genetic trait associated with risk of coronary disease (LDL subclass pattern B)
• Possible mechanisms of atherogenicity
– greater arterial uptake
uptake by macrophages
oxidation susceptibility
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HDL Atherosclerosis Treatment Study (HATS)
NIH-funded, the HDL Atherosclerosis Treatment Study is a double-blind, placebo controlled, factorial design, 3-year angiographic trial. Patients (n=160) 15% had diabetes, 10% had impaired glucose tolerance. Patients randomized into four (4) treatment goups:1. Niacin (2-4 grams/day) + Simvastatin (10-20 mg/day) plus Antioxidant Vitamins
2. Placebo (Niacin+Simvastatin) plus Antioxidant Vitamins
3. Niacin (2-4 grams/day) + Simvastatin (10-20 mg/day) plus Placebo (Vitamins)
4. Placebo (Niacin + Simvastatin) plus Placebo (Vitamins)
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HDL Atherosclerosis Treatment Study
(HATS)
Mean Baseline Lipid Levels:LDL-C 126 mg/dlHDL-C 31 mg/dlTriglycerides 217 mg/dl
after Niacin + Simvastatin therapy (average dose: 3.2 gms niacin, 12 mg simvastatin)
LDL-C 82 mg/dl reduced 35%HDL-C 40 mg/dl increased 30%Triglycerides 144 mg/dl reduced 34%
Niacin+Simvastatin HDL increased 30% LP A-1 increased 75%Niacin+Simvastatin+Vitamins HDL increased 20% LP A-1 increased 17%
Antioxidant Vitamins blunted the effect of Niacin+Simvastatin on
HDL, specifically HDL2
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HDL Atherosclerosis Treatment Study (HATS)
Primary quantitative angiographic patient endpoint was the average change in percent stenosis of the 9 worst lesions in 9 standard coronary segments:
Placebo + 34%
Antioxidant Vitamins + 15%
Niacin + Simvastatin + Antioxidants + 7%
Niacin + Simvastatin - 4%
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HDL Atherosclerosis Treatment Study (HATS)
Primary clinical endpoint was the Kaplan-Meier intention-to-treat time to first event:CAD death, MI, Stroke, Hospital-confirmed unstable ischemia+ revascularization. 15% of the patients were diabetic while 10% of the patients had impaired glucose tolerance.
Patients on Niacin + Simvastatin had clinical events reduced by 70%. The addition of Antioxidant Vitamins to Niacin + Simvastatin resulted in only a 15% reduction in clinical events.
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Gould AL et al. Circulation. 1998;97:946-952.
Clinical Benefits of Cholesterol Reduction
• A recent meta-analysis of 38 trials demonstrated that for every 10% reduction in TC– CHD mortality decreased by 15% (P<0.001)– total mortality decreased by 11% (P<0.001)
• Decreases were similar for all treatment modalities• Cholesterol reduction did not increase non-CHD
mortality
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US Adults Who May Require Drug Therapy for Elevated LDL-C
Jacobson TA, et al. Arch Intern Med. 2000;160:1361-1369.
3,34,1
17,5
6,8
28,4
1,6
5.5
10.4
0
5
10
15
20
25
30Cutpoints
Clinical judgment
<2 RF andno CHD
2 RF andno CHD
With CHD Total
Millions