-9 -20 -28 -24 5 -20 -35 -30 -25 -20 -15 -10 -5 0 5 10 TC LDL- C HDL- C Nonfat al MI/CHD death CHD deat h All- cause mortali ty *As compared to placebo. † P=0.003. Lowering on Lipid Values and Coronary Events in CHD Patients With Average Cholesterol %+ * * * * * * † †
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TC LDL- 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.
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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
%+
**
**
**
††
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
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.
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
%
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)
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
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
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
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
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
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
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)
Event Reduction in Angiographic Plaque Regression Trials
+% stenosis*
Event reduction
(%)
%%
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
LIPID† pravastatin 9,014 6 22% total mortality 24% death from CHD
angina
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
*
*
* ** *
LDL Particle Size Subclass
IDLIDL L3L3 L2L2 L1L1
large, large, buoyantbuoyant
small, densesmall, dense
AA BBABAB
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
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
Antioxidant Vitamins blunted the effect of Niacin+Simvastatin on
HDL, specifically HDL2
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%
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.
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
US Adults Who May Require Drug Therapy for Elevated LDL-C
Jacobson TA, et al. Arch Intern Med. 2000;160:1361-1369.