-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)

-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

(%)

%%

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

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.

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.

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.

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

-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)†

-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

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

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

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

3. Niacin (2-4 grams/day) + Simvastatin (10-20 mg/day) plus Placebo (Vitamins)

4. Placebo (Niacin + Simvastatin) plus Placebo (Vitamins)

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

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.

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