Landmark clinical trials with pravastatin

WOS CARE LIPID

Major HMG Trials

Placebo MI rate per 100 subjects per 5 years

4S

22.6

n=4,444 TC 6.8 mmol/l

With CHD + high cholesterol

15.9/13.2

LIPID
n=9,014 TC 5.6 mmol/l

CARE
n=4,159 TC 5.4 mmol/l

With CHD + normal cholesterol

7.9 2.8

WOS
n=6,595 TC 7.0 mmol/l

Without CHD + high cholesterol Without CHD + low HDL

TexCAPS
n=6,605 TC 5.7 mmol/l

WOS : NEJM 1995; 333 : 1301-1307 CARE : NEJM 1996; 335 : 1001-1009 LIPID : NEJM 1998; 339: 1349-1357 4S : Lancet 1994; 344 : 1383-1389 TexCAPS: JAMA 1998; 279: 1615-1622

Pravastatin Therapy in Post-MI Patients with Average Cholesterol

CARE: Study Design
4159 men and women post-MI Total Cholesterol <6.2 mmol/l (mean 5.4 mmol/l) Pravastatin 40 mg, follow-up 5.0 years 83% aspirin, 40% beta-blockers, 54% PTCA/CABG at baseline Prespecified end points:
Nonfatal MI and CHD death CHD death Revascularizations Stroke

Pravastatin Therapy in Post-MI Patients with Average Cholesterol

CARE: Results Summary
CHD death or nonfatal MI
0

CHD death

CABG/PTCA

Stroke

% Risk reduction

10

20

20% 24%*

30

27%*
31%*

40
*P < 0.05 vs placebo
Sacks et al: N Engl J Med 1996;335:10011009

CARE: Pravastatin Reduces Risk of Stroke

5 4
% with event

128 strokes in total 83% of patients on antiplatelet therapy

32% P=0.03 Placebo

3 2 Pravastatin 1 0 0 1 2
Time (yr)

Plehn et al: Circulation 1999;99:216223

LIPID: Pravastatin Reduces Risk of Stroke

6

419 strokes in total 83% of patients on antiplatelet therapy

% with event

4 Placebo

19% P=0.048

Pravastatin

0
0 1 2 3
Time (yr)
The LIPID Study Group: N Engl J Med 1998;339:13491357

Size of the Benefit with Pravastatin

Events Prevented in CARE
Event
Fatal coronary heart disease Nonfatal MI CABG
Events prevented per 1,000 patients treated for 5 years

11 26 25 37 13 38 150

PTCA
Stroke/TIA Other cardiovascular events All cardiovascular events
Sacks et al. NEJM. 1996;335:1001-1009

Pravastatin Therapy in Patients with MI or Unstable Angina and Average Cholesterol

LIPID: Study Design

9014 men and women with MI or unstable angina Total Cholesterol 4-7 mmol/l (mean 5.6 mmol/l) Pravastatin 40 mg, follow-up 6.1 years 83% aspirin, 47% beta-blockers, 41% PTCA/CABG at baseline Prespecified end points:
CHD mortality Revascularizations Total mortality Stroke

Pravastatin Therapy in Patients With MI or Unstable Angina and Average Cholesterol

LIPID: Results Summary
CHD mortality Total mortality
PTCA/CABG Stroke

0 5
% Risk reduction

10 15 20 25 30 35
All risk reductions are P < 0.05 vs placebo

24%

22%

20%

19%

The LIPID Study Group: N Engl J Med 1998;339:13491357

Size of the Benefit with Pravastatin

Events Prevented in LIPID

Event
Deaths Nonfatal MI CABG PTCA Unstable Angina Episodes Nonfatal Stroke
The LIPID Study Group. N Engl J Med 1998;339:1349-1357

Events prevented per 1,000 patients treated over 6 years

30 28 23 20 82 9

Pravastatin Therapy in a Population at Risk for CHD

WOS: Study Design
6595 men without history of CHD Total Cholesterol 6.5 mmol/l (mean 7.0 mmol/l) Pravastatin 40 mg, follow-up 4.9 years 3% aspirin, 7% beta-blockers, 0% PTCA/CABG at baseline Prespecified end points:
Nonfatal MI and CHD death CHD mortality Total mortality Revascularizations

Pravastatin Therapy in a Population at Risk for CHD

WOS: Results Summary
Nonfatal MI / CHD death
0

CHD mortality

Total mortality

CABG/ PTCA

% Risk reduction

10

20

22%
30

31%
40
Shepherd et al: N Engl J Med 1995;333:13011307

33% 37%
All risk reductions are P 0.05 vs placebo

Size of the Benefit with Pravastatin

Events Prevented in WOS

Event
Deaths Nonfatal MI PTCA/CABG Coronary Angiograms

Events prevented per 1,000 patients treated over 5 years

9 20 8 14

Shepherd et al: N Engl J Med 1995;333:13011307

Clinical Benefit of Pravastatin

Evidence of Protection
0

Total mortality
LIPID

First MI WOS

Recurrent MI
CARE

PTCA/ CABG
CARE

Stroke CARE

% Risk reduction

10

20
22% In patients with MI or unstable angina 24% In post-MI patients with average cholesterol

30

40

31% In patients with high cholesterol

27% In post-MI patients with average cholesterol

31% In post-MI patients with average cholesterol

All risk reductions are P < 0.05 vs placebo

Shepherd et al: N Engl J Med 1995;333:13011307; The LIPID Study Group: N Engl J Med 1998;339:13491357; Sacks et al: N Engl J Med 1996;335:10011009

Clinical Benefit of Pravastatin

Broad Range of Patients
Women Elderly (65 yr) Diabetics Unstable angina patients Mixed hyperlipidemia

0 10 20 30 40 50

CARE
% Risk reduction

CARE

CARE

LIPID

LIPID

25%* 32%*

24% 29%

46%*
All risk reductions are P < 0.05 vs placebo

* CHD death, nonfatal MI, CABG, or PTCA CHD death and nonfatal MI

Lewis et al: J Am Coll Cardiol 1998;32:140146; Lewis et al: Ann Intern Med 1998; 129:681-689 Goldberg et al: Circulation 1998;98:25132519 The LIPID Study Group: N Engl J Med 1998;339:13491357

Weight of Clinical Evidence

20,000
No. patients in clinical event trials

18,000 16,000 14,000 12,000 10,000 8,000

CARE 4159

WOS 6595

6,000
4,000 2,000 0

LIPID 9014 4S 4444

TexCAPS 6605

*
Lovastatin Atorvastatin, cerivastatin, and fluvastatin

Pravastatin
* No long-term clinical trials published

Simvastatin

Analysis of Coronary Heart Disease Event Reduction and Cholesterol Reduction with Pravastatin
Observations from Landmark Clinical Trials

MRFIT
Age-Adjusted CHD Death Rate and Serum Cholesterol in 361,662 US Men
18 16
6-yr CHD death rate per 1,000 men

14 12 10 8 6 4 2 0 4 5 6 7
Serum cholesterol (mmol/l)

Martin et al: Lancet 1986;2:933936

Pravastatin Event Reduction Analysis

Overall Objectives

To determine the relationship between reduction in CHD events and change in LDL-C with pravastatin To evaluate whether LDL-C reduction alone adequately explains the observed reduction in CHD events

Influence of Pravastatin and Plasma Lipids on Clinical Events in the West of Scotland Coronary Prevention Study (WOS)
West of Scotland Coronary Prevention Study Group

Circulation, 1998;97:1440-1445

WOS Results Summary

0

-10
% Risk Reduction

-20 -31
NFMI or CHD Death

-22
Total mortality

-30

-32
NFMI

-32
-37
CABG/PTCA CV mortality

-40

Are these impressive results seen in WOS entirely explained by the change in LDL-C ?
Shepherd et al: N Engl J Med. 1995;333:1301-1307

All risk reductions are P 0.05 vs placebo

Pravastatin Event Reduction Analysis

Components of the WOS Analysis

Quintile Analysis
Objective: To examine the relationship between reduction in CHD events and reduction in LDL-C levels

Overlap Analysis Framingham Analysis

Quintile Analysis Methods

1. Rank all pravastatin subjects on the basis of percent change in LDL-C

2. Divide group into quintiles of equal subject numbers (n 500/quintile)

Quintile

3. Derive Kaplan-Meier risk of cardiac event for each quintile

Quintile Analysis Results

10.0

n 500/quintile

7.5 4.4 Yr CHD Event Rate (%)

5.0

2.5

0 0% 12% 24% 31% 39% Mean % LDL-C Reduction

Baseline LDL-C On-treatment LDL-C

Circulation, 1998; 97:1440-1445

4.9 4.9

4.9 4.3

5.0 3.7

5.0 3.4

5.1 3.0

Quintile Analysis Results

LDL-C lowering was an important contributor to CHD event reduction with pravastatin in WOS Maximum risk reduction (~45%) occurred in pravastatin-treated subjects whether the LDL-C was decreased by 25% or by 40% or more

Pravastatin Event Reduction Analysis

Components of the WOS Analysis

Quintile Analysis Overlap Analysis

Objective: To determine whether subjects on placebo or pravastatin therapy who had similar LDL-C levels had similar CHD risk

Framingham Analysis

Overlap Analysis: Methods

14
12
Percentage of patients Overlap (3.6 - 4.6 mmol/l) Pravastatin Placebo

10
8 6 4 2 0 2 3 4 5 6
On-treatment LDL-C (mmol/l)

Adapted from WOS Group: Circulation 1998;97:14401445

Overlap Analysis Results

Pravastatin subjects with similar LDL-C levels had lower risk
LDL-C range, 3.64.6 mmol/l
12
4.4-yr event rates (%)

10 8

9.6%

(n=2191)

6.3%

4
2 0

36% lower risk

(P=0.014)*

Placebo
Mean LDL-C, 4.38 mmol/l

Pravastatin
Mean LDL-C, 4.10 mmol/l

*Adjusted for risk factors

WOS Group: Circulation 1998;97:14401445

Overlap Analysis Results

Pravastatin subjects had a 36% lower event rate compared to placebo subjects with similar LDL-C levels (P=0.014) Analysis of different LDL-C ranges of overlap supported the same conclusion

Pravastatin Event Reduction Analysis Components of the WOS Analysis

Quintile Analysis Overlap Analysis Framingham Analysis

Objective: To compare on-treatment event rates for WOS to the event rates predicted by the Framingham model

Framingham Analysis Results

Predicted vs Actual CHD Event Rate in WOS
Placebo Group Pravastatin Group

14

Observed Predicted

14

Observed
Predicted

12
Event Rate (%)

12
Event Rate (%)

10 8 6 4 2 0 1

P = 0.58

10 8 6 4 2 0

P = 0.026

Quintiles of Predicted Framingham Risk

Circulation, 1998; 97:1440-1445

Framingham Analysis Results

Risk reduction with pravastatin was greater than predicted

Predicted*
0 10 20 30
24% P = 0.026

Actual

% Risk reduction

35%

40
*Based on lipid changes achieved by pravastatin Nonfatal MI, CHD death, CABG, PTCA
WOS Group: Circulation 1998;97:14401445

Framingham Analysis Results

When event rates in WOS were compared to those predicted by Framingham, subjects on pravastatin therapy had greater risk reduction than predicted from lipid changes

Circulation, 1998; 97:1440-1445

Relationship Between Plasma LDL Concentrations During Treatment with Pravastatin and Recurrent Coronary Events in the CARE Trial
Frank M. Sacks, Lemuel A. Moye, Barry R. Davis, Thomas G. Cole, Jean L. Rouleau, David Nash, Marc A. Pfeffer, Eugene Braunwald for the CARE Investigators

Circulation, 1998;97:1446-1452

CARE Results Summary

Risk Reduction with Pravastatin Therapy
0

-10
% Risk Reduction

-13 -20 -24

CHD Death

Unstable Angina

-20
CHD -30 Death or Nonfatal MI *

-23
Nonfatal MI *

-23 -26
CABG * PTCA *

-31
Stroke *

-37
Fatal MI

-40

* p < 0.05 vs. placebo

Sacks et al: N Engl J Med 1996;335.

Pravastatin Treatment Analysis Results

Pravastatin Treatment Group CARE
1.2

Relative Risk 0.8 of an Event* 0.6 ( ) 0.4

0.2
0.0 2 2.5 3 3.5

1.0

Follow-up LDL-C (mmol/l) Decile # Median follow-up LDL-C % LDL-C decrease 1 2 3 4 5 6 1.8 2.0 2.2 2.3 2.4 2.5 43 38 35 33 31 30 7 2.7 26 8 2.8 25 9 3.0 21 10 3.5 9

*CHD death, nonfatal MI, CABG / PTCA Circulation, 1998;97:1446-1452

Pravastatin Treatment Analysis Results

CARE: CHD Events and Achieved LDL-C

The relationship between follow-up LDL-C levels and coronary events was not linear

Maximal benefit was observed when LDL-C was lowered to the range of 1.8 - 3.2 mmol/l
90% of subjects in the pravastatin group achieved this maximal benefit

Pravastatin Event Reduction Analysis

Consistent Results from Two Independent trials, WOS and CARE: The relationship between CHD risk and LDL-C concentration was found to be nonlinear

The absolute or the percent LDL-C reduction did not predict the event rate
Maximum risk reduction (~45%) occurred in pravastatin subjects whether the LDL-C was decreased by 25% or by 40% or more

Pravastatin Event Reduction Analysis

Implications Epidemiology does not fully explain the results of treatment Extreme LDL-C reductions may not be necessary with pravastatin treatment Additional mechanisms beyond LDL-C lowering may account for some of the benefit with pravastatin LDL-C changes alone do not explain the full benefit of pravastatin therapy

Additional Mechanisms for Coronary Event Reduction

Plaque stabilisation Reduced thrombus formation Anti-inflammatory effects

Atherosclerosis Involves More Than Just Lipids

Thrombus Fibrous Cap Lipid Core

Atherosclerosis Involves More Than Just Lipids

Inflammatory Cells More SMCs

Few SMCs

Thin Fibrous Cap

Thick Fibrous Cap

Lack of Inflammatory Cells

Eroded Endothelium Activated Macrophages

Intact Endothelium Foam Cells

Unstable plaque
Adapted from Libby: Circulation. 1995;91:2844-2850.

Stable plaque

Most MIs Arise From Smaller Stenoses

70

68%

MI patients (%)

50

30

18%
10
0

14%

<50%

50%70%
% Stenosis

>70%

Falk et al: Circulation 1995;92:657671

Atherosclerosis Involves More Than Just Lipids: Effects of Statins

Common to all statins
Lipid modification Lipoprotein oxidation

Differences among statins

Effect on smooth muscle cells Effect on inflammation? Effect on platelet thrombus formation?

Endothelial function

Rosenson et al: JAMA 1998;279:16431650

Effects of Pravastatin
Effects on lipids Additional mechanisms

Pravastatin 40 mg*: TC-25%, LDL -34% TG-24%, HDL+12%

No inhibition SMCs Reduced thrombus formation Anti-inflammatory effects

Effects on atherosclerosis

Reduction cardiovascular morbidity/mortality (including MI and stroke) *Jones: Clin Cardiol 1991;14:146-151

Effects of Pravastatin On Plaque Composition in Humans*

Effect of Pravastatin (n=11) vs. Control (n=13)

Parameter Lipid Content Oxidized LDL Macrophages # T-cells # Cell Death Smooth Muscle Cells #
ApoB, ICAM-1, VCAM-1 and NF-KB didnt differ between the 2 graphs

P value <0.05 <0.001 <0.05 <0.05 <0.05 NS

* Carotid endarterectomy samples following 3 months pravastatin therapy

Crisby et al: The Lancet Conference. The Challenge of Stroke, October 1998.

Smooth Muscle Cells Foster Plaque Stability

Smooth Muscle Cells:

Strengthen the fibrous cap

Regulate synthesis of interstitial collagen

Are involved in the healing process after plaque rupture

Lafont A., Libby P.: J Am Coll Cardiol 1998;32:283-285

Effects of Statins on Smooth Muscle Cells

Drug concentration required to inhibit 25% of human smooth muscle cell proliferation in vitro
40

37.6

4
IC25 (mol/L)

3 2 1

0.8 0.02 0.2

Simvastatin

1.0

0.4
Fluvastatin Lovastatin Atorvastatin Pravastatin

0
Cerivastatin

Adapted from Negre-Aminou et al: Biochim Biophys Acta 1997;1345:259268

Pravastatin Reduces Platelet Thrombus Formation

5
Platelet thrombus formation (m2/mm) 4.8

3
2 1 0
Baseline After Pravastatin Hypercholesterolemic patients (n=16) 2.0*

Adapted from Lacoste et al: Circulation 1995;92:31723177

*P < 0.05 vs baseline

Reduced Thrombus Formation With Pravastatin but not with Simvastatin

3.0
Platelet thrombus formation (m2/mm)

2.5
2.0

2.1

2.0

2.0 1.5
1.0*

1.0 0.5 0.0

Baseline

Treatment

Baseline

Treatment

Includes ASA 325 mg/d *P < 0.05 vs baseline P < 0.05 vs simvastatin
Lacoste et al: J Am Coll Cardiol 1996 ;27:413A

Pravastatin (n=16)

Simvastatin (n=16)

Effects of Statins on Inflammation

Inflammation is associated with initiation and progression of atherosclerosis Markers of inflammation have been shown to predict risk of vascular events Preventive agents may have differential effects on inflammation

Ridker et al: Circulation. 1998;98:839-844.

CARE: Pravastatin Reduces Risk Posed by Inflammation

P trend = 0.005
3
Relative risk of an event P = 0.007

Pravastatin

Placebo

Pravastatin

Placebo

Inflammation Absent
Ridker et al: Circulation 1998;98:839844

Inflammation Present ( CRP and SAA)

Inflammation, Pravastatin and Events Conclusion

Evidence of inflammation after MI is associated with increased risk of recurrent coronary events The effect of inflammation on coronary risk may be lowered by pravastatin therapy

. . . the efficacy of pravastatin may result in part from anti-inflammatory as well as lipid-lowering properties . . .
Ridker et al: Circulation. 1998;98:839-844.

The Complexity of Atherosclerosis: Beyond Cholesterol Lowering

Conclusions
Apart from lipid modification, other mechanisms may play a role in the net benefits of statin therapy Statins may differ in their effect on: Smooth muscle cells Platelet thrombus formation Inflammation Others

Since the nonlipid properties of statins differ despite comparable LDL cholesterol level lowering, the net clinical efficacy of these agents requires validation by randomised clinical trials.

Rosenson: JAMA 1998; 279 : 1643-1650