Transcript Evidence Based Medicine in Prevention of Myocardial

Landmark clinical trials with
pravastatin
• WOS
• CARE
• LIPID
Placebo MI rate per 100 subjects per 5 years
Major HMG Trials
4S
22.6
15.9/13.2
7.9
n=4,444
TC 6.8 mmol/l
With CHD +
high cholesterol
LIPID
CARE
n=9,014
TC 5.6 mmol/l
n=4,159
TC 5.4 mmol/l
WOS
n=6,595 TC 7.0 mmol/l
TexCAPS
2.8
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
n=6,605 TC 5.7 mmol/l
With CHD +
normal cholesterol
Without CHD +
high cholesterol
Without CHD +
low HDL
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
CHD death
CABG/PTCA
Stroke
% Risk reduction
0
–10
–20
–20%
–24%*
–30
–27%*
–31%*
–40
*P < 0.05 vs placebo
Sacks et al: N Engl J Med 1996;335:1001–1009
CARE: Pravastatin Reduces Risk of Stroke
5
128 strokes in total
83% of patients on antiplatelet therapy
% with event
4
–32%
P=0.03
3
Placebo
2
Pravastatin
1
0
0
1
2
3
Time (yr)
Plehn et al: Circulation 1999;99:216–223
4
5
LIPID: Pravastatin Reduces Risk of Stroke
6
% with event
419 strokes in total
83% of patients on antiplatelet therapy
–19%
P=0.048
4
Placebo
Pravastatin
2
0
0
1
2
3
Time (yr)
The LIPID Study Group: N Engl J Med 1998;339:1349–1357
4
5
6
Size of the Benefit with Pravastatin
Events Prevented in CARE
Event
Events prevented per 1,000
patients treated for 5 years
Fatal coronary heart disease
11
Nonfatal MI
26
CABG
25
PTCA
37
Stroke/TIA
13
Other cardiovascular events
38
All cardiovascular events
Sacks et al. NEJM. 1996;335:1001-1009
150
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
0
CHD
mortality
Total
mortality
PTCA/CABG
Stroke
% Risk reduction
–5
–10
–15
–20
–25
–24%
–22%
–20%
–19%
–30
–35
All risk reductions are P < 0.05 vs placebo
The LIPID Study Group: N Engl J Med 1998;339:1349–1357
Size of the Benefit with Pravastatin
Events Prevented in LIPID
Event
Events prevented per
1,000 patients treated
over 6 years
Deaths
30
Nonfatal MI
28
CABG
23
PTCA
20
Unstable Angina Episodes
82
Nonfatal Stroke
The LIPID Study Group. N Engl J Med 1998;339:1349-1357
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
CHD
mortality
Total
mortality
CABG/
PTCA
% Risk reduction
0
–10
–20
–22%
–30
–31%
–40
–33%
–37%
All risk reductions are P  0.05 vs placebo
Shepherd et al: N Engl J Med 1995;333:1301–1307
Size of the Benefit with Pravastatin
Events Prevented in WOS
Event
Events prevented per
1,000 patients treated
over 5 years
Deaths
9
Nonfatal MI
20
PTCA/CABG
8
Coronary Angiograms
14
Shepherd et al: N Engl J Med 1995;333:1301–1307
Clinical Benefit of Pravastatin
Evidence of Protection
% Risk reduction
0
Total
mortality
First MI
Recurrent
MI
PTCA/
CABG
Stroke
LIPID
WOS
CARE
CARE
CARE
–10
–20
–30
–40
–22%
In patients
with MI or
unstable
angina
–31%
In patients
with high
cholesterol
–24%
In post-MI
patients with
average
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;333:1301–1307; The LIPID Study Group: N Engl J Med 1998;339:1349–1357;
Sacks et al: N Engl J Med 1996;335:1001–1009
Clinical Benefit of Pravastatin
Broad Range of Patients
% Risk reduction
0
Women
Elderly
(65 yr)
Diabetics
Unstable
angina
patients
CARE
CARE
CARE
LIPID
Mixed
hyperlipidemia
LIPID
–10
–20
–25%*
–30
–29%†
–32%*
–40
–50
–24%†
–46%*
* CHD death, nonfatal MI, CABG, or PTCA
† CHD death and nonfatal MI
All risk reductions are P < 0.05 vs placebo
Lewis et al: J Am Coll Cardiol 1998;32:140–146; Lewis et al: Ann Intern Med 1998; 129:681-689
Goldberg et al: Circulation 1998;98:2513–2519 The LIPID Study Group: N Engl J Med 1998;339:1349–1357
Weight of Clinical Evidence
No. patients in clinical event trials
20,000
18,000
16,000
CARE
4159
14,000
12,000
WOS
6595
10,000
8,000
6,000
4,000
LIPID
9014
4S
4444
2,000
TexCAPS
6605
*
0
Pravastatin
* No long-term clinical trials published
Simvastatin
Lovastatin
Atorvastatin,
cerivastatin, and
fluvastatin
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
6-yr CHD death rate per
1,000 men
16
14
12
10
8
6
4
2
0
4
5
6
Serum cholesterol (mmol/l)
Martin et al: Lancet 1986;2:933–936
7
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
-22
-20
-30
Total
mortality
-31
-32
NFMI
or
CHD Death
NFMI
-40
-32
-37
CV
mortality
CABG/PTCA
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
1
2
3
3. Derive Kaplan-Meier risk of cardiac event for each quintile
4
5
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
Overlap
(3.6 - 4.6 mmol/l)
Percentage of patients
12
Pravastatin
Placebo
10
8
6
4
2
0
2
3
4
5
On-treatment LDL-C (mmol/l)
Adapted from WOS Group: Circulation 1998;97:1440–1445
6
Overlap Analysis – Results
Pravastatin subjects with similar LDL-C levels had lower risk
LDL-C range, 3.6–4.6 mmol/l
4.4-yr event rates (%)
12
9.6%
10
(n=2191)
8
6.3%
6
36% lower risk
4
(P=0.014)*
2
0
Placebo
Pravastatin
Mean LDL-C, 4.38 mmol/l
Mean LDL-C, 4.10 mmol/l
*Adjusted for risk factors
WOS Group: Circulation 1998;97:1440–1445
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
Pravastatin Group
14
Observed
14
Observed
12
Predicted
12
Predicted
10
Event Rate (%)
Event Rate (%)
Placebo Group
P = 0.58
8
6
10
8
6
4
4
2
2
0
0
1
2
3
4
5
P = 0.026
1
2
Quintiles of Predicted Framingham Risk
Circulation, 1998; 97:1440-1445
3
4
5
Framingham Analysis – Results
Risk reduction with pravastatin was greater than predicted
Predicted*
Actual
% Risk reduction†
0
–10
–20
–30
–24%
P = 0.026
–35%
–40
*Based on lipid changes achieved by pravastatin
†Nonfatal MI, CHD death, CABG, PTCA
WOS Group: Circulation 1998;97:1440–1445
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
-13
% Risk
Reduction
Unstable
Angina
-20
-20
-24
CHD
-30 Death
or
Nonfatal
MI
*
-40
-23
-23
CHD
Death
Nonfatal
MI
*
-37
-26
CABG
*
PTCA
*
-31
Stroke
*
Fatal MI
* p < 0.05 vs. placebo
Sacks et al: N Engl J Med 1996;335.
Pravastatin Treatment Analysis – Results
Pravastatin Treatment Group CARE
1.2
1.0
Relative
Risk
0.8
of an
Event* 0.6
()
0.4
0.2
0.0
2
2.5
3
3.5
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
Few
SMCs
Thin
Fibrous Cap
Inflammatory
Cells
Eroded
Endothelium
More
SMCs
Thick
Fibrous Cap
Lack of
Inflammatory
Cells
Intact
Endothelium
Activated
Macrophages
Unstable plaque
Adapted from Libby: Circulation. 1995;91:2844-2850.
Foam Cells
Stable plaque
Most MIs Arise From Smaller Stenoses
MI patients (%)
70
68%
50
30
18%
14%
10
0
<50%
50%–70%
% Stenosis
Falk et al: Circulation 1995;92:657–671
>70%
Atherosclerosis Involves More Than Just Lipids:
Effects of Statins
•
Common to all statins
– Lipid modification
– Lipoprotein oxidation
– Endothelial function
Rosenson et al: JAMA 1998;279:1643–1650
• Differences among statins
– Effect on smooth muscle cells
– Effect on inflammation?
– Effect on platelet thrombus
formation?
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 didn’t
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
IC25 (µmol/L)
4
3
2
1
0.02
0.2
0.8
1.0
Lovastatin
Atorvastatin
0.4
0
Cerivastatin
Simvastatin
Fluvastatin
Adapted from Negre-Aminou et al: Biochim Biophys Acta 1997;1345:259–268
Pravastatin
Pravastatin Reduces Platelet Thrombus Formation
Platelet thrombus formation
(µm2/mm)
5
4.8
4
3
2.0*
2
1
0
Baseline
After Pravastatin
Hypercholesterolemic patients (n=16)
Adapted from Lacoste et al: Circulation 1995;92:3172–3177
*P < 0.05 vs baseline
Reduced Thrombus Formation With Pravastatin
but not with Simvastatin
Platelet thrombus formation
(µm2/mm)
3.0
2.5
2.1
2.0
2.0
2.0
1.5
1.0*†
1.0
0.5
0.0
Baseline
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
Treatment
Pravastatin
(n=16)
Baseline
Treatment
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
Relative risk of an event
3
P = 0.007
2
1
0
Pravastatin
Placebo
Inflammation Absent
Ridker et al: Circulation 1998;98:839–844
Pravastatin
Placebo
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