Transcript Pravastatin-Aspirin Combination 7asdf René Belder, M.D. Executive Director

Pravastatin-Aspirin Combination
René Belder, M.D.
Executive Director
Clinical Design and Evaluation, Metabolics
Pharmaceutical Research Institute
Bristol-Myers Squibb
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Speakers for This Morning
Dr. René Belder
 Mechanism of action of components
 PK analysis
 Safety and tolerability of combination
 Dose combinations available
 Efficacy – based on individual trials
Dr. Donald Berry
 Efficacy – based on meta-analyses
 Efficacy – presence of consistent benefit
Dr. Thomas Pearson
 Medical Need
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Different Mechanisms of Action
of Components
Aspirin
 Reduces platelet aggregation by inhibiting
cyclo-oxygenase
Pravastatin
 Reduces cholesterol levels by inhibiting
HMG CoA reductase
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No Pharmacokinetic Interaction in
Single Dose Cross-Over Study
Cmax
60
Pravastatin
level
AUC
Salicylate
level
92% (82-103%)*
Salicylate
level
95% (85-105%)*
120
50
µg/mL
140
Pravastatin
level
102% (99-105%)*
100
40
µg•h/mL
80
30
102% (95-108%)*
20
60
40
10
20
0
0
Prava Prava
+ASA
Prava ASA
+ASA
Product Administered
*Ratio of Geometric Least Square Means (90%CI)
Prava Prava
+ASA
Prava ASA
+ASA
Product Administered
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Changes in Mean Lipid Levels by Month 3
in CARE
Prava+ASA
Prava alone
10
Percent Change
from Baseline
0
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Total cholesterol
LDL-C
Triglycerides
HDL-C
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Pravastatin Atherosclerosis
Intervention Program (1)
Prevention Program
No. of Subjects
 Secondary prevention
– Long-term Intervention with Pravastatin in
Ischemic Disease study (LIPID)
9,014
– Cholesterol and Recurrent Events (CARE)
4,159
 Primary prevention
– West of Scotland Coronary Prevention Study
(WOSCOPS)
6,595
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Pravastatin Atherosclerosis
Intervention Program (2)
Regression Program
 Regression Growth Evaluation Statin Study
No. of Subjects
885
(REGRESS)
 Pravastatin Limitation of Atherosclerosis in
408
the Coronary Arteries (PLAC I)
 Pravastatin Limitation of Atherosclerosis in
151
the Carotid Arteries (PLAC II)
 Kuopio Atherosclerosis Intervention Study
447
(KAPS)
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Contribution of Trials to Total
CHD Patient-Years of Exposure
LIPID
68%
CARE
28%
REGRESS
2%
PLAC-I
1%
PLAC-II
1%
Total Exposure = 73,900 Patient-Years
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Reassuring Safety of the Combination
 CK abnormalities
– no signal
 Liver Function Test abnormalities
– no signal
 Gastrointestinal bleeds
– no signal
 Hemorrhagic stroke
– no signal
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Appropriate Dosing of Pravastatin
 40mg approved as the starting dose
 All prevention studies used the same pravastatin
dose: 40mg
 This dose was extremely well tolerated and safe
 In these trials, no titration occurred for safety
 No need for lower doses in elderly
 Lower dose of pravastatin only indicated in patients
requiring complex management:
– renal or hepatic impairment
– post transplant
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Appropriate Dosing of Aspirin
 For secondary prevention the aspirin label
advises: 75-325mg once daily and indefinite
continuation of therapy
 Aspirin dose available in combination product:
81 or 325mg
– 81mg: most widely used for secondary
prevention in U.S.
– 325mg: upper end of approved dose range
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Is Pravastatin + Aspirin More Effective
than Aspirin Alone?
 Investigation of efficacy of pravastatin
in aspirin-users
– LIPID
– CARE
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Aspirin Usage in
Secondary Prevention Trials
 ‘Aspirin-users’ defined as those using aspirin
at baseline
 Dose level of aspirin not collected
 97% of baseline aspirin-users were still using it
at the end of the trials
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Evaluated Endpoints
 For individual trials: primary endpoints
– LIPID: CHD death
– CARE: CHD death or non-fatal MI
 In addition, the following endpoints*, based on
the overlap of the pravastatin and aspirin labels,
were evaluated
– Fatal or non-fatal MI
– Ischemic stroke
– CHD death, non-fatal MI, CABG, PTCA
or ischemic stroke
*These endpoints were also prospectively defined in the individual trials
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LIPID Trial Details
 9,014 post-MI or unstable angina patients
 Mean follow-up of 6.1 years
 Primary endpoint of CHD death
 Randomized to pravastatin 40mg or placebo
 83% also taking aspirin
Prava
Placebo
All Patients
4512
4502
Aspirin Users
3730
3698
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LIPID Trial Results:
Superiority of Combination vs Aspirin Alone
RRR*
p value
8.3%
24.0%
<0.001
Prava
Placebo
(+ASA)
(+ASA)
RRR*
p value
N = 3730
N = 3698
CHD Death
5.8%
8.1%
28.3%
<0.001
Fatal or Non-fatal MI
7.1%
10.4%
34.7%
<0.001
Ischemic Stroke
2.6%
3.6%
29.7%
0.008
CHD Death, NF-MI, CABG,
PTCA, Ischemic Stroke
23.5%
29.7%
23.9%
<0.001
All Patients
CHD Death
Aspirin Users
Prava
Placebo
N = 4512
N = 4502
6.4%
* Relative risk reduction based on Cox Proportional Hazards model
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CARE Trial Details
 4,159 post-MI subjects
 Mean follow-up of 5 years
 Normal cholesterol
 Primary endpoint – CHD death or non-fatal MI
 Randomized to pravastatin 40mg or placebo
 83.7% also taking aspirin
Prava
Placebo
All Patients
2081
2078
Aspirin Users
1742
1735
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CARE Trial Results:
Superiority of Combination vs Aspirin Alone
RRR*
p value
13.2%
24.0%
0.003
Prava
Placebo
(+ASA)
(+ASA)
RRR*
p value
N = 1742
N = 1735
CHD Death or Non-fatal MI
9.3%
12.6%
28.2%
0.001
Fatal or Non-fatal MI
10.1%
12.5%
20.6%
0.02
Ischemic Stroke
2.0%
2.7%
28.9%
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CHD Death, NF-MI, CABG,
PTCA, Ischemic Stroke
21.6%
27.4%
23.6%
0.0001
All Patients
CHD Death or Non-fatal MI
Aspirin Users
Prava
Placebo
N = 2081
N = 2078
10.2%
* Relative risk reduction based on Cox Proportional Hazards model
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The combination of pravastatin and aspirin is
significantly more effective than aspirin alone,
as evidenced by randomized comparisons
from the secondary prevention trials:
 LIPID
 CARE
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Is Pravastatin+Aspirin More Effective
than Pravastatin Alone?
 Aspirin studies were conducted before
statins were widely used
 Placebo-controlled trial with aspirin
is not feasible
 Investigation of pravastatin database
to explore this question
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