B-1 Pravastatin-Aspirin Combination René Belder, M.D. Executive Director Clinical Design and...
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Transcript of B-1 Pravastatin-Aspirin Combination René Belder, M.D. Executive Director Clinical Design and...
B-1B-1
Pravastatin-Aspirin CombinationPravastatin-Aspirin Combination
René Belder, M.D.
Executive DirectorClinical Design and Evaluation, Metabolics
Pharmaceutical Research InstituteBristol-Myers Squibb
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B-2B-2
Speakers for This MorningSpeakers 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
B-3B-3
Different Mechanisms of Action Different Mechanisms of Action of Componentsof Components
Aspirin
Reduces platelet aggregation by inhibiting cyclo-oxygenase
Pravastatin
Reduces cholesterol levels by inhibiting HMG CoA reductase
B-4B-4*Ratio of Geometric Least Square Means (90%CI)
No Pharmacokinetic Interaction in No Pharmacokinetic Interaction in Single Dose Cross-Over StudySingle Dose Cross-Over Study
0
20
40
60
80
100
120
140
µg/mL µg•h/mL
Cmax AUC
0
10
20
30
40
50
6095% (85-105%)*92% (82-103%)*
102% (99-105%)*
102% (95-108%)*
Prava+ASA
Prava ASA
Pravastatin level
Salicylate level
Prava+ASA
Prava+ASA
Prava ASA
Pravastatin level
Salicylate level
Prava+ASA
Product Administered Product Administered
B-5B-5
-40
-30
-20
-10
0
10
Total cholesterol LDL-C Triglycerides HDL-C
Prava+ASA Prava alone
Changes in Mean Lipid Levels by Month 3 Changes in Mean Lipid Levels by Month 3 in CAREin CARE
Percent Change from Baseline
B-6B-6
Pravastatin Atherosclerosis Pravastatin Atherosclerosis Intervention Program (1)Intervention Program (1)
Prevention Program
Secondary prevention
– Long-term Intervention with Pravastatin in Ischemic Disease study (LIPID)
– Cholesterol and Recurrent Events (CARE)
Primary prevention
– West of Scotland Coronary Prevention Study (WOSCOPS)
No. of Subjects
9,014
4,159
6,595
B-7B-7
Pravastatin Atherosclerosis Pravastatin Atherosclerosis Intervention Program (2)Intervention Program (2)
No. of Subjects
885
408
151
447
Regression Program
Regression Growth Evaluation Statin Study (REGRESS)
Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC I)
Pravastatin Limitation of Atherosclerosis in the Carotid Arteries (PLAC II)
Kuopio Atherosclerosis Intervention Study (KAPS)
B-8B-8
Contribution of Trials to TotalContribution of Trials to TotalCHD Patient-Years of ExposureCHD Patient-Years of Exposure
Total Exposure = 73,900 Patient-Years
LIPID LIPID 68%68%
CARECARE28%28%
REGRESSREGRESS2%2%
PLAC-IPLAC-I1%1%
PLAC-IIPLAC-II1%1%
B-9B-9
Reassuring Safety of the CombinationReassuring Safety of the Combination
CK abnormalities– no signal
Liver Function Test abnormalities– no signal
Gastrointestinal bleeds– no signal
Hemorrhagic stroke– no signal
B-10B-10
Appropriate Dosing of PravastatinAppropriate 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
B-11B-11
Appropriate Dosing of AspirinAppropriate 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
B-12B-12
Is Pravastatin + Aspirin More EffectiveIs Pravastatin + Aspirin More Effectivethan Aspirin Alone?than Aspirin Alone?
Investigation of efficacy of pravastatinin aspirin-users
– LIPID
– CARE
B-13B-13
Aspirin Usage in Aspirin Usage in Secondary Prevention TrialsSecondary 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
B-14B-14
Evaluated EndpointsEvaluated 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, PTCAor ischemic stroke
*These endpoints were also prospectively defined in the individual trials
B-15B-15
LIPID Trial DetailsLIPID 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
All Patients
Prava
4512
Placebo
4502
Aspirin Users 3730 3698
B-16B-16
LIPID Trial Results:LIPID Trial Results:Superiority of Combination vs Aspirin Alone
* Relative risk reduction based on Cox Proportional Hazards model
CHD Death, NF-MI, CABG, PTCA, Ischemic Stroke 23.5% 29.7% 23.9% <0.001
Fatal or Non-fatal MI 7.1% 10.4% 34.7%
Ischemic Stroke 2.6% 3.6% 29.7%
<0.001
0.008
All Patients N = 4512 N = 4502
PlaceboPrava RRR* p value
CHD Death 6.4% 8.3% 24.0% <0.001
Aspirin Users N = 3730 N = 3698
CHD Death 5.8% 8.1% 28.3% <0.001
Placebo(+ASA)
Prava(+ASA) RRR* p value
All Patients N = 4512 N = 4502
PlaceboPrava RRR* p value
CHD Death 6.4% 8.3% 24.0% <0.001
B-17B-17
CARE Trial DetailsCARE 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
All Patients
Prava
2081
Placebo
2078
Aspirin Users 1742 1735
B-18B-18
CARE Trial Results:CARE Trial Results:Superiority of Combination vs Aspirin Alone
* Relative risk reduction based on Cox Proportional Hazards model
CHD Death, NF-MI, CABG, PTCA, Ischemic Stroke 21.6% 27.4% 23.6% 0.0001
Fatal or Non-fatal MI 10.1% 12.5% 20.6%
Ischemic Stroke 2.0% 2.7% 28.9%
0.02
0.13
All Patients N = 2081 N = 2078
PlaceboPrava RRR* p value
CHD Death or Non-fatal MI 10.2% 13.2% 24.0% 0.003
Aspirin Users N = 1742 N = 1735
CHD Death or Non-fatal MI 9.3% 12.6% 28.2% 0.001
Placebo(+ASA)
Prava(+ASA) RRR* p value
All Patients N = 2081 N = 2078
PlaceboPrava RRR* p value
CHD Death or Non-fatal MI 10.2% 13.2% 24.0% 0.003
B-19B-19
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
B-20B-20
Is Pravastatin+Aspirin More EffectiveIs Pravastatin+Aspirin More Effectivethan Pravastatin Alone? than Pravastatin Alone?
Aspirin studies were conducted beforestatins were widely used
Placebo-controlled trial with aspirinis not feasible
Investigation of pravastatin databaseto explore this question