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