# Presentation: 892719

## 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

**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**

## Different Mechanisms of Action of Components

**Different Mechanisms of Action of Components**

**Aspirin**
**Reduces platelet aggregation by inhibiting cyclo-oxygenase**
**Pravastatin**
**Reduces cholesterol levels by inhibiting HMG CoA reductase**

## No Pharmacokinetic Interaction in Single Dose Cross-Over Study

***Ratio of Geometric Least Square Means (90%CI)**

**No Pharmacokinetic Interaction in Single Dose Cross-Over Study**

**μg/mL**

**μg•h/mL**

**C****max**

**AUC**

**95% (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**

## Changes in Mean Lipid Levels by Month 3 in CARE

**Changes in Mean Lipid Levels by Month 3 in CARE**

**Percent Change **
**from Baseline**

## Pravastatin Atherosclerosis Intervention Program (1)

_**Prevention Pro**_**g**_**ram**_
**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 Sub**_**j**_**ects**_
**9,014**
**4,159**
**6,595**

## Pravastatin Atherosclerosis Intervention Program (2)

_**No. of Sub**_**j**_**ects**_
**885**
**408**
**151**
**447**

_**Re**_**g**_**ression Pro**_**g**_**ram**_
**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)**

## Contribution of Trials to TotalCHD Patient-Years of Exposure

**Contribution of Trials to Total****CHD Patient-Years of Exposure**

***Total Exposure = 73,900 Patient-Years***

**LIPID *****68%***

**CARE*****28%***

**REGRESS*****2%***

**PLAC-I*****1%***

**PLAC-II*****1%***

**Notes:**
Despite the progression in prevention, diagnosis and treatment, cardiovascular disease still remains by far the leading cause of death in industrialized nations. In the U.S., cardiovascular disease is responsible for more years of potential life lost before the age of 75 than any other condition and it creates immense economic burden in healthcare costs and lost productivity.

## Reassuring Safety of the Combination

** ****CK abnormalities**
**no signal**
**Liver Function Test abnormalities**
**no signal **
**Gastrointestinal bleeds**
**no signal**
** ****Hemorrhagic stroke**
**no signal**

## Appropriate Dosing of Pravastatin

**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**

## Appropriate Dosing of Aspirin

**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**

## Is Pravastatin + Aspirin More Effectivethan Aspirin Alone?

**Investigation of efficacy of pravastatin****in aspirin-users**
**LIPID**
**CARE**

## Aspirin Usage in Secondary Prevention Trials

**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**

## Evaluated Endpoints

**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**

## 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**

**All Patients**

**Prava**

**4512**

**Placebo**

**4502**

**Aspirin Users**

**3730**

**3698**

## LIPID Trial Results:Superiority of Combination vs Aspirin Alone

*** Relative risk reduction based on Cox Proportional Hazards model**

## 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**

**All Patients**

**Prava**

**2081**

**Placebo**

**2078**

**Aspirin Users**

**1742**

**1735**

## CARE Trial Results:Superiority of Combination vs Aspirin Alone

**CARE Trial Results:**Superiority of Combination vs Aspirin Alone

*** Relative risk reduction based on Cox Proportional Hazards model**

## 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

**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**

## Is Pravastatin+Aspirin More Effectivethan Pravastatin Alone? 

**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**

## Slide 21