# Presentation: 544851

## René Belder, MD

Executive DirectorClinical Design and Evaluation, Metabolics
Pharmaceutical Research InstituteBristol-Myers Squibb

**Executive Director****Clinical Design and Evaluation, Metabolics**
**Pharmaceutical Research Institute****Bristol-Myers Squibb**

**Pravastatin-Aspirin****Safety and Dosing Considerations**

## Top Line Overview

**Top Line Overview**

**Cardiovascular disease remains the leading cause of death in the U.S.**
**Both pravastatin and aspirin are indicated for secondary prevention**
**The pravastatin-aspirin combination will provide a useful tool for health care providers and patients **

## Brief Summary of Data Presented Previously 

## Efficacy and Safety of Pravastatin-AspirinBased on Meta-analysis of 5 Pravastatin trials

**Trial**

**LIPID**

**CARE**

**REGRESS**

**PLAC I**

**PLAC II**

***Totals***

**Number of Subjects***

**% on Aspirin**

**82.7**

**83.7**

**54.4**

**67.5**

**42.7**

***80.4***

**Primary Endpoint**

**CHD mortality**

**CHD death & non-fatal MI**

**Atherosclerotic progression ****(& events)**

**9014**

**4159**

**885**

**408**

**151**

***14,617***

**Atherosclerotic progression ****(& events)**

**Atherosclerotic progression ****(& events)**

***99.7% of pravastatin-treated subjects received 40mg dose**
**Total exposure 79,300 patient years**

**Efficacy and Safety of Pravastatin-Aspirin****Based on Meta-analysis of 5 Pravastatin trials**

## Greater Relative Risk Reduction for Pravastatin-AspirinCox Proportional Hazards – All Trials

**RRR = Relative Risk Reduction**

**Relative Risk (95% CI)**

**RRR**

**Greater Relative Risk Reduction for ****Pravastatin-Aspirin****Cox Proportional Hazards – All Trials**

## Reassuring Safety of the Combination in the Pravastatin Trials

**Reassuring Safety of the Combination in the Pravastatin Trials**

**No increased incidence of**
**CK abnormalities**
**Liver Function Test abnormalities**
**Gastrointestinal bleeds**
**Hemorrhagic stroke**

## Issues To Be Discussed

**Issues To Be Discussed**

**Choice of pravastatin doses to be offered **
**Potential for excessive bleeding should pravastatin-aspirin not be discontinued prior to surgery **
**Potential for inappropriate discontinuation of pravastatin**

## Pravastatin Dose Flexibility

**Pravastatin Dose Flexibility**

**To allow physicians greater flexibility to select the desired dose of each component, the following****co-packaged combinations will be available:**

**81mg**

**325mg**

**Aspirin**

## Issues To Be Discussed

**Issues To Be Discussed**

**Choice of pravastatin doses to be offered **
**Potential for excessive bleeding should pravastatin-aspirin not be discontinued prior to surgery **
**Potential for inadvertent continuation of aspirin **
**Risk associated with aspirin use during surgery**
**Potential for inappropriate discontinuation of pravastatin**

## OTC Aspirin Use in Secondary Prevention

**OTC Aspirin Use in ****Secondary Prevention**

**Ambiguity for both patient and health care provider**
**OTC aspirin-only products are available at a variety of doses, including higher analgesic doses**

## OTC “Aspirin Only” Products

**Brand****	****No. of Products****	****ASA Doses (mg)**
**Aspergum****®****	****1****	****227**
**Norwich****®****	****2****	****325, 500, 650**
**Bayer****®****	****13****	****81, 325, 500**
**St. Joseph****®****	****1****	****81**
**Ecotrin****®****	****3****	****81, 325, 500**
**Halfprin****®****	****2****	****81, 162**
**Ascriptin****®****	****5****	****81, 325, 500**
**Bufferin****®****	****4****	****81, 325, 500**
**Adprin****®****	****1****	****325**
**Alka-Seltzer****®****	****3****	****325, 500**

**OTC “Aspirin Only” Products**

## OTC Aspirin Use in Secondary Prevention

**OTC Aspirin Use in ****Secondary Prevention**

**Ambiguity for both patient and health care provider**
**OTC aspirin-only products are available at a variety of doses, including higher analgesic doses**
**OTC aspirin combination products contain active ingredients possibly inappropriate for use by patients with existing CV disease**

## OTC Aspirin-Containing Products

**Brand****	****No. of Products****	****ASA Doses (mg)****	****Other Ingredients**
**Goody’s****®****	****3****	****260, 500, 520****	****acetaminophen+caffeine**
**Vanquish****®****	****1****	****227****	****acetaminophen+caffeine**
**Excedrin****®****	****6****	****250****	****acetaminophen+caffeine**
**Block****®****	****3****	****650, 742****	****caffeine+salicylamide**
**Anacin****®****	****3****	****400, 500****	****caffeine**
**Alka-Seltzer****®****	****1****	****325****	****sodium bicarbonate,****	****	****	****citric acid**
**Cope****®****	****1****	****421****	****caffeine**
**Gelprin****®****	****1****	****240****	****acetaminophen+caffeine**
**Supac****®****	****1****	****230****	****acetaminophen+caffeine**
**Stanback****®****	****1****	****650****	****caffeine+salicylamide**
**Aspirin plus Calcium****®****	****1****	****81****	****calcium**

## OTC Aspirin Use in Secondary Prevention

**OTC Aspirin Use in ****Secondary Prevention**

**Ambiguity for both patient and health care provider**
**OTC aspirin-only products are available at a variety of doses, including higher analgesic doses**
**OTC aspirin combination products contain active ingredients possibly inappropriate for use by patients with existing CV disease**
**Other OTC products such as acetaminophen can be and are mistaken as “aspirin substitutes” **

## OTC Aspirin Use in Secondary Prevention

**Cook et al, (1999) Med Gen Med, www.medscape.com**

**OTC Aspirin Use in ****Secondary Prevention**

**Mis-medication:**** Among patients who thought they were taking aspirin for secondary prevention, 15% were actually taking a non-aspirin analgesic**
**Under-utilization:**** Only 51% of patients with known cardiovascular disease reported they were taking aspirin or an ‘equivalent’**
**National Survey 26,976 persons >40 years of age ****3,818 reported prior CVD**

## OTC “No Aspirin” Products

**OTC “No Aspirin” Products**

**Tylenol****®****	****acetaminophen**
**Advil****®****	****ibuprofen**
**Aleve****®****	****naproxen**
**Motrin****®****	****ibuprofen**
**Anacin****®**** (aspirin-free)****	****acetaminophen**
**Excedrin****®**** (aspirin-free)****	****acetaminophen**

## Prescription Aspirin Use in Secondary Prevention

**Prescription Aspirin Use in ****Secondary Prevention**

**Prescribing physicians will be better able to ensure that aspirin***** *****is used rather than a substitute**
**Other physicians will be better able to determine the patient’s use of aspirin and recommend discontinuation as appropriate**

## Awareness of Aspirin Contentof Combination Products

## Pravastatin-Aspirin Packaging

**Pravastatin-Aspirin Packaging**

## Slide 20

## Issues To Be Discussed

**Issues To Be Discussed**

**Choice of pravastatin doses to be offered **
**Potential for excessive bleeding should pravastatin-aspirin not be discontinued prior to surgery **
**Potential for inadvertent continuation of aspirin **
**Risk associated with aspirin use during surgery**
**Potential for inappropriate discontinuation of pravastatin**

## Benefits and Risks of Perioperative Aspirin:Large Studies and Meta-Analyses

**Benefits and Risks of Perioperative Aspirin:****Large Studies and Meta-Analyses**

**Study**

**APTC Meta-analysis (1994):**
**8,000 vascular surgery pts**
**46 studies**

**coronary intervention/ ****grafting**

**Patient Types**

**Major Outcomes**

**peripheral grafting**

**hemodialysis access**

****** ****Occlusion**

****** ****Occlusion**

****** ****Occlusion**

**Bleeding**

**“****No large excess of bleeding was apparent”**

**APTC Meta-analysis (1994):**
**8,400 general and orthopedic surgery pts**
**53 studies**

**general surgery**

**elective orthopedic surgery**

**traumatic orthopedic surgery**

**Increased need for transfusion but no increase in fatal bleeding**

****** ****DVT  ******** PE**

****** ****DVT**

****** ****PE**

**Pulmonary Embolism Prevention Trial (2000):**
**17,444 hip fracture surgery and elective arthroplasty pts**

**hip fracture surgery and elective arthroplasty **

**Increased need for transfusion but no increase in fatal bleeding**

****** ****DVT  ******** PE**

## Aspirin in CABG Studies

**Aspirin in CABG Studies**

**Author**

**Goldman**

**Goldman**

**Gaveghan**

**Goldman**

**Kallis**

**Reich**

**Tuman**

**Munoz**

**Dacey**

**Year**

**1988**

**1989**

**1991**

**1994**

**1994**

**1996**

**1999**

**2000**

**1991**

**No. of Patients**

**555**

**406**

**239**

**100**

**197**

**317**

**12,555**

**8,641**

**351**

**Main Conclusions**

****** ****Occlusion rate**

****** ****Occlusion rate**

****** ****Platelet aggregation**

**NS**

**NS**

****** ****Reoperation rate**

****** ****In-hospital mortality**

**NS**

**Efficacy**

****** ****Transfusion rate**
****** ****Reoperation rate**

**NS**

****** ****Tube drainage**

**NS**

****** ****Transfusion rate**
****** ****Reoperation rate**

**Safety**

**NS = Not Significant**

****** ****Blood loss**
****** ****Transfusion rate**

**NS**

## Aspirin in Surgical Patients

**Aspirin in Surgical Patients**

**Concern about inadvertent use has decreased**
**Improved surgical procedures reduce bleeding complications**

## Improved Procedures During Surgery Reduce Bleeding Complications

**Improved Procedures During Surgery Reduce Bleeding Complications**

**Source: Munoz et al (1999) Ann Thorac Surg 68:1321**

**Adjusted **** Rate of ****Re-Exploration for Bleeding****(%)**

**Number of Patients****	****N=6,261****	****N=6,294**
**antifibrinolytic use****	****4%  ****	****78%* **
**pre-op heparin use****	****43%  ****	****74%****† **
**pre-op aspirin use****	****22%  ****	****78%* **

*** ****	****p<0.001  ****† ****p<0.04**

**3.6%**

**2.0%***

**12,555 CABGs in Northern New England **

## Aspirin in Surgical Patients

**Concern about inadvertent use has decreased**
**Improved surgical procedures reduce bleeding complications**
**Emerging data suggest potential net benefit of continuation**

## Emerging Data Suggests PotentialNet Benefit of Continuation

**Source: Dacey et al (2000) Ann Thorac Surg 70:1986**

**Emerging Data Suggests Potential****Net Benefit of Continuation**

**Observational study in 8,641 CABG patients**
**Pre-operative aspirin use associated with**
**no increase in rate of re-exploration for bleeding**
**no difference in need for blood products**
**significant reduction in in-hospital mortality**

## Aspirin in Surgical Patients

**Concern about inadvertent use has decreased**
**Improved surgical procedures reduce bleeding complications**
**Emerging data suggest potential net benefit of continuation**
**Lack of consensus about continuation / discontinuation**

## Lack of Consensus About Continuation / Discontinuation

**Lack of Consensus About ****Continuation / Discontinuation**

**ACC/AHA Guidelines for Perioperative Medical Therapy in patients with CHD do not provide specific recommendations with respect to continuation or discontinuation of aspirin before noncardiac surgery**
**Source: JACC (2002) 39;543**

## Aspirin in Surgical Patients

**Aspirin in Surgical Patients**

**Reduced concern about inadvertent aspirin use**
**Improved surgical procedures reduce bleeding complications**
**Emerging data suggest potential net benefit of continuation**
**Lack of consensus about continuation / discontinuation**
**With the availability of pravastatin-aspirin as a prescription product, the likelihood of inadvertent use is reduced**

## Issues To Be Discussed

**Issues To Be Discussed**

**Choice of pravastatin doses to be offered **
**Potential for excessive bleeding should pravastatin-aspirin not be discontinued prior to surgery**** **
**Potential for inappropriate discontinuation of pravastatin**

## Interruption of Combination Therapy

**Interruption of Combination Therapy**

**No known consequences of temporary discontinuation of statin therapy**
**Individual components remain available to manage temporary discontinuation of one component and continuation of the other**

## Summary of BMS Actions

**Three pravastatin doses available**
**Current recommended starting dose (40mg) as well as 80mg & 20mg**
**Each with two aspirin doses: 81mg & 325mg**
**Packaging and labeling that clearly identifies  aspirin content**
**Increasing awareness by the physician and patient of the aspirin content of the product **