B-1B-1

René Belder, MD

Executive DirectorClinical Design and Evaluation, Metabolics

Pharmaceutical Research InstituteBristol-Myers Squibb

Pravastatin-AspirinPravastatin-AspirinSafety and Dosing ConsiderationsSafety and Dosing Considerations

B-2B-2

Top Line OverviewTop 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

B-3B-3

Brief Summary of Data Brief Summary of Data Presented Previously Presented Previously

B-4B-4

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 doseTotal exposure 79,300 patient years

Efficacy and Safety of Pravastatin-AspirinEfficacy and Safety of Pravastatin-AspirinBased on Meta-analysis of 5 Pravastatin trialsBased on Meta-analysis of 5 Pravastatin trials

B-5B-5RRR = Relative Risk Reduction

Relative Risk (95% CI) RRR

Prava+ASA vs ASA alone

Prava+ASA vs Prava alone

Fatal or Non-Fatal MI

0.400 0.800 1.0000.600

0.400 0.800 1.0000.600

CHD Death, Non-Fatal MI, CABG, PTCA, or Ischemic Stroke

Prava+ASA vs ASA alone

Prava+ASA vs Prava alone

24%0.76

13%0.87

31%0.69

26%0.74

Prava+ASA vs ASA alone

Prava+ASA vs Prava alone

29%0.71

31%0.69

Ischemic Stroke

0.400 0.800 1.0000.600

Greater Relative Risk Reduction for Greater Relative Risk Reduction for Pravastatin-AspirinPravastatin-Aspirin

Cox Proportional Hazards – All TrialsCox Proportional Hazards – All Trials

B-6B-6

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

No increased incidence of

–CK abnormalities

– Liver Function Test abnormalities

–Gastrointestinal bleeds

–Hemorrhagic stroke

B-7B-7

Issues To Be DiscussedIssues 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

B-8B-8

20mg

80mg

40mg

Pravastatin

Pravastatin Dose FlexibilityPravastatin Dose Flexibility To allow physicians greater flexibility to select the

desired dose of each component, the followingco-packaged combinations will be available:

81mg 325mg

Aspirin

• Provided for physicians desiring more cholesterol lowering

• Pravastatin dose used in all the clinical outcomes trials

• Provided for physicians to manage patients with renal / hepatic impairment or on immunosuppressants

B-9B-9

Issues To Be DiscussedIssues 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

B-10B-10

OTC Aspirin Use in OTC Aspirin Use in Secondary PreventionSecondary Prevention

Ambiguity for both patient and health care providerOTC aspirin-only products are available at a

variety of doses, including higher analgesic doses

B-11B-11

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” ProductsOTC “Aspirin Only” Products

B-12B-12

OTC Aspirin Use in OTC Aspirin Use in Secondary PreventionSecondary Prevention

Ambiguity for both patient and health care provider– OTC aspirin-only products are available at a

variety of doses, including higher analgesic dosesOTC aspirin combination products contain active

ingredients possibly inappropriate for use by patients with existing CV disease

B-13B-13

OTC Aspirin-Containing ProductsOTC 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

B-14B-14

OTC Aspirin Use in OTC Aspirin Use in Secondary PreventionSecondary 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”

B-15B-15Cook et al, (1999) Med Gen Med, www.medscape.com

OTC Aspirin Use in OTC Aspirin Use in Secondary PreventionSecondary 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

B-16B-16

OTC “No Aspirin” ProductsOTC “No Aspirin” Products

Tylenol® acetaminophen

Advil® ibuprofen

Aleve® naproxen

Motrin® ibuprofen

Anacin® (aspirin-free) acetaminophen

Excedrin® (aspirin-free) acetaminophen

B-17B-17

Prescription Aspirin Use in Prescription Aspirin Use in Secondary PreventionSecondary 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

B-18B-18

Awareness of Aspirin ContentAwareness of Aspirin Contentof Combination Productsof Combination Products

B-19B-19

Pravastatin-Aspirin PackagingPravastatin-Aspirin Packaging

B-20B-20

THIS PRODUCT CONTAINS ASPIRIN

PATIENT INFORMATION

[TRADENAME]

(buffered aspirin tablets and pravastatin sodium tablets)

Q.1 What is [TRADENAME]?[TRADENAME] is made up of two well-studied drugs, buffered aspirin and pravastatin sodium (PRAVACHOL®), taken together as a pair of tablets. [TRADENAME] is clinically proven to help prevent heart attack and stroke, or to reduce the risk of death from a heart attack, in people with heart disease including those who have had previous heart attacks. While taking [TRADENAME], continue to exercise and follow the diet advised by your doctor.

B-21B-21

Issues To Be DiscussedIssues 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

B-22B-22

Benefits and Risks of Perioperative Aspirin:Benefits and Risks of Perioperative Aspirin:Large Studies and Meta-AnalysesLarge Studies and Meta-AnalysesStudy

APTC Meta-analysis (1994):8,000 vascular surgery pts46 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 pts53 studies

general surgery

elective orthopedic surgerytraumatic 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

B-23B-23

Aspirin in CABG StudiesAspirin in CABG StudiesAuthor

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

B-24B-24

Aspirin in Surgical PatientsAspirin in Surgical Patients Concern about inadvertent use has decreased

Improved surgical procedures reduce bleeding complications

B-25B-25

0

1

2

3

4

5

6

1/92 1/93 1/94 1/95 1/96 1/97

Improved Procedures During Surgery Improved Procedures During Surgery Reduce Bleeding ComplicationsReduce 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=6,294antifibrinolytic 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

B-26B-26

Aspirin in Surgical PatientsAspirin in Surgical Patients Concern about inadvertent use has decreased

– Improved surgical procedures reduce bleeding complications

Emerging data suggest potential net benefit of continuation

B-27B-27Source: Dacey et al (2000) Ann Thorac Surg 70:1986

Emerging Data Suggests PotentialEmerging Data Suggests PotentialNet Benefit of ContinuationNet 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

B-28B-28

Aspirin in Surgical PatientsAspirin 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

B-29B-29

Lack of Consensus About Lack of Consensus About Continuation / DiscontinuationContinuation / 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

B-30B-30

Aspirin in Surgical PatientsAspirin 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

B-31B-31

Issues To Be DiscussedIssues 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

B-32B-32

Interruption of Combination TherapyInterruption 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

B-33B-33

Summary of BMS ActionsSummary 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