Ren

1
Pravastatin-AspirinSafety and Dosing
Considerations

• René Belder, MD
• Executive DirectorClinical Design and
  Evaluation, Metabolics
• Pharmaceutical Research InstituteBristol-Myers
  Squibb

2
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

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Brief Summary of Data Presented Previously
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Efficacy and Safety of Pravastatin-AspirinBased
on Meta-analysis of 5 Pravastatin trials
Trial
Number of Subjects
on Aspirin
Primary Endpoint
LIPID
82.7
CHD mortality
9014
CARE
83.7
CHD death non-fatal MI
4159
REGRESS
54.4
Atherosclerotic progression ( events)
885
PLAC I
67.5
408
Atherosclerotic progression ( events)
PLAC II
42.7
151
Atherosclerotic progression ( events)
Totals
80.4
14,617
99.7 of pravastatin-treated subjects received
40mg dose Total exposure 79,300 patient years
5
Greater Relative Risk Reduction for
Pravastatin-AspirinCox Proportional Hazards
All Trials
Relative Risk (95 CI)
RRR
RRR Relative Risk Reduction
6
Reassuring Safety of the Combination in the
Pravastatin Trials

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

7
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

8
Pravastatin Dose Flexibility

• To allow physicians greater flexibility to select
  the desired dose of each component, the
  followingco-packaged combinations will be
  available

Aspirin
81mg
325mg
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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

10
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

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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 Ecotri
n 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
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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

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OTC Aspirin-Containing Products
Brand No. of Products ASA Doses (mg) Other
Ingredients Goodys 3 260, 500,
520 acetaminophencaffeine Vanquish 1 227 acetami
nophencaffeine Excedrin 6 250 acetaminophencaff
eine Block 3 650, 742 caffeinesalicylamide Anaci
n 3 400, 500 caffeine Alka-Seltzer 1 325 sodium
bicarbonate, citric acid Cope 1 421 caffeine Ge
lprin 1 240 acetaminophencaffeine Supac 1 230 a
cetaminophencaffeine Stanback 1 650 caffeinesal
icylamide Aspirin plus Calcium 1 81 calcium
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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

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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 gt40 years of age
  3,818 reported prior CVD

Cook et al, (1999) Med Gen Med, www.medscape.com
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OTC No Aspirin Products

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

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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 patients use of aspirin and recommend
  discontinuation as appropriate

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Awareness of Aspirin Contentof Combination
Products
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Pravastatin-Aspirin Packaging
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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

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Benefits and Risks of Perioperative
AspirinLarge Studies and Meta-Analyses

• Study

Patient Types
Major Outcomes
Bleeding

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

coronary intervention/ grafting
? Occlusion
No large excess of bleeding was apparent
peripheral grafting
? Occlusion
hemodialysis access
? Occlusion

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

general surgery
Increased need for transfusion but no increase in
fatal bleeding
? DVT ? PE
elective orthopedic surgery
? DVT
traumatic orthopedic surgery
? 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
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Aspirin in CABG Studies

• Author

Year
No. of Patients
Main Conclusions
Efficacy
Safety
Goldman
1988
555
? Occlusion rate
? Transfusion rate ? Reoperation rate
Goldman
1989
406
Gaveghan
1991
239
? Occlusion rate
NS
Goldman
1991
351
NS
? Transfusion rate ? Reoperation rate
Kallis
1994
100
? Platelet aggregation
? Blood loss ? Transfusion rate
Reich
1994
197
NS
? Tube drainage
Tuman
1996
317
NS
NS
Munoz
1999
12,555
? Reoperation rate
Dacey
2000
8,641
? In-hospital mortality
NS
NS Not Significant
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Aspirin in Surgical Patients

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

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Improved Procedures During Surgery Reduce
Bleeding Complications

• 12,555 CABGs in Northern New England

3.6
Adjusted Rate of Re-Exploration for
Bleeding()
2.0
Number of Patients N6,261 N6,294 antifibrinolyti
c use 4 78 pre-op heparin use 43 74
pre-op aspirin use 22 78
plt0.001 plt0.04
Source Munoz et al (1999) Ann Thorac Surg 681321
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Aspirin in Surgical Patients

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

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Emerging Data Suggests PotentialNet 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

Source Dacey et al (2000) Ann Thorac Surg 701986
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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

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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) 39543

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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

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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

32
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

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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