b-1 rené belder, md executive director clinical design and evaluation, metabolics pharmaceutical...
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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-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 doses
OTC 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-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-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
B-23B-23
Aspirin in CABG StudiesAspirin 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
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