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B-1 René Belder, MD Executive Director Clinical Design and Evaluation, Metabolics Pharmaceutical Research Institute Bristol-Myers Squibb Pravastatin-Aspirin.

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Presentation on theme: "B-1 René Belder, MD Executive Director Clinical Design and Evaluation, Metabolics Pharmaceutical Research Institute Bristol-Myers Squibb Pravastatin-Aspirin."— Presentation transcript:

1 B-1 René Belder, MD Executive Director Clinical Design and Evaluation, Metabolics Pharmaceutical Research Institute Bristol-Myers Squibb Pravastatin-Aspirin Safety and Dosing Considerations

2 B-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

3 B-3 Brief Summary of Data Presented Previously

4 B-4 Trial LIPID CARE REGRESS PLAC I PLAC II Totals Number of Subjects*% on Aspirin Primary Endpoint CHD mortality CHD death & non-fatal MI Atherosclerotic progression (& events) ,617 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

5 B-5 RRR = Relative Risk Reduction Relative Risk (95% CI) RRR Prava+ASA vs ASA alone Prava+ASA vs Prava alone Fatal or Non-Fatal MI CHD Death, Non-Fatal MI, CABG, PTCA, or Ischemic Stroke Prava+ASA vs ASA alone Prava+ASA vs Prava alone 24% % % % 0.74 Prava+ASA vs ASA alone Prava+ASA vs Prava alone 29% % 0.69 Ischemic Stroke Greater Relative Risk Reduction for Pravastatin-Aspirin Cox Proportional Hazards – All Trials

6 B-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 B-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 B-8 20mg 80mg 40mg Pravastatin Pravastatin Dose Flexibility To allow physicians greater flexibility to select the desired dose of each component, the following co-packaged combinations will be available: 81mg325mg 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

9 B-9 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 B-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

11 B-11 BrandNo. of ProductsASA Doses (mg) Aspergum ® 1227 Norwich ® 2325, 500, 650 Bayer ® 1381, 325, 500 St. Joseph ® 181 Ecotrin ® 381, 325, 500 Halfprin ® 281, 162 Ascriptin ® 581, 325, 500 Bufferin ® 481, 325, 500 Adprin ® 1325 Alka-Seltzer ® 3325, 500 OTC “Aspirin Only” Products

12 B-12 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

13 B-13 OTC Aspirin-Containing Products BrandNo. of ProductsASA Doses (mg)Other Ingredients Goody’s ® 3260, 500, 520acetaminophen+caffeine Vanquish ® 1227acetaminophen+caffeine Excedrin ® 6250acetaminophen+caffeine Block ® 3650, 742caffeine+salicylamide Anacin ® 3400, 500caffeine Alka-Seltzer ® 1325sodium bicarbonate, citric acid Cope ® 1421caffeine Gelprin ® 1240acetaminophen+caffeine Supac ® 1230acetaminophen+caffeine Stanback ® 1650caffeine+salicylamide Aspirin plus Calcium ® 181calcium

14 B-14 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”

15 B-15 Cook et al, (1999) Med Gen Med, 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

16 B-16 OTC “No Aspirin” Products Tylenol ® acetaminophen Advil ® ibuprofen Aleve ® naproxen Motrin ® ibuprofen Anacin ® (aspirin-free)acetaminophen Excedrin ® (aspirin-free)acetaminophen

17 B-17 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

18 B-18 Awareness of Aspirin Content of Combination Products

19 B-19 Pravastatin-Aspirin Packaging

20 B-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.

21 B-21 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

22 B-22 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 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

23 B-23 Aspirin in CABG Studies Author Goldman Gaveghan Goldman Kallis Reich Tuman Munoz Dacey Year No. of Patients ,555 8, Main Conclusions  Occlusion rate  Platelet aggregation 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

24 B-24 Aspirin in Surgical Patients Concern about inadvertent use has decreased  Improved surgical procedures reduce bleeding complications

25 B-25 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 PatientsN=6,261N=6,294 antifibrinolytic use4% 78%* pre-op heparin use43% 74% † pre-op aspirin use22% 78%* * p<0.001 † p< % 2.0%* 12,555 CABGs in Northern New England

26 B-26 Aspirin in Surgical Patients Concern about inadvertent use has decreased –Improved surgical procedures reduce bleeding complications  Emerging data suggest potential net benefit of continuation

27 B-27 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

28 B-28 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

29 B-29 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

30 B-30 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

31 B-31 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 B-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

33 B-33 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


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