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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 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) *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 0.4000.8001.0000.600 0.4000.8001.0000.600 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 0.4000.8001.0000.600 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, 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

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 1988 1989 1991 1994 1996 1999 2000 1991 No. of Patients 555 406 239 100 197 317 12,555 8,641 351 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<0.04 3.6% 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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