1 / 33

Pravastatin-Aspirin Safety and Dosing Considerations

Pravastatin-Aspirin Safety and Dosing Considerations. René Belder, MD Executive Director Clinical Design and Evaluation, Metabolics Pharmaceutical Research Institute Bristol-Myers Squibb. Top Line Overview. Cardiovascular disease remains the leading cause of death in the U.S.

galen
Download Presentation

Pravastatin-Aspirin Safety and Dosing Considerations

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

  3. Brief Summary of Data Presented Previously

  4. Efficacy and Safety of Pravastatin-AspirinBased on Meta-analysis of 5 Pravastatin trials Trial Number of Subjects* % on Aspirin Primary Endpoint LIPID 9014 82.7 CHD mortality CARE 4159 83.7 CHD death & non-fatal MI REGRESS 885 54.4 Atherosclerotic progression (& events) PLAC I 408 67.5 Atherosclerotic progression (& events) PLAC II 151 42.7 Atherosclerotic progression (& events) Totals 14,617 80.4 *99.7% of pravastatin-treated subjects received 40mg dose Total exposure 79,300 patient years

  5. Fatal or Non-Fatal MI 0.76 24% Prava+ASA vs ASA alone 0.87 13% Prava+ASA vs Prava alone Ischemic Stroke 0.69 Prava+ASA vs ASA alone 31% 0.74 26% Prava+ASA vs Prava alone CHD Death, Non-Fatal MI, CABG, PTCA, or Ischemic Stroke 0.71 29% Prava+ASA vs ASA alone 0.69 31% Prava+ASA vs Prava alone 0.400 0.400 0.400 0.600 0.600 0.600 0.800 0.800 0.800 1.000 1.000 1.000 Greater Relative Risk Reduction for Pravastatin-AspirinCox Proportional Hazards – All Trials RRR Relative Risk (95% CI) 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 • 40mg • Pravastatin dose used in all the clinical outcomes trials •  •  • 80mg • Provided for physicians desiring more cholesterol lowering •  •  • 20mg • Provided for physicians to manage patients with renal / hepatic impairment or on immunosuppressants •  •  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

  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. 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. 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 • 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

  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. OTC 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

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

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

  17. Prescription Aspirin Use in Secondary Prevention • Prescribing physicians will be better able to ensure that aspirinis 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. Awareness of Aspirin Contentof Combination Products

  19. Pravastatin-Aspirin Packaging

  20. 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. THIS PRODUCT CONTAINS ASPIRIN

  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. Benefits and Risks of Perioperative Aspirin:Large Studies and Meta-Analyses • Patient Types • Major Outcomes • Bleeding • Study • 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 •  DVT  PE • Increased need for transfusion but no increase in fatal bleeding • 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 •  DVT  PE • Increased need for transfusion but no increase in fatal bleeding

  23. Aspirin in CABG Studies • Year • No. of Patients • Main Conclusions • Efficacy • Safety • Author • 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

  24. Aspirin in Surgical Patients • Concern about inadvertent use has decreased • Improved surgical procedures reduce bleeding complications

  25. 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 N=6,261 N=6,294 antifibrinolytic use 4% 78%* pre-op heparin use 43% 74%† pre-op aspirin use 22% 78%* * p<0.001 † p<0.04 Source: Munoz et al (1999) Ann Thorac Surg 68:1321

  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. 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 70:1986

  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. 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. 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. 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

  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

More Related