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PR avastatin O r ator V astatin E valuation and I nfection T herapy (TIMI 22)

PR avastatin O r ator V astatin E valuation and I nfection T herapy (TIMI 22).

macey-nunez
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PR avastatin O r ator V astatin E valuation and I nfection T herapy (TIMI 22)

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  1. PRavastatin Or atorVastatin Evaluation and Infection Therapy (TIMI 22) Disclosure Statement: Dr. Cannon currently receives research grant support from Bristol-Myers Squibb, Merck and Sanofi-Synthelabo. He serves as a consultant to AstraZeneca, Glaxo Smith Kline, Guilford Pharmaceuticals and Vertex

  2. Statin therapy is highly effective vs. placebo in long-term treatment of CHD Are statins effective in reducing events in patients with an acute coronary syndrome (ACS)? Does “intensive” LDL-C lowering to an average of 65 mg/dL achieve a greater reduction in clinical events than “standard” LDL-C lowering to an average of 95 mg/dL? Background

  3. PROVE IT - TIMI 22: Study Design 4,162 patients with an Acute Coronary Syndrome < 10 days ASA + Standard Medical Therapy Double-blind “Standard Therapy” Pravastatin 40 mg “Intensive Therapy” Atorvastatin 80 mg 2x2 Factorial: Gatifloxacin vs. placebo Duration: Mean 2 year follow-up (>925 events) Primary Endpoint: Death, MI, Documented UA requiring hospitalization, revascularization (> 30 days after randomization), or Stroke

  4. Patient Population • Inclusion Criteria: • Hospitalization for acute MI or high-risk unstable angina < 10 d • Total cholesterol < 240 mg/dL (< 200 mg/dL if on Lipid  Rx) • Stabilized (i.e., without ischemia, CHF, post PCI if performed) • Major Exclusion Criteria: • Co-morbidity: patient survival < 2 years • Current therapy with simvastatin or atorvastatin 80 mg • Need for, or anticipated use of fibrates or niacin • CABG for treatment of qualifying ACS • Liver disease or unexplained CK elevations • Strong inhibitors of CYP450 3A4 (2o atorvastatin metabolism)

  5. Patient Enrollment by Country # Sites # Pts Australia A. Tonkin, I. Meridith 18 266 Canada J. Rouleau 20 349 France A. Castaigne 20 132 Germany H. Darius 21 93 Italy G. DeFerrari 15 86 Spain J. Velasco 14 102 United Kingdom G. Jackson 20 186 United States C. Cannon 221 2948 Total 349 4162

  6. Top Ten Enrolling Clinical Centers Principal ResearchHospital Investigator Coordinator Huntsville Hospital, Huntsville AL W. Haught K. Griffin Fremantle Hospital, Fremantle WA R. Hendriks D. Greenwell Detar Hospital, Victoria, TX H. Chandna D. Holly St. Francis Hospital, Tulsa, OK J. M. Cassidy N. Ritchie Advanced Health Institute, Galax, VA J. Puma E. Jones Michigan Heart, Ypsilanti, MI J. Bengtson C. Carulli N. Mississippi Medical Center, Tupelo, MS B. Bertolet M. Jones Wilford Hall Med Center, Lackland AFB, TX R. Krasuski U. Ward Queen Elizabeth Hospital, Woodville, Sa J. Horowitz R. Prideaux Moses H. Cone Hospital, Greensboro, NC T. Kelly K. Cochran

  7. Trial Organization TIMI Study Group Eugene Braunwald, MD Brigham and Women’s Hosp. Christopher Cannon, MD Carolyn McCabe, BS Data Coordinating Center Allan Skene PhD. Nottingham Karen Hill Sponsors: Rene Belder, MD Bristol-Myers Squibb Steven Joyal, MD and Sankyo Co. LTD Gabriella Cucinotta Chen-Sheng Lin, PhD Clinical Events Committee: Marc Pfeffer, MD, PhD

  8. Baseline Characteristics Atorvastatin 80mg Pravastatin 40mg (2099) (2063) Mean Age (years) 58 58 Male/Female (%) 78 / 22 78 / 22 History of HTN (%) 51 49 Current Smoker (%) 36 37 History of Diabetes (%) 19 18 History of CHD (%) 37 39 STEMI / NSTEMI / UA (%) 36 / 36 / 29 33 / 37 / 30 Prior Statin Use (%) 26 25

  9. Concomitant Therapies PCI for initial ACS pre-Rand 69% Aspirin 93% Warfarin 8% Clopidogrel (initial) 72% (at F/U) 20% B-blockers 85% ACE 69% ARB 14%

  10. Changes from (Post-ACS) Baseline in Median LDL-C Median LDL-C (Q1, Q3) 95 (79, 113) 62 (50, 79) 120 100 Pravastatin 40mg 21% 80 LDL-C (mg/dL) 60 Atorvastatin 80mg 49%  40 P<0.001 20 <24h Rand. 30 Days 4 Mos. 8 Mos. 16 Mos. Final • Note: Changes in LDL-C may differ from prior trials: • 25% of patients on statins prior to ACS event • ACS response lowers LDL-C from true baseline

  11. 0 30 3 6 9 12 15 18 21 24 27 All-Cause Death or Major CV Events in All Randomized Subjects 30 Pravastatin 40mg (26.3%) 25 20 % with Event Atorvastatin 80mg (22.4%) 15 10 16% RR (P = 0.005) 5 0 Months of Follow-up

  12. Primary Endpoint Over Time Events Rates RRAtorva 80 Prava 40 17% 1.9% 2.2% 18% 6.3% 7.7% 14% 12.2% 14.1% 16% 22.4%* 26.3%* 30 Days 90 Days 180 Days End of Follow-up 0.5 0.75 1.0 1.25 1.5 *2-year event rates Atorvastatin 80mg Better Pravastatin 40mg Better

  13. CHD Death Revasc > 30 d UA Req Hosp Reductions in Major Cardiac Endpoints 2 Year Event Rates RRAtorva 80 Prava 40 28% 2.2% 3.2% 30% 1.1% 1.4% 13% 6.6% 7.4% 18% 8.3% 10.0% 14% 16.3% 18.8% 29% 3.8% 5.1% 25% 12.9% 16.7% All-Cause Mortality MI Death or MI Death/MI/Urg.Revasc 0.5 0.75 1.0 1.25 1.5 Atorvastatin 80 mg Better Pravastatin 40 mg Better

  14. 20 % with Event 15 10 5 0 0 3 6 9 12 15 18 21 24 27 30 All-Cause Death, Non-Fatal MI, or Urgent Revascularization Pravastatin 40mg16.7% Atorvastatin 80mg12.9% 25% RRP = 0.0004 Months of Follow-up

  15. Subgroups: Reduction in All-Cause Mortality or Major CV Events 2 Year Event Rates Atorva 80 Prava 40 23.0% 26.2% 20.3% 27.0% 28.8% 34.6% 21.0% 24.6% 28.1% 29.5% 20.1% 25.0% 27.5% 28.9% 20.6% 25.5% 21.7% 26.7% 23.1% 26.0% 20.1% 28.2% 23.5% 25.6% % of Pts 78 22 18 82 30 70 25 75 44 56 27 73 Male Female Diabetes No Diabetes Age > 65 Age < 65 Prior Statin No Prior Statin HDL-C > 40 HDL-C < 40 LDL-C > 125 pi = 0.02 LDL-C < 125 All pinteraction = NS except as noted 0.5 0.75 1.0 1.25 1.5 Atorvastatin 80 mg Better Pravastatin 40 mg Better

  16. Liver and Muscle Effects Atorvastatin 80mg Pravastatin 40mg P-value ALT > 3 ULN 3.3% 1.1% <0.001 CK >3 ULN 1.5% 1.1% 0.24 D/C for Myalgia/CK elevations3.3% 2.7% 0.23

  17. Summary • In patients recently hospitalized within 10 days for an acute coronary syndrome: • “Intensive” high-dose LDL-C lowering (median LDL-C 62 mg/dL) compared to “moderate” standard-dose lipid-lowering therapy (median LDL-C 95 mg/dL) reduced the risk of all cause mortality or major cardiac events by 16% (p=0.005) • Benefits emerged within 30 days post ACS with continued benefit observed throughout the 2.5 years of follow-up • Benefits were consistent across all cardiovascular endpoints, except stroke, and most clinical subgroups

  18. PROVE-IT Conclusion MARCH 8, 2004 • Our findings indicate that patients recently hospitalized for an acute coronary syndrome benefit from early and continued lowering of LDL-C to levels substantially below current target levels. Cannon CP, Braunwald E, McCabe CH, et al. N Engl J Med 2004;350:15 www.nejm.org

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