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The PROVE IT Trial

The PROVE IT Trial. Pravastatin or Atorvastatin Evaluation and Infection Therapy. Overview. Rationale Design Results and conclusions. What Is PROVE IT?. Background: Lipid-lowering therapy with statins reduces the risk of CV events, but the optimal level of LDL-C is unclear

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The PROVE IT Trial

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  1. The PROVE IT Trial Pravastatin or Atorvastatin Evaluation and Infection Therapy

  2. Overview • Rationale • Design • Results and conclusions

  3. What Is PROVE IT? • Background: Lipid-lowering therapy with statins reduces the risk of CV events, but the optimal level of LDL-C is unclear • Objective: To compare the effects of moderate lipid lowering with pravastatin 40 mg to an LDL-C level of ~2.6 mmol/L (100 mg/dL) with intensive lipid lowering with atorvastatin 80 mg to a lower level of ~1.8 mmol/L (70 mg/dL) on the prevention of death or major CV events in patients with ACS • Significance: The first head-to-head morbidity and mortality trial involving statins • PROVE IT was funded by Bristol-Myers Squibb Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.

  4. PROVE IT Is the First Head-to-Head Morbidity and Mortality Trial Involving Statins Follow-up 1st efficacy RR reductionStudy Comparator (y) parameter (%) 1st prevention WOSCOPS1 Placebo 4.9 MI + CHD death 31 AFCAPS/TexCAPS2 Placebo 5.2 MI/CHD death/UA 36 ASCOT3 Placebo 3.3 MI + CHD death 36 1st/2nd prevention HPS4 Placebo 5.0 MI + CHD death 24 2nd prevention 4S5 Placebo 5.4 Total mortality 30 CARE6 Placebo 5.0 MI + CHD death 24 LIPID7 Placebo 6.1 CHD death 24 PROVE IT8 Head-to-head 2.0 All cause mortality/ ??? Major CV event 1 Shepherd J, et al. N Engl J Med. 1995;333:1301-1307. 2 Downs JR, et al. JAMA. 1998;279:1615-1622. 3 Sever PS, et al. Lancet. 2003;361:1149-1158. 4 Heart Protection Collaborative Group. Lancet. 2002;360:7-22. 5 Scandinavian Simvastatin Study Group. Lancet. 1994;344:1383-1389. 6 Sacks FM, et al. N Engl J Med. 1996;335:1001-1009. 7 LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 8 Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators.N Engl J Med. 2004;350:1495-1504. 2Downs JR, et al. JAMA 1998;279:1615-1622. 3Sever PS, et al. Lancet. 2003;361:1149-1158. 4Heart Protection Collaborative Group. Lancet 2002;360:7-22. 5Scandinavian Simvastatin Study Group. Lancet 1664;344:1383-9.

  5. Moderate LDL-C lowering(pravastatin 40 mg) Intensive LDL-C lowering(atorvastatin 80 mg) Is Aggressive LDL-C Lowering More Effective in Reducing Clinical Events? Baseline LDL-C  25-35%  50% Current NCEP III LDL-C goal 2.6 mmol/L (100 mg/dL) On-treatment LDL-C EVENT REDUCTION ???? Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.

  6. Overview • Rationale • Design • Results and conclusions

  7. PROVE IT: Study Design Randomized, double-blind trial in 4162 patients with ACS < 10 days and TC  6.2 mmol/L (240 mg/dL) ASA + standard medical therapy Pravastatin 40 mg/d Atorvastatin 80 mg/d Gatifloxacin* Placebo* Gatifloxacin* Placebo* Duration: mean 2-y follow-up (925 events) Primary end point: death, MI, stroke, unstable angina requiring hospitalization, or revascularization (> 30 days after randomization) *2x2 factorial design. Results of the antibiotic arm are not reported in this slide set. Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.

  8. Patient Population • Inclusion criteria: • Hospitalization for acute MI or high-risk unstable angina < 10 days • TC ≤ 6.2 mmol/L (240 mg/dL) (< 5.2 mmol/L [200 mg/dL] if on lipid  Rx) • Stabilized (ie, without ischemia, CHF, post–PCI if performed) • Major exclusion criteria: • Comorbidity: patient survival < 2 y • 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 CPK elevations • Strong inhibitors of CYP450 3A4 (2nd atorvastatin metabolism) Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.

  9. Overview • Rationale • Design • Results and conclusions

  10. Baseline Characteristics Atorvastatin 80 mg Pravastatin 40 mg (n = 2099) (n = 2063) Mean age (y) 58 58 Male/Female (%) 78/22 78/22 History of hypertension (%) 51 49 Current smoker (%) 36 37 History of diabetes (%) 18 18 Prior MI (%) 18 19 STEMI-NSTEMI-UA (%) 36/36/29 33/37/30 Prior statin use (%) 26 25 MI, myocardial infarction; STEMI, ST-elevation myocardial infarction;NSTEMI, non–ST-elevation myocardial infarction; UA, unstable angina. Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.

  11. Concomitant Medications Given During Treatment Period Concomitant medication % of overall patient population Aspirin 93 Warfarin 8 Clopidogrel or ticlopidine At study start 72 After 1 y 20 β-Blocker 85 ACE inhibitor 69 Angiotensin-receptor blocker 14 ACE, angiotensin-converting enzyme. Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.

  12. Changes From Baseline (Post–ACS) in Median LDL-C 120 100 Pravastatin 40 mg 80 LDL-C (mg/dL) 60 Atorvastatin 80 mg 40 20 Baseline 30 days 4 mo 8 mo 16 mo Final Time of visit Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.

  13. Moderate LDL-C lowering(pravastatin 40 mg) Intensive LDL-C lowering(atorvastatin 80 mg) Atorvastatin 80 mg Reduced LDL-C More Than Pravastatin 40 mg Baseline LDL-Cmmol/L (mg/dL) 2.74 (106) 2.74 (106) Current NCEP III LDL-C goal 2.6 mmol/L (100 mg/dL) End-of-study LDL-Cmmol/L(mg/dL) 2.46 (95) 1.60 (62) Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.

  14. 16% reduction Effects on Primary End Point Atorvastatin 80 mg had a significantly greater effect than pravastatin 40 mg on the incidence of death or a major CV event 30 Pravastatin 40 mg26.3% 25 20 Atorvastatin 80 mg22.4% % patients with event* 15 10 5 P = 0.005 0 0 3 6 9 12 15 18 21 24 27 30 Months of follow-up *All-cause mortality or major CV event. Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.

  15. 0.5 0.75 1.0 1.25 1.5 Primary End Point Over Time Event rates RR Atorvastatin Pravastatin 80 mg 40 mg Hazard ratio (95% CI) 30 days 17% 1.9% 2.2% 90 days 18% 6.3% 7.7% 180 days 14% 12.2% 14.1% End of follow-up 16% 22.4% 26.3% Atorvastatin Better Pravastatin Better Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.

  16. Reductions in Major Cardiac End Points 2-y event rates RR Atorvastatin Pravastatin 80 mg 40 mg Hazard ratio (95% CI) 28% 2.2% 3.2% Death from any cause 30% 1.1% 1.4% Death from CHD 27% 1.2% 1.8% Death—other causes 13% 6.6% 7.4% MI 18% 8.3% 10.0% Death or MI 16% 7.2% 8.3% Death from CHD or MI 14% 16.3% 18.8% Revascularization MI, revascularization,or death from CHD 14% 19.7% 22.3% UA requiringhospitalization 29% 3.8% 5.1% -9% 1.0% 1.0% Stroke 0.5 1.0 1.5 Atorvastatin Better Pravastatin Better Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.

  17. Subgroups: Reduction in All-Cause Mortality or Major CV Events 2-y event rates Atorvastatin Pravastatin 80 mg 40 mg % of patients Hazard ratio 23.0% 26.2%20.3% 27.0% Male 78 Female 22 28.1% 29.5%20.1% 25.0%  65 y 30 < 65 y 70 28.8% 34.6%21.0% 24.6% Diabetes 18 No diabetes 82 22.8% 26.5%21.3% 25.9% Prior smoker 74 Not prior smoker 26 27.5% 28.9%20.6% 25.5% Prior statin 25 No prior statin 75 26.5% 31.4%19.0% 24.1% 22.6% 24.2% UA† 29 NSTMI† 36 STMI† 35 20.1% 28.2%23.5% 25.6% LDL-C*  3.2 (125) 27 LDL-C* < 3.2 (125) 73 21.7% 26.7%23.1% 26.0% HDL-C*  1.0 (40) 44 HDL-C* < 1.0 (40) 56 0.5 1.0 1.5 Atorvastatin Better Pravastatin Better *mmol/L (mg/dL) Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.

  18. Safety: Adverse Events Atorvastatin Pravastatin 80 mg 40 mg P-value Discontinued due to AEs 1 y 22.8% 21.4% 0.30 2 y 30.4% 33.0% 0.11 ALT elevation > 3 x ULN 3.3% 1.1% < 0.001 Dosage reduction* 1.9% 1.4% 0.20 Discontinued for myalgia/CPK 3.3% 2.7% 0.23 There were no cases of rhabdomyolysis in either group. *Dosage reduced due to side effects or liver function abnormalities. AE, adverse event; ALT, alanine aminotransferase; ULN, upper limit of normal; CPK, creatinine phosphokinase. Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.

  19. Summary • PROVE IT is the first head-to-head morbidity and mortality trial involving statins • Atorvastatin 80 mg/d demonstrated superior clinical benefits over pravastatin 40 mg/d and a comparable safety profile in patients with ACS • Superiority of atorvastatin 80 mg/d began to emerge at 30 days, was significant at 180 days, and was maintained throughout the study • Results especially compelling given the short duration and study design Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.

  20. PROVE IT Supports and Extends Results From REVERSAL • PROVE IT demonstrates that the difference between atorvastatin 80 mg and pravastatin 40 mg in effects on atherosclerotic progression translate to differences in effects on CV end points in patients with ACS • PROVE IT confirms the findings from REVERSAL: atorvastatin 80 mg has a comparable safety profile to pravastatin 40 mg • Results of PROVE IT substantiate the use of IVUS in the REVERSAL study as an early predictive tool for assessing the clinical benefits of a cardiopreventive intervention Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. N Engl J Med. 2004;350:1495-1504.

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