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The REVERSAL Trial

The REVERSAL Trial. Reversing Atherosclerosis With Aggressive Lipid Lowering. Atherosclerosis: A Progressive Process. PHASE I: Initiation PHASE II: Progression PHASE III: Complication. Disease progression. Effects of Lipid-Lowering Therapy on CHD Events in Statin Trials.

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The REVERSAL Trial

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  1. The REVERSAL Trial Reversing Atherosclerosis With Aggressive Lipid Lowering

  2. Atherosclerosis: A Progressive Process PHASE I: Initiation PHASE II: Progression PHASE III: Complication Disease progression

  3. Effects of Lipid-Lowering Therapy on CHD Events in Statin Trials Secondary 4S - P 25 prevention Primary 20 prevention 4S - S Simvastatin LIPID - P 15 CARE - P Pravastatin Patients with CHD event (%) HPS - P Lovastatin LIPID - S 10 WOSCOPS - P Atorvastatin CARE - S WOSCOPS - S HPS - S * ASCOT - P S = statin-treated 5 * ASCOT - S P = placebo-treated AFCAPS - P AFCAPS - S *Extrapolated to 5 y 0 90 110 130 150 170 190 210 LDL-C (mg/dL) Modified from Kastelein JJP. Atherosclerosis. 1999;143(suppl 1): S17-S21.

  4. What Is REVERSAL? • Multicenter, randomized, double-blind, active- controlled trial • Comparing the effects of atorvastatin 80 mg/d with pravastatin 40 mg/d administered for 18 months • Using IVUS to measure progression of atherosclerosis

  5. Effects of Lipid Lowering With Statins on Progression of CHD 0.06 Drug Placebo PLAC I 0.05 CCAIT REGRESS 0.04 LCAS PLAC I 0.03 Progression (MLD decrease), mm/y MARS MAAS CCAIT 0.02 MARS REGRESS LCAS 0.01 MAAS 0 -40 -30 -20 -10 0 10 LDL-C reduction (%)

  6. REVERSAL: Study Design Double-blind period Screeningvisit* Placeborun-inphase Atorvastatin 80 mg/d Randomization 654 patients Pravastatin 40 mg/d *Includes baseline IVUS 18-month follow-up with IVUS Design: Prospective, multicenter, randomized, double-blind trial Setting: 34 community and tertiary-care hospitals in the USA

  7. REVERSAL: Study Objective To compare the effects of aggressive lipid-lowering therapy (atorvastatin 80 mg/d) vs moderate lipid-lowering therapy (pravastatin 40 mg/d) on percent change in TAV using IVUS imaging of the coronary arteries in patients with CHD

  8. REVERSAL: Why Was Pravastatin 40 mg Used? • REVERSAL is the first active-controlled, cholesterol- lowering, coronary atherosclerosis progression trial • Previous large-scale trials used placebo as a comparator • Pravastatin has an indication to slow progression of atherosclerosis based on angiographic studies • PLAC I: 264 patients for 3 y vs placebo • REGRESS: 885 patients for 2 y vs placebo • 40 mg was the highest approved dose of pravastatin at the initiation of REVERSAL

  9. REVERSAL: Patient Population • Inclusion criteria: • Patients requiring diagnostic coronary angiography for a clinical indication • Aged 30-75 y • LDL-C  3.2 mmol/L (125 mg/dL) but  5.4 mmol/L (210 mg/dL) • TGs < 6.8 mmol/L (600 mg/dL) • Angiographic inclusion criteria: • Angiographic evidence of CHD defined as  1 lesion with  20% reduction in lumen diameter in any coronary artery •  50% reduction in lumen diameter of the left main coronary artery • The vessel undergoing IVUS evaluation (the “target” vessel) should have  50% stenosis throughout a segment of minimum length 30 mm

  10. REVERSAL: Patient Population • Exclusion criteria: • Target vessel was considered suitable only if the artery had not undergone PTCA or CABG surgery • Left ventricular ejection fraction of < 0.4 • Moderate or more severe CHF • Clinically significant valvular heart disease • Uncontrolled hypertension • Second- or third-degree heart block • Sustained ventricular tachyarrhythmia or an implantedcardiac defibrillator • Known major hematologic, neoplastic, metabolic, gastrointestinal, or endocrine dysfunction

  11. What Is TAV?

  12. REVERSAL: Primary Efficacy Parameter The percent change from baseline in TAV for all slices of anatomically comparable segments of the target coronary artery as measured by IVUS

  13. REVERSAL: Selected Secondary Efficacy Parameters • Nominal change from baseline in TAV • Change from baseline in PAV • Change from baseline in lipid parameters • Change from baseline in CRP

  14. REVERSAL: Baseline Characteristics Characteristic Atorvastatin 80 mg (n = 253) Pravastatin 40 mg (n = 249) 55.8 ± 9.8 71 90 30.5 ± 6.5 26 20 68 6.0 ± 0.9][231.8 ± 34.2] 3.9 ± 0.7 [150.2 ± 27.9] 2.2 ± 1.2 [197.2 ± 95.7] 1.1 ± 0.3 [42.3 ± 9.9] Age* (y) Male (%) White (%) BMI* (kg/m2) Current smoker (%) Diabetes (%) Hypertension (%) TC* (mmol/L [mg/dL]) LDL-C* (mmol/L [mg/dL]) TG* (mmol/L [mg/dL]) HDL-C* (mmol/L [mg/dL]) 56.6±9.2 73 87 30.5±5.6 27 18 70 6.0 ± 0.9 [232.6 ± 34.1] 3.9 ± 0.7 [150.2 ± 25.9] 2.2 ± 1.1 [197.7 ± 105.6] 1.1 ± 0.3 [42.9 ± 11.4] *Mean ± SD.

  15. Change From Baseline in Lipid Parameters 10 2.9 5.6 0 -6.8 -10 -20 -18.4 Change from baseline (%) -20.0* Pravastatin -25.2 -30 Atorvastatin -34.1* -40 -46.3* -50 TC LDL-C TGs HDL-C *P < 0.001 vs pravastatin. Data are mean percent change from baseline to 18-month follow-up.

  16. P = 0.02 Primary End Point: Percent Change in TAV 3 2.7* 2 Change in TAV (%) 1 0 -0.4† -1 Pravastatin Atorvastatin No significant change frombaseline; atheroscleroticprogression was stopped Significant atheroscleroticprogression from baseline *Progression vs baseline (P = 0.001);†No change vs baseline (P = 0.98).

  17. P < 0.001 Secondary Efficacy Parameters Nominal change in TAV Change in PAV P = 0.02 5 1.8 1.6* 4.4* 1.6* 4 1.5 3 1.2 2 % mm3 0.9 1 0.6 0 0.2† 0.2† 0.3 -1 -0.9† -0.9† -2 0 Atorvastatin Pravastatin Pravastatin Atorvastatin *Progression vs baseline (P = 0.01).†No change vs baseline (P = 0.72). *Progression vs baseline (P < 0.001).†No change vs baseline (P = 0.18).

  18. Change in CRP Levels From Baseline CRP (mg/L) Pravastatin Atorvastatin Baseline 3.0 2.8 18 months 2.9 1.8 0 -5.2 -10 Change (%) -20 -30 -36.4* -40 Pravastatin Atorvastatin *P < 0.001 vs pravastatin.

  19. Nominal Change in TAV for 10-mm Vessel Subsegment With Greatest Disease Severity 0 -1 -1.2* -2 mm3 -3 -4 -4.2† -5 P = 0.01 Atorvastatin Pravastatin *Regression vs baseline (P = 0.049). †Regression vs baseline (P < 0.001).

  20. Selected Prespecified Subgroup Analyses 5 4.8* 4 3.9* 3.2† 3.2* 3 2.5* 2.3† 2.1‡ 2 1 0.7‡ 0.7‡ 0.5‡ 0.2‡ Change in TAV (%) 0 -0.2‡ -1 -0.8‡ -1.2‡ -1.5‡ -2 -2.3‡ -3 -4 Yes No Yes No  Median < Median Male Female Diabetes Metabolic syndrome Age Gender *P  0.01 for progression. †P  0.05 for progression. ‡P = NS for progression. Pravastatin Atorvastatin

  21. Percent Change in TAV Among Patients Reaching NCEP ATP III Goal Subgroup reaching NCEP ATP III goal (< 2.59 mmol/L [100 mg/dL]) 161/249 (65%) pravastatin patients (mean LDL-C = 2.27 mmol/L [87.5 mg/dL]) 246/253 (97%) atorvastatin patients (mean LDL-C = 1.75 mmol/L [67.7 mg/dL]) 3 1.9* 2 Change in TAV (%) 1 0 -1 -0.9† Pravastatin Atorvastatin Significant atherosclerotic progression from baseline occurred even among pravastatin patients reaching NCEP ATP III goal *Progression vs baseline (P = 0.01); †No change vs baseline (P = 0.93).

  22. Comparison of LDL-C Reduction and Change in Atheroma Volume Both treatment groups (n = 502) 20 15 10 5 Change in atheroma volume (mm3) 0 -5 -10 -15 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 % change in LDL-C Regardless of the agent used, an LDL-C reduction of at least 50% was required to halt progression The dashed lines indicate upper and lower 95% CIs for the mean values.Nissen SE, et al. JAMA. 2004;291:1071-1080.

  23. -80 -80 -70 -70 -60 -60 -50 -50 -40 -40 -30 -30 -20 -20 -10 -10 0 0 10 10 20 20 Comparison of LDL-C Reduction and Change in Atheroma Volume Pravastatin group (n = 249) Atorvastatin group (n = 253) 20 15 10 5 Change in atheroma volume (mm3) 0 -5 -15 -20 % change in LDL-C Patients receiving pravastatin who experienced LDL-C reductions > 50% continued to show disease progression The progression rate at any level of LDL-C reduction was lower with atorvastatin than with pravastatin The dashed lines indicate upper and lower 95% CIs for the mean values.Nissen SE, et al. JAMA. 2004;291:1071-1080.

  24. Safety—AEs Atorvastatin 80 mg (n = 327) Pravastatin 40 mg (n = 327) Cardiovascular end point Death (any cause), n (%) 1 (0.3%) 1 (0.3%) MI, n (%) 4 (1.2%) 7 (2.1%) Stroke, n (%) 1 (0.3%) 1 (0.3%) Laboratory abnormality ALT > 3 ULN, n (%) 7/311 (2.3%) 5/316 (1.6%) AST > 3 ULN, n (%) 2/311 (0.6%) 2/316 (0.6%) CPK > 10 ULN, n (%) 0/311 (0%) 0/316 (0%) • Rates of CV end points were similar between groups • Rates of liver- and muscle-enzyme abnormalities were low and similar between groups

  25. Safety—Drug Discontinuations Atorvastatin 80 mg (n = 327) Pravastatin 40 mg (n = 327) Drug discontinuation, n (%) 21 (6.4) 22 (6.7) Musculoskeletal complaint, n (%) 9 (2.8) 12 (3.4) Abdominal complaint, n (%) 3 (0.9) 5 (1.5) Cancer, n (%) 0 2 (0.6) Chest pain, n (%) 0 2 (0.6) ALT/AST < 3 ULN, n (%) 4 (1.2) 0 Other, n (%) 5 (1.5) 1 (0.6)

  26. Summary and Conclusions • First large-scale trial to compare the impact of 2 statins on atherosclerotic disease progression by using IVUS, a more sensitive approach than QCA, to measure plaque burden • There was no change in TAV in the atorvastatin 80-mg group, indicating that atorvastatin stopped the progression of atherosclerosis • Atorvastatin significantly impacted LDL-C, TGs, and the biomarker CRP to a greater extent than did pravastatin • The safety profile of atorvastatin 80 mg was comparable to that of pravastatin 40 mg Treatment with atorvastatin stopped further progression of atherosclerosis

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