1. Clinical Trial Results. org RAAVE Luis M. Moura, MD; Sandra F. Ramos, MSc; José L. Zamorano, MD, PhD; Isabel M. Barros, MD; Luis F. Azevedo, MD; Francisco Rocha-Gonçalves, MD, PhD; Nalini M. Rajamannan, MD Published in the Journal of the American College of Cardiology February 6, 2007 Rosuvastatin Affecting Aortic Valve Endothelium to Slow the Progressions of Aortic Stenosis: RAAVE

2. Clinical Trial Results. org RAAVE: Background Recent retrospective studies support the hypothesis that statins slow the progression of aortic stenosis.Recent retrospective studies support the hypothesis that statins slow the progression of aortic stenosis. The objective of this study was to test the effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (Rosuvastatin) on the progression of moderate to severe aortic stenosis as measured by echocardiography.The objective of this study was to test the effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (Rosuvastatin) on the progression of moderate to severe aortic stenosis as measured by echocardiography. Recent retrospective studies support the hypothesis that statins slow the progression of aortic stenosis.Recent retrospective studies support the hypothesis that statins slow the progression of aortic stenosis. The objective of this study was to test the effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (Rosuvastatin) on the progression of moderate to severe aortic stenosis as measured by echocardiography.The objective of this study was to test the effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (Rosuvastatin) on the progression of moderate to severe aortic stenosis as measured by echocardiography. Moura, et al. JACC 2007; 49(5): 554-61

3. Clinical Trial Results. org RAAVE: Study Design  Primary Endpoint: Progression of aortic stenosis  Secondary Endpoint: Improvement in inflammatory (serum) markers and improvement in LDL cholesterol  Primary Endpoint: Progression of aortic stenosis  Secondary Endpoint: Improvement in inflammatory (serum) markers and improvement in LDL cholesterol Rosuvastatin (LDL > 130mg/dl) n=61 Rosuvastatin (LDL > 130mg/dl) n=61 Control Group (LDL < 130mg/dl) n=60 Control Group (LDL < 130mg/dl) n=60 121 patients presenting consecutively with moderate to severe aortic stenosis as defined by an aortic valve area between 1.0 and 1.5cm 2 Open-Label. Prospective. Follow-up every 6 months for 18 months Exclusion Criteria: Patients on angiotensin-converting enzyme inhibitors, coronary artery disease as measured by clinical history, echocardiographic evidence of rheumatic mitral valve disease, previous statin therapy, congenital heart disease (bicuspid aortic valve), subaortic obstruction, creatinine > 2.0 mg/dl, active or chronic liver disease, mild aortic regurgitation, and previous aortic valve surgery. 121 patients presenting consecutively with moderate to severe aortic stenosis as defined by an aortic valve area between 1.0 and 1.5cm 2 Open-Label. Prospective. Follow-up every 6 months for 18 months Exclusion Criteria: Patients on angiotensin-converting enzyme inhibitors, coronary artery disease as measured by clinical history, echocardiographic evidence of rheumatic mitral valve disease, previous statin therapy, congenital heart disease (bicuspid aortic valve), subaortic obstruction, creatinine > 2.0 mg/dl, active or chronic liver disease, mild aortic regurgitation, and previous aortic valve surgery. every 6 mos. for 18 mos. Moura, et al. JACC 2007; 49(5): 554-61

4. Clinical Trial Results. org RAAVE: Baseline Characteristics Characteristic Statin Treated n=61Untreatedn=60p-value Age (yrs) 73.4 ± 8.5 73.9 ± 9.4 0.749 Men, n (%) 21 (34.4) 36 (60.0) 0.006 Arterial Hypertension, n (%) 45 (73.8) 32 (53.3) 0.024 Diabetes, n (%) 26 (42.6) 13 (21.7) 0.019 Smokers, n (%) 0 (0) 4 (6.7) 0.057 Total Cholesterol (mg/dl) 243.0 ± 40.5 192.0 ± 45.8 <0.001 Moura, et al. JACC 2007; 49(5): 554-61

5. Clinical Trial Results. org RAAVE: Baseline Characteristics Characteristic Statin Treated n=61Untreatedn=60p-value HDL (mg/dl) 55.0 ± 13.2 53.1 ± 12.2 0.399 LDL (mg/dl) 158.2 ± 31.7 116.5 ± 20.9 <0.001 Peak Jet Velocity (m/s) 3.65 ± 0.64 3.62 ± 0.61 0.788 Peak Gradient (mm Hg) 54.7 ± 18.9 53.9 ± 18.2 0.828 Mean Gradient (mm Hg) 35.3 ± 13.4 36.1 ± 13.4 0.752 Aortic Valve Area (cm 2 ) 1.23 ± 0.42 1.20 ± 0.35 0.636 Moura, et al. JACC 2007; 49(5): 554-61

6. Clinical Trial Results. org RAAVE: Primary Endpoint (Cont’d) Aortic Valve Area (cm 2 /yr) n = 60 Moura, et al. JACC 2007; 49(5): 554-61 Peak Aortic Valve Velocity (m/s/yr) n =61 n = P=0.041 Control Treated n = 60 n =61 P=0.007 Data indicate a slowing of progression of aortic valve disease by echocardiography. Data indicate a slowing of progression of aortic valve disease by echocardiography.

7. Clinical Trial Results. org RAAVE: Primary Endpoint Characteristic Control Group Baseline Follow-Up P-Value Treated Group Baseline Follow-up p-value Peak Jet Velocity (m/s) 3.56 ± 0.56 3.86 ± 0.62 <0.001 3.64 ± 0.65 3.73 ± 0.74 0.112 Peak Gradient (mm HG) 52.1 ± 16.2 61.3 ± 19.4 <0.001 54.3 ± 19.1 57.7 ± 22.3 0.072 Mean Gradient 34.7 ± 12.1 40.4 ± 14.7 <0.001 34.9 ± 13.7 39.1 ± 16.6 0.004 Aortic Valve Area 1.24 ± 0.35 1.11 ± 0.35 <0.001 1.22 ± 0.40 1.16 ± 0.42 0.010 Moura, et al. JACC 2007; 49(5): 554-61

8. Clinical Trial Results. org RAAVE: Secondary Endpoints Characteristic Control Group Baseline Follow-Up p-val Treated Group Baseline Follow-Up p-value Cholesterol (mg/dl) 193.7 ± 47.9 195.1 ± 37.1 0.830 245.5 ± 41.7 175.4 ± 31.6 <0.001 LDL (mg/dl) 118.6 ± 37.4 117.8 ± 29.2 0.882 159.7 ± 33.4 93.3 ± 21.1 <0.001 Triglycerides (mg/dl) 116.2 ± 71.1 116.7 ± 60.0 0.945 153.9 ± 107.8 124.0 ± 57.8 0.003 HS-CRP (mg/l) 2.4 (1.0-6.9) 1.9(0.8-4.9)0.3632.7(1.1-6.9)2.3(0.9-5.10.030 IL-612.5(9.8-19.1)2.9(2.9-7.8)<0.00112.7(9.4-18.0)2.9(2.9-5.2)<0.001 sCD40L 2.01 ± 0.97 0.93 ± 0.55 <0.001 2.36 ± 1.04 1.06 ± 0.93 <0.001 HS-CRP=high-sensitivity C-reactive protein, IL-6=Interleukin 6, sCD40L=soluble cd40 ligand Moura, et al. JACC 2007; 49(5): 554-61

9. Clinical Trial Results. org RAAVE: Secondary Endpoints (cont’d) Treated patients had lowering of all the serum markers: total cholesterol, LDL cholesterol, triglycerides, hsCRP, IL-6, and sCD40L.Treated patients had lowering of all the serum markers: total cholesterol, LDL cholesterol, triglycerides, hsCRP, IL-6, and sCD40L. Moura, et al. JACC 2007; 49(5): 554-61

10. Clinical Trial Results. org RAAVE: Limitations This was a relatively small prospective trial that did not take into account timing of therapy and characteristics of the valve lesion.This was a relatively small prospective trial that did not take into account timing of therapy and characteristics of the valve lesion. Moura, et al. JACC 2007; 49(5): 554-61

11. Clinical Trial Results. org RAAVE: Summary The clinical, epidemiologic, and experimental evidence of this prospective study suggests that aortic valve stenosis progression can be slowed with the treatment of statins.The clinical, epidemiologic, and experimental evidence of this prospective study suggests that aortic valve stenosis progression can be slowed with the treatment of statins. The RAAVE study also suggests that earlier treatment with statins is more efficacious in the prevention of progression of aortic valve stenosis than late treatment.The RAAVE study also suggests that earlier treatment with statins is more efficacious in the prevention of progression of aortic valve stenosis than late treatment. The clinical, epidemiologic, and experimental evidence of this prospective study suggests that aortic valve stenosis progression can be slowed with the treatment of statins.The clinical, epidemiologic, and experimental evidence of this prospective study suggests that aortic valve stenosis progression can be slowed with the treatment of statins. The RAAVE study also suggests that earlier treatment with statins is more efficacious in the prevention of progression of aortic valve stenosis than late treatment.The RAAVE study also suggests that earlier treatment with statins is more efficacious in the prevention of progression of aortic valve stenosis than late treatment. Moura, et al. JACC 2007; 49(5): 554-61