Trial The lower, The better Is it True for Plaque Regression? Statin alone versus Combination of Ezetimibe and Statin Juntendo University, Department of Cardiology, Tokyo, Japan Katsumi Miyauchi, Naohisa Nakajima, Satoshi Suwa, Hiroyuki Daida
Presenter Disclosure Information < Katsumi Miyauchi, MD > The following relationships exist related to this presentation: : FINANCIAL DISCLOSURES Honoraria MSD K.K. Bayer Health Care ASTELLAS Inc Pfizer Inc. 2
% Change in Plaque Volume Statin Reduced Plaque Volume ESTABLISH and JAPAN-ACS Control Atorvastatin 20mg Pitavastatin 4mg Atorvastatin 20mg Okazaki S et al. Circulation. 2004; 110: 1061-1068, Hiro T et al. J Am Coll Cardiol 2009; 54: 293-302 3
Percent change in plaque volume (%) Plaque Change Correlated with LDL-C ESTABLISH 40 30 20 10 0-80 -60-40 -20 0 20 40 60-10 -20-30 y = 0.3589x + 5.4008 R=0.612 p<0.0001-40 Percent change in LDL-cholesterol (%) Okazaki S et al. Circulation. 2004; 110: 1061-1068 4
Plaque Change Correlated with LDL-C 1.8 1.2 CAMELOT placebo REVERSAL pravastatin Median Change In Percent Atheroma Volume (%) -0.6 0.6 0 REVERSAL atorvastatin ASTEROID rosuvastatin A-Plus placebo -1.2 50 60 70 80 90 100 110 120 Mean Low-Density Lipoprotein Cholesterol (mg/dl) Nissen, S. E. et al. JAMA 2006; 295: 1556-65 ACTIVATE placebo r 2 = 0.95 p<0.001 5
Introductions These IVUS studies suggest the need for intensive lipid lowering therapy in patients with CAD in order to reduce coronary plaque volume. However, these studies used maximum doses of statin alone and did not investigate the potential effect of more aggressive lipid lowering therapy. So, the next clinical question is whether further or more aggressive lipid-lowering therapy than statin alone would further reduce the coronary plaque volume. 6
Introductions In clinical practice, lipid lowering therapy with statin alone is limited, for example maximum doses of statin achieved 70mg/dl of LDL-C level. The combination of ezetimibe and statin produces greater reductions in LDL-C compared to statin alone. 7
Aims The goal of this study is to determine whether combination therapy of ezetimibe plus a statin was superior a statin alone in reducing plaque volume in Japanese patients with acute coronary syndrome (ACS) undergoing successfully percutaneous coronary intervention (PCI). We hypothesized very aggressive reduction of the LDL- C with combination ezetimibe and statin could induce a greater degree of plaque regression in ACS patients compared to statin alone.. 8
Study Design Atorvastatin + Ezetimibe n=51 Atorvastatin N=44 Ext-ESTABLISH R Control N=56 Historical control 9
Study Design Atorvastatin + Ezetimibe n=51 ACS Control n=56 Atorvastatin 20mg/day n=44 24-weeks Historical Control PCI IVUS Study period : 2008.12.1. 2010.5.31. Study chair : Daida, H. Co-Director: : Miyauchi, K. Suwa S. IVUS Core Lab: Yokoyama, T. Secretary: Nozawa, Y. IVUS 10
Primary Endpoint = % Change in Plaque Volume (%) plaque volume at follow up - plaque volume at baseline plaque volume at baseline X 100 Follow up - Baseline = Baseline X 100 11
IVUS Imaging 4 5 6 7 8 3 2 1 2 3 4 5 6 7 8 9 10 11 9 10 1 11 Okazaki S et al. Circulation. 2004; 110: 1061-1068 12
Baseline Characteristics Control (n=56) Statin (n=44) Combination (n=51) P Age (years) 62.5±1.45 61.2±1.67 63.3±1.55 0.65 Gender (Male) 80.4 84.1 80.4 0.86 BMI 24.2±0.46 24.9±0.52 23.6±0.48 0.20 Diabetes (%) 35.7 40.9 27.5 0.37 Hypertension(%) 51.8 67.4 70.6 0.10 MetS (%) 46.0 44.3 44.1 0.88 Family History(%) 34.5 28.6 38.2 0.45 Smoking (%) 36.5 31.4 41.2 0.66 13
Baseline Characteristics Control (n=56) Statin (n=44) Combination (n=51) P TC (mg/dl) 193.2±4.9 184.6±5.5 187.0±5.1 0.47 LDL (mg/dl) 127.5±4.2 114.9±4.7 116.1±4.4 0.83 TG (mg/dl) 108.0±8.3 117.0±9.3 105.7±8.6 0.65 HDL (mg/dl) 43.5±1.8 45.7±2.0 50.3±1.9 0.032 non-hdl (mg/dl) 149.6±4.8 139.0±5.4 136.7±5.0 0.14 hs-crp (mg/dl) 0.6±0.31 0.8±0.33 1.8±0.31 0.024 HbA1c (%) 5.8±0.2 5.9±0.2 5.8±0.2 0.96 14
Baseline Characteristics Control n=56 Statin n=44 Combination n=51 P Type of ACS STEMI (%) 44.6 45.5 45.1 0.66 NSTEMI (%) 21.4 13.6 19.6 UAP (%) 33.9 40.9 35.3 Concomitant Drugs at Discharge ACEI (%) 21.4 18.1 19.6 0.63 ARB (%) 35.7 40.0 49.0 0.44 β-blocker (%) 39.2 45.5 52.9 0.31 15
Baseline IVUS Characteristics Control (n=56) Statin (n=44) Combination (n=51) P Lesion length 8.19±0.4 8.21±0.5 10.20±0.4 0.0017 Vessel Volume 138.6±9.9 165.7±11.2 155.6±10.4 0.18 Lumen Volume 73.6±5.7 88.1±6.4 82.0±5.9 0.23 Plaque Volume 65.1±5.5 77.55±6.2 73.6±5.7 0.29 16
HDL LDL TG Laboratory Results (Change in Lipid Parameters) 140 120 100 127,5 116,1 114,9 p=0.09 120,2 P<.0001 140,0 120,0 100,0 80,0 60,0 40,0 20,0 P=0.31 126,5 117,0 122,7 108,0 P=0.08 105,7 98,9 P=0.26 80 60 40 P<.0001 72,1 55,0 0,0 52 50 48 46 Baseline 50,3 45,7 P=0.13 P=0.45 Restudy 49,3 48,3 45,7 20 Control Statin Combination 44 42 43,5 P=0.06 0 Baseline Restudy 40 Baseline Restudy 17
Laboratory Results (% Change in Lipid Parameters) LDL p<.0001 18
Representative Cases of Volumetric IVUS analysis Control Atorvastatin Combination Baseline After 6months 19
% Change in Plaque Volume % Change in Plaque Volume p<0.0001 p=0.0002 p=0.30 Control Statin Combination n=56 n=54 n=51 Mean±SD 1.8±14.7-9.1±12.3-11.4±14.3 Median (IQR * ) 1.3(-25.6 ~ 45.6) -9.1 (-36.2 ~ -18.2) -12.1(-45.0 ~ 27.0) 20
Relationship Between LDL-C and % Change in Plaque Volume Follow up LDL-C level % change in LDL-C (%) n=151 r=0.32 p<0.0001 (%) n=151 r=0.31 p<0.0001 (mg/dl) (%) 21
Relationship Between % Change in LDL-C and % Change in Plaque Volume Statin and Combination group r=0.02 p=0.88 r=0.15 p=0.14 22
% change in LDL-C LDL-C change in Patients with or without Diabetes Mellitus (%) 0-10 -1.5 ±3.9 n=36 Diabetes ( - ) n=99-0.5 ±5.9 n=20 Diabetes ( + ) n= 52-20 mean±sd ( ): number of patients 2 sample t-test (between groups) -30-40 -50-60 1 sample t-test (each group) *** : p < 0.001 p<.0001-35.0 ±4.6 n=26-51.7 ±3.9 n=37 Control -30.8 ±6.2 n=18 p<.0001 Atorvastatin Combination n=14-57.8 ±7.0 23
Plaque Volume Change in Patients with or without Diabetes Mellitus (%) 4 2.04 ±2.3 2 Diabetes ( - ) n=99 1.1 ±3.3 Diabetes ( + ) n=52 0-2 n=36 n=20-4 -6-8 -10-12 -14-10.5-10.9 ±2.7 ±2.3 n=26 n=37 Control -7.0 ±3.4 p=0.02 n=18 Atorvastatin n=14-12.6 ±3.9 Combination 24
% Change in Plaque Volume % Change in Plaque Volume in Diabetes P=0.01 p=0.15 p=0.05 n=20 n=18 n=14 Control Statin Combination n=20 n=18 n=14 Mean±SD 1.1±13.6-7.0±13.2-12.6±8.6 Median (IQR * ) -0.2(-17.3 ~ 34.8) -9.1 (-35.6 ~ -18.2) -13.8(-40.0~12.0) 25
Conclusions 1. Ezetimibe in combination with a statin is effective in decreasing LDL-C. 2. Early intensive lipid-lowering therapy using atorvastatin or atorvastatin and ezetimibe in patients after ACS results in remarkable regression of coronary plaque volume (PV). 3. Additional LDL-C reduction with ezetimibe and statin provide no statistically significant further plaque regression. 4. However, in diabetic patients, further reduction of LDL-C was associated with a significantly greater reduction in PV. 26