대한심장학회춘계학술대회 Satellite Symposium

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1 대한심장학회춘계학술대회 Satellite Symposium Coronary Plaque Regression and Compositional Changes by Lipid-Lowering Therapy: IVUS Substudy in Livalo (Pitavastatin) in Acute Myocardial Infarction Study (LAMIS) Livalo Acute Myocardial Infarction Study (LAMIS) Group : Young Joon Hong, Myung Ho Jeong, Youngkeun Ahn, Tae Hoon Ahn, Jang Ho Bae, Seung Ho Hur, Seung Woon Rha, Kee Sik Kim, In Ho Chae, Jong Hyun Kim, Kyeong Ho Yun, Sang Wook Kim

2 Plaque Regression by Statin Atherosclerosis is usually viewed as a chronic progressive disease characterized by continuous accumulation of atheroma within the arterial wall. Intravascular ultrasound (IVUS) has emerged as the most sensitive and reliable measure of the progression of coronary disease. Prior angiographic and IVUS trials have shown reduced progression of coronary atherosclerosis with statin therapy.

3 Lipid Lowering and Plaque Regression: Monotherapy Studies Treatment group % Stenosis %Event Study Regimen LDL-C (P ) reduction NHLBI II D + R STARS D + R (<0.01) 89 Heidelberg D + E 8 4.0(0.05) -27* CCAIT D+L (0.039) 039) MARS D + L BECAIT D + F LCAS D + Fl (0.043) 33 Post-CABG D + L (0.001) *A -27% reduction means a 27% increase (NS). D=diet; R=resin; E=exercise program; F=fibrate-type drug; Fl=fluvastatin; L=lovastatin. Levine GN et al. N Engl J Med. 1995;332: Brown BG, Fuster V. In Fuster V et al, eds. Atherosclerosis and Coronary Artery Disease. Philadelphia, Lippincott-Raven, p Jukema JW et al. Circulation. 1995;91: Post-CABG Investigators. N Engl J Med. 1997;336:

4 Lipid Lowering and Plaque Regression: Combination Therapy Studies Treatment group % Stenosis % Event Study Regimen LDL (P ) reduction CLAS I D + R + N POSCH (5y) D+PIB± R (62) Lifestyle V + M + E (0.001) FATS (N+C) D + R + N (0.005) 80 FATS (L+C) D+R+L (0.02) 02) 70 CLAS II D + R + N USCF-SCOR D + R + N ± L (0.04) SCRIP D+(R+N+L+F)+E, BP HARP D+P+N+C+F Post-CABG D+L+C C=cholestyramine; D=diet; E=exercise program; F=fibrate-type drug; L=lovastatin; M=relaxation techniques; N=nicotinic acid; P= pravastatin; PIB=partial ileal bypass; R=resin; V=vegetarian diet. Levine GN et al. N Engl J Med. 1995;332: Brown BG, Fuster V. In: Fuster V et al, eds. Atherosclerosis and Coronary Artery Disease. Philadelphia, Lippincott-Raven, p. 194.

5 IVUS: Normal and diseased anatomy Aventitia EEM Border Media Intima Lumen Catheter Guide wire Wire Sh d Shadow Normal Anatomy Concentric Disease Eccentric Disease

6 Analysis of atheroma area Atheroma area = (EEM area) (Lumen area)

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8 ASTEROID Trial (40mg Rosuvastatin) Frequency of Regression vs. Progression of Plaque Volume (%) Modified from Nissen et al. JAMA 2006:295;

9 Recent Coronary IVUS Progression Trials Relationship between LDL-C and Progression Rate CAMELOT placebo REVERSAL pravastatin Median Change in Percent Atheroma Volume (%) ASTEROID rosuvastatin REVERSAL atorvastatin A-Plus placebo ACTIVATE placebo r 2 = 0.95 p< Mean Low-Density Lipoprotein Cholesterol (mg/dl)

10 Basis for Study of Atheroma Burden

11 IVUS Plaque Progression vs. Actual CV Events Chang ge in %Pl laque Are ea (%) Regression Progression CV Events of Individual Pts Modified from von Birgelen et al. Circulation 2004:110;

12 Relationship Between Plaque Progression and Clinical Events % P&M/yr Adverse events No adverse events Any event* (n=18) MI (n=5) MI/USA (n=12) *Death, MI, USA, or PCI

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16 The Effect of Rosuvastatin 20 mg and Atorvastatin 40 mg on Plaque Regression in Patients with Mild to Moderate Degree of Coronary Stenosis Hong YJ et al., Korean Circ J 2008;38: , Presented at AHA 2009

17 Baseline Follow up

18 Baseline Follow up mm mm2 Plaque burden 67% Plaque burden 63% Rosuvastatin 20mg/d

19 Changes of Lipid Profiles at Follow-up Follow-up duration: 11.0±6.9 months in Rosuvastatin vs. 11.3±8.1 months in Atorvastatin (mg/dl) 60 P=0.3 P=0.5 P=0.13 P= Rosuvastatin(n=44) Atorvastatin(n=36) TC TG LDL-C HDL-C

20 Changes of LDL-Cholesterol at Follow-up (mg/dl) % From baseline to FU Rosuvastatin(n=44) P< % P=0.4 0 Baseline Follow-up Atorvastatin(n=36) P<0.001 Follow-up duration: 11.0±6.9 months in Rosuvastatin vs. 11.3±8.1 months in Atorvastatin

21 Follow-up LDL-Cholesterol < 70mg/dl Follow-up duration: 11.0±6.9 months in Rosuvastatin vs. 11.3±8.1 months in Atorvastatin (%) 100 P= Rosuvastatin (n=44) Atorvastatin (n=36)

22 (mg/dl) Changes of Apo-B/A1 at Follow-up 1.2 From baseline to FU 1 36% Rosuvastatin(n=44) P< Atorvastatin(n=36) P< % P=0.5 0 Baseline Follow-up Follow-up duration: 11.0±6.9 months in Rosuvastatin vs. 11.3±8.1 months in Atorvastatin

23 Changes of Volumetric IVUS Parameters at tfollow-up Follow-up duration: 11.0±6.9 months in Rosuvastatin vs. 11.3±8.1 months in Atorvastatin P=0.5 P=0.057 P=0.2 Vo olume (m mm 3 ) Rosuvastatin(n=63) Atorvastatin(n=57) Vessel Lumen Atheroma

24 Correlation Between Follow-up LDL-C and Atheroma Volume r=0.274 P=0.003

25 Correlation Between Follow-up Apo B/A1 and Atheroma Volume r=0.234 P=0.011

26 Conclusion Plaque Regression by Statin in Native Coronary Artery Both rosuvastatin 20 mg and atorvastatin 40 mg could contribute to the regression in Korean patients t with mild to moderate stenosis.

27 Laboratory Findings vs. Plaque Progression in Patients Who Use Moderate Dose of Statins

28 128 patients t who underwent baseline and followup IVUS (mean 11 months) for non-intervened intermediate t coronary stenosis 66 patients received 20mg/day of rosuvastatin and 62 patients received 40mg/day of atorvastatin from baseline to follow-up. - Plaque volume progression group (n=29): 23% - Plaque volume regression group (n=99): 77%

29 (mg/dl) Follow-Up LDL-Cholesterol 120 p= Plaque progression (n=29) Plaque regression (n=99)

30 Plaque Progression According to (%) Follow-Up LDL-Cholesterol (17/50) p= Follow-up LDL-cholesterol 70 mg/dl 15 (12/78) Follow-up LDL-cholesterol < 70 mg/dl

31 (mg/dl) 5 Baseline hs-crp p= Plaque progression (n=29) 0.54 Plaque regression (n=99)

32 Plaque Progression According to (%) Baseline hs-crp (6/16) p= (23/112) Baseline hs-crp 1.0 mg/dl Baseline hs-crp < 1.0 mg/dl

33 Plaque Progression According to (%) Follow-Up hs-crp p= (11/30) (18/98) 5 0 Follow-up hs-crp 0.1 mg/dl Follow-up hs-crp < 0.1 mg/dl

34 Conclusion Labroratory Findings vs. Plaque Progression by Statin In patients t who use 20mg/day of rosuvastatin and 40mg/day of atorvastatin, follow-up LDL-C and baseline and follow-up hs-crp are associated with plaque progression.

35 Hong YJ et al., J Am Coll Cardiol 2009;53:

36 5 r= P<0.001 Plaqu ue area (mm 2 ) Follow-up LDL-cholesterol (mg/dl)

37 eline) area (mm m 2 ) (follow w-up min nus bas 2 SVG Lumen Plaque 1.5 P=0.177 P=0.001 P< ±1.09 ±1.20 ±1.44 ±0.53 ±1.02 ±1.04 FU LDL-cholesterol 100 mg/dl (n=31) FU LDL-cholesterol <100 mg/dl (n=19)

38 eline) area (mm m 2 ) (follow w-up min nus bas SVG Lumen Plaque P=0.363 P=0.095 P= ±1.22 ±0.75 ±1.21 ±1.40 ±1.24 ±0.83 (+) Statin (n=40) ( ) Statin (n 40) (-) Statin (n=10)

39 Conclusion - SVG Lumen loss in non-intervened SVG segments correlated with an increase in plaque area and a decrease in SVG area (plaque growth and negative e remodeling) with a linear relationship between plaque growth vs. follow-up LDL-cholesterol leading to long-term lumen loss.

40 Baseline Plaque Components vs. on Plaque Progression in Patients with Angina Pectoris Who Uses Usual Dose of Rosuvastatin

41 66 patients who underwent baseline and 9-month follow-up VH-IVUS for non-intervened intermediate coronary stenosis Patients with angina pectoris who used 10 mg/d of rosuvastatin At the baseline minimum lumen area (MLA) site - Plaque progression group (n=22) - Plaque regression group (n=44)

42 Plaque Progression at 9-Month Follow-Up Baseline Follow-up

43 Plaque Regression at 9-Month Follow-Up Baseline Follow-up

44 9-Month Follow-Up LDL-Cholesterol (mg/dl) 140 p= Plaque progression (n=22) Plaque regression (n=44)

45 (%) 80 p=0.094 Baseline Minimum lumen site Relative plaque area p=0.008 p= p=0.004 Progression (n=22) Regression (n=44) %FT %FF %DC %NC

46 Baseline Thin-Cap Fibroatheroma (%) 40 p= Progression (n=22) Regression (n=44) 9

47 the MLA site (mm 2 ) P P&M CSA at r=0.375 p=0.002 he MLA site (mm 2 ) P& &M CSA at t Baseline %NC area at the MLA site is an independent predictor of plaque progression at follow-up (OR 1.265, 95% CI , 1.497, p=0.006) Baseline %NC area at the MLA site (%) Baseline %FF area at the MLA site (%) r= p=0.001 m 2 ) MLA site (m r= p=0.050 P&M CSA at the Baseline %FT area at the MLA site (%)

48 Conclusion Plaque Components vs. Plaque Progression In patients with angina pectoris who uses usual dose of rosuvastatin and reaches follow-up LDL-cholesterol around 80 mg/dl, baseline NC component is associated with plaque progression.

49 Livalo (Pitavastatin) in Acute Myocardial Infarction Study (LAMIS)

50 IVUS and VH-IVUS analysis in LAMIS (n=50) Pitavastatin 2mg / day Non-culprit, Non-intervened segments

51 Baseline Follow up

52 Baseline Follow up 12.2 mm mm 2 Plaque burden 48% Plaque burden 46%

53 Baseline Follow up

54 Change of LDL-Cholesterol From Baseline to FU (Mean 7.7 Months) 180 estero ol (mg/ /dl) LDL L-chol Baseline 86 Follow-up 30% P<0.001

55 Change of hs-crp From Baseline to FU (Mean 7.7 Months) g/dl) 1.5 hs-c RP (m Baseline Follow-up 70% P<

56 Changes of Grey-Scale IVUS Parameters From Baseline to FU (Mean 7.77 Months) (mm 3 ) Vessel volume Lumen volume Plaque volume PAV (%)

57 Plaque Progression/Regression g at FU (%)

58 Changes of VH-IVUS Parameters From Baseline to FU (Mean 7.77 Months) (mm 3 ) 15 Absolute Plaque Component Fibrotic volume Fibro-fatty volume Dense calcium volume Necrotic core volume

59 Changes of VH-IVUS Parameters From Baseline to FU (Mean 7.77 Months) (%) Relative Plaque Component %Fibrotic volume %Fibro-fatty volume %Dense calcium volume %Necrotic core volume

60 Conclusion IVUS Study in LAMIS Usual dose of pitavastatin (2mg/day) decreased LDL-C and CRP levels effectively It had some effect on plaque regression and compositional change in non-culprit, non-intervened segments in AMI patients. With more intensive dose of statin, plaque regression and plaque compositional change probably could be more rapidly achieved.

61 IVUS/VH-IVUS Intensive lipid-lowering therapy Clinical Event

62 Future Perspectives in LAMIS More long-term follow-up data High dose Livalo (4mg) More IVUS and VH-IVUS follow-up data -- Plaque regression -- Plaque compositional change Other imaging i modality: OCT, CT, MR

63 Thank You For Your Attention! LAMIS Group