Role of lipid-lowering therapy
AggressiveAggressive lipid-loweringlipid-lowering therapytherapy withwith “atorvastatin and probucol” for coronary atherosclerosis determined by 3D-IVUS
Nihon University School of Medicine Cardiovascular Division Satoshi Saito MD
NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine Background Glistening yellow
Main findings of the current studies
1) Asakura et al. used angioscoy to show that yellow plaque, indicating potentially vulnerable plaque, was observed with equal frequency in infarct-related and non-infarct-related arteries. 2) Plaque ruptures occur not only in patients with MI or unstable angina, but are also found in patients with stable angina or no symptoms. 3) Multiple ruptuers were seen in 15% of patients in the current population. 4) Ruptured plaques are usually eccentric with positive remodeling.
G.Rioufol et al. Circulation. 2002; 106:804, Moriuchi M, Saito S, et al. Heart and Vessels, 1997 A.Maehara et al. JACC. 2002;40:904, JACC 2002;40:904, JACC 2001, 37:1284
NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine Background SuchSuch lesionslesions frequentlyfrequently appearappear asas non-significantnon-significant oror mildmild toto moderatemoderate stenosisstenosis on on coronarycoronary angiography.angiography. PlaquePlaque rupturerupture ofof thethe lesionlesion leadsleads toto acuteacute coronarycoronary CAG IVUS syndromesyndrome ..
Eccentric soft lesion with lipid pool and positive remodeling
Angiographically non-significant Stenosis
NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine Background
Therefore,Therefore, itit hashas beenbeen emphasizedemphasized thatthat treatmenttreatment toto achieveachieve lesionlesion stabilitystability and/orand/or regressionregression iiss beneficial.beneficial.
LargeLarge primaryprimary andand secondarysecondary preventionprevention trialstrials withwith StatinStatin have have demonstrateddemonstrated thatthat lipid-loweringlipid-lowering therapytherapy waswas effectiveeffective oror preventingpreventing cardiaccardiac events.events.
NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine Background
Recent studies show that
1) Aggressive LDL-C lowering with HMG-CoA reductase inhibition, atorvastatin, likely leads to a slowdown of plaque growth and a change in plaque composition.(GAIN) 2) Reversal study 3) Probucol has been reported to prevent atherogenesis by acting as an anti-oxidant and suppressing the oxidative modification of LDL-C and Probucol could stabilize plaque.
M. Schartl et al. Circulation; 104:387 Y. Sasayama et al. JACC; 39:610
NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine REVERSALREVERSAL
The REVERSing Atherosclerosis with Aggressive Lipid Lowering Study
Nissen SE et al. JAMA 2004 291:1071-80 NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine REVERSALREVERSAL trialtrial
1.1. 654 654 patientspatients enrolledenrolled andand 502502 hadhad evaluatedevaluated byby IVUSIVUS atat baselinebaseline andand 18mo18mo followfollow upup afterafter lipidlipid loweringlowering therapytherapy withwith PravastatinPravastatin 40mg 40mg oror AtorvastatinAtorvastatin 80mg 80mg forfor thethe patientspatients withwith coronarycoronary arteryartery disease.disease.
•• VolumetricVolumetric IVUSIVUS analysisanalysis waswas performedperformed forfor plaqueplaque volume.volume.
Nissen SE et al. JAMA 2004 291:1071-80 NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine ᰂᎌ ᎌ᎙ ᎊᎯᎨᎵᎮᎬᎺ፧ᎶᎭ፧᎗ᎳᎨᎸᎼᎬ፧ᎽᎶᎳᎼᎴᎬ ᎈ᎓ ̜Ǣ˨ƥᬡŬǃŸᯘȫÜ᭓ᮞ᭴ᮈᮞ᭳ᯙ wGOdWUWWXQP Z YU^ w ̜ h Ǣ Y ˨ dWUWY† ƥ ᬡ The plaques in Pravastatin group still Ŭ X progressed, however the progression ǃ rather stopped in Atorvastatin group. Ÿ W Changes of plaque volume plaque of Changes TWU[ TX uGGOdWU`_QP
Q ~ GG Nissen SE et al. JAMA 2004 291:1071-80 † ~ GG NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine Background
Recent studies show that
1) Aggressive LDL-C lowering with HMG-CoA reductase inhibition, atorvastatin, likely leads to a slowdown of plaque growth and a change in plaque composition. (GAIN) 2) Reversal study 3) Probucol has been reported to prevent atherogenesis by acting as an anti-oxidant and suppressing the oxidative modification of LDL-C and Probucol could stabilize plaque.
M. Schartl et al. Circulation; 104:387 Y. Sasayama et al. JACC; 39:610
NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine TherapeuticTherapeutic StrategyStrategy ofof ACSACS
Aggressive LDL-C lowering
Suppressing the oxidative modification of LDL-C
NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine PurposePurpose
ToTo evaluateevaluate thethe combinedcombined effectseffects ofof aggressiveaggressive LDL-CLDL-C loweringlowering therapytherapy withwith atorvastatinatorvastatin and and anti-oxidantanti-oxidant therapytherapy withwith probucolprobucol onon changeschanges inin plaqueplaque volumevolume andand echogenicityechogenicity by by intravascularintravascular ultrasoundultrasound (IVUS).(IVUS).
NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine Methods:Methods: PatientsPatients
1.1. 65 65 non-culpritnon-culprit lesionslesions inin patientspatients withwith ACSACS 2.2. Mild Mild toto moderatemoderate lesionlesion (<(< 50%50% onon QCA)QCA) 3.3. Baseline Baseline andand follow-upfollow-up studiesstudies (>(> 66 months)months) withwith CAGCAG andand IVUSIVUS (volmetric(volmetric and and densitometricdensitometric analysis)analysis) 4.4. 3 3 groupsgroups accordingaccording toto LDL-CLDL-C level:level: GroupGroup AA (Atorvastatin):(Atorvastatin): LDL-CLDL-C 140140 mg/dlmg/dl GroupGroup PP (Probucol):(Probucol): LDL-CLDL-C << 140140 mg/dlmg/dl GroupGroup A+P:A+P: LDL-CLDL-C 140140 mg/dlmg/dl
NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine Methods:Methods: StudyStudy DesignDesign
Medication:Medication: GroupGroup A:A: atorvastatinatorvastatin 10mg/day 10mg/day GroupGroup P:P: probucolprobucol 500mg/day500mg/day GroupGroup A+P:A+P: atorvastatinatorvastatin 10mg/day 10mg/day andand probucolprobucol 500mg/day500mg/day
NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine IVUSIVUS analysisanalysis
1.1. 40MHz 40MHz AtrantisAtrantis (Boston (Boston ScientificScientific ScimedScimed Inc.) Inc.) 2.2. Using Using anan automaticautomatic motormotor drivedrive unitunit andand pull-pull- backback speedspeed atat 0.5mm/sec0.5mm/sec 3.3. Off-line Off-line volumetricvolumetric IVUSIVUS analysisanalysis (Netra(Netra IVUS, IVUS, Scimage)Scimage) LumenLumen volumevolume VesselVessel volumevolume PlaquePlaque volumevolume
NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine TextureTexture VideodensitometricVideodensitometric Analysis Analysis
1.1. Using Using ContrastContrast TimeTime AnalistAnalist in in CardioCardio 20002000 WinWin (Fukuda(Fukuda DenshiDenshi Co.Co. Ltd.)Ltd.) 2.2. Contrast Contrast TimeTime InvestigationInvestigation analyzesanalyzes thethe changechange ofof contrastcontrast (gray(gray values)values) inin aa sequencesequence ofof IVUSIVUS images.images. 3.3. Regions Regions ofof interestinterest (ROI)(ROI) 4.4. Gray Gray scalesscales (between(between blackblack andand white,white, divideddivided intointo 256256 values)values) forfor echogenicity.echogenicity.
NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine TextureTexture VideodensitometricVideodensitometric Analysis Analysis Regions of interest (ROI)
ROIROI plaqueplaque ROIROI adventitiaadventitia Average gray scale of the lesion for plaque echogenicity.
NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine PatientPatient CharacteristicsCharacteristics GroupGroup AA GroupGroup PP GroupGroup A+PA+P (n=23)(n=23) (n=21) (n=21) (n=21) (n=21) AgeAge (mean)(mean) 62.2 62.212.012.0 64.4 64.48.38.3 57.6 57.65.25.2 Follow-upFollow-up periodperiod 6.8 6.82.12.1 6.4 6.41.21.2 6.4 6.41.11.1 PreviousPrevious MIMI 5 5 (50%)(50%) 8 8 (80%)(80%) 6 6 (60%)(60%) LADLAD 10 10 (40%)(40%) 8 8 (20%)(20%) 7 7 (30%)(30%) LCXLCX 7 7 (40%)(40%) 6 6 (20%)(20%) 5 5 (20%)(20%) RCARCA 6 6 (20%)(20%) 7 7 (60%)(60%) 9 9 (50%)(50%) SmokingSmoking 15 15 (70%)(70%) 14 14 (80%)(80%) 16 16 (80%)(80%) HyperlipidemiaHyperlipidemia 15 15 (70%)(70%) 14 14 (70%)(70%) 15 15 (80%)(80%) HypertentionHypertention 14 14 (70%)(70%) 9 9 (40%)(40%) 10 10 (40%)(40%) DiabetesDiabetes MellitusMellitus 5 5 (0%)(0%) 7 7 (40%)(40%) 5 5 (20%)(20%) FamilyFamily historyhistory 4 4 (20%)(20%) 3(10%) 3(10%) 4 4 (20%)(20%)
NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine ChangesChanges inin TotalTotal CholesterolCholesterol
250250 200200 ** ** * 150150 * BaselineBaseline 100100 Follow-upFollow-up 5050 00 GroupGroup AA Group Group PP Group Group ** pp << 0.050.05 A+PA+P NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine ChangesChanges inin LDL-CLDL-C
200200
150150 ** ** 100100 * * BaselineBaseline Follow-upFollow-up 5050
00 GroupGroup AA Group Group PP Group Group ** pp << 0.050.05 A+PA+P
NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine %% ChangeChange inin atheromaatheroma volume volume
፹፵፷
፷፵፷
፴፹፵፷ ᎈ፧ᎮᎹᎶᎼᎷ ፴፻፵፷ ᎗፧ᎮᎹᎶᎼᎷ ᎈ፲᎗፧ᎮᎹᎶᎼᎷ ፴፵፷ * ፴፵፷ * p<0.05 ፴፸፷፵፷
NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine %% changechange in in LumenLumen volumevolume
፸፹፵፷
ᎀ፵፷ * ᎈ፧ᎮᎹᎶᎼᎷ ፵፷ ᎗፧ᎮᎹᎶᎼᎷ ᎈ፲᎗፧ᎮᎹᎶᎼᎷ
፺፵፷ * p<0.05 ፷፵፷
NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine %% changeschanges inin vesselvessel volumevolume
፺፵፷
፹፵፷ ᎈ፧ᎮᎹᎶᎼᎷ ᎗፧ᎮᎹᎶᎼᎷ ᎈ፲᎗፧ᎮᎹᎶᎼᎷ ፸፵፷
፷፵፷
NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine % changes in plaque echogenicity (%)
* 100
75
* 50
25
0 Group P Group A Group A+P ** pp << 0.050.05 ImprovementImprovement raterate (%)(%)ᯭᯭ ᯘᯘ PlaquePlaque GVGV (follow)(follow)ᯝᯝPlaquePlaque GVGV (baseline(baselineᯙᯙ // PlaquePlaque GVGV (baseline)(baseline) ᏽᏽ100100
NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine CoronaryCoronary angiographyangiography
BaselineBaseline ProbucolProbucol ++ AtorvastatinAtorvastatin 67y/o,67y/o, MaleMale NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine Changes in Plaque Area and Echogenicity
BeforeBefore treatmenttreatment AtorvastatinAtorvastatin + + ProbucolProbucol
LDL-C 146 mg/dl LDL-C 68 mg/dl
Plaque area:14.96mm2 Plaque area: 13.67mm2 MeanMean graygray value:value: 52.052.0 MeanMean graygray value:value: 65.365.3
M.I.,M.I., 67y.o.67y.o. RCA,RCA, MaleMale NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine 3D-IVUS3D-IVUS measurementsmeasurements LDLLDL 146146 mg/dlmg/dl BaselineBaseline
LDLLDL 6868 mg/dlmg/dl 66 momo f/pf/p
NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine SummarySummary
1.1. Increase Increase inin echogenicityechogenicity on on videodensitometricvideodensitometric analysis analysis waswas recognizedrecognized inin allall groups,groups, especiallyespecially inin GroupGroup A+PA+P >> GroupGroup P.P. 2.2. Significant Significant reductionreduction inin plaqueplaque volumevolume withwith concomitantconcomitant increaseincrease inin lumenlumen volumevolume waswas obtainedobtained inin GroupGroup A+P.A+P.
NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine ConclusionsConclusions
1.1. LDL-C LDL-C shouldshould bebe reducedreduced lessless thanthan 100100 mg/dlmg/dl toto slowdownslowdown oror stopstop plaqueplaque growth.growth. 2.2. Anti-oxidant Anti-oxidant therapytherapy withwith probucolprobucol mightmight stabilizestabilize plaqueplaque composition.composition. 3.3. Combination Combination therapytherapy withwith atorvastatinatorvastatin and and probucolprobucol maymay leadlead toto plaqueplaque regressionregression andand stabilizationstabilization ofof minorminor lesions.lesions. 4.4. This This therapytherapy couldcould bebe veryvery usefuluseful toto preventprevent cardiaccardiac eventsevents afterafter PCIs.PCIs. 5.5. First First reportreport ofof plaqueplaque regression!regression!
NihonNihon UniversityUniversity SchoolSchool ofof MedicineMedicine