Adding Cilostazol to Dual Antiplatelet Therapy Achieves Greater Platelet Inhibition
Compared with High Maintenance Dose Clopidogrel in Patients with Acute Myocardial
Infarction ACCEL-AMI studyACCEL-AMI study
Adding Cilostazol to Dual Antiplatelet Therapy Achieves Greater Platelet Inhibition
Compared with High Maintenance Dose Clopidogrel in Patients with Acute Myocardial
Infarction ACCEL-AMI studyACCEL-AMI study
1 Gyeongsang National University Hospital, Jinju, Korea.2 Asan Medical Center, Seoul, Korea.
Young-Hoon Jeong,1 Jin-Yong Hwang,1 In-Suk Kim,1 Yongwhi Park,1 Seok-Jae Hwang,1 Seung-Whan Lee,2
Choong Hwan Kwak,1 Seong-Wook Park2
Circulation Cardiovascular Intervention 2010;1:17-26.
BackgroundBackgroundBackgroundBackground
• Enhanced platelet reactivity may mainly underlie the risk of adverse cardiovascular disease in the early phase of AMI.
• High post-clopidogrel platelet reactivity (HPPR) in patients with AMI has been associated with ischemic clinical events including stent thrombosis.
Efficacy and Safety Correlated with IPA
ASA+prasugrel
ASA+clopidogrel
ASA+clopidogrel
ASA
ASA
Placebo
Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71Yusuf et alYusuf et al. N Engl J Med. 2001;345:494Wiviott et al. N Engl J Med 2007;357:2001-2015Wallentin et al. N Engl J Med 2009;361:1-13
% IPA
Re
lati
ve
Rat
e
ASA+ticagrelor
ASA+prasugrel
EFFICACY= Death/MI/Stroke
BLEEDING= Non-CABG Major
ASA+ticagrelor
*IPA = inhibition of platelet aggregation
The impact of adjunctive cilostazol in STEMI patients
The impact of adjunctive cilostazol in STEMI patients
Chen KY et al. Circulation 2009:119:3207-14.
26%
• Palpitation• Tachycardia
• Vasodilatory action • Inhibition of proliferation, migration and matrix synthesis• Headache
• Inhibition of aggregation
• Inhibition of expression of
adhesion molecules
cAMP actions (selected)Targets
cardiocyte
• Inhibition of expression of adhesion molecules• Angiogenesis
endothelial cell
platelet
smooth muscle cellATP
5’AMP
cAMP
PDE3A
Adenosine A2
A1
ONH
(CH2)4ONN
NN H
Cilostazol
Mechanism of Cilostazol: Inhibition of phosphodiesterase 3 Mechanism of Cilostazol: Inhibition of phosphodiesterase 3
Elevation of cAMP and adenosine in diverse
cardiovascular system
Role of cAMP / Protein Kinase ARole of cAMP / Protein Kinase A
cAMP
b g ACa
2Pi
ATP
NucleusATP
ADP
Regulatory subunit of PKA binds cAMP dissociates from the catalytic subunit
PKA catalytic subunit phosphorylates CREB* and activates transcription
Inactive protein kinase A (PKA)
GTP
ATPADP
Free PKA catalytic subunit migrates to nucleus
P
P
Altered Gene Expression
Altered Protein Function
PKA can phosphorylate many different proteins depending on tissue type and status PKA can activate enzymes or gene regulatory proteins
• Inhibition of Oxidative Stress
• Restoration from Endothelial Senescence
• Reduction of Adhesion molecule
• Reduced leukocyte adhesiveness
• Inhibition of Vascular Smooth Muscle Cell growth
• Reduction of ischemia-reperfusion injury
• Enhanced angiogenesis
• Inhibition of adenosine uptake
• Platelet inhibition and anti-thrombosis
Pleiotropic Effects of Cilostazol
Postulated Modulation of P2Y12 Receptor SignallingAngiolillo DJ et al. Eur Heart J 2008; 29:2202.
Purpose of StudyPurpose of StudyPurpose of StudyPurpose of Study
• It has not been established whether the benefit of
adjunctive cilostazol to dual antiplatelet therapy
(“triple antiplatelet therapy”: TAPT) may be related
with greater inhibition of ADP-induced platelet
aggregation in AMI patients.
• We compared the degree of platelet inhibition by
adjunctive cilostazol (100mg twice a day) vs. high-
MD clopidogrel (150 mg/d) in AMI patients undergoing
coronary stenting.
Study PopulationStudy PopulationStudy PopulationStudy Population
• Enrollment - ≥ 18 years of age - AMI patients undergoing uneventful coronary stenting
• Exclusion criteria - a history of active bleeding and bleeding diatheses - oral anticoagulation therapy with coumadin - contraindication to antiplatelet therapy - LV ejection fraction < 30% - leukocyte < 3,000/mm3 and/or platelet < 100,000/mm3 - AST or ALT level ≥ 3 times upper normal - serum creatinine level ≥ 2.5 mg/dl - non-cardiac disease with a life expectancy < 1 year
Exclusion criteria (n = 25) Low LV ejection faction
anticoagulation etc.
Patients undergoing coronary stenting for AMI (n = 120)
Clopidogrel 600mg loading 75 mg/d before randomization
Refusal (n = 5)
Randomization after pre-discharge platelet reactivity assessment: 3-5 days after coronary stenting (n = 90)
Adjunctive cilostazol 100 mg twice daily (n =
30)
High MD clopidogrel 150 mg/d (n = 30)
Platelet reactivity at 30-day follow-up (n = 30)
Standard MD clopidogrel 75 mg/d (n = 30)
Platelet reactivity at 30-day follow-up (n = 30)
Platelet reactivity at 30-day follow-up (n = 30)
Study MeasurementStudy MeasurementStudy MeasurementStudy Measurement
• Method 1. Conventional aggregometry with 5 and 20 μM ADP - maximal aggregation (Aggmax)
and late aggregation at 5 minutes (Agglate) 2. VerifyNow
P2Y12 assay - P2Y12
reaction units (PRU) and % inhibition
• Parameters IPA (inhibition of platelet aggregation, %) = [(Aggbase – AggFU)/(Aggbase)]
X100 Percent change of PRU (%) = [(PRUbase –
PRUFU)/(PRUbase)] X100 Rate of HPPR (%) = 5 or 20 μM ADP-induced Aggmax > 50%
ADP
(5 μM)
ADP
(20 μM)
ADP+PGE1 Arachidonic acid
(1.6 mM)
AggRAM aggregometer
VerifyNowVerifyNowTMTM (Ultegra rapid platelet function assay)(Ultegra rapid platelet function assay)
• Turbidimetric based optical detection system – to measure PLT induced aggregation as an increase in light transmission
• Simple, rapid report, not require specialized technician “Point-of-care system”
Baseline Characteristics (I)Baseline Characteristics (I)Baseline Characteristics (I)Baseline Characteristics (I)
Variables, n (%) Standard group(n = 30)
High-MD group(n = 30)
Triple group(n = 30)
p Value
Age, yrs 64.0 ± 13.3 61.1 ± 10.8 61.3 ± 12.1 0.580
Male 22 (73.3) 23 (76.7) 21 (70.0) 0.772
BMI, kg/m2 24.4 ± 2.8 23.8 ± 2.4 23.7 ± 2.1 0.641
STEMI 17 (56.7) 17 (56.7) 14 (46.7) 0.440
Diabetes mellitus 4 (13.3) 6 (20.0) 9 (30.0) 0.116
Hypertension 11 (36.7) 11 (36.7) 17 (56.7) 0.120
Hypercholesterolemia 13 (43.3) 14 (46.7) 9 (30.0) 0.295
Current smoking 21 (70.0) 22 (73.3) 16 (53.3) 0.432
Chronic kidney disease 5 (16.7) 5 (16.7) 8 (26.7) 0.336
Previous MI 1 (3.3) 1 (3.3) 0 (0) 0.384
Previous PCI 0 (0) 0 (0) 1 (3.3) 0.221
Previous stroke 0 (0) 1 (3.3) 0 (0) 1.000
Baseline Characteristics (II)Baseline Characteristics (II)Baseline Characteristics (II)Baseline Characteristics (II)
Variables, n (%) Standard group(n = 30)
High-MD group(n = 30)
Triple group(n = 30)
p Value
CYP 3A4 metabolized statin 29 (96.7) 28 (93.3) 28 (93.3) 0.575
Beta blocker 27 (90.0) 27 (90.0) 26 (86.7) 0.683
ACEI 10 (33.3) 6 (20.0) 7 (23.3) 0.377
ARB 20 (66.7) 24 (80.0) 21 (70.0) 0.774
Nitrate 28 (93.3) 26 (86.7) 26 (86.7) 0.414
Calcium channel blocker 2 (6.7) 1 (3.3) 5 (16.7) 0.176
LV ejection fraction, % 56 ± 9 55 ± 9 56 ± 8 0.827
Hemoglobin, g/dl 13.8 ± 1.3 14.4 ± 1.4 14.4 ± 1.5 0.194
Platelet count, x103/mm3 290 ± 67 258 ± 61 281 ± 89 0.225
HbA1C, % 6.0 ± 0.8 6.5 ± 1.5 6.5 ± 1.5 0.373
Creatinine clearnace, ml/min 81 ± 16 84 ± 17 74 ± 21 0.115
Total cholesterol, mg/dl 195 ± 43 200 ± 44 190 ± 36 0.154
Baseline Characteristics (III)Baseline Characteristics (III)Baseline Characteristics (III)Baseline Characteristics (III)Variables, n (%) Standard group
(n = 30)High-MD group
(n = 30)Triple group
(n = 30)p Value
Infarct-related vessel 0.273
Left anterior descending 10 (33.3) 19 (63.3) 12 (40.0)
Left circumflex artery 9 (30.0) 5 (16.7) 12 (40.0)
Right coronary artery 11 (36.7) 6 (20.0) 6 (20.0)
Initial TIMI flow grade 0.614
0 13 (43.3) 12 (40.0) 11 (36.7)
1 9 (30.0) 8 (26.7) 4 (13.3)
2 8 (26.7) 6 (20.0) 10 (33.3)
3 0 (0) 4 (13.3) 5 (16.7)
Aspiration thrombectomy 8 (26.7) 6 (20.0) 4 (13.3) 0.199
Administration of GPI 1 (3.3) 3 (10.0) 0 (0) 0.533
Stent type 0.259
Sirolimus eluting 10 (33.3) 14 (46.7) 7 (23.3)
Paclitaxel eluting 17 (56.7) 15 (50.0) 20 (66.7)
Zotarolimus eluting 3 (10.0) 1 (3.3) 3 (10.0)
Stent diameter, mm 3.0 ± 0.3 3.2 ± 0.3 3.2 ± 0.4 0.286
Stents per patient 1.3 ± 0.6 1.4 ± 0.6 1.4 ± 0.6 0.648
Total stent length, mm 31 ± 14 34 ± 16 33 ± 15 0.725
Platelet Reactivity by Conventional Aggregometry Platelet Reactivity by Conventional Aggregometry Variables Standard group
(n=30)High-MD group
(n=30)Triple group
(n=30)p Value
Maximal aggregation, %
20 μM ADP
Pre-discharge 61.3 ± 14.4 61.9 ± 13.4 60.3 ± 12.7 0.891
30-day follow-up 57.1 ± 12.6 50.6 ± 17.0 34.9 ± 14.6* < 0.001
5 μM ADP
Pre-discharge 48.1 ± 15.1 47.8 ± 12.4 48.3 ± 13.1 0.987
30-day follow-up 43.6 ± 12.6 36.8 ± 14.4 24.3 ± 10.5* < 0.001
Late aggregation, %
20 μM ADP
Pre-discharge 52.5 ± 20.4 53.0 ± 20.3 51.5 ± 15.5 0.954
30-day follow-up 45.3 ± 17.7 36.7 ± 22.7 17.7 ± 16.8† < 0.001
5 μM ADP
Pre-discharge 39.6 ± 19.6 38.2 ± 17.4 39.7 ± 17.1 0.962
30-day follow-up 31.4 ± 15.7 23.7 ± 16.0 11.9 ± 9.5† < 0.001
* p < 0.001 for Triple group vs. High-MD group † p = 0.001 for Triple group vs. High-MD group
Platelet Reactivity by VerifyNow P2Y12 assay Platelet Reactivity by VerifyNow P2Y12 assay
Variables Standard group(n=30)
High-MD group(n=30)
Triple group(n=30)
p Value
P2Y12 reaction unit
Pre-discharge 260.8 ± 67.9 257.9 ± 76.8 263.0 ± 69.9 0.962
30-day follow-up 231.9 ± 78.5 183.6 ± 87.5 147.2 ± 72.8* < 0.001
% inhibition
Pre-discharge 19.2 ± 18.5 19.2 ± 18.4 19.2 ± 16.6 1.000
30-day follow-up 29.6 ± 22.4 42.6 ± 25.7 55.5 ± 19.9† < 0.001
* p = 0.085 for Triple group vs. High MD group
† p = 0.034 for Triple group vs. High MD group
0
10
20
30
40
50
60
70
80
90
100
Standard group
High-MD group
Triple group
(%)
5 μM ADP 20 μM ADP
Inhibition of Maximal Platelet AggregationInhibition of Maximal Platelet AggregationInhibition of Maximal Platelet AggregationInhibition of Maximal Platelet Aggregation
p < 0.001 by ANOVA
p < 0.001 by ANOVA
7±21
24±20
49±20
6±13
19±19
42±21
p = 0.002
p < 0.001
p < 0.001
p = 0.003
p < 0.001
p < 0.001
0
10
20
30
40
50
60
70
80
90
100
Standard group
High-MD group
Triple group
(%)
5 μM ADP 20 μM ADP
Inhibition of Late Platelet AggregationInhibition of Late Platelet AggregationInhibition of Late Platelet AggregationInhibition of Late Platelet Aggregationp < 0.001 p < 0.001
17±43
40±31
71±26
11±36
38±42
66±34
p = 0.018
p < 0.001
p < 0.001
p = 0.008
p = 0.006
p < 0.001
0
10
20
30
40
50
60
70
80
90
100
Standard group
High-MD group
Triple group
(%)
p < 0.001 by ANOVA
11±23
31±28
43±24
p = 0.003
p = 0.071
p < 0.001
Change of P2YChange of P2Y1212 reaction unit reaction unitChange of P2YChange of P2Y1212 reaction unit reaction unit
0
10
20
30
40
50
60
70
80
90
100
Standard group
High-MD group
Triple group
(%)
Pre-discharge 30-day follow-up
Rate of HPPR Rate of HPPR ((5 μM ADP-induced Aggmax > 50%)
Rate of HPPR Rate of HPPR ((5 μM ADP-induced Aggmax > 50%)
p = 0.602 by ANOVA
p = 0.003 by ANOVA
p = 0.601
p = 1.000
p = 0.795
p = 0.532
p = 0.021
p = 0.003
0
10
20
30
40
50
60
70
80
90
100
Standard group
High-MD group
Triple group
(%)
Pre-discharge 30-day follow-up
Rate of HPPR Rate of HPPR ((20 μM ADP-induced Aggmax > 50%)
Rate of HPPR Rate of HPPR ((20 μM ADP-induced Aggmax > 50%)
p = 0.737 by ANOVA
p = 0.003 by ANOVA
p = 0.170
p = 0.001
p < 0.001
Achieving Balance: efficacy vs. bleedingAchieving Balance: efficacy vs. bleeding
• Superiority of Ticagrelor to Prasugrel in terms of cardiovascular mortality - ↓ myocardial infarction > ↑ major bleeding - elevated level of adenosine: inhibition of adenosine reuptake by red blood cells
• No increase of major bleeding by TAPT 1) Endothelium-targeted antithrombotic therapy: Cilostazol reduces the number of partially activated platelets by interacting with activated endothelial cells. 2) Adjunctive cilostazol to aspirin or clopidogrel does not prolong bleeding time. 3) Cilostazol has the relatively short recovery time of platelet function.
Beneficial role of Cilostazol in AMI patients Beneficial role of Cilostazol in AMI patients
• Additive platelet inhibition irrespective of CYP2C19 genotyping - Carrier of CYP2C19 mutant allele: East Asian 55-60% vs. Caucasian 25-30% - Hepatic metabolism of Cilostazol: mainly CYP3A system
• Elevated level of adenosine
• Activation of RISK (PI3/Akt) pathway - Reduction of ischemia-reperfusion injury
• Control of diverse pathway of atherothrombosis - oxidative stress - endothelial dysfunction - expression of adhesion molecule - inflammation cascade - cholesterol oxidation
Juggling AntiplateletsJuggling Antiplatelets
• Choice of intensified antiplatelet regimens
(TAPT vs. prasugrel vs. ticagrelor) - efficacy - bleeding risk - tolerability - cost - duration - additional pleiotropic effect ex) control of neointimal hyperplasia
• “Head to head comparison” is needed.
Efficacy and Safety Correlated with IPA
ASA+prasugrel
ASA+clopidogrel
ASA+clopidogrel
ASA
ASA
Placebo
Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71Yusuf et alYusuf et al. N Engl J Med. 2001;345:494Wiviott et al. N Engl J Med 2007;357:2001-2015Wallentin et al. N Engl J Med 2009;361:1-13
% IPA
Re
lati
ve
Rat
e
ASA+ticagrelor
ASA+prasugrel
EFFICACY= Death/MI/Stroke
BLEEDING= Non-CABG Major
ASA+ticagrelor
*IPA = inhibition of platelet aggregation
TAPT
TAPT
Adjunctive Cilostazol:
Pleiotropic effects on diverse cardiovascular system