Adding Cilostazol to Dual Antiplatelet Therapy Achieves Greater Platelet Inhibition Compared with High Maintenance Dose Clopidogrel in Patients with Acute Myocardial Infarction ACCEL-AMI study - PowerPoint PPT Presentation

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Adding Cilostazol to Dual Antiplatelet Therapy Achieves Greater Platelet Inhibition Compared with High Maintenance Dose Clopidogrel in Patients with Acute Myocardial Infarction ACCEL-AMI study

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Title: Adding Cilostazol to Dual Antiplatelet Therapy Achieves Greater Platelet Inhibition Compared with High Maintenance Dose Clopidogrel in Patients with Acute Myocardial Infarction ACCEL-AMI study


1
Adding Cilostazol to Dual Antiplatelet Therapy
Achieves Greater Platelet Inhibition
Compared with High Maintenance
Dose Clopidogrel in
Patients with Acute Myocardial Infarction
ACCEL-AMI study
Circulation Cardiovascular Intervention
2010117-26.
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
1 Gyeongsang National University Hospital, Jinju,
Korea. 2 Asan Medical Center, Seoul, Korea.
2
Background
  • 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.

3
Efficacy and Safety Correlated with IPA
ASAprasugrel
ASAticagrelor
ASAclopidogrel
BLEEDING Non-CABG Major
ASA
Relative Rate
EFFICACY Death/MI/Stroke
Placebo
ASAprasugrel
ASA
ASAclopidogrel
ASAticagrelor
IPA
Antithrombotic Trialists Collaboration. BMJ.
200232471 Yusuf et al. N Engl J Med.
2001345494 Wiviott et al. N Engl J Med
20073572001-2015 Wallentin et al. N Engl J Med
20093611-13
IPA inhibition of platelet aggregation
4
The impact of adjunctive cilostazol
in STEMI patients
26
Chen KY et al. Circulation 20091193207-14.
5
Mechanism of Cilostazol Inhibition of
phosphodiesterase 3
cAMP actions (selected)
Targets
Cilostazol
5AMP
  • Inhibition of aggregation
  • Inhibition of expression of
  • adhesion molecules

PDE3A
platelet
  • Inhibition of expression of
  • adhesion molecules
  • Angiogenesis

cAMP
endothelial cell
A2
Adenosine
  • Vasodilatory action
  • Inhibition of proliferation,
  • migration and matrix synthesis
  • Headache

A1
ATP
smooth muscle cell
  • Palpitation
  • Tachycardia

Elevation of cAMP and adenosine in diverse
cardiovascular system
cardiocyte
6
Role of cAMP / Protein Kinase A
PKA catalytic subunit phosphorylates
CREB and
activates transcription
AC
a
b
g
ATP
GTP
2Pi
Altered Protein Function
Inactive protein kinase A (PKA)
cAMP
P
ADP
Nucleus
ATP
ATP
ADP
P
Free PKA catalytic subunit migrates to nucleus
Regulatory subunit of PKA binds cAMP
dissociates from the catalytic subunit
Altered Gene Expression
? PKA can phosphorylate many different proteins
depending on tissue type and status ? PKA can
activate enzymes or gene regulatory proteins
7
Pleiotropic Effects of Cilostazol
  • 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

8
Postulated Modulation of P2Y12 Receptor Signalling
Angiolillo DJ et al. Eur Heart J 2008 292202.
9
Purpose 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.

10
Study 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 lt 30
    - leukocyte lt
    3,000/mm3 and/or platelet lt 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 lt
    1 year

11
Patients undergoing coronary stenting for AMI (n
120) Clopidogrel 600mg loading ? 75 mg/d before
randomization
Exclusion criteria (n 25) Low LV ejection
faction anticoagulation etc.
Refusal (n 5)
Randomization after pre-discharge platelet
reactivity assessment 3-5 days after coronary
stenting (n 90)
High MD clopidogrel 150 mg/d (n 30)
Adjunctive cilostazol 100 mg
twice daily (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)
Platelet reactivity at 30-day
follow-up (n 30)
12
Study 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 gt
    50

13
AggRAM aggregometer
ADP (5 µM)
ADP
(20 µM)
Arachidonic acid (1.6 mM)
ADPPGE1
14

VerifyNowTM (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

15
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
16
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
17
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
18
Platelet Reactivity by Conventional Aggregometry
Variables Standard group (n30) High-MD group (n30) Triple group (n30) 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 lt 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 lt 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 lt 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 lt 0.001
p lt 0.001 for Triple group vs. High-MD group
p 0.001 for Triple group vs. High-MD group
19
Platelet Reactivity by VerifyNow P2Y12 assay
Variables Standard group (n30) High-MD group (n30) Triple group (n30) 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 lt 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 lt 0.001
p 0.085 for Triple group vs. High MD group
p 0.034 for Triple group vs. High MD group
20
Inhibition of Maximal Platelet Aggregation
()
p lt 0.001 by ANOVA
p lt 0.001 by ANOVA
p lt 0.001
p lt 0.001
p lt 0.001
p lt 0.001
4920
4221
p 0.002
p 0.003
2420
1919
721
613
5 µM ADP
20 µM ADP
21
Inhibition of Late Platelet Aggregation
()
p lt 0.001
p lt 0.001
p lt 0.001
p lt 0.001
p lt 0.001
p 0.006
7126
6634
p 0.018
p 0.008
4031
3842
1743
1136
5 µM ADP
20 µM ADP
22
Change of P2Y12 reaction unit
()
p lt 0.001 by ANOVA
p lt 0.001
p 0.071
4324
p 0.003
3128
1123
23
Rate of HPPR
(5 µM ADP-induced
Aggmax gt 50)
()
p 0.602 by ANOVA
p 0.003 by ANOVA
p 0.795
p 1.000
p 0.601
p 0.003
p 0.021
p 0.532
Pre-discharge
30-day follow-up
24
Rate of HPPR
(20 µM ADP-induced
Aggmax gt 50)
()
p lt 0.001
p 0.737 by ANOVA
p 0.001
p 0.170
p 0.003 by ANOVA
Pre-discharge
30-day follow-up
25
Achieving Balance efficacy vs. bleeding
  • Superiority of Ticagrelor to Prasugrel
    in terms
    of cardiovascular mortality
    - ?
    myocardial infarction gt ? 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.

26
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

27
Juggling 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.

28
Efficacy and Safety Correlated with IPA
ASAprasugrel
TAPT
ASAticagrelor
ASAclopidogrel
Adjunctive Cilostazol Pleiotropic effects on
diverse cardiovascular system
BLEEDING Non-CABG Major
ASA
Relative Rate
EFFICACY Death/MI/Stroke
Placebo
ASAprasugrel
TAPT
ASA
ASAclopidogrel
ASAticagrelor
IPA
Antithrombotic Trialists Collaboration. BMJ.
200232471 Yusuf et al. N Engl J Med.
2001345494 Wiviott et al. N Engl J Med
20073572001-2015 Wallentin et al. N Engl J Med
20093611-13
IPA inhibition of platelet aggregation
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