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