ACCEL AMI

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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
         Circulation Cardiovascular Intervention 2010;1:17-26.



   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.
               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.
     Efficacy and Safety Correlated with IPA
                                       3.5
                                                                                        ASA+prasugrel
                                                                 y = 0.0297x + 1.1407
                                        3                             R² = 0.9815

                                       2.5                                       ASA+ticagrelor
                       Relative Rate



                                                   ASA+clopidogrel
                                                                                        BLEEDING= Non-CABG Major
                                        2
                                                 ASA
                                       1.5
                                                                                        EFFICACY= Death/MI/Stroke
                                                 Placebo          y = -0.0076x + 0.9271
                                        1                               R² = 0.9311
                                                                                       ASA+prasugrel
                                                 ASA
                                       0.5
                                                             ASA+clopidogrel ASA+ticagrelor
                                        0
                                             0              20           40             60          80
                                                                         % IPA
Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71
Yusuf et al. N Engl J Med. 2001;345:494
Wiviott et al. N Engl J Med 2007;357:2001-2015
Wallentin et al. N Engl J Med 2009;361:1-13                                  *IPA = inhibition of platelet aggregation
The impact of adjunctive cilostazol
        in STEMI patients

                                                        26%




         Chen KY et al. Circulation 2009:119:3207-14.
                                                                                 H   O
Mechanism of Cilostazol:                                    N
                                                                N    (CH2)4O
                                                                                 N

                                                                    N H
Inhibition of phosphodiesterase 3                               N




                               Targets             cAMP actions (selected)
   Cilostazol
                 5’AMP                           • Inhibition of aggregation
                                                 • Inhibition of expression of
      PDE3A                 platelet               adhesion molecules
                                                 • Inhibition of expression of
                cAMP                               adhesion molecules
                            endothelial cell
                                                 • Angiogenesis
                    A2
    Adenosine                                    • Vasodilatory action
                    A1                           • Inhibition of proliferation,
                 ATP                               migration and matrix synthesis
                            smooth muscle cell
                                                 • Headache
                                                 • Palpitation
    Elevation of cAMP and                        • Tachycardia
                            cardiocyte
     adenosine in diverse
    cardiovascular system
 Role of cAMP / Protein Kinase A
                                                                  PKA catalytic subunit
                                                                  phosphorylates CREB*
              b g         a   AC        ATP                       and activates transcription
                       GTP
                                         2Pi
Inactive protein              Altered Protein Function
 kinase A (PKA)
                                                       P
                       cAMP
                                        ATP
                                                                            ATP
                                                                                    Nucleus
                                                                              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
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
Postulated Modulation of P2Y12 Receptor Signalling
                               Angiolillo DJ et al. Eur Heart J 2008; 29:2202.
              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.
                 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 < 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
              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)




Standard MD clopidogrel        High MD clopidogrel           Adjunctive cilostazol
    75 mg/d (n = 30)            150 mg/d (n = 30)          100 mg twice daily (n = 30)




  Platelet reactivity at        Platelet reactivity at         Platelet reactivity at
30-day follow-up (n = 30)     30-day follow-up (n = 30)      30-day follow-up (n = 30)
                 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 > 50%
AggRAM aggregometer




             ADP        ADP     ADP+PGE1   Arachidonic acid
             (5 μM)   (20 μM)                 (1.6 mM)
                    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”
                  Baseline Characteristics (I)

Variables, n (%)         Standard group   High-MD group   Triple group   p Value
                             (n = 30)        (n = 30)        (n = 30)
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)
Variables, n (%)               Standard group   High-MD group   Triple group   p Value
                                   (n = 30)        (n = 30)        (n = 30)
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)
Variables, n (%)            Standard group   High-MD group   Triple group   p Value
                                (n = 30)        (n = 30)        (n = 30)
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
Variables                    Standard group   High-MD group    Triple group   p Value
                                 (n=30)           (n=30)          (n=30)
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

Variables               Standard group     High-MD group     Triple group    p Value
                            (n=30)             (n=30)           (n=30)
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
   Inhibition of Maximal Platelet Aggregation
(%) 100
             p < 0.001              p < 0.001
     90
            by ANOVA               by ANOVA
     80
            p < 0.001
     70
                                    p < 0.001
     60
                  p < 0.001
                                         p < 0.001      Standard group
                         49±20
     50                                                 High-MD group
                                                42±21
                                                        Triple group
     40
          p = 0.002
                                 p = 0.003
     30
                 24±20
                                        19±19
     20

     10   7±21                   6±13

      0
            5 μM ADP               20 μM ADP
          Inhibition of Late Platelet Aggregation
(%) 100
                p < 0.001               p < 0.001
     90         p < 0.001
                                        p < 0.001
                      p < 0.001
     80
                                              p = 0.006
                             71±26
     70                                              66±34

     60
                                                             Standard group
     50       p = 0.018
                                      p = 0.008              High-MD group
                     40±31                                   Triple group
     40                                      38±42

     30

     20      17±43
                                     11±36
     10

      0
                5 μM ADP               20 μM ADP
          Change of P2Y12 reaction unit
(%) 100

     90        p < 0.001 by ANOVA
     80
                     p < 0.001
     70
                            p = 0.071
     60
                                   43±24   Standard group
     50                                    High-MD group
                                           Triple group
     40         p = 0.003
     30
                       31±28
     20

     10      11±23

      0
                        Rate of HPPR
(%) 100         (5 μM ADP-induced Aggmax > 50%)

     90    p = 0.602              p = 0.003
     80
          by ANOVA               by ANOVA
            p = 0.795
     70
                p = 1.000
     60
          p = 0.601                p = 0.003       Standard group
     50                                            High-MD group
                                       p = 0.021   Triple group
     40
                                 p = 0.532
     30

     20

     10

      0
          Pre-discharge        30-day follow-up
                       Rate of HPPR
(%)              (20 μM ADP-induced Aggmax > 50%)
      100                            p < 0.001
             p = 0.737
       90   by ANOVA                    p = 0.001
                                  p = 0.170
       80

       70                                        p = 0.003
       60
                                                by ANOVA
                                                      Standard group
       50                                             High-MD group
                                                      Triple group
       40

       30

       20

       10

        0
            Pre-discharge        30-day follow-up
Achieving 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
•   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 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
                                       3.5
                                                                                        ASA+prasugrel
                                                                 y = 0.0297x + 1.1407
                                        3                             R² = 0.9815
                                                                          TAPT
                                       2.5                                         ASA+ticagrelor
                       Relative Rate



                                                   ASA+clopidogrel
                                                                                        BLEEDING= Non-CABG Major
                                        2
                                                 ASA
                                       1.5
                                                                                        EFFICACY= Death/MI/Stroke
                                                 Placebo          y = -0.0076x + 0.9271
                                        1                               R² = 0.9311
                                                                            TAPT       ASA+prasugrel
                                                 ASA
                                       0.5
                                                             ASA+clopidogrel ASA+ticagrelor
                                        0
                                             0              20           40             60          80
                                                                         % IPA
Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71
Yusuf et al. N Engl J Med. 2001;345:494
Wiviott et al. N Engl J Med 2007;357:2001-2015
Wallentin et al. N Engl J Med 2009;361:1-13                                  *IPA = inhibition of platelet aggregation

				
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