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					LES NOUVEAUX ANTI-PLAQUETTAIRES
    Optimisation thérapeutique ciblée




              I. ELALAMY
    UNITE HEMOSTASE-THROMBOSE
      HOPITAL TENON – UR2 UPMC
                PARIS
               ANTIPLAQUETTAIRES:
                  points d'impact


                                       1 Reconnaissance du signal
     3 Liaison
IIbIIIa- fibrinogène
                                                      Membrane
                                                      plaquettaire


                               ++
                          Ca



                       2 Transmission du signal
                            et activation
                                       ADP



         P2Y1                                            P2Y12
ATP

P2X1
                             Protéine Gq
                                                           Protéine Gi
                    +                              -

                Phospholipase C              Adenylyl cyclase

  Ca2+                                        Synthèse d’AMPc
          Mobilisation du Ca
          Changement de forme                Sécrétion granulaire
          Initiation de l’agrégation         Stabilité des agrégats
        ANTIPLAQUETTAIRES:
        RECEPTEURS DE L’ADP
– Ticlopidine (Ticlid®) Clopidogrel (Plavix®)
– Nouveaux inhibiteurs:
   • Prasugrel (Efient® Eli Lilly & Co./Daiichi Sankyo)
   Thiénopyridine 3ème Gen., oral od, indirect CYP3A4, irréversible,
   Pic 30 min, demi-vie 7h-10h, pas d’interférence médicamenteuse
   • Ticagrelor ( Brilinta® AstraZeneca)
   Dérivé pyrimidine, analogue ADP, direct, réversible, oral bid,
   Pic 2-4 h, demi-vie 12 h, abolition effet 1 à 2 j
   • Cangrelor (Medicines Comp)
   Analogue ADP; IV, direct, réversible, demi-vie 3 à 6 min,
     abolition effet en 30-60 min
   • Elinogrel (Portola)
   Direct, réversible, compétitif, IV et oral, pic 20 min,
   demi-vie 12h, élimination 50% rein/50%foie
Métabolisme du Clopidogrel
                   O            OCH3
                                              Esterases

                   N                               ~85% 
                                                   Inactive
                                                   Metabolites
             S
                        Cl

                       CYP2C19
                       CYP1A2
                                              O           OCH3
                       CYP2B6


                                                  N
                    O
                                S
                                                   Cl
                 CYP3A4
                 CYP2C19
                 CYP2C9                 O               OCH3
                 CYP2B6


                                          N
                 HOOC
                           HS
                                              Cl

                                    Bhatt et al, N Engl J Med 2008
Biotransformation et mode d’action




                             Bhatt et al, N Engl J Med 2008
Inhibition d’agrégation après 4 heures
100

 90   300mg
                                       ISAR-CHOICE – Von Beckerhat et al .Circulation 2005
                                                   ALBION – Montalescot et al. JACC 2007
 80                                                   DIPSERSE 2 – Storey et al. JACC 2007
              600mg                      PRINCIPLE TIMI-44 – Wiviot et al. Circulation 2007
                                                    RELOAD – Collet et al. Circulation 2008
 70                      900mg
 60

 50
                                                                10mg
 40
                                   90mg                                       60mg
 30
               CURRENT




                                            180mg
                          RELOAD




                                                                    TRITON
 20
                                    PLATO
       CURE




 10

  0
        Clopidogrel                Ticagrelor                         Prasugrel
                                               Early onset and high inhibition

                                               Dose de charge
Inhibition of Platelet Aggregation (%)



                                         100
                                                                     *       *       *        *
                                                                *
                                                                         Pras 60mg LD
                                          80                                 †       †
                                                                                          †
                                                                     !
                                          60              *
                                                                         Clop 600 mg LD


                                          40                    !
                                                                         Clop 300 mg LD
                                          20                                                      *p<0.001 vs. Clop 300 mg
                                                                                                   or 600 mg LD
                                                                                                  †
                                                                                 mean ± SEM           p<0.001 vs. Clop 300
                                           0                                       20 μM ADP      !
                                                                                                  p<0.05 vs. Clop 300

                                               0   0.25   0.5   1    2       4       6 24
                                                     Temps après dose de charge (hrs)
                                TRITON and PLATO
                         Primary endpoint = CV Death / MI / Stroke 12-15 months
                 15

                                                                         12.1
                                                                                   NNT=46
                                   Clopidogrel 75mg                                NNH=135
                                                                         9.9    Prasugrel
                 10                                            10.65
  Endpoint (%)




                                                                                  10mg
                                                                                Ticagrelor
                                                               9.02              90mg x2


                  5                      HR 0.81 (0.73-0.90)
                                             p=0.0004*

                                         HR 0.84 (0.77–0.92)
                                             p=0.0003*

                  0
                      0 30 60 90          180         270          360      450 days
N Engl J Med 2007;357
N Engl J Med. 2009;361:1045–1057
                   TIMI Major Non-CABG Bleeds
                         (12-15 months)

                                                                                              Prasugrel
                                         7                                                    Ticagrelor
                                                                                              Clopidogrel 75
                                         6
                                             p=0.001                p=0.03*       p=0.025*
                    K-M estimated rate



                                                *
                                         5
                                             +27%                   +25%               +22%
                                         4   3.7

                                                   2.7                            2.8
                                         3                         2.4
                                                                                        2.2
                                         2                               1.8
                                                   ASA only




                                         1

                                         0
                                             CURE                  TRITON         PLATO
                                             360 days               450 days      360 days
N Engl J Med 2007;357                                         NNH = 167 , p=0.003
N Engl J Med. 2009;361:1045–1057                              NNH=10 si CABG p<0,001
                               Diabetic Subgroup (n=3146)

                     18                                             Clopidogrel
                                                                                      17.0
                     16
                              CV Death / MI / Stroke
                     14
      Endpoint (%)




                                                                                      12.2
                     12
                                                                                     HR 0.70
                     10                                              Prasugrel       P<0.001
                                                                                    NNT = 21
                      8

                      6

                      4                   TIMI Major                  Clopidogrel         2.6
                                       NonCABG Bleeds
                      2                                                                   2.5
                                                                       Prasugrel
                      0
                          0   30 60 90          180           270         360       450
                                                       Days
                                                                                                11
Circulation. 2008;118:
                               CYP2C19 Polymorphisms and CV Death,
                               MI, or Stroke: Clopidogrel and Prasugrel


                                                 Clopidogrel                                                                  Prasugrel
                               14                                                                            14
                               13     CYP2C19                          12.1                                  13
CV Death, MI, or Stroke (%)1




                                                                              CV Death, MI, or Stroke (%)2
                               12     Reduced-Function                                                       12
                               11     Allele Carriers                                                        11                         Noncarriers   9.8
                               10                                                                            10
                               9                         Noncarriers    8.0                                   9
                               8                                                                              8                                       8.5
                               7                                                                              7                       CYP2C19
                               6                                                                              6                       Reduced-Function
                               5                                                                              5                       Allele Carriers
                               4                                                                              4
                                                        Hazard Ratio: 1.53
                               3                                                                              3                       Hazard Ratio: 0.89
                               2
                                                        (95% CI 1.07-2.19)
                                                                                                              2                       (95% CI 0.60-1.31)
                               1                        P=0.01
                                      N=1459                                                                  1     N=1466            P=0.27
                               0                                                                              0
                                    0 30    90    180    270    360     450                                       0 30   90    180    270     360     450
                                           Days After Randomization                                                      Days After Randomization

                  CI=confidence interval; CV=cardiovascular; MI=myocardial infarction.
                  1Reprinted with permission from Mega JL, et al. N Engl J Med. 2009;360(4):354-362. 2Reprinted with permission from

                  Mega JL, et al. Circulation. 2009;119(19):2553-2560.
  ACUITY: Major Bleeding by Age Groups
            in PCI Patients

                               Bleeding Rate With Heparin + GPI
                               Bleeding Rate With Bivalirudin Alone
                               NNT
Percentage (%)




                 <55   55-64             65-74                    ≥75

                         Patient Age (y)

                                Lopes RD, et al. J Am Coll Cardiol. 2009;53(12):1021-1030.
    Prasugrel and Ticagrelor in the Elderly
                                            (1ry End Point)




P
R
A
S   <60 kg
    ATCD d’AIT, AVC
U




T
I
C
    Pb Céphalées
A   Effet adénosine?

Wiviott et al. N Engl J Med 2007;357:2001-5; Wallentin L, et al. N Engl J Med. 2009;361(11):1045-1057.
           Cangrelor CHAMPION Trial Designs :
                   PCI and PLATFORM
                                               Start PCI              1 hr     2 hr
CHAMPION PCI
    N=9000
    SA/UA/NSTEMI/STEMI
    Not Thienopyridine
    Naive
 * Enrollment stopped early by IARC;
   Actual N=8885 (98% of planned)
                                                       End of PCI procedure



                                                Start PCI               1 hr   2 hr
CHAMPION PLATFORM
     N=6400
     SA/UA/NSTEMI
     Thienopyridine
     Naive
  * Enrollment stopped early by IARC;
     Actual N=5362 (84% of planned)
                                                       End of PCI procedure

               Screening       Randomization                  Drug Infusion           Follow
                       Platelet Substudy Results
                            (CHAMPION-PCI)
• More robust platelet inhibition with cangrelor during infusion
• No evidence of attenuation of clopidogrel effect at 12-24 hours
                                             Cangrelor                Clopidogrel
                 600
                             P=0.4915                    P<0.0001                       P=0.1949
from VerifyNow
 Median PRU




                 400



                 200



                   0
                            Baseline*                Peri-procedural**                  12-24 h
                             n=197                         n=138                     Post procedure†
                                                                                          n=176

 **Baseline-Before the first infusion,
 **Peri-procedural- During study drug/placebo infusion
 † Post procedure - 1st sample within 12 to 24 hours relative to 1st Infusion.


                                                       Bhatt et al. N Engl J Med 2009; Harrington et al. N Engl J Med. 2009
                     Summary of Clinical Efficacy

   48 hour Events
                                                                       OR [95% CI]           P value
   PLATFORM
     Death/MI/IDR*                                                    0.87 (0.71,1.07)      0.17
     Death/Q-MI/IDR                                                   0.55 (0.33,0.93)      0.02
     Death/Q-MI/ST                                                    0.38 (0.20,0.72)      0.002
   PCI
     Death/MI/IDR*                                                    1.05 (0.89,1.24)      0.57
     Death/Q-MI/IDR                                                   0.66 (0.42,1.05)      0.08
     Death/Q-MI/ST                                                    0.74 (0.43,1.27)      0.27
   POOLED
     Death/MI/IDR                                                     0.97 (0.86,1.11)      0.68
     Death/Q-MI/IDR                                                   0.61 (0.43,0.86)      0.005
     Death/Q-MI/ST                                                    0.55 (0.36,0.83)      0.004

                            0.2    0.5     1.0       2.0        5.0

* Primary Analysis      Cangrelor Better          Comparator Better


                                                 Bhatt et al. N Engl J Med 2009; Harrington et al. N Engl J Med. 2009
                                 Landmark Analysis
                           48-Hour/30-Day Stent Thrombosis


                           1.0
                                             1.0
                                     Cangrelor              Comparator
Estimated Event Rate (%)




                           0.8               0.8


                           0.6               0.6      0.6%
                                                                                                                        0.5%
                           0.4               0.4
                                                   P=0.02                                                                   P=0.65
                                                                                                                        0.4%
                                                     0.2%
                           0.2               0.2


                           0.0               0.0
                                 0   12   24   36 0 48      5     10       15        20        25        30        35
                           Hours from Randomization              Days from Randomization




                                                                   Bhatt et al. N Engl J Med 2009; Harrington et al. N Engl J Med. 2009
                                         Landmark Analysis
                                      48-Hour/30-Day Mortality


                           1.0
                                     Cangrelor              Comparator                                               1.1
                                                                                                                     %          1.1%
Estimated Event Rate (%)




                                           1.0

                           0.8                                                                                             P=0.97
                                           0.8          0.7%
                           0.6
                                           0.6        P=0.02
                           0.4
                                           0.4
                                                       0.2%
                           0.2             0.2


                           0.0             0.0
                                 0   12   24     36
                                                  0    48    5      10         15         20        25         30          35
                           Hours from Randomization                 Days from Randomization




                                                                     Bhatt et al. N Engl J Med 2009; Harrington et al. N Engl J Med. 2009
               INOVATE-PCI Schéma

 ARM 1:
 clopidogrel       ACUTE PHASE                                CHRONIC
                          Peri-PCI                             PHASE
                                                                 Post-PCI
ARM 1:                   300-600mg
clopidogrel             Loading Dose           PCI              75 mg QD            n=200




ARM 2:                   80 mg IV
elinogrel             Bolus+ 50mg PO           PCI              50 mg BID           n=200



ARM 3:                   120 mg IV
                         80mg IV
elinogrel            Bolus + 100mg PO
                     Bolus + 100mg PO         PCI              100 mg BID           n=200




ARM 4:                    80mg IV
                         120 mg IV
elinogrel            Bolus + 150mg PO         PCI              150 mg BID           n=200


   • April 8, 2009 (116 pts enrolled): The DSMC recommended discontinuation of the
     50 mg BID dose and increasing IV bolus dose to 120 mg as per protocol
   • April 16, 2009: Chronic phase extended from 60 days to 120 days of treatment
                                                     Pharmacodynamic Effect of
                                                      Elinogrel vs. Clopidogrel

                                                                          PD Sub-study
     5 uM ADP - Peak
                                                                                                                                 C (N=17)
                                           70                                    Peri-PCI                                      E100 (N=12)
                                                                                                                               E150 (N=17)


                                           60
      Extent of platelet aggregation (%)




                                           50
                                                 *                     pre-2nd                              pre-3rd
                                                                        oral                               oral dose
                                                                        dose                                   or
                                                                                                           discharge
                                           40         *
                                           30                                                                 *
                                                                                                                       clopidogrel
                                           20
                                                                                                                       120mg IV + 150mg oral
                                                                                                                       120mg IV + 100mg oral
                                           10

                                           0
                                                0 0.5 2           6      8                                   20
                                                                       TIME AFTER DOSING (hrs)
                                                     74% of pts represented above were on maintenance clopidogrel
22
        * p<0.025 for both elinogrel vs. clopidogrel comparisons                                                  Median, quartiles
                             Efficacy at 24h-120 Days

                               Rates and 95% confidence intervals

                      8                          Pooled Clopidogrel (n=208)

                      7                          Pooled Elinogrel 100mg (n=200)
                                                 Pooled Elinogrel 150mg (n=204)
                      6
     Event Rate (%)




                      5
                      4
                      3
                      2
                      1
                      0
                          Death/MI/Stroke/uTVR                      Death/MI/Stroke/uTVR/ST



23
                      Bleeding at 24 hrs or d/c – TIMI Scale
                                         Rates and 95% confidence intervals

                      14
                      13                             Pooled Clopidogrel (n=208)
                      12                             Pooled Elinogrel 80mg IV (n=122)
                      11
                                                     Pooled Elinogrel 120mg IV (n=312)
                      10
                       9
     Event Rate (%)




                       8
                       7
                       6
                       5
                       4
                       3
                       2
                       1
                       0

                                TIMI Major                    TIMI Minor                 Bleeding Requiring
                                                                                         Medical Attention *
                           * Mainly at access site
24
                       Adverse Events



                                        Clopidogrel       Pooled elinogrel      Pooled elinogrel
                                          N=208               100 mg                150 mg
                                                              N=201                 N=207

Any SAE                                   11.1%                14.9%                 12.6%
Drug d/c due to AE or SAE                  7.2%                 7.5%                 10.1%
Dyspnea*                                   4.3%                15.4%                 12.1%
Bradycardia                                0.5%                 1.0%                  0.5%
Syncope                                    0.5%                 1.5%                  0.5%
ALT/AST > 3x^                              1.0%                 4.0%                  4.8%
       ALT/AST > 5x                         0.5%                  2.0%                  3.4%


* Dyspnea was generally mild, transient, and infrequently led to discontinuation
^ Most cases occurred within first 60 days and were asymptomatic; All cases resolved, even when
treatment was continued; No Hy’s Law cases.
            VOIE DE L'AMP CYCLIQUE


ATP                   AMPc                  5'AMP

   Adénylyl Cyclase           Phosphodiestérase
                       AMPc
                       bloque
                      l’efflux
 Stimuler           de Calcium            Bloquer
Prostacycline:                         Dipyridamole:
époprosténol     STD --> Cytoplasme
                                       Persantiner,
Iloprost,        = INHIBITEUR          Théophylline,
taprostène,                             Adénosine
Béraprost                               Cilostazol...
        Strategies to Enhance P2Y12
     Inhibition in Patients With Diabetes


• Increase clopidogrel dosing
  (eg, 150 mg maintenance dosing)

• Using more potent P2Y12 inhibitors
  (eg, prasugrel, ticagrelor, cangrelor, elinogrel)

• Adding agents that modulate intraplatelet cAMP
  (eg, triple therapy: ASA + clopidogrel + cilostazol)
            Optimisation Thérapeutique


    High-on                                         High-on
   treatment                                       treatment
    platelet                                        platelet
   reactivity                                      inhibition


     Stent                   On target               Major
  thrombosis                                         bleed

VerifyNowP2Y12   30% (180)                       80% (30)


Prasugrel 10mg          Prasugrel 10mg - 5 mg?    Clopidogrel 75mg
                                                             28
 CYP2C19*2                                          CYP2C19*17
BX667
BX048




                             5


        NCX4016




                                Michelson,
         Terutroban   Nature Reviews 2010

				
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