I nuovi farmaci antiaggreganti
inibitori del P2Y12
Marco Cattaneo
Ospedale San Paolo
Università degli Studi di Milano
Cumulative Hazard Rates for the First Primary Outcome (Death from Cardiovascular Causes,
Nonfatal Myocardial Infarction, or Stroke) during the 12 Months of the Study
(patients with ACS, on treatment with aspirin)
The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators.
N Engl J Med 2001;345:494-502
TIENOPIRIDINE
METABOLITI ATTIVI
N
S
HOOC
HS
Cl
N
Cl
Ticlopidine
O
CH3
N
S
Cl
Clopidogrel
O
HOOC
HS
CH3
N
Cl
agonista
ADP
ADP
specific
receptor
P2Y12
Gq
Gi
++
δ
PI3K
+
stabilizzazione
Attivazione/aggregazione piastrinica
Cattaneo M, Blood 2011
Ruoli del P2Y12 nell’attivazione/aggregazione piastrinica
agonista
ADP
ADP
specific
receptor
P2Y12
Gq
++
δ
prostaciclina
IP receptor
Gi
Gs
PI3K
AC
cAMP
+
stabilizzazione
Attivazione/aggregazione piastrinica
Cattaneo M, Blood 2011
AD
P
agonista
O
N
HOOC
ADP
SADP
S
specific
receptor
P2Y12
Gq
Gi
δ
CH3
Cl
prostaciclina
IP receptor
Gs
AC
cAMP
Attivazione/aggregazione piastrinica
Problemi del Clopidogrel
• Lento inizio dell’azione farmacologica
• Lento recupero della funzione piastrinica
dopo sospensione del farmaco (inibizione
irreversibile del P2Y12)
• Elevata variabilità inter-individuale di risposta
Distribution of Platelet Reactivity Units (PRU), measure with VerifyNow P2Y12
in Clopidogrel-treated Patients, by Study and Quartile
Brar et al, JACC 2011:58:1945–54
Distribution of Platelet Reactivity Units (PRU), measure with VerifyNow P2Y12
in Clopidogrel-treated Patients, by Study and Quartile
~35% with
high on-treatment
platelet reactivity
(non/poor responders)
230
Brar et al, JACC 2011:58:1945–54
Incidence of MACE for Normal and High On-Treatment Platelet Reactivity:
Meta-analysis of Studies of ACS Patients on Treatment with Clopidogrel
PRU ≥230
PRU<230
Brar et al, JACC 2011:58:1945–54
Variabili che influenzano la risposta al clopidogrel
• Ridotto assorbimento (portatori della mutazione TT3435 del
gene ABCB1, che codifica la P-glicoproteina)
• Inadeguata attivazione del pro-farmaco in portatori di mutazioni
di isoforme del CYP, che ne alterano la funzione enzimatica
• Interazione con altri farmaci (PPI, alcune statine, etc)
• Età
• Indice di massa corporea
• Diabete mellito
• Fumo di sigaretta
• ……
• ADERENZA!!
Variabilità di risposta al Clopidogrel
La soluzione?
“Terapia personalizzata”:
Aumentare la dose di clopidogrel o usare terapie
alternative nei pazienti in cui si dimostri una
inadeguata inibizione della funzione piastrinica
(in base ai risultati di test di laboratorio)
Quale test di funzione piastrinica?
•
•
•
•
•
•
•
•
•
Tempo di emorragia
Aggregazione piastrinica (aggregometria a trasmissione di luce)
Aggregazione piastrinica (ipedenziometria)
PFA-100®
Verify Now P2Y12
Impact – Cone-and-Plate(let) Analyzer
VASP-Phosphorylation
TEG
……
Quale test «dice la verità»?
Paniccia et al, T&H 2010
La «terapia personalizzata» con
clopidogrel è efficace e sicura?
RECLOSE 2-ACS
Incidence of Primary End Point Events at 2y F.U. in ACS patients on DAPT
undergoing PCI, according to their platelet reactivity at baseline and F.U.
HRPR
LRPR
P
14.6%
8.7%
0.003
therapy adjustment
HRPR
at F.U.
LRPR
at F.U.
Parodi et al, JAMA 2011;306:1215-23
RECLOSE 2-ACS
Incidence of Primary End Point Events at 2y F.U. in ACS patients on DAPT
undergoing PCI, according to their platelet reactivity at baseline and F.U.
HRPR
LRPR
P
14.6%
8.7%
0.003
therapy adjustment
HRPR
at F.U.
LRPR
at F.U.
14.9%
14.4%
0.91
Parodi et al, JAMA 2011;306:1215-23
Cumulative Kaplan-Meier Estimates of the Time to the First
Adjudicated Occurrence of the Primary Efficacy End Point
Price, M. J. et al. JAMA 2011;305:1097-1105
Proportion of patients with
primary outcome events
Collet et al, NEJM 2012
Cumulative Kaplan-Meier Estimates of the Time to the First
Adjudicated Occurrence of the Primary Efficacy End Point
Solo 39.8% dei pazienti con UA/ACS!!!
Price, M. J. et al. JAMA 2011;305:1097-1105
Proportion of patients with primary outcome
events
Solo 27% dei pazienti con ACS!!!
Collet et al, NEJM 2012
Incidence of MACE for Normal and High On-Treatment Platelet Reactivity:
Meta-analysis of Studies of ACS Patients on Treatment with Clopidogrel
PRU ≥230
PRU<230
Brar et al, JACC 2011:58:1945–54
Incidence of MACE for Normal and High On-Treatment Platelet Reactivity:
Meta-analysis of Studies of ACS Patients on Treatment with Clopidogrel
PRU ≥230
PRU<230
Solo 35% dei pazienti con ACS!!!
Brar et al, JACC 2011:58:1945–54
RECLOSE 2-ACS
Incidence of Primary End Point Events at 2y F.U. in ACS patients on DAPT
undergoing PCI, according to their platelet reactivity at baseline and F.U.
HRPR
LRPR
P
14.6%
8.7%
0.003
«Solo» 100% dei pazienti con ACS!!!
therapy adjustment
HRPR
at F.U.
LRPR
at F.U.
14.9%
14.4%
0.91
Parodi et al, JAMA 2011;306:1215-23
Variabilità di risposta al Clopidogrel
Un’altra soluzione?
Usiamo farmaci migliori
TIENOPIRIDINE
METABOLITI ATTIVI
N
S
HOOC
HS
Cl
N
Cl
Ticlopidine
O
CH3
N
S
Cl
O
HOOC
HS
CH3
N
Cl
Clopidogrel
O
O
CH3 O
N
S
O
F
Prasugrel
HOOC
HS
N
F
Reletionship between IPA by Clopidogrel 300 mg or
Prasugrel 60 mg in response to 20 μM ADP 24 h after the loading dose
“Responders”
“Non Responders”
Brandt et al, Am Heart J 2007
Cumulative Kaplan-Meier Estimates of the Rates of Key Study End Points
during the Follow-up Period , in TRITON-TIMI 38
(patients with ACS, scheduled for PCI)
Wiviott S et al. N Engl J Med 2007
TICAGRELOR
• direct-acting, competitive, reversible P2Y12
• pIC50 of 7.9 with 30 M ADP –induced platelet aggregation
(PRP)
• Highly selective for P2Y12 (apparently, does not inhibit P2Y1 or
other purinergic receptors)
• T1/2 7-8.5h (BID drug)
• Tmax 2 h
DISPERSE Study: Faster and More Consistent IPA
With AZD6140 Than With Clopidogrel (Final Extent)
Clopidogrel 75 mg qd
Day 1
AZD6140 100 mg bid
Day 14
Day 1
100
Mean % Inhibition
Mean % Inhibition
100
Day 14
80
60
40
20
80
60
40
20
2 4
8
12
2 4
8
Time, h
12
24
2 4
8
12
2 4
8
12
24
Time, h
Husted S. Presented at ESC 2005.
Cumulative Kaplan-Meier Estimates of the Time to the First Adjudicated Occurrence of
the Primary Efficacy End Point in the PLATO trial
(patients with ACS, undergoing medical therapy or PCI)
HR = 0.84 (0.77–0.92)
P<0.001
Wallentin L et al. N Engl J Med 2009;361:1045-1057
Incidence of TIMI-major non-CABG bleeding in
studies comparing drugs inhibiting P2Y12
Comparison
N. of
patients
Increase
in TIMImajor
bleeding
P
Study
Prasugrel vs clopidogrel
13,457
32%
0.03 TRITON-TIMI38, NEJM
2007;357:2001-15
Ticagrelor vs clopidogrel
18,421
25%
0.03 PLATO, NEJM
2009;361:1045-57
Clopidogrel responders vs
clopidogrel non-responders
1,608
85%
0.25 Sibbing et al, JACC
2009;53:849-56
Reletionship between IPA by Clopidogrel 300 mg or
Prasugrel 60 mg in response to 20 μM ADP 24 h after the loading dose
“Responders”
“Non Responders”
Brandt et al, Am Heart J 2007
DISPERSE Study: Faster and More Consistent IPA
With AZD6140 Than With Clopidogrel (Final Extent)
Clopidogrel 75 mg qd
Day 1
AZD6140 100 mg bid
Day 14
Day 1
100
Mean % Inhibition
Mean % Inhibition
100
Day 14
80
60
40
20
80
60
40
20
2 4
8
12
2 4
8
Time, h
12
24
2 4
8
12
2 4
8
12
24
Time, h
Husted S. Presented at ESC 2005.
Incidence of TIMI-major non-CABG bleeding in
studies comparing drugs inhibiting P2Y12
Comparison
N. of
patients
Increase
in TIMImajor
bleeding
P
Study
Prasugrel vs clopidogrel
13,457
32%
0.03 TRITON-TIMI38, NEJM
2007;357:2001-15
Ticagrelor vs clopidogrel
18,421
25%
0.03 PLATO, NEJM
2009;361:1045-57
Clopidogrel responders vs
clopidogrel non-responders
1,608
85%
0.25 Sibbing et al, JACC
2009;53:849-56
Differenze tra ticagrelor e prasugrel?
(CONFRONTI INDIRETTI!!!)
1.
Ticagrelor ha ridotto significativamente la mortalità CV
e totale nello studio PLATO (rispetto a clopidogrel)
Incidence of death at 12 months in the PLATO trial
End point
Ticagrelor
(n=9,333)
Clopidogrel
(n=9,291)
HR for ticagrelor
(95% CI)
P value
Death from any
causes
399
(4.5%)
506
(5.9%)
0.78 (0.69-0.89)
<0.001
Death from
vascular causes
353
(4.0%)
442
(5.1%)
0.79 (0.69-0.91)
0.001
Death from
causes other
than vascular
causes
46
(0.5%)
64
(0.8%)
0.71 (0.49-1.04)
0.08
Wallentin L et al. N Engl J Med 2009;361:1045-1057
2.
Ticagrelor ha aumentato l’incidenza di dispnea in tutti
gli studi in cui è stato confrontato con il clopidogrel
Comparison of the incidence of dyspnea in patients treated with
ticagrelor and patients treated with clopidogrel
Study
drug
Patients
(n)
Dose
Duration
A.
Percent
dyspnea
in study
group
B.
Percent
dyspnea in
clopidogre
l group
A/B
Study
Ticagrelor
Atherosler
(200)
50-400 mg
bid
28 d
10-20
0
∞
DISPERSE
Ticagrelor
ACS (990)
90 mg bid
180 mg bid
12 wk
12 wk
10.5
15.8
6.4
6.4
1.64
2.47
DISPERSE
2
Ticagrelor
Stab. CAD
(123)
90 mg bid
6 wk
38.6
9.3
4.15
ONSET/
OFFSET
Ticagrelor
Stab. CAD
(98)
90 mg bid
14 d
13
4
3.25
RESPOND
Ticagrelor
ACS
(18,624)
90 mg bid
12 mo
13.8
7.8
1.77
PLATO
Ticagrelor e dispnea
• Nella maggior parte dei casi, la dispnea era insorta
entro I primi 7 giorni dall’inizio della terapia, era
lieve/moderata, si risolveva spontaneamente
• Studi approfonditi hanno dimostrato che la dispnea
associata con l’uso del ticagrelor NON era causata da
– disfunzione polmonare
– disfunzione cardiaca
– acidosi
Storey et al, JACC 2010; Am J Cardiol 2011; Eur Heart J 2011
TICAGRELOR
Effetti «Off-target»
Residual adenosine concentrations, measured in whole blood by
LC-UV over time, after the addition of
7.1μmol/L adenosine
Dipyridamole ( )
Ticagrelor ( )
PAM ( )
DMSO (X)
Meccanismi di inibizione della funzione piastrinica
da parte del ticagrelor
Nylander et al, JTH 2013
Effetto del ticagrelor sull’adenosina
• Spiega l’effetto del farmaco sulla mortalità?
Effetto del ticagrelor sull’adenosina
• Spiega l’effetto del farmaco sulla mortalità?
• Spiega l’aumento della dispnea associato con
l’uso del farmaco?
Rappresentazione schematica delle vie afferenti della dispnea dai
recettori vagali e da chemorecettori periferici al SNC
Burki, Chest 2010
Dispnea e farmaci antiaggreganti
P2Y12 inhibition
Adenosine
increase
Dyspnea
Ticagrelor
YES (reversible)
YES
YES
Cangrelor
YES (reversible)
NO
YES
Elinogrel
YES (reversible)
NO
YES
Dipyridamole
NO
YES
NO
Cilostazol*
NO
YES
NO
Clopidogrel
YES (irreversible)
NO
YES**
* D. Angiolillo: personal communication
** albeit to a much lower extent than ticagrelor, elinogrel and cangrelor
Dispnea e farmaci antiaggreganti
P2Y12 inhibition
Adenosine
increase
Dyspnea
Ticagrelor
YES (reversible)
YES
YES
Cangrelor
YES (reversible)
NO
YES
Elinogrel
YES (reversible)
NO
YES
Dipyridamole
NO
YES
NO
Cilostazol*
NO
YES
NO
Clopidogrel
YES (irreversible)
NO
YES**
* D. Angiolillo: personal communication
** albeit to a much lower extent than ticagrelor, elinogrel and cangrelor
Inibitori del recettore P2Y12:
reversibili vs irreversibili
Cellule che esprimono il P2Y12
•
•
•
•
•
•
•
Piastrine
Cellule gliali
Neuroni
Cellule muscolari lisce
Leucociti
Macrofagi
…
Thienopyridines
Time (h)
Plasma drug concentration
Inhibition of P2Y12 on platelets
Inhibition of P2Y12 on nucleated cells
Cattaneo, Thromb Haemost 2012
Thienopyridines
Reversible P2Y12 inhibitors
Time (h)
Time (h)
Plasma drug concentration
Inhibition of P2Y12 on platelets
Inhibition of P2Y12 on nucleated cells
Cattaneo, Thromb Haemost 2012
Conclusioni - 1
• L’inibizione della funzione piastrinica da parte
dei «nuovi» farmaci anti-P2Y12, prasugrel and
ticagrelor, è meno variabile ( mediamente
maggiore), rispetto al clopidogrel
• I «nuovi» P2Y12 antagonisti hanno un rapporto
rischio/beneficio più favorevole del clopidogrel
• Pertanto, i «nuovi» P2Y12 antagonisti
rappresentano una valida soluzione al problema
della variabilità di risposta al clopidogrel
Conclusioni - 2
• Ticagrelor inibisce la funzione piastrinica anche
aumentando la concentrazione plasmatica di
adenosina
• Alcuni effetti clinici (sia benefici che avversi) del
ticagrelor potrebbero essere mediati da:
– aumento della concentrazione plasmatica di
adenosina
– inibizione permanente delle funzioni P2Y12dipendenti in cellule nucleate
Conflitti di interesse
• Supporto per la ricerca e onorari: AstraZeneca,
Eli Lilly, Daiichi-Sankyo, Evolva
• Onorari: Sanofi
• Dirigo un laboratorio per lo studio della funzione
piastrinica nell’Ospedale in cui opero