Cangrelor on Platelet P2Y 12 Receptor Mediated Signaling in Prasugrel Treated Patients Fabiana Rollini Francesco Franchi Antonio TelloMontoliu Ronakkumar Patel Andrew Darlington ID: 385880
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Pharmacodynamic Effects of Cangrelor on Platelet P2Y12 Receptor Mediated Signaling in Prasugrel Treated Patients
Fabiana Rollini, Francesco Franchi, Antonio Tello-Montoliu, Ronakkumar Patel, Andrew Darlington, José Luis Ferreiro, Jung Rae Cho, Ana Muniz-Lozano, Bhaloo Desai, Martin M. Zenni, Luis A. Guzman, Theodore A. Bass and Dominick J. Angiolillo.
University of Florida College of Medicine-Jacksonville, Jacksonville, FL, USA
JACC
Cardiovasc
Interv
. 2014 Apr;7(4):426-34.Slide2
Authors and disclosuresThe present study was funded by a grant from The Medicines Company. The study was designed and undertaken by the investigators who had final responsibility for the decision to publish these results.Dominick J. Angiolillo: Received payment as an individual for: a) Consulting fee or honorarium from Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly, Daiichi Sankyo, The Medicines Company, AstraZeneca, Merck, Evolva, Abbott Vascular and PLx Pharma; b) Participation in review activities from Johnson & Johnson, St. Jude, and Sunovion. Institutional payments for grants from Bristol Myers Squibb, Sanofi-Aventis,
Glaxo Smith Kline, Otsuka, Eli Lilly, Daiichi Sankyo, The Medicines Company, AstraZeneca, Evolva, Gilead; and has other financial relationships with Esther and King Biomedical Research Grant.José Luis Ferreiro: reports honoraria for lectures from Eli Lilly Co; Daiichi Sankyo, Inc.; Astra Zeneca.Theodore A. Bass: has received research funds (paid to Institution) from Baxter.All other authors have not disclosures to report.Slide3
BACKGROUND Despite the more rapid and potent levels of platelet inhibition achieved compared with clopidogrel, pharmacodynamic studies have shown interindividual variability in prasugrel effects (1-5)In particular, delayed antiplatelet effects and high rates of high on platelete reactivity
have been shown especially in the early hours after prasugrel administration in patients with STEMI undergoing primary PCI (6,7)The use of orally administered antiplatelet agents may be challenging in patients unable to swallow (e.g. patients sedated, intubated, in shock, or those with nausea or vomiting)These observations support the need for intravenous antiplatelet therapies able to yield more prompt and potent platelet inhibitory effects, which are unlikely to be achieved with oral medications (5) Cangrelor, is a potent intravenous direct-acting and reversible P2Y12 receptor antagonist which has shown to reduce ischemic complications, including stent thrombosis, in P2Y12 inhibitor naïve patients undergoing PCI (8,9)
1
)
Alexopoulos
D et al.
Curr
Pharm Des.
2013;19:5121-6;
2
)
Bonello
L et
al. J Am
Coll
Cardiol
.
2011;58:467-73;
3
)
Alexopoulos
D et al.
Int
J
Cardiol
.
2012;154:333-4
;
4
)Ferreiro JL et al.
JACC Cardiovasc Interv.
2013;6:182-4
;
5
)Ferreiro
JL et al. Circ Cardiovasc Interv.
2012;5:433-45
;
6
)Alexopoulos
D et al. Circ Cardiovasc Interv.
2012;5:797-804
;
7
)Parodi
G et al. J Am Coll Cardiol.
2013;61:1601-6;
8
)Bhatt
DL et al. N Engl J Med.
2013;368:1303-13;
9
)Steg
PG et al. Lancet.
2013;382:1981-92.Slide4
STUDY AIMThe aim of this prospective, randomized, pharmacodynamic investigation was to assess by whole blood vasodilator-stimulated phosphoprotein (VASP) the in vitro effects of cangrelor on platelets from patients with coronary artery disease on maintenance prasugrel 10mg/day therapy
treated with two reloading dose (30mg or 60mg) regimens.PRIMARY END-POINTThe primary endpoint of the study was the comparison between PRI before and after in vitro incubation with cangrelor at baseline, while patients were on maintenance prasugrel 10mg/day. Slide5
Inclusion criteria:Age between 18 and 74 years oldaspirin (81 mg/day) and prasugrel (10 mg/day) for at least 14 daysstable coronary artery disease
Exclusion criteria:age ≥ 75 years oldactive bleedingprior cerebrovascular eventbody weight < 60 kgclinical instability after the index eventuse of oral anticoagulationplatelet count < 100x106/µl
hemoglobin <10 g/dl
creatinine
> 2
mg/dl
hepatic enzymes >2.5 times the upper limit of
normal
pregnant and lactating females
STUDY POPULATION
Slide6
STUDY DESIGN
Patients on aspirin (81 mg/day) and prasugrel (10mg/day) ≥ 14 days post-PCI
Prasugrel
30 mg
Reload
Prasugrel
60
mg
Reload
Pharmacodynamic
testing:
1
hour
Pharmacodynamic
testing:
Baseline
Pharmacodynamic
testing:
4 hours
Pharmacodynamic testing
(VASP) with
and without
in vitro
cangrelor
500
nMSlide7
PLATELET FUNCTION TESTWhole blood vasodilator-stimulated phosphoprotein (VASP)The VASP assay was used to determine the platelet reactivity index (PRI) according to standard protocols . VASP was performed before and after in vitro incubation with 500 nM
cangrelor at each time point. In brief, VASP phosphorylation (VASP-P) was measured by quantitative flow cytometry using commercially available labelled monoclonal antibodies (Biocytex Inc, Marseille, France). A reduced PRI is indicative of greater inhibition of the P2Y12 signalling pathway. Slide8
STATISTICAL ANALYSISConformity to the normal distribution was evaluated for continuous variables with the Kolmogorov-Smirnov testChi-square test or Fisher’s exact test (if expected value in any cell was fewer than 5) were used to compare categorical variables between two groupsA repeated measures analysis of variance (ANOVA) model was used to evaluate intra-group comparisons and the overall difference between groups, using Bonferroni approach to correct for multiple comparisonsAn analysis of covariance (ANCOVA) method with a general linear model, using the baseline value of platelet reactivity as a covariate, was used to evaluate all between-groups comparisons
A 2-tailed p value of < 0.05 was considered to indicate a statistically significant difference for all the analyses performedSlide9
RESULTS (1)Baseline CharacteristicsSlide10
RESULTS (2)Comparison of platelet reactivity values between 30 mg and 60 mg prasugrel re-loading dose in the absence of cangrelor
Baseline1 hour4 hours
Prasugrel
30 mg
Prasugrel
60 mg
p=0.481
p=0.001
Prasugrel
30 mg
Intragroup ANOVA p<0.001
Baseline
vs
1hr p<0.001
Baseline
vs
4hrs p<0.001
1hr
vs
4hrs p=0.065
Prasugrel
60 mg
Intragroup ANOVA p<0.001
Baseline
vs
1hr p<0.001
Baseline
vs
4hrs p<0.001
1hr vs
4hrs p=0.001
Platelet Reactivity Index %
ANOVA p=0.935Slide11
RESULTS (3)Comparison of platelet reactivity values between 30 mg and 60 mg prasugrel re-loading dose in the presence of cangrelor
Baseline + cangrelor
1 hour
4 hours
Prasugrel
30
mg +
cangrelor
Prasugrel
60
mg +
cangrelor
p=0.604
p=0.334
Platelet Reactivity Index %
ANOVA p=0.373
Prasugrel
30 mg +
cangrelor
Intragroup ANOVA p<0.001
Baseline
vs
1h p=0.002
Baseline
vs
4
hs
p<0.001
1h
vs
4hs p=0.401
Prasugrel
60 mg +
cangrelor
Intragroup ANOVA p=0.001
Baseline
vs
1hr p=0.124
Baseline
vs
4
hrs
p=0.005
1
hr
vs
4
hrs
p=0.016Slide12
RESULTS (4)p<0.001
p=0.013p=0.001ANOVA p=0.001
Platelet Reactivity Index %
Comparison of
PRI
expressed as
percentages
measured by VASP
across time points
in the
prasugrel
30 mg reload group in presence and absence of
cangrelorSlide13
RESULTS (5)Comparison of PRI expressed as percentages measured by VASP across time points in the
prasugrel 60 mg reload group in presence and absence of cangrelorp<0.001p=0.002p=0.325
ANOVA p<0.001
Platelet Reactivity Index %Slide14
Baseline + cangrelor
1 hour4 hoursΔ Platelet Reactivity Index %
p
>0.999
p
>0.999
ANOVA p=0.290
Prasugrel
60
mg +
cangrelor
Prasugrel
30
mg +
cangrelor
RESULTS
(6)
Absolute change or delta (Δ) between
PRI
values in the absence and presence of
cangrelor
in each arm (30 mg and 60 mg
prasugrel
re-load)Slide15
CONCLUSIONS In vitro cangrelor is associated with enhanced platelet inhibition when added to platelets of patients on prasugrel maintenance therapy as well as when exposed to a reloading dosePlatelet inhibitory effects of in vitro
cangrelor are immediate and faster than prasugrel reloading aloneComparable levels of platelet reactivity to that achieved with in vitro cangrelor were observed only 4 hours after a 60 mg prasugrel reloading doseRollini F. et al. JACC Cardiovasc Interv. 2014 Apr;7(4):426-34