Transcript Slides - Clinical Trial Results

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.
Authors and disclosures
The 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.
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.
STUDY AIM
The 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-POINT
The 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.
STUDY POPULATION
Inclusion criteria:
Exclusion criteria:
 Age between 18 and 74 years old
 age ≥ 75 years old
 aspirin (81 mg/day) and prasugrel
(10 mg/day) for at least 14 days
 stable coronary artery disease
 active bleeding
 prior cerebrovascular event
 body weight < 60 kg
 clinical instability after the index event
 use of oral anticoagulation
 platelet 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 DESIGN
Patients on aspirin (81 mg/day) and prasugrel
(10mg/day) ≥ 14 days post-PCI
Pharmacodynamic testing:
Baseline
Prasugrel 30 mg
Reload
Prasugrel 60 mg
Reload
Pharmacodynamic testing:
1 hour
Pharmacodynamic testing:
4 hours
Pharmacodynamic testing (VASP) with and without in vitro cangrelor 500 nM
PLATELET FUNCTION TEST
Whole 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.
STATISTICAL ANALYSIS
 Conformity to the normal distribution was evaluated for continuous variables with the
Kolmogorov-Smirnov test
 Chi-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 groups
 A repeated measures analysis of variance (ANOVA) model was used to evaluate intragroup comparisons and the overall difference between groups, using Bonferroni
approach to correct for multiple comparisons
 An 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 betweengroups comparisons
 A 2-tailed p value of < 0.05 was considered to indicate a statistically significant
difference for all the analyses performed
RESULTS (1)
Baseline Characteristics
RESULTS (2)
Comparison of platelet reactivity values between 30 mg and 60 mg
prasugrel re-loading dose in the absence of cangrelor
60
ANOVA p=0.935
Platelet Reactivity Index %
50
Prasugrel 30 mg
40
Prasugrel 60 mg
30
p=0.481
20
p=0.001
10
0
Baseline
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
1 hour
4 hours
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
RESULTS (3)
Comparison of platelet reactivity values between 30 mg and 60 mg
prasugrel re-loading dose in the presence of cangrelor
60
Platelet Reactivity Index %
ANOVA p=0.373
50
Prasugrel 30 mg + cangrelor
40
Prasugrel 60 mg + cangrelor
30
20
p=0.604
p=0.334
10
0
Baseline + cangrelor
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
1 hour
4 hours
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=0.016
RESULTS (4)
Comparison of PRI expressed as percentages measured by VASP across time points
in the prasugrel 30 mg reload group in presence and absence of cangrelor
60
ANOVA p=0.001
Platelet Reactivity Index %
50
40
Prasugrel 30 mg
p<0.001
Prasugrel 30 mg + cangrelor
30
p=0.013
20
p=0.001
10
0
Baseline
1hour
4hours
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 cangrelor
60
ANOVA p<0.001
Platelet Reactivity Index %
50
Prasugrel 60 mg
40
p<0.001
Prasugrel 60 mg + cangrelor
30
p=0.002
20
p=0.325
10
0
Baseline
1hour
4hours
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)
60
ANOVA p=0.290
Δ Platelet Reactivity Index %
50
Prasugrel 30 mg + cangrelor
40
Prasugrel 60 mg + cangrelor
30
20
p>0.999
p>0.999
10
0
Baseline + cangrelor
1 hour
4 hours
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 dose
 Platelet inhibitory effects of in vitro cangrelor are immediate and faster than prasugrel
reloading alone
 Comparable levels of platelet reactivity to that achieved with in vitro cangrelor were
observed only 4 hours after a 60 mg prasugrel reloading dose
Rollini F. et al. JACC Cardiovasc Interv. 2014 Apr;7(4):426-34