1
Novel Antiplatelet Agents: AZD6140, Cangrelor, TRA
2Meadows TA, Bhatt DL. Circ Res. 2007;100:1261
Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. 3
1. van Giezen JJ, Humphries RG. Semin Thromb Hemost 2005;31:195-204.
AZD6140 Characteristics The first reversible oral adenosine diphosphate (ADP) receptor
antagonist1
New class of P2Y12 inhibitors• Cyclo-pentyl-triazolo-pyrimidine (CPTP) • Not a thienopyridine or ATP analog • Direct-acting (not a prodrug); does not require metabolic activation
Reversible binding; degree of inhibition reflects plasma concentration• half-life of approximately 12 h• More rapid reversal of effect—full recovery of platelet function
Rapid onset (within 2 hours); peak plasma levels within 2 to 3 hours Greater and more consistent inhibition of ADP-induced platelet
aggregation versus clopidogrel
Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51.
Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. 4
RandomizationV1
Day 1
V2 V3 V4 Follow-up
Week 4 Week 8 Week 12 Final Visit+7 days
AZD6140 90 mg bid (n = 334)
AZD6140 180 mg bid (n = 323)
Clopidogrel 75 mg qd (n = 327)
ACS Patients;Onset of chestpain and 48 h maximum torandomization
N = 990
*Of the 990 randomized patients, 984 who received ≥1 dose of study drug and were included in the safety analysis dataset.GP = glycoprotein; LMWH = low-molecular-weight heparin.
DISPERSE2 Main Study Design
All patients received aspirin (≤325 mg first dose, then 75–100 mg qd) and heparin/LMWH and/or a GPIIb/IIIa antagonist
• 50% of AZD6140 patients in each arm received a 270-mg loading dose• In the clopidogrel group, thienopyridine-naïve patients received a 300-mg loading dose
Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51.
Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. 5
*p < 0.05 for AZD6140 versus clopidogrel. Mean ± SD.
DISPERSE2 PK/PD Substudy: Inhibition of Platelet Aggregation After Initial Doses on Day 1 in Clopidogrel Naïve patients
0 2 4 6 8 10 120
25
50
75
100
Time postdose (h)
Mea
n %
inhi
bitio
n
**
*
**
*
* **
**
*
0 2 4 6 8 10 120
20
40
60
80
100
**
**
**
**
*
**
*
Time postdose (h)
Mea
n %
inhi
bitio
n
Maximum Aggregation Response Final Aggregation Response
AZD6140 180 mgAZD6140 90 mg Clopidogrel 300 mgAZD6140 270 mg
Storey R, et al. J Am Coll Cardiol 2007;50:1852-6.
Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. 6
*p < 0.05 for AZD6140 versus clopidogrel.
0 2 4 6 8 10 120
20
40
60
80
**
*
*
**
*
**
**
*
Time postdose (h)
Mea
n %
pla
tele
t agg
rega
tion
DISPERSE2 PK/PD Substudy: Suppression of Platelet Aggregation in Clopidogrel-Pretreated Patients
Clopidogrel 75 mg
AZD6140 180 mgAZD6140 90 mg
AZD6140 270 mg
Storey R, et al. J Am Coll Cardiol 2007;50:1852-6.
Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. 7
*Minor bleeding without major bleeding.
Week 4 (Primary End Point)
0
2
4
6
8
10
12
AZD6140 90 mg bid
AZD6140 180 mg bid
Clopidogrel 75 mg qd
Tot
al B
leed
ing
Rat
e, %
Overall
0
2
4
6
8
10
12
AZD6140 90 mg bid
AZD6140 180 mg bid
Clopidogrel 75 mg qd
9.6
7.78.0
10.2 10.29.2
Tot
al B
leed
ing
Rat
e, %
MajorMinor*
DISPERSE2 Protocol-Defined Bleeding Rates (%) Week 4 and Overall (Week 12)
Protocol-defined total bleeding rates were similar for all groups No evidence of dose-response pattern for major bleeds
Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51.
Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. 8
20%
10%
5%
01
15%
Cum
ulat
ive
Ris
k of
an
Eve
nt
11 21 31 41 51 61 71 81 91
AZD6140 90 mg bidAZD6140 180 mg bidClopidogrel 75 mg daily
Study Day
DISPERSE2 Cumulative Adjudicated Clinical End Point of CV Death/MI/StrokeKaplan-Meier Estimates
Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51.
Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. 9
Discontinuation rates due to adverse events were low and similar among all groups• 6%, 7%, and 6% discontinued in the AZD6140 90 mg bid, AZD6140 180 mg bid, and clopidogrel 75
mg qd groups, respectively*p < 0.05 vs. clopidogrel. All other values are not significant.
DISPERSE2 Crude Incidence ofNon-Bleeding Adverse Events (%)
Preferred termAZD6140 90 mg bid
n = 334AZD6140 180 mg bid
n = 323Clopidogrel 75 mg qd
n = 327
Dyspnea* 10.5 15.8 * 6.4
Chest pain 7.5 7.4 8.9
Headache 9.6 6.5 8.6
Nausea 6.6 6.5 3.4
Dyspepsia 4.8 3.1 2.8
Insomnia 5.4 4.6 2.8
Diarrhea 3.0 7.4 * 3.4
Hypotension 4.2 * 3.7 * 0.6
Dizziness 4.2 3.4 3.1
Syncope 1.2 1.5 0.6
Rash 0.9 1.9 0.6
Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51.
Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. 10
ECG = electrocardiogram; NSVT = nonsustained ventricular tachycardia; VT = ventricular tachycardia.
DISPERSE2 Arrhythmia Events Detected From Post-Hoc Analysis of ECG Monitoring (%)
AZD6140 90 mg bid n = 305
AZD6140 180 mg bid
n = 283
Clopidogrel 75 mg qd
n = 297
Ventricular tachycardia
Patients with sustained VT >30 s 0.0 0.3 0.3
Patients with at least 1 NSVT 22 26 22
Patients with at least 1 triplet 29 27 31
Ventricular pauses
Patients with at least 1 pause >2.5 s 5.5 9.9 4.3
Patients with at least 1 pause >5 s 1.6 2.1 0.3 Ventricular pauses were mostly asymptomatic Continuous ECG monitoring began at randomization for 885 patients (89.4% of patients enrolled) There was no difference in rates of VT among the 3 groups
Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51.
Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. 11
DISPERSE2 Conclusions AZD6140 had greater platelet inhibition than clopidogrel AZD6140 shows similar safety and tolerability to
clopidogrel
AZD6140, a reversible inhibitor of the P2Y12 receptor, offers potential for flexibility by allowing rapid initiation of surgical procedures following discontinuation of drug
With lack of increased major bleeding and encouraging trends in efficacy, this agent is now being studied in the PLATlet inhibition and patient Outcomes (PLATO) outcomes study
Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51.
®*
AZD6140 90 mg bid
Clopidogrel 300/600mg load: 75mg od
V1 V2 V3 V4 V5 V6End of
TreatmentFollow-up
Onset of chest pain <24h
1 mo
3 mo
6 mo
6 to 12 mo
EOT + 1 mo
* N=9000 per treatment arm
Study DesignStudy Design
9 mo
12 mo
Cangrelor (AR-C69931MX)Parenteral ADP-P2Y12 receptor antagonist
ATP analogue Molecular weight 800 DaltonsPlasma half-life of 5-9 minutes20 minutes for return to normal platelet function
N N
NN
NH
SCF3
OHOH
OO
PO
O
PP
OO
OClCl
OO
O
S
4Na+
Cangrelor Phase II Clinical Data: Compared with
Abciximab in PCIDouble-blind randomized trial performed in US
Incidence of events up to 7 days
5.7%5.4%
2.1%
1.0%
Death, MI, revascularization Major bleed (TIMI criteria)
Abciximab (N=94)
Cangrelor (N=105)
0%
1%
2%
3%
4%
5%
6%P=NS
Greenbaum, AB et al. Am Heart J. 2006;151;689.e1-689.e10.
CHAMPION Program
Phase III program underway
1O Endpoint – superiority for ischemic events
vs. clopidogrel 600 mg at the start of PCI
vs. clopidogrel 600 mg at the end of PCI
N = 9,000 pts N = 6,300 pts
TRANSCENDENCE-PCI
Subjects Undergoing Non-Urgent PCI or Cardiac Catheterization
No PCI**
Cardiac Catheterization
Safety: TIMI Major plus Minor BleedingEfficacy: Death/MACE
CABG Medical Management
Quantify Postoperative Chest-
Tube Drainage, Transfusions, and
Re-exploration
Safety: TIMI Major plus Minor Bleeding
No**
0.5 mgn~100
1 mgn~100
2.5 mgn~100
Placebon~100
PCI - Subjects Receive Clopidogrel and Antithrombin
Randomization #2
Randomization #1 3:1 SCH 530348 : PlaceboSingle Loading Dose Prior to Catheterization
TRANSCENDENCE-PCI, Thrombin Receptor Antagonist for Clinical Event Reduction Over Standard Concominant therapies in Percutaneous Coronary Intervention.
Prior MI, Ischemic CVA, or PAD
SCH 530348SCH 530348
PlaceboPlacebo
RANDOMIZE 1:1 DOUBLE BLINDStratify by CAD, CVD or PAD
and intent to use thienopyridine
Follow up VisitsDay 30, Mo 4, Mo 8, Mo 12
Q6 months
Standard care, including oral antiplt rx
Final Visit
Primary EPCV Death, MI, Stroke,
Urgent Coronary Revascularization
Major Secondary EP: CV death, non-fatal MI, non-fatal stroke
Trial FeaturesGlobal: 31 countries~1000 sites~19,500 subjectsDouble-blindEvent-driven
Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50