Ponencia presentada por el Dr. José Luis Ferreiro en la Reunión EuroIMAT 2020, celebrada en Barcelona (20 y 21 de febrero de 2020).

1. PHARMACOLOGICAL CHARACTERISTICS OF
PARENTERAL ANTIPLATELET AGENTS
Dr. José Luis Ferreiro
Hospital Universitario de Bellvitge – IDIBELL
Interventional Cardiology Unit – Cardiovascular Research Lab
L’Hospitalet de Llobregat, Barcelona, Spain

2. CONFLICTS OF INTEREST
• Honoraria for lectures:
• Eli Lilly Co; Daiichi Sankyo, Inc.; AstraZeneca; Roche Diagnostics; Pfizer; Abbott; Boehringer Ingelheim; Ferrer;
Bristol-Myers Squibb
• Advisory boards:
• AstraZeneca; Eli Lilly Co; Ferrer; Boston Scientific, Pfizer, Boehringer Ingelheim; Daiichi Sankyo,Inc.; Bristol-
Myers Squibb
• Research grants:
• AstraZeneca

3. INDEX
• Glycoprotein IIb/IIIa inhibitors
• Cangrelor: Pharmacological characteristics and transition to oral agents

4. GLYCOPROTEIN IIB/IIIA INHIBITORS

5. AVAILABLE ANTIPLATELET DRUGS IN ACS/PCI
Modified from Ferreiro JL et al. Circ Cardiovasc Interv 2012;5:433-45.

6. Abciximab Tirofiban Eptifibatide
Molecular structure Fab of a monoclonal antibody Non-peptide synthetic molecule Synthetic cyclic heptapeptide
Molecular mass 47.615 Da 495 Da 832 Da
Reversibility Yesa Yes Yes
Affinity Very high High Intermediate
Specifity Nob Yes Yes
Plasmatic half-life
Biphasic: <10 min and ~30
minutes
~2 hours ~2,5 hours
Duration of antiplatelet effect
after discontinuation
Platelet life-span ~4-8 hours ~4 hours
PCI Dosing
Bolus: 0.25 mg/kg
Infusion: 0.125 µg/kg/min
(maximum 10mg/min)
Bolus: 25 µg/kg
Infusion: 0.15 µg/kg/min
Bolus: 180 µg/kg + second 180 µg/kg
bolus 10 min after the first one
Infusion: 2 µg/kg/min
Renal adjustment No
In patients with CrCl <30 mL/min,
reduce infusion by 50%
In patients with CrCl <50 mL/min,
reduce infusion by 50%
CrCl: Creatinine clearance; Da: Dalton; Fab: antigen-binding fragment
aOften reported as irreversible due to its great affinity for the receptor.
bIt also binds to the vitronectin receptor on vascular cells and to the activated MAC-1 receptor on leucocytes.
Ferreiro JL, Franchi F. Platelet-inhibitor agents. In: SCAI Interventional Cardiology Review.3rd ed. 2018. 27-37.
GPIS

7. PHARMACODYNAMIC EFFICACY OF GPIS
PPCI (n=114)
Platelet inhibition 10min after bolus
PPCI (n=40)
Platelet inhibition 0-2h after PCI
Van Werkum JW et al. Neth Heart J. 2007;15:375-82Danzi GB et al. Am J Cardiol. 2006;97:489-93
PCI (n=120)
Platelet inhibition after PCI
Mardikar HM. Am Heart J. 2007;154:344e1-e5
Several small PD studies with conflicting results…
No clear-cut difference in initial PD efficacy between GPIs

8. MULTISTRATEGY trial
Primary PCI: abciximab vs. tirofiban
No obvious differences in clinical efficacy between GPIs in STEMI-PPCI
EVA-AMI trial
Primary PCI: abciximab vs. eptifibatide
GPIS IN PRIMARY PCI
Valgimigil M et al. JAMA. 2008;299:1788-99 Zeymer U et al. J Am Coll Cardiol. 2010;56:463-9

9. GPIS: IC OR IV ADMINISTRATION?
GpIIb/IIIa Receptor-Blockade
%Receptor-Blockade
0
10
20
40
30
60
50
70
80
90
100
110
Peripheral blood Blood coronary sinus
Bolus 1 Bolus 2 Bolus 1 Bolus 2
P=0.013 P=0.995 P<0.001 P=0.001
Deibele AJ et al. Circulation. 2010;121:784-91
Improvement in TFC with ic administration
ICE trial: ACS-PCI patients
Complete reperfusion (TFG 3, TMPG 3, ST Res≥70%)
was associated with a greater % of receptors occupied
Gibson CM et al. Circulation. 2004;110:679-84
INTEGRITI substudy: STEMI patients (n=70)

10. GPIS: IC OR IV ADMINISTRATION?
AIDA STEMI trial (n=2,065)
Thiele H et al. Lancet. 2012;379:923-31 De Rosa S et al. Int J Cardiol. 2013;168:1298-305
De Luca G et al. Atherosclerosis. 2012;222:426-33 Tang X et al. PLoS One. 2015;10:e0129718.
O’Gara PT et al. J Am Coll Cardiol. 2013;61:e78-140
No clear-cut evidence of a clinical benefit of ic or iv bolus administration of GPIs

11. FABOLUS SYNCHRO Trial: 73 NSTEACS patients on DAPT
(ASA + 600mg clopidogrel + abciximab bolus vs. ASA + 300mg clopidogrel + abciximab bolus and infusion)
GPIS: BOLUS + INFUSION IF DAPT?
Valgimigli M et al. J Thromb Haemost. 2010;8:1903-11

12. “Small molecule” agents: Need for infusion (after bolus) if a potent oral P2Y12 inhibitor is used?
GPIS: BOLUS + INFUSION?
Valgimigli M et al. JACC Cardiovasc Intv. 2012;5:268-77
FABOLUS PRO trial: STEMI patients (n=100)

13. REVASCULARIZATION GUIDELINES
STEMI
NSTEACS
SCAD
Neuman FJ et al. Eur Heart J. 2019;40:87-165

14. NOVEL SC GPI?: RUC-4 PHASE 1 TRIAL
Presented by Kereiakes DJ at ESC Congress, Paris, 2019
RUC-4 in healthy volunteers RUC-4 in SCAD patients on aspirin

15. CANGRELOR: PHARMACOLOGICAL CHARACTERISTICS
AND TRANSITION TO ORAL AGENTS

16. AVAILABLE ANTIPLATELET DRUGS IN ACS/PCI
Modified from Ferreiro JL et al. Circ Cardiovasc Interv 2012;5:433-45.

17. Sequential dephosphorylation to the nucleoside
• Stabilized ATP analogue
• Direct-acting P2Y12 antagonist
• Reversible receptor binding
• No hepatic or renal metabolisation: NO interactions
• Extremely short half-life: 3-6 minutes
• Instant onset of action: steady-state in 30 minutes
• Platelet function recovered in 60-90 minutes
• Great IPA: >90%
CANGRELOR: ATP ANALOG
van Giezen JJJ, Humphries RG. Semin Thromb Hemost. 2005;31:195-204.

18. 0
20
40
60
80
100
120
140
160
0
100
200
300
400
500
600
700
800
0 20 40 60 80 100 120 140 160
Recovery time
~60-90 minutesConcentration(ng/mL)
%PlateletActivity
Time (minutes)
Platelet
activity
Plasma
concentration
infusion
bolus
Almost instant
onset of action
Great IPA>90%
Akers et al. J Clin Pharmacol. 2010;50:27-35
CANGRELOR: PHARMACODYNAMICS

19. Effect of Cangrelor on ADP-Induced Platelet Aggregation
in Patients with NSTE-ACS
Whole Blood Impedance Aggregometry
In vitro administration of cangrelor:
Effect on other signaling pathways
CANGRELOR: PHARMACODYNAMICS
Dose-dependent effect
Potent P2Y12 blockade impact other platelet signaling pathways
Ferreiro JL et al. J Thromb Thrombolysis. 2013;35:155-64Storey RF et al. Thromb Haemost. 2001;85:401-7
Virtual effect of GPI

20. Similar platelet inhibition (just ADP stimulus).
Longer duration of abciximab.
Double-blind randomized trial in PCI
CANGRELOR VS. ABCIXIMAB
Cangrelor is not a GPI!!!
Increase in bleeding with abciximab
Greenbaum AB et al. Am Heart J. 2006;151:689

21. Bhatt DL et al. N Engl J Med. 2013;368:1303-13
CHAMPION PHOENIX: STUDY DESIGN
Primary endpoint: Death / MI / IDR at 48 hours
Primary safety EP: GUSTO Severe Bleeding at 48 hours
0
1
2
3
4
5
6
7
8
0 6 12 18 24 30 36 42 48
Patient at Risk Hours from Randomization
Cangrelor: 5472 5233 5229 5225 5223 5221 5220 5217 5213
Clopidogrel: 5470 5162 5159 5155 5152 5151 5151 5147 5147
5.9%
4.7%
Log Rank P Value = 0.006
EventRate(%)
Death/ MI/ IDR/ Stent Thrombosis within 48 Hours
Limitations of RCTs with cangrelor
• No comparison with prasugrel or ticagrelor
• Issue of pretreatment

22. CHAMPION PHOENIX: EFFICACY AND SAFETY
Bhatt DL et al. N Engl J Med. 2013;368:1303-13
No significant increase in severe bleeding
Dyspnea: 1.2 vs. 0.3%

23. CANGRELOR
2015 APPROVAL
EMA
FDA
STEMI, NSTEACS, SCAD
Neumann FJ et al. Eur Heart J. 2019;40:87-165

24. CANGRELOR: POSSIBLE CLINICAL SCENARIOS
STEMI - PPCI
No oral P2Y12 inhibitor (cardiac arrest, intubation, vomiting…)
Suitable scenario for the pharmacological properties of cangrelor
Important delay of action of P2Y12 inhibitors
SCAD - Elective PCI
High-risk or complex PCI and no pretreatment with P2Y12 inhibitors
NSTEACS - PCI
High-risk or complex PCI (high thrombus burden) and no
pretreatment with P2Y12 inhibitors
Other
Bridge therapy
Patients in cardiogenic shock needing P2Y12 inhibitors

25. Response to clopidogrel (given at FMC)
when initiating primary PCI (median time 85 min)
ORAL P2Y12 INHIBITORS IN STEMI
HTPR rates with prasugrel vs. ticagrelor in STEMI patients
undergoing pPCI
Parodi G et al. J Am Coll Cardiol. 2013;61:1601-6.Ferreiro JL et al. Thromb Haemost 2013;110:110-7

26. Patients with an ACS or treated with a coronary stent (BMS or DES) on a
thienopyridine awaiting CABG.
CANGRELOR: BRIDGE THERAPY
Angiolillo DJ et al. JAMA. 2012;307:265-74.
Phase I: Identify infusion dose that achieves >60% inhibition in >80% samples.
Cangrelor infusion of 0.75 g/kg/min met the efficacy endpoint (94.4%, 95% CI 83.9% – 100%), and was
implemented for the stage II of the trial

27. Cangrelor improves platelet inhibition in
patients receiving chronic clopidogrel
Storey RF et al. Thromb Haemost. 2002;88:488-94
CANGRELOR ON TOP OF P2Y12 INHIBITORS
CANTIC trial: Cangrelor on top of crushed
ticagrelor in STEMI patients
Franchi F et al. Circulation. 2019;13:1661-70

28. 0
Cangrelor = 30 μg/kg IV bolus + 4 μg/kg/min infusion; clopidogrel = 600 mg loading dose.
Data are means ± standard error.
1 h cangrelor, then clopidogrelClopidogrel Clopidogrel (T=0) + 2 h cangrelor
Time, h
14
16
Impedance,ohms
10
12
6
8
2
4
0
1.0 2.0 3.0 4.0 5.0 6.0 7.0
Whole-Blood Impedance Aggregometry
Caution with transition: gap in platelet inhibition
Steinhubl SR et al. Thromb Res. 2008;121:527-34.
CANGRELOR: TRANSITION TO ORAL P2Y12 INHIBITORS

29. Thienopyridines LD*
CANGRELOR
Bolus + Infusion
0
Time (minutes)
60 120
*A small pharmacodynamic study has suggested that prasugrel might be administered 30 minutes before ending the infusion of cangrelor.
Marcano AL and Ferreiro JL. Curr Atheroscler Rep. 2016;18:66
CANGRELOR: TRANSITION TO ORAL P2Y12 INHIBITORS

30. CANGRELOR
Bolus + Infusion
0
Time (minutes)
60 120
Ticagrelor LD
Marcano AL and Ferreiro JL. Curr Atheroscler Rep. 2016;18:66
CANGRELOR: TRANSITION TO ORAL P2Y12 INHIBITORS

31. • GPIs
• Most potent antiplatelet agents: no clear differences in maximal PD efficacy between them
• Main difference: length of action (abciximab >>> tirofiban / eptifibatide)
• Bolus ± short infusion (small molecule): individualize
• Clinical scenarios: bail-out situation, great thrombus burden
• Cangrelor
• Very attractive from a pharmacological standpoint
• Bolus + infusion
• Approval: PCI in patients not (pre)treated with an oral P2Y12 inhibitor
• Clinical scenarios: STEMI (best), complex or high-risk PCI and no pretreatment with oral P2Y12 inhibitors
• Other: bridging, cardiogenic shock…
• Watch out transition to oral agents
CONCLUSIONS

32. THANKS FOR YOUR ATTENTION