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

1. How to use cangrelor?
Tobias Geisler, Tuebingen/Germany

2. Disclosures
Company Name Relationship
Eli Lilly / Daiichi Sankyo Research / educational grants, honoraria, consultant
Astra Zeneca Honoraria, consultant
Ferrer Honoraria, consultant
MSD Honoraria
The Medicines Company Research grants, honoraria
Bristol Myers Squibb Research / educational grants, honoraria, consultant
Bayer HealthCare Research / educational grants, honoraria, consultant
Boehringer Ingelheim Honoraria, consultant

3. Généreux, J Am Coll Cardiol 2014
Geisler T, Eur Heart J.
2010;31(1):59-66.
Geisler T, Eur Heart J. 2010;31(1):59-66.

4. HR [95%CI] =
2.54 [1.55, 4.16]
P=0.0001
PRU >208 (n=3610)
PRU ≤208 (n=4839)
Stentthrombosis
(def/prob)(%)
0
1
2
Months
0 3 6 9 12
3610 3450 3420 3380 3152
4839 4688 4654 4631 4341
Number at risk:
PRU > 208
PRU ≤ 208
1.3%
0.5%
Event Adj HR [95%CI] P value
ST, def/prob 2.49 [1.43, 4.31] 0.001
- Definite 3.05 [1.62, 5.75] 0.0006
MI 1.42 [1.09, 1.86] 0.01
Major bleeding 0.73 [0.61, 0.89] 0.002
Death, all-cause 1.20 [0.85, 1.70] 0.30
ADAPT-DES: Multivariable propensity score adjusted risk
of VerifyNow PRU >208 for subsequent 1-year adverse
events (n=8,583)
Stone GW, presented at TCT & Lancet 2013; 382: 614–23
Platelet reactivity and clinical outcomes after coronary
artery implantation of drug-eluting stents (ADAPT-DES):
a prospective multicentre registry study

5. Cangrelor Pharmacology
PK and PD
0
0
%PlateletAggregation
(Impedance)
20 40 60 80 100 120
100
200
300
400
500
600
700
800
Concentration(ng/mL)
Time (Minutes)
Recovery Time
~60 minutes
Infusion 4 mcg/kg/min
Bolus 30 mcg/kg
Plasma
Concentration
Platelet
Activity
160
140
120
100
80
60
40
20
0
160140
Blood levels of cangrelor (green line/PK), and platelet
activity (blue line/PD) with administration of a 30 mcg/kg IV
bolus followed by a 4 mcg/kg/min IV infusion.
0 20 40 60 80 100 120
Time (Minutes)
160140
Akers et al Clin Pharmacol 2010;50:27-35

6. Cangrelor Pharmacology
– compared to oral P2Y12-Inhibitors
Roffi M, et al. European Heart Journal (2016) 37, 267–315

7. Angiolillo DJ, Circulation. 2017;136:00–00
Kairuz V, presented at
ACC, JACC Volume 71,
Issue 11 Supplement,
March 2018

8. Cangrelor compared to clopidogrel
– randomized clinical trials

9. Comparison of platelet function with newer
P2Y12 inhibitors at the end of PCI in
matched* cohorts
Mean(95%CI)impedance
plateletaggregation(ADP)/Units
20
40
Control
(Prasugrel/Ticagrelor LD before PCI)
Cangrelor
0
60
P<0.001
*Matching according to type
of ACS, gender, age
Procedure time comparable in both groups
Droppa M, Geisler T, Int J Cardiol. 2016 Nov 15;223:848-851.

10. Platelet Inhibition With Cangrelor and Crushed Ticagrelor in
Patients With STEMI Undergoing P-PCI- Results of the CANTIC
Study
Franchi F, Circulation. 2019;139:1661–1670.

11. Transition from IV to oral P2Y12 inhibitors
Angiolillo DJ, Circulation. 2017;136:00–00. DOI: 10.1161/CIRCULATIONAHA.117.031164
* According to the package insert of the European Medical Agency, but not that of the US Food and Drug Administration, prasugrel may also be
administered 30 minutes before infusion is stopped. Preliminary studies have shown that prasugrel given at the start of a 2 hour infusion of
cangrelor results in insufficient platelet inhibition, but this strategy cannot be routinely recommended until more data are available.

12. Schneider DJ, Coronary Artery Disease 2016, 27:65–69
Transition from IV to oral P2Y12 inhibitors

13. Cangrelor Pharmacology
– compared to oral P2Y12-Inhibitors
Roffi M, et al. European Heart Journal (2016) 37, 267–315

14. Mean(95%CI)impedanceplatelet
aggregation(ADP)/Units
Baseline End of PCI End of
infusion
2h after infusion
P<0.001
(compared to all other TPs)
ns
0
20
40
60
Droppa M, Geisler T, Int J Cardiol. 2016 Nov 15;223:848-851.
Course of platelet function when giving ticagrelor concomitantly to cangrelor
infusion and prasugrel 30 min before till end of infusion in ACS patients

15. Randomized Comparison of Oral P2Y12-Receptor Inhibitor
Loading Strategies for Transitioning From Cangrelor -
The Excelsior LOAD2 Trial
Hochholzer W, et al., JACC Cardiovasc Interv 2017;10(2):121-129

16.  Cardiogenic shock, Anterior Myocardial infarction (subacute,
symptom onset 2 days ago), atrial fibrillation
 unknown cardiomyopathy (tachycardiomyopathy??)
 no pretreatment with P2Y12 Inhibitors
Clinical use in real life: Case 1

17. Vaduganathan, JACC 2017
Cangrelor indication
Pooled CHAMPION 11.3 %
STEMI
Real World 49% STEMI
(Single Centre) and 98%
SCAAR
CS/Cardiac arrest 25% (Single
Centre), 18% SCAAR
Grimfjärd P, Eur Heart J - Cardiovasc
Pharmacother (2019) 5, 151–157

18. Cardiogenic shock strongest predictor for stent
thrombosis
Iqbal etz al, EuroIntervention 2013;9:62-69
Incidence and predictors of stent thrombosis: a single-centre study of 5,833 consecutive patients undergoing
coronary artery stenting

19. GPI´s in cardiogenic shock
Thiele et al. Eur Heart J 2015;36:1223-1230

20. Vaduganathan JAMA Cardiol. 2017;2(2):127-135.
Evaluation of Ischemic and Bleeding Risks Associated With 2 Parenteral
Antiplatelet Strategies Comparing Cangrelor With Glycoprotein IIb/IIIa
Inhibitors: An Exploratory Analysis From the CHAMPION Trials

22. Mazzeffi M, et al. Ann Thorac Surg 2016;101:682–9

23. Start PCI
Cangrelor Bolus (15ml)—> Cangrelor Infusion (120ml/h)
2h
Prasugrel 60mg LD
(crushed)
Stop PCI
50min
periprocedural heparin
anticoagulation:
pTT guided full dose
heparinization
Prasugrel 10mg od
(crushed)
Rationale:
• Fast onset of platelet inhibition desirable, high risk for stent thrombosis
• Poor metabolization of oral P2Y12 inhibitors due do decreased absorption in cardiogenic shock
• high risk for periprocedural bleeding at vascular access sites (Impella 13F right femoral artery, ECLS
venous canula (24F) and arterial canula (17F) left femoral artery
• controllable, short acting P2Y12 receptor antagonists desirable —> cangrelor

24. Cangrelor use prior to left ventricular assist
device surgery: a case series
Washam JB, J Thromb Thrombolysis. 2018;46(2):131-133.

25. N= 600 patients with CS
enrolled in IABP shock II trial
N= 147 consecutive patients with CS
treated with cangrelor
1:1 matching
according to STEMI, subsequent oral P2Y12 inhibition, use of
Glycoprotein IIb/IIIa-Inhibitors, cardiac arrest and culprit lesion
88 CS control patients treated with oral
P2Y12 inhbitors only
88 CS treated with cangrelor
12-month follow-up available in 87 patients
(98.9%)
6-month follow-up available in 88 patients
(100%)
6-month follow-up available in 88 patients
(100%)
12-month follow-up available in 88 patients
(100%)

26. Cangrelor in cardiogenic shock PCI patients – comparative analysis
Boston/Tuebingen cohort with patients from IAPB-SHOCK II trial
(matched according to STEMI (70.5%), Clopidogrel versus Prasugrel/Ticagrelor (43.2%/56.8%),
GPI use (13.6%), cardiac arrest (46.6%) and Culprit lesion LM/LAD (47.7%)
19,3
34,1
47,1
81,2
22,6
29,5
36,4
95,1
0
25
50
75
100
Gusto moderate / severe bleeding 30 day mortality 12 month mortality TIMI-Flow improvement PCI %
IABP-SHOCK II Cangrelor
P=0.34
P=0.079
P=0.71
P=0.036
Droppa M, Geisler T , Resuscitation. 2019;137:205-212

27. DAPT-SHOCK Randomized trial
Estimated Enrollment : 304 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Official Title: Cangrelor Versus Ticagrelor In Patients With Acute Myocardial Infarction Complicated With Initial Cardiogenic Shock
Actual Study Start Date : August 1, 2018
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : June 2021
Primary Outcome Measures : Clinical endpoint
[ Time Frame: Within 30 days after randomization ]
Combined endpoint defined as Death/Myocardial infarction/Stroke
Laboratory endpoint [ Time Frame: Periprocedural (periPCI)
period ]
Early achievement of efficient inhibition of ADP-induced platelet aggregation. Efficient inhibition is defined by the Platelet
Reactivity Index (determined based on the VASP protein phosphorylation) < 50%.
Secondary Outcome Measures : Key secondary net-clinical
endpoint [ Time Frame: Within 30 days after randomization ]
Death/Myocardial infarction/Urgent revascularisation of the infarct-related artery /Stroke/Major bleeding BARC ≥ 3
Key safety endpoint [ Time Frame: Within 30 days after
randomization ]
Incidence of bleeding according to the BARC definition
ClinicalTrials.gov Identifier: NCT03551964

28. Clinical use in real life: Case 2
 89 year old female patient chronic OAC with apixaban
 Fell at home with left temporal subdural bleeding
 resuscitation due to ventricular fibrillation
 no pretreatment with P2Y12 Inhibitors

29. Andexanet in bleeding under Factor Xa
inhibitor treatment
Primary Efficacy Endpoints:
- % change in anti-fXa activity
- hemostatic efficacy at 12hs from end of andexanet Infusion.
Acute overt major bleeding ≤ 18 hours of anti-Xa medication
Andexanet IV bolus and 2 hour infusion
Pts on apixaban or
>7 h from last rivaroxaban dose
Bolus 400 mg +
Infusion 480 mg @ 4 mg/min
Pts on enoxaparin and edoxaban or
≤ 7 h from last rivaroxaban dose‡
Bolus 800 mg+
Infusion 960 mg @ 8 mg/min
Secondary Efficacy Objective: Relationship between decrease in anti-fXa and achievement of
hemostatic efficacy
Safety Objectives: including adjudicated thrombotic events and antibodies to fX, fXa, and andexanet
and 30-day mortality

30. Am J Gastroenterol Suppl 2016; 3:22–28

32. Cangrelor Pharmacology
PK and PD
0
0
%PlateletAggregation
(Impedance)
20 40 60 80 100 120
100
200
300
400
500
600
700
800
Concentration(ng/mL)
Time (Minutes)
Recovery Time
~60 minutes
Infusion 4 mcg/kg/min
Bolus 30 mcg/kg
Plasma
Concentration
Platelet
Activity
160
140
120
100
80
60
40
20
0
160140
Blood levels of cangrelor (green line/PK), and
platelet activity (blue line/PD) with
administration of a 30 mcg/kg IV bolus
followed by a 4 mcg/kg/min IV infusion.
Akers et al Clin Pharmacol 2010;50:27-35

33. Antithrombotic regimen
Start PCI
2h
Clopidogrel 600mg
75 mg o.d.
Stop PCI
30min
periprocedural bivalirudin
anticoagulation:
Rationale:
STEMI high risk for stent thrombosis, increased risk for progression of subdural
bleeding
Cangrelor Bolus (8ml)—>
Cangrelor Infusion (66ml/h)
Cangrelor Bridging regimen (0.75 microgr/kg
per/minute)
48h

35. Lavender MA, Circ Cardiovasc Interv. 2017;10:e005257.

36. 2 hours later 4 hours later 14 hours later
3 days later 7 days later 6 weeks later

37. When to use cangrelor
 STEMI / particularly cardiogenic shock
 Inability to absorb quickly new AP agents
 High risk for early ST
 awaiting CABG or other surgical procedure after a recent
ACS and/or stenting
 undergoing ad hoc PCI without P2Y12 inhibitor
pretreatment
 in patients with a transiently increased bleeding risk

38. Thank you for your attention!

39. Abnousi F, Am Heart J 2017;188:147-55.
Cangrelor reduces the risk of ischemic complications in patients with single-vessel and multi-
vessel disease undergoing percutaneous coronary intervention: Insights from the CHAMPION
PHOENIX trial

40. Results: 48-hour Stent thrombosis (key secondary endpoint)
According to the number of angiographic risk factors per patient and randomization
0,1 0,9
1,1
1,00,3
1,1
1,4
2,3
1,
2,
3,
0 1 2 ≥3
STat48hrs(%)
Cangrelor (n=5426) Clopidogrel (n=5428)
Stone GW et al. TCT 2015.
High-risk characteristics:
•Long (>20 mm)
•Bifurcation (DS ≥50%)
•Eccentric
•Thrombus
•Tortuous (mod/sev)
•Angulated (mod/sev)
•Calcified (mod/sev)
•Left main (DS ≥50%)
•Multi-lesion PCI

41. Mazzeffi M, et al. Ann Thorac Surg 2016;101:682

42. Short-acting P2Y12 blockade to reduce platelet dysfunction and coagulopathy during
experimental extracorporeal circulation and hypothermia
Human blood Animal (Pig) model
Krajewski S, Br J Anaesth. 2012;108(6):912-21.