1. When to Switch and How to Switch
Antiplatelet (P2Y12 Receptor Inhibitors) Therapy
8th Platelet Colloquium
dddd8th Platelet Colloquium
Dominick J. Angiolillo, MD, PhD
Professor of Medicine
Medical Director - Cardiovascular Research
Program Director – Interventional Cardiology Fellowship
University of Florida College of Medicine - Jacksonville

2. Presenter Disclosure Information
Name: Dominick J Angiolillo
Within the past 12 months, the presenter or their spouse/partner have had a financial interest/arrangement or affiliation with the organization listed below.
Received payment as an individual for:
a) Consulting fee or honorarium from Amgen, Bayer, Chiesi, Sanofi, Eli Lilly, Daiichi-Sankyo, The Medicines Company, AstraZeneca, Merck, Abbott Vascular, Pfizer, and PLx Pharma;
b) Honorarium for participation in review activities (DSMB member) from CeloNova, Johnson & Johnson, St. Jude, and Sunovion.
c) Honorarium from the American Board of Internal Medicine (Interventional Cardiology Subspecialty Exam Writing Committee Member)
Institutional payments for:
a) Grant support industry: from Amgen, Glaxo-Smith-Kline, Eli Lilly, Daiichi-Sankyo, The Medicines Company, AstraZeneca, Janssen Pharmaceuticals, Inc., Osprey Medical, Inc., Novartis, CSL Behring, and Gilead.
b) Grant in gift: Spartan; Scott R. MacKenzie Foundation
c) Federal agency: NIH

3. Mechanisms of action of P2Y12 inhibitors
Franchi, F. & Angiolillo, D. J. Nat. Rev. Cardiol. 2015;12:30-47

4. Binding properties of Oral P2Y12-receptor inhibitors
a | ADP binds to the P2Y12 receptor, which b | leads to a conformational change of the receptor and to G‑protein activation.
c | Competitive binding of the active metabolite of thienopyridines to the P2Y12 receptor. Binding is irreversible, which renders the receptor nonfunctional for the life of the platelet.
d | Ticagrelor binds reversibly to the P2Y12 receptor at a site that is distinct from the ADP-binding site (noncompetitive binding). Ticagrelor inhibits ADP signalling and conformational change of the receptor by ‘locking’ the receptor in an inactive state (ADP can still bind at its binding site); the receptor is functional after dissociation of the ticagrelor molecule.
Rollini F, Franchi F, & Angiolillo DJ. Nat. Rev. Cardiol. 2016

5. Switching between oral and intravenous antiplatelet agents:
Practical Recommendations
Rollini F, Franchi F, & Angiolillo DJ. Nat. Rev. Cardiol. 2016;13:11-27

6. Most Common Switching Conundrums
Switching from clopidogrel to newer generations P2Y12 receptor inhibitors
Switching between newer generation P2Y12 receptor inhibitors
Switching from newer generation P2Y12 receptor inhibitors to clopidogrel
Switching from cangrelor to oral P2Y12 receptor inhibitors

7. Most Common Switching Conundrums
Switching from clopidogrel to newer generations P2Y12 receptor inhibitors
Switching between newer generation P2Y12 receptor inhibitors
Switching from newer generation P2Y12 receptor inhibitors to clopidogrel
Switching from cangrelor to oral P2Y12 receptor inhibitors

8. Practical Considerations: Switching from Clopidogrel to Ticagrelor and Prasugrel in Acute Settings
PLATO: patients pre-treated with clopidogrel were eligible for randomization (~50% of trial population) and switched with a ticagrelor 180mg LD. Consistent benefit on primary efficacy endpoint and no safety concerns.
RESPOND: PD study supporting enhanced IPA when switching with a ticagrelor 180mg LD (irrespective of clopidogrel responsiveness).
Prasugrel: In TRITON-TIMI 38, patients pre-treated with clopidogrel were not eligible for randomization. Need for dedicated trial.

9. Maximum Platelet Aggregation (20 µM ADP)
SWAP: SWITCHING ANTIPLATELET THERAPY
Maximum Platelet Aggregation (20 µM ADP)
Similar findings obtained with MPA to 5 µM ADP, VASP PRI, and Verify Now® PRU
Angiolillo DJ et al. J Am Coll Cardiol 2010; 56:

10. TRIPLET Time Course: Pharmacodynamic Population
TRIPLET Study
TRIPLET Time Course: Pharmacodynamic Population
PRU (LS mean), PD population
% Inhibition (LS mean), PD population * * ** * * * * * * *
[Source: TRIPLET for EuroPCR oral_ FINAL: Slide 12]
At 24 hours, inhibition of platelet aggregation there was a modest difference (P=0.049) between the placebo/prasugrel 60 mg group and the clopidogrel 600 mg/prasugrel 60 mg group
REFERENCE:
European Society of Cardiology-PCR
Post LD
Post LD
*P=NS at each time point vs. placebo/prasugrel 60 mg, **P=0.049 between the placebo/prasugrel 60 mg group and the clopidogrel 600 mg/prasugrel 60 mg group
LD=Loading Dose, LS=Least Square, PD=Pharmacodynamic, PRU= P2Y12 Reaction Units
Diodati & Angiolillo. Circ Cardiovasc Interv. 2013;6:

11. TRIPLET Study
Biologic Plausibility: No Difference in PD Between Prasugrel LD Alone vs. Clopidogrel + Prasugrel LDs?
[Source: TRIPLET for EuroPCR oral_ FINAL: Slide 16]
The hypothesis is that prasugrel active metabolite binds irreversibly to the majority of P2Y12 receptors on a platelet (left side). Clopidogrel also binds irreversibly to P2Y12 receptors on the platelet, although to a lesser extent, due to lesser production of the active metabolite.
Prasugrel administration to a patient already loaded with clopidogrel would then bind to the remaining available receptors. Thus, P2Y12 receptor occupancy with prasugrel added to clopidogrel would be similar to prasugrel alone.
REFERENCE:
European Society of Cardiology-PCR
PRASUGREL LD ALONE
CLOPIDOGREL
+ PRASUGREL LDs
PRASUGREL (AM)
CLOPIDOGREL (AM)
Platelet P2Y12 Receptor
AM=Active Metabolite; LD=Loading Dose, PD=Pharmacodynamic
Diodati & Angiolillo. Circ Cardiovasc Interv. 2013;6:

12. Most Common Switching Conundrums
Switching from clopidogrel to newer generations P2Y12 receptor inhibitors
Switching between newer generation P2Y12 receptor inhibitors
Switching from newer generation P2Y12 receptor inhibitors to clopidogrel
Switching from cangrelor to oral P2Y12 receptor inhibitors

13. Practical Considerations: Switching between newer generation P2Y12 receptor inhibitors
Many ACS patients may be pre-treated with ticagrelor, but there may be a desire to switch to prasugrel because of dyspnea or compliance issues with ticagrelor (twice daily administration).
Patients treated with prasugrel, may need to switch to ticagrelor because inadvertently treated in patient with prior TIA/stroke, discussion surround mortality benefit, drug access (insurance coverage).

14. SWAP-2: Ticagrelor to Prasugrel PRU Over Time
Prasugrel 60 mg LD/
350
10 mg MD
Prasugrel 10 mg MD
Prasugrel Total
300
Ticagrelor
250
SD)
230
208
200
PRU (mean
150
100 50
Pre-Run-In
Pre-
2 hrs Post
4 hrs Post
24 hrs Post
48 hrs Post
7 Days Post
Baseline
Rand.
First
First
First
First
First
Baseline
Rand.
Rand.
Rand.
Rand.
Rand.
Dose
Dose
Dose
Dose
Dose
PRU increased at 24 and 48 hours in the prasugrel MD only group relative to pre-randomization values
Smaller increase in the prasugrel LD group compared with the prasugrel MD only group
PRU was higher in the prasugrel total group compared with the ticagrelor group at 7 days post-randomization
Angiolillo DJ et al. J Am Coll Cardiol. 2014;63:

15. SWAP-3: Prasugrel to Ticagrelor PRU Over Time
Prospective, randomized, open-label, non-inferiority, pharmacodynamic study
Franchi F et al. JACC Cardiovasc Interv. 2016;9:

16. Most Common Switching Conundrums
Switching from clopidogrel to newer generations P2Y12 receptor inhibitors
Switching between newer generation P2Y12 receptor inhibitors
Switching from newer generation P2Y12 receptor inhibitors to clopidogrel
Switching from cangrelor to oral P2Y12 receptor inhibitors

17. Practical Considerations: Switching from newer generation P2Y12 receptor inhibitors to clopidogrel
Many ACS patients initiate treatment (e.g. first weeks/months) with a novel P2Y12 receptor inhibitor but switch to clopidogrel mostly due to costs and bleeding concerns.
Clopidogrel is still an effective drug for many patients, inexpensive, patient and physician comfort.

18. PD Effects of Switching from Ticagrelor or Prasugrel to Clopidogrel
1/3 patients poor responders
Gurbel P A et al. Circulation 2010
Kerneis M et al. JACC Interv 2013

19. Adverse Events at 1 Month FU
SCOPE (Switching from Clopidogrel to New Oral Antiplatelet Agents during PErcutaneous Coronary Intervention)
Adverse Events at 1 Month FU %
1363 ACS patients undergoing PCI enrolled during a 3-month period
at 40 Italian medium-to-high volume centers
De Luca L et al., submitted

20. ClinicalTrials.gov Identifier:
Study design
TESTING RESPONSIVENESS TO PLATELET INHIBITION ON CHRONIC ANTIPLATELET TREATMENT FOR ACUTE CORONARY SYNDROMES TRIAL
acute phase
subacute / chronic phase
ClinicalTrials.gov Identifier:
NCT

21. Price & Angiolillo. J Am Coll Cardiol. 2012;59:2338-43
Individual Subject Data Over Time for Clopidogrel and Prasugrel: Primary Population (RECOVERY trial)
Prasugrel
Clopidogrel
Source: Slides 30 and 33 from CS747S-B-U4001 slide deck.
Day Post Treatment
Prasugrel: Baseline Mean PRU = ± 45.95
Mean Day 1 PRU = 78.4 ± 35.97
Platelet inhibition (PI), % = 72.3 ± 11.8
Clopidogrel : Baseline Mean PRU = ± 46.73
Mean Day 1 PRU = ± 81.81
Platelet inhibition (PI), % = 35.4 ± 23.4
Price & Angiolillo. J Am Coll Cardiol. 2012;59:

22. Ticagrelor Offset of IPA Over Time
BRILINTA
Clopidogrel
Placebo
Time to achieve full antiplatelet effects with clopidogrel 75mg/day (5-7 days)
IPA (%) Induced by 20 M ADP
Time (day)
100 90 80 70 60 50 40 30 20 10 1 2 3 4 5 6 7 8 9
IPA=inhibition of platelet aggregation Gurbel et al. Circulation. 2009;120(25):

23. The CAPITAL OPTI-CROSS Study
A Randomized Study for Optimizing Crossover From Ticagrelor To Clopidogrel In Patients With Acute Coronary Syndrome:
The CAPITAL OPTI-CROSS Study
Platelet reactivity post-transition
Time (hours)
PRU 12 24 48 72
100
200
300
400 54 60
208
P<0.001
600mg Bolus
No Bolus
Pourdjabbar A et al. Thromb Haemost. 2017;117:

24. SWAP-4: Ticagrelor to Clopidogrel
Patients on aspirin (<100 mg OD) and clopidogrel 75 mg MD
Stop clopidogrel and start ticagrelor 180 mg LD followed by 90 mg BID for 5±2 days
A. Clopidogrel 600 mg LD (24 h after last ticagrelor MD) followed by 75 mg MD for 10±3 days
B. Clopidogrel 600 mg LD (12 h after last ticagrelor MD) followed by 75 mg MD for 10±3 days
C. Clopidogrel 75 mg MD (24 h after last ticagrelor MD) for 10±3 days
D. Continue ticagrelor 90 mg BID for 10±3 days
Randomization
24 h after wash out (groups A and C only)
Platelet function testing
Run-in Baseline
After run-in
2 hours
4 hours
24 hours
48 hours
72 hours
10±3 days
NCT

25. Most Common Switching Conundrums
Switching from clopidogrel to newer generations P2Y12 receptor inhibitors
Switching between newer generation P2Y12 receptor inhibitors
Switching from newer generation P2Y12 receptor inhibitors to clopidogrel
Switching between cangrelor and oral P2Y12 receptor inhibitors

26. Platelet reactivity by day
Cangrelor dose: 0.75 mg/Kg/min infusion (no bolus)
Derived from dose findings studies with VerifyNow™ P2Y12 leading to > 60% inhibition in 80% of daily samples
400
Cangrelor
Placebo
n=84
n=78
350
n=84
n=75
n=76
n=73
n=57
n=34
n=24
n=14
n=86
n=2
300
n=80
n=70
n=55
n=33
n=7
n=1
n=6
n=85
250
200
VerifyNow PRU
150
100 50
Baseline
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Last on-infusion sample
Pre-CABG sample
Time Point
N indicates number of patients with valid samples in the intention to treat population; PRU= P2Y12 reaction units; Data expressed as mean±SD
Angiolillo DJ & Topol EJ. JAMA 2012: 307:

27. Cangrelor to clopidogrel transition20 40 60 80
100
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
Time (hours)
Light Transmittance (%)
Clopidogrel 600mg
Clopidogrel 600mg at time of cangrelor bolus and 2hr infusion
Clopidogrel 600mg given at the end of a cangrelor infusion
N=10 Healthy Volunteers, platelet aggregation 20 μM ADP
Steinhubl Thromb Res 2008;121:527-34

28. Platelet Reactivity Units (PRU)
Platelet reactivity, PRU
1000 *
cangrelor
placebo
800
p>0.999
*p<0.001
p=0.859
p=0.521
p=0.473
p=0.958
600
Platelet Reactivity Units (PRU)
400
200
VerifyNow ADP cartridges
baseline
during infusion
1 - 6 hr after infusion
hr after infusion
hr after infusion
hr after infusion
Platelet Reactivity Units (PRU) assessed by VerifyNow P2Y12 assay; The central box defines the values between the 25th and 75th percentile, and the middle line is the median. Error bars indicate the 10th and 90th percentile and outliers are indicated by individual points * indicates p-value <0.001
Angiolillo DJ et al. J Thromb Thrombolysis ;34:44-55.

29. CANGRELOR + THIENOPYRIDINE
Cangrelor to thienopyridine transition
Active metabolites of thienopyridines are very unstable with rapid clearance from systemic circulation. They will not bind to the P2Y12 receptor if occupied and thus should be administered after discontinuation of cangrelor infusion.
EMA label: Prasugrel can be administered 30 minutes prior to discontinuation of cangrelor infusion.
CANGRELOR
CANGRELOR + THIENOPYRIDINE
Adapted from Rollini F, Franchi F & Angiolillo DJ. Nat. Rev. Cardiol. 2016

30. CANGRELOR + TICAGRELOR
Cangrelor to ticagrelor transition
Ticagrelor and its major metabolite will not bind to the P2Y12 receptor when occupied. However, given their half-lives of ~10-12 hrs, they will be available for binding once cangrelor has been cleared. Therefore, ticagrelor can be administered before, during of after cangrelor infusion.
CANGRELOR
CANGRELOR + TICAGRELOR
Adapted from Rollini F, Franchi F & Angiolillo DJ. Nat. Rev. Cardiol. 2016

31. % Inhibition of Aggregation (final, 20 µM ADP)
Transition From Cangrelor to Oral P2Y12 Inhibitors MDCO-CAN-12-03, MDCO-CAN-13-01, MDCO-CAN-13-02
Cangrelor
Bolus 30µg/kg
Clopidogrel at 120 min.
Prasugrel at 90 min.
Cangrelor 4µg/kg/min
Ticagrelor at 30 min.
After the infusion of Cangrelor, patients should be transitioned to a chronic P2Y12 inhibitor.
The Phase 3 PHOENIX study evaluated the transition from Cangrelor to clopidogrel.
Based on Phase 1 data, an interaction was noted for clopidogrel and Cangrelor.
Therefore, we concluded that clopidogrel should be delivered only at the end of the Cangrelor infusion.
With bolus dosing and 2 hours of Cangrelor infusion you can see near complete platelet inhibition in the first half the slide.
[CLICK]
In the Phase 1 studies, Cangrelor infusion was followed by 600mg clopidogrel.
Platelet function returned over about one hour while the Cangrelor effect is diminishing and the clopidogrel effect is increasing.
A similar interaction was noted for Prasugrel but the onset of effect is quicker.
No such interaction was noted for ticagrelor and therefore ticagrelor can be administered at any time during the Cangrelor infusion. 90 60
150
% Inhibition of Aggregation (final, 20 µM ADP)
Time (minutes)
Final Platelet Aggregation Response to 20 µm ADP as Measured by Light Transmittance Aggregometry During the Transition from Cangrelor to Clopidogrel, Prasugrel, or Ticagrelor