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Home , Cangrelor, Prasugrel, Ticagrelor

Switching to and from : When and How?

Dominick J. Angiolillo, MD, PhD, FACC, FESC, FSCAI Professor of Medicine Program Director, Interventional Cardiology Fellowship Director, Cardiovascular Research University of Florida College of Medicine - Jacksonville 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, Biosensors, 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, Biosensors, 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 Expert Consensus Recommendations on Switching

SWITCHING BETWEEN ORAL INHIBITORS • Escalation (Switching From to or )

• De-escalation (Switching From Prasugrel or Ticagrelor to Clopidogrel)

• Change (Switching Between Prasugrel and Ticagrelor)

SWITCHING BETWEEN INTRAVENOUS AND ORAL P2Y12 INHIBITORS

• Bridge (Switching from Oral P2Y12 Inhibitors to Cangrelor)

• Transition (Switching from Cangrelor to Oral P2Y12 Inhibitors) Expert Consensus Recommendations on Switching

SWITCHING BETWEEN ORAL P2Y12 INHIBITORS • Escalation (Switching From Clopidogrel to Prasugrel or Ticagrelor)

• De-escalation (Switching From Prasugrel or Ticagrelor to Clopidogrel)

• Change (Switching Between Prasugrel and Ticagrelor)

SWITCHING BETWEEN INTRAVENOUS AND ORAL P2Y12 INHIBITORS

• Bridge (Switching from Oral P2Y12 Inhibitors to Cangrelor)

• Transition (Switching from Cangrelor to Oral P2Y12 Inhibitors) Expert Consensus Recommendations on Switching

SWITCHING BETWEEN ORAL P2Y12 INHIBITORS • Escalation (Switching From Clopidogrel to Prasugrel or Ticagrelor)

• De-escalation (Switching From Prasugrel or Ticagrelor to Clopidogrel)

• Change (Switching Between Prasugrel and Ticagrelor)

SWITCHING BETWEEN INTRAVENOUS AND ORAL P2Y12 INHIBITORS

• Bridge (Switching from Oral P2Y12 Inhibitors to Cangrelor)

• Transition (Switching from Cangrelor to Oral P2Y12 Inhibitors) Expert Consensus Recommendations on Switching: Bridging

• Although cangrelor is being used in real-world clinical practice as a bridging strategy, there are limited data to support the safety and efficacy of this approach.

• The BRIDGE trial showed that among patients who discontinue therapy before cardiac , the use of cangrelor compared with placebo resulted in a higher rate of maintenance of inhibition.

• The dose of cangrelor used for bridging (0.75μg/kg/min infusion without a bolus) derives from a dose-finding study that identified levels of platelet inhibition similar to those achieved in patients with a good response to clopidogrel and is substantially lower than that used in PCI (30μg/kg bolus and 4μg/kg/min infusion).

• The PD results from the BRIDGE study do not suggest any type of DDI, likely

because there are still unoccupied receptors in patients treated with oral P2Y12 inhibitors that can be bound and inhibited by cangrelor. This is in line with in vitro and ex vivo studies showing no interaction when cangrelor is administered on top of or ticagrelor and is associated with enhanced antiplatelet effects. 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

350 n=2 n=75 300 n=57 n=34 n=24 n=84 n=14 n=86 n=73 250 n=76 n=78

200 n=85

150

n=55 n=33 100 n=70 VerifyNowPRU n=7 n=6 n=80 n=84 50 n=1 0 Baseline Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Last Pre-CABG on-infusion sample 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 et al. JAMA 2012: 307:265-74. Effects of In Vitro Cangrelor with Prasugrel and Ticagrelor Re-Load: Results of Prospective, Randomized, Pharmacodynamic Studies All patients on maintenance therapy with prasugrel (10mg) and ticagrelor (90mg bid)

Platelet reactivity index (PRI) - VASP

Prasugrel 60mg re-load ± in vitro cangrelor Ticagrelor 180mg re-load ± in vitro cangrelor

60 ANOVA p<0.001 50 Prasugrel 60 mg Prasugrel 60 mg + Cangrelor 40 p<0.001

30 p=0.002 20 p=0.003 p=0.004 p=0.001 10 p=0.325 Platelet Index Platelet Reactivity (%) Index Platelet Reactivity (%) 0 Baseline 1hour 4hours

Rollini F, Franchi F & Angiolillo DJ. Rollini F, Franchi F & Angiolillo DJ. JACC Cardiovasc Interv. 2014;7:426-34 JACC Cardiovasc Interv. 2017;10:1374–1375 Expert Consensus Recommendations on Switching

Bridging from oral to intravenous P2Y12 inhibitors

• For both cardiac and noncardiac surgery, if withdrawal of P2Y12 inhibiting therapy is needed, clopidogrel and ticagrelor should be discontinued for 5 days and prasugrel for 7 days. • It is reasonable to start cangrelor bridging up to 3 to 4 days after prasugrel discontinuation and 2 to 3 days of clopidogrel and ticagrelor discontinuation. Platelet function testing may be considered to help guide timing of starting cangrelor infusion. • After surgery, regardless of bridging strategy, clopidogrel should be resumed with a loading dose (LD) as soon as oral administration is possible and the risk of severe is acceptable (prasugrel and ticagrelor administration should be discouraged). If the use of oral P2Y12-inhibiting therapy is not possible, postsurgery bridging with an intravenous agent should be considered.

Angiolillo DJ et al. Circulation. 2017 (in press) Multidisciplinary Approach on the Perioperative Management of Patients with Coronary Stents undergoing Surgery: Surgery after Stenting 2

Use the SAS 2 app!

Rossini R & Angiolillo DJ – SAS 2- JACC Cardiovasc Interv 2018;11:417-434 Expert Consensus Recommendations on Switching

SWITCHING BETWEEN ORAL P2Y12 INHIBITORS • Escalation (Switching From Clopidogrel to Prasugrel or Ticagrelor)

• De-escalation (Switching From Prasugrel or Ticagrelor to Clopidogrel)

• Change (Switching Between Prasugrel and Ticagrelor)

SWITCHING BETWEEN INTRAVENOUS AND ORAL P2Y12 INHIBITORS

• Bridge (Switching from Oral P2Y12 Inhibitors to Cangrelor)

• Transition (Switching from Cangrelor to Oral P2Y12 Inhibitors) Expert Consensus Recommendations on Switching: Transition

• Cangrelor was approved for clinical use on the basis of the results of the CHAMPION PHOENIX trial, which showed that cangrelor significantly reduced the rate of ischemic events, driven by a reduction in stent thrombosis and , with no significant increase in severe bleeding in patients undergoing PCI.

• In patients treated with cangrelor, a clopidogrel LD was administered immediately after discontinuation of cangrelor infusion.

• This approach was used to avoid a potential DDI between cangrelor and clopidogrel.

• Given the different pharmacological properties of cangrelor and the oral P2Y12 inhibitors, several studies have investigated the potential for DDI when these agents are concomitantly administered. Cangrelor to clopidogrel transition

Clopidogrel 600mg at Clopidogrel 600mg Clopidogrel 600mg given at time of cangrelor the end of a cangrelor bolus and 2hr infusion infusion 100

80

60

40

Light Light Transmittance(%) 20

0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 Time (hours)

N=10 Healthy Volunteers, platelet aggregation 20 μM ADP

Steinhubl Thromb Res 2008;121:527-34 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 * 400

200 Platelet Reactivity Units (PRU) Units Reactivity Platelet

0 baseline during 1 - 6 hr 6 - 12 hr 12 - 18 hr 18 - 24 hr infusion after after after after infusion infusion infusion 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 . 2012 ;34:44-55. Cangrelor to thienopyridine transition

Active metabolites of thienopyridines EMA label: Prasugrel can be are very unstable with rapid clearance administered 30 minutes prior to from systemic circulation. They will not discontinuation of cangrelor infusion. bind to the P2Y12 if occupied and thus should be administered after discontinuation of cangrelor infusion.

CANGRELOR CANGRELOR + THIENOPYRIDINE

Adapted from Rollini F, Franchi F, Angiolillo DJ. Nat Rev Cardiol. 2016;13:11–27. 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;13:11–27. CANTIC: Pharmacodynamic assessment measured by VerifyNow P2Y12 (PRU) following administration of cangrelor versus placebo

PRU levels at 30 minutes (primary end point) were significantly lower with cangrelor compared with placebo [63 (32-93) vs. 214 (183-245); mean difference: 152; 95% CI: 108-195; p<0.001].

300 p<0.001 Placebo p<0.001 p<0.001 250 Cangrelor p<0.001

200 p=0.002

Absence of DDI 150 p=0.885 PRU p=0.574 100

50

0 in s n lu iionon io m min PCI s s 5 f bo u usionu 30 mino t bolus t bolus f f d o in ndn ost bolus t-infus t-inf E posp pos s s h popost- po 1 h 2 h pos h h post-in 1 h 2 Time

All patients concomitantly treated with 180mg LD of crushed ticagrelor at time of randomization (time 0) End of PCI: 41 (21-54) minutes

Franchi F, Rollini F, & Angiolillo DJ. Circulation 2019 (in press) Expert Consensus Recommendations on Switching

Transition from intravenous to oral agents P2Y12 inhibitors

• An LD should always be used when transitioning from cangrelor to an oral agent. • In the case of thienopyridines (clopidogrel or prasugrel), this should be administered immediately after discontinuation of cangrelor infusion. • Ticagrelor can be administered before, during, or immediately after cangrelor infusion, although earlier administration (eg, at the time of PCI) should be considered. • *According to the package insert of the EMEA, but not that of the FDA, 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 sufficient platelet inhibition, but this strategy cannot be routinely recommended until more data are available.

Angiolillo DJ et al. Circulation. 2017; 136:1955-1975 Dominick J. Angiolillo, Fabiana Rollini, Robert F. Storey, Deepak L. Bhatt, Stefan James, David J. Schneider, Dirk Sibbing, Derek YF So, Dietmar Trenk, Dimitrios Alexopoulos, Paul A. Gurbel, Willibald Hochholzer, Leonardo De Luca, Laurent Bonello, Daniel Aradi, Thomas Cuisset, Udaya S. Tantry, Tracy Y. Wang, Marco Valgimigli, Ron Waksman, Roxana Mehran, Gilles Montalescot, Francesco Franchi, Matthew J. Price

Circulation. 2017; 136:1955-1975