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The Safety and Efficacy Of Cangrelor, a Short Acting, IV, Reversible, Platelet P2Y 12 Inhibitor In Patients Awaiting Ca

The Safety and Efficacy Of Cangrelor, a Short Acting, IV, Reversible, Platelet P2Y 12 Inhibitor In Patients Awaiting Cardiac Surgery: Results Of the BRIDGE Trial.

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The Safety and Efficacy Of Cangrelor, a Short Acting, IV, Reversible, Platelet P2Y 12 Inhibitor In Patients Awaiting Ca

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  1. The Safety and Efficacy Of Cangrelor, a Short Acting, IV, Reversible, Platelet P2Y12Inhibitor In Patients Awaiting Cardiac Surgery: Results Of the BRIDGE Trial Dominick J. Angiolillo MD, PhD, Michael S. Firstenberg MD, Matthew J. Price MD, Pradyumna E. Tummala MD, Martin Hutyra MD, Ian J. Welsby MD, Michele D. Voeltz MD, Harish Chandna MD, Chandrashekhar Ramaiah MD, Miroslav Brtko MD, PhD, Louis Cannon MD, Cornelius Dyke MD Tiepu Liu MD, PhD, Gilles Montalescot MD, Steven V. Manoukian MD, Jayne Prats PhD, Eric J. Topol MDfor the BRIDGE Investigators

  2. Disclosures The BRIDGE trial was funded by The Medicines Company. Statistical analyses were performed by The Medicines Company and independently validated by Penn State University. Dr. Angiolillo has received honoraria for lectures (speaker’s bureau) from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly Co, Daiichi Sankyo, Inc., honoraria for consulting/advisory board from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly Co, Daiichi Sankyo, Inc., The Medicines Company, Portola Pharmaceuticals, Novartis, Arena Pharmaceuticals, Accumetrics, Medicure, Evolva, Abbott Vascular, and research grants (paid to Institution) from GlaxoSmithKline, Otsuka, Accumetrics, Eli Lilly Co, Daiichi Sankyo, Inc., The Medicines Company, Portola Pharmaceuticals, Schering-Plough, AstraZeneca, Johnson & Johnson, Bristol-Myers Squibb, Sanofi-Aventis This presentation includes off label and/or investigational uses of drugs.

  3. Unmet need & rationale • Surgeryisfrequent in patients presentingwith an ACS or treatedwithstents(1-2) • 10–15% of patients presenting with ACS have to undergo CABG • 5% to 25% of patients have to undergo non-cardiac surgery • Oral P2Y12 therapy following ACS and coronary stenting is Guideline-recommended for up to 12 months (3-4) • Continue or stop P2Y12therapy? (5-10) • Continuation puts patients at ∼35% incidence of bleeding. Bleeding and transfusion are associated with increased risk of mortality • Preoperative discontinuation of anti-platelet therapy is associated with ∼20% incidence of ischemic events • No proven and efficacious alternative solution for bridging to surgery is currently available (11-12) • 1. Vicenzi MN, et al. Br J Anaesth2006; 96: 686–693; 2. Ebrahimi R., et al. J ACC 2009; 53: 1965–19724;3. King, S.B., 3rd, et al. JACC 2008; 51: 172–209; 4. Patrono C, et al. Chest 2008; 133: 199S-233S; 5. Berger JS, et al. JACC 2008; 52: 1693–1701; 6. Kaluza GL, et al. JACC 2000; 35: 1288–1294; 7. Berger PB, et al. JACC CardiovascInterv2010; 3:.920-7; 8. Rao SV, et al. Eur Heart J 2007; 28: 1193–1204; 9. Hajjar LA, et al. J Am Med Assoc2010; 304: 1559–1567; 10. Murphy GJ, et al. Circulation 2007; 116: 2544–255; 11.Hamm C et al Eur Heart J 2011 Sep 21. [Epub ahead of print]; 12. Anderson J et al. Circulation. 2011;123:e426-e579.

  4. S H N N + 4Na N O O O C F O N 3 N S O P P P O O O O O Cl Cl O H H O Cangrelor • Intravenous ADP–P2Y12 receptor antagonist • Rapid acting: quick onset, quick offset • Plasma half-life of 3 – 6 minutes • 60 minutes for return to normal platelet function

  5. Study objective / hypothesis • Objective: To evaluate the use of cangrelor, an IV, reversible P2Y12 platelet inhibitor, for bridging thienopyridine-treated patients to CABG • Hypothesis:Cangrelor infusion provides a level of platelet inhibition equivalent to that expected to be maintained if oral thienopyridine was not discontinued

  6. Bridge Stage I: Identification of Effective Cangrelor Infusion Dose 100 Identify infusion dose that achieves/maintains>60% platelet inhibition in >80% samples. CABG 75 50 Platelet Inhibition (%) Treat per Standard of Care Cangrelor Step-Up Infusion 0.50 to 2.0 µg/kg/min IV 25 (CABG rule-in) 0 -1 0 1 2 3 4 5-7 Thru Hospital Discharge Elapsed Days Trial design: Stage IDose Identification Clopidogrel or prasugrel Cangrelor IV infusion was to be administered to cohorts of 5 patients at a time in a step-wise fashion at pre-determined doses (0.5 g/kg/min, 0.75 g/kg/min, 1.0 g/kg/min and 1.5 g/kg/min) until platelet inhibition measured by VerifyNow™ P2Y12was > 60% in 80% of daily samples or a dose of 2.0 g/kg/min was reached. • Cangrelor infusion of 0.75 g/kg/min met the efficacy endpoint (94.4%, 95% confidence interval [CI]: 83.9% – 100%), and was implemented for the randomized, double-blind, placebo-controlled stage II of the trial

  7. Bridge Stage II: Demonstration of Effective Cangrelor Infusion Dose 400 Demonstrate that cangrelor infusion of maintains PRU< 240 CABG 300 Cangrelor/Placebo Infusion Dose Determined in Stage I :0.75 µg/kg/min 200 PRU Treat per Standard of Care 100 (CABG rule-in) 0 -1 0 1 2 3 4 5-7 Thru Hospital Discharge Elapsed Days Trial design: Stage IIRandomized, Double-Blind, Placebo-Controlled Clopidogrel or prasugrel • Patients with an ACS or treated with a coronary stent (BMS or DES) on a thienopyridine (ticlopidine, clopidogrel or prasugrel) awaiting CABG. • After thienopyridine discontinuation (<72 hours), patients were administered cangrelor/placebo for at least 48 hours and up to 7 days, which was discontinued 1-6 hours prior to CABG. • Objective: demonstrate that cangrelor would maintain levels of platelet reactivity <240 P2Y12 Reaction Units (PRU) throughout the pre-operative period as measured by the VerifyNow™ P2Y12 test.

  8. Global implementation • First patient enrolled on October, 2009 • Last patient enrolled on April 30th, 2011 Number of patients enrolled in each country: US – 125 Czech Republic – 55 UK – 12 Netherlands – 11 Austria – 7 Maintenance of platelet inhiBition with cangreloR after dIscontinuationof thienopyriDines in patients undergoing surGEry

  9. Trial organization Executive Committee Eric Topol, MD (PI) Cornelius Dyke, MD David Holmes, MD Giles Montalescot, MD Matthew Price, MD Nicolas Chronos, MD Steven Manoukian, MD DSMB David Faxon, MD Charles Davis, PhD Magnus Ohman, MD National Coordinator Petr Widimsky, MD (Czech)

  10. Patient distribution Enrolled patients requiring bridging from oral thienopyridine prior to CABG (N=210) 1:1 RANDOMIZATION CANGRELOR (N=106) PLACEBO (N=104) Withdrew Consent (N=1) — Physician Decision (N=1) — Lost to Follow-up (N=0) — Death (N=3) — Other (N=0) — — Withdrew Consent (N=2) — Physician Decision (N=0) — Lost to Follow-up (N=1) — Death (N=5) — Other (N=2) — No Study Drug Received(N=1) — No Study Drug Received(N=2) 30 day complete(N=101) 30 day complete(N=94) Unblinded in Dose — Incorrect Study — Drug Received(N=1) Confirmation Analysis(N=12) — Incorrect Study Drug Received (N=1) — Unblinded in Dose Confirmation Analysis (N=12) Safety CANGRELOR (N=106) Primary Efficacy/ITT CANGRELOR(N=93) Primary Efficacy/ITT PLACEBO(N=90) Safety PLACEBO (N=101)

  11. Baseline characteristics

  12. Primary endpoint • Percent of patients with PRU<240 for all on-treatment samples: • p<0.0001 OR (95% CI) 353 (45.6-2728)

  13. Platelet reactivity by day Cangrelor Placebo 400 350 n=2 n=75 n=34 n=84 n=57 n=24 300 n=14 n=73 n=86 n=78 n=76 250 200 n=85 VerifyNow PRU 150 100 n=55 n=33 n=70 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 on-infusionsample Pre-CABGsample 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

  14. Pharmacodynamic (con’t) • Intenion to treat population; Chi-square test was performed for proportions. Logistic regression was performed adjusted for the expected days to surgery (either ≤3 days or >3 days). Analysis of variance was used for PRU value. NA =Not Applicable.

  15. Bleeding endpoint • Excessive CABG-related bleeding (primary safety endpoint)* • *Excessive CABG-related bleeding is defined as the occurrence of one or more of the following 3 components during the CABG procedure or post-operative hospitalization: Surgical re-exploration, 24 hour CT output > 1.5 liters, Incidence of PRBC transfusion > 4 units. • P=0.76

  16. CABG-related bleeding events • CABG-related bleeding during the procedure through hospital discharge, safety population • *Excessive CABG-related bleeding is defined as the occurrence of one or more of the following 3 components during the CABG procedure or post-operative hospitalization: Surgical re-exploration, 24 hour CT output > 1.5 liters, Incidence of PRBC transfusion > 4 units • PBRC= packed red blood cells; BARC= Bleeding Academic Research Consortium; †BARC CABG-related,Type 4

  17. Pre-operative* bleeding • *From randomization until surgical incision • ACUITY: Acute Catheterization and Urgent Intervention Triage Strategy; GUSTO: Global Use of Strategies To Open coronary arteries; TIMI: Thrombolysis in Myocardial Infarction

  18. Ischemic events* • *Ischemic events not adjudicated; site reported • MI= myocardial infarction; IDR= ischemia-driven revascularization

  19. Summary results • When used as a bridging strategy to CABG after thienopyridine discontinuation, cangrelor (at 0.75 µg/kg/min) achieves levels of platelet inhibition known to be associated with a low risk of thrombotic events: • Without increased risk of bleeding before or during CABG, although with a numerical increase in minor pre-CABG bleeding • Independent of prior thienopyridinedose & time of discontinuation • Consistent pharmaocdynamic effect during IV infusion • Rapid offset after IV discontinuation prior to surgery • No increased incidence of adverse events (e.g. dyspnea) or laboratory abnormalities despite extended dosing.

  20. Conclusions • The results of the BRIDGE trial support the hypothesis that IV cangrelor is a feasible and safe management strategy in patients who require prolonged platelet P2Y12 inhibition after thienopyridine discontinuation prior to cardiac surgery. • Larger patient samples are warranted to more definitively assert the safety and efficacy of cangrelor as a bridging therapy in patients with ACS or treated with coronary stents who require surgery.

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