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1
Bridging Anti-Platelet Therapy With the
Intravenous Agent Cangrelor In Patients
Undergoing Cardiac Surgery
: BRIDGE Tria...
Unmet need & rationale
● Surgery is frequent in patients presenting with an ACS or treated with stents (1-2)
– 10–15% of p...
Cangrelor
● Intravenous ADP–P2Y12 receptor antagonist
– Rapid acting: quick onset, quick offset
– Plasma half-life of 3 – ...
Study objective / hypothesis
4
● Objective: To evaluate the use of cangrelor, an IV,
reversible P2Y12 platelet inhibitor, ...
Trial design: Stage I
Dose Identification
5
Treat per Standard of Care
(CABG
rule-in)
0
25
50
75
100
-1 0 1 2 3 4 5-7
Elap...
Global implementation
● First patient enrolled on October, 2009
● Last patient enrolled on April 30th, 2011
Number of pati...
Enrolled patients requiring bridging from oral
thienopyridine prior to CABG (N=210)
1:1 RANDOMIZATION
CANGRELOR
(N=106)
PL...
Trial design: Stage II
Randomized, Double-Blind,
Placebo-Controlled
8
Treat per Standard of Care
(CABG
rule-in)
0
100
200
...
Baseline characteristics
Cangrelor
(N= 106)
Placebo
(N= 101)
Age, yrs 65.0 (42, 84) 62.0 (39, 89)
Female 24.5% 26.7%
Diabe...
Primary endpoint
● Percent of patients with PRU<240 for all on-treatment samples:
PRU:P2Y12 Reactivity units measured to s...
0
50
100
150
200
250
300
350
400
Baseline Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Last
on-infusion
sample
Pre-CABG
sampl...
Pharmacodynamic (con’t)
Intenion to treat population; Chi-square test was performed for proportions. Logistic regression w...
Bleeding endpoint
● Excessive CABG-related bleeding (primary safety endpoint)*
*Excessive CABG-related bleeding is defined...
Pre-operative* bleeding
14
Cangrelor
(N= 106)
Placebo
(N= 101)
Odds Ratio
(95% CI)
p-value
GUSTO Criteria
Severe/Life
thre...
Ischemic events*
*Ischemic events not adjudicated; site reported
MI= myocardial infarction; IDR= ischemia-driven revascula...
Summary results
● When used as a bridging strategy to CABG after thienopyridine
discontinuation, cangrelor (at 0.75 µg/kg/...
Conclusions
● The results of the BRIDGE trial support the
hypothesis that IV cangrelor is a feasible and safe
management s...
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Bridge presentation slides

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Bridging Anti-Platelet Therapy With the Intravenous Agent Cangrelor In Patients Undergoing Cardiac Surgery
: BRIDGE Trial

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Bridge presentation slides

  1. 1. 1 Bridging Anti-Platelet Therapy With the Intravenous Agent Cangrelor In Patients Undergoing Cardiac Surgery : BRIDGE Trial BY Dr Salman
  2. 2. Unmet need & rationale ● Surgery is frequent in patients presenting with an ACS or treated with stents (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 (clopidogrel,prasugrel,ticlopidine) following ACS(NSTEMI & STEMI) and coronary stenting is Guideline-recommended for up to 12 months (3-4) ● Continue or stop P2Y12 therapy? (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 ● Guideline recommends d/c of the P2y12 inhibitors 5-7 days prior to surgery 2
  3. 3. 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 3
  4. 4. Study objective / hypothesis 4 ● Objective: To evaluate the use of cangrelor, an IV, reversible P2Y12 platelet inhibitor, for bridging thienopyridine-treated patients Awaiting CABG ● Hypothesis: Cangrelor infusion provides a level of platelet inhibition equivalent to that expected to be maintained if oral thienopyridine was not discontinued (<240 PRU)
  5. 5. Trial design: Stage I Dose Identification 5 Treat per Standard of Care (CABG rule-in) 0 25 50 75 100 -1 0 1 2 3 4 5-7 Elapsed Days PlateletInhibition(%) Bridge Stage I: Identification of Effective Cangrelor Infusion Dose CABG Thru Hospital Discharge Identify infusion dose that achieves/maintains >60% platelet inhibition in >80% samples. Cangrelor Step-Up Infusion 0.50 to 2.0 µg/kg/min IV 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™ P2Y12 was > 60% in 80% of daily samples or a dose of 2.0 g/kg/min was reached. Clopidogrel or prasugrel 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
  6. 6. 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 dIscontinuation of thienopyriDines in patients undergoing surGEry 6
  7. 7. Enrolled patients requiring bridging from oral thienopyridine prior to CABG (N=210) 1:1 RANDOMIZATION CANGRELOR (N=106) PLACEBO (N=104) End Point: effective antiplatelet reactivity;1)percentage of patients Having PRU <240 2)CABG related Bleeding Patient distribution 7
  8. 8. Trial design: Stage II Randomized, Double-Blind, Placebo-Controlled 8 Treat per Standard of Care (CABG rule-in) 0 100 200 300 400 -1 0 1 2 3 4 5-7 Elapsed Days PRU Bridge Stage II: Demonstration of Effective Cangrelor Infusion Dose CABG Thru Hospital Discharge Demonstrate that cangrelor infusion of maintains PRU< 240 Cangrelor/Placebo Infusion Dose Determined in Stage I : 0.75 µg/kg/min • 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 2 days 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 and CABG related bleeding Clopidogrel or prasugrel
  9. 9. Baseline characteristics Cangrelor (N= 106) Placebo (N= 101) Age, yrs 65.0 (42, 84) 62.0 (39, 89) Female 24.5% 26.7% Diabetes mellitus 46.2% 46.5% Current smoker 29.2% 37.6% Hypertension 82.1% 82.2% Hyperlipidemia 71.7% 76.2% Stroke/TIA 8.5% 4.0% Prior MI 43.4% 35.6% Prior PCI 50.0% 45.5% Congestive HF 15.1% 5.9% STEMI 15.1% 11.9% NSTEMI 32.1% 44.5% 9
  10. 10. Primary endpoint ● Percent of patients with PRU<240 for all on-treatment samples: PRU:P2Y12 Reactivity units measured to see the aspirin and clopidogrel induced platelet dysfuntion graeter the PRU lesser is the inhibition 10 98.8% 19.0% 0% 20% 40% 60% 80% 100% Cangrelor Placebo p<0.0001 OR (95% CI) 353 (45.6-2728)
  11. 11. 0 50 100 150 200 250 300 350 400 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=80 n=70 n=55 n=33 n=7 n=1 n=6 n=85 n=84 n=78 Cangrelor Placebo VerifyNowPRU N indicates number of patients with valid samples in the intention to treat population; PRU= P2Y12 reaction units; Data expressed as mean±SD Platelet reactivity by day n=76 n=73 n=57 n=34 n=24 n=14 n=86 n=2 n=84 n=75 11
  12. 12. 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. 12 Cangrelor (N= 93) Placebo (N= 90) Odds Ratio (95% CI) p-value Prior to Study Drug Infusion Patients with platelet reactivity PRU <240 62.4% 52.3% 1.5 (0.8 – 2.8) 0.185 PRU values, Mean SD 210.9 94.0 214.1 85.9 NA 0.817 During Study Drug Infusion Samples with platelet reactivity PRU <240 99.6% 33.3% 516 (71.3 - 3732) <0.001 Total samples with > 60% platelet inhibition 83.8% 3.7% 133 (66.9 - 264) <0.001 Patients with last-on infusion sample with PRU <240 98.8% 31.0% 185 (24.4 - 1403) <0.001 PRU values last sample during infusion, Mean SD 68.9 67.8 263.7 68.3 NA <0.001
  13. 13. 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. 13 11.8% 10.4% 0% 5% 10% 15% Cangrelor Placebo Excessive CABG-related bleeding P=0.76
  14. 14. Pre-operative* bleeding 14 Cangrelor (N= 106) Placebo (N= 101) Odds Ratio (95% CI) p-value GUSTO Criteria Severe/Life threatening 0% 0% NA NA Moderate 1.9% 1.0% 1.92 (0.17, 21.5) 0.596 Mild 17.9% 9.9% 1.99 (0.88, 4.51) 0.101 TIMI Major 0.9% 0% NA NA Minor 0.9% 0% NA NA TIMI: Major: IC bleed or > 5g/dl dec in Hb >15% dec: in hct: Minor: obsreverd with >3g/dl dec: or >10% dec: in hct GUSTO: Sevre:ic bleed or bleeding or results in hemodynamic compromise Mod: requires transfusion no hemodynamic compromise Mild : requires no transfusion
  15. 15. Ischemic events* *Ischemic events not adjudicated; site reported MI= myocardial infarction; IDR= ischemia-driven revascularization 15 Parameter Cangrelor (N= 106) Placebo (N= 101) Incidence of Pre-Procedure Ischemic endpoints (randomization to surgery) Death/MI/IDR/Stroke 2.8% 4.0% Death 0.9% 3.0% MI 1.9% 0% IDR 0.9% 0.0% Stroke 0% 0% Incidence of Post Surgery ischemic endpoints (through 30 days) Death/MI/IDR/Stroke 3.9% 4.2% Death 1.0% 2.1% MI 2.0% 1.0% IDR 2.5% 0%
  16. 16. 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 thienopyridine dose & 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. 16
  17. 17. 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. 17

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