1

Bridging Anti-Platelet Therapy With the Intravenous Agent Cangrelor In Patients

Undergoing Cardiac Surgery: BRIDGE Trial

BY Dr Salman

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

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

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

Trial design: Stage IDose Identification

Treat per Standard of Care

(CABG rule-in)

0

25

50

75

100

-1 0 1 2 3 4 5-7Elapsed Days

Pla

tele

t In

hibi

tion

(%)

Bridge Stage I: Identification of Effective Cangrelor Infusion Dose

CABGCABG

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

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

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

Trial design: Stage IIRandomized, Double-Blind, Placebo-Controlled

8

Treat per Standard of Care

(CABG rule-in)

0

100

200

300

400

-1 0 1 2 3 4 5-7Elapsed Days

PR

U

Bridge Stage II: Demonstration of Effective Cangrelor Infusion Dose

CABGCABG

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

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

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

Cangrelor Placebo0%

20%

40%

60%

80%

100%98.8%

19.0%

p<0.0001

OR (95% CI)353 (45.6-2728)

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-CABGsample

Time Point

n=80n=70

n=55 n=33n=7

n=1

n=6

n=85

n=84

n=78

Cangrelor Placebo

Ver

ifyN

ow P

RU

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=76n=73

n=57 n=34 n=24

n=14n=86

n=2n=84

n=75

11

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.

 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

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.

Cangrelor Placebo

-5%

0%

5%

10%

15%

11.8%10.4%

Excessive CABG-related bleeding

P=0.76

14

Pre-operative* bleeding

  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

Ischemic events*

*Ischemic events not adjudicated; site reportedMI= 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%

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

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