1 Bridging Anti-Platelet Therapy With the Intravenous Agent Cangrelor In Patients Undergoing Cardiac Surgery : BRIDGE Trial BY Dr Salman
Dec 18, 2014
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