Document

Report
The Safety and Efficacy Of
Cangrelor, a Short Acting, IV,
Reversible, Platelet P2Y12 Inhibitor
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 MD for the
BRIDGE Investigators
1
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, SanofiAventis, 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.
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 following ACS and coronary stenting is Guidelinerecommended 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
● No proven and efficacious alternative solution for bridging to surgery is currently
available (11-12)
1. Vicenzi MN, et al. Br J Anaesth 2006; 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 Cardiovasc Interv 2010; 3:.920-7; 8. Rao SV, et al. Eur Heart J 2007; 28: 1193–1204; 9. Hajjar LA, et al. J
Am Med Assoc 2010; 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.
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
S
HN
N
4Na+
O
O
O
O O
P
P
Cl
O
Cl
O
P
N
O
N
N
S
CF
3
O
O
HO
OH
4
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
5
Trial design: Stage I
Dose Identification
Platelet Inhibition (%)
Bridge Stage I: Identification of Effective Cangrelor Infusion Dose
100
Clopidogrel
or prasugrel
75
Identify infusion dose that achieves/maintains
>60% platelet inhibition in >80% samples.
CABG
50
25
0
(CABG
rule-in)
-1
Treat per Standard of Care
Cangrelor Step-Up Infusion
0.50 to 2.0 µg/kg/min IV
0
1
2
3
4
Elapsed Days
5-7
Thru Hospital Discharge
Cangrelor IV infusion was to be administered to cohorts of 5 patients at a time in a stepwise 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.
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
Trial design: Stage II
Randomized, Double-Blind,
Placebo-Controlled
Bridge Stage II: Demonstration of Effective Cangrelor Infusion Dose
400 Clopidogrel
PRU
300
or prasugrel
Demonstrate that cangrelor infusion
of maintains PRU< 240
200
100
0
-1
CABG
Cangrelor/Placebo Infusion
Dose Determined in Stage I :
0.75 µg/kg/min
(CABG
rule-in)
0
1
2
3
4
Elapsed Days
Treat per Standard of Care
5-7
Thru Hospital Discharge
• 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.
7
Global implementation
● First patient enrolled on October 14th, 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
8
Trial organization
Executive Committee
DSMB
Eric Topol, MD (PI)
David Faxon, MD
Cornelius Dyke, MD
Charles Davis, PhD
David Holmes, MD
Magnus Ohman, MD
Giles Montalescot, MD
Matthew Price, MD
National Coordinator
Nicolas Chronos, MD
Petr Widimsky, MD (Czech)
Steven Manoukian, MD
9
Patient distribution
Enrolled patients requiring bridging from oral
thienopyridine prior to CABG (N=210)
1:1 RANDOMIZATION
Withdrew Consent (N=1) —
Physician Decision (N=1) —
CANGRELOR
(N=106)
Lost to Follow-up (N=0) —
PLACEBO
(N=104)
— No Study
Drug
Received
(N=1)
Death (N=3) —
Other (N=0) —
— Physician Decision (N=0)
— No Study
Drug
Received
(N=2)
30 day
complete
(N=101)
— Lost to Follow-up (N=1)
— Death (N=5)
— Other (N=2)
30 day
complete
(N=94)
Incorrect Study —
— Incorrect Study
Drug Received
(N=1)
Drug Received
(N=1)
Unblinded in Dose —
Confirmation
Analysis
(N=12)
Safety
CANGRELOR
(N=106)
— Withdrew Consent (N=2)
Primary
Efficacy/ITT
CANGRELOR
(N=93)
— Unblinded in Dose
Confirmation
Analysis (N=12)
Primary
Efficacy/ITT
PLACEBO
(N=90)
Safety
PLACEBO
(N=101)
10
Baseline characteristics
Age, yrs
Cangrelor
(N= 106)
65.0 (42, 84)
Placebo
(N= 101)
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
Prior MI
Prior PCI
8.5%
43.4%
50.0%
4.0%
35.6%
45.5%
Congestive HF
15.1%
5.9%
STEMI
NSTEMI
15.1%
32.1%
11.9%
44.5%
11
Primary endpoint
● Percent of patients with PRU<240 for all on-treatment samples:
100%
98.8%
p<0.0001
80%
OR (95% CI)
353 (45.6-2728)
60%
40%
19.0%
20%
0%
Cangrelor
Placebo
12
Platelet reactivity by day
400
Cangrelor
Placebo
350
VerifyNow PRU
300
250
200
n=57
n=86
n=76
n=2
n=34
n=84
n=24
n=75
n=14
n=73
n=78
n=85
150
100
n=80
n=70
n=55
n=33
n=7
n=6
50
n=84
n=1
0
Baseline
Day 1
Day 2
Day 3
Day 4
Day 5
Time Point
Day 6
Day 7
Last
Pre-CABG
on-infusion sample
sample
N indicates number of patients with valid samples in the intention to treat population; PRU= P2Y12 reaction units; Data expressed as mean±SD
13
Bleeding endpoint
● Excessive CABG-related bleeding (primary safety endpoint)*
15%
Excessive CABG-related bleeding
11.8%
P=0.76
10.4%
10%
5%
0%
Cangrelor
Placebo
*Excessive CABG-related bleeding is defined as the occurrence of one or more of the following 3 components during the CABG procedure or postoperative hospitalization: Surgical re-exploration, 24 hour CT output > 1.5 liters, Incidence of PRBC transfusion > 4 units.
14
CABG-related bleeding events
● CABG-related bleeding during the procedure through
hospital discharge, safety population
Cangrelor
(N= 106)
11.8%
Protocol-defined excessive bleeding*
Placebo
Odds Ratio
p(N= 101)
(95% CI)
value
10.4% 1.15 (0.47, 2.79) 0.763
Surgical re-exploration
2.0%
2.1%
0.94 (0.13, 6.81) 0.951
24h chest tube output of >1.5 liters
7.8%
5.2%
1.55 (0.49, 4.91) 0.457
Incidence of PRBC transfusions > 4 U
5.9%
8.3%
0.69 (0.23, 2.06) 0.503
Bleeding
Transfusions
4 hour chest tube output (mL), median
BARC definition
Fatal bleeding ( BARC Type 5)
Perioperative intracranial bleed <48 h†
32.1%
254
9.8%
0%
0%
34.7%
250
10.4%
0%
0%
0.89 (0.50, 1.59) 0.694
NA
0.985
0.93 (0.37, 2.36) 0.886
NA
NA
NA
NA
2.0%
2.1%
0.94 (0.13, 6.81) 0.951
6.9%
8.3%
0.81 (0.28, 2.33) 0.696
2.9%
4.2%
0.70 (0.15, 3.20) 0.642
Reoperation for bleeding†
Transfusion of ≥ 5Uof whole blood or
PRBC < 48h†
Chest tube output ≥ 2 L <24 h†
*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
15
Pre-operative* bleeding
Cangrelor
(N= 106)
Placebo
(N= 101)
Odds Ratio
(95% CI)
p-value
Major
2.8%
1.0%
2.91 (0.30, 28.5)
0.358
Minor
17.9%
9.9%
1.99 (0.88, 4.51)
0.101
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
Major
0.9%
0%
NA
NA
Minor
0.9%
0%
NA
NA
ACUITY
GUSTO
Severe/Life
threatening
TIMI
*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
16
Ischemic events*
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%
1.0%
Stroke
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%
Stroke
1.0%
1.0%
*Ischemic events not adjudicated; site reported
MI= myocardial infarction; IDR= ischemia-driven revascularization
17
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.
18
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.
19
● Back-up slides
20
Pharmacodynamic (con’t)
Cangrelor
(N= 93)
Placebo
(N= 90)
Odds Ratio
(95% CI)
p-value
62.4%
52.3%
1.5 (0.8 – 2.8)
0.185
210.9 ± 94.0
214.1 ±
85.9
NA
0.817
99.6%
33.3%
516 (71.3 - 3732) <0.001
83.8%
3.7%
133 (66.9 - 264) <0.001
98.8%
31.0%
185 (24.4 - 1403) <0.001
68.9 ± 67.8
263.7 ±
68.3
Prior to Study Drug Infusion
Patients with platelet reactivity
PRU <240
PRU values, Mean ± SD
During Study Drug Infusion
Samples with platelet reactivity
PRU <240
Total samples with > 60%
platelet inhibition
Patients with last-on infusion
sample with PRU <240
PRU values last sample during
infusion, Mean ± SD
NA
<0.001
After End of Study Drug Infusion
26.9%
20.0%
1.5 (0.7 – 3.1)
0.313
279.7 ±
297.8 ±
NAfor the expected0.212
PRU
values,
Mean
±
SD
Intenion to treat population; Chi-square test was performed for proportions.
Logistic regression
was performed adjusted
days to
106.5
67.3
surgery (either ≤3 days or >3 days). Analysis of variance was used for PRU value. NA =Not Applicable.
Patients with PRU <240
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