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Dr Jonathan Day
Senior Director Global Medical
The Medicines Company
Bivalirudin
For patients with STEMI undergoing primary PCI
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MY CONFLICTS OF INTEREST ARE
The Medicines Company (Employee)
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New Indication for STEMI
– Approved in the European Union in 2004As an anticoagulant in patients undergoing percutaneous coronary intervention (PCI)
– Type II variation approved in 2008For the treatment of patients with ACS undergoing early or urgent intervention
– Type II variation approved in 2009As an anticoagulant in patients undergoing percutaneous coronary intervention (PCI) including primary PCI
“The only anticoagulant approved for patients undergoing PPCI”
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Broad spectrum of experience with bivalirudin in clinical trials27,735 patients undergoing invasive management of CAD
REPLACE-2(N=6,002)
CADPlanned PCI
BAT(N=4,312)
UA, NQWMIPlanned PTCA
ACUITY(N=13,819)
NSTE-ACSPCI <72h
HORIZONS(N=3,602)
STEMIEmergency PCI
Increasing risk of ischaemic complications
Lincoff et alJAMA, 2003
Bittl et alAHJ, 2001
Stone et alNEJM, 2006
Stone et alNEJM, 2007
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0 1 2
Consistent trial results
● Meta-analysis of REPLACE-2, ACUITY and HORIZONS
● 14,258 patients given aspirin, clopidogrel prior to angio/intervention
Risk ratio ±95% CI P-value
Death, MI or revasc 30d 1.0 (0.88-1.13) 0.941
All cause death 30d 0.73 (0.54-0.99) 0.043
All cause death 1y 0.80 (0.66-0.96) 0.015
Major bleeding 30d 0.54 (0.4-.63) <0.0001
Bivalirudin better Heparin+GPI better
Data on file The Medicines CompanyMehran ESC 2009
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●The data source for the analysis is the Premier Perspective Database
●A total of 127,185 PCI procedures were identified from the database between June 2003 through December 2006
●Patients received either bivalirudin plus provisional GPI or the comparator, heparin plus GPIIb/IIIa
Rassen JA et al Eur Heart J 2009
PREMIER Dataset
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Hazard Ratio ± 95% CI OR (95% CI)
Fully adjusted HR for transfusion 0.67 (0.61–0.73)
Fully adjusted HR for repeat PCI 0.96 (0.90–1.03)
Fully adjusted HR for death 0.51 (0.44–0.60)
0 1 2
Bivalirudin Better
Bivalirudin Better
Heparin + GP IIb/IIIa Inhibitor Better
Heparin + GP IIb/IIIa Inhibitor Better
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ANGIOX is Effective in Routine Care
● Angiox reduced the risk of in-hospital death and blood transfusions
Rassen JA et al Eur Heart J 2009
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Primary PCI Strategy
Aspirin, thienopyridine
3,000 pts eligible for stent randomisation
Bare metal stent paclitaxel-eluting stent
Clinical FU at 30 days, 1 yr, 2 years Clinical FU at 30 days, 1 yr, 2 years
HORIZONS AMI Trial Design● Open-label, randomised, prospective, multicenter trial
FU=follow-up; pts=patients; R=randomised; UFH=unfractionated heparin.
Stone GW. NEJM 2008;358:2218-30.
UFH + GP IIb/IIIa inhibitor(abciximab or eptifibatide)
Bivalirudin monotherapy(± provisional GP IIb/IIIa)
3,602 pts with STEMI with symptom onset ≤12 hours
R 1:3
R 1:1
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30-day Clinical Outcomes30
-day
eve
nt
rate
s (%
)
NACE Major Bleeding† MACE‡
*In HORIZONS AMI, 93% of bivalirudin patients received monotherapy, without provisional GP IIb/IIIa.
†Not related to CABG.
‡MACE=all-cause death, reinfarction, ischaemic TVR, or stroke.
Stone GW. NEJM 2008;358:2218-30:9
Diff = 0.0% [-1.6, 1.5] RR = 0.99 [0.76, 1.30]
Psup = 0.95
Diff = -3.3% [-5.0, -1.6] RR = 0.60 [0.46, 0.77]
PNI ≤ 0.0001Psup ≤ 0.0001
Diff = -2.9% [-4.9, -0.8]RR = 0.76 [0.63, 0.92]
PNI ≤ 0.0001Psup = 0.005
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30-day MACE Components
10
Bivalirudin(n=1,800)*
UFH + GP IIb/IIIa(n=1,802) P value
Mortality† 2.1% 3.1% 0.047
- Cardiac 1.8% 2.9% 0.03
- Noncardiac 0.3% 0.2% 0.75
Reinfarction 1.8% 1.8% 0.90
- Q-wave 1.4% 1.2% 0.66
- Non–Q-wave 0.4% 0.7% 0.37
Ischaemic TVR 2.6% 1.9% 0.18
Stroke 0.7% 0.6% 0.68
*In HORisONS AMI, 93% of bivalirudin patients received monotherapy, without provisional GP IIb/IIIa. †Adjudicated. TLR=target lesion revascularisation.
Stone GW. NEJM 2008;358:2218-30
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2-Year Reinfarction
1800 1644 1603 1554 12981802 1621 1576 1500 1244
p= 0.038
HR [95%CI]=0.75 [0.56, 0.98]
5.1%
6.9%
Re
infa
rcti
on
(%
)
0
1
2
3
4
5
6
7
8
9
10
0 3 6 9 12 15 18 21 24
Number at riskBivalirudin aloneHeparin+GPIIb/IIIa
Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802)
Months
Stone GW TCT 2009
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HORIZONS 2 year follow-up
● Cardiac mortality in ITT population
↓41%*
2.5%
4.2%
0
1
2
3
4
5
Months0 3 6 9 12 15 18 21 24
Ca
rdia
c m
ort
alit
y (%
)
2.1%
3.7 %
↓43%*
1.8%
2.9%
↓38%*
All p≤0.03
*Relative risk reduction
Bivalirudin UFH+GPI
Stone et al TCT 2009
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HORIZONS
Stent thrombosis
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30 Day Stent Thrombosis (N=3,124)
UFH + GP IIb/IIIa
(N=1553)
Bivalirudin(N=1571)
PValue
ARC definite or probable* 1.9% 2.5% 0.33
- definite 1.4% 2.2% 0.11
- probable 0.5% 0.3% 0.26
- acute (≤24 hrs) 0.3% 1.3% 0.0009
- subacute (>24 hrs – 30d) 1.7% 1.2% 0.30
*Protocol definition of stent thrombosis, CEC adjudicated*Protocol definition of stent thrombosis, CEC adjudicated
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HORIZONS ST to 30 days
● Increase in acute ST offset by decrease in sub-acute ST
Bivalirudin UFH+GPI
Est
ima
ted
eve
nt
rate
(%
)
Days from randomisation
0
1
2
3
4
5
5 10 15 20 25 300 0.5 1
24 acute ST
4 acute ST
30 sub-acute ST
20 sub-acute ST
Stone et al NEJM, 2008
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GPIIb/IIIa and stent thrombosis● Cumulative distribution for time to development of ST according to GPIIb-IIIa
inhibitor exposure. Among patients who received GPIIb-IIIa blockade, the median time to development of ST was increased from 2 to 5 days (P = .002).
0 5 10 15 20 25 30
1.0
0.8
0.6
0.4
0.2
0
Cum
ulat
ive
Fre
quen
cy o
f ST
Days
No GP IIb/IIIa Pretreatment
GP IIb/IIIa Pretreatment
P = .002
Rinaldi Am Heart J 2008;155:654-60
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Timing of Stent Thrombosis in Patients Treated with Tirofiban.
Assali AR J Invasive Cardiol. 2000 Sep;12(9):460-3
Retrospective analysis of a single-center intervention database between January1997 and October 1999 . 13 patients identified with
acute or subacute stent thrombosis
The median time from stent deployment to ST was 7 hours (IQR, 2.5-33 hours) in patients not receiving a GPIIb/IIIa antagonist compared to 84.5 hours (IQR, 56-124.5 hours) in patients receiving one.
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ST Type Bivalirudin (N=1800)
UFH + GPI
(N=1802)
Risk of death (n/N [%])
ST Death ST Death
Acute 23 1 4 1 2/27 (7.4)
Subacute 19 3 30 14 17/49 (34.7)
30 Day Stent Thrombosis – Risk of Subsequent Death
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Deaths at 1 year subsequent to major events
Number of deaths
Major event BivalirudinUFH +
GP IIb/IIIa Total Delta
Acute ST 1 1 2 0
Subacute ST 3 16 19 13
Late ST 3 6 9 3
Major Bleeding 13 31 44 18
Re-Infarction 5 11 16 6
Stroke 5 4 9 1
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HORIZONS Review
Did the dose of clopidogrel impact outcomes?
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Clopidogrel 300mg versus 600mg
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• The impact of bivalirudin was independent of the clopidogrel loading dose. Interaction P values = 0.48 (NACE) 0.41 (Major bleeding), and 0.75 (MACE).
• Significant decrease in MACE in patients treated with 600mg versus 300mg clopidogrel
MACE at 30 days
Clopidogrel 300mg Clopidogrel 600mg P-valueBivalirudin 43/595 (7.2) 46/1125 (4.1) 0.0052
UFH + GP IIb/IIIa 43/618 (7.0) 48/1091 (4.4) 0.0236
Dangas et al, JACC 2009
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Clopidogrel and Stent Thrombosis
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0
1
2
3
0 5 10 15 20 25 30
0
1
2
3
0 0.5 1
1204 1190 1188 1157 1147 1134
2203 2183 2181 2143 2124 2113
111 103 103 100 98 98
Days from RandomisationPatients at Risk
Clopidogrel 300mg:
Clopidogrel 600mg:
No Clopidogrel
Est
imat
ed E
vent
Rat
e (%
)
2.4%
Clopidogrel 300mg (A)
Clopidogrel 600mg (B)
No Clopidogrel (C)
1.2%
0%
Log Rank P–value24 hrs. A vs B: 0.939924 hrs. A vs C: 0.030624 hrs. B vs C: 0.0189
2.8%
0.7% 0.8%
Log Rank P–value30 days A vs B: 0.006730 days A vs C: 0.006730 days B vs C: 0.2803
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Optimising outcomes with bivalirudin
● Early adjunctive therapy
Early adjunctive therapy with guideline recommended therapies (which should include aspirin and clopidogrel and may include UFH) was associated with a reduced rate of AST in both arms of HORIZONS
● Adequate PY12 inhibition
Treatment with Clopidogrel 600 mg vs. 300mg resulted in improved MACE in both arms
Prasugrel 60 mg may be better than clopidogrel
● Prolonged bivalirudin infusion
A post PCI infusion of bivalirudin at 0.25/mg/kg infusion for up to 4 hours does not increase bleeding (BAT) and does not affect sheath pull times (AFRICA)
Prolonged antithrombin therapy until such time that P2Y12 inhibition is effective may further reduce AST
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Krumholz,. et al. JAMA 2009;302:767-773.
Trends in 30d mortality after AMI
● All-Cause risk-standardised mortality 1995-2006
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Conclusion● In HORIZONS-AMI the significant reductions in cardiac-
related death at 30-days, 1-year and 2-years are important.
● For every 59 patients with STEMI undergoing primary PCI with bivalirudin compared to conventional therapies one cardiac related death might be avoided (NNT= 59 at 1 yr).
● The important implications of the HORIZONS study are now reflected in the recently updated ACC/AHA guidelines for the management of patients with STEMI undergoing primary PCI where bivalirudin received a (Class IB) recommendation [Kushner et al., 2009].
● In conclusion, the favourable risk–benefit profile of bivalirudin, make it clinically important alternative to current treatments for the contemporary management of STEMI patients undergoing primary PCI.