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Bivalirudin For patients with STEMI undergoing primary PCI. Dr Jonathan Day Senior Director Global Medical The Medicines Company. MY CONFLICTS OF INTEREST ARE The Medicines Company (Employee). New Indication for STEMI. Approved in the European Union in 2004 - PowerPoint PPT Presentation
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Dr Jonathan Day
Senior Director Global Medical
The Medicines Company
Bivalirudin
For patients with STEMI undergoing primary PCI
MY CONFLICTS OF INTEREST ARE
The Medicines Company (Employee)
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”
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
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
●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
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
7
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
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
8
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
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
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
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
HORIZONS
Stent thrombosis
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
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
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
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.
18
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
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
HORIZONS Review
Did the dose of clopidogrel impact outcomes?
Clopidogrel 300mg versus 600mg
21
• 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
Clopidogrel and Stent Thrombosis
22
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
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
23
Krumholz,. et al. JAMA 2009;302:767-773.
Trends in 30d mortality after AMI
● All-Cause risk-standardised mortality 1995-2006
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.