Post on 19-Mar-2020
Julinda Mehilli, MD, FESC
Deutsches Herzzentrum,
Technische Universität, München
Do We Need Individualized Anticoagulation during Percutaneous Coronary
Interventions?
Aggregation Activation
Prothrombin
Factor Xa
Thrombus stabilisation
Antithrombin
Modified from Kulkarni et al., JCI 2000
Pathophysiology of Arteriel Thrombosis
Coagulation
Adesion Tethering
Fibrinbildung
Clopidogrel
Abciximab
Heparin
Direct
Thrombin-Inhibitor
Thrombocyte Recruitment
Thrombin
Adjunct Antithrombotic Therapy
15%
16%
24%
45%SAP
STEMI
NSTEMI
IAP ISAR-REACT Kastrati et al.,
N Engl J Med 2004
ISAR-REACT 3 Kastrati et al.,
N Engl J Med 2008
BRAVE 3 Mehilli et al.,
Circulation 2009
HORIZONS AMI Stone et al., N Engl J Med 2008
ISAR-REACT 2 Kastrati et al., JAMA 2006
ISAR-REACT 4 Kastrati et al., N Engl J Med 2011
ACUITY Stone et al., N Engl J Med 2006
Spectrum of Clinical Presentation
at Cath Lab of Patients with CAD
10-Year Experience in Deutsches Herzzentrum and RdI
- ~20,000 patients with CAD and PCI -
Stable AP
STEMI
NSTEMI
Unstable AP
Ndrepepa et al, Cardiology 2009
0
5
10
15
20
0 1 2 3 4 5 6 7 8 9 10 11 12
Mortality
Months after PCI
OR = 3.00 [2.56-3.51], P<0.001 for STEMI vs. IAP
OR = 2.58 [2.20-3.04], P<0.001 for NSTEMI vs. IAP %
Ndrepepa et al.,Cardiology 2009
Clinical Presentation and Mortality after PCI
STEMI
NSTEMI
IAP
%
Clinical Presentation and Peri-PCI Events
REACT 3A EHJ 2009
ACUITY NEJM 2006
HORIZONS AMI NEJM 2008
Ndrepepa et al.,Cardiology 2009
n=5.384
Ndrepepa et al.,JACC 2008
ISAR-REACT, ISAR-SWEET, ISAR-SMART-2 und ISAR-REACT-2 Trials
% HR 2.96 (1.96-4.48), p<0.001
% HR 2.29 (1.52-3.46), p<0.001
Balance Between Antiischemic and Pro-bleeding Effects
Mortality Mortality
Adjunct Antithrombotic Therapy
15%
16%
24%
45%SAP
STEMI
NSTEMI
IAP ISAR-REACT Kastrati et al.,
N Engl J Med 2004
ISAR-REACT 3 Kastrati et al.,
N Engl J Med 2008
ISAR-REACT 3A Schulz et al.,
Eur Heart J 2010
ISAR-REACT 2 Kastrati et al., JAMA 2006
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11 12 Months after randomization
%
75.3%
74.6%
UFH+Abciximab vs. UFH+Placebo
RR = 1.01[ 95% CI, 0.85 -1.20]
Death, MI, TVR, %
ISAR-REACT, EHJ 2005 ISAR-REACT, NEJM 2004
Patients with Stable Angina
Heparin alone or with GPI ISAR-REACT n = 2951
ISAR-REACT, NEJM 2004
Patients with Unstable Angina
Heparin alone or with GPI
UFH+Abciximab vs. UFH+Placebo
0
5
10
15
20
0 5 10 15 20 25 30 Days after randomization
Death/MI/urg. TVR, %
Troponin-Negative: RR=0.99 [0.56-1.76]
ISAR-REACT 2
ISAR-REACT-2, JAMA 2006 ISAR-REACT 2, JAMA 2006
0
2
4
6
8
10
0 5 10 15 20 25 30 Days after randomization
5.0%
5.9%
RR = 1.16 [95% CI, 0.91-1.49]
Death/MI/urgTVR
%
Bivalirudin vs. UFH
ISAR-REACT, NEJM 2008
Patients with Stable/Unstable Angina
Heparin alone or Bivalirudin
ISAR-REACT 3 n= 4570
ISAR-REACT 3, NEJM 2008
Incid
ence (
%)
P=0.008 P=0.0001 P=0.15
UFH 140 IU/kg
ISAR-REACT, NEJM 2008
Patients with Stable/Unstable Angina
Heparin alone or Bivalirudin
ISAR-REACT 3, NEJM 2008
Days After Inclusion
Qua
dru
ple
en
dp
oin
t (%
)
0
5
10
15
20
0 5 10 15 20 25 30
HR 0.81 [0.67-1.00]; P=0.045
Adjusted HR 0.75 [0.60-0.92]; P=0.007
140 U/kg UFH: 8.7%
100 U/kg UFH: 7.3%
ISAR-REACT 3A, Eur Heart J 2010
Patients with Stable/Unstable Angina
High or Low Dose Heparin
Death,MI,urgTVR,major Bleeding ISAR-REACT 3A n= 4786
ISAR-REACT 3A, Eur Heart J 2009
UFH 100 U/kg
UFH 140 U/kg
6.2
3.6
9.9
4.6
0
2
4
6
8
10
12
Major Bleeding Minor Bleeding
HR 0.79 [0.59-1.05]; P=0.11
Adjusted HR 0.71 [0.53-0.97]; P=0.03
Incid
en
ce
(%
)
Incid
ence (
%) 4.4
5.0
0
1
2
3
4
5
6
7
Secondary (Triple) Endpoint:
Death, MI or uTVR
HR 0.87 [0.67-1.13]; P=0.29
Adjusted HR 0.82 [0.62-1.08]; P=0.15
ISAR-REACT 3A, Eur Heart J 2010
Patients with Stable/Unstable Angina
High or Low Dose Heparin
ISAR-REACT 3A, Eur Heart J 2009
Adjunct Antithrombotic Therapy
15%
16%
24%
45%SAP
STEMI
NSTEMI
IAP ISAR-REACT 2 Kastrati et al., JAMA 2006
ISAR-REACT 4 Kastrati et al., N Engl J Med 2011
ACUITY Stone et al., N Engl J Med 2006
Patients with NSTEMI
Heparin alone or with GPI
UFH+Abciximab vs. UFH+Placebo
0
5
10
15
20
0 5 10 15 20 25 30 Days after randomization
Death/MI/urg. TVR, %
Troponin-Positive: RR=0.71 [0.54-0.95]
ISAR-REACT 2, JAMA 2006
ISAR-REACT 2
n= 1049
ISAR-REACT 2, JAMA 2006
%
P=0.29 P=0.46 P=0.008 P>0.99
Heparin+Abciximab Heparin+Placebo
Patients with NSTEMI
Heparin alone or with GPI
ISAR-REACT 2, JAMA 2006
PNI <0.0001
PSup = 0.015
PNI = 0.011
PSup = 0.32
PNI <0.0001
PSup <0.0001
Patients with NSTEMI
Heparin with GPI or Bivalirudin?
ACUITY, NEJM 2006 ACUITY, NEJM 2006
ISAR-REACT 4 Trial flow-chart
Bivalirudin Abciximab
1,721 Pts with NSTEMI Pre-treated with 600 mg of clopidogrel
Double-blind
(double-dummy drug)
Bolus of 0.25 mg/kg
Infusion of 0.125 μg/kg/min for 12h
Unfractionated heparin Bolus of 70 U/kg
Bolus of 0.75 mg/kg
Infusion of 1.75 mg/kg/hr
for duration of PCI
No PCI: 2 patients 2 patients
861 pts 860 pts
Primary endpoint Death, large MI, uTVR, major bleeding
Days since Randomization
0
5
10
15
20
0 5 10 15 20 25 30
Cu
mu
lative
In
cid
en
ce
(%
)
Relative risk, 0.99 (95% CI, 0.74–1.32)
P=0.94
Bivalirudin
Abciximab 10.9%
11.0%
ISAR-REACT 4, N Engl J Med 2011
Primary endpoint analysis in various subsets Death, large MI, uTVR, major bleeding
Age
>68.3 yr
≤68.3 yr
SexWomenMen
Troponin T>0.12 μg/l≤0.12 μg/l
Relative Risk (95% CI)
0 1 2
Diabetes
YesNo
Abciximab better Bivalirudin better
Body Mass Index
>27.3 kg/m2
≤27.3 kg/m2
48/450 (10.7) 49/443 (11.1)
Abciximab Bivalirudin
46/411 (11.2) 46/417 (11.0)
31/200 (15.5) 25/199 (12.6)
63/661 (9.5) 70/661 (10.6)
27/257 (10.5) 24/243 (9.9)
67/604 (11.1) 71/617 (11.5)
42/435 (9.7) 46/426 (10.8)
52/426 (12.2) 49/434 (11.3)
56/424 (13.2) 66/425 (15.5)
38/437 (8.7) 29/435 (6.7)
P Value for
Interaction
0.94
0.27
0.71
0.51
0.15
no. of events/total no. (%)Subgroup
Glomerular filtration rate
≤83 ml/min 47/440 (10.7) 51/420 (12.1)
0.41>83 ml/min 47/421 (11.2) 44/440 (10.0)
Secondary efficacy endpoint - Death, any MI, uTVR
Bivalirudin
Abciximab
Relative risk, 0.96 (95% CI, 0.74–1.25)
P=0.76
0
5
10
15
20
0 5 10 15 20 25 30
Cu
mu
lative
In
cid
en
ce
(%
)
Days since Randomization
Abciximab Bivalirudin
Death, % 1.4 1.6
Any MI, % 12.0 11.4
uTVR, % 0.8 1.3
12.8%
13.4%
ISAR-REACT 4, N Engl J Med 2011
Secondary safety endpoint - Major bleeding
0
5
10
15
20
0 5 10 15 20 25 30
Cu
mu
lative
In
cid
en
ce
(%
)
Days since Randomization
Relative risk, 1.84 (95% CI, 1.10–3.07)
P=0.02
Bivalirudin
Abciximab 4.6%
2.6%
ISAR-REACT 4, N Engl J Med 2011
Adjunct Antithrombotic Therapy
15%
16%
24%
45%SAP
STEMI
NSTEMI
IAP
BRAVE 3 Mehilli et al.,
Circulation 2009
HORIZONS AMI Stone et al., N Engl J Med 2008
Patients with STEMI
Heparin alone or with GPI
Placebo
399 pts
Abciximab
401 pts
PCI
800 Patients with STEMI Pretreatment with 600 mg of clopidogrel
Primary endpoint: Scintigraphic final infarct size
Double-blind
Final infarct size Mean
15.7 16.6
0
10
20
30
40
% LV P = .47
Abciximab Placebo
BRAVE 3, Circulation 2009 BRAVE 3, Circulation 2009
%
P = .48 P = .46 P = .39
Patients with STEMI
Heparin alone or with GPI
BRAVE 3, Circulation 2009
Heparin+Abciximab Heparin+Placebo
BRAVE 3, Circulation 2009
HORIZONS AMI, NEJM 2008
RR = 0.99 [0.76, 1.30]
Psup = 0.95 RR = 0.60 [0.46, 0.77]
PNI ≤ 0.0001
Psup ≤ 0.0001
RR = 0.76 [0.63, 0.92]
PNI ≤ 0.0001
Psup = 0.005
Patients with STEMI
Heparin and GPI or Bivalirudin
HORIZONS AMI, N Engl J Med 2008
Stone, Lancet 2010
HORIZONS AMI, NEJM 2008
HORIZONS AMI, NEJM 2008 & Lancet 2011
Patients with STEMI
Heparin and GPI or Bivalirudin
Adjunct Antithrombotic Therapy
15%
16%
24%
45%SAP
STEMI
NSTEMI
IAP
Heparin bolus 70-100 U/Kg
ACT Monitoring for long
procedures
Bivalirudin as effective as
UFH + Abciximab
regarding ischemic events
superior to
UFH + Abciximab
regarding bleeding events