high risk acs: pci & real life data eurovision registry martial hamon, md, fesc university...
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High Risk ACS: PCI & Real LIFE data EUROVISION registry
Martial HAMON, MD, FESCUniversity Hospital of Caen
INSERM 744, IPL
EURO-VISION EUROpean biValIrudin utiliSatION in practice
Disclosure Statement of Financial Interest
● Grant/Research Support:
GlaxoSmithKline, Lilly, The Medicines Company.
● Consulting Fees/Honoraria:
Terumo, The Medicines Company, Biotronik, Cordis, Medtronic.
Affiliation/Financial Relationship
www.angiosoft.netwww.angiosoft.net
EURO-VISION EUROpean biValIrudin utiliSatION in practice
Real World Studies
Premier Perspective Database
EUROVISION
Diversity across PCIpatients
BATACUITY-PCI
REPLACE-2
HORIZONSAMI
Meta-analyses
Time
Clinical data across randomized trials and real world use in PCI
Bivalirudin: direct thrombin inhibitor
EURO-VISION EUROpean biValIrudin utiliSatION in practice
Central Role of Thrombin in Thrombosis
Rupture, Erosion, Fissuration
Hoffman et al Thromb Haemost. 2001 Becker R. Am Heart J. 2005
1.Initiation: Tissue factor
2.Amplification: Platelets
Thrombin platelet activation
3.Propagation
Massive thrombin production
Adapted from Mann K et al. Arterioscler Thromb Vasc Biol. 2003Coughlin S et al. Thromb Haem. 2001
Thrombin Generation in Thrombosis
0 2 4 6 8 10 12 14 16 18 20
Clot Time 4.7 ± 0.2
Initiation
Threshold of Amplification
Propagation
>96% of thrombin produced afterthe clot is seen
Time (min)
Thro
mbi
n-an
tithr
ombi
n co
mpl
ex (
nM)
0
200
400
600
800
1,000
Whole blood from 35 healthy volunteers,tissue factor and phospholipid added to induce clotting
EURO-VISION EUROpean biValIrudin utiliSatION in practice
ADP+
TXA2
NeutrophilsMonocytes
Activated platelets
Endothelial cells
Activated platelets
Resting platelets
Monocyte
Resting platelets
IITenasecomplex
Thrombin
Prothrombin
Prothrombinasecomplex
TF
Activatedplatelets
Fibrin
THROMBIN
Croce K et al. Curr Opin Hematol. 2007Coughlin SR. Nature. 200
Mann KG. Chest. 2003Monroe DM et al. ATVBiol. 2002
The critical roles of thrombin
EURO-VISION EUROpean biValIrudin utiliSatION in practice
2
1
AntithrombinThrombin
Antithrombin
Heparin
Pentasaccharide sequence
AntithrombinFactor
Xa
LMWH
Pentasaccharide sequence
Heparin chains with pentasaccharide sequence
(~30%) bind to AT causing a conformational change
Thrombin inhibition requires “bridging” by heparin chain
(at least 18 units)
LMWH has greater activity against Xa than thrombin
Heparin/LMWH: mechanism of action
Hirsh J et al. Chest. 2001; 119:64S–94S
Heparin concentration (units/mL)
Inh
ibiti
on
(%
)
0
50
100
0.1 0.2 0.4 1.0
Soluble thrombin Clot-bound thrombin
Weitz JI et al. J Clin Invest. 1990
Unpredictable anticoagulant responseNarrow therapeutic windowLimited activity in the presence of platelet-rich clotProcoagulant effect (Heparin-induced platelet activation)Heparin-induced thrombocytopenia (Heparin-PF4 Ab)
Heparin Limitations
Hirsh J et al. Chest. 1995; Weitz JI et al. Circulation. 2002; Hirsh J et al. Chest. 1998;Sobel M et al. J Vasc Surg. 2001; Anand SX et al. Am J Cardiol. 2007.
EURO-VISION EUROpean biValIrudin utiliSatION in practice
1.00 2.00 3.00 4.00 5.0040
0
30
20
10
Time (min:sec)
1.00 2.00 3.00 5.00 7.00
Time (min:sec)
4.00 6.00 8.00
70
0
50
30
10
60
40
20
60
0
50
30
10
40
20
2.00 3.00 4.00 5.00
Time (min:sec)
Plat
elet
agg
rega
tion
(%)
Plat
elet
agg
rega
tion
(%)
Gra
nule
secr
etion
2 µM ADP
+3 µM/mlFond.
ADP 2 µM NaClLMWH 0.2U/ml
LMWH+ ADP
ADP
UFH+ ADP
ADP
UFH+ ADP
ADP
Heparin or NaClADP 2 µM
These agents bind directly to and activate the GP IIb/IIIa receptor
Platelet activation increasedWith UFH, LMWH, Fondaparinux
Ex vivo data based on human platelet -rich plasma; concentrations of heparin used were 0.1 to 1 U/mL, to simulate therapeutic range;
similar concentrations of LMWH and fondaparinux used.
Adapted from Gao C. et al and supplemental data Blood 2011; 117(18):4946-52.
EURO-VISION EUROpean biValIrudin utiliSatION in practice
Bivalirudin mechanism of action
(Gly)4
D-Phe-Pro-Arg-Pro(active-site-binding portion)
C-terminal dodecapeptide(Substrate recognition:Exosite 1-binding portion)
Bivalirudin binds to active siteand substrate recognition site
of thrombin
Bivalirudin slowly cleavedallowing thrombin to resume
its hemostatic function
Maraganore J et al Biochemistry 1990;30:7095-101
Direct and reversible binding to thrombin
Thrombin
PCIDose
InitialDose
0
1
2
3
4
5
6
7
8
9
-1 -0 .5 0 0 .5 1 1 .5 2 2 .5 3 3 .5
Mea
n Pl
asm
a Co
nc. (
mcg
/mL)
Elapsed Time From Start of Bivalirudin Bolus (Hours)
BB B III
0.75 mg/kg bolus B + 1.75 mg/kg/h infusion I*2
Initial 0.1 mg/kg B + 0.25 mg/kg/h I;
At the time of PCI 0.5 mg/kg B + 1.75 mg/kg/h I†3
Shown to provide adequate anticoagulation in PCI (6.5 mcg/mL) 4
= 25-minutes half-life
† Dose used in the ACUITY trial. PCI dose derived from phase 2 dose ranging study used in REPLACE-1 & 2.2Lincoff AM et al. JAMA 2003; 289: 853-863. 3Stone G et al. Am Heart J. 2004;148:764-75. 4Topol E, et al. Circulation 1993; 87:1622.
Bivalirudin: predictable pharmacology
EURO-VISION EUROpean biValIrudin utiliSatION in practice
110%
0.01 0.1 1 10 100 1000Bivalirudin concentration (mcg/mL)
% a
ggre
gatio
n re
spon
se
Thrombin (0.5 U/mL)
therapeutic plasma level
range90
70
50
30
10
Bivalirudin: Platelet inhibition via thrombinThrombin is the most potent platelet agonist known
Coughlin SR, Nature 2000Weitz J, et al. Am J Cardiol 2001.
Anand SX et al. Am J Cardiol. 2007
Control platelets Platelets treated with UFH
Platelets treated with Bivalirudin
Platelets from healthy volunteers treated with 30 min bivalirudin (12μg/mL) or 0.1 to 1.0 U/mL of heparin
Schneider et al Cor Ar Dis 2006
UFH 1.2 U/mL UFH 2 U/mL UFH + EptifibatideBivalirudin%
of p
late
lets
exp
ress
ing
p-se
lect
in
% of Activated Platelets
% o
f pla
tele
ts b
indi
ng P
AC
-1
Thrombin U/mL
EURO-VISION EUROpean biValIrudin utiliSatION in practice
*Ischemic endpoints: death, MI, and revascularization
REPLACE-21
N=6,002UFH +GP IIb/IIIa vsBivalirudin(Urgent/elective PCI)
ACUITY2
N=9,215UFH + GPIIb/IIIa vsBivalirudin(ACS)
HORIZONS-AMI3
N=3,602UFH ± GP IIb/IIIa vsBivalirudin (primary PCI)
Heparin + GP IIb/IIIa Bivalirudin
Ischemia Bleeding Ischemia Bleeding Ischemia Bleeding
7.3%
5.7%
3.0%
7.8%
0%
2%
4%
6%
8%
10%P=.32
P<.0016.2%
4.2%
2.4%
7.0%
0%
2%
4%
6%
8%
10%P=.23
P<.001 5.5%
8.3%
4.9%5.4%
0%
2%
4%
6%
8%
10%
P=.95
P<.001
30 d
ay e
vent
s (%
)Bivalirudin Trials Ischemic and Bleeding Outcomes
Lincoff AM et al. JAMA. 2003;289:853-863. 2 Stone GW et al. NEJM. 2006;355:2203-2216. 3 Stone GW. NEJM 2008;358:2218-30
EURO-VISION EUROpean biValIrudin utiliSatION in practice
Cardiac mortality30 days to 3 years
Bivalirudin (n=1800)Bivalirudin (n=1800)Heparin + GPIIb/IIIa (n=1802)Heparin + GPIIb/IIIa (n=1802)
Card
iac
Mor
talit
y (%
)
P=0.001
3-yr† HR [95%CI]=0.56 [0.40, 0.80]
2.9%
5.1%
P=0.005
1-yr† HR [95%CI]=0.57 [0.38, 0.84]
0 12 15 18 21 24 27 30 33 36
Months3 6 9
0
1
6
5
4
3
2
3.8%
2.1%
30-d† HR [95% CI] 0.62; [0.40,0.96]
P = 0.03
1.8%
2.9%
In hospital and 30 day outcomes in all-comer PCI with BivalirudinInitial report of the prospective EUROVISION Registry.
Hamon M1, Nienaber C2, Galli S3, Huber K4, Gulba D5, Hill J6, Lafont A7, Cequier A8, Bernstein D9, Deliargyris E9 on Behalf of the Eurovision Investigators
1. Centre Hospitalier Universitaire de Caen, France. 2. Department of Cardiology and Angiology, University Hospital Rostock, Rostock School of Medicine, Rostock, Germany. 3. Department of Cardiovascular Sciences, University of Milan, Centro
Cardiologico Monzino, IRCCS, Milan, Italy. 4. Third Department of Medicine, Cardiology and Emergency Medicine, Wilhelminen hospital, Vienna, Austria. 5. Department of Cardiology, Krankenhaus Düren, Düren, Germany. 6. King's College Hospital, King's
College, London, UK. 7. Cardiology Department, University Paris-Descartes; AP-HP; European Georges Pompidou Hospital, Paris, France. 8. Hospital de Bellvitge, Barcelona, Spain. 9. The Medicines Company, Parsippany NJ, USA.
EURO-VISION EUROpean biValIrudin utiliSatION in practice
13
● Purpose: The EUROVISION Registry was designed to capture patterns of bivalirudin utilization and short term outcomes associated with the use of bivalirudin (BIV) during PCI procedures in Europe.
● Methods: consecutive BIV-treated patients included from 58 sites in 5 countries (Germany, Italy, France, Austria, United Kingdom).
● Outcomes: In-hospital and 30-day assessments
- Death, MI, stroke and urgent revascularization
- major bleeding according to ACUITY definition
- and minor bleeding any bleeding not included in the definition of major bleeding
Objectives and Methods
● In the ImproveR registry bolus only dosing was observed in EU clinical practice.
● Bolus only dosing was associated with increased in-hospital ischaemic events (MACE)
● The safety and efficacy of a bolus only dose of ANGIOX has not been evaluated and is not recommended even if a short PCI procedure is planned.
EURO-VISION EUROpean biValIrudin utiliSatION in practice
0 1 2 3 4 5 6 7 8 9Ischaemic events less
frequentIschaemic events more
frequent
Odds ratio [95% CI]
UFH/LMWH <24h after PCI (n=1069)
Age >65 years (n=2230)
Angiox double bolus (n=268)
STEMI (n=407)
PCI >45 minutes (n=1074)
Coumarins (n=99)
GP IIb/IIIa inhibitors (n=179)
ImproveR Registry
Madsen JK et al. EuroIntervention 2008:3:610-6
● An observational study of Angiox use in 4552 patients undergoing PCI.
– 26.3% of patients received a single bolus dose – no subsequent infusion
– 7.1% of patients received a double bolus dose – no subsequent infusion
– Bolus only dosing associated with in-hospital ischaemic events (MACE)
EURO-VISION EUROpean biValIrudin utiliSatION in practice
Study Population
2018 PCI-patients from 58 sitesin 5 European countries
French Investigators, Top 12:- Dr Lipiecki (n=96)- Dr Elhadad (n=88)- Pr Paganelli (n=87)- Pr Lafont (n=60)- Dr Hassani (n=36)- Pr Schiele (n=30)- Pr Carrié (n=25)- Dr Caussin (n=21)- Dr Loubeyre (n=18)- Dr Vilarem (n=15)- Dr Dibon (n=15)- Pr Steg (n=9)
Top Investigators (n>100):Pr Galli, Dr Goldman, Pr Huber,Dr Helmreich.
EURO-VISION EUROpean biValIrudin utiliSatION in practice
Distribution of PCI-patients: Indication
Overall, 58% of patients were cardiac marker -positive
N=523 N=315 N=499 N=678
- Overall, P2Y12 inhibitor preloading occurred in 95% of patients
- 91% clopidogrel (65% with 600 mg, 33% with 300 mg) and 9% prasugrel
- 45% of patients received other antithrombin therapy prior to PCI and were then switched to bivalirudin
- Activated clotting time was checked in only 2.8%
EURO-VISION EUROpean biValIrudin utiliSatION in practice
n/N Bivalirudin (N=2018)
Age (yrs), mean ± SD 65.5 ± 11.9
Age >65 yr 1122 /2018 55.6%
Female 499 /2018 24.7%
Weight (kg) mean ± SD - 79.8 ± 14.9
Prior MI 486 /2018 24.1%
Dyslipidemia 1215 /2018 60.2%
Prior PCI 636 /2018 31.5%
Hypertension 1385 /2018 68.6%
Previous CABG 145 /2018 7.2%
Congestive Heart Failure 130 /2018 6.4%
Current Smoker 588 /2018 29.1%
Family history of PVD 405 /2018 20.1%
Diabetes 482 /2018 23.9%
Baseline characteristics
EURO-VISION EUROpean biValIrudin utiliSatION in practice
n/N Bivalirudin (N=2018)
# diseased vessels >1 1086 /2018 53.8%
Actual treatment PCI 1933 /2018 95.8%
Actual treatment CABG 13 /2018 0.6%
Medical management 70 /2018 3.5%
Femoral access 1353 /1936 69.9%
Radial access 580 /1936 30.0%
Intervention Type:
Balloon Angioplasty 883 /2018 43.8%
Drug-Eluting Stent 1219 /2018 60.4%
Non drug-Eluting Stent 626 /2018 31.0%
Procedure duration, mean ±SD 36.0 ± 43.6
GP IIb/IIIa use 85 /2017 4.2%
Procedural characteristics
EURO-VISION EUROpean biValIrudin utiliSatION in practice
EUROVISION: 30-day Efficacy outcomes%
of E
vent
s
All patients n=2018
EURO-VISION EUROpean biValIrudin utiliSatION in practice
EUROVISION: 30-day Safety outcomes
All patients n=2018
% o
f Eve
nts
EURO-VISION EUROpean biValIrudin utiliSatION in practice
Overall rate of stent thrombosis 0.3% (6/2018)
Stent thrombosis by diagnosis
EURO-VISION EUROpean biValIrudin utiliSatION in practice
Deaths at 1 yearsubsequent to an event
UFH + GP IIb/IIIa inhibitorBivalirudin
Acute ST (<24 H)
Sub-acute ST (24 H to 30 d)
Late ST (30 days to 1 y)
Protocol Major Bleeding (1 y)
Re-infarction (1 y)
Stroke (1 y)
Mortality rate at 1 Year % (n/N)* Event
*In this post-hoc analysis, the mortality rate, n/N, is defined as the number of patients, n, who died after 1 year out of the number of patients, N, who had the event per treatment group
EURO-VISION EUROpean biValIrudin utiliSatION in practice
Outcomes by post-PCI infusion
Bivalirudin post-PCI infusion
n=916
Bivalirudin no post-PCI infusion
n=1017
Death/ MI/ Stroke/ Revasc 2.4% 3.3%
Death/ MI/ Revasc/ Stroke/ Major Bleed
3.4% 5.1%
Death 0.9% 1.2%
Stent thrombosis 0.4% 0.2%
Acute 0.1% 0.1%
Sub-acute 0.3% 0.1%
Major bleed 1.1% 2.0%
Among STEMI patients, 62% received a post-procedural bivalirudin infusion for a median duration of 122 minutes
EURO-VISION EUROpean biValIrudin utiliSatION in practice
EUROVISION: 30-day Diabetes - Efficacy
No Diabetes n=1514 Diabetes n=482
% o
f Eve
nts
EURO-VISION EUROpean biValIrudin utiliSatION in practice
EUROVISION: 30-day Diabetes - Safety
No Diabetes n=1514 Diabetes n=482
% o
f Eve
nts
EURO-VISION EUROpean biValIrudin utiliSatION in practice
EUROVISION: 30-day Diabetes - Summary
No Diabetes n=1514 Diabetes n=482
EURO-VISION EUROpean biValIrudin utiliSatION in practice
Country
Bivalirudin Femoral(N=1353)
Bivalirudin Radial
(N=580)
France 14.6% 62.9%
Italy 16.0% 28.3%
Austria 21.4% 0.7%
United Kingdom 4.4% 3.6%
Germany 43.5% 4.5%
Diagnosis
Stable Angina 29.3% 15.5%
Unstable Angina 14.7% 18.1%
NSTEMI 20.8% 33.8%
STEMI 35.1% 32.6%
Access route by country and diagnosis
EURO-VISION EUROpean biValIrudin utiliSatION in practice
Baseline Characteristics
Bivalirudin Femoral(n=1353)
Bivalirudin Radial
(n=580)p-value
Age (yrs), mean ± SD 65.7 ± 11.6 65.4 ± 12.2 NS
Female 23.7% 24.3% NS
Weight (kg) mean ± SD 80.0 ± 14.9 79.3 ± 14.9 NS
Prior MI 26.5% 19.8% 0.003
Dyslipidemia 63.3% 54.1% <0.0001
Prior PCI 35.3% 24.7% <0.0001
Hypertension 72.7% 59.5% <0.0001
Previous CABG 8.2% 5.0% 0.0436
Congestive Heart Failure 8.0% 3.4% <0.0001
Current Smoker 29.2% 28.8% <0.0001
Family history of PVD 21.5% 16.4% <0.0001
Diabetes 24.4% 20.9% NS
EURO-VISION EUROpean biValIrudin utiliSatION in practice
30 day Ischemic Outcomes (unadjusted)
Femoral(n=1353)
Radial(n=580) P-value
Death/ MI/ Stroke/ Revasc 3.2% 2.2% 0.2605
Death/MI/ Revasc/ Stroke/ Major Bleed 4.7% 3.3% 0.1483
Death 1.1% 0.9% 0.6234
MI 1.6% 0.2% 0.0088
Unplanned revasc 0.7% 1.4% 0.1233
Stroke 0.3% 0% 0.1899
Stent thrombosis 0.2% 0.5% 0.2844
Acute 0.1% 0.2% 0.5370
Sub-acute 0.1% 0.3% 0.3824
There were no differences noted in ischemic events at 30 daysbetween the two groups
EURO-VISION EUROpean biValIrudin utiliSatION in practice
Bleeding Outcomes (unadjusted)
Femoral(n=1353)
Radial(n=580) P-value
Major Bleeding 1.7% 1.2% 0.4216
Minor Bleeding 4.8% 1.9% 0.0026
Thrombocytopenia 0% 0% -
Access Site Bleed 3.6% 1.0% 0.0017
Non-Access Site Bleed 1.6% 0.9% 0.1897
EURO-VISION EUROpean biValIrudin utiliSatION in practice
Odds Ratio (95% CI)
P-value
Ischemic events(D/MI/UR/Stroke)Congestive heart failure
2.37 [1.22-4.61] 0.011
Major bleeding (ACUITY)Renal impairment 3.99 [1.93-8.26] <0.001
Independent predictors ofischemic events and major bleeding
EURO-VISION EUROpean biValIrudin utiliSatION in practice
Odds Ratio (95% CI)
P-value
Age ≥ 65 1.96 [1.15 - 3.33] 0.013
Hypertension 2.86 [1.40 - 5.87] 0.004
Prior PCI 0.58 [0.34 - 0.98] 0.044
Radial access 0.40 [0.21 - 0.79] 0.007
Independent predictors of minor bleeding
EURO-VISION EUROpean biValIrudin utiliSatION in practice
CONCLUSION (1)
● Adoption of BIV as the foundation for all-comer PCI including high percentage of STEMI and NSTEMI patients is :
- associated with excellent ischemic protection
- and unsurpassed safety.
● The use of Bivalirudin negated the risk associated with diabetes
● In the context of bivalirudin monotherapy during PCI, both ischemic and major bleeding complication rates at 30 days were similar irrespective of a femoral versus radial access site choice.
● The choice of radial access, however, was associated with lower rates of both minor and access site bleeding.
● Outcomes at 30 day observed in EUROVISION compare favorably to other large existing registry datasets
EURO-VISION EUROpean biValIrudin utiliSatION in practice
ESC/ EACTS 2010 Guidelines for Myocardial Revascularization
Wijns et al Eur Heart J. 2010 Oct;31(20):2501-55
STEMIClass Level
I B Bivalirudin (monotherapy)I C UFHIII B Fondaparinux
NSTE-ACS
Class Level
Very high-risk of ischaemia
I B Bivalirudin (monotherapy) or
I C UFH (+GPIIb-IIIa antagonists)
Medium-to-high-risk of ischaemia
I B Bivalirudin
I C UFH
I B Fondaparinux
EURO-VISION EUROpean biValIrudin utiliSatION in practice
High Risk PCI: 1 year mortality /Risk factorsREPLACE-2, ACUITY & HORIZONS-AMI (n= 14,258 DAPT)
Risk Factors included in the stratification model:1) Age>65, 2) Diabetes, 3) Hypertension, 4) Creatinine clearance<60mg/mL, 5) LVEF<35%, 6)NSTEMI, 7)STEMI, 8)Previous MI and 9) hematocrit<36.
EURO-VISION EUROpean biValIrudin utiliSatION in practice
One year mortality and risk factors
Pooled analysis: REPLACE-2, ACUITY & HORIZONS-AMI (n= 14,258 DAPT)
† fixed model ‡random effects model
RR (95% CI) P-value
REPLACE-2 0.76 (0.52,1.09) 0.14
ACUITY 0.92 (0.70,1.20) 0.53
HORIZONS 0.67 (0.48, 0.94) 0.018
Pooled analysis† 0.80 (0.66, 0.96) 0.015
Pooled analysis‡ 0.79 (0.66, 0.96) 0.018
Bivalirudin betterBivalirudin better UFH/GPIIbIIIa betterUFH/GPIIbIIIa better
Pooled analysis, 1-year mortalityRisk factor (n / N) RR (95% Cl)
P-value
Age >65 (314 / 5797) 0.79 (0.64, 0.98) 0.036
Diabetes (159 / 3598) 0.77 (0.57, 1.05) 0.097
Hypertension (313 / 9130) 0.84 (0.68, 1.05) 0.121
CrCl<60 mg/mL (171 / 2370) 0.75 (0.56, 1.00) 0.049
LVEF <35 (82 / 682) 0.47 (0.30, 0.72) 0.0004
biomarkers (NSTEMI) (139 / 3494) 0.91 (0.66, 1.26) 0.573
STEMI (135 / 3490) 0.67 (0.48, 0.94) 0.019
Previous MI (144 / 4088) 0.89 (0.64, 1.22) 0.463
Hematocrit <36% (102 /1684) 0.86 (0.59, 1.25) 0.418
Bivalirudin betterBivalirudin better UFH/GPIIbIIIa betterUFH/GPIIbIIIa better
1-year mortality and subgroup analysis
20% RR Death reduction with Bivalirudin Consistent results among subgroups
EURO-VISION EUROpean biValIrudin utiliSatION in practice
One year mortality and risk factors
REPLACE-2, ACUITY & HORIZONS-AMI (n= 14,258 DAPT)
RR (95% CI) P-value
30- day death
0, 1 or 2 risk factors 0.87 (0.45, 1.67) 0.67
3 or more risk factors 0.71 (0.51, 1.00) 0.047
1-year death
0, 1 or 2 risk factors 0.94 (0.66, 1.35) 0.75
3 or more risk factors 0.76 (0.61, 0.94) 0.01
30-day and 1-year Mortality Low Risk = 8082High Risk = 6176
Bivalirudin betterBivalirudin better UFH/GPIIbIIIa betterUFH/GPIIbIIIa better
1-ye
ar d
eath
(%)
Log Rank P-Value: Estimate:
Overall: 0.0083 Biv: 4.9%
Biv* vs Hep: 0.0083 Hep: 7.1%
1-year mortality, ≥ 3 risk factors (n=6,176)
Bivalirudin better in high risk PCI
EURO-VISION EUROpean biValIrudin utiliSatION in practice
1-year mortality, LVEF <35%● (n=682, overall 1 year mortality rate of 12%)
Patients at Risk:
Biv 351 342 335 334 329 328 328 323 323 322 319 314 247
Hep 331 305 300 296 295 291 289 286 279 278 273 269 209
16.9%
7.8%
p=0.0003
RR (95% Cl) P-value
REPLACE-2 LVEF <35 (N=214) 0.46 (0.19, 1.12) 0.078
ACUITY LVEF <35 (N=253) 0.51 (0.26, 0.99) 0.044
HORIZONS LVEF <35 (N=215) 0.43 (0.20, 0.91) 0.022
Pooled LVEF <35 (N=682) 0.47 (0.30, 0.72) 0.0004
REPLACE-2 LVEF ≥35 (N=3703) 0.85 (0.53, 1.37) 0.499
ACUITY LVEF ≥35 (N=3499) 1.06 (0.74, 1.53) 0.739
HORIZONS LVEF ≥35 (N=2744) 0.80 (0.51, 1.24) 0.311
Pooled LVEF ≥35 (N=9946) 0.92 (0.72, 1.17) 0.496
Bivalirudin betterBivalirudin better UFH/GPIIbIIIa betterUFH/GPIIbIIIa better
Consistent effectREPLACE-2, ACUITY, HORIZONS
1-year mortality by LVEF
Bivalirudin better in high risk PCI
EURO-VISION EUROpean biValIrudin utiliSatION in practice
Risk of Death, MI, Revasc. up to 7-days
Pooled meta-analysisCleveland Clinic F (n=16,519)
GPIIb-IIIawith heparin(n=7,629)
≥14,000 Uheparin(n=2,151)
7-10,000 Uheparin(n=4,578)
Angiomax(n=2,161)R
isk
of
TIM
I m
ajo
r B
leed
ing
in
Ho
spti
al
02
2Indirect and unpredictable thrombin
inhibition by UFH provides inadequate ischemic protection in high risk ACS
Addition of GPI’s improves ischemic protection at the cost of increased bleeding – modest if any mortality benefit
Bivalirudin trials have consistently demonstrated equivalent efficacy to GPI+UFH with reduced bleeding
Progress in High Risk ACS/PCIConclusion (2)
EURO-VISION EUROpean biValIrudin utiliSatION in practice
ESC/ EACTS 2010 Guidelines for Myocardial Revascularization
Wijns et al Eur Heart J. 2010 Oct;31(20):2501-55
STEMIClass Level
I B Bivalirudin (monotherapy)I C UFHIII B Fondaparinux
NSTE-ACS
Class Level
Very high-risk of ischaemia
I B Bivalirudin (monotherapy) or
I C UFH (+GPIIb-IIIa antagonists)
Medium-to-high-risk of ischaemia
I B Bivalirudin
I C UFH
I B Fondaparinux
EURO-VISION EUROpean biValIrudin utiliSatION in practice
THANK YOU FOR YOUR ATTENTION
EURO-VISION EUROpean biValIrudin utiliSatION in practice
0 1 2 3 4 5 6 7
Bleeding Risk: Access and non-access bleeding
Jolly S et al Lancet 2011;377:1409-20
RIVAL TrialPCI-patients randomized to radial
or femoral access, N=7021
2.1
0.8
0.8
1.6
0
1
2
3
4
5
6
TIMI Major + Minor%
of
pa
tie
nts
Access Site Only Both Non-Access Site Only No Location
Sources and incidence of bleedingPooled analysis REPLACE-2, ACUITY-PCI, HORIZONS-AMI: N=17,393
5.3% (n=925)
Non- access site
61.4% (n=568)
Access site only
38.6% (n=375)
Verheugt JACC Cardio Interv 2011;4:191-7
3.3%
2.1%
Hazard ratio
Access site 1.82 (1.17–2.83) 0.008
Non-access site 3.94 (3.07–5.15) <0.0001
No Bleed TIMI Major + Minor Bleed
1-year (adjusted) mortality hazardbleeding vs no bleeding
1-year mortality risk non-access site vs access site bleedingHR 2.27 (95%CI 1.42-3.64), p=0.0007
EURO-VISION EUROpean biValIrudin utiliSatION in practice
Bleeding Risk / Pharmacotherapy strategy
0 0.5 1 1.5 2
TIMI Major + Minor Bleeding Relative Risk P-Value
Access only 0.45 (0.35-0.58) <0.0001
All non-access 0.62 (0.51-0.75) <0.0001
Both 0.31 (0.19-0.49) <0.0001
Non-access only 0.70 (0.47-1.04) 0.08
Indeterminate 0.75 (0.58-0.96) 0.02
Bivalirudin better Hep + GPI better
Verheugt JACC Cardio Interv 2011;4:191-7
Relative risk of bleeding by treatmentPooled analysis REPLACE-2, ACUITY-PCI, HORIZONS-AMI, N=17,393
Bleeding Risk Access/PharmacotherapyBy bleeding risk category (n=982,077)
Marso et al. ACC/i2 Scientific Sessions 2010; abstract 2505-458
Low*(<1%)
Intermediate*(1-3%)
High*(>3%)
Overall*
MC BV R BR MC BV R BR MC BV R BR MC BV R BR
*P<0.001, 4-way comparison
MC = Manual compressionBV = Bivalirudin R = Radial PCIBR = Bivalirudin + radial
P=0.05 P=0.06
Records from NCDR 2004-2008
Synergistic effect of radial and bivalirudin for reducing major bleedingAnd subsequent potential deleterious outcomes
EURO-VISION EUROpean biValIrudin utiliSatION in practice
Risk of Death, MI, Revasc. up to 7-days
Summary resultsRR (95% CI)
GPIIb-IIIa inh.+UFH/LMWH
HeparinLMWH
Bivalirudin
Ris
k o
f T
IMI
maj
or
Ble
edin
g i
n H
osp
tial
0 2
2Indirect and unpredictable thrombin
inhibition by UFH provides inadequate ischemic protection in high risk ACS
Addition of GPI’s improves ischemic protection at the cost of increased bleeding – modest if any mortality benefit
Bivalirudin trials have consistently demonstrated equivalent efficacy to GPI+UFH with reduced bleeding
Progress in High Risk ACS/PCIConclusion (2)