bivalirudin with provisional gpiib/iiia inhibition – the data are clear!
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Bivalirudin with Provisional GPIIb/IIIa Inhibition – the Data
are Clear!Gregg W. Stone MD
Columbia University Medical Center Cardiovascular Research Foundation
Bivalirudin vs. Heparin + GPI (n=18,819)30d TIMI major or minor bleeding by treatment and study
p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001
REPLACE-2 ACUITY HORIZONS-AMI
Pooled0
2
4
6
8
10
3.9
6.6
9.6
6.3
1.9
4.0
5.9
3.7
Heparin + GPI (n=9413) Bivalirudin (n=9406)
TIM
I Ble
edin
g (%
)
347/9405 596/9413106/1800 173/1802183/4612 306/460358/2993 117/3008
Lincoff AM et al. JAMA 2003;289:853-63Stone GW et al. NEJM 2006;355:2203-16Stone GW et al. NEJM 2008;358:2218-30
p = 0.0003
Bivalirudin vs. Heparin + GPI (n=18,819)Acquired thrombocytopenia (<100,000) by treatment and study
p = 0.049 p = 0.003 p < 0.0001
REPLACE-2 ACUITY HORIZONS-AMI
Pooled0
1
2
3
4
1.72.2
2.9
2.2
0.7
1.71.1 1.2
Heparin + GPI (n=9413) Bivalirudin (n=9406)
Thro
mbo
cyto
peni
a (%
)
116/9145 201/911919/1665 48/185377/4612 103/460320/2868 50/2863
Lincoff AM et al. JAMA 2003;289:853-63Stone GW et al. NEJM 2006;355:2203-16Stone GW et al. NEJM 2008;358:2218-30
Bivalirudin(n=9406)
H+GPI(n=9413)
Adjusted HR [95%CI] P
REPLACE-2 1.9%(56/2994)
2.4%(72/3008)
0.78 (0.55 to 1.10) 0.16
ACUITY 3.7%(170/4612)
3.9%(178/4603)
0.96 (0.77 to 1.18) 0.67
HORIZONS-AMI 3.4%(61/1800)
4.8%(86/1802)
0.71 (0.51 to 0.98) 0.038
Pooled 3.1%(287/9406)
3.6%(336/9413)
0.84 (0.72 to 0.99) 0.035
Bivalirudin vs. Heparin + GPI (n=18,819)Mortality at 1-year by treatment and study
Lincoff AM et al. JAMA 2004;292:696-703Stone GW et al. JAMA 2007;298:2497-506Mehran R et al. Lancet. 2009;374:1149-59
Rassen JA et al. EHJ 2010;31:561-72
N = 127,185 pts undergoing PCI 2003-2006(Premier Perspective Database, ~1/6th of all US hosps; bival in 26%)
Bivalirudin vs. Heparin + GPIIb/IIIa
In-hospital transfusionBivalirudin H+GPI
3.0% 4.6%Adjusted HR [95%CI]
0.67 [0.61 - 0.73]
33% Transfusion
Favors Bival Favors H+GPI**30 days
Unadjusted (All)Adjusted (All)
Adjusted (urgent subgroup)Adjusted (elective subgroup)
REPLACE-2**ACUITY**
HORIZONS-AMI**ISAR-REACT**
0.1 101
N = 127,185 pts undergoing PCI 2003-2006(Premier Perspective Database, ~1/6th of all US hosps; bival in 26%)
Bivalirudin vs. Heparin + GPIIb/IIIa
In-hospital deathBivalirudin H+GPI
0.8% 2.1%Adjusted HR [95%CI]
0.51 [0.44 – 0.60]
49% Death
**30 days
Unadjusted (All)Adjusted (All)
Adjusted (urgent subgroup)Adjusted (elective subgroup)
REPLACE-2**ACUITY**
HORIZONS-AMI**ISAR-REACT**
0.1 101
Favors Bival Favors H+GPI
Rassen JA et al. EHJ 2010;31:561-72
Pinto DS et al. Circ CV Qual Outcomes 2012;5:52-61
Primary PCI in 59,917 STEMI pts 2004-2008(Premier Perspective Database, ~1/6th of all US hosps)
Bivalirudin vs. Heparin + GPIIb/IIIa
3:1 propensity adjusted matchingIn-hospital outcomes
Bivalirudin(N=5,329)
UFH + GPI(N=15,987) OR (95% CI) P value
Bleeding 6.9% 10.5% 0.52 (0.41, 0.66) <0.0001
Transfusion 5.9% 7.6% 0.75 (0.66–0.86) <0.0001
Bleeding + transf 1.6% 3.0% 0.63 (0.56–0.71) <0.0001
Death 3.2% 4.0% 0.80 (0.67– 0.95) 0.01
Length of stay (days) 4.3 ± 4.5 4.5 ± 4.4 - <0.0001
Total cost (median) $14,462 $15,772 - <0.0001
N = 458,448 PCI pts 2004-2008 at 299 hosps(Premier Perspective Database, ~1/5th of all US hosp discharges; bival in 41%)
Wise GR et al. J Interv Cardiol 2012;25:278–88
Bleeding + Transfusion
In-hospital events, propensity adjusted Mortality
Comparator Better
Heparin + GPI Better
(n=182,948)
0 21
0.71 (0.66, 0.76)Heparin alone(n=85,870) <0.0001
0.96 (0.87, 1.06)Bivalirudin + GPI(n=33,566) 0.37
0.51 (0.48, 0.55)Bivalirudin monotherapy(n=156,064)
<0.0001
OR(95% CI)Comparator P Value
Comparator Better
Heparin + GPI Better
(n=182,948)
0 21
0.88 (0.82, 0.96)Heparin alone(n=85,870) 0.003
0.82 (0.72, 0.94)Bivalirudin + GPI(n=33,566) 0.004
0.59 (0.54, 0.65)Bivalirudin monotherapy(n=156,064)
<0.0001
OR(95% CI)Comparator P Value
Anticoagulation Regimens During PCI
OR(95% CI)
OR(95% CI)
16 studies (3 rand, 13 reg), 32,492 pts undergoing PCI:Bivalirudin vs UFH Monotherapy Meta-analysis
Major Bleeding
Bertrand OF et al. Am J Cardiol 2012;110:599–606
Studyor subgroup Events
Odds Ratio M-H, Random, 95% CI
Odds Ratio M-H, Random, 95% CITotal
BivalirudinEvents
Heparin
0.01Favors Bivalirudin
0.1 1 10 100Favors Heparin
Total Events 244 431Test for heterogeneity: Tau2=0.08, Chi2=21.99, df=13 (P=0.06),I2=41%Test for overall effect: Z=4.38 (P<0.0001)Test for subgroup differences: Chi2=0.47, df=1 (P=0.49),I2=0%
Total (95% CI)
Observational
RandomizedKastrati 2008Parodi 2010Patti 2011Subtotal (95% CI)
0.55 [0.43, 0.72]11648
Total Events 16 34Test for heterogeneity: Tau2=0.00, Chi2=0.37, df=2 (P=0.83),I2=0%Test for overall effect: Z=2.60 (P=0.009)
1231
0.50 [0.25, 0.99]0.31 [0.08, 1.19]0.51 [0.05, 5.67]0.45 [0.25, 0.82]
2289363198
2850
2482
Total Events 228 397Test for heterogeneity: Tau2=0.11, Chi2=20.84, df=10 (P=0.02),I2=52%Test for overall effect: Z=3.55 (P=0.0004)
41223102656
1011238
0.52 [0.18, 1.47]0.55 [0.05, 6.12]0.30 [0.07, 1.31]0.97 [0.49, 1.90]0.52 [0.21, 3.17]0.32 [0.21, 0.49]1.21 [0.23, 6.33]0.39 [0.16, 0.95]0.87 [0.65, 1.16]0.82 [0.39, 1.74]0.47 [0.32, 0.70]0.57 [0.42, 0.78]
3355421656679
1207267503
1771228915118798
352141420
101226891678
Wolfram 2003Rha 2005Chu 2006Bonello 2009Lemesle 2009Lemesle 2009-bDelhaye 2010Lindsey 2010Lopes 2010Schultz 2010Bangalore 2011Subtotal (95% CI)
Total
13206
2281308203
2792
154360
45633392
1559129861136525051551
10414
45%↓
16 studies (3 rand, 13 reg), 32,492 pts undergoing PCI:Bivalirudin vs UFH Monotherapy Meta-analysis
Mortality
Bertrand OF et al. Am J Cardiol 2012;110:599–606
Studyor subgroup Events
Odds Ratio M-H, Random, 95% CI
Odds Ratio M-H, Random, 95% CITotal
BivalirudinEvents
Heparin
0.01Favors Bivalirudin
0.1 1 10 100Favors Heparin
Total Events 96 196Test for heterogeneity: Tau2=0.00, Chi2=13.90, df=14 (P=0.46),I2=0%Test for overall effect: Z=4.15 (P<0.0001)Test for subgroup differences: Chi2=0.00, df=1 (P=0.97),I2=0%
Total (95% CI)
Observational
RandomizedKastrati 2008Parodi 2010Patti 2011Subtotal (95% CI)
0.58 [0.45, 0.75]14563 17929
Total Events 5 8Test for heterogeneity: Tau2=0.00, Chi2=1.96, df=2 (P=0.38),I2=0%Test for overall effect: Z=0.78 (P=0.44)
311
0.75 [0.17, 3.34]0.21 [0.02, 1.89]
3.09 [0.13, 76.33]0.63 [0.20, 2.01]
2289363198
2850
440
Total Events 91 188Test for heterogeneity: Tau2=0.03, Chi2=11.92, df=11 (P=0.37),I2=8%Test for overall effect: Z=2.98 (P=0.003)
030736348501231
1.53 [0.06, 37.70]0.69 [0.15, 3.11]Not estimable
1.66 [0.61, 4.53]0.82 [0.21, 3.17]1.18 [0.29, 4.74]0.87 [0.19, 4.00]0.48 [0.34, 0.67]
2.44 [0.28, 21.13]0.19 [0.01, 3.52]0.51 [0.25, 1.06]0.66 [0.16, 2.75]0.12 [0.02, 1.00]0.62 [0.45, 0.85]
33586454
216205156679
1207267503
177122891511
11713
1409734
12414
1858
Wolfram 2003Gurm 2005Rha 2005Chu 2006Gurm 2007Bonello 2009Lemesle 2009Lemesle 2009-bDelhaye 2010Lindsey 2010Lopes 2010Schultz 2010Bangalore 2011Subtotal (95% CI)
Total
22813082032792
154380160456
392233392
1559129861
136525051551
15137
42%↓
NCDR CathPCI Registry 2004-2008: PCI in 1,522,935 ptsManual compression alone, closure devices, bivalirudin, or both
were used in 35%, 24%, 23%, and 18% of pts, respectively. Major bleeding occurred in 30,429 pts (2.0%)
Impact of Bleeding Avoidance Strategies
Marso SP et al. JAMA. 2010;303:2156-64
All pts Low Intermediate High0
2
4
6
8
2.8
0.9
2.3
6.1
2.1
0.9
1.9
4.6
1.6
0.61.4
3.8
0.90.4
0.8
2.3
Manual compression (n=529,247)Vascular closure devices (n=363,583)Bivalirudin (n=353,769)Bivalirudin + VCD (n=276,336)
Maj
or b
leed
ing
(%)
All P<0.001
Risk from NCDR CathPCI bleeding model
NCDR CathPCI Registry 2004-2008: PCI in 1,522,935 ptsManual compression alone, closure devices, bivalirudin, or both
were used in 35%, 24%, 23%, and 18% of pts, respectively. Propensity-adjusted bleeding
Impact of Bleeding Avoidance Strategies
Marso SP et al. JAMA. 2010;303:2156-64
All pts0
2
4
6
8
2.7 2.51.9
1.0
Manual compression (n=508,455) Vascular closure devices (n=205,606)Bivalirudin (n=172,471) Bivalirudin + VCD (n=130,378)
Maj
or b
leed
ing
(%)
23%↓
Adj OR (95%CI) =0.77 (0.73 – 0.80)
NNT = 148 Adj OR (95%CI) =0.67 (0.63 – 0.70)
NNT = 118 Adj OR (95%CI) =0.38 (0.35 – 0.42)
NNT = 70
33%↓ 62%↓
Impact of Access and Non-Access Site Bleeding after PCI
17,393 pts underwent PCI in REPLACE-2, ACUITY and HORIZONS
357(38.6%)142
(15.4%)
145(15.7%)
281(30.4%)
Access site only (2.1%)
Indeterminate (1.6%)
Non access site (0.8%)
Access + non access site (0.8%)
568(61.4%)
non accesssite related
925 pts (5.3%) had TIMI major or minor bleeding within 30 days
Source of bleeding (absolute rate)
Indeterminate – most likely intraprocedural (catheter
exchanges) or baseline anemia with lower transfusion threshold
Verheugt FWA et al. JACC Int 2011;4;191-197
Impact of Access and Non-Access Site Bleeding after PCI
17,393 pts underwent PCI in REPLACE-2, ACUITY and HORIZONS925 pts (5.3%) had TIMI major or minor bleeding within 30 days
Time-updated multivariable risk of death within 1-year
Adjusted risk of 1-year mortality
TIMI Bleed - All
TIMI Bleed – Non Access Site
TIMI Bleed – Access Site Only
0.1 81
HR [95%CI] P
3.17 [2.51, 4.00] <0.0001
3.94 [3.07, 5.15] <0.0001
1.82 [1.17, 2.83] 0.008
Verheugt FWA et al. JACC Int 2011;4;191-197
Impact of Access and Non-Access Site Bleeding after PCI
17,393 pts underwent PCI in REPLACE-2, ACUITY and HORIZONS925 pts (5.3%) with 30-day TIMI major or minor bleeding
Impact of bivalirudin on bleeding according to siteRelative
Risk P-Value
Access site 0.45 <0.0001
Non Access Site 0.62 <0.0001
- Non Access + Access Site 0.31 <0.0001
- Non Access Site Only 0.70 0.08
- Indeterminate 0.75 0.02
Bivalirudin better Hep + GPI better
NNT for bivalirudin to prevent 1 non-access site-related TIMI bleed = 71NNT for bivalirudin to prevent 1 access site-related TIMI bleed = 74
Impact of Access and Non-Access Site Bleeding after PCI
17,393 pts underwent PCI in REPLACE-2, ACUITY and HORIZONS925 pts (5.3%) with 30-day TIMI major or minor bleeding
Impact of bivalirudin on non-access site bleedingHep + GPI
(%)Bivalirudin
(%)Relative
Risk
Intracranial 0.04 0.03 0.66
GI 0.6 0.28 0.44
GU 0.64 0.28 0.44
HEENT 0.33 0.22 0.66
Pulmonary 0.18 0.05 0.31
Other 0.30 0.15 0.49
Indeterminate 1.87 1.40 0.75
All Non-Access Site 3.66 2.27 0.62
Bivalirudin better H + GPI better
0 0.5 1 1.5 2
HORIZONS-AMI: Cardiac Mortality in Pts with Major Bleeding
HR [95%CI] = 0.39 (0.17 - 0.89)
P=0.025
0%
2%
4%
6%
8%
10%
12%
14%
16%
Car
diac
mor
talit
y* (%
)
121 104 94 59Bivalirudin185 151 138 86UFH + GPI
0 1 2 3
Years
Heparin + GPI (n=185)Bivalirudin (n=121)
5.8%
14.6%
*From the time of a major bleed
0%
1%
2%
3%
4%
5%
1800 1569 1521 1039Bivalirudin1802 1506 1441 957UFH+GPI
0 1 2 3
HR [95%CI] = 0.67 (0.46 to 1.00)
P=0.046
*KM curve with censoring at time of major bleed
HORIZONS-AMI: Cardiac Mortality in Pts without Major Bleeding*
Car
diac
mor
talit
y (%
)
Years
Heparin + GPI (n=1802)Bivalirudin (n=1800)
2.6%
3.8%
Adj HR [95%CI] = 0.65 (0.44 to 0.97)
P=0.033
HORIZONS-AMI: Multivariable Model for 3-Year Cardiac Mortality, Including
Adverse Events Risk factor Hazard ratio (95% CI) P-value
Age (per 5 years) 1.34 (1.23 to 1.46) <0.001
WBC (per 109 cells/L) 1.15 (1.09 to 1.21) <0.001
S. creatinine (per 0.1 mg/dl) 1.10 (1.05 to 1.16) <0.001
Killip class 2-4 2.17 (1.41 to 3.35) <0.001
LAD PCI 1.68 (1.13 to 2.50) 0.007
Diabetes, medically treated 1.50 (1.01 to 2.23) 0.045
Major bleeding 2.97 (1.88 to 4.69) <0.001
Acquired thrombocytopenia 2.10 (1.36 to 3.24) 0.001
Bivalirudin (vs UFH+GPI) 0.54 (0.38 to 0.79) 0.002
Excludes 145 pts with thrombocytopenia at baseline. Other variables in model:current smoker, female gender, prior MI, # vessels treated, hemoglobin
Conclusion: Bivalirudin is the anticoagulant of choice for all PCI procedures
1. Compared to UFH + GPI, bivalirudin reduces mortality across the spectrum of pts undergoing PCI
2. The mortality benefit of bivalirudin can be attributed to a complex interplay of reduced rates of major bleeding (especially non-access site related), thrombocytopenia, and reinfarction, as well as reduced death in pts with these complications
3. These benefits are realized in all PCI pts - including those undergoing radial intervention
4. By reducing major bleeding, bivalirudin is cost-saving
Procedural anticoagulant use during PCI
LMWH UFH Bivalirudin GPIIb/IIIa inhibitor
0
20
40
60
80
100
9.9
51.1 55.9
28.7
Med
icat
ion
(%)
CathPCI Registry (~85% cath labs in the US)
941,248 PCIs between Jan 2010 and June 2011
Dehmer DJ et al. J Am Coll Cardiol 2012;60:2017–31
ESC/EACTS Guidelines•PCI in STEMI and NSTE-ACS
I
Bivalirudin in ACS: The Guidelines
ACC/AHA Guidelines •PCI in STEMI and NSTE-ACS•Pts with HIT or HITTS
I
EHJ 2010Circulation and JACC 2005, 2007, 2009, 2011
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