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