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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.

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bivalirudin with provisional gpiib iiia inhibition the data are clear

Bivalirudin with Provisional GPIIb/IIIa Inhibition – the Data are Clear!

Gregg W. Stone MD

Columbia University Medical Center Cardiovascular Research Foundation

slide2

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

58/2993

117/3008

183/4612

306/4603

106/1800

173/1802

347/9405

596/9413

Lincoff AM et al. JAMA 2003;289:853-63

Stone GW et al. NEJM 2006;355:2203-16

Stone GW et al. NEJM 2008;358:2218-30

slide3

Bivalirudin vs. Heparin + GPI (n=18,819)

Acquired thrombocytopenia (<100,000) by treatment and study

p = 0.0003

p = 0.049

p = 0.003

p < 0.0001

20/2868

50/2863

77/4612

103/4603

19/1665

48/1853

116/9145

201/9119

Lincoff AM et al. JAMA 2003;289:853-63

Stone GW et al. NEJM 2006;355:2203-16

Stone GW et al. NEJM 2008;358:2218-30

bivalirudin vs heparin gpi n 18 819 mortality at 1 year by treatment and study
Bivalirudin vs. Heparin + GPI (n=18,819)Mortality at 1-year by treatment and study

Lincoff AM et al. JAMA 2004;292:696-703

Stone GW et al. JAMA 2007;298:2497-506

Mehran R et al. Lancet. 2009;374:1149-59

slide5

Bivalirudin vs. Heparin + GPIIb/IIIa

N = 127,185 pts undergoing PCI 2003-2006

(Premier Perspective Database, ~1/6th of all US hosps; bival in 26%)

In-hospital transfusion

Bivalirudin

H+GPI

Unadjusted (All)

Adjusted (All)

Adjusted (urgent subgroup)

Adjusted (elective subgroup)

REPLACE-2**

ACUITY**

HORIZONS-AMI**

ISAR-REACT**

3.0%

4.6%

Adjusted HR [95%CI]

0.67 [0.61 - 0.73]

33% 

Transfusion

0.1

1

10

**30 days

Favors Bival

Favors H+GPI

Rassen JA et al. EHJ 2010;31:561-72

slide6

Bivalirudin vs. Heparin + GPIIb/IIIa

N = 127,185 pts undergoing PCI 2003-2006

(Premier Perspective Database, ~1/6th of all US hosps; bival in 26%)

In-hospital death

Bivalirudin

H+GPI

Unadjusted (All)

Adjusted (All)

Adjusted (urgent subgroup)

Adjusted (elective subgroup)

REPLACE-2**

ACUITY**

HORIZONS-AMI**

ISAR-REACT**

0.8%

2.1%

Adjusted HR [95%CI]

0.51 [0.44 – 0.60]

49% 

Death

0.1

1

10

**30 days

Favors Bival

Favors H+GPI

Rassen JA et al. EHJ 2010;31:561-72

slide7

Bivalirudin vs. Heparin + GPIIb/IIIa

Primary PCI in 59,917 STEMI pts 2004-2008

(Premier Perspective Database, ~1/6th of all US hosps)

3:1 propensity adjusted matching

Pinto DS et al. Circ CV Qual Outcomes 2012;5:52-61

slide8

Anticoagulation Regimens During PCI

N = 458,448 PCI pts 2004-2008 at 299 hosps

(Premier Perspective Database, ~1/5th of all US hosp discharges; bival in 41%)

In-hospital events, propensity adjusted

Bleeding + Transfusion

Mortality

OR

(95% CI)

OR

(95% CI)

Comparator

OR

(95% CI)

Comparator

OR

(95% CI)

P Value

P Value

Bivalirudin

monotherapy

(n=156,064)

Bivalirudin monotherapy

(n=156,064)

0.51 (0.48, 0.55)

0.59 (0.54, 0.65)

<0.0001

<0.0001

Bivalirudin + GPI

(n=33,566)

Bivalirudin + GPI

(n=33,566)

0.96 (0.87, 1.06)

0.82 (0.72, 0.94)

0.37

0.004

Heparin alone

(n=85,870)

Heparin alone

(n=85,870)

0.71 (0.66, 0.76)

0.88 (0.82, 0.96)

<0.0001

0.003

0

1

2

0

1

2

Comparator Better

Heparin + GPI Better

(n=182,948)

Comparator Better

Heparin + GPI Better

(n=182,948)

Wise GR et al. J Interv Cardiol 2012;25:278–88

slide9

Bivalirudin vs UFH Monotherapy Meta-analysis

Major Bleeding

16 studies (3 rand, 13 reg), 32,492 pts undergoing PCI:

Study

or subgroup

Events

Bivalirudin

Total

Events

Heparin

Total

Odds Ratio M-H, Random, 95% CI

Odds Ratio M-H, Random, 95% CI

Observational

Wolfram 2003

Rha 2005

Chu 2006

Bonello 2009

Lemesle 2009

Lemesle 2009-b

Delhaye 2010

Lindsey 2010

Lopes 2010

Schultz 2010

Bangalore 2011

Subtotal (95% CI)

4

1

2

23

10

26

5

6

101

12

38

335

54

216

566

79

1207

267

503

1771

2289

1511

8798

35

2

14

14

20

101

2

26

89

16

78

1543

60

456

333

92

1559

129

861

1365

2505

1551

10414

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]

Total Events 228 397

Test 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)

Randomized

Kastrati 2008

Parodi 2010

Patti 2011

Subtotal (95% CI)

12

3

1

2289

363

198

2850

24

8

2

2281

308

203

2792

0.50 [0.25, 0.99]

0.31 [0.08, 1.19]

0.51 [0.05, 5.67]

0.45 [0.25, 0.82]

Total Events 16 34

Test 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)

45%↓

0.55 [0.43, 0.72]

Total (95% CI)

11648

13206

Total Events 244 431

Test 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%

0.01

0.1

1

10

100

Favors Bivalirudin

Favors Heparin

Bertrand OF et al. Am J Cardiol 2012;110:599–606

slide10

Bivalirudin vs UFH Monotherapy Meta-analysis

Mortality

16 studies (3 rand, 13 reg), 32,492 pts undergoing PCI:

Study

or subgroup

Events

Bivalirudin

Total

Events

Heparin

Total

Odds Ratio M-H, Random, 95% CI

Odds Ratio M-H, Random, 95% CI

Observational

Wolfram 2003

Gurm 2005

Rha 2005

Chu 2006

Gurm 2007

Bonello 2009

Lemesle 2009

Lemesle 2009-b

Delhaye 2010

Lindsey 2010

Lopes 2010

Schultz 2010

Bangalore 2011

Subtotal (95% CI)

0

3

0

7

3

6

3

48

5

0

12

3

1

335

864

54

216

2051

566

79

1207

267

503

1771

2289

1511

11713

1

4

0

9

7

3

4

124

1

4

18

5

8

1543

801

60

456

3922

333

92

1559

129

861

1365

2505

1551

15137

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]

Total Events 91 188

Test 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)

Randomized

Kastrati 2008

Parodi 2010

Patti 2011

Subtotal (95% CI)

3

1

1

2289

363

198

2850

4

4

0

2281

308

203

2792

0.75 [0.17, 3.34]

0.21 [0.02, 1.89]

3.09 [0.13, 76.33]

0.63 [0.20, 2.01]

Total Events 5 8

Test 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)

42%↓

0.58 [0.45, 0.75]

Total (95% CI)

14563

17929

Total Events 96 196

Test 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%

0.01

0.1

1

10

100

Favors Bivalirudin

Favors Heparin

Bertrand OF et al. Am J Cardiol 2012;110:599–606

slide11

Impact of Bleeding Avoidance Strategies

NCDR CathPCI Registry 2004-2008: PCI in 1,522,935 pts

Manual 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%)

All P<0.001

Risk from NCDR CathPCI bleeding model

Marso SP et al. JAMA. 2010;303:2156-64

slide12

Impact of Bleeding Avoidance Strategies

NCDR CathPCI Registry 2004-2008: PCI in 1,522,935 pts

Manual compression alone, closure devices, bivalirudin, or both were used in 35%, 24%, 23%, and 18% of pts, respectively.

Propensity-adjusted bleeding

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

23%↓

33%↓

62%↓

Marso SP et al. JAMA. 2010;303:2156-64

slide13

Impact of Access and Non-Access Site Bleeding after PCI

17,393 pts underwent PCI in REPLACE-2, ACUITY and HORIZONS

925 pts (5.3%) had TIMI major or minor bleeding within 30 days

Source of bleeding (absolute rate)

568

(61.4%)

non access

site related

Indeterminate – most likely intraprocedural (catheter exchanges) or baseline anemia with lower transfusion threshold

Verheugt FWA et al. JACC Int 2011;4;191-197

slide14

Impact of Access and Non-Access Site Bleeding after PCI

17,393 pts underwent PCI in REPLACE-2, ACUITY and HORIZONS

925 pts (5.3%) had TIMI major or minor bleeding within 30 days

Time-updated multivariable risk of death within 1-year

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

TIMI Bleed - All

TIMI Bleed – Non Access Site

TIMI Bleed – Access Site Only

0.1

1

8

Adjusted risk of 1-year mortality

Verheugt FWA et al. JACC Int 2011;4;191-197

slide15

Impact of Access and Non-Access Site Bleeding after PCI

17,393 pts underwent PCI in REPLACE-2, ACUITY and HORIZONS

925 pts (5.3%) with 30-day TIMI major or minor bleeding

Impact of bivalirudin on bleeding according to site

Relative

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 = 71

NNT for bivalirudin to prevent 1 access site-related TIMI bleed = 74

slide16

Impact of Access and Non-Access Site Bleeding after PCI

17,393 pts underwent PCI in REPLACE-2, ACUITY and HORIZONS

925 pts (5.3%) with 30-day TIMI major or minor bleeding

Impact of bivalirudin on non-access site bleeding

Hep

+ 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

0

0.5

1

1.5

2

Bivalirudin better

H + GPI better

slide17

HORIZONS-AMI: Cardiac Mortality in Pts with Major Bleeding

16%

14.6%

14%

12%

HR [95%CI] = 0.39 (0.17 - 0.89)

P=0.025

Heparin + GPI (n=185)

10%

Bivalirudin (n=121)

Cardiac mortality* (%)

8%

5.8%

6%

4%

2%

0%

0

1

2

3

Years

UFH + GPI

185

151

138

86

Bivalirudin

121

104

94

59

*From the time of a major bleed

slide18

HORIZONS-AMI: Cardiac Mortality in Pts without Major Bleeding*

5%

4%

3.8%

Heparin + GPI (n=1802)

3%

Bivalirudin (n=1800)

2.6%

Cardiac mortality (%)

2%

HR [95%CI] = 0.67 (0.46 to 1.00)

P=0.046

Adj HR [95%CI] = 0.65 (0.44 to 0.97)

P=0.033

1%

0%

0

1

2

3

Years

UFH+GPI

1802

1506

1441

957

Bivalirudin

1800

1569

1521

1039

*KM curve with censoring at time of major bleed

slide19

HORIZONS-AMI: Multivariable Model for 3-Year Cardiac Mortality, Including Adverse Events

Excludes 145 pts with thrombocytopenia at baseline. Other variables in model:

current smoker, female gender, prior MI, # vessels treated, hemoglobin

slide20

Conclusion: Bivalirudin is the anticoagulant of choice for all PCI procedures

Compared to UFH + GPI, bivalirudin reduces mortality across the spectrum of pts undergoing PCI

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

These benefits are realized in all PCI pts - including those undergoing radial intervention

By reducing major bleeding, bivalirudin is cost-saving

procedural anticoagulant use during pci
Procedural anticoagulant use during PCI

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

slide22

Bivalirudin in ACS: The Guidelines

ACC/AHA Guidelines

I

  • PCI in STEMI and NSTE-ACS
  • Pts with HIT or HITTS

ESC/EACTS Guidelines

I

  • PCI in STEMI and NSTE-ACS

Circulation and JACC 2005, 2007, 2009, 2011

EHJ 2010