Gregg W. Stone, Tim Clayton, Roxana Mehran, Efthymios N. Deliargyris, Jayne Prats, Stuart J. Pocock...

Gregg W. Stone, Tim Clayton, Roxana Mehran, Efthymios N. Deliargyris, Jayne Prats, Stuart J. Pocock

TCT 2012; JACC 2012;60(17SupplB):B16

The HORIZONS-AMI Trial

Bivalirudin Reduces Cardiac Mortality in Patients with and Without Major Bleeding

Background

● In the HORIZONS-AMI trial, treatment with bivalirudin compared to heparin + a GPIIb/IIIa inhibitor in patients with STEMI undergoing primary PCI resulted in markedly reduced rates of cardiac mortality, which is usually attributed to decreased bleeding

● Whether the reduction in mortality with bivalirudin can be fully ascribed to reduced bleeding is unknown

Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16

Cardiac Mortality30 days to 3 years*

'

Bivalirudin (n=1800)Heparin + GPIIb/IIIa (n=1802)

Stone GW et al NEJM 2008;358:2218-30; Mehran R et al Lancet. 2009;374:1149-59; Stone GW et al. Lancet 2011;377:2193-204

Car

diac

Mor

talit

y (%

)

3-yr† HR [95%CI]=0.56 [0.40, 0.80]

P=0.001

2.9%

5.1%1-yr† HR [95%CI]=0.57 [0.38, 0.84]

P=0.005

0 12 15 18 21 24 27 30 33 36

Months

3 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%

*All cause mortality at 3 years was also consistently lower with bivalirudin (5·9% vs 7·7%), HR 0·75 [0·58–0·97]; p=0·03 †These timepoints were prespecified analyses

Risk factor Hazard ratio (95% CI) P-value

Age (per 5 years) 1.31 (1.21 to 1.43) <0.001

WBC (per 109 cells/L) 1.12 (1.07 to 1.18) <0.001

Creatinine (per 0.1 mg/dL) 1.11 (1.06 to 1.16) <0.001

Killip class 2-4 2.41 (1.62 to 3.60) <0.001

LAD PCI 1.68 (1.16 to 2.45) 0.007

Diabetes, medically treated 1.54 (1.06 to 2.23) 0.02

Bivalirudin (vs UFH+GPIIb/IIIa) 0.57 (0.40 to 0.81) 0.001

3-Year Cardiac Mortality

Other variables in model: current smoker, female gender, prior MI, # vessels treated, hemoglobin


● In all patients, multivariable model

12

0

4

6

8

10

2

0

12 15 18 21 24 27 30 33 36

3-yr HR [95%CI]=0.64 [0.51, 0.80]

P<0.001

6.9%

10.5%

Maj

or B

leed

ing,

non

-CA

BG

(%

)

Months

3 6 9

Δ=64major bleeds

3-Year Major Bleeding*

* Intracranial intraocular, retroperitoneal, access site bleed requiring intervention/surgery, hematoma ≥5 cm, Hgb ↓ ≥3g/dL with or ≥4g/dL w/o overt source; reoperation for bleeding; or blood product transfusion

Stone GW et al. Lancet 2011;377:2193-204

Bivalirudin (n=1800)Heparin + GPIIb/IIIa (n=1802)

HR [95%CI] = 5.81 [3.92, 8.62]

P<0.001

3.3%

11.6%

Years

Car

diac

mor

talit

y (%

)

12% No major bleed (n=3296)Major bleed (n=306)

10%

8%

6%

4%

2%

0%

0 1 2 3

Impact of Major Bleeding


% major bleed in patients with cardiac death

14.0%(7/50)

30.7%(27/88)

P=0.03

Heparin + GPI Bivalirudin0

5

10

15

20

14.6

5.83.8

2.6

Major bleeding No major bleeding

3-Y

ea

r C

ard

iac

Mo

rta

lity

(%)

HR [95%CI] = 4.62 [2.04, 10.45]

P=0.002

HR [95%CI] = 5.67 [3.59, 8.96]

P<0.0001

7/121 43/167927/185 61/1617

Pint = 0.34

3-year Cardiac Mortality


● In patients with vs without major bleeding

Major bleeding No major bleeding0

5

10

15 14.6

3.8

5.8

2.6

Heparin + GPIIb/IIIa (n=1802) Bivalirudin (n=1800)

3-Y

ea

r C

ard

iac

Mo

rta

lity

(%)

27/185 7/121 61/1617 43/1679

HR [95%CI] = 2.56 [1.12, 5.88]

P=0.02

HR [95%CI] = 1.47 [1.00, 2.17]

P=0.048

∆ = 20 deaths ∆ = 18 deaths# fewer cardiac

deaths with bivalirudin

Pint = 0.34



● In patients with vs without major bleeding, according to treatment

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 + GPIIb/IIIa

0 1 2 3

Years

Heparin + GPIIb/IIIa (n=185)

Bivalirudin (n=121)

5.8%

14.6%

3-year Mortality

*From the time of a major bleed


● In patients with major bleeding, according to treatment

Risk factor HR (95% CI) P-value

Age (per 5 years) 1.33 (1.13 to 1.56) 0.001

WBC (per 109 cells/L) 1.23 (1.12 to 1.36) <0.001



Other variables in model: diabetes, Killip class, LAD treated, hemoglobin, creatinine


● In patients with major bleeding, multivariable model

Baseline Nadir Decrease0

5

10

15 14.3

10.5

3.9

13.8

10.1

3.7


Hg

b (

g/d

L)

± 1.9 ± 2.3

P=0.03

± 1.9 ± 2.0

± 1.7 ± 2.0

P=0.08

P=0.31

Hemoglobin Levels


● In patients with major bleeding

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 290

5

10

15

20

25

30

35

Median # units(among patients transfused)

UFH + GPIIb/IIIa: 2 [2, 5] Bivalirudin: 3 [2, 5]

P=0.10

Number of RBC units transfused

Num

ber

of p

atie

nts

RBC Transfusions


0%

1%

2%

3%

4%

5%

0 1 2 3

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

P=0.046Car

diac

mor

talit

y (%

)

Years

Heparin + GPIIb/IIIa (n=1802)

Bivalirudin (n=1800)

2.6%

3.8%

3-year Mortality

*KM curve with censoring at time of major bleed


● In patients without major bleeding*


LMS PCI 10.57 (3.76 - 29.70 <0.001

LAD PCI 1.72 (1.10 - 2.69) 0.02

Age (per 5 years) 1.29 (1.16 - 1.43) <0.001

Killip class 2-4 2.86 (1.82 - 4.51) <0.001

S. creatinine (per 0.1 mg/dl) 1.14 (1.08 - 1.20) <0.001

WBC (per 109 cells/L) 1.08 (1.02 - 1.14) 0.009

Diabetes, insulin treated 1.92 (1.01 - 3.65) 0.047

Hemoglobin (per g/dl) 0.86 (0.76 - 0.98) 0.03

Bivalirudin (vs UFH+GPIIb/IIIa) 0.65 (0.44 - 0.97) 0.035

Other variables in model: current smoker, female gender, prior MI, # vessels treated* patients censored at time of bleed



● In patients without major bleeding*, multivariable model

0

5

10

15

20

Heparin + GPIIb/IIIa (n=1721)Bivalirudin (n=1736)

13.2%

10.1%

P=0.004

3.1%

8.1%

HR [95%CI] = 2.76 [1.85, 4.14]

P<0.001

ThrombocytopeniaYears

Car

diac

mor

talit

y (%

)

Acquired thrombocytopenia (n=404)No thrombocytopenia (n=3053)

0

10%

8%

6%

4%

2%

0%

1 2 3

Acquired thrombocytopenia,*in-hospital

* Nadir platelet count <150,000 in patients w/o baseline thrombocytopenia



5

10

15

20

12.3

2.33.5

2.5

Thrombocytopenia No thrombocytopenia

3-Y

ea

r C

ard

iac

Mo

rta

lity

(%)

HR [95%CI] = 1.44 [0.50, 4.12]

P=0.51

HR [95%CI] = 4.36 [2.73, 6.95]

P<0.0001

4/176 39/156028/228 52/1493

9.3%(4/43)

35.0%(28/80)

P=0.002% thrombocytopenia in patients with cardiac death

Pint = 0.006



● In patients with and without in-hospital acquired thrombocytopenia

Thrombocytopenia No thrombocytopenia0

5

10

15

12.3

3.52.3 2.5


3-Y

ea

r C

ard

iac

Mo

rta

lity

(%) HR (95%CI) =

5.56 (2.00, 16.67)P=0.0001

HR (95%CI) = 1.41 (0.47 to 1.09)

P=0.12

4/176 39/156028/228 52/1493

Pint = 0.006


Nadir platelet count <150,000 in patients w/o baseline thrombocytopenia


● In patients with and without thrombocytopenia, according to treatment

Both bleeding and thrombocytopenia

Bleeding alone Thrombocytopenia alone

No thrombocy-topenia or bleeding

0

5

10

15

20

25

30

17.3

8.3

5.6

2.6

3-Y

ea

r C

ard

iac

Mo

rta

lity

(%)

Ptrend <0.0001

14/81 17/205 18/323 74/2848

P=0.005P=0.03

% of 123 cardiac deaths

11.4%(n=14)

14.6%(n=18)

13.8%(n=17)

60.2%(n=74)

Interaction between major bleeding and acquired thrombocytopenia*


*Excluding patients with baseline thrombocytopenia


5

10

15

20

25

30

26.0

3.2

9.6

6.38.4

2.12.9 2.3

Bleed + thrombocytopenia Bleed only

Thrombocytopenia only Neither

3-Y

ea

r C

ard

iac

Mo

rta

lity

(%)

Ptrend <0.0001

13/50 12/125 15/178 40/1368 1/31 5/80 3/145 34/1480

Ptrend = 0.17

Interaction between major bleeding, thrombocytopenia* and treatment

*Excluding patients with baseline thrombocytopeniaStone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16


Excludes 145 patients with thrombocytopenia at baseline. Other variables in model: current smoker, female gender, prior MI, # vessels treated, hemoglobin


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



● Multivariable model, including adverse events

Conclusions

● In HORIZONS-AMI, treatment with bivalirudin rather than UFH + GPIIb/IIIa resulted in a marked reduction in cardiac mortality in patients with STEMI undergoing primary PCI– ~Half of the reduction in cardiac deaths with bivalirudin

occurred in patients without major bleeding

● In addition to reducing major bleeding, bivalirudin reduced the occurrence of thrombocytopenia, which contributed to the improved survival in patients with and without major bleeding

● The adverse effects of major bleeding and thrombocytopenia are mitigated in patients treated with bivalirudin rather than UFH + GPIIb/IIIa, and bivalirudin was strongly associated with reduced cardiac mortality even after accounting for bleeding and thrombocytopenia – further studies are required to identify the non-hematolgic benefits of bivalirudin


Gregg W. Stone, Tim Clayton, Roxana Mehran, Efthymios N. Deliargyris, Jayne Prats, Stuart J. Pocock...

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