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
Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16
● 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
Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16
% 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
Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16
● 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
3-Year Cardiac Mortality
Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16
● 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
Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16
● 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
Bivalirudin (vs UFH+GPIIb/IIIa) 0.32 (0.14 to 0.78) 0.006
3-Year Cardiac Mortality
Other variables in model: diabetes, Killip class, LAD treated, hemoglobin, creatinine
Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16
● 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
Heparin + GPIIb/IIIa (n=185) Bivalirudin (n=121)
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
Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16
● 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
Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16
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
Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16
● In patients without major bleeding*
Risk factor Hazard ratio (95% CI) P-value
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
3-Year Cardiac Mortality
Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16
● 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
Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16
Heparin + GPI Bivalirudin0
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
3-year Cardiac Mortality
Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16
● In patients with and without in-hospital acquired thrombocytopenia
Thrombocytopenia No thrombocytopenia0
5
10
15
12.3
3.52.3 2.5
Heparin + GPIIb/IIIa (n=1721) Bivalirudin (n=1736)
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
3-year Cardiac Mortality
Nadir platelet count <150,000 in patients w/o baseline thrombocytopenia
Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16
● 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*
Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16
*Excluding patients with baseline thrombocytopenia
Heparin + GPI Bivalirudin0
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
3-Year Cardiac Mortality
Excludes 145 patients with thrombocytopenia at baseline. Other variables in model: current smoker, female gender, prior MI, # vessels treated, hemoglobin
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+GPIIb/IIIa) 0.54 (0.38 to 0.79) 0.002
Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16
● 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
Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16