Transcript HORIZONS –AMI A Prospective, Multicenter Randomized Trial of Heparin Plus GPIIb/IIIa Inhibitors vs.

HORIZONS –AMI
A Prospective, Multicenter Randomized Trial of
Heparin Plus GPIIb/IIIa Inhibitors vs. Bivalirudiin
STEMI: Final 3-year results from the HORIZONSAMI Trial
Stone GW et al. Lancet 2011: Published online June 13, DOI:10.1016/S0140-6736(11)60764-2
Background
● At 1-year in the 2x2 factorial prospective, randomized
HORIZONS-AMI trial:
– Bivalirudin alone compared to heparin plus GPIIb/IIIa inhibitors
resulted in comparable rates of MI and stent thrombosis, with
significantly reduced rates of major bleeding and mortality (allcause and cardiac)
● 3-year results are assessed in this report
– Prespecified endpoints in the pharmacology arm at 3 years
included death, reinfarction, ischemia driven target lesion
revascularization, stroke, and the composite of these (MACE);
non-CABG major bleeding and the composite of all net adverse
clinical events (NACE).
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
Harmonizing Outcomes with Revascularization and Stents in AMI
3602 pts with STEMI with symptom onset ≤12 hours
Aspirin, thienopyridine
R
1:1
UFH + GP IIb/IIIa inhibitor
(abciximab or eptifibatide)
Bivalirudin monotherapy
(± provisional GP IIb/IIIa)
Emergent angiography, followed by triage to…
CABG – Primary PCI
3006 pts eligible for stent randomization
Paclitaxel-eluting TAXUS stent
– Medical Rx
R
3:1
Bare metal EXPRESS stent
Clinical FU at 30 days, 6 months, 1 year, and then
yearly through 3 years; angio FU at 13 months
Stone, GW N Engl J Med 2008;358:2218-30.
Harmonizing Outcomes with Revascularization and Stents in AMI
3602 pts with STEMI
R
1:1
Randomized
UFH + GP IIb/IIIa
N=1802
28
1-Year FU Eligible
1-Year FU
3-Year FU
Bivalirudin
N=1800
• • • Not true MI* • • •
N=1774
29
N=1771
26
• • • Withdrew • • •
22
46
• • • Lost to FU • • •
53
N=1702
N=1696
17
• • • Withdrew • • •
18
57
• • • Lost to FU • • •
44
N=1628
N=1634
* Biomarkers WNL and no DS >50% by core lab determination (30 day FU only)
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
Pharmacology Randomization:
Aspirin and Thienopyridine Use
Regular* aspirin use (%)
Regular* thieno. use (%)
Antiplatelet agent use (%)
Heparin + GPIIb/IIIa(n=1802)
100
97%
98%
80
97%
97%
96%
97%
96%
Bivalirudin alone (n=1800)
95%
94%
100
96% 95%
95%
80
93.%
93%
87%
94% 93%
88%
66%
60
All P = NS
68%
60
33%
40
40
All P = NS
20
20
0
0
D/C 30 D 6 Mo 1 Yr 2 Yr 3 Yr
26%
36%
27%
D/C
30 D
6 Mo
1 Yr
2 Yr
3 Yr
*Taken >50% of days since last visit
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
3-Year Major Bleeding
(non-CABG)*
Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802)
12
10.5%
Major Bleeding (%)
10
9.4%
8
6.9%
6
6.0%
3-yr HR (95%CI)
4
0.64 (0.51, 0.80)
P=0.0001
2
0
0
3
6
9
12
15
18
21
24
27
30
33
36
Months
* 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 Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
Time in Months
'
Time in Months
3-Year Cardiac Mortality
Heparin + GPIIb/IIIa (n=1802)
3-yr HR (95%CI)
0.56 (0.40, 0.80)
P=0.001
6
5
Cardiac Mortality (%)
Bivalirudin alone (n=1800)
5.1%
4
3.8%
3
2.9%
2
2.1%
1
0
0
3
6
9
12
15
18
21
24
Months
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
27
30
33
36
3-Year Cardiac Mortality
Landmark analysis
Heparin + GP IIb/IIIa (n=1802)
Bivalirudin (n=1800)
Cardiac mortality (%)
5
30 day HR (95% CI)
0.62 (0.40 – 0.96)
p=0.03
4
3
3 year HR (95% CI)
0.49 0.28 –0.86
p=0.01
2.9%
2.2%
2
1.8%
1.1%
1
0
0
3
6
9
12
15
18
21
Months
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
24
27
30
33
36
3-Year Reinfarction
Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802)
10
9
8.2%
Reinfarction (%)
8
7
6.2%
6
5
4.4%
4
3-yr HR (95%CI)
0.76 (0.59, 0.99)
P=0.04
3
3.6%
2
1
0
0
3
6
9
12
15
18
21
24
Months
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
27
30
33
36
3-Year Reinfarction
Landmark analysis
10
Heparin + GPIIb/IIIa (n=1802)
Bivalirudin (n=1800)
9
30-day HR (95% CI)
1.07 (0.66 – 1.73)
p=0.79
Reinfarction (%)
8
7
3-year HR (95% CI)
0.66 (0.49 – 0.90)
p=0.007
6.5%
6
5
4.4%
4
3
1.9%
1.8%
2
1
0
0
3
6
9
12
15
18
21
Months
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
24
27
30
33
36
All-cause mortality or reinfarction (%)
3-Year All-Cause Mortality
or Reinfarction Landmark analysis
Heparin + GPIIb/IIIa (n=1802)
Bivalirudin (n=1800)
3-year HR (95% CI)
30-day HR (95% CI)
0.72 (0.58 – 0.91)
0.84 (0.61 – 1.16)
p=0.005 10.6%
p=0.30
5
4
3
7.8%
2
4.5%
3.8%
1
0
0
3
6
9
12
15
18
21
24
Months
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
27
30
33
36
3-year MACE Components*
UFH + GPI Bivalirudin
(N=1802) (N=1800)
Death
HR [95%CI]
Number
P Value needed
to treat
7.7%
5.9%
0.75 (0.58,0.97)
0.03
54
- Cardiac
5.1%
2.9%
0.56 (0.40,0.80)
0.001
45
- Non cardiac
2.8%
3.1%
Reinfarction
8.2%
6.2%
- Q-wave
3.8%
3.4%
0.61
- Non Q-wave
4.9%
3.2%
0.009
58
Death or reinfarction
14.5%
11.3%
0.005
31
Ischemic TVR
12.1%
14.2%
0.06
Stroke
2.0%
1.7%
0.50
*Kaplan-Meier estimates, CEC adjudicated
0.62
0.76 (0.59,0.92)
0.72 (0.58,0.91)
0.04
52
MACE= death, reinfarction, ischemia-driven target vessel revascularization, stroke
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
3-year Bleeding Endpoints
Number
P Value needed
to treat
UFH + GPI
(N=1802)
Bivalirudin
(N=1800)
Major bleeding, nonCABG
10.5%
6.9%
0.64 (0.51-0.80) 0.0001
28
Major bleeding,
including CABG
12.8%
8.9%
<0.0001
25
Blood transfusion
5.1%
3.5%
0.01
61
TIMI Major or Minor
10.9%
7.0%
<0.0001
26
TIMI Major
6.1%
4.1%
0.007
51
TIMI Minor
5.0%
3.2%
0.007
56
GUSTO (any)
12.7%
8.8%
0.0001
26
GUSTO severe/lifethreatening
0.9%
1.0%
0.74
GUSTO moderate
6.3%
4.7%
0.03
GUSTO mild
6.2%
4.0%
0.003
HR (95% CI)
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
63
3-Year Stent Thrombosis
(ARC Definite/Probable)
Bivalirudin alone (n=1611)
Heparin + GPIIb/IIIa (n=1591)
6
5.1%
4.5%
Stent Thrombosis (%)
5
3.5%
4
HR (95%CI)
0.89 (0.65, 1.23)
p=0.49
3
3.0%
2
1
0
0
3
6
9
12
15
18
21
Months
ARC= Academic Research Consortium
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
24
27
30
33
36
3-Year Stent Thrombosis*
(N=3202)
UFH + GPI
(N=1591)
Bivalirudin
(N=1611)
P
Value
ARC definite
4.1%
4.2%
0.87
ARC probable
1.0%
0.3%
0.02
ARC definite or probable
5.1%
4.5%
0.49
Early <30 days
2.1%
2.6%
0.31
Late (30 days to 1 year)
1.0%
0.9%
0.64
Very late (> 1 year)
2.2%
1.1%
0.02
<24 hours
0.3%
1.5%
0.0002
24 hours to 3 years
4.8%
3.1%
0.01
ARC= Academic Research Consortium
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
*All Kaplan-Meier estimates; all CEC adjudicated
Limitations
● Open label design, but high compliance to study processes
● Study applicable to patients enrolled, although there were few
exclusions
● Slight imbalances between baseline groups and outpatient
thienopyridine use, but none of the results were altered in
multivariable adjustment
● Results were not adjusted for multiple comparisons and should
be regarded as hypothesis-generating
● 8.0% of patients in the pharmacology randomization were not
available for 3-year follow-up
● The impact of a comparison with heparin alone, or with higher
use of radial access are not known
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
Conclusions:
Pharmacology Randomization
● In this large-scale, prospective, randomized trial of pts with
STEMI undergoing primary PCI, the initial treatment with
bivalirudin alone compared to heparin plus GPIIb/IIIa inhibitors
at 3 years resulted in:
– A significant 36% reduction in major bleeding and a
significant 24% reduction in reinfarction, with non
significantly different rates of stent thrombosis, TVR and
stroke
– A significant 44% reduction in cardiac mortality and a 25%
reduction in all-cause mortality, the latter representing 18
lives saved per 1000 patients treated with bivalirudin (NNT =
54 to save 1 life)
Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2