1. Stone p2203/Abstract/ Conclusions
HORIZONS –AMI
A Prospective, Multicenter Randomized Trial of Heparin Plus GPIIb/IIIa Inhibitors vs. Bivalirudiin STEMI: Final 3-year results from the HORIZONS- AMI Trial
Lincoff p853/Abstract/ Conclusions
Key Message: HORIZONS AMI builds on a wealth of experience with bivalirudin across a spectrum of patients with acute coronary syndromes (ACS) undergoing PCI and supports the major landmark trials REPLACE-21 and ACUITY.2
References
1. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA. 2003;289:
2. Stone GW, McLaruin BT, Cox DA, for the ACUITY Investigators. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006;355:
Lincoff p853/Abstract/ Conclusions
Stone p2203/Abstract/ Conclusions
Stone GW et al. Lancet 2011: Published online June 13, DOI: /S (11) 1

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 (all- cause 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: /S (11)

3. Harmonizing Outcomes with Revascularization and Stents in AMI
3602 pts with STEMI with symptom onset ≤12 hours
UFH + GP IIb/IIIa inhibitor
(abciximab or eptifibatide)
Bivalirudin monotherapy
(± provisional GP IIb/IIIa)
Aspirin, thienopyridine R
1:1
Emergent angiography, followed by triage to…
Primary PCI
CABG –
Medical Rx
3006 pts eligible for stent randomization R
3:1
Bare metal EXPRESS stent
Paclitaxel-eluting TAXUS 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:

4. Harmonizing Outcomes with Revascularization and Stents in AMI
3602 pts with STEMI R
1:1
UFH + GP IIb/IIIa
N=1802
Bivalirudin
N=1800
N=1628
N=1634
N=1774
N=1771
N=1702
Randomized 28
• • • Not true MI* • • • 29
1-Year FU Eligible 26 46
• • • Withdrew • • •
• • • Lost to FU • • • 22 53
1-Year FU
N=1696 17 57
• • • Withdrew • • •
• • • Lost to FU • • • 18 44
3-Year FU
* Biomarkers WNL and no DS >50% by core lab determination (30 day FU only)
Stone, GW Lancet 2011 Published online June 13. DOI: /S (11)

5. Pharmacology Randomization: Aspirin and Thienopyridine Use
Regular* aspirin use (%)
Regular* thieno. use (%)
Heparin + GPIIb/IIIa(n=1802)
Bivalirudin alone (n=1800)
97%
97%
96%
96%
93.%
95%
94%
93%
87%
98%
97%
97%
96%
95%
95%
94%
93%
88%
66%
68%
Antiplatelet agent use (%)
All P = NS
33%
26%
36%
All P = NS
27%
*Taken >50% of days since last visit
Stone, GW Lancet 2011 Published online June 13. DOI: /S (11)

6. 3-Year Major Bleeding (non-CABG)*12 4 6 8 10
0.64 (0.51, 0.80) 2 15 18 21 24 27 30 33 36
P=0.0001
3-yr HR (95%CI)
6.9%
10.5%
Major Bleeding (%)
Months 3 9
Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802)
9.4%
6.0%
* 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: /S (11)

7. 3-Year Cardiac Mortality
Time in Months '
Time in Months
3-Year Cardiac Mortality
Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802)
Cardiac Mortality (%)
P=0.001
3-yr HR (95%CI)
0.56 (0.40, 0.80)
2.9% 12 15 18 21 24 27 30 33 36
Months 3 6 9 1 5 4 2
3.8%
2.1%
5.1%
Stone, GW Lancet 2011 Published online June 13. DOI: /S (11)

8. 3-Year Cardiac Mortality Landmark analysis5 4 3 2 1 6 9 12 15 18 21 24 27 30 33 36
Heparin + GP IIb/IIIa (n=1802)
Bivalirudin (n=1800)
3 year HR (95% CI)
–0.86
p=0.01
30 day HR (95% CI)
0.62 (0.40 – 0.96)
p=0.03
2.2%
1.1%
Cardiac mortality (%)
1.8%
2.9%
Months
Stone, GW Lancet 2011 Published online June 13. DOI: /S (11)

9. 3-Year Reinfarction 8.2% 6.2% 3-yr HR (95%CI) 0.76 (0.59, 0.99) P=0.04
Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802)
6.2%
8.2%
Reinfarction (%) 1 2 3 4 5 6 7 8 9 10
P=0.04
3-yr HR (95%CI)
0.76 (0.59, 0.99) 12 15 18 21 24 27 30 33 36
Months
4.4%
3.6%
Stone, GW Lancet 2011 Published online June 13. DOI: /S (11)

10. 3-Year Reinfarction Landmark analysis10 8 6 4 2 3 9 12 15 18 21 24 27 30 33 36
3-year HR (95% CI) 0.66 (0.49 – 0.90)
p=0.007
30-day HR (95% CI)
1.07 (0.66 – 1.73)
p=0.79
6.5%
4.4%
Reinfarction (%)
1.8%
1.9% 7 5 1
Months
Heparin + GPIIb/IIIa (n=1802)
Bivalirudin (n=1800)
Stone, GW Lancet 2011 Published online June 13. DOI: /S (11)

11. 3-Year All-Cause Mortality or Reinfarction Landmark analysis5 4 3 2 1 6 9 12 15 18 21 24 27 30 33 36
Heparin + GPIIb/IIIa (n=1802)
Bivalirudin (n=1800)
3-year HR (95% CI)
0.72 (0.58 – 0.91)
p=0.005
30-day HR (95% CI)
0.84 (0.61 – 1.16)
p=0.30
10.6%
7.8%
All-cause mortality or reinfarction (%)
3.8%
4.5%
Months
Stone, GW Lancet 2011 Published online June 13. DOI: /S (11)

12. 3-year MACE Components*
UFH + GPI
(N=1802)
Bivalirudin
(N=1800)
HR [95%CI]
P Value
Number needed to treat
Death
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%
0.62
Reinfarction
8.2%
6.2%
0.76 (0.59,0.92)
0.04 52
- 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%
0.72 (0.58,0.91)
0.005 31
Ischemic TVR
12.1%
14.2%
0.06
Stroke
2.0%
1.7%
0.50
*Kaplan-Meier estimates, CEC adjudicated
MACE= death, reinfarction, ischemia-driven target vessel revascularization, stroke
Stone, GW Lancet 2011 Published online June 13. DOI: /S (11)

13. 3-year Bleeding Endpoints
UFH + GPI
(N=1802)
Bivalirudin
(N=1800)
HR (95% CI)
P Value
Number needed to treat
Major bleeding, non-CABG
10.5%
6.9%
0.64 ( )
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% 26
TIMI Major
6.1%
4.1%
0.007 51
TIMI Minor
5.0%
3.2% 56
GUSTO (any)
12.7%
8.8%
GUSTO severe/life-threatening
0.9%
1.0%
0.74
GUSTO moderate
6.3%
4.7%
0.03 63
GUSTO mild
6.2%
4.0%
0.003
Stone, GW Lancet 2011 Published online June 13. DOI: /S (11)

14. 3-Year Stent Thrombosis (ARC Definite/Probable)6 2 3 4 5
0.89 (0.65, 1.23) 1 12 15 18 21 24 27 30 33 36
p=0.49
HR (95%CI)
4.5%
5.1%
Stent Thrombosis (%)
Months 9
Bivalirudin alone (n=1611)
Heparin + GPIIb/IIIa (n=1591)
3.5%
3.0%
ARC= Academic Research Consortium
Stone, GW Lancet 2011 Published online June 13. DOI: /S (11)

15. 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)
0.9%
0.64
Very late (> 1 year)
2.2%
1.1%
<24 hours
1.5%
0.0002
24 hours to 3 years
4.8%
3.1%
0.01
ARC= Academic Research Consortium
*All Kaplan-Meier estimates; all CEC adjudicated
Stone, GW Lancet 2011 Published online June 13. DOI: /S (11)

16. 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: /S (11)

17. 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: /S (11)