1. Professor of Medicine (Cardiology), and Health Policy
ACS and Acute MI Management: How Did HORIZONS AMI Change MY Practice and Why?
Roxana Mehran, MD
Professor of Medicine (Cardiology), and Health Policy
Director, Interventional Cardiovascular Research and Clinical Trials Mount Sinai School of Medicine

2. Roxana Mehran, MD Institutional Grant/Research Support :
Bristol-Myers Squibb/Sanofi
The Medicines Company
Consulting Fees/Honoraria
Astra Zeneca,
Regado Biosciences,
Janssen

3. ACS and PCI: Pathophysiology
Ruptured or dissected plaque with thrombus 3 3

4. STE/NSTE-ACS Aspirin loading Parenteral anticoagulant
Primary PCI / Early Invasive
Lytics / Early Conservative
Aspirin loading
Parenteral anticoagulant
UFH Bolus / infusion
LMWH
Fondaparinux
Bivalirudin
Parenteral antiplatelet
Abciximab Pre / post cath
Eptifibatide Pre / post cath
Tirofiban Pre / post cath
Oral antiplatelet
Clopidogrel 300 mg Pre / post cath
Ticagrelor Pre / post cath
Clopidogrel 600 mg Pre / post cath
Prasugrel Pre / post cath
ESC guidelines NSTE-ACS I-A, STE-ACS I-B
11 anti-thrombotic agents with 384 possible treatment combinations
ESC = European Society of Cardiology, LMWH = low-molecular-weight heparin, UFH = unfractionated heparin.
Bassand JP, et al. Eur Heart J. 2007;28: Van de Werf F, et al. Eur Heart J. 2008;29:

5. ACS/AMI Treatment Strategies
Reperfusion/Revascularization Choices
Medical
therapy
Thrombolysis
CABG
PCI (with/
without stenting)
Antithrombotic Cotherapy Options
ASA
UFH
LMWH
Penta.
DTI
GP IIb/ IIIa
ADP antagonist
Acute and Long-term Medical Therapy
Nitrates
BBs
ACEIs
ARBs
CCBs
Statins
APT
PCI = percutaneous coronary intervention; CABG = coronary artery bypass grafting; ASA = aspirin; UFH = unfractionated heparin; LMWH = low-molecular-weight heparin; Penta. = pentasaccharide; DTI = direct thrombin inhibitors; GP IIb/IIIa = glycoprotein IIb/IIIa inhibitors; ADP antagonist = adenosine diphosphate antagonist; BBs = -blockers; ACEI = angiotensin-converting enzyme inhibitors; ARBs = angiotensin receptor blockers; CCBs = calcium channel blockers; APT = antiplatelet therapy.

6. Issues in Pharmacotherapy and PCI:
bleeding
Stent Thrombosis
Bleeding

7. Relationship Between Myocardial Salvage and Survival
100
Mortality reduction (%) 80
Median U.S. Sx-ER: 2° 60
Modifying factors
Collaterals
Ischemic preconditioning
MVO2
Lytic given: 30’ % 40
Median U.S. PCI Sx-bal: 3.5°
Lytic works: 60’ 20
Extent of salvage (% of area at risk)
Hours 1 3 6 12 24
Treatment objectives
Gersh B. JAMA 2005
Time to treatment is critical
Opening the IRA (PCI > lysis)

8. 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 5 years; angio FU at 13 months

9. Primary Outcome Measures (ITT)
Diff = -2.9% [-4.9, -0.8]
RR = 0.76 [0.63, 0.92]
PNI ≤
Psup = 0.006
Diff = -3.3% [-5.0, -1.6]
RR = 0.60 [0.46, 0.77]
PNI ≤
Psup ≤
Diff = 0.0% [-1.6, 1.5]
RR = 0.99 [0.76, 1.30]
Psup = 1.00
1 endpoint
1 endpoint
*Not related to CABG
**MACE = All cause death, reinfarction, ischemic TVR or stroke

10. HORIZONS: 30 Day Adverse Events
P<0.001
P = 0.90
*Not related to CABG
** Plat cnt <100,000 cells/mm3
Stone GW et al. NEJM 2008;358:

11. HORIZONS: 1-Year All-Cause Mortality5
Bivalirudin alone (n=1800)
4.8%
Heparin + GPIIb/IIIa (n=1802)
Δ = 1.4% 4
3.4%
3.1% 3
Mortality (%)
HR [95%CI] =
0.69 [0.50, 0.97]
P=0.029 2
2.1%
Δ = 1.0%
P=0.049 1 1 2 3 4 5 6 7 8 9 10 11 12
Time in Months
Number at risk
Bivalirudin alone
1800
1705
1684
1669
1520
Heparin+GPIIb/IIIa
1802
1678
1663
1646
1486
Mehran R et al. Lancet 2009:on-line

12. HORIZONS: Time-updated covariate adjusted Cox model relating MACE events to 1-year mortality - Complete model with MACE components and major bleeding -
Attributable
Deaths
HR (95% CI)
HR [95% CI]
P-value
Risk Factor
Reinfarction
Incidence 138 (3.8%)
16 deaths after event
3.94
[1.73, 8.96]
12*
[7, 14]
0.001
Major bleeding
(non CABG)
Incidence 268 (7.4%)
44 deaths after event
3.39
[2.29, 5.03]
31**
[25, 35]
<0.0001
0.1 1 10
*8.2% of 147 total deaths
**21.1% of 147 total deaths
Hazard Ratio [95% CI]
Attributable deaths = N deaths among pts with the
time updated event (attribute) X (adj. HR – 1)/adj. HR

13. Three-Year All-Cause Mortality
P=0.03
3-yr HR [95%CI]=
0.75 [0.58, 0.97]
5.9%
7.7%
All-Cause Mortality (%) 1 2 3 4 5 6 9 10
1611
1568
1660
1689
1670
1800
Bivalirudin alone 12 15 18 21 24 27 30 33 36
1098
1802
1643
Months
Number at risk
Heparin+GPIIb/IIIa
1633
1593
1574
1525
1043
0.71 [0.51, 0.98]
P=0.04
1-yr HR [95%CI]=
Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802) 7 8
4.8%
3.4%

14. Three-Year All-Cause Mortality
P=0.31
3-yr HR [95%CI]=
0.84 [0.60, 1.17]
5.6%
6.6%
All-Cause Mortality (%) 1 2 3 4 5 6 7 8
TAXUS DES (n=2257)
EXPRESS BMS (n=749)
P=0.97
1-yr HR [95%CI]=
0.99 [0.64, 1.55]
2072
674
2138
2170
713
2257
TAXUS DES 12 15 18 21 24 27 30 33 36
749
702
Months 9
Number at risk
EXPRESS BMS
2097
683
2026
657
443
1409
3.5%

15. Three-Year Stent Thrombosis (ARC Definite/Probable)
Bivalirudin alone (n=1611) 6
Heparin + GPIIb/IIIa (n=1591)
5.1% 5
4.5%
3.5% 4
HR [95%CI]=
Stent Thrombosis (%) 3
3.0%
0.89 [0.65, 1.23]
p=0.49 2
HR [95%CI]=
1.16 [0.79, 1.71] 1
p=0.45 3 6 9 12 15 18 21 24 27 30 33 36
Months
Number at risk
Bivalirudin
1611
1509
1478
1453
1432
1398
971
Heparin+GPIIb/IIIa
1591
1484
1456
1401
1373
1335
906

16. HORIZONS-CLOPIDOGREL study Flow chart
3602 STEMI pts enrolled in the HORIZONS AMI trial
Pre-randomization thienopyridines
N=143
Ticlopidine loading
N=13
Clopidogrel other loading dose
N=27
Data missing
N=108
300 mg clopidogrel loading dose
N=1153 pts
600 mg clopidogrel loading dose
N=2158 pts
Dangas et al, SCAI-ACCi2 2008

17. Primary Outcome Measures (ITT)
300 mg LD
600 mg LD
P=0.15
P=0.01
P=0.56
P=0.01
P=0.002
P=0.71
The impact of Biv was independent of the dose of clopidogel loading. Interaction P values for the above 3 endpoints = 0.48 (NACE) 0.41 (Major bleeding), and 0.75 (MACE).
Dangas et al, SCAI-ACCi2 2008

18. New P2Y12 in PCI for STEMI:iDeath
Major Bleeding
New P2Y Clopidogrel
Bellemain-Appaix A . et al. JACC 2010

19. HORIZONS-STENT THROMBOSIS
Population Flowchart
Randomized ITT
N=3602
Bivalrudin
N=1800
Heparin
N=1802
Stented
N=1611
Heparin
N=1591
Any DES
N=1136
Only BMS
N=434
Unknown
N=41
Any DES
N=1125
Only BMS
N=427
Unknown
N=39
Only DES
N=1112
Only DES
N=1101
Dangas et al, Circulation 2011

20. HORIZONS-STENT THROMBOSIS: 2-year Events
Effect of DES Use
Any DES 5
BMS only
4.4%
4.4% 4 3
Def/Prob Stent Thrombosis (%) 2 1
HR: 1.00 [95% CI: 0.68, 1.46]
p= 0.984 2 4 6 8 10 12 14 16 18 20 22 24
Time in Months
Number at risk
Any DES
2261
2142
2114
2077
2022
2006
1679
BMS only
872
813
798
793
771
760
634
Dangas et al, Circulation 2011

21. HORIZONS-STENT THROMBOSIS: 2-year Events
Effect of Clopidogrel Loading in Bivalirudin group
1-Day and 1-Month Landmark Analyses
600mg Clopidogrel
600mg Clopidogrel
300mg Clopidogrel
300mg Clopidogrel 6 6
HR: 1.07 [95% CI: 0.46, 2.50]
HR: 0.61 [95% CI: 0.38, 0.96] 5
p= 0.879 5
p= 0.033
4.3% 4 4
Def/Prob Stent Thrombosis (%)
3.1%
3.2%
Def/Prob Stent Thrombosis (%) 3 3
2.1% 2 2
1.9%
2.0% 1 1
0.8%
0.7%
HR: 0.70 [95% CI: 0.48, 1.04]
HR: 0.96 [95% CI: 0.57, 1.64]
p= 0.074
p= 0.890
24h 3 6 9 12 15 18 21 24
30dy 3 6 9 12 15 18 21 24
Time in Months
Time in Months
Number at risk
Number at risk
600 mg
2031
2005
1909
1868
1813
1487
600 mg
2031
1982
1935
1894
1839
1510
300 mg
1087
1070
1011
986
949
812
300 mg
1087
1056
1035
1009
970
829
Dangas et al, Circulation 2011 rev

22. HORIZONS-STENT THROMBOSIS: 2-year Events
Effect of Antithrombin Randomization: 1-Day Landmark 5
Bivalirudin monotherapy
Heparin + GPIIb/IIIa inhibitor
4.4% 4
HR: 5.74 [95% CI: 1.98, 16.6]
p = <0.001 3
2.9%
Definite/Probable Stent Thrombosis (%) 2
HR: 0.64 [95% CI: 0.44, 0.94]
1.4%
p = 0.02 1
0.3%
24h 3 6 9 12 15 18 21 24
Time in Months
Number at risk
Bivalirudin
1611
1573
1509
1475
1443
1204
UFH+GPIIb/IIIa
1591
1580
1482
1449
1386
1153
Dangas et al, Circulation 2011 rev

23. HORIZONS-STENT THROMBOSIS: 2-year Events
Effect of Early Heparin (prerandomization): 1-Day Landmark
Pre-Randomization Heparin 7
No Pre-Randomization Heparin 6 5
HR: 0.24 [95% CI: 0.11, 0.52]
p = <0.001
4.2% 4
Definite/Probable Stent Thrombosis (%)
3.3% 3
1.8% 2
HR: 0.77 [95% CI: 0.52, 1.15]
p = 0.20 1
0.4%
24h 3 6 9 12 15 18 21 24
Time in Months
Number at risk
P-R Heparin
2277
2253
2143
2088
2027
1684
No P-R Heparin
923
898
847
835
801
673
Dangas et al, Circulation 2011 rev

24. HORIZONS-STENT THROMBOSIS: 1st Day
Effect of Early Heparin Use (prerandomization)
3.5
No Pre-Randomization Heparin
Pint antithrombin x pre-rand heparin = 0.39
Pre-Randomization Heparin
3.0
2.6%
Bivalirudin
2.5
2.0
Def/Prob Stent Thrombosis (%)
HR [95%CI] = 3.07 [1.33,7.09], P = 0.006
1.5
0.9%
Bivalirudin
1.0
0.8%
UFH+GPI
0.5
HR [95%CI] = 9.64 [1.00,92.70], P = 0.02
UFH+GPI
0.1%
0.0 6 12 18 24
Number at risk
Time in Hours
P-R Heparin
1066
1052
1051
1050
1049
No P-R Heparin
545
531
529
528
528
P-R Heparin
1211
1208
1207
1207
1207
No P-R Heparin
378
377
375
374
374
Dangas et al, Circulation 2011 rev

25. HORIZONS-STENT THROMBOSIS: 2-Year Events
Independent Predictors of ANY Definite/Probable ARC ST
Variables
H.R. (95% C.I.) p
Insulin-Treated Diabetes
2.88 ( 1.64, 5.07)
0.0002
Angiographic Aneurysm
2.54 ( 1.04, 6.22)
0.041
History of Previous PCI
2.36 ( 1.53, 3.64)
0.0001
Angiographic Ulceration
2.25 ( 1.04, 4.86)
0.039
Current Smoking
1.66 ( 1.16, 2.38)
0.006
Baseline flow grade TIMI 0/1
1.59 ( 1.07, 2.36)
0.021
Baseline Platelet Count
( , )
<.0001
Pre-Randomization Heparin
0.55 ( 0.39, 0.79)
0.001
Dangas et al, Circulation 2011 rev

26. How has HORIZONS AMI changed my practice in AMI?
Acute therapy in STEMI with complete focus on reperfusion and antithrombotic therapy: Time to reperfusion- Number one priority
Reasonable options
Good history to ascertain risk of bleeding in all pts
Consider new antiplatelet agents (Prasugrel, Ticagrelor) in pts without overt risk of bleeding, in others 600 mg Clopid. Loading for all
Bivalirudin in all pts, even if the pt received heparin prior to cath
IIb IIIa reserved only in special situations- no reflow, giant thrombus
Choice of BMS v. DES dependent of risk of RS and the pt.
Acute therapy in STEMI focuses on reperfusion and antithrombotic therapy.
Reasonable options for hospitals without on-site PCI capability include
Fibrinolytic therapy (goal: door-to-needle time ≤30 minutes) Code 30!
Transfer for primary PCI if fibrinolysis is contraindicated (goal: door-to-balloon time ≤90 minutes) Code 90!
Transfer for rescue PCI if reperfusion with lytic fails
No clinical benefit for facilitated PCI has been seen to date
Clopidogrel in combination with aspirin results in significant further improvements in the outcomes of patients with STEMI (CLARITY–TIMI 28/COMMIT).

27. Balancing Safety and Efficacy
Inhibition of platelet aggregation
High risk of
ischemic events
bleeding events
Risk of any event
“Sweet spot”
Ischemic risk
Bleeding risk
Ferreiro & Angiolillo. Thromb Haemost 2010 (in press)