1. For the HORIZONS AMI Investigators
A Prospective, Randomized Comparison of Bivalirudin vs. Heparin Plus Glycoprotein IIb/IIIa Inhibitors During Primary Angioplasty in Acute Myocardial Infarction
– 30 Day Results –
Gregg W. Stone MD
For the HORIZONS AMI Investigators

2. Disclosures Gregg W. Stone MD
Research support from The Medicines Company and Boston Scientific
Honoraria from Eli Lilly Co.

3. Background
In addition to suppressing periprocedural ischemia, prevention of hemorrhagic complications has emerged as a priority in patients undergoing PCI
In patients with stable angina and NSTEMI, the direct thrombin inhibitor bivalirudin has been shown to result in similar rates of composite ischemia as heparin plus GP IIb/IIIa inhibitors, while significantly reducing major bleeding
Whether bivalirudin has comparable safety and efficacy in patients with STEMI undergoing primary PCI is unknown

4. Harmonizing Outcomes with Revascularization and Stents in AMI
≥3400* 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
3000 pts eligible for stent randomization R
1:3
Bare metal stent
TAXUS paclitaxel-eluting stent
Clinical FU at 30 days, 6 months,
1 year, and then yearly through 5 years
*To rand 3000 stent pts

5. Harmonizing Outcomes with Revascularization and Stents in AMI
≥3400* 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
Pharmacology Arm
Primary Endpoints*
30 Day
Intention to Treat Population
* All stent randomization results are still blinded

6. 30 Day Study Objectives
In patients with STEMI undergoing a primary PCI strategy, compared to UFH plus the routine use of GP IIb/IIIa inhibitors, bivalirudin monotherapy will result in:
Similar or reduced rates of net adverse clinical events (the composite of major adverse cardiovascular events and major bleeding) at 30 days
Similar or reduced rates of major bleeding at 30 days

7. Inclusion Criteria STEMI >20 mins and <12 hours in duration
ST-segment elevation of 1 mm in 2 contiguous leads; or
Presumably new left bundle branch block; or
True posterior MI with ST depression of 1 mm in 2 contiguous anterior leads
Patients with cardiogenic shock, left main disease, etc., were not excluded
Age ≥18 years
Written, informed consent

8. Principal Exclusion Criteria
Contraindication to any of the study medications
Prior administration of thrombolytic therapy, bivalirudin, GP IIb/IIIa inhibitors, LMWH or fondaparinux for the present admission (prior UFH allowed)
Current use of coumadin
History of bleeding diathesis or known coagulopathy (including HIT), or will refuse blood transfusions
History of intracerebral mass, aneurysm, AVM, or hemorrhagic stroke; stroke or TIA within 6 months or any permanent neurologic deficit; GI or GU bleed within 2 months, or major surgery within 6 weeks; recent or known platelet count <100,000 cells/mm3 or hgb <10 g/dL
Planned elective surgical procedure that would necessitate interruption of thienopyridines during the first 6 months post enrollment

9. Study Medications (i) Unfractionated heparin Bivalirudin
60 U/kg IV*; subsequent boluses titrated by nomogram to ACT secs; terminated at procedure end unless prolonged antithrombin needed
Bivalirudin
Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to ACT; terminated at procedure end unless prolonged antithrombin needed (0.25 mg/kg/hr infusion)
Glycoprotein IIb/IIIa inhibitors
Routine use in UFH arm; recommended only for giant thrombus or refractory no reflow in bivalirudin arm
Abciximab or double bolus eptifibatide as per investigator discretion – dosing per FDA label, renal adjusted; continued for 12 (abcx) or 12-18 (eptif)
* If pre randomization UFH administered, ACT is checked first
** If pre randomization UFH administered, started 30’ after last bolus

10. Study Medications (ii)
Aspirin
324 mg chewed non enteric coated or 500 mg IV in the ER, followed by mg/day in-hospital and mg/day as out patient indefinitely
Thienopyridines
Clopidogrel 300 mg or 600 mg loading dose (per investigator discretion) in the ER followed by 75 mg PO QD for at least 6 months (1 year or longer recommended)
Ticlopidine load + daily dose permissible if clopiodgrel is unavailable or patient is allergic
Other
Beta blockers: IV pre procedure followed by PO QD in the absence of contraindications; ACE inhibitors for HTN, CHF or LVEF <40%; Statin if LDL >100 mg/dl

11. 2 Primary Endpoints (at 30 Days)
1) Net Adverse Clinical Events
and
2) Major Bleeding (non CABG)
Intracranial bleeding
intraocular bleeding
Retroperitoneal bleeding
Access site bleed requiring
intervention/surgery
Hematoma ≥5 cm
Hgb ≥3g/dL with an overt source
Hgb ≥4g/dL w/o overt source
Reoperation for bleeding
Blood product transfusion

12. 2 Primary Endpoints (at 30 Days)
1) Net Adverse Clinical Events =
2) Major Bleeding (non CABG) or
Major adverse
cardiovascular events
(major secondary endpoint)
All cause death
Reinfarction
Ischemic TVR
Stroke

13. Statistical Methodology
Randomization stratification
Administration of non protocol pre-procedural heparin
Planned administration of 300 or 600 mg of clopidogrel or 500 mg of ticlopidine prior to cardiac catheterization
Whether the patient will receive abciximab or eptifibatide
U.S. vs. non-U.S. site
Primary analysis is by ITT among all randomized pts; secondary analysis is ITT among primary PCI cohort
Sequential noninferiority and superiority testing
NI for net adverse clinical events  NI for major bleeding  Sup for major bleeding  Sup for adverse clinical net events
One-sided α=0.025 for NI; Two-sided α=0.05 for Sup
Primary analyses conducted using binomial proportions

14. Horizons Enrollment - Centers
3,602 pts randomized at 123 centers in 11 countries
between March 25th, 2005 and May 7th, 2007
(2) Norway
(3) Netherlands
Poland (9)
(6) UK
Germany (16)
Austria (5)
USA (57)
Israel (10)
(1) Spain
Italy (2)
Argentina (12)

15. Horizons Enrollment - Patients
3,602 pts randomized at 123 centers in 11 countries
between March 25th, 2005 and May 7th, 2007
(79, 2.2%) Norway
(133, 3.7%) Netherlands
Poland (582, 16.2%)
(102, 2.8%) UK
Germany (791, 22%)
USA
(814, 22.6%)
Austria (143, 4.0%)
Israel (526, 14.6%)
(6, 0.2%) Spain
Italy (219, 6.1%)
Argentina (207, 5.7%)

16. Harmonizing Outcomes with Revascularization and Stents in AMI
3602 pts with STEMI R
1:1
UFH +
GP IIb/IIIa
N=1802
Bivalirudin
Monotherapy
N=1800
Randomized 9 15
• • • Withdrew • • •
• • • Lost to FU • • • 10 13
N=1778
(98.7%)
N=1777
(98.7%)
30 day FU*
ITT population
N=1802
N=1800
* Range ±7 days

17. Baseline Characteristics (i)
UFH + GP IIb/IIIa
(N=1802)
Bivalirudin
(N=1800)
Age (years)
60.7 [52.9, 70.1]
59.8 [51.9, 69.5]
Male
76.1%
77.1%
Diabetes
17.3%
15.6%
Hypertension
55.2%
51.8%
Hyperlipidemia
42.7%
43.4%
Current smoking
45.0%
47.2%
Prior MI
11.4%
10.4%
Prior PCI
11.0%
10.5%
Prior CABG
2.6%
3.3% *
*P=0.04

18. Baseline Characteristics (ii)
UFH + GP IIb/IIIa
(N=1802)
Bivalirudin
(N=1800)
Weight (kg)
80 [71, 90]
Chest pain – ER, hrs
2.1 [1.3, 3.9]
2.2 [1.3, 4.0]
Killip class 2-4
8.5%
Anterior MI
43.9%
41.2%
LVEF
50 [41, 59]
50 [45, 60]
Femoral a. access
93.6%
93.9%
Venous access
8.4%
9.3%
Closure device
27.7%
28.3%

19. Study Drugs UFH + GP IIb/IIIa (N=1802) Bivalirudin (N=1800)
UFH pre randomization
65.6%
Antithrombin in CCL
- UFH
98.9%
4.1%
- Bivalirudin
0.4%
96.9%
- Peak ACT
264 [228, 320]
357 [300, 402]
GP IIb/IIIa in CCL
94.5%
7.2%
- Bail-out per protocol* -
4.4%
- Abciximab
49.9%
4.0%
- Eptifibatide
44.4%
3.1%
- Tirofiban
0.2%
0.1%
* For giant thrombus or refractory no reflow after PCI.
CCL = cardiac catheterization laboratory

20. Primary Management Strategy*
UFH + GP IIb/IIIa Inhibitor
N=1802
Bivalirudin Monotherapy
N=1800
Primary PCI
Deferred PCI
CABG
Medical Rx
*Primary ITT analysis includes all pts regardless of treatment

21. 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

22. 30 Day Net Adverse Clinical Events
Heparin + GPIIb/IIIa inhibitor (n=1802)
Bivalirudin monotherapy (n=1800)
12.2%
9.3%
Net adverse clinical events (%)*
Primary Endpoint
HR [95%CI] =
0.75 [0.62, 0.92]
P=0.006
Time in Days
Number at risk
Bivalirudin
Heparin + GPIIb/IIIa
*MACE or major bleeding (non CABG)

23. 30 Day Major Bleeding (non-CABG)
Heparin + GPIIb/IIIa inhibitor (n=1802)
Bivalirudin monotherapy (n=1800)
8.4%
Primary Endpoint
Major Bleeding (%)
5.0%
HR [95%CI] =
0.59 [0.45, 0.76]
P<0.0001
Time in Days
Number at risk
Bivalirudin
Heparin + GPIIb/IIIa

24. 30 Day Major Bleeding Components
UFH + GP IIb/IIIa
(N=1802)
Bivalirudin
(N=1800)
P Value
Major bleeding (non CABG)*
8.3%
4.9%
<0.0001
- Intracranial/intraocular 0%
1.0
- Retroperitoneal
0.5%
0.3%
0.42
- Access site requiring
intervention/surgery
0.1%
0.29
- Hematoma ≥5 cm
2.4%
1.1%
0.0048
- Hgb ≥3 with source
2.2%
1.3%
0.058
- Hgb ≥4 w/o source
4.4%
2.5%
0.002
- Reoperation for bleed
0.2%
0.62
- Transfusion
3.5%
2.1%
0.01
*CEC adjudicated

25. 30 Day Bleeding Endpoints (CEC Adjudicated)
UFH + GP IIb/IIIa
(N=1802)
Bivalirudin
(N=1800)
P Value
Protocol Major, non CABG*
8.3%
4.9%
<0.0001
Protocol Major, All
10.8%
6.8%
Protocol Minor
15.4%
8.6%
Blood transfusion
3.5%
2.1%
0.01
TIMI Major
5.0%
3.1%
0.003
TIMI Minor
4.6%
2.8%
0.008
TIMI Major or Minor
9.6%
5.9%
GUSTO LT** or Severe
0.6%
0.4%
0.65
GUSTO Moderate
GUSTO LT or Sev or Mod
5.6%
*Primary endpoint; **Life threatening

26. Thrombocytopenia P = 0.002 P = 0.04 P = 0.04 <100,000 cells/mm3

27. 30 Day Major Adverse CV Events
Heparin + GPIIb/IIIa inhibitor (n=1802)
Bivalirudin monotherapy (n=1800)
5.5%
5.5%
Major adverse CV events (%)*
HR [95%CI] =
1.00 [0.75, 1.32]
P=0.98
Time in Days
Number at risk
Bivalirudin
Heparin + GPIIb/IIIa
*MACE = All cause death, reinfarction, ischemic TVR or stroke

28. 30 Day MACE Components* UFH + GP IIb/IIIa (N=1802) Bivalirudin
P Value
Death
3.1%
2.1%
0.058
- Cardiac
2.9%
1.8%
0.035
- Non cardiac
0.2%
0.3%
0.75
Reinfarction
0.90
- Q-wave
1.2%
1.4%
0.66
- Non Q-wave
0.7%
0.4%
0.50
Ischemic TVR
1.9%
2.6%
0.18
- Ischemic TLR
2.5%
0.14
- Ischemic remote TVR
1.0
Stroke
0.6%
0.69
*CEC adjudicated

29. 30 Day Mortality 3.1% Death (%) 2.1% P=0.048 HR [95%CI] =
Heparin + GPIIb/IIIa inhibitor (n=1802)
Bivalirudin monotherapy (n=1800)
3.1%
Death (%)
2.1%
HR [95%CI] =
0.66 [0.44, 1.00]
P=0.048
Time in Days
Number at risk
Bivalirudin
Heparin + GPIIb/IIIa

30. 30 Day Mortality: Cardiac and Non Cardiac
Heparin + GPIIb/IIIa inhibitor (n=1802)
Bivalirudin monotherapy (n=1800)
HR [95%CI] =
0.62 [0.40, 0.96]
P=0.029
2.9%
Death (%)
Cardiac
1.8%
Non cardiac
0.3%
0.2%
Time in Days
Number at risk
Bivalirudin
Heparin + GPIIb/IIIa

31. Impact of Peak ACT on Control Arm Event Rates
new
Impact of Peak ACT on Control Arm Event Rates
P = 0.10
P = 0.12
P = 0.35
P = 0.30
[232,338]
[231,357]
[239,332]
[227,319]
[228,320]
[2134,329]
[227,320]
[228,320]
N=210
N=1528
N=144
N=1594
N=96
N=1642
N=54
N=1684
*Not related to CABG
**MACE = All cause death, reinfarction, ischemic TVR or stroke

32. Primary PCI Procedure (N=3,340; 92.7%)
UFH + GP IIb/IIIa
(N=1662)
Bivalirudin
(N=1678)
IA = LM, LAD, LCX, RCA, SVG
0.4%, 42.0%, 15.1%, 41.5%, 1.0%
0.7%, 39.3%, 16.5%, 42.5%, 1.0%
Door to balloon, mins
100 [73, 135]
98 [73, 135]
Multiple lesions, vessels treated
10.1%, 4.0%
10.7%, 4.1%
GP IIb/IIIa used in CCL
97.7%
7.5%
- Bail-out per protocol* -
4.7%
Peak ACT (seconds)
266 [230, 325]
360 [304, 406]
Stent implanted
95.4%
95.6%
Aspiration catheter used
11.2%
11.9%
Thrombectomy used
1.1%
1.0%
Distal protection used
0.7%
0.5%
TIMI 3, pre │ post (site)
19.6% │ 91.7%
17.7% │ 91.5%
IA = infarct artery; * For giant thrombus or refractory no reflow

33. Primary PCI Cohort (N=3,340; 92.7%)
Diff = -3.0% [-5.2, -2.9]
RR = 0.75 [0.62, 0.92]
PNI ≤
Psup = 0.005
Diff = -3.5% [-5.2, -1.7]
RR = 0.59 [0.46, 0.77]
PNI ≤
Psup ≤
Diff = -0.1% [-1.6, 1.5]
RR = 0.99 [0.75, 1.32]
Psup = 1.00
*Not related to CABG
**MACE = All cause death, reinfarction, ischemic TVR or stroke

34. 30 Day Net Clinical Events: PCI Cohort
Heparin + GPIIb/IIIa inhibitor (n=1662)
Bivalirudin monotherapy (n=1678)
12.3%
9.2%
Net Adverse Clinical Events (%)*
HR [95%CI] =
0.74 [0.60, 0.92]
P=0.005
Time in Days
Number at risk
Bivalirudin
Heparin + GPIIb/IIIa
*MACE or major bleeding (non CABG)

35. 30 Day Major Bleeding: PCI Cohort
Heparin + GPIIb/IIIa inhibitor (n=1662)
Bivalirudin monotherapy (n=1678)
8.6%
Major Bleeding (Non-CABG) (%)
5.1%
HR [95%CI] =
0.58 [0.44, 0.76]
P<0.0001
Time in Days
Number at risk
Bivalirudin
Heparin + GPIIb/IIIa

36. 30 Day Major Adverse CV Events: PCI Cohort
Heparin + GPIIb/IIIa inhibitor (n=1662)
Bivalirudin monotherapy (n=1678)
5.5%
5.4%
Major Adverse CV Events (%)*
HR [95%CI] =
1.00 [0.74, 1.33]
P=0.98
Time in Days
Number at risk
Bivalirudin
Heparin + GPIIb/IIIa
*MACE = All cause death, reinfarction, ischemic TVR or stroke

37. 30 Day Stent Thrombosis (N=3,124)
UFH + GP IIb/IIIa
(N=1553)
Bivalirudin
(N=1571) P
Value
ARC definite or probable*
1.9%
2.5%
0.33
- definite
1.4%
2.2%
0.11
- probable
0.5%
0.3%
0.26
- acute (≤24 hrs)
1.3%
0.0009
- subacute (>24 hrs – 30d)
1.7%
1.2%
0.30
*Protocol definition of stent thrombosis, CEC adjudicated

38. 30 Day Mortality: PCI Cohort
Heparin + GPIIb/IIIa inhibitor (n=1662)
Bivalirudin monotherapy (n=1678)
HR [95%CI] =
0.63 [0.40, 0.99]
P=0.049
2.8%
Death (%)
Cardiac
1.8%
Non cardiac
0.2%
0.1%
Time in days
Number at risk
Bivalirudin
Heparin + GPIIb/IIIa

39. Impact of Definite Stent Thrombosis and Major Bleeding* on Mortality
No major bleed
Stent thrombosis
No stent thrombosis
9.5%
8.8%
Death (%)
1.6%
1.2%
Time in Days
Number at risk
Stent thrombosis
No stent thrombosis
Major bleed
No major bleed
*Not related to CABG

40. Impact of Definite Stent Thrombosis and Major Bleeding* on Mortality
30d mortality with event
30d mortality without event
Risk or excess wrt bivalirudin
Definite stent thrombosis
8.8%
1.6%
5.5x ↑
Major bleeding
9.5%
1.2%
7.9x ↑
UFH + GPI
Bivalirudin
1.4% (22)
2.2% (35)
+0.8% (+13)
8.3% (149)
4.9% (89)
-3.4% (-60)
Death
3.1% (56)
2.1% (37)
-1.0% (-19)
*Not related to CABG

41. Limitations Open label design
Potential bias was mitigated by high protocol procedure compliance and use of blinded clinical event adjudication committees and core laboratories
Underpowered for MACE and low frequency safety endpoints
The virtually identical rates of MACE in the bivalirudin and UFH plus GP IIb/IIIa inhibitor arms makes it unlikely major differences favoring control exist, especially given the lower cardiac mortality with bivalirudin

42. Conclusions
In this large scale, prospective, randomized trial of pts with STEMI undergoing a primary PCI management strategy, compared to UFH plus the routine use of GP IIb/IIIa inhibitors, bivalirudin monotherapy with GP IIb/IIIa inhibitors reserved for suboptimal PCI outcomes resulted in:
A significant 24% reduction in the 30 day primary endpoint of net adverse clinical events
A significant 40% reduction in the 30 day primary endpoint of major bleeding

43. Conclusions
The long-term impact of treatment with bivalirudin monotherapy rather than heparin plus GP IIb/IIIa inhibitors in patients with STEMI undergoing primary PCI will be determined by the ongoing 5 year follow-up of patients randomized in this trial
The primary endpoint results of the second randomized arm of the HORIZONS AMI trial (paclitaxel-eluting vs. bare metal stents) will be available for presentation at TCT 2008