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
– One Year Results –
Roxana Mehran MD
For the HORIZONS-AMI Investigators

2. Background
Numerous studies have demonstrated a strong association between hemorrhagic complications and subsequent mortality in pts with ACS and after PCI
In the HORIZONS-AMI trial, among high risk pts with STEMI undergoing primary PCI, randomization to bivalirudin monotherapy compared to UFH + GPI resulted in reduced rates of bleeding, thrombo- cytopenia, and blood transfusions; non significantly different rates of reinfarction, stent thrombosis and TVR; and improved survival at 30 days
Whether these benefits are maintained at 1-year is unknown

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 or medical therapy
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

4. 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
Pharmacology Arm
Primary and Secondary Endpoints
1-Year
Intention to Treat Population
Outcomes in the 4 randomized groups

5. 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

6. 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

7. 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

8. 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 clopidogrel 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

9. 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

10. 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

11. Harmonizing Outcomes with Revascularization and Stents in AMI
3602 pts with STEMI R
1:1
UFH + GP IIb/IIIa
N=1802
Bivalirudin
N=1800
Randomized
30 Day FU
N=1791 (99.4%)
N=1787 (99.3%) 28
• • • Not true MI* • • • 29
1-Year FU Eligible
N=1774
N=1771 26 46
• • • Withdrew • • •
• • • Lost to FU • • • 22 53
1-Year FU
N=1702 (95.9%)
N=1696 (95.8%)
* Biomarkers WNL and no DS >50% by core lab determination → 30 day FU only

12. 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
Stone GW et al. NEJM 2008;358:

13. 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%
Aspiration catheter
11.1%
11.9%
Stone GW et al. NEJM 2008;358:

14. Study Drugs UFH + GP IIb/IIIa (N=1802) Bivalirudin (N=1800)
UFH pre randomization
65.6%
Antithrombin in CCL
- UFH
98.9%
2.6%
- Bivalirudin
0.2%
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
0.1%
*97.7% and 7.5% during PCI. ** For giant thrombus or refractory no reflow after PCI. CCL = cardiac catheterization laboratory

15. 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

16. Primary Endpoints at 30 Days
Diff = -2.9% [-4.9, -0.8]
RR = 0.76 [0.63, 0.92]
PNI ≤
Psup = 0.005
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 = 0.95
1 endpoint
1 endpoint
Major 2 endpoint
Stone GW et al. NEJM 2008;358:

17. Aspirin and Thienopyridine Use
Regular* aspirin use (%)
Regular* thieno. use (%)
98.1%
97.3%
97.0%
96.1%
93.7%
93.3%
87.8%
97.1%
96.7%
96.3%
95.7%
92.7%
92.9%
87.2%
68.0%
Antiplatelet agent use (%)
65.8%
All P = NS
All P = NS
*Taken >50% of days since last visit

18. 1-Year Net Adverse Clinical Events* *MACE or major bleeding (non CABG)
Number at risk
Bivalirudin alone
Heparin+GPIIb/IIIa
1800
1559
1514
1483
1343
1802
1499
1459
1427
1281
NACE (%) 2 4 6 8 10 12 14 16 18 20
Time in Months 1 3 5 7 9 11
Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802)
18.3%
15.7%
Diff [95%CI] = % [-5.1, -0.1]
HR [95%CI] = [0.71, 0.98]
P=0.03
*MACE or major bleeding (non CABG)

19. 1-Year Major Bleeding (non-CABG)
Number at risk
Bivalirudin alone
Heparin+GPIIb/IIIa
1800
1621
1601
1586
1448
1802
1544
1532
1515
1368
Major Bleeding (%) 1 2 3 4 5 6 7 8 9 10 11 12
Time in Months
Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802)
9.2%
5.8%
Diff [95%CI] = % [-5.2, -1.7]2
HR [95%CI] =
0.61 [0.48, 0.78]
P<0.0001

20. 1-Year Bleeding Endpoints*
UFH + GP IIb/IIIa
(N=1802)
Bivalirudin
(N=1800)
P Value
Protocol Major, non CABG**
9.2%
5.8%
<0.0001
Protocol Major, All
11.8%
7.7%
Protocol Minor
16.5%
9.1%
Blood transfusion
4.0%
2.7%
0.02
TIMI Major
5.5%
3.6%
0.005
TIMI Minor
4.8%
3.0%
0.008
TIMI Major or Minor
10.2%
6.5%
GUSTO LT*** or Severe
0.7%
0.8%
0.70
GUSTO Moderate
5.4%
3.7%
0.01
GUSTO LT or Sev or Mod
6.0%
4.4%
*Kaplan-Meier estimates; all CEC adjudicated, except protocol minor;
**Primary endpoint; ***Life threatening

21. 1-Year Major Adverse CV Events*15
Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802) 14
11.9% 13 12
11.9% 11 10 9 8
Diff [95%CI] = % [-2.1, 2.2]
HR [95%CI] = [0.83, 1.21]
P=0.98
MACE (%) 7 6 5 4 3 2 1 1 2 3 4 5 6 7 8 9 10 11 12
Time in Months
Number at risk
Bivalirudin alone
1800
1627
1579
1544
1394
Heparin+GPIIb/IIIa
1802
1619
1573
1540
1380
*MACE = All cause death, reinfarction, ischemic TVR or stroke

22. 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 (%)
Diff [95%CI] =
-1.5% [-2.8,-0.1]
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

23. 1-Year Mortality: Cardiac and Non Cardiac
Bivalirudin alone (n=1800)
HR [95%CI] =
0.57 [0.38, 0.84] P=0.005 5
Heparin + GPIIb/IIIa (n=1802) 4
3.8% 3
Δ = 1.7%
2.9%
Cardiac
Mortality (%)
2.1% 2
1.8%
Δ = 1.1%
P=0.03 1
Non Cardiac
1.3%
1.1% 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

24. 1-Year Death or Reinfarction10
Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802) 9
8.5% 8 7
6.6% 6
4.5%
Δ = 1.9%
Death or MI (%) 5 4
HR [95%CI] =
0.77 [0.61, 0.98]
P=0.04
3.8% 3
Δ = 0.7%
P=0.30 2 1 1 2 3 4 5 6 7 8 9 10 11 12
Time in Months
Number at risk
Bivalirudin alone
1800
1670
1638
1617
1469
Heparin+GPIIb/IIIa
1802
1648
1617
1593
1431

25. 1-Year MACE Components*
UFH + GPI
(N=1802)
Bivalirudin
(N=1800)
HR [95%CI]
P Value
Death
4.8%
3.4%
0.69 [0.50,0.97]
0.029
- Cardiac
3.8%
2.1%
0.57 [0.38,0.84]
0.005
- Non cardiac
1.1%
1.3%
1.14 [0.62,2.11]
0.67
Reinfarction
4.4%
3.6%
0.81 [0.58,1.14]
0.22
- Q-wave
2.2%
1.06 [0.67,1.67]
0.81
- Non Q-wave
2.7%
1.4%
0.53 [0.32,0.86]
0.01
Death or reinfarction
8.5%
6.6%
0.77 [0.61,0.98]
0.04
Ischemic TVR
5.9%
7.2%
1.23 [0.94,1.60]
0.12
- Ischemic TLR
4.5%
6.0%
1.34 [1.00,1.80]
0.051
- Ischemic remote TVR
2.0%
2.3%
1.13 [0.71,1.79]
0.60
Stroke
1.2%
1.00 [0.54,1.85]
0.99
*All Kaplan-Meier estimates, CEC adjudicated

26. Adverse Events Between 30 Days and 1-Year
UFH + GPI
(N=1802)
Bivalirudin
(N=1800)
P Value
Death
1.8%
1.4%
0.31
- Cardiac
0.9%
0.4%
0.046
- Non cardiac
1.0%
0.75
Reinfarction
2.8%
1.7%
0.04
Death or reinfarction
4.4%
3.0%
0.02
Ischemic TVR
4.3%
4.7%
0.57
Stroke
0.5%
0.77
MACE
7.3%
6.8%
0.52
Major bleeding (non CABG)
0.7%
0.8%
0.71
NACE
7.8%
*Kaplan-Meier estimates, landmark analysis, CEC adjudicated

27. 1-Year Stent Thrombosis (ARC Definite/Probable)
Number at risk
Bivalirudin alone
Heparin+GPIIb/IIIa
1611
1525
1504
1486
1356
1591
1495
1475
1457
1315
Stent Thrombosis (%) 1 2 3 4 5
Time in Months 6 7 8 9 10 11 12
Bivalirudin alone (n=1611)
Heparin + GPIIb/IIIa (n=1591)
Δ = 0.3%
3.5%
3.2%
2.7%
HR [95%CI] =
1.11 [0.76, 1.63]
P=0.59
2.2%
Δ = 0.5%
P=0.31

28. 1-Year Stent Thrombosis* (N=3,202)
UFH + GPI
(N=1591)
Bivalirudin
(N=1611) P
Value
ARC definite or probable, ≤24 hrs
0.3%
1.5%
0.0002
- definite, ≤24 hours
0.2%
1.4%
<0.0001
- probable, ≤24 hours
0.1%
1.0
ARC definite or probable, >1 - ≤30d
1.9%
1.3%
0.14
- definite, >1 day - ≤30 days
1.1%
0.60
- probable, >1 day - ≤30 days
0.6%
0.049
ARC definite or probable, >30d – 1y
0.9%
0.53
- definite, >30 days – 1-year
1.0%
0.65
- probable, >30 days – 1-year
0.55
ARC definite or probable, ≤1-year
3.2%
3.5%
0.59
- definite, ≤1-year
2.4%
0.15
- probable, ≤1-year
0.8%
0.06
*All Kaplan-Meier estimates except ≤24 hours; all CEC adjudicated

29. Harmonizing Outcomes with Revascularization and Stents in AMI
3602 pts with STEMI R
1:1
UFH + GP IIb/IIIa
N=1802
Bivalirudin
N=1800
Stent rand.
eligible
N=1479
N=1527 R
3:1 R
3:1
Stratified by 1st rand.
TAXUS
N=1111
EXPRESS
N=368
TAXUS
N=1146
EXPRESS
N=381

30. Interaction Between Drug and Stent Randomization 30 Day Pharmacology Endpoints (N=3006)
Kaplan-Meier estimates
UFH + GPI
(N=1479)
Bivalirudin
(N=1527)
HR [95%CI]
Pint
NACE, all*
11.3%
8.7%
0.76 [0.60,0.95] -
- TAXUS subgroup
11.5%
9.1%
0.78 [0.60,1.01]
0.95
- EXPRESS subgroup
10.6%
7.4%
0.69 [0.42,1.11]
Major bleeding, all**
8.4%
5.1%
0.59 [0.44,0.78]
8.9%
5.4%
0.59 [0.43,0.81]
1.0
7.1%
4.2%
0.58 [0.31,1.09]
MACE, all***
4.7%
4.9%
1.05 [0.75,1.45]
4.6%
1.11 [0.76,1.62]
0.89
0.86 [0.44,1.69]
*MACE or major bleeding; **Protocol defined (non CABG); ***Death, reinfarction, stroke or ischemic TVR

31. Interaction Between Drug and Stent Randomization 1-Year Stent Endpoints (N=3006)
Kaplan-Meier estimates
TAXUS
(N=2257)
EXPRESS
(N=749)
HR [95%CI]
Pint
Ischemic TLR, all
4.5%
7.5%
0.59 [0.43,0.83] -
- UFH + GPI subgroup
3.3%
7.9%
0.42 [0.25,0.68]
0.17
- Bivalirudin subgroup
5.6%
7.1%
0.78 [0.50,1.24]
Safety MACE, all*
8.1%
8.0%
1.02 [0.76, 1.36]
8.2%
8.8%
0.92 [0.66,1.27]
0.89
7.2%
1.17 [0.83,1.64]
Binary restenosis, all**
10.0%
22.9%
0.44 [0.33, 0.57]
10.9%
19.2%
0.57 [0.38,0.84]
0.18
9.2%
26.7%
0.34 [0.24,0.49]
*Death, reinfarction, stroke or stent thrombosis
**1081 lesions in the TAXUS group, 332 in the EXPRESS group

32. 1-Year Mortality (All-Cause)
Heparin + GPI / TAXUS (n=1111)
Heparin + GPI / EXPRESS (n=368)
Bivalirudin / TAXUS (n=1146)
Bivalirudin / EXPRESS (n=381) 5
4.6%
4.0% 4
3.0% 3
2.6%
Mortality (%) 2
Pint = 0.75 1 1 2 3 4 5 6 7 8 9 10 11 12
Time in Months

33. 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 low frequency safety endpoints and subgroup interactions
All such observations should be considered hypothesis-generating

34. Conclusions
In this large scale, prospective, randomized trial of pts with STEMI undergoing a primary PCI management strategy, bivalirudin monotherapy compared to UFH plus the routine use of GP IIb/IIIa inhibitors resulted in:
A significant 16% reduction in the 1-year rate of composite net adverse clinical events
A significant 39% reduction in the 1-year rate of major bleeding

35. Conclusions
In this large scale, prospective, randomized trial of pts with STEMI undergoing a primary PCI management strategy, bivalirudin monotherapy compared to UFH plus the routine use of GP IIb/IIIa inhibitors resulted in:
Significant 31% and 43% reductions in the year rates of all-cause and cardiac mortality (absolute 1.4% and 1.7% reductions), with non significantly different rates of reinfarction, stent thrombosis, stroke and TVR at 1-year

36. Clinical Implications
HORIZONS has demonstrated that the prevention of hemorrhagic complications after primary PCI in STEMI results in improved early and late survival
Optimal drug selection and technique to minimize bleeding are essential to enhance outcomes for pts undergoing interventional therapies