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
 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
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 Bivalirudin monotherapy

(abciximab or eptifibatide) (± provisional GP IIb/IIIa)

Emergent angiography, followed by triage to primary PCI, CABG or medical therapy

3006 pts eligible for stent randomization
R
3:1

Paclitaxel-eluting TAXUS stent Bare metal EXPRESS stent

Clinical FU at 30 days, 6 months,

1 year, and then yearly through 5 years
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 Bivalirudin monotherapy

(abciximab or eptifibatide) (± provisional GP IIb/IIIa)

Pharmacology Arm
Primary and Secondary Endpoints
1-Year
Intention to Treat Population
Outcomes in the 4 randomized groups
 Study Medications (i)
 Unfractionated heparin
– 60 U/kg IV*; subsequent boluses titrated by nomogram
to ACT 200-250 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
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
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
Harmonizing Outcomes with Revascularization and Stents in AMI
3602 pts with STEMI
R
1:1

UFH + GP IIb/IIIa Bivalirudin

Randomized
N=1802 N=1800

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 • • • Withdrew • • • 22
46 • • • Lost to FU • • • 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
 Baseline Characteristics (i)
UFH + GP IIb/IIIa Bivalirudin
(N=1802) (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;358:2218-30
 Baseline Characteristics (ii)
UFH + GP IIb/IIIa Bivalirudin
(N=1802) (N=1800)
Weight (kg) 80 [71, 90] 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% 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;358:2218-30

 Study Drugs
UFH + GP IIb/IIIa Bivalirudin
(N=1802) (N=1800)
UFH pre randomization 65.6% 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 0.2% 0.1%
*97.7% and 7.5% during PCI. ** For giant thrombus or refractory no
reflow after PCI. CCL = cardiac catheterization laboratory
 Primary Management Strategy*
UFH + GP IIb/IIIa Inhibitor Bivalirudin Monotherapy
N=1802 N=1800

Primary PCI Deferred PCI CABG Medical Rx

*Primary ITT analysis includes all pts regardless of treatment

Primary Endpoints at 30 Days
Diff = -2.9% [-4.9, -0.8] Diff = -3.3% [-5.0, -1.6] Diff = 0.0% [-1.6, 1.5]
RR = 0.76 [0.63, 0.92] RR = 0.60 [0.46, 0.77] RR = 0.99 [0.76, 1.30]
PNI ≤ 0.0001 PNI ≤ 0.0001 Psup = 0.95
Psup = 0.005 Psup ≤ 0.0001

1° endpoint 1° endpoint Major 2° endpoint

Stone GW et al. NEJM 2008;358:2218-30

 Aspirin and Thienopyridine Use
Regular* aspirin use (%) Regular* thieno. use (%)

98.1% 97.3% 97.0% 96.1% 93.7% 93.3%

87.8%
Antiplatelet agent use (%)

97.1% 96.7% 96.3% 95.7% 92.7% 92.9%

87.2% 68.0%

65.8%

All P = NS All P = NS

*Taken >50% of days since last visit

 1-Year Net Adverse Clinical Events*
20 Bivalirudin alone (n=1800)
18 Heparin + GPIIb/IIIa (n=1802) 18.3%
16 15.7%
14
NACE (%)

12
10 Diff [95%CI] =
-2.6% [-5.1, -0.1]
8
HR [95%CI] =
6
0.84 [0.71,
4 0.98]
2 P=0.03
0
0 1 2 3 4 5 6 7 8 9 10 11 12

Time in Months
Number at risk
Bivalirudin alone 1800 1559 1514 1483 1343
Heparin+GPIIb/IIIa 1802 1499 1459 1427 1281

*MACE or major bleeding (non CABG)

 1-Year Major Bleeding (non-CABG)
12 Bivalirudin alone (n=1800)
11 Heparin + GPIIb/IIIa (n=1802)
Major Bleeding (%) 10
9.2%
9
8
7
6
5.8%
5 Diff [95%CI] =
4 -3.4% [-5.2, -1.7]
2

3 HR [95%CI] =
2 0.61 [0.48, 0.78]
1
P<0.0001
0
0 1 2 3 4 5 6 7 8 9 10 11 12

Time in Months
Number at risk
Bivalirudin alone 1800 1621 1601 1586 1448
Heparin+GPIIb/IIIa 1802 1544 1532 1515 1368
 1-Year Bleeding Endpoints*
UFH + GP IIb/IIIa Bivalirudin
P Value
(N=1802) (N=1800)
Protocol Major, non CABG** 9.2% 5.8% <0.0001
Protocol Major, All 11.8% 7.7% <0.0001
Protocol Minor 16.5% 9.1% <0.0001
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% <0.0001
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% 0.02
*Kaplan-Meier estimates; all CEC adjudicated, except protocol minor;
**Primary endpoint; ***Life threatening
 1-Year Major Adverse CV Events*
15 Bivalirudin alone (n=1800)
14 Heparin + GPIIb/IIIa (n=1802)
13
12
11.9%
11 11.9%
MACE (%)
10
9
8 Diff [95%CI] =
7 0.0% [-2.1, 2.2]
6
5 HR [95%CI] =
4 1.00 [0.83, 1.21]
3
2 P=0.98
1
0
0 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

 1-Year All-Cause Mortality
5 Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802) 4.8%
4 Δ = 1.4%
Mortality (%)

3.4%
3 3.1%

Diff [95%CI] =
2 -1.5% [-2.8,-0.1]
2.1%
HR [95%CI] =
Δ = 1.0%
1 0.69 [0.50, 0.97]
P=0.049
P=0.029
0
0 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
 1-Year Mortality: Cardiac and Non Cardiac
5 Bivalirudin alone (n=1800) HR [95%CI] =
Heparin + GPIIb/IIIa (n=1802) 0.57 [0.38, 0.84]

4
P=0.005
3.8%
Mortality (%)

3 Δ = 1.7%
2.9% Cardiac

2 2.1%
1.8%
1 Δ = 1.1%
P=0.03
Non Cardiac
1.3%
0 1.1%
0 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
 1-Year Death or Reinfarction
10 Bivalirudin alone (n=1800)
9 Heparin + GPIIb/IIIa (n=1802)
Death or MI (%)
8
8.5%
7
6.6%
6
4.5%
5 Δ = 1.9%

4 HR [95%CI] =
3.8%
3 0.77 [0.61, 0.98]
2 Δ = 0.7%
P=0.04
1 P=0.30
0
0 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
 1-Year MACE Components*
UFH + GPI Bivalirudin P
HR [95%CI]
(N=1802) (N=1800) 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 2.1% 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% 1.1% 1.00 [0.54,1.85] 0.99

*All Kaplan-Meier estimates, CEC adjudicated

Adverse Events Between 30 Days and 1-Year
UFH + GPI Bivalirudin
P Value
(N=1802) (N=1800)
Death 1.8% 1.4% 0.31
- Cardiac 0.9% 0.4% 0.046
- Non cardiac 0.9% 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% 0.4% 0.77
MACE 7.3% 6.8% 0.52
Major bleeding (non CABG) 0.7% 0.8% 0.71
NACE 7.8% 7.3% 0.52
*Kaplan-Meier estimates, landmark analysis, CEC adjudicated
1-Year Stent Thrombosis (ARC Definite/Probable)
5 Bivalirudin alone (n=1611)
Heparin + GPIIb/IIIa (n=1591)
Δ = 0.3%
Stent Thrombosis (%) 4
3.5%
3 2.7% 3.2%

2 2.2% HR [95%CI] =
1.11 [0.76, 1.63]
Δ = 0.5%
1 P=0.31 P=0.59

0
0 1 2 3 4 5 6 7 8 9 10 11 12

Time in Months
Number at risk
Bivalirudin alone 1611 1525 1504 1486 1356
Heparin+GPIIb/IIIa 1591 1495 1475 1457 1315
 1-Year Stent Thrombosis* (N=3,202)
UFH + GPI Bivalirudin P
(N=1591) (N=1611) 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% 0.1% 1.0
ARC definite or probable, >1 - ≤30d 1.9% 1.3% 0.14
- definite, >1 day - ≤30 days 1.3% 1.1% 0.60
- probable, >1 day - ≤30 days 0.6% 0.2% 0.049
ARC definite or probable, >30d – 1y 1.1% 0.9% 0.53
- definite, >30 days – 1-year 1.0% 0.9% 0.65
- probable, >30 days – 1-year 0.1% 0.1% 0.55
ARC definite or probable, ≤1-year 3.2% 3.5% 0.59
- definite, ≤1-year 2.4% 3.2% 0.15
- probable, ≤1-year 0.8% 0.3% 0.06
*All Kaplan-Meier estimates except ≤24 hours; all CEC adjudicated
Harmonizing Outcomes with Revascularization and Stents in AMI

3602 pts with STEMI

R
1:1

UFH + GP IIb/IIIa Bivalirudin

N=1802 N=1800

Stent rand.
N=1479 N=1527
eligible
R R
3:1 Stratified by 1st rand. 3:1

TAXUS EXPRESS TAXUS EXPRESS

N=1111 N=368 N=1146 N=381
Interaction Between Drug and Stent Randomization
30 Day Pharmacology Endpoints (N=3006)
UFH + GPI Bivalirudin
Kaplan-Meier estimates HR [95%CI] Pint
(N=1479) (N=1527)
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] -
- TAXUS subgroup 8.9% 5.4% 0.59 [0.43,0.81]
1.0
- EXPRESS subgroup 7.1% 4.2% 0.58 [0.31,1.09]
MACE, all*** 4.7% 4.9% 1.05 [0.75,1.45] -
- TAXUS subgroup 4.6% 5.1% 1.11 [0.76,1.62]
0.89
- EXPRESS subgroup 4.9% 4.2% 0.86 [0.44,1.69]
*MACE or major bleeding; **Protocol defined (non CABG);
***Death, reinfarction, stroke or ischemic TVR
 Interaction Between Drug and Stent Randomization
1-Year Stent Endpoints (N=3006)
TAXUS EXPRESS
Kaplan-Meier estimates HR [95%CI] Pint
(N=2257) (N=749)
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] -
- UFH + GPI subgroup 8.2% 8.8% 0.92 [0.66,1.27]
0.89
- Bivalirudin subgroup 8.0% 7.2% 1.17 [0.83,1.64]
Binary restenosis, all** 10.0% 22.9% 0.44 [0.33, 0.57] -
- UFH + GPI subgroup 10.9% 19.2% 0.57 [0.38,0.84]
0.18
- Bivalirudin subgroup 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
 1-Year Mortality (All-Cause)
Heparin + GPI / TAXUS (n=1111)
5 Heparin + GPI / EXPRESS (n=368)
Bivalirudin / TAXUS (n=1146)
Bivalirudin / EXPRESS (n=381) 4.6%
4 4.0%
Mortality (%)

3 3.0%
2.6%
2

1 Pint = 0.75

0
0 1 2 3 4 5 6 7 8 9 10 11 12

Time in Months
 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
 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
 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
1-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
 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