A Prospective, Randomized A Prospective, Randomized Comparison of Bivalirudin vs. Comparison of Bivalirudin vs.

Heparin Plus Glycoprotein IIb/IIIa Heparin Plus Glycoprotein IIb/IIIa Inhibitors During Primary Inhibitors During Primary

Angioplasty in Acute Myocardial Angioplasty in Acute Myocardial InfarctionInfarction

– – 3030 Day Results – Day Results –

Gregg W. Stone MDGregg W. Stone MDFor the HORIZONS AMI For the HORIZONS AMI

InvestigatorsInvestigators

A Prospective, Randomized A Prospective, Randomized Comparison of Bivalirudin vs. Comparison of Bivalirudin vs.

Heparin Plus Glycoprotein IIb/IIIa Heparin Plus Glycoprotein IIb/IIIa Inhibitors During Primary Inhibitors During Primary

Angioplasty in Acute Myocardial Angioplasty in Acute Myocardial InfarctionInfarction

– – 3030 Day Results – Day Results –

Gregg W. Stone MDGregg W. Stone MDFor the HORIZONS AMI For the HORIZONS AMI

InvestigatorsInvestigators

Disclosures

Gregg W. Stone MD– Research support from The Medicines

Company and Boston Scientific

– Honoraria from Eli Lilly Co.

Background In addition to suppressing periprocedural ischemia, In addition to suppressing periprocedural ischemia,

prevention of hemorrhagic complications has emerged as prevention of hemorrhagic complications has emerged as a priority in patients undergoing PCIa priority in patients undergoing PCI

In patients with stable angina and NSTEMI, the direct In patients with stable angina and NSTEMI, the direct thrombin inhibitor bivalirudin has been shown to result in thrombin inhibitor bivalirudin has been shown to result in similar rates of composite ischemia as heparin plus GP similar rates of composite ischemia as heparin plus GP IIb/IIIa inhibitors, while significantly reducing major IIb/IIIa inhibitors, while significantly reducing major bleedingbleeding

Whether bivalirudin has comparable safety and efficacy in Whether bivalirudin has comparable safety and efficacy in patients with STEMI undergoing primary PCI is unknownpatients with STEMI undergoing primary PCI is unknown

HHarmonizing armonizing OOutcomes with utcomes with RRevascularevascularizizatiationon and and SStents in AMItents in AMI

≥≥3400* pts with STEMI with symptom onset ≤12 hours3400* pts with STEMI with symptom onset ≤12 hours

Emergent angiography, followed by triage to…Emergent angiography, followed by triage to…

Primary PCIPrimary PCICABGCABG –– Medical RxMedical Rx––

UFH + GP IIb/IIIa inhibitorUFH + GP IIb/IIIa inhibitor(abciximab or eptifibatide)(abciximab or eptifibatide)

Bivalirudin monotherapyBivalirudin monotherapy(± provisional GP IIb/IIIa)(± provisional GP IIb/IIIa)

Aspirin, thienopyridineAspirin, thienopyridine R 1:1

3000 pts eligible for stent randomization3000 pts eligible for stent randomization R 1:3

Bare metal stentBare metal stent TAXUS paclitaxel-eluting stentTAXUS paclitaxel-eluting stent

*To rand 3000 stent pts*To rand 3000 stent pts

Clinical FU at 30 days, 6 months,1 year, and then yearly through 5 years

Clinical FU at 30 days, 6 months,1 year, and then yearly through 5 years

HHarmonizing armonizing OOutcomes with utcomes with RRevascularevascularizizatiationon and and SStents in AMItents in AMI

≥≥3400* pts with STEMI with symptom onset ≤12 hours3400* pts with STEMI with symptom onset ≤12 hours

UFH + GP IIb/IIIa inhibitorUFH + GP IIb/IIIa inhibitor(abciximab or eptifibatide)(abciximab or eptifibatide)

Bivalirudin monotherapyBivalirudin monotherapy(± provisional GP IIb/IIIa)(± provisional GP IIb/IIIa)

Aspirin, thienopyridineAspirin, thienopyridine R 1:1

Pharmacology ArmPharmacology ArmPrimary Endpoints*Primary Endpoints*

30 Day 30 Day Intention to Treat PopulationIntention to Treat Population

* All stent randomization results are still blinded * All stent randomization results are still blinded

30 Day Study Objectives30 Day Study Objectives

In patients with STEMI undergoing a primary In patients with STEMI undergoing a primary PCI strategy, compared to UFH plus the PCI strategy, compared to UFH plus the routine use of GP IIb/IIIa inhibitors, bivalirudin routine use of GP IIb/IIIa inhibitors, bivalirudin monotherapy will result in:monotherapy will result in:

– Similar or reduced rates of net adverse clinical Similar or reduced rates of net adverse clinical events (the composite of ischemic major events (the composite of ischemic major adverse cardiovascular events and major adverse cardiovascular events and major bleeding) at 30 daysbleeding) at 30 days

– Similar or reduced rates of major bleeding Similar or reduced rates of major bleeding at 30 daysat 30 days

2 Primary Endpoints (at 30 Days)2 Primary Endpoints (at 30 Days)

1) Net Adverse Clinical Events1) Net Adverse Clinical Events

2) Major Bleeding (non CABG)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

andand

2 Primary Endpoints (at 30 Days)2 Primary Endpoints (at 30 Days)

1) Net Adverse Clinical Events1) Net Adverse Clinical Events

2) Major Bleeding (non CABG)2) Major Bleeding (non CABG)

==

oror

• All cause death• Reinfarction• Ischemic TVR

• Stroke

Major adverseMajor adversecardiovascular eventscardiovascular events

(major secondary endpoint)(major secondary endpoint)

HHarmonizing armonizing OOutcomes with utcomes with RRevascularevascularizizatiationon and and SStents in AMItents in AMI

UFH +GP IIb/IIIaN=1802

BivalirudinMonotherapy

N=1800

R 1:1

RandomizedRandomized

30 day FU*30 day FU*

* Range ±7 days* Range ±7 days

ITT populationITT population

N=1778(98.7%)

N=1777(98.7%)

N=1802 N=1800

• • • • • • Withdrew • • •Withdrew • • •

• • • • • • Lost to FU • • •Lost to FU • • •99

15151010

1313

3602 pts with STEMI3602 pts with STEMI

Primary Management Strategy*Primary Management Strategy*

UFH + GP IIb/IIIa InhibitorN=1802

Bivalirudin MonotherapyN=1800

Primary PCI Deferred PCI CABG Medical Rx

*Primary ITT analysis includes all pts regardless of treatment*Primary ITT analysis includes all pts regardless of treatment

Diff = Diff = 0.0% [-1.6,1.5] RR = 0.99RR = 0.99 [0.76,1.30]

PPsupsup = 1.00 = 1.00

Primary Outcome Measures (ITT)

Diff = Diff = -3.3% [-4.0,-1.6] RR = RR = 0.60 [0.46,0.77]

PPNINI ≤ 0.0001 ≤ 0.0001

PPsupsup ≤ 0.0001 ≤ 0.0001

Diff = Diff = -2.9% [-4.9,-0.8]RR = RR = 0.76 [0.63,0.92]

PPNINI ≤ 0.0001 ≤ 0.0001

PPsupsup = 0.006 = 0.006

1 endpoint 1 endpoint

*Not related to CABG*Not related to CABG**MACE = All cause death, reinfarction, ischemic TVR or stroke**MACE = All cause death, reinfarction, ischemic TVR or stroke

30 Day MACE Components*30 Day MACE Components*UFH + GP IIb/IIIaUFH + GP IIb/IIIa

(N=1802)(N=1802)BivalirudinBivalirudin(N=1800)(N=1800) P ValueP Value

DeathDeath 3.1%3.1% 2.1%2.1% 0.0580.058

- Cardiac- Cardiac 2.9%2.9% 1.8%1.8% 0.0350.035

- Non cardiac- Non cardiac 0.2%0.2% 0.3%0.3% 0.750.75

ReinfarctionReinfarction 1.8%1.8% 1.8%1.8% 0.900.90

- Q-wave- Q-wave 1.2%1.2% 1.4%1.4% 0.660.66

- Non Q-wave- Non Q-wave 0.7%0.7% 0.4%0.4% 0.500.50

Ischemic TVRIschemic TVR 1.9%1.9% 2.6%2.6% 0.180.18

- Ischemic TLR- Ischemic TLR 1.8%1.8% 2.5%2.5% 0.140.14

- Ischemic remote TVR- Ischemic remote TVR 0.3%0.3% 0.3%0.3% 1.01.0

StrokeStroke 0.6%0.6% 0.7%0.7% 0.690.69

*CEC adjudicated*CEC adjudicated

ConclusionsConclusions In this large scale, prospective, randomized trial of In this large scale, prospective, randomized trial of

pts with STEMI undergoing a primary PCI pts with STEMI undergoing a primary PCI

management strategy, compared to UFH plus the management strategy, compared to UFH plus the

routine use of GP IIb/IIIa inhibitors, bivalirudin routine use of GP IIb/IIIa inhibitors, bivalirudin

monotherapy with GP IIb/IIIa inhibitors reserved for monotherapy with GP IIb/IIIa inhibitors reserved for

suboptimal PCI outcomes resulted in:suboptimal PCI outcomes resulted in:

– A significant 24% reduction in the 30 day primary A significant 24% reduction in the 30 day primary

endpoint of net adverse clinical eventsendpoint of net adverse clinical events

– A significant 40% reduction in the 30 day primary A significant 40% reduction in the 30 day primary

endpoint of major bleedingendpoint of major bleeding