A Prospective, Randomized Comparison of Bivalirudin vs. Heparin Plus Glycoprotein IIb/IIIa...

A Prospective, Randomized Comparison of A Prospective, Randomized Comparison of Bivalirudin vs. Heparin Plus Glycoprotein Bivalirudin vs. Heparin Plus Glycoprotein

IIb/IIIa Inhibitors During Primary IIb/IIIa Inhibitors During Primary Angioplasty in Acute Myocardial InfarctionAngioplasty in Acute Myocardial Infarction

– – One Year Results –One Year Results –

Roxana Mehran MDRoxana Mehran MDFor the HORIZONS-AMI InvestigatorsFor the HORIZONS-AMI Investigators

A Prospective, Randomized Comparison of A Prospective, Randomized Comparison of Bivalirudin vs. Heparin Plus Glycoprotein Bivalirudin vs. Heparin Plus Glycoprotein

IIb/IIIa Inhibitors During Primary IIb/IIIa Inhibitors During Primary Angioplasty in Acute Myocardial InfarctionAngioplasty in Acute Myocardial Infarction

– – One Year Results –One Year Results –

Roxana Mehran MDRoxana Mehran MDFor the HORIZONS-AMI InvestigatorsFor the HORIZONS-AMI Investigators

Background Numerous studies have demonstrated a strong Numerous studies have demonstrated a strong

association between hemorrhagic complications and association between hemorrhagic complications and subsequent mortality in pts with ACS and after PCIsubsequent mortality in pts with ACS and after PCI

In the HORIZONS-AMI trial, In the HORIZONS-AMI trial, among high risk pts among high risk pts with STEMI undergoing primary PCI, randomization with STEMI undergoing primary PCI, randomization to bivalirudin monotherapy compared to UFH + GPI to bivalirudin monotherapy compared to UFH + GPI resulted in reduced rates of bleeding, thrombo-resulted in reduced rates of bleeding, thrombo-cytopenia, and blood transfusions; non significantly cytopenia, and blood transfusions; non significantly different rates of reinfarction, stent thrombosis and different rates of reinfarction, stent thrombosis and TVR; and improved survival at 30 daysTVR; and improved survival at 30 days

Whether these benefits are maintained at 1-year is Whether these benefits are maintained at 1-year is unknownunknown

HHarmonizing armonizing OOutcomes with utcomes with RRevascularevascularizizatiationon and and SStents in tents in AMIAMI

3602 pts with STEMI with symptom onset ≤12 hours3602 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

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

3006 pts eligible for stent randomization3006 pts eligible for stent randomization

R 3:1

Bare metal EXPRESS stentBare metal EXPRESS stentPaclitaxel-eluting TAXUS stentPaclitaxel-eluting TAXUS stent

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


3602 pts with STEMI with symptom onset ≤12 hours3602 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 and Secondary EndpointsPrimary and Secondary Endpoints

1-Year1-YearIntention to Treat PopulationIntention to Treat Population

Outcomes in the 4 randomized groupsOutcomes in the 4 randomized groups

Study Medications (i)Study Medications (i) Unfractionated heparinUnfractionated heparin– 60 U/kg IV*; subsequent boluses titrated by nomogram to 60 U/kg IV*; subsequent boluses titrated by nomogram to

ACT 200-250 secs; terminated at procedure end unless ACT 200-250 secs; terminated at procedure end unless prolonged antithrombin neededprolonged antithrombin needed

BivalirudinBivalirudin– Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to

ACT; terminated at procedure end unless prolonged ACT; terminated at procedure end unless prolonged antithrombin needed (0.25 mg/kg/hr infusion)antithrombin needed (0.25 mg/kg/hr infusion)

Glycoprotein IIb/IIIa inhibitorsGlycoprotein IIb/IIIa inhibitors– Routine use in UFH arm; recommended only for giant Routine use in UFH arm; recommended only for giant

thrombus or refractory no reflow in bivalirudin armthrombus or refractory no reflow in bivalirudin arm

– Abciximab or double bolus eptifibatide as per investigator Abciximab or double bolus eptifibatide as per investigator discretion – dosing per FDA label, renal adjusted; continued discretion – dosing per FDA label, renal adjusted; continued for 12for 12 (abcx) or 12-18 (abcx) or 12-18 (eptif) (eptif)

* If pre randomization UFH administered, ACT is checked first* If pre randomization UFH administered, ACT is checked first** If pre randomization UFH administered, started 30’ after last bolus** If pre randomization UFH administered, started 30’ after last bolus

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)


UFH + GP IIb/IIIaN=1802

BivalirudinN=1800

R 1:1

RandomizedRandomized

* Biomarkers WNL and no DS >50% by core lab determination → 30 day FU only* Biomarkers WNL and no DS >50% by core lab determination → 30 day FU only

1-Year FU Eligible1-Year FU Eligible

30 Day FU30 Day FU N=1791 (99.4%) N=1787 (99.3%)

N=1774 N=1771

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

• • • • • • Lost to FU • • •Lost to FU • • •2626

46462222

5353

3602 pts with STEMI3602 pts with STEMI

• • • • • • Not true MI* • • •Not true MI* • • •2828 2929

1-Year FU1-Year FU N=1702 (95.9%) N=1696 (95.8%)

Baseline Characteristics (i)Baseline Characteristics (i)

UFH + GP IIb/IIIaUFH + GP IIb/IIIa(N=1802)(N=1802)

BivalirudinBivalirudin(N=1800)(N=1800)

Age (years)Age (years) 60.7 [52.9, 70.1]60.7 [52.9, 70.1] 59.8 [51.9, 69.5]59.8 [51.9, 69.5]

MaleMale 76.1%76.1% 77.1%77.1%

DiabetesDiabetes 17.3%17.3% 15.6%15.6%

HypertensionHypertension 55.2%55.2% 51.8%51.8%

HyperlipidemiaHyperlipidemia 42.7%42.7% 43.4%43.4%

Current smokingCurrent smoking 45.0%45.0% 47.2%47.2%

Prior MIPrior MI 11.4%11.4% 10.4%10.4%

Prior PCIPrior PCI 11.0%11.0% 10.5%10.5%

Prior CABGPrior CABG 2.6%2.6% 3.3%3.3%

*P=0.04*P=0.04

**

Stone GW et al. NEJM Stone GW et al. NEJM 2008;358:2218-302008;358:2218-30

Baseline Characteristics (ii)Baseline Characteristics (ii)

UFH + GP IIb/IIIaUFH + GP IIb/IIIa(N=1802)(N=1802)


Weight (kg)Weight (kg) 80 [71, 90]80 [71, 90] 80 [71, 90]80 [71, 90]

Chest pain – ER, hrsChest pain – ER, hrs 2.1 [1.3, 3.9]2.1 [1.3, 3.9] 2.2 [1.3, 4.0]2.2 [1.3, 4.0]

Killip class 2-4Killip class 2-4 8.5%8.5% 8.5%8.5%

Anterior MIAnterior MI 43.9%43.9% 41.2%41.2%

LVEFLVEF 50 [41, 59]50 [41, 59] 50 [45, 60]50 [45, 60]

Femoral a. accessFemoral a. access 93.6%93.6% 93.9%93.9%

Venous accessVenous access 8.4%8.4% 9.3%9.3%

Closure deviceClosure device 27.7%27.7% 28.3%28.3%

Aspiration catheterAspiration catheter 11.1%11.1% 11.9%11.9%


Study DrugsStudy DrugsUFH + GP IIb/IIIaUFH + GP IIb/IIIa

(N=1802)(N=1802)BivalirudinBivalirudin(N=1800)(N=1800)

UFH pre randomizationUFH pre randomization 65.6%65.6% 65.6%65.6%

Antithrombin in CCLAntithrombin in CCL

- UFH- UFH 98.9%98.9% 2.6%2.6%

- Bivalirudin- Bivalirudin 0.2%0.2% 96.9%96.9%

- Peak ACT- Peak ACT 264 [228, 320]264 [228, 320] 357 [300, 402]357 [300, 402]

GP IIb/IIIa in CCLGP IIb/IIIa in CCL 94.5%*94.5%* 7.2%*7.2%*

- Bail-out per protocol**- Bail-out per protocol** -- 4.4%4.4%

- Abciximab- Abciximab 49.9%49.9% 4.0%4.0%

- Eptifibatide- Eptifibatide 44.4%44.4% 3.1%3.1%

- Tirofiban- Tirofiban 0.2%0.2% 0.1%0.1%

*97.7% and 7.5% during PCI. ** For giant thrombus or refractory *97.7% and 7.5% during PCI. ** For giant thrombus or refractory no reflow after PCI. CCL = cardiac catheterization laboratoryno reflow after PCI. CCL = cardiac catheterization laboratory

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 = 0.95 = 0.95

Primary Endpoints at 30 Days

Diff = Diff = -3.3% [-5.0, -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 = 0.005 = 0.005

1 endpoint 1 endpoint


Major 2 endpoint

Aspirin and Thienopyridine UseAspirin and Thienopyridine UseA

nti

pla

tele

t ag

ent

use

(%

)A

nti

pla

tele

t ag

ent

use

(%

)

Regular* aspirin use (%)Regular* aspirin use (%) Regular* thieno. use (%)Regular* thieno. use (%)

*Taken >50% of days since last visit*Taken >50% of days since last visit

97.1%

98.1%

96.7%

97.3%

96.3%

97.0%

95.7%

96.1%

92.7%

93.7%

92.9%

93.3%

87.2%

87.8%

65.8%

68.0%

All P = NSAll P = NSAll P = NSAll P = NS

1-Year Net Adverse Clinical Events*1-Year Net Adverse Clinical Events*

*MACE or major bleeding (non CABG)*MACE or major bleeding (non CABG)

Number at riskNumber at riskBivalirudin aloneBivalirudin aloneHeparin+GPIIb/IIIaHeparin+GPIIb/IIIa

18001800 15591559 15141514 14831483 1343134318021802 14991499 14591459 14271427 12811281

NA

CE

(%

)N

AC

E (

%)

00

22

44

66

88

1010

1212

1414

1616

1818

2020

Time in MonthsTime in Months

00 11 22 33 44 55 66 77 88 99 1010 1111 1212

18.3%18.3%

15.7%15.7%

Diff [95%CI] = Diff [95%CI] = -2.6% [-5.1, -0.1]-2.6% [-5.1, -0.1]

HR [95%CI] = HR [95%CI] = 0.84 [0.71, 0.84 [0.71,

0.98] 0.98]

P=0.03P=0.03

Bivalirudin alone (n=1800)Bivalirudin alone (n=1800)

Heparin + GPIIb/IIIa (n=1802)Heparin + GPIIb/IIIa (n=1802)


18001800 16211621 16011601 15861586 1448144818021802 15441544 15321532 15151515 13681368

Maj

or

Ble

edin

g (

%)

Maj

or

Ble

edin

g (

%)

00

11

22

33

44

55

66

77

88

99

1010

1111

1212


00 11 22 33 44 55 66 77 88 99 1010 1111 1212

9.2%9.2%

5.8%5.8%Diff [95%CI] = Diff [95%CI] = -3.4% [-5.2, -1.7]-3.4% [-5.2, -1.7]22

HR [95%CI] =HR [95%CI] =

0.61 [0.48, 0.78] 0.61 [0.48, 0.78]

P<0.0001P<0.0001

1-Year Major Bleeding (non-CABG)1-Year Major Bleeding (non-CABG)



1-Year Bleeding Endpoints*1-Year Bleeding Endpoints*UFH + GP IIb/IIIaUFH + GP IIb/IIIa

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

Protocol Major, non CABG**Protocol Major, non CABG** 9.2%9.2% 5.8%5.8% <0.0001<0.0001

Protocol Major, AllProtocol Major, All 11.8%11.8% 7.7%7.7% <0.0001<0.0001

Protocol MinorProtocol Minor 16.5%16.5% 9.1%9.1% <0.0001<0.0001

Blood transfusionBlood transfusion 4.0%4.0% 2.7%2.7% 0.020.02

TIMI MajorTIMI Major 5.5%5.5% 3.6%3.6% 0.0050.005

TIMI MinorTIMI Minor 4.8%4.8% 3.0%3.0% 0.0080.008

TIMI Major or MinorTIMI Major or Minor 10.2%10.2% 6.5%6.5% <0.0001<0.0001

GUSTO LT*** or SevereGUSTO LT*** or Severe 0.7%0.7% 0.8%0.8% 0.700.70

GUSTO ModerateGUSTO Moderate 5.4%5.4% 3.7%3.7% 0.010.01

GUSTO LT or Sev or ModGUSTO LT or Sev or Mod 6.0%6.0% 4.4%4.4% 0.020.02

*Kaplan-Meier estimates; all CEC adjudicated, except protocol minor; *Kaplan-Meier estimates; all CEC adjudicated, except protocol minor; **Primary endpoint; ***Life threatening**Primary endpoint; ***Life threatening

1-Year Major Adverse CV Events*1-Year Major Adverse CV Events*




18001800 16271627 15791579 15441544 1394139418021802 16191619 15731573 15401540 13801380

MA

CE

(%

)M

AC

E (

%)

00112233445566778899

101011111212131314141515


00 11 22 33 44 55 66 77 88 99 1010 1111 1212

11.9%11.9%11.9%11.9%

Diff [95%CI] = Diff [95%CI] = 0.0% [-2.1, 2.2]0.0% [-2.1, 2.2]

HR [95%CI] = HR [95%CI] = 1.00 [0.83, 1.21] 1.00 [0.83, 1.21]

P=0.98P=0.98

*MACE = All cause death, reinfarction, ischemic TVR or stroke*MACE = All cause death, reinfarction, ischemic TVR or stroke

1-Year All-Cause Mortality

Number at riskBivalirudin aloneHeparin+GPIIb/IIIa

1800 1705 1684 1669 15201802 1678 1663 1646 1486

Mo

rtal

ity

(%)

0

1

2

3

4

5

Time in Months

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

Bivalirudin alone (n=1800)

Heparin + GPIIb/IIIa (n=1802) 4.8%

3.4%

Diff [95%CI] =

-1.5% [-2.8,-0.1]

HR [95%CI] =

0.69 [0.50, 0.97]

P=0.029

3.1%

2.1%

Δ = 1.0%

P=0.049

Δ = 1.4%

1-Year Mortality: 1-Year Mortality: Cardiac and Non CardiacCardiac and Non Cardiac




18001800 17051705 16841684 16691669 1520152018021802 16781678 16631663 16461646 14861486

CardiacCardiac

Non CardiacNon Cardiac

Mo

rtal

ity

(%)

Mo

rtal

ity

(%)

00

11

22

33

44

55


00 11 22 33 44 55 66 77 88 99 1010 1111 1212

3.8%

2.1%

1.3%1.1%

HR [95%CI] =0.57 [0.38, 0.84]

P=0.005

2.9%

1.8%

Δ = 1.1%P=0.03

Δ = 1.7%

1-Year Death or Reinfarction


18001800 16701670 16381638 16171617 1469146918021802 16481648 16171617 15931593 14311431

Dea

th o

r M

I (%

)D

eath

or

MI (

%)

00

11

22

33

44

55

66

77

88

99

1010


00 11 22 33 44 55 66 77 88 99 1010 1111 1212

8.5%

6.6%

HR [95%CI] =

0.77 [0.61, 0.98]0.77 [0.61, 0.98]

P=0.04

4.5%

3.8%

Δ = 0.7%

P=0.30

Δ = 1.9%



1-Year MACE Components*1-Year MACE Components*UFH + GPIUFH + GPI(N=1802)(N=1802)

BivalirudinBivalirudin(N=1800)(N=1800) HR [95%CI]HR [95%CI] P P

ValueValue

DeathDeath 4.8%4.8% 3.4%3.4% 0.69 [0.50,0.97]0.69 [0.50,0.97] 0.0290.029

- Cardiac- Cardiac 3.8%3.8% 2.1%2.1% 0.57 [0.38,0.84]0.57 [0.38,0.84] 0.0050.005

- Non cardiac- Non cardiac 1.1%1.1% 1.3%1.3% 1.14 [0.62,2.11]1.14 [0.62,2.11] 0.670.67

ReinfarctionReinfarction 4.4%4.4% 3.6%3.6% 0.81 [0.58,1.14]0.81 [0.58,1.14] 0.220.22

- Q-wave- Q-wave 2.1%2.1% 2.2%2.2% 1.06 [0.67,1.67]1.06 [0.67,1.67] 0.810.81

- Non Q-wave- Non Q-wave 2.7%2.7% 1.4%1.4% 0.53 [0.32,0.86]0.53 [0.32,0.86] 0.010.01

Death or reinfarctionDeath or reinfarction 8.5%8.5% 6.6%6.6% 0.77 [0.61,0.98]0.77 [0.61,0.98] 0.040.04

Ischemic TVRIschemic TVR 5.9%5.9% 7.2%7.2% 1.23 [0.94,1.60]1.23 [0.94,1.60] 0.120.12

- Ischemic TLR- Ischemic TLR 4.5%4.5% 6.0%6.0% 1.34 [1.00,1.80]1.34 [1.00,1.80] 0.0510.051

- Ischemic remote TVR- Ischemic remote TVR 2.0%2.0% 2.3%2.3% 1.13 [0.71,1.79]1.13 [0.71,1.79] 0.600.60

StrokeStroke 1.2%1.2% 1.1%1.1% 1.00 [0.54,1.85]1.00 [0.54,1.85] 0.990.99

*All Kaplan-Meier estimates, CEC adjudicated*All Kaplan-Meier estimates, CEC adjudicated

Adverse Events Between 30 Days and 1-YearAdverse Events Between 30 Days and 1-Year

UFH + GPIUFH + GPI(N=1802)(N=1802)


P P ValueValue

DeathDeath 1.8%1.8% 1.4%1.4% 0.310.31

- Cardiac- Cardiac 0.9%0.9% 0.4%0.4% 0.0460.046

- Non cardiac- Non cardiac 0.9%0.9% 1.0%1.0% 0.750.75

ReinfarctionReinfarction 2.8%2.8% 1.7%1.7% 0.040.04

Death or reinfarctionDeath or reinfarction 4.4%4.4% 3.0%3.0% 0.020.02

Ischemic TVRIschemic TVR 4.3%4.3% 4.7%4.7% 0.570.57

StrokeStroke 0.5%0.5% 0.4%0.4% 0.770.77

MACEMACE 7.3%7.3% 6.8%6.8% 0.520.52

Major bleeding (non CABG)Major bleeding (non CABG) 0.7%0.7% 0.8%0.8% 0.710.71

NACENACE 7.8%7.8% 7.3%7.3% 0.520.52

*Kaplan-Meier estimates, landmark analysis, CEC adjudicated*Kaplan-Meier estimates, landmark analysis, CEC adjudicated

1-Year Stent Thrombosis (ARC Definite/Probable)1-Year Stent Thrombosis (ARC Definite/Probable)


16111611 15251525 15041504 14861486 1356135615911591 14951495 14751475 14571457 13151315

Ste

nt

Th

rom

bo

sis

(%)

Ste

nt

Th

rom

bo

sis

(%)

00

11

22

33

44

55


00 11 22 33 44 55 66 77 88 99 1010 1111 1212



3.5%3.2%

HR [95%CI] =

1.11 [0.76, 1.63]

P=0.59

2.7%

2.2%

Δ = 0.5%P=0.31

Δ = 0.3%

1-Year Stent Thrombosis* (N=3,202)1-Year Stent Thrombosis* (N=3,202)UFH + GPIUFH + GPI(N=1591)(N=1591)


PPValueValue

ARC definite or probable, ≤24 hrsARC definite or probable, ≤24 hrs 0.3%0.3% 1.5%1.5% 0.00020.0002

- definite, ≤24 hours- definite, ≤24 hours 0.2%0.2% 1.4%1.4% <0.0001<0.0001

- probable, ≤24 hours- probable, ≤24 hours 0.1%0.1% 0.1%0.1% 1.01.0

ARC definite or probable, >1 - ≤30dARC definite or probable, >1 - ≤30d 1.9%1.9% 1.3%1.3% 0.140.14

- definite, >1 day - ≤30 days- definite, >1 day - ≤30 days 1.3%1.3% 1.1%1.1% 0.600.60

- probable, >1 day - ≤30 days- probable, >1 day - ≤30 days 0.6%0.6% 0.2%0.2% 0.0490.049

ARC definite or probable, >30d – 1yARC definite or probable, >30d – 1y 1.1%1.1% 0.9%0.9% 0.530.53

- definite, >30 days – 1-year- definite, >30 days – 1-year 1.0%1.0% 0.9%0.9% 0.650.65

- probable, >30 days – 1-year- probable, >30 days – 1-year 0.1%0.1% 0.1%0.1% 0.550.55

ARC definite or probable, ≤1-yearARC definite or probable, ≤1-year 3.2%3.2% 3.5%3.5% 0.590.59

- definite, ≤1-year- definite, ≤1-year 2.4%2.4% 3.2%3.2% 0.150.15

- probable, ≤1-year- probable, ≤1-year 0.8%0.8% 0.3%0.3% 0.060.06

*All Kaplan-Meier estimates except ≤24 hours; all CEC adjudicated*All Kaplan-Meier estimates except ≤24 hours; all CEC adjudicated


R 1:1

3602 pts with STEMI3602 pts with STEMI

Stent rand.eligible

UFH + GP IIb/IIIaN=1802

N=1479

TAXUSN=1111

EXPRESSN=368

BivalirudinN=1800

N=1527

TAXUSN=1146

EXPRESSN=381

R 3:1

R 3:1Stratified by 1st rand.

Interaction Between Drug and Stent RandomizationInteraction Between Drug and Stent Randomization30 Day Pharmacology Endpoints (N=3006)30 Day Pharmacology Endpoints (N=3006)

Kaplan-Meier estimatesKaplan-Meier estimatesUFH + GPIUFH + GPI(N=1479)(N=1479)

BivalirudinBivalirudin(N=1527)(N=1527) HR [95%CI]HR [95%CI] PPintint

NACE, all*NACE, all* 11.3%11.3% 8.7%8.7% 0.76 [0.60,0.95]0.76 [0.60,0.95] --

- TAXUS subgroup- TAXUS subgroup 11.5%11.5% 9.1%9.1% 0.78 [0.60,1.01]0.78 [0.60,1.01]0.950.95

- EXPRESS subgroup- EXPRESS subgroup 10.6%10.6% 7.4%7.4% 0.69 [0.42,1.11]0.69 [0.42,1.11]

Major bleeding, all**Major bleeding, all** 8.4%8.4% 5.1%5.1% 0.59 [0.44,0.78]0.59 [0.44,0.78] --



MACE, all***MACE, all*** 4.7%4.7% 4.9%4.9% 1.05 [0.75,1.45]1.05 [0.75,1.45] --



*MACE or major bleeding; **Protocol defined (non *MACE or major bleeding; **Protocol defined (non CABG); ***Death, reinfarction, stroke or ischemic TVRCABG); ***Death, reinfarction, stroke or ischemic TVR

Interaction Between Drug and Stent RandomizationInteraction Between Drug and Stent Randomization1-Year Stent Endpoints (N=3006)1-Year Stent Endpoints (N=3006)

Kaplan-Meier estimatesKaplan-Meier estimatesTAXUSTAXUS

(N=2257)(N=2257)EXPRESSEXPRESS(N=749)(N=749) HR [95%CI]HR [95%CI] PPintint

Ischemic TLR, allIschemic TLR, all 4.5%4.5% 7.5%7.5% 0.59 [0.43,0.83]0.59 [0.43,0.83] --

- UFH + GPI subgroup- UFH + GPI subgroup 3.3%3.3% 7.9%7.9% 0.42 [0.25,0.68]0.42 [0.25,0.68]0.170.17

- Bivalirudin subgroup- Bivalirudin subgroup 5.6%5.6% 7.1%7.1% 0.78 [0.50,1.24]0.78 [0.50,1.24]

Safety MACE, all*Safety MACE, all* 8.1%8.1% 8.0%8.0% 1.02 [0.76, 1.36]1.02 [0.76, 1.36] --



Binary restenosis, all**Binary restenosis, all** 10.0%10.0% 22.9%22.9% 0.44 [0.33, 0.57]0.44 [0.33, 0.57] --



*Death, reinfarction, stroke or stent thrombosis*Death, reinfarction, stroke or stent thrombosis**1081 lesions in the TAXUS group, 332 in the EXPRESS group**1081 lesions in the TAXUS group, 332 in the EXPRESS group

1-Year Mortality (All-Cause)1-Year Mortality (All-Cause)Heparin + GPI / TAXUS (n=1111)Heparin + GPI / TAXUS (n=1111)Heparin + GPI / EXPRESS (n=368)Heparin + GPI / EXPRESS (n=368)Bivalirudin / TAXUS (n=1146)Bivalirudin / TAXUS (n=1146)Bivalirudin / EXPRESS (n=381)Bivalirudin / EXPRESS (n=381)

4.0%4.0%

3.0%3.0%

PPintint = 0.75 = 0.75

4.6%4.6%

2.6%2.6%

Mo

rtal

ity

(%)

Mo

rtal

ity

(%)

00

11

22

33

44

55


00 11 22 33 44 55 66 77 88 99 1010 1111 1212

LimitationsLimitations Open label designOpen label design

– Potential bias was mitigated by high Potential bias was mitigated by high protocol procedure compliance and use protocol procedure compliance and use of blinded clinical event adjudication of blinded clinical event adjudication committees and core laboratoriescommittees and core laboratories

Underpowered for low frequency safety Underpowered for low frequency safety endpoints and subgroup interactionsendpoints and subgroup interactions

– All such observations should be All such observations should be considered hypothesis-generatingconsidered hypothesis-generating

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

trial of pts with STEMI undergoing a primary trial of pts with STEMI undergoing a primary PCI management strategy, bivalirudin PCI management strategy, bivalirudin monotherapy compared to UFH plus the monotherapy compared to UFH plus the routine use of GP IIb/IIIa inhibitors resulted in:routine use of GP IIb/IIIa inhibitors resulted in:

– A significant 16% reduction in the 1-year rate A significant 16% reduction in the 1-year rate of composite net adverse clinical events of composite net adverse clinical events

– A significant 39% reduction in the 1-year rate A significant 39% reduction in the 1-year rate of major bleeding of major bleeding

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

of pts with STEMI undergoing a primary PCI of pts with STEMI undergoing a primary PCI management strategy, bivalirudin monotherapy management strategy, bivalirudin monotherapy compared to UFH plus the routine use of GP compared to UFH plus the routine use of GP IIb/IIIa inhibitors resulted in:IIb/IIIa inhibitors resulted in:

– Significant 31% and 43% reductions in the Significant 31% and 43% reductions in the

1-year rates of all-cause and cardiac mortality 1-year rates of all-cause and cardiac mortality

(absolute 1.4% and 1.7% reductions), (absolute 1.4% and 1.7% reductions), with non with non

significantly different rates of reinfarction, stent significantly different rates of reinfarction, stent

thrombosis, stroke and TVR at 1-year thrombosis, stroke and TVR at 1-year

Clinical ImplicationsClinical Implications HORIZONS has demonstrated that the HORIZONS has demonstrated that the

prevention of hemorrhagic complications prevention of hemorrhagic complications

after primary PCI in STEMI results in after primary PCI in STEMI results in

improved early and late survival improved early and late survival

– Optimal drug selection and technique to Optimal drug selection and technique to

minimize bleeding are essential to minimize bleeding are essential to

enhance outcomes for pts undergoing enhance outcomes for pts undergoing

interventional therapiesinterventional therapies

A Prospective, Randomized Comparison of Bivalirudin vs. Heparin Plus Glycoprotein IIb/IIIa...

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