Horizons 1Year Pharm

8/14/2019 Horizons 1Year Pharm

1/33

A Prospective, Randomized Comparison ofA Prospective, Randomized Comparison of

Bivalirudin vs. Heparin Plus GlycoproteinBivalirudin vs. Heparin Plus Glycoprotein

IIb/IIIa Inhibitors During Primary Angioplasty inIIb/IIIa Inhibitors During Primary Angioplasty in

Acute Myocardial InfarctionAcute Myocardial Infarction

One Year Results One Year Results

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


2/33

Background

Numerous studies have demonstrated a strongNumerous studies have demonstrated a strong

association between hemorrhagic complications andassociation between hemorrhagic complications andsubsequent 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 ptsamong high risk pts

with STEMI undergoing primary PCI, randomizationwith STEMI undergoing primary PCI, randomization

to bivalirudin monotherapy compared to UFH + GPIto 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 significantlycytopenia, and blood transfusions; non significantly

different rates of reinfarction, stent thrombosis anddifferent 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 isWhether these benefits are maintained at 1-year is

unknownunknown


3/33

HHarmonizingarmonizing OOutcomes withutcomes with RRevascularevascularizizatiationon andand SStents intents 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, thienopyridineR

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


4/33


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, thienopyridineR

1:1

Pharmacology ArmPharmacology Arm

Primary 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


5/33

Study Medications (i)Study Medications (i) Unfractionated heparinUnfractionated heparin

60 U/kg IV*; subsequent boluses titrated by nomogram60 U/kg IV*; subsequent boluses titrated by nomogramto ACT 200-250 secs; terminated at procedure endto ACT 200-250 secs; terminated at procedure end

unless prolonged antithrombin neededunless prolonged antithrombin needed

BivalirudinBivalirudin

Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titratedBolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated

to ACT; terminated at procedure end unless prolongedto 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 giantRoutine 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 perAbciximab or double bolus eptifibatide as per

investigator discretion dosing per FDA label, renalinvestigator discretion dosing per FDA label, renal

adjusted; continued for 12adjusted; continued for 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


6/33

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


7/33

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 adverse

cardiovascular eventscardiovascular events(major secondary endpoint)(major secondary endpoint)


8/33

HH

armonizingarmonizing

OO

utcomes withutcomes with

RR

evascularevascular

iziz

atiati

onon

andand

SS

tents intents in

AMIAMI

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

4646

2222

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%)


9/33

Baseline Characteristics (i)Baseline Characteristics (i)

UFH + GP IIb/IIIaUFH + GP IIb/IIIa

(N=1802)(N=1802)


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


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Baseline Characteristics (ii)Baseline Characteristics (ii)


(N=1802)(N=1802)


(N=1800)(N=1800)

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%



11/33

Study DrugsStudy Drugs


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


12/33

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


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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


14/33

Aspirin and Thienopyridine UseAspirin and Thienopyridine Use

Antiplateletagentuse

(%)

Antiplateletagentuse

(%)

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


15/33

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 risk

Bivalirudin aloneBivalirudin alone

Heparin+GPIIb/IIIaHeparin+GPIIb/IIIa

18001800 15591559 15141514 14831483 13431343

18021802 14991499 14591459 14271427 12811281

NA

CE(%)

NA

CE(%)

00

22

44

66

88

1010

1212

1414

16161818

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)


16/33




18001800 16211621 16011601 15861586 14481448

18021802 15441544 15321532 15151515 13681368

MajorB

leeding(%)

MajorB

leeding(%)

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


17/33

1-Year Bleeding Endpoints*1-Year Bleeding Endpoints*


(N=1802)(N=1802)


(N=1800)(N=1800)

P ValueP Value

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


18/33

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






18001800 16271627 15791579 15441544 13941394

18021802 16191619 15731573 15401540 13801380

MA

CE(%)

MA

CE(%)

00

11

22

33

44

5566

77

88

99

1010

1111

12121313

1414

1515


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


19/33

1-Year All-Cause Mortality

Number at risk

Bivalirudin alone

Heparin+GPIIb/IIIa

1800 1705 1684 1669 1520

1802 1678 1663 1646 1486

Mor

tality(%)

0

1

2

3

4

5

Time in Months0 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%

= 1.0%

P=0.049

= 1.4%


20/33

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






18001800 17051705 16841684 16691669 15201520

18021802 16781678 16631663 16461646 14861486

CardiacCardiac

Non CardiacNon Cardiac

Mor

tality(%)

Mor

tality(%)

00

11

22

33

44

55

Time in MonthsTime in Months00 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%

= 1.1%

P=0.03

= 1.7%


21/33

1-Year Death or Reinfarction




18001800 16701670 16381638 16171617 14691469

18021802 16481648 16171617 15931593 14311431

Death

orMI(%)

Death

orMI(%)

00

11

22

33

44

55

66

77

8899

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%

= 0.7%

P=0.30

= 1.9%




22/33

1-Year MACE Components*1-Year MACE Components*

UFH + GPIUFH + GPI


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

PP

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


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

UFH + GPIUFH + GPI

(N=1802)(N=1802)


(N=1800)(N=1800)

P ValueP Value

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


24/33

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




16111611 15251525 15041504 14861486 13561356

15911591 14951495 14751475 14571457 13151315

StentTh

rombosis(%)

StentTh

rombosis(%)

00

11

22

33

44

55

Time in MonthsTime in Months00 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%

= 0.5%

P=0.31

= 0.3%


25/33

1-Year Stent Thrombosis* (N=3,202)1-Year Stent Thrombosis* (N=3,202)

UFH + GPIUFH + GPI


(N=1611)(N=1611)PP

ValueValue

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% 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


26/33


R

1:1

3602 pts with STEMI3602 pts with STEMI

Stent rand.

eligible

UFH + GP IIb/IIIaN=1802

N=1479

TAXUS

N=1111

EXPRESS

N=368

BivalirudinN=1800

N=1527

TAXUS

N=1146

EXPRESS

N=381

R3:1

R3:1

Stratified by 1st rand.


27/33

Interaction Between Drug and Stent RandomizationInteraction Between Drug and Stent Randomization

30 Day Pharmacology Endpoints (N=3006)30 Day Pharmacology Endpoints (N=3006)

Kaplan-Meier estimatesKaplan-Meier estimates

UFH + GPIUFH + GPI

(N=1479)(N=1479)


(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 subgroup10.6%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] --


- EXPRESS subgroup- EXPRESS subgroup 7.1%7.1% 4.2%4.2% 0.58 [0.31,1.09]0.58 [0.31,1.09]

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


- EXPRESS subgroup- EXPRESS subgroup 4.9%4.9% 4.2%4.2% 0.86 [0.44,1.69]0.86 [0.44,1.69]

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

S


28/33

Interaction Between Drug and Stent RandomizationInteraction Between Drug and Stent Randomization

1-Year Stent Endpoints (N=3006)1-Year Stent Endpoints (N=3006)

Kaplan-Meier estimatesKaplan-Meier estimates

TAXUSTAXUS

(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 subgroup5.6%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] --


- Bivalirudin subgroup- Bivalirudin subgroup 8.0%8.0% 7.2%7.2% 1.17 [0.83,1.64]1.17 [0.83,1.64]

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] --


- Bivalirudin subgroup- Bivalirudin subgroup 9.2%9.2% 26.7%26.7% 0.34 [0.24,0.49]0.34 [0.24,0.49]

*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


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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%

Mortality(%)

Mortality(%)

00

11

22

33

44

55


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


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LimitationsLimitations

Open label designOpen label design

Potential bias was mitigated by highPotential bias was mitigated by high

protocol procedure compliance and useprotocol procedure compliance and use

of blinded clinical event adjudicationof blinded clinical event adjudication

committees and core laboratoriescommittees and core laboratories

Underpowered for low frequency safetyUnderpowered for low frequency safety

endpoints and subgroup interactionsendpoints and subgroup interactions

All such observations should beAll such observations should be

considered hypothesis-generatingconsidered hypothesis-generating


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ConclusionsConclusions

In this large scale, prospective, randomizedIn this large scale, prospective, randomized

trial of pts with STEMI undergoing a primarytrial of pts with STEMI undergoing a primary

PCI management strategy, bivalirudinPCI management strategy, bivalirudin

monotherapy compared to UFH plus themonotherapy 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 rateA significant 16% reduction in the 1-year rate

of composite net adverse clinical eventsof composite net adverse clinical events

A significant 39% reduction in the 1-year rateA significant 39% reduction in the 1-year rate

of major bleedingof major bleeding


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ConclusionsConclusions

In this large scale, prospective, randomizedIn this large scale, prospective, randomized

trial of pts with STEMI undergoing a primarytrial of pts with STEMI undergoing a primary

PCI management strategy, bivalirudinPCI management strategy, bivalirudin

monotherapy compared to UFH plus themonotherapy compared to UFH plus the

routine use of GP IIb/IIIa inhibitors resulted in:routine use of GP IIb/IIIa inhibitors resulted in:

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

1-year rates of all-cause and cardiac1-year rates of all-cause and cardiac

mortality (absolute 1.4% and 1.7% reductions),mortality (absolute 1.4% and 1.7% reductions),with non significantly different rates ofwith non significantly different rates of

reinfarction, stent thrombosis, stroke and TVRreinfarction, stent thrombosis, stroke and TVR

at 1-yearat 1-year


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Clinical ImplicationsClinical Implications

HORIZONS has demonstrated that theHORIZONS has demonstrated that the

prevention of hemorrhagic complicationsprevention of hemorrhagic complications

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

improved early and late survivalimproved early and late survival

Optimal drug selection and techniqueOptimal drug selection and technique

to minimize bleeding are essential toto minimize bleeding are essential to

enhance outcomes for pts undergoingenhance outcomes for pts undergoing

interventional therapiesinterventional therapies

Documents

Horizons 1Year Pharm