two-year follow-up from a prospective, randomized trial of heparin plus glycoprotein iib/iiia...

Two-Year Follow-up from a Prospective, Randomized Trial of Heparin Plus Glycoprotein IIb/IIIa Inhibitors vs.

Bivalirudin and Paclitaxel-Eluting vs. Bare-Metal Stents in STEMI

Gregg W. Stone MDFor the HORIZONS-AMI Investigators

Disclosures Gregg W. Stone MD

– Advisory Board for Boston Scientific and Abbott Vascular

– Research support from The Medicines Company

Background At 1-year in the 2x2 factorial prospective,

randomized HORIZONS-AMI trial:

– Bivalirudin alone compared to heparin plus GPIIb/IIIa inhibitors resulted in comparable rates of MI and stent thrombosis, with significantly reduced rates of major bleeding and mortality (all-cause and cardiac)

– TAXUS PES compared to EXPRESS BMS reduced clinical and angiographic restenosis, with comparable rates of death, reinfarction and stent thrombosis

Whether these findings are sustained at 2 years has not been reported

Harmonizing Outcomes with Revascularization and Stents in AMI

3602 pts with STEMI with symptom onset ≤12 hours

Emergent angiography, followed by triage to…

Primary PCICABG – Medical Rx–

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

Bivalirudin monotherapy(± provisional GP IIb/IIIa)

Aspirin, thienopyridine R 1:1

3006 pts eligible for stent randomization R 3:1

Bare metal EXPRESS stentPaclitaxel-eluting TAXUS stent

Clinical FU at 30 days, 6 months, 1 year, and thenyearly through 5 years; angio FU at 13 months

Clinical FU at 30 days, 6 months, 1 year, and thenyearly through 5 years; angio FU at 13 months


UFH + GP IIb/IIIaN=1802

BivalirudinN=1800

R 1:1

Randomized

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

1-Year FU Eligible

2-Year FU N=1672 (94.4%) N=1693 (95.6%)

N=1772 N=1771• • • Withdrew • • •

• • • Lost to FU • • •

26

13

22

19

3602 pts with STEMI

• • • Not true MI* • • •30 29

1-Year FU N=1733 (97.8%) N=1730 (97.7%)• • • Withdrew • • •

• • • Lost to FU • • •

13

48

12

25

0

20

40

60

80

100

Discharge 30 Days 6 Months 1 Year 2 Year

An

tip

late

let

agen

t u

se (

%)

0

20

40

60

80

100


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

*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%

87.1%

87.7%

65.6%

67.8%

All P = NSAll P = NS

Pharmacology Randomization: Aspirin and Thienopyridine Use

35.8%

32.7%

95.2%

95.2%

Bivalirudin alone (n=1800)Heparin + GPIIb/IIIa (n=1802)

Two-Year Major Bleeding (non-CABG)*

*Intracranial intraocular, retroperitoneal, access site bleed requiring intervention/surgery, hematoma ≥5 cm, hgb ↓ ≥3g/dL with or ≥4g/dL w/o overt source; reoperation for bleeding; or blood product transfusion

1800 1603 1571 1540 12901802 1535 1505 1453 1218

p<0.001

HR [95%CI]=0.64 [0.51, 0.81]

6.4%

9.6%M

ajo

r B

leed

ing

(%

)

0

2

4

6

8

10

12

Months

0 3 6 9 12 15 18 21 24

Bivalirudin alone (n=1800)

Heparin + GPIIb/IIIa (n=1802)

Number at riskBivalirudin aloneHeparin+GPIIb/IIIa

Two-Year Major Adverse CV Events*

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

1800 1584 1513 1400 11591802 1577 1518 1399 1142

p= 0.99

HR [95%CI]=1.00 [0.86, 1.17]

18.7%

18.8%M

AC

E (

%)

0

4

8

12

16

20

24

Months

0 3 6 9 12 15 18 21 24




Two-Year All-Cause Mortality

1800 1690 1658 1627 13591802 1669 1637 1579 1324

p= 0.049

HR [95%CI]=0.75 [0.56, 1.00]

4.6%

6.1%

All-

Ca

use

Mo

rta

lity

(%

)

0

1

2

3

4

5

6

7

8

0 3 6 9 12 15 18 21 24



Months

3.1%

2.1% 1 monthP=0.049


1800 1690 1658 1627 13591802 1669 1637 1579 1324

p= 0.005

HR [95% CI]=0.59 [0.41, 0.86]

2.5%

4.2%

Cardiac Mortality

0

1

2

3

4

5

Months

0 3 6 9 12 15 18 21 24

Two-Year Mortality: Cardiac and Non Cardiac


Mo

rtal

ity

(%)

Bivalirudin alone (n=1800)Heparin + GPIIb/IIIa (n=1802)

1800 1690 1658 1627 13591802 1669 1637 1579 1324

p= 0.69

HR [95% CI]=1.10 [0.69, 1.76]

2.2% 2.0%

Non Cardiac Mortality

0

1

2

3

4

5

Months

0 3 6 9 12 15 18 21 24

Two-Year Reinfarction

1800 1644 1603 1554 12981802 1621 1576 1500 1244

p= 0.038

HR [95%CI]=0.75 [0.56, 0.98]

5.1%

6.9%

Rei

nfa

rcti

on

(%

)

0

1

2

3

4

5

6

7

8

9

10

0 3 6 9 12 15 18 21 24




Months

Two-Year Death or Reinfarction

1800 1644 1603 1554 12981802 1621 1576 1500 1244

p= 0.007

HR [95%CI]=0.75 [0.61, 0.93]

9.1%

12.0%D

ea

th o

r re

infa

rcti

on

(%

)

0

3

6

9

12

15

0 3 6 9 12 15 18 21 24




Months

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

Bivalirudin(N=1800)

HR [95%CI]P

Value

Death 6.1% 4.6% 0.75 [0.56,1.00] 0.049

- Cardiac 4.2% 2.5% 0.59 [0.41,0.86] 0.005

- Non cardiac 2.0% 2.2% 1.10 [0.69,1.76] 0.69

Reinfarction 6.9% 5.1% 0.75 [0.56,0.98] 0.038

- Q-wave 3.4% 3.1% 0.92 [0.63,1.34] 0.67

- Non Q-wave 3.9% 2.2% 0.56 [0.37,0.83] 0.004

Death or reinfarction 12.0% 9.1% 0.75 [0.61,0.93] 0.007

Ischemic TVR 11.0% 12.7% 1.17 [0.96,1.42] 0.12

- Ischemic TLR 8.7% 10.2% 1.19 [0.95,1.49] 0.12

- Ischemic remote TVR 3.8% 4.5% 1.19 [0.85,1.66] 0.31

Stroke 1.7% 1.5% 0.88 [0.52,1.52] 0.65

*All Kaplan-Meier estimates, CEC adjudicated

Adverse Events Between 30 Days and 2-Years

UFH + GPI(N=1802)

Bivalirudin(N=1800) P Value

Death 3.1% 2.6% 0.41

- Cardiac 1.3% 0.7% 0.08

- Non cardiac 1.8% 1.9% 0.76

Reinfarction 5.2% 3.2% 0.005

Death or reinfarction 7.9% 5.5% 0.006

Ischemic TVR 9.5% 10.2% 0.53

Stroke 1.0% 0.7% 0.41

MACE 14.7% 13.9% 0.53

Major bleeding (non CABG) 1.0% 1.3% 0.55

NACE 15.2% 14.6% 0.63

*Kaplan-Meier estimates, landmark analysis, CEC adjudicated

2-Year Stent Thrombosis(ARC Definite/Probable)

1611 1509 1475 1444 12061591 1482 1449 1386 1153

p= 0.73

HR [95%CI]=0.94 [0.67, 1.32]

4.3% 4.6%

Ste

nt

Th

rom

bo

sis

(%

)

0

1

2

3

4

5

6

0 3 6 9 12 15 18 21 24




Months

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

UFH + GPI(N=1591)

Bivalirudin(N=1611)

PValue

ARC definite or probable, ≤24 hours 0.3% 1.5% <0.001

- definite, ≤24 hours 0.2% 1.5% <0.001

- probable, ≤24 hours 0.1% 0.0% 0.32

ARC definite or probable, >24h – 2y 4.4% 2.9% 0.03

- definite, >24 hours – 2 year 3.6% 2.6% 0.11

- probable, >24 hours – 2 year 0.8% 0.3% 0.08

ARC definite or probable, ≤2 years 4.6% 4.3% 0.73

- definite, ≤2-year 3.8% 3.9% 0.71

- probable, ≤2-year 0.8% 0.3% 0.05

*All Kaplan-Meier estimates; all CEC adjudicated

TAXUS DESN=2257

EXPRESS BMSN=749Randomized

1 year FU N=2223 (98.5%) N=729 (97.3%)

• • • Withdrew • • •

• • • Lost to FU • • •

18

16

7

13

R 3:1

3006 pts eligible for stent rand.

Primary Medical Rx 193Primary CABG 62Deferred PCI 2

Index PCI, not eligible - PTCA only 119 - Stented 220

UFH + GPI (n=1802)

Bivalirudin (n=1800)

R 1:13602 pts with STEMI

93.1% of all stented pts were randomized

2 year FU N=2157 (95.6%) N=715 (95.5%)

• • • Withdrew • • •

• • • Lost to FU • • •

12

54

6

8

13 month angiographic FU 942 307


Stent Randomization: Aspirin and Thienopyridine Use

0

20

40

60

80

100


An

tip

late

let

agen

t u

se (

%)

0

20

40

60

80

100


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

*Taken >50% of days since last visit

99.1%

98.6%

98.5%

98.3% 97.5%

98.3%

97.1%

97.5%99.4%

98.9%

98.7%

97.8%

94.6%

87.5% 72.8%

63.8%

P<0.001

P<0.001

97.5%

96.2%

P=0.004

36.8%

30.7%

All P=NS

TAXUS DES (n=2257) EXPRESS BMS (n=749)

Primary Efficacy Endpoint: Ischemic TLR

P<0.001

HR [95%CI]=0.58 [0.44, 0.76]

6.8%

11.6%Is

chem

ic T

LR

(%

)

0

3

6

9

12

15 TAXUS DES (n=2257)

EXPRESS BMS (n=749)

2257 2105 2041 1949 1618

749 677 654 611 507

0 3 6 9 12 15 18 21 24

Number at riskTAXUS DESEXPRESS BMS

Months

Primary Efficacy Endpoint: Ischemic TLR

2257 2105 2041 1949 1618

749 677 654 611 507

P<0.001

HR [95%CI]=0.58 [0.44, 0.76]

6.8%

11.6%Is

chem

ic T

LR

(%

)

0

3

6

9

12

15

0 3 6 9 12 15 18 21 24

TAXUS DES (n=2257)

EXPRESS BMS (n=749)


Months

p= 0.002

1-yr HR [95%CI]=

0.60 [0.43, 0.84]

13 mo angio FU

Secondary Efficacy Endpoint: Ischemic TVR

P<0.001

p= 0.007

HR [95%CI]=0.66 [0.51, 0.84]

1-yr HR [95%CI]=

0.66 [0.49, 0.89]

8.9%

13.3%Is

chem

ic T

VR

(%

)

0

3

6

9

12


EXPRESS BMS (n=749)

2257 2085 2016 1912 1587

749 671 646 600 498

0 3 6 9 12 15 18 21 24


Months

Primary Safety Endpoint: Safety MACE*

* Safety MACE = death, reinfarction, stroke, or stent thrombosis

p= 0.90

HR [95%CI]=0.98 [0.77, 1.26]

11.0%11.2%

Saf

ety

MA

CE

(%

)

0

2

4

6

8

10

12

14


EXPRESS BMS (n=749)

2257 2094 2035 1958 1619

749 684 667 645 530

0 3 6 9 12 15 18 21 24


Months

Two-Year All-Cause Mortality

p= 0.32

HR [95%CI]=0.83 [0.57, 1.20]

4.3%

5.2%

All-

Ca

use

Mo

rta

lity

(%

)

0

1

2

3

4

5

6

7


EXPRESS BMS (n=749)

2257 2170 2134 2083 1742

749 714 700 680 566

0 3 6 9 12 15 18 21 24


Months

Two-Year Cardiac Mortality

p= 0.43

HR [95%CI]=0.83 [0.52, 1.33]

2.7%

3.3%

Ca

rdia

c M

ort

alit

y (

%)

0

1

2

3

4

5

6

0 3 6 9 12 15 18 21 24

TAXUS DES (n=2257)

EXPRESS BMS (n=749)

2257 2170 2134 2083 1742

749 714 700 680 566

0 3 6 9 12 15 18 21 24


Months

Two-Year Reinfarction

p= 0.64

HR [95%CI]=0.92 [0.65, 1.30]

5.7% 6.1%

Rei

nfa

rcti

on

(%

)

0

1

2

3

4

5

6

7

8

9

10

0 3 6 9 12 15 18 21 24

TAXUS DES (n=2257)

EXPRESS BMS (n=749)

2257 2118 2062 1998 1645

749 690 674 651 538

0 3 6 9 12 15 18 21 24


Months

Two-Year Stent Thrombosis(ARC Definite or Probable)

p= 0.99

HR [95%CI]=1.00 [0.66, 1.51]

4.1% 4.1%

Ste

nt

Th

rom

bo

sis

(%)

0

1

2

3

4

5


EXPRESS BMS (n=749)

0 3 6 9 12 15 18 21 24

2238 2108 2061 1998 1661

744 696 681 661 547


Months

2-Year Stent Thrombosis*TAXUS

(N=2238)EXPRESS(N=744)

PValue

ARC definite or probable, ≤30 days 2.2% 2.7% 0.45

- definite, ≤30 days 1.8% 2.3% 0.45

- probable, ≤30 days 0.4% 0.4% 0.86

ARC definite or probable, >30d - 1y 1.0% 0.7% 0.45

- definite, >30 days – 1-year 0.9% 0.7% 0.58

- probable, >30 days – 1-year 0.1% 0.0% 0.42

ARC definite or probable, 1y - 2y 1.1% 0.7% 0.40

- definite, 1-year – 2-year 1.1% 0.6% 0.27

- probable, 1-year – 2-year 0.0% 0.1% 0.41

ARC definite or probable, ≤2 years 4.1% 4.1% 0.99

- definite, ≤2-year 3.7% 3.6% 0.96

- probable, ≤2-year 0.5% 0.6% 0.88

*All Kaplan-Meier estimates; all CEC adjudicated

Two Year Composite Safety Endpoints*TAXUS


HR [95%CI] P Value

Safety MACE 11.0% 11.2% 0.98 [0.77,1.26] 0.89

Death, all-cause 4.3% 5.2% 0.83 [0.57,1.20] 0.32

- Cardiac 2.7% 3.3% 0.83 [0.52,1.33] 0.43

- Non cardiac 1.6% 2.0% 0.82 [0.44,1.52] 0.53

Reinfarction 5.7% 6.1% 0.92 [0.65,1.30] 0.64

- Q-wave 3.1% 2.9% 1.06 [0.65,1.72] 0.83

- Non Q-wave 3.0% 3.2% 0.91 [0.57,1.47] 0.71

Stent thrombosis 4.1% 4.1% 1.00 [0.66,1.51] 0.99

- ARC definite 3.7% 3.6% 1.01 [0.65,1.57] 0.96

- ARC probable 0.6% 0.5% 0.91 [0.29,2.87] 0.88

Stroke 1.4% 1.1% 1.24 [0.57,2.70] 0.59

*Kaplan-Meier estimates

Adverse Events Between 1 and 2 Years*TAXUS


HR [95%CI]P

Value

Safety MACE 3.4% 3.5% 0.96 [0.60,1.53] 0.86

Death, all-cause 0.8% 1.8% 0.46 [0.22,0.97] 0.04

- Cardiac 0.3% 0.6% 0.49 [0.14,1.74] 0.26

- Non cardiac 0.5% 1.2% 0.45 [0.18,1.12] 0.08

Reinfarction 2.3% 1.5% 1.58 [0.80,3.12] 0.19

- Q-wave 1.1% 0.9% 1.20 [0.49,2.97] 0.69

- Non Q-wave 1.4% 0.6% 2.30 [0.81,6.55] 0.11

Stent thrombosis 1.1% 0.7% 1.51 [0.58,3.98] 0.40

- ARC definite 1.1% 0.6% 1.81 [0.62,5.25] 0.27

- ARC probable 0.05% 0.14% 0.33 [0.02,5.24] 0.41

Stroke 0.4% 0.5% 0.87 [0.23,3.29] 0.84

Ischemic TLR 2.6% 4.7% 0.55 [0.35,0.85] 0.006

Ischemic TVR 3.4% 5.2% 0.65 [0.43,0.97] 0.03

*Kaplan-Meier estimates

Two-Year Mortality (All-Cause)

Pint = 0.73

4.7%

6.1%

3.8% 4.3%

All-

Cau

se M

ort

alit

y (%

)

0

1

2

3

4

5

6

7

8

Months

0 3 6 9 12 15 18 21 24

Heparin + GPI / TAXUS (n=1111)Heparin + GPI / EXPRESS (n=368)Bivalirudin / TAXUS (n=1146)Bivalirudin / EXPRESS (n=381)

Conclusions: Pharmacology Randomization

In this large-scale, prospective, randomized trial of pts with STEMI undergoing primary PCI, at 2 years initial treatment with bivalirudin alone compared to heparin plus GPIIb/IIIa inhibitors resulted in:

– A significant 36% reduction in major bleeding and a significant 25% reduction in reinfarction, with comparable rates of stent thrombosis, TVR and stroke

– A significant 41% reduction in cardiac mortality and a 25% reduction in all-cause mortality, the latter representing 15 lives saved per 1000 patients treated with bivalirudin (NNT = 67 to save 1 life)

Conclusions: Stent Randomization Among pts with STEMI undergoing primary PCI, at 2 years

the implantation of TAXUS paclitaxel-eluting EXPRESS stents compared to EXPRESS bare metal stents resulted in:

– Significant 42% and 34% reductions in ischemic TLR and TVR respectively, with no evidence of late catch-up

– Comparable rates of all-cause and cardiac mortality, reinfarction and stent thrombosis, with no safety concerns apparent

TLR, TVR and mortality were reduced between 1 and 2 years in pts treated with TAXUS EXPRESS compared to EXPRESS BMS, observations that should be considered hypothesis generating given their borderline significance and possible influence of routine angiographic follow-up

two-year follow-up from a prospective, randomized trial of heparin plus glycoprotein iib/iiia...

Documents

year probable

year fu n

year definite

year fu eligible

days probable

days definite

fu lost

bivalirudin n