HORIZONS –AMI A Prospective, Multicenter Randomized Trial of Heparin Plus GPIIb/IIIa Inhibitors...

HORIZONS –AMI

A Prospective, Multicenter Randomized Trial of Heparin Plus GPIIb/IIIa Inhibitors vs. Bivalirudiin STEMI: Final 3-year results from the HORIZONS-AMI Trial

Stone GW et al. Lancet 2011: Published online June 13, DOI:10.1016/S0140-6736(11)60764-2

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)

● 3-year results are assessed in this report

– Prespecified endpoints in the pharmacology arm at 3 years included death, reinfarction, ischemia driven target lesion revascularization, stroke, and the composite of these (MACE); non-CABG major bleeding and the composite of all net adverse clinical events (NACE).

Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

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 3 years; angio FU at 13 months

Clinical FU at 30 days, 6 months, 1 year, and thenyearly through 3 years; angio FU at 13 months

Stone, GW N Engl J Med 2008;358:2218-30.

Harmonizing Outcomes with Revascularization and Stents in AMI

R 1:1

Randomized

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

1-Year FU Eligible

3-Year FU

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

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

2626

4646

2222

5353

3602 pts with STEMI

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

1-Year FU

UFH + GP IIb/IIIaN=1802

BivalirudinN=1800

N=1628 N=1634

N=1774 N=1771

N=1702 N=1696

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

• • • • • • Lost to FU • • •Lost to FU • • •1717

5757

1818

4444


0

20

40

60

80

100

D/C 30 D 6 Mo 1 Yr 2 Yr 3 Yr

Ant

ipla

tele

t age

nt u

se (

%)

0

20

40

60

80

100

D/C 30 D 6 Mo 1 Yr 2 Yr 3 Yr

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

*Taken >50% of days since last visit

98%

97%

97%

97%

97%

96%

96%

96%

94%

93.%

93%

93%

88%

87%

68%

66%

All P = NS

All P = NS

Pharmacology Randomization: Aspirin and Thienopyridine Use

33%

36%

95%

95%

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

94%

95%

26%

27%


3-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

12

00

4

6

8

10

0.64 (0.51, 0.80)0.64 (0.51, 0.80)

2

0

1212 1515 1818 2121 2424 2727 3030 3333 3636

P=0.0001P=0.0001

3-yr HR (95%CI)3-yr HR (95%CI)

6.9%6.9%

10.5%10.5%

Maj

or B

leed

ing

(%)

Months

33 66 99

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

9.4%

6.0%


3-Year Cardiac Mortality'

5.1%%

Time in MonthsTime in Months


Car

diac

Mor

talit

y (%

)

P=0.001P=0.001

3-yr HR (95%CI)3-yr HR (95%CI)0.56 (0.40, 0.80)0.56 (0.40, 0.80)

2.9%%

0 12 15 18 21 24 27 30 33 36

Months

3 6 9

0

1

6

5

4

3

2

3.8%

2.1%


3-Year Cardiac MortalityLandmark analysis

5

4

3

2

1

0

0 3 6 9 12 15 18 21 24 27 30 33 36

Heparin + GP IIb/IIIa (n=1802)Bivalirudin (n=1800)

3 year HR (95% CI) 0.49 0.28 –0.86

p=0.01

30 day HR (95% CI) 0.62 (0.40 – 0.96)

p=0.03

2.2%

1.1%

Car

diac

mor

talit

y (%

)

1.8%

2.9%

Months


3-Year Reinfarction


6.2%

8.2%

Rei

nfar

ctio

n (%

)

00

11

22

33

44

55

66

77

88

99

1010

P=0.04

3-yr HR (95%CI)

0.76 (0.59, 0.99)

00 1212 1515 1818 2121 2424 2727 3030 3333 3636

Months

33 66 99

4.4%

3.6%


3-Year ReinfarctionLandmark analysis

10

8

6

4

2

00 3 6 9 12 15 18 21 24 27 30 33 36

3-year HR (95% CI) 0.66 (0.49 – 0.90)

p=0.007

30-day HR (95% CI)1.07 (0.66 – 1.73)

p=0.79 6.5%

4.4%

Rei

nfar

ctio

n (%

)

1.8%1.9%

9

7

5

3

1

Months

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


3-Year All-Cause Mortality or Reinfarction Landmark analysis

5

4

3

2

1

00 3 6 9 12 15 18 21 24 27 30 33 36

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

3-year HR (95% CI) 0.72 (0.58 – 0.91)

p=0.005

30-day HR (95% CI)0.84 (0.61 – 1.16)

p=0.30 10.6%

7.8%

All-

caus

e m

orta

lity

or r

einf

arct

ion

(%)

3.8%4.5%

Months


3-year MACE Components*

UFH + GPI(N=1802)

Bivalirudin(N=1800)

HR [95%CI] P ValueNumber needed to treat

Death 7.7%7.7% 5.9%5.9% 0.75 (0.58,0.97) 0.03 54

- Cardiac- Cardiac 5.1%5.1% 2.9%2.9% 0.56 (0.40,0.80) 0.001 45

- Non cardiac- Non cardiac 2.8%2.8% 3.1%3.1% 0.62

Reinfarction 8.2%8.2% 6.2%6.2% 0.76 (0.59,0.92) 0.04 52

- Q-wave- Q-wave 3.8%3.8% 3.4%3.4% 0.61

- Non Q-wave- Non Q-wave 4.9%4.9% 3.2%3.2% 0.009 58

Death or reinfarction 14.5%14.5% 11.3%11.3% 0.72 (0.58,0.91) 0.005 31

Ischemic TVR 12.1%12.1% 14.2%14.2% 0.06

Stroke 2.0%2.0% 1.7%1.7% 0.50

*Kaplan-Meier estimates, CEC adjudicated


MACE= death, reinfarction, ischemia-driven target vessel revascularization, stroke

3-year Bleeding Endpoints

UFH + GPI(N=1802)

Bivalirudin(N=1800)

HR (95% CI) P ValueNumber needed to treat

Major bleeding, non-CABG 10.5%10.5% 6.9%6.9% 0.64 (0.51-0.80) 0.0001 28

Major bleeding, including CABG 12.8%12.8% 8.9%8.9% <0.0001 25

Blood transfusion 5.1%5.1% 3.5%3.5% 0.01 61

TIMI Major or Minor 10.9%10.9% 7.0%7.0% <0.0001 26

TIMI Major 6.1%6.1% 4.1%4.1% 0.007 51

TIMI Minor 5.0%5.0% 3.2%3.2% 0.007 56

GUSTO (any) 12.7%12.7% 8.8%8.8% 0.0001 26

GUSTO severe/life-threatening 0.9%0.9% 1.0%1.0% 0.74

GUSTO moderate 6.3%6.3% 4.7%4.7% 0.03 63

GUSTO mild 6.2%6.2% 4.0%4.0% 0.003


3-Year Stent Thrombosis(ARC Definite/Probable)

66

00

22

33

44

55

0.89 (0.65, 1.23)

11

00

1212 1515 1818 2121 2424 2727 3030 3333 3636

p=0.49

HR (95%CI)

4.5% 5.1%

Ste

nt T

hrom

bosi

s (%

)

MonthsMonths

33 66 99


3.5%3.5%

3.0%3.0%


ARC= Academic Research Consortium

3-Year Stent Thrombosis*(N=3202)

UFH + GPI(N=1591)

Bivalirudin(N=1611)

PValue

ARC definite 4.1% 4.2% 0.87

ARC probable 1.0% 0.3% 0.02

ARC definite or probable 5.1% 4.5% 0.49

Early <30 days 2.1% 2.6% 0.31

Late (30 days to 1 year) 1.0% 0.9% 0.64

Very late (> 1 year) 2.2% 1.1% 0.02

<24 hours 0.3% 1.5% 0.0002

24 hours to 3 years 4.8% 3.1% 0.01

*All Kaplan-Meier estimates; all CEC adjudicated


ARC= Academic Research Consortium

Limitations

● Open label design, but high compliance to study processes

● Study applicable to patients enrolled, although there were few exclusions

● Slight imbalances between baseline groups and outpatient thienopyridine use, but none of the results were altered in multivariable adjustment

● Results were not adjusted for multiple comparisons and should be regarded as hypothesis-generating

● 8.0% of patients in the pharmacology randomization were not available for 3-year follow-up

● The impact of a comparison with heparin alone, or with higher use of radial access are not known


Conclusions: Pharmacology Randomization

● In this large-scale, prospective, randomized trial of pts with STEMI undergoing primary PCI, the initial treatment with bivalirudin alone compared to heparin plus GPIIb/IIIa inhibitors at 3 years resulted in:

– A significant 36% reduction in major bleeding and a significant 24% reduction in reinfarction, with non significantly different rates of stent thrombosis, TVR and stroke

– A significant 44% reduction in cardiac mortality and a 25% reduction in all-cause mortality, the latter representing 18 lives saved per 1000 patients treated with bivalirudin (NNT = 54 to save 1 life)


HORIZONS –AMI A Prospective, Multicenter Randomized Trial of Heparin Plus GPIIb/IIIa Inhibitors...

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