Horizons 1year Des

A Prospective, Randomized Comparison of Paclitaxel-eluting TAXUS Stents vs. Bare Metal Stents During Primary Angioplasty in Acute Myocardial Infarction – One Year Results – Gregg W. Stone MD For the HORIZONS-AMI Investigators

Background 

No consensus exists regarding the safety and efficacy of drug-eluting stents in pts with STEMI undergoing primary PCI – TLR and restenosis rates tend to be lower in STEMI vs. elective PCI patients because of less plaque burden and non viable myocardium – The safety of implanting DES in ruptured plaques with thrombus has been questioned



Outcomes from registry studies of DES vs. BMS in STEMI have been conflicting, and no large-scale randomized trials have been performed

Harmonizing Outcomes with Revascularization and Stents in AMI

3602 pts with STEMI with symptom onset ≤12 hours Aspirin, thienopyridine

R 1:1

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

Bivalirudin monotherapy (± provisional GP IIb/IIIa)

Emergent angiography, followed by triage to…

CABG – Primary PCI – Medical Rx 3000 pts eligible for stent randomization

Paclitaxel-eluting TAXUS stent

R 3:1

Bare metal EXPRESS stent

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

Stent Randomization Hypotheses 

In patients with STEMI undergoing primary PCI, the use of paclitaxel-eluting TAXUS stents rather than bare metal EXPRESS stents will be: – Efficacious, as evidenced by reduced rates of ischemia-driven target lesion revascularization at 1-year and angiographic binary restenosis at 13 months; and – Safe, with non-inferior rates of the composite measure of death, reinfarction, stent thrombosis or stroke at 1-year

Clinical Inclusion Criteria 

STEMI >20 mins and <12 hours in duration – ST-segment elevation of ≥1 mm in ≥2 contiguous leads; or – Presumably new left bundle branch block; or – True posterior MI with ST depression of ≥1 mm in ≥2 contiguous anterior leads – Patients with cardiogenic shock, left main disease, etc., were not excluded



Age ≥18 years



Written, informed consent

Principal Clinical Exclusion Criteria 

Contraindication to any of the study medications



Prior administration of thrombolytic therapy, bivalirudin, GP IIb/IIIa inhibitors, LMWH or fondaparinux for the present admission (prior UFH allowed)



Current use of coumadin



History of bleeding diathesis or known coagulopathy (including HIT), or will refuse blood transfusions



History of intracerebral mass, aneurysm, AVM, or hemorrhagic stroke; stroke or TIA within 6 months or any permanent neurologic deficit; GI or GU bleed within 2 months, or major surgery within 6 weeks; recent or known platelet count <100,000 cells/mm3 or hgb <10 g/dL



Planned elective surgical procedure that would necessitate interruption of thienopyridines during the first 6 months post enrollment

Angiographic Inclusion Criteria 

The presence of least 1 acute infarct artery target vessel* in which: – a) ALL significant lesions are eligible for stenting with study stents, and – b) ALL such lesions have a visually estimated reference diameter ≥2.25 mm and ≤4.0 mm



Expected ability to deliver the stent(s) to all culprit lesions (absence of excessive proximal tortuosity or severe calcification)



Expected ability to fully expand the stent(s) at all culprit lesions (absence of marked calcification)

*Arteries containing multiple lesions may be randomized if all lesions are study stent eligible; multiple vessels may be randomized if all lesions in each vessel are study stent eligible

Angiographic Exclusion Criteria 

Bifurcation lesion definitely requiring implantation of stents in both the main vessel + side branch



Infarct related artery is an unprotected left main



>100 mm of study stent length anticipated



Infarction due to stent thrombosis, or infarct lesion at the site of a previously implanted stent



High likelihood of CABG within 30 days anticipated

2 Primary Stent Endpoints (at 12 Months) 1) Ischemia-driven TLR* and

2) Composite Safety MACE = All

cause death, reinfarction, stent thrombosis (ARC definite or probable)**, or stroke

Major Secondary Endpoint (at 13 Months) Binary angiographic restenosis * Related to randomized stent lesions (whether study or non study stents were implanted); ** In randomized stent lesions with ≥1 stent implanted (whether study or non study stents)

Statistical Methodology 

Second randomization stratification i. Results from the first randomization ii. Presence of medically treated diabetes mellitus iii. Presence of any lesion >26 mm in length (requiring overlapping stents by protocol) iv. U.S. vs. non-U.S. site



Primary analysis conducted in the ITT cohort using Kaplan-Meier methodology, with the groups compared by log-rank



1-sided α=0.025 for NI; 2-sided α=0.05 for Sup

Power Analysis With 2,850 pts randomized 3:1* Assumed event rates Test

EXPRESS

TAXUS

δ

Power

Ischemic TLR

Superiority

9.0%

5.0%

-

95%

Composite Safety MACE

Noninferiority

7.5%

7.5%

3.0%

80%

One Year

With angiographic FU in 1,125 randomized pts (analyzable) Assumed event rates 13 Months

Test

EXPRESS

TAXUS

δ

Power

Restenosis

Superiority

26.0%

15.6%

-

96%

* Assumed 5% withdrew or lost to FU at 1 year → 3000 randomized

Study Organization 

Sponsor:

The Cardiovascular Research Foundation



Grant Support:

Boston Scientific Corporation The Medicines Company



Principal Investigator:

Gregg W. Stone MD



Steering Committee:

Gregg W. Stone (Chair), Bruce R. Brodie, David A. Cox, Cindy L. Grines, Barry D. Rutherford



European Steering Committee:

H Bonnier, A Colombo, Eulogio Garcia, E Grube, G Guagliumi, A Kastrati, P Serruys, H Suryapranata



Additional Country Leaders:

Y Almagor, A Banning, J Belardi, D Dudek, L Grinfeld, K Huber, D Nilsen, G Olivecrona, L Rasmussen



Pharmacology Committee:

Deepak Bhatt, George Dangas, Fred Feit, Magnus Ohman

(unrestricted)

Study Organization 

Data Management:

CRF, Roxana Mehran (Director), Lynn Vandertie, Louise Gambone (Ops), Allison Kellock (Programming), Helen Parise (Stats)



Clinical Events Committee:

CRF, S. Chiu Wong (Chair)



Site and Data Monitoring:

J. Tyson and Associates (USA), Premier (Europe), Tango (S.A.)



Angiographic Core Lab:

CRF, Alexandra Lansky (Director), Ecaterina Cristea (Ops)



ECG Core Lab:

CRF, James Reiffel (Director)



IVUS Core lab:

CRF, Akiko Maehara (Director)



DSMB:

Bernhard Gersh (Chair), David Faxon, Spencer King, Stuart Pocock, David Williams

Sponsored by CRF

The Cardiovascular Research Foundation (CRF) HORIZONS-AMI Team

Horizons Enrollment - Centers 3,602 pts randomized at 123 centers in 11 countries between March 25th, 2005 and May 7th, 2007 (2) Norway (3) Netherlands (6) UK USA (57) (1) Spain

Argentina (12)

Poland (9) Germany (16) Austria (5) Israel (10) Italy (2)

Top 20 Enrolling Sites 1. B. Witzenbichler, Germany

11. H. Suryapranata, Netherlands

2. G. Guagliumi, Italy

12. K. Huber, Austria

3. J. Peruga, Poland

13. J. Wöehrle, Germany

4. B. Brodie, USA

14. C. Metzger, USA

5. R. Kornowski, Israel

15. M. Desaga, Germany

6. F. Hartmann, Germany

16. K. Zmudka, Poland

7. M. Moeckel, Germany

17. J. Kochman, Poland

8. A. Ochala, Poland

18. D. Nilsen, Norway

9. W. Ruzyllo, Poland

19. D. Dudek, Poland

10. V. Guetta, Israel

20. A. Finkelstein, Israel

Harmonizing Outcomes with Revascularization and Stents in AMI Primary Medical Rx Primary CABG Deferred PCI Index PCI, not eligible - PTCA only - Stented

193 62 2 119 220

93.1% of all stented pts were randomized

Randomized

3602 pts with STEMI

UFH + GPI (n=1802) Bivalirudin (n=1800)

3006 pts eligible for stent rand. R 3:1

TAXUS DES N=2257 18 53

1 year FU

R 1:1

N=2186 (96.9%)

EXPRESS BMS N=749 • • • Withdrew • • • • • • Lost to FU • • •

7 27

N=715 (95.5%)

Baseline Characteristics (i) TAXUS (N=2257) Age (years)

EXPRESS (N=749)

59.9 [52.4, 69.4] 59.3 [51.8, 69.2]

Male

77.0%

76.0%

Diabetes

16.1%

15.2%

Hypertension

51.2%

51.9%

Hyperlipidemia

42.2%

41.1%

Current smoking

46.3%

Prior MI

9.1%

Prior PCI

9.5%

7.7%

Prior CABG

2.2%

1.9%

*P=0.009

*

51.9% 10.9%

Baseline Characteristics (ii) TAXUS (N=2257)

EXPRESS (N=749)

80 [71, 90]

80 [71, 90]

Killip class 2-4

8.8%

8.0%

Anterior MI

42.2%

44.7%

50 [44, 59]

50 [43, 58]

3.7 [2.7, 5.5]

3.8 [2.7, 5.8]

Femoral a. access

93.6%

92.9%

Venous access

8.5%

8.0%

Closure device

30.1%

28.8%

Aspiration catheter

11.4%

10.7%

Weight (kg)

LVEF (%), site Symptoms – PCI, hrs

Study Drugs Aspirin at home Aspirin load pre PCI Thienopyridine at home Thienopyridine loading dose - clopidogrel 300 mg - clopidogrel 600 mg - clopidogrel other - ticlopidine UFH pre randomization UFH as the procedural antithrombin Bivalirudin administered GP IIb/IIIa inhibitor administered

TAXUS (N=2257) 22.7%

EXPRESS (N=749) 20.5%

97.0% 2.1%

97.2% 2.5%

98.9% 34.2%

98.3% 35.5%

63.3% 1.2%

61.3% 1.3%

0.5% 65.2%

0.3% 65.8%

49.8% 50.7%

50.1% 50.9%

52.0%

51.5%

Procedural Data (Site Reported) TAXUS (N=2257, L=2495)

EXPRESS (N=749, L=815)

1.1 ± 0.4

1.1 ± 0.4

- ≥ 2 lesions treated

11.1%

9.0%

- ≥ 2 vessels treated

4.5%

3.1%

Direct stenting attempted

30.4%

33.7%

N lesions treated

Stent target lesion: LAD, LCX, RCA, LM, SVG

40.1%, 14.6%, 42.4%, 15.9%, 45.1%, 0.3%, 0.3% 41.3%, 0.4%, 0.4%

N stents implanted

1.5 ± 0.9

Total stent length**

30.8 ± 17.8

* **

1.4 ± 0.7 27.3 ± 14.9

Max balloon dia. (mm)

3.00 [2.75, 3.50]

3.00 [2.90, 3.50]

Max pressure (atm.)

14.0 [12.0, 16.0]

14.0 [12.0, 16.0]

*P=0.002; **P<0.0001

Quantitative Coronary Angiography TAXUS (L=2642, V=2353)

EXPRESS (L=857, V=771)

Pre RVD (mm)

2.89 ± 0.51

2.90 ± 0.50

Pre MLD (mm)

0.35 ± 0.45

0.35 ± 0.45

Pre %DS

87.6 ± 15.4

87.4 ± 15.4

Pre lesion length (mm)

17.5 ± 10.1

Pre TIMI 0/1, 2, 3

†

16.2 ± 8.8

60.6%, 13.6%, 25.7% 57.4%, 15.2%, 27.4%

Post RVD (mm)

2.93 ± 0.51

2.95 ± 0.50

Post MLD (mm)*

2.36 ± 0.55

2.37 ± 0.52

Post %DS*

19.9 ± 11.6

19.5 ± 11.1

Acute gain (mm)**

2.04 ± 0.64

2.05 ± 0.62

Post TIMI 0/1, 2, 3

1.7%, 10.7%, 87.6%

0.9%, 9.3%, 89.8%

*Analysis segment, all lesions, whether stented or not; **stented lesions only; †P=0.006

Aspirin and Thienopyridine Use

Antiplatelet agent use (%)

Regular* aspirin use (%) 99.1%

98.5%

98.3%

97.5%

98.6%

98.3%

97.5%

97.1%

*Taken >50% of days since last visit

Regular* thieno. use (%) 99.4%

98.7%

98.9%

97.8%

94.7%

73.1% 87.5%

P<0.001

63.9%

P<0.001

Primary Efficacy Endpoint: Ischemic TLR 10 9

Ischemic TLR (%)

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

Diff [95%CI] = -3.0% [-5.1, -0.9]

8 7

HR [95%CI] = 0.59 [0.43, 0.83]

6

P=0.002

7.5%

5

4.5%

4 3 2 1 0 0

Number at risk TAXUS DES 2257 EXPRESS BMS 749

1

2

3

4

5

6

7

8

9

10

11

12

Time in Months 2132 697

2098 675

2069 658

1868 603

Secondary Efficacy Endpoint: Ischemic TVR 10 9

Ischemic TVR (%)

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

Diff [95%CI] = -3.0% [-5.2, -0.7]

8 7

HR [95%CI] = 0.65 [0.48, 0.89]

6

P=0.006

8.7% 5.8%

5 4 3 2 1 0 0

Number at risk TAXUS DES 2257 EXPRESS BMS 749

1

2

3

4

5

6

7

8

9

10

11

12

Time in Months 2119 695

2078 669

2045 650

1848 598

Primary Safety Endpoint: Safety MACE* 10

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

Safety MACE (%)

9

8.1% 8.0%

8 7 6

Diff [95%CI] = 0.1% [-2.1, 2.4]

5 4

HR [95%CI] = 1.02 [0.76, 1.36]

3

PNI=0.01 PSup=0.92

2 1 0 0

Number at risk TAXUS DES EXPRESS BMS

1

2

3

4

5

6

7

8

9

10

11

12

Time in Months 2257 749

2115 697

2086 683

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

2057 672

1856 619

One-Year All-Cause Mortality 5

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

Mortality (%)

4

3.5% 3.5%

3

2

HR [95%CI] = 0.99 [0.64,1.55]

1

P=0.98

0 0 Number at risk TAXUS DES EXPRESS BMS

1

2

3

4

5

6

7

8

9

10

11

12

Time in Months 2257 749

2180 716

2161 712

2147 702

1949 648

One-Year Cardiac Mortality Cardiac Mortality (%)

5

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

4

3

2.7% 2.4%

2

HR [95%CI] = 0.90 [0.54,1.50]

1

P=0.68 0 0

1

2

3

4

5

6

7

8

9

10

11

12

Time in Months Number at risk TAXUS DES EXPRESS BMS

2257 749

2180 716

2161 712

2147 702

1949 648

One-Year Death or Reinfarction TAXUS DES (n=2257) EXPRESS BMS (n=749)

8

Death or MI (%)

7

7.0% 6.8%

6 5

HR [95%CI] = 0.97 [0.70,1.32]

4 3

P=0.83

2 1 0 0

Number at risk TAXUS DES EXPRESS BMS

1

2

3

4

5

6

7

8

9

10

11

12

Time in Months 2257 749

2140 703

2110 689

2083 678

1882 625

Stent Thrombosis (ARC Definite or Probable) Stent Thrombosis (%)

4

TAXUS DES (n=2238) EXPRESS BMS (n=744)

3.4% 3.1%

3

2

HR [95%CI] = 0.92 [0.58,1.45]

P=0.72

1

0 0

1

2

3

4

5

6

7

8

9

10

11

12

Time in Months Number at risk TAXUS DES 2238 EXPRESS BMS 744

2122 701

2098 694

2078 683

1884 629

Stent Thrombosis Rates* TAXUS EXPRESS (N=2238) (N=744) Stent thrombosis, ≤30 days

Hazard ratio [95%CI]

P Value

2.3%

2.7%

0.87 [0.52,1.46]

0.60

- ARC definite

1.9%

2.3%

0.83 [0.47,1.45]

0.51

- ARC probable

0.5%

0.4%

1.11 [0.31,4.05]

0.87

1.0%

0.7%

1.39 [0.52,3.68]

0.51

- ARC definite

0.9%

0.7%

1.25 [0.47,3.35]

0.65

- ARC probable

0.1%

0%

-

0.42

3.1%

3.4%

0.92 [0.58,1.45]

0.72

- ARC definite

2.6%

3.0%

0.86 [0.53,1.41]

0.55

- ARC probable

0.5%

0.4%

1.33 [0.38,4.73]

0.65

Stent thrombosis, >30d – 1y

Stent thrombosis, ≤1 year

*Kaplan-Meier estimates

One Year Composite Safety Endpoints* TAXUS EXPRESS (N=2257) (N=749)

HR [95%CI]

P Value

Safety MACE**

8.1%

8.0%

1.02 [0.76,1.36]

0.92

Death, all-cause

3.5%

3.5%

0.99 [0.64,1.55]

0.98

- Cardiac

2.4%

2.7%

0.90 [0.54,1.50]

0.68

- Non cardiac

1.1%

0.8%

1.32 [0.54,3.22]

0.55

Reinfarction

3.7%

4.5%

0.81 [0.54,1.21]

0.31

- Q-wave

2.0%

1.9%

1.07 [0.59,1.94]

0.83

- Non Q-wave

1.8%

2.7%

0.68 [0.39,1.17]

0.16

Stent thrombosis†

3.1%

3.4%

0.92 [0.58,1.45]

0.72

- ARC definite

2.6%

3.0%

0.86 [0.53,1.41]

0.55

- ARC probable

0.5%

0.4%

1.33 [0.38,4.73]

0.65

1.0%

0.7%

1.52 [0.58,4.00]

0.39

Stroke

*Kaplan-Meier estimates; **Primary safety endpoint; †ARC definite or probable

Angiographic Follow-up 1800 consecutive eligible pts assigned to 13 month angiographic FU* Randomized

TAXUS DES N=1348

EXPRESS BMS N=452

40 • • • Died before angio FU • • • 11

Eligible

N=1308

N=441 366 • Angio FU not performed • 134

Completed Angio FU

N=942 (72.0%)

N=307 (69.6%)

28 • • Not received/analyzable • • 14 • • • • Out of window • • • • 3 0

Analyzed

N=911

1081 • • • Lesions • • •

332

* Randomized in stent arm; stent procedure successful (DS <10%, TIMI-3 flow, ≤NHLBI type A peri-stent dissection); no stent thrombosis or CABG w/i 30 days

N=293

Follow-up QCA TAXUS EXPRESS P (L=1081, V=964) (L=332, V=302)

value

TIMI flow - 0/1

2.8%

3.6%

0.45

-2

7.0%

5.0%

0.22

-3

90.2%

91.4%

0.55

FU RVD (mm)

2.91 ± 0.49

2.90 ± 0.48

0.97

FU MLD in-stent (mm)

2.36 ± 0.75

1.98 ± 0.82

<0.0001

FU MLD in-segment (mm)

2.08 ± 0.69

1.84 ± 0.76

<0.0001

FU %DS in-stent

18.8 ± 22.9

32.6 ± 24.9

<0.0001

FU %DS in-segment

28.8 ± 19.6

37.4 ± 22.0

<0.0001

Aneurysm

0.5%

0.9%

0.40

Ulcerated

0.5%

0.6%

0.67

Ectasia

0.7%

0.9%

0.73

Binary Analysis Segment Restenosis at 13 Months Patient and Lesion Level Analysis*

RR [95%CI] = 0.44 [0.33, 0.57] P<0.0001

RR [95%CI] = 0.44 [0.33, 0.57] P<0.0001

Major 2° endpoint

* ITT: Includes all stent randomized lesions, whether or not a stent implanted, and whether or not non study stents were placed ** Any lesion with restenosis  per pt restenosis

was

Angiographic Late Loss at 13 Month Lesions with Stents Implanted

P<0.0001 P<0.0001

± 0.70

± 0.64

P = 0.07 ± 0.64

P = 0.18 ± 0.56

± 0.50 ± 0.47

± 0.54 ± 0.42

Binary Angiographic Restenosis at 13 Months Lesions with Stents Implanted RR [95%CI] = 0.39 [0.29, 0.52] P<0.0001

P = 0.42

RR [95%CI] = 0.42 [0.32, 0.54] P<0.0001

P = 0.13

Limitations 

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



Underpowered for stent thrombosis and death – The virtually identical rates of MACE in the TAXUS and EXPRESS groups makes it unlikely that major safety differences exist favoring either stent type at 1-year

Conclusions 

In this large-scale, prospective, randomized trial of pts with STEMI undergoing primary stenting, the implantation of paclitaxel-eluting TAXUS stents compared to bare metal EXPRESS stents resulted in: – A significant 41% reduction in the 1-year primary efficacy endpoint of ischemia-driven TLR, and a significant 56% reduction in the 13 month major secondary efficacy endpoint of binary restenosis – Non inferior rates of the primary composite safety endpoint of all cause death, reinfarction, stent thrombosis or stroke at 1-year

Conclusions 

The long-term safety and efficacy profile of paclitaxel-eluting TAXUS stents compared to bare metal EXPRESS stents in STEMI will be determined by the ongoing 5 year follow-up of patients randomized in the HORIZONS-AMI trial