A Prospective, Randomized Comparison Of Bivalirudin Vs. Heparin Plus Glycoprotein Iib/iiia Inhibitors During Primary Angioplasty In Acute Myocardial Infarction

A Prospective, Randomized Comparison of Bivalirudin vs. Heparin Plus Glycoprotein IIb/IIIa Inhibitors During Primary Angioplasty in Acute Myocardial Infarction – One Year Results – Roxana Mehran MD For the HORIZONS-AMI Investigators

Background 

Numerous studies have demonstrated a strong association between hemorrhagic complications and subsequent mortality in pts with ACS and after PCI



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



Whether these benefits are maintained at 1-year is unknown

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 primary PCI, CABG or medical therapy

3006 pts eligible for stent randomization R 3:1

Paclitaxel-eluting TAXUS stent

Bare metal EXPRESS stent

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

Harmonizing Outcomes with Revascularization and Stents in AMI

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

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

R 1:1

Bivalirudin monotherapy (± provisional GP IIb/IIIa)

Pharmacology Arm Primary and Secondary Endpoints 1-Year Intention to Treat Population Outcomes in the 4 randomized groups

Study Medications (i) 

Unfractionated heparin – 60 U/kg IV*; subsequent boluses titrated by nomogram to ACT 200-250 secs; terminated at procedure end unless prolonged antithrombin needed



Bivalirudin – Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to ACT; terminated at procedure end unless prolonged antithrombin needed (0.25 mg/kg/hr infusion)



Glycoprotein IIb/IIIa inhibitors – Routine use in UFH arm; recommended only for giant thrombus or refractory no reflow in bivalirudin arm – Abciximab or double bolus eptifibatide as per investigator discretion – dosing per FDA label, renal adjusted; continued for 12° (abcx) or 12-18° (eptif)

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

2 Primary Endpoints (at 30 Days) 1) Net Adverse Clinical Events and

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

2 Primary Endpoints (at 30 Days) 1) Net Adverse Clinical Events

= 2) Major Bleeding (non CABG)

or Major adverse cardiovascular events (major secondary endpoint)

• All cause death • Reinfarction • Ischemic TVR • Stroke

Harmonizing Outcomes with Revascularization and Stents in AMI

3602 pts with STEMI R 1:1

Randomized

UFH + GP IIb/IIIa N=1802

Bivalirudin N=1800

30 Day FU

N=1791 (99.4%)

N=1787 (99.3%)

28

1-Year FU Eligible

N=1774 26 46

1-Year FU

• • • Not true MI* • • •

29

N=1771 • • • Withdrew • • • • • • Lost to FU • • •

N=1702 (95.9%)

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

22 53

N=1696 (95.8%)

Baseline Characteristics (i) UFH + GP IIb/IIIa (N=1802)

Bivalirudin (N=1800)

60.7 [52.9, 70.1]

59.8 [51.9, 69.5]

Male

76.1%

77.1%

Diabetes

17.3%

15.6%

Hypertension

55.2%

Hyperlipidemia

42.7%

Current smoking

45.0%

47.2%

Prior MI

11.4%

10.4%

Prior PCI

11.0%

10.5%

Prior CABG

2.6%

3.3%

Age (years)

*P=0.04

*

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

51.8% 43.4%

Baseline Characteristics (ii) UFH + GP IIb/IIIa (N=1802)

Bivalirudin (N=1800)

80 [71, 90]

80 [71, 90]

2.1 [1.3, 3.9]

2.2 [1.3, 4.0]

Killip class 2-4

8.5%

8.5%

Anterior MI

43.9%

41.2%

50 [41, 59]

50 [45, 60]

Femoral a. access

93.6%

93.9%

Venous access

8.4%

9.3%

Closure device

27.7%

28.3%

Aspiration catheter

11.1%

11.9%

Weight (kg) Chest pain – ER, hrs

LVEF

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

Study Drugs UFH + GP IIb/IIIa (N=1802)

Bivalirudin (N=1800)

65.6%

65.6%

- UFH

98.9%

2.6%

- Bivalirudin

0.2%

96.9%

- Peak ACT

264 [228, 320]

357 [300, 402]

94.5%*

7.2%*

-

4.4%

- Abciximab

49.9%

4.0%

- Eptifibatide

44.4%

3.1%

- Tirofiban

0.2%

0.1%

UFH pre randomization Antithrombin in CCL

GP IIb/IIIa in CCL - Bail-out per protocol**

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

Primary Management Strategy* UFH + GP IIb/IIIa Inhibitor N=1802 Primary PCI

Deferred PCI

Bivalirudin Monotherapy N=1800 CABG

*Primary ITT analysis includes all pts regardless of treatment

Medical Rx

Primary Endpoints at 30 Days Diff = -2.9% [-4.9, -0.8] RR = 0.76 [0.63, 0.92]

Diff = -3.3% [-5.0, -1.6] RR = 0.60 [0.46, 0.77]

Diff = 0.0% [-1.6, 1.5] RR = 0.99 [0.76, 1.30]

PNI ≤ 0.0001 Psup = 0.005

PNI ≤ 0.0001 Psup ≤ 0.0001

Psup = 0.95

1° endpoint

1° endpoint

Major 2° endpoint

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

Aspirin and Thienopyridine Use Regular* aspirin use (%)

Antiplatelet agent use (%)

98.1%

97.3%

97.0%

96.1%

Regular* thieno. use (%)

93.7%

93.3% 87.8%

97.1%

96.7%

96.3%

95.7%

92.7%

92.9% 87.2%

68.0% 65.8%

All P = NS

*Taken >50% of days since last visit

All P = NS

1-Year Net Adverse Clinical Events* 20

Bivalirudin alone (n=1800)

18

Heparin + GPIIb/IIIa (n=1802)

18.3% 15.7%

NACE (%)

16 14 12

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

10 8

HR [95%CI] = 0.84 [0.71, 0.98]

6 4

P=0.03

2 0 0

1

2

3

4

5

6

7

8

9

10

11

12

Time in Months Number at risk Bivalirudin alone Heparin+GPIIb/IIIa

1800 1802

1559 1499

*MACE or major bleeding (non CABG)

1514 1459

1483 1427

1343 1281

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

12 11

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

10

9.2%

9 8 7

5.8%

6 5 4

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

3 2

HR [95%CI] = 0.61 [0.48, 0.78]

1 0

P<0.0001

2

0

1

2

3

4

5

6

7

8

9

10

11

12

Time in Months Number at risk Bivalirudin alone Heparin+GPIIb/IIIa

1800 1802

1621 1544

1601 1532

1586 1515

1448 1368

1-Year Bleeding Endpoints* UFH + GP IIb/IIIa Bivalirudin P Value (N=1802) (N=1800) Protocol Major, non CABG**

9.2%

5.8%

<0.0001

Protocol Major, All

11.8%

7.7%

<0.0001

Protocol Minor

16.5%

9.1%

<0.0001

Blood transfusion

4.0%

2.7%

0.02

TIMI Major

5.5%

3.6%

0.005

TIMI Minor

4.8%

3.0%

0.008

TIMI Major or Minor

10.2%

6.5%

<0.0001

GUSTO LT*** or Severe

0.7%

0.8%

0.70

GUSTO Moderate

5.4%

3.7%

0.01

GUSTO LT or Sev or Mod

6.0%

4.4%

0.02

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

MACE (%)

1-Year Major Adverse CV Events* Bivalirudin alone (n=1800)

15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0

Heparin + GPIIb/IIIa (n=1802)

11.9% 11.9% Diff [95%CI] = 0.0% [-2.1, 2.2] HR [95%CI] = 1.00 [0.83, 1.21]

P=0.98 0

1

2

3

4

5

6

7

8

9

10

11

12

Time in Months Number at risk Bivalirudin alone Heparin+GPIIb/IIIa

1800 1802

1627 1619

1579 1573

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

1544 1540

1394 1380

1-Year All-Cause Mortality Bivalirudin alone (n=1800)

5

4.8%

Heparin + GPIIb/IIIa (n=1802)

Δ = 1.4%

Mortality (%)

4

3.4%

3.1%

3

2

Diff [95%CI] = -1.5% [-2.8,-0.1]

2.1%

HR [95%CI] = 0.69 [0.50, 0.97]

Δ = 1.0%

1

P=0.049

P=0.029

0 0

1

2

3

4

5

6

7

8

9

10

11

12

Time in Months Number at risk Bivalirudin alone Heparin+GPIIb/IIIa

1800 1802

1705 1678

1684 1663

1669 1646

1520 1486

1-Year Mortality: Cardiac and Non Cardiac Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802)

5

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

P=0.005

Mortality (%)

4

3

3.8% Δ = 1.7%

Cardiac

2.9%

2.1%

2

1.8% Δ = 1.1% P=0.03

1

Non Cardiac

1.3% 1.1%

0 0

1

2

3

4

5

6

7

8

9

10

11

12

Time in Months Number at risk Bivalirudin alone Heparin+GPIIb/IIIa

1800 1802

1705 1678

1684 1663

1669 1646

1520 1486

1-Year Death or Reinfarction 10

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

Death or MI (%)

9

8.5%

8 7

6.6%

6

4.5%

5 4

Δ = 1.9% HR [95%CI] = 0.77 [0.61, 0.98]

3.8%

3 2

Δ = 0.7%

1

P=0.30

P=0.04

0 0

1

2

3

4

5

6

7

8

9

10

11

12

Time in Months Number at risk Bivalirudin alone Heparin+GPIIb/IIIa

1800 1802

1670 1648

1638 1617

1617 1593

1469 1431

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

Bivalirudin (N=1800)

4.8%

3.4%

0.69 [0.50,0.97] 0.029

- Cardiac

3.8%

2.1%

0.57 [0.38,0.84] 0.005

- Non cardiac

1.1%

1.3%

1.14 [0.62,2.11] 0.67

Reinfarction

4.4%

3.6%

0.81 [0.58,1.14] 0.22

- Q-wave

2.1%

2.2%

1.06 [0.67,1.67] 0.81

- Non Q-wave

2.7%

1.4%

0.53 [0.32,0.86] 0.01

Death or reinfarction

8.5%

6.6%

0.77 [0.61,0.98] 0.04

Ischemic TVR

5.9%

7.2%

1.23 [0.94,1.60] 0.12

- Ischemic TLR

4.5%

6.0%

1.34 [1.00,1.80] 0.051

- Ischemic remote TVR

2.0%

2.3%

1.13 [0.71,1.79] 0.60

1.2%

1.1%

1.00 [0.54,1.85] 0.99

Death

Stroke

*All Kaplan-Meier estimates, CEC adjudicated

HR [95%CI]

P Value

Adverse Events Between 30 Days and 1-Year UFH + GPI (N=1802) Death

Bivalirudin P Value (N=1800)

1.8%

1.4%

0.31

- Cardiac

0.9%

0.4%

0.046

- Non cardiac

0.9%

1.0%

0.75

Reinfarction

2.8%

1.7%

0.04

Death or reinfarction

4.4%

3.0%

0.02

Ischemic TVR

4.3%

4.7%

0.57

Stroke

0.5%

0.4%

0.77

MACE

7.3%

6.8%

0.52

Major bleeding (non CABG)

0.7%

0.8%

0.71

NACE

7.8%

7.3%

0.52

*Kaplan-Meier estimates, landmark analysis, CEC adjudicated

1-Year Stent Thrombosis (ARC Definite/Probable) Bivalirudin alone (n=1611) Heparin + GPIIb/IIIa (n=1591)

Stent Thrombosis (%)

5

Δ = 0.3%

4

3.5% 3.2%

3

2.7%

2

2.2%

1

Δ = 0.5% P=0.31

HR [95%CI] = 1.11 [0.76, 1.63]

P=0.59

0 0

1

2

3

4

5

6

7

8

9

10

11

12

Time in Months Number at risk Bivalirudin alone Heparin+GPIIb/IIIa

1611 1591

1525 1495

1504 1475

1486 1457

1356 1315

1-Year Stent Thrombosis* (N=3,202) UFH + GPI Bivalirudin (N=1591) (N=1611) ARC definite or probable, ≤24 hrs

P Value

0.3%

1.5%

0.0002

- definite, ≤24 hours

0.2%

1.4%

<0.0001

- probable, ≤24 hours

0.1%

0.1%

1.0

1.9%

1.3%

0.14

- definite, >1 day - ≤30 days

1.3%

1.1%

0.60

- probable, >1 day - ≤30 days

0.6%

0.2%

0.049

1.1%

0.9%

0.53

- definite, >30 days – 1-year

1.0%

0.9%

0.65

- probable, >30 days – 1-year

0.1%

0.1%

0.55

3.2%

3.5%

0.59

- definite, ≤1-year

2.4%

3.2%

0.15

- probable, ≤1-year

0.8%

0.3%

0.06

ARC definite or probable, >1 - ≤30d

ARC definite or probable, >30d – 1y

ARC definite or probable, ≤1-year

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

Harmonizing Outcomes with Revascularization and Stents in AMI

3602 pts with STEMI R 1:1

UFH + GP IIb/IIIa N=1802

Bivalirudin N=1800

N=1479

Stent rand. eligible

N=1527

R 3:1

Stratified by 1st rand.

R 3:1

TAXUS N=1111

EXPRESS N=368

TAXUS N=1146

EXPRESS N=381

Interaction Between Drug and Stent Randomization

30 Day Pharmacology Endpoints (N=3006) UFH + GPI (N=1479)

Bivalirudin (N=1527)

HR [95%CI]

Pint

11.3%

8.7%

0.76 [0.60,0.95]

-

- TAXUS subgroup

11.5%

9.1%

0.78 [0.60,1.01]

- EXPRESS subgroup

10.6%

7.4%

0.69 [0.42,1.11]

Major bleeding, all**

8.4%

5.1%

0.59 [0.44,0.78]

- TAXUS subgroup

8.9%

5.4%

0.59 [0.43,0.81]

- EXPRESS subgroup

7.1%

4.2%

0.58 [0.31,1.09]

4.7%

4.9%

1.05 [0.75,1.45]

- TAXUS subgroup

4.6%

5.1%

1.11 [0.76,1.62]

- EXPRESS subgroup

4.9%

4.2%

0.86 [0.44,1.69]

Kaplan-Meier estimates

NACE, all*

MACE, all***

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

0.95 1.0 0.89

Interaction Between Drug and Stent Randomization

1-Year Stent Endpoints (N=3006) TAXUS (N=2257)

EXPRESS (N=749)

HR [95%CI]

Pint

4.5%

7.5%

0.59 [0.43,0.83]

-

- UFH + GPI subgroup

3.3%

7.9%

0.42 [0.25,0.68]

- Bivalirudin subgroup

5.6%

7.1%

0.78 [0.50,1.24]

8.1%

8.0%

1.02 [0.76, 1.36]

- UFH + GPI subgroup

8.2%

8.8%

0.92 [0.66,1.27]

- Bivalirudin subgroup

8.0%

7.2%

1.17 [0.83,1.64]

Binary restenosis, all**

10.0%

22.9%

0.44 [0.33, 0.57]

- UFH + GPI subgroup

10.9%

19.2%

0.57 [0.38,0.84]

- Bivalirudin subgroup

9.2%

26.7%

0.34 [0.24,0.49]

Kaplan-Meier estimates

Ischemic TLR, all

Safety MACE, all*

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

0.17 0.89 0.18

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

5

4.6% 4.0%

Mortality (%)

4

3.0% 2.6%

3

2

Pint = 0.75

1

0 0

1

2

3

4

5

6

7

Time in Months

8

9

10

11

12

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 low frequency safety endpoints and subgroup interactions – All such observations should be considered hypothesis-generating

Conclusions 

In this large scale, prospective, randomized trial of pts with STEMI undergoing a primary PCI management strategy, bivalirudin monotherapy compared to UFH plus the routine use of GP IIb/IIIa inhibitors resulted in: – A significant 16% reduction in the 1-year rate of composite net adverse clinical events – A significant 39% reduction in the 1-year rate of major bleeding

Conclusions 

In this large scale, prospective, randomized trial of pts with STEMI undergoing a primary PCI management strategy, bivalirudin monotherapy compared to UFH plus the routine use of GP IIb/IIIa inhibitors resulted in: – Significant 31% and 43% reductions in the 1-year rates of all-cause and cardiac mortality (absolute 1.4% and 1.7% reductions), with non significantly different rates of reinfarction, stent thrombosis, stroke and TVR at 1-year

Clinical Implications 

HORIZONS has demonstrated that the prevention of hemorrhagic complications after primary PCI in STEMI results in improved early and late survival – Optimal drug selection and technique to minimize bleeding are essential to enhance outcomes for pts undergoing interventional therapies