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LBCT March 29, 08

ISAR ISAR ISAR REACT 3REACT 3REACT 3

A. Kastrati, F.-J. Neumann, J. Mehilli, S. Schulz, G. Richardt, R. Iijima, R.A. Byrne,

P.B. Berger, A. Schömig

Bivalirudin Versus Unfractionated Heparin in Biomarker Negative Patients With

Stable and Unstable Angina Undergoing PCI

ISAR-REACT 3(Intracoronary Stenting and Antithrombotic Regimen-

Rapid Early Action for Coronary Treatment 3)

ClinicalTrials.gov Identifier

NCT00262054

LBCT March 29, 08

ISAR ISAR ISAR REACT 3REACT 3REACT 3 Disclosures

The trial

was supported

in part

by

a grant

from Nycomed

Pharma GmbH, Unterschleißheim, Germany

The company

did not participate in the design and conduct of the study, in the collection, analysis,

and interpretation of the data, or in the preparation, review, or approval of the presentation.

No other

conflict

of interest

to disclose

LBCT March 29, 08

ISAR ISAR ISAR REACT 3REACT 3REACT 3 Participating

Centers and

Principal

Investigators•

Deutsches Herzzentrum, Munich. Germany (PI: J. Pache)

•

1. Med. Klinik rechts der Isar, Munich. Germany (PI: J. Dirschinger)

•

Herzzentrum Bad Krozingen, Bad Krozingen. Germany (PI: F.-J. Neumann)

•

Herzzentrum Segeberger

Kliniken, Bad Segeberg. Germany (PI: G. Richardt)

•

Geisinger Clinic, Danville (PA). United States (PI: P.B. Berger)

•

Med. Klinik I, Garmisch-Partenkirchen. Germany (PI: F. Dotzer)

•

Herz-

und Gefäß-Klinik, Bad Neustadt. Germany (PI: M. Schneider)

Study

Chairman: A. Schömig Study

Principal

Investigator: A. Kastrati

Data Coordinating

Center: J. Mehilli

LBCT March 29, 08

ISAR ISAR ISAR REACT 3REACT 3REACT 3 Background

Bivalirudin

has not been compared with unfractionated heparin during PCI in the modern era, or in patients who have received optimal pretreatment

with clopidogrel.

LBCT March 29, 08

ISAR ISAR ISAR REACT 3REACT 3REACT 3 Prior RCTs

Comparing

Bivalirudin and Heparin•

BAS (NEJM 1995)

-

Control

group: UFH bolus

of 175 U/kg + 18-24 hr

infusion-

Different dose of bivalirudin than

curently

used

as well

-

Balloon

angioplasty

only-

No pretreament

with

clopidogrel

•

REPLACE 2 (JAMA 2003) -

Control group: UFH plus GPIIb/IIIa

inhibitors

-

Fictional comparator of UFH alone; no pts actually received it

-

Clopidogrel pretreatment in <85%; 300 mg load-

Provisional IIb/IIIa inhibitors in 7.2% of bivalirudin pts

LBCT March 29, 08


•

REPLACE 1 (AJC 2004) -

Bivalirudin vs

UFH; GPIIb/IIIa

inhibitors in 72%

in both groups -

Open-label

-

Clopidogrel pretreatment in <60%, 300 mg

•

ACUITY and HORIZONS

–

not relevant; compared bivalirudin with UFH and

a GPIIb/IIIa

inhibitor

in high risk ACS/STEMI

pts

Prior RCTs

Comparing Bivalirudin and Heparin

LBCT March 29, 08

ISAR ISAR ISAR REACT 3REACT 3REACT 3 Aim

To compare

bivalirudin alone

to unfractionated heparin

alone

in biomarker

negative pts

undergoing

PCI pretreated with

clopidogrel 600 mg for

>2 hours

HypothesisBivalirudin

is superior to UFH for biomarker

negative patients undergoing PCI after optimal pretreatment with clopidogrel

LBCT March 29, 08

ISAR ISAR ISAR REACT 3REACT 3REACT 3 Inclusion

Criteria

•

Patients older than 18 years of age undergoing PCI who were biomarker negative at study entry

•

Clopidogrel loading ≥

2 hrs prior to PCI

LBCT March 29, 08

ISAR ISAR ISAR REACT 3REACT 3REACT 3 Exclusion Criteria

•

Acute coronary syndromes with positive biomarkers or ST-segment elevation on ECG

•

Cardiogenic shock•

Active bleeding, bleeding diathesis

•

Impaired renal function (creatinine >3 mg/dl)

LBCT March 29, 08

ISAR ISAR ISAR REACT 3REACT 3REACT 3 Treatment Regimens

Clopidogrel 600 mg at least 2 hours

before

PCIAspirin >325 mg orally

or

intravenously

Bivalirudin group•

Bolus

of 0.75 mg/kg

•

Infusion of 1.75 mg/kg/hr

UFH group•

Bolus

of 140 U/kg

•

Placebo Infusion

Clopidogrel 75-150 mg/day until discharge

(≤3 days) 75 mg/day for at least 6 months

Aspirin 80-325 mg/day

indefinitely

Double-blind randomization; double-dummy administration

LBCT March 29, 08

ISAR ISAR ISAR REACT 3REACT 3REACT 3Primary

(Quadruple) Endpoint

at 30 Days•

Composite rate of:– Death– Myocardial infarction

(defined as CK-MB ≥2x upper limit normal)– Urgent target vessel revascularization– Major bleeding

(according to the REPLACE-2 criteria, JAMA ′03)•

Intracranial, intraocular, or retroperitoneal bleeding, or

•

Clinically overt bleeding resulting in a decrease in Hb>3 g/dL, or•

Any decrease in Hb>4 g/dL, or

•

Transfusion of >2 units of packed red blood cells or whole blood

LBCT March 29, 08

ISAR ISAR ISAR REACT 3REACT 3REACT 3 Secondary

(Triple) Endpoint

at 30 Days

•

Composite rate of:– Death– Myocardial infarction– Urgent target vessel revascularization

LBCT March 29, 08

ISAR ISAR ISAR REACT 3REACT 3REACT 3 Sample Size Calculation

•

Assumed incidence of the 1o

quadruple endpoint:–

8.0% in UFH group

–

5.8% in bivalirudin group (a 27.5% reduction with bivalirudin)

•

Power = 82% •

Two-sided

α

level =

0.05

•

Enrollment

of 4500 patients required

LBCT March 29, 08


2,289 Pts

30-day Follow-up

2,281 Pts

UFHBivalirudin

PCI

4,570 Patients

Study Population

LBCT March 29, 08

ISAR ISAR ISAR REACT 3REACT 3REACT 3 Baseline Characteristics

Bivalirudin UFHAge, yrs 67 67Male 76 77Body mass

index, kg/m2 28 28

Diabetes,% 27 28Hypertension, % 89 90Current

smoker, % 14 15

Hypercholesterolemia, % 81 79History

of MI, % 32 30

History

of CABG, % 13 11Unstable angina, % 18 18Stable angina, % 82 82Serum creatinine, mg/dl 1 1

LBCT March 29, 08

ISAR ISAR ISAR REACT 3REACT 3REACT 3Angiographic Characteristics

Bivalirudin UFHEjection fraction, % 58 58Multivessel disease, % 80 80Number of lesions/patient 2 2Vessel treated, %

left mainleft anterior descendingcircumflexright coronarybypass graft

63923302

53724322

B2/C lesion, % 64 64

LBCT March 29, 08


DES 84% DES 82%BMS

PTCA

6%

10%7%

11%

Type of PCI

Bivalirudin UFH

LBCT March 29, 08


0.10.5

5.6

0.60.8

0.20.4

4.8

0.40.7

0

1

2

3

4

5

6

Death Definite ST MI Q-wave MI UTVR

Incidence

(%)

P=0.70

P=0.24

P=0.75P=0.52 P=0.30

Ischemic Events

BivalirudinUFH

LBCT March 29, 08


Cumulative incidence (%)

0

2

4

6

8

10

0 5 10 15 20 25 30

Days after

randomization

Secondary (Triple) Endpoint Death, MI, UTVR

5.0%5.9%

RR=1.16 [95% CI, 0.91-1.49], P=0.23

Bivalirudin

UFH

LBCT March 29, 08


3.1

6.8

1.3

4.6

9.9

1.8

0

2

4

6

8

10

12

Major bleeding Minor bleeding Transfusion

Incidence

(%)P=0.008

Bleeding Events

P=0.0001 P=0.15

BivalirudinUFH

LBCT March 29, 08


0.09

0.3

0.1

0.4

0

0.2

0.4

0.6

0.8

1

Severe Moderate

Incidence

(%)

P=0.99

Thrombocytopenia

P=0.61

50,000 to <100,000 cells/mm3 20,000 to <50,000 cells/mm3

BivalirudinUFH

LBCT March 29, 08


Days after

randomization

Cumulative incidence (%)

0

2

4

6

8

10

0 5 10 15 20 25 30

Primary

(Quadruple) Endpoint Death, MI, UTVR, Major Bleeding

8.3%8.7%

RR=0.94 [95% CI, 0.77-1.15], P=0.57

Bivalirudin

UFH

LBCT March 29, 08


Age>67.6 yrs≤67.6 yrs

SexWomenMen

AnginaUnstableStable

Relative Risk

(95% Confidence

Intervals)

0 1 2

DiabetesYesNo

Prespecified

Subgroup

Analyses Primary

(Quadruple) Endpoint

Bivalirudin better UFH better

Creatinine>0.9 mg/dl≤0.9 mg/dl

LBCT March 29, 08


4.1

0.5

1.3

3.4

1

2.2

0

1

2

3

4

5

MI TIMI major TIMI minor

Incidence

(%)

Rates of MI and Bleeding Using

Alternative Definitions

TIMI Bleeding

P=0.22 P=0.04 P=0.01

Q-wave

or

3x ↑

CK-MB

BivalirudinUFH

LBCT March 29, 08

ISAR ISAR ISAR REACT 3REACT 3REACT 3 Limitations

•The total dose of UFH (140 U/kg bolus without ACT guidance and with no additional doses) might be higher than that used in other recent PCI trials in the USA; whether and to what degree this affected outcome cannot be determined

•The results ought not

be generalized to pts not pretreated

with clopidogrel

LBCT March 29, 08

ISAR ISAR ISAR REACT 3REACT 3REACT 3 Conclusion

In biomarker negative patients with stable and unstable angina undergoing PCI pretreated

with

clopidogrel 600 mg for >2 hours, bivalirudin does not improve “net clinical benefit”

–

the quadruple endpoint –

at 30 days compared to UFH,

although it significantly reduces bleeding

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