ISAR-REACT 4: DiscussionISAR-REACT 4: Discussion

Deepak L. Bhatt MD, MPH, FACC, FAHA

Chief of Cardiology, VA Boston Healthcare System

Director, Integrated Interventional Cardiovascular Program at Brigham and Women’s Hospital and the VA Boston Healthcare System

Associate Professor of Medicine, Harvard Medical School

Senior Investigator, TIMI Study Group

Disclosure for Dr. Bhatt

Research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, The Medicines Company.

This presentation discusses off-label and/or investigational uses of various drugs and devices.

Background

• Majority of patients with NSTEMI undergo PCI, as the

evidence supports

• ISAR-REACT 2 showed that abciximab plus heparin was

superior to heparin alone in PCI of NSTEMI patients

• ACUITY showed that in NSTE-ACS, bivalirudin was non-

inferior to GPIIb/IIIa inhibitors plus heparin versus heparin

alone, with significantly less major bleeding

Bavry et al. AJM 2006.Kastrati et al. JAMA 2006. Stone et al. NEJM 2006.

Primary EndpointDeath, Large MI, UTVR, Major Bleeding

Days since Randomization

0

5

10

15

20

0 5 10 15 20 25 30

Cu

mu

lativ

e In

cid

en

ce (

%)

Relative risk, 0.99 (95% CI, 0.74–1.32)P=0.94

Bivalirudin

Abciximab 10.9%

11.0%

Kastrati et al. NEJM 2011.

Curves virtually superimposable

Secondary Efficacy EndpointDeath, Any MI, UTVR

Bivalirudin

Abciximab

Relative risk, 0.96 (95% CI, 0.74–1.25)P=0.76

0

5

10

15

20

0 5 10 15 20 25 30

Cu

mu

lativ

e In

cid

en

ce (

%)

Days since Randomization

Abciximab Bivalirudin

Death, % 1.4 1.6Any MI, % 12.0 11.4uTVR, % 0.8 1.3

12.8%

13.4%

Kastrati et al. NEJM 2011.

Even with increased power of a more sensitive MI definition curves appear identical

Secondary Safety EndpointMajor Bleeding

0

5

10

15

20

0 5 10 15 20 25 30

Cu

mu

lativ

e In

cid

en

ce (

%)

Days since Randomization

Relative risk, 1.82 (95% CI, 1.10–3.07)P=0.02

Bivalirudin

Abciximab 4.6%

2.6%

Kastrati et al. NEJM 2011.

Large relative and absolute risk reduction

ISAR-REACT 4: Strengths

• Rigorous double-blind, double-dummy design (ACUITY

was open-label, which - in theory - could affect

ascertainment of non-fatal endpoints)

• Comparison was against abciximab (which some still

consider the gold standard GPIIb/IIIa inhibitor)

• Strict definition of bleeding (intracranial, intraocular, or

retroperitoneal; Hb decrease >4g/dL plus either overt

bleeding or need for transfusion of 2 or more units) –

difficult to argue with the importance of that

ISAR-REACT 4: Caveats

• Patients pretreated with ASA + clopidogrel 600 mg

– Results may not apply to ASA/clop untreated

• Prasugrel or ticagrelor not used

– Difficult to see how this would change the results

• Bleeding advantage would have been attenuated if more

radial cases were performed

– But still numerically lower pericardial, GI, and GU

bleeds, and no apparent loss of efficacy

Conclusions

• In patients pretreated w/ ASA and clopidogrel 600 mg,

– Bivalirudin results in less major bleeding than heparin +

abciximab; also lower rate of severe thrombocytopenia

– Similar efficacy

– Shorter duration infusion

– Likely lower cost

• Coupled with HORIZONS-AMI, data from ISAR-REACT 4

support use of bivalirudin during PCI across the full

spectrum of ACS