Risk Stratification Based on Ischemia Detected on Continuous ECG Monitoring

in Non-ST-elevation Acute Coronary Syndromes

Risk Stratification Based on Ischemia Detected on Continuous ECG Monitoring

in Non-ST-elevation Acute Coronary Syndromes

Benjamin Scirica, MD MPHBenjamin Scirica, MD MPHInvestigator, TIMI Study GroupInvestigator, TIMI Study Group

Associate Physician, Brigham and Women’s HospitalAssociate Physician, Brigham and Women’s Hospital

Instructor in Medicine, Harvard Medical SchoolInstructor in Medicine, Harvard Medical School

Disclosures

The TIMI Study Group has received research/grant The TIMI Study Group has received research/grant support in the past 2 years through the support in the past 2 years through the Brigham and Women’s Hospital from :Brigham and Women’s Hospital from :

AstraZenecaAstraZeneca

Bristol-Myers Squibb CompanyBristol-Myers Squibb Company

CV Therapeutics, Inc. CV Therapeutics, Inc.

Eli Lilly and CompanyEli Lilly and Company

Daiichi SankyoDaiichi Sankyo

GlaxoSmithKlineGlaxoSmithKlineMerck & Co., Inc.Merck & Co., Inc.Millennium Pharmaceuticals, Inc. Millennium Pharmaceuticals, Inc. Novartis PharmaceuticalsNovartis PharmaceuticalsNuvelo, Inc. Nuvelo, Inc. Ortho-Clinical Diagnostics, Inc. Ortho-Clinical Diagnostics, Inc. Pfizer Inc Pfizer Inc Sanofi-AventisSanofi-AventisSanofi-Synthelabo RechercheSanofi-Synthelabo RechercheSchering-Plough Research InstituteSchering-Plough Research Institute

Dr Scirica has received research support from:Dr Scirica has received research support from:

AstraZeneca AstraZeneca

Bristol-Myers SquibbBristol-Myers Squibb

CV Therapeutics, Inc. CV Therapeutics, Inc.

Daiichi SankyoDaiichi Sankyo

Novartis PharmaceuticalsNovartis PharmaceuticalsSanofi-AventisSanofi-Aventis

Dr Scirica is on the speaker’s bureau of:Dr Scirica is on the speaker’s bureau of:

Pfizer Inc Pfizer Inc

Dr Scirica has received honoraria for educational Dr Scirica has received honoraria for educational presentations/advisory boards from:presentations/advisory boards from:

CV Therapeutics, Inc. CV Therapeutics, Inc.

Novartis PharmaceuticalsNovartis Pharmaceuticals

ACUTE CORONARY SYNDROMESACUTE CORONARY SYNDROMESACUTE CORONARY SYNDROMESACUTE CORONARY SYNDROMES

NQWMIUA QwMI

Tn

CK-MB

ST-elevation ACSST-elevation ACSST-elevation ACSST-elevation ACSNon–ST-elevation ACSNon–ST-elevation ACSNon–ST-elevation ACSNon–ST-elevation ACS

UAUAUAUA NSTEMINSTEMINSTEMINSTEMI STEMISTEMISTEMISTEMI

Duration - 13.5 min

ST

dev

iati

on

fro

m b

asel

ine

Typical Episode of Ischemic ST-segment Depression

TIMI ECGCore Laboratory

TIMI CECG Core Lab ST Depression Analysis

Max ST dev.2.1 mm

Before Episode During IschemicEpisode

Definition of Ischemia

ST depression > 1 mm from baseline lasting > 1 min in

duration

Clinical Significance of Recurrent Ischemia in NSTEACS

9

1.53

16

0

5

10

15

20

MI Urgent Revasc

Inci

den

ce (

%)

(Gottlieb SO, et al. NEJM 314;1986

No Ischemia Ischemia

P<0.01P<0.001

N=37 N=33

P<0.001

N=37 N=33

(Jernberg, et al. JACC 1999)

FAST Study (n=630 pt)

P<0.001

Adj HR 5.7P<0.001

P<0.02

2.9 1.6

9.96.6

11.1

9.8

1.4

3.4

0

5

10

15

20

0 1 to 2 2 to 5 >5

Clinical Significance of Recurrent Ischemia in Non-STEMI ACS

1.5 1.6

5.63.66.3

9.9

0.13.2

0

5

10

15

20

0 1 to 2 2 to 5 >5

Meta-analysis of 995 patients from CAPTURE, PURSUIT, and FROST

Inci

den

ce (

%)

of D

ea

th a

nd D

eat

h/M

I

(Akkerhuis, et al. Eur Heart J 2001;22:1997)

DeathMI

5 Day 30 Day

P<0.001 P<0.001

Number of Events / 24hrs

N=724 N=137 N=63 N=71 N=724 N=137 N=63 N=71

UA/NSTEMIUA/NSTEMI(Moderate-High Risk)(Moderate-High Risk)

RanolazineRanolazineIV to POIV to PO

Placebo Placebo Matched IV/POMatched IV/PO

RANDOMIZE (1:1)RANDOMIZE (1:1)Double-blindDouble-blind

HolterHolterContinuous Continuous

7-day recording7-day recording

Long-term Follow-upLong-term Follow-up(Median 348 Days)(Median 348 Days)

Standard TherapyStandard Therapy

N = 6560N = 6560

Baseline CharacteristicsBaseline Characteristics

RANOLAZINE(n=3,162)

PLACEBO(n=3,189)

Age (yrs, median)Female (%)Prior MI (%)DM (%)Prior Revasc (%)TRS (%) Low (0-2) Moderate (3-4) High (>4)NSTEMI on admission (%)Cath during Index Event (%)

6436343426

2753205169

6434343427

2752215159

Holter Cohort6,351 pts (97% of entire trial)

ResultsResults

Clinical Correlates of IschemiaClinical Correlates of Ischemia

0.5 1 5

+ Ultra TnI 1.2 (0.99, 1.4)

BNP >80 pg/ml 1.4 (1.2, 1.7)

No Early Inv. Rx 1.1 (0.98, 1.3)

High TRS 2.6 (2.1, 3.3)

Mod TRS 1.5 (1.2, 1.8)

Low TRS 1.0 (referent)

Female 1.3 (1.1, 1.5)

Hazard Ratio

Adj HR (95% CI)Variable

No episodes [869 / 5095]1 to 2 episodes [156 / 590]> 2 episodes [191 / 648]

0 100 200 300 400 500

0

10

20

30

40

Days from randomization

CV

dea

th /

MI /

Rec

urr

ent

Isch

emia

(%

)

Primary endpoint according to number episodes of Primary endpoint according to number episodes of ischemia ischemia excludingexcluding events during first 7 days events during first 7 days

p<0.0001

Days from randomization

CV

dea

th (

%)

No episodes [173 / 5095]1 to 2 episodes [42 / 590]> 2 episodes [71 / 648]

0 100 200 300 400 500

0

5

10

15

CV death according to number episodes of CV death according to number episodes of ischemia ischemia excludingexcluding events during first 7 days events during first 7 days

p<0.0001

CV Death / MI / Severe Recurrent Ischemia CV Death / MI / Severe Recurrent Ischemia by TIMI Risk Score and Presence of Ischemia on CECGby TIMI Risk Score and Presence of Ischemia on CECG

11.1%

17.0%

24.5%

15.8%

29.8%

42.7%

0%

10%

20%

30%

40%

50%

Low (0-2) Moderate (3-4) High (5-7)

No Ischemia Ischemia

1657 259 638 3427582701

p=0.02

p<0.001

p<0.001

TIMI Risk Score Category

CV Death by TIMI Risk Score and CV Death by TIMI Risk Score and Presence of Ischemia on CECGPresence of Ischemia on CECG

1.6%3.3%

6.7%

2.7%

8.9%

16.1%

0%

5%

10%

15%

20%

Low (0-2) Moderate (3-4) High (5-7)

No Ischemia Ischemia

1657 259 638 3427582701

p=0.2

p<0.001

p<0.001

TIMI Risk Score Category

Days from randomization

CV

dea

th /

MI /

Rec

urr

ent

Isch

emia

(%

)

0 100 200 300 400 500

0

10

20

30

40

50

No episodes [611 / 3038]1 to 2 episodes [106 / 337]> 2 episodes [249 / 475]

Primary Endpoint by Occurrence of Ischemia Conservative Strategy

p<0.0001

No episodes [386 / 2142]1 to 2 episodes [83 / 272]> 2 episodes [63 / 191]

Primary Endpoint by Occurrence of Ischemia Early Invasive Strategy

0 100 200 300 400 500

0

10

20

30

40

Days from randomization

CV

dea

th /

MI /

Rec

urr

ent

Isch

emia

(%

)

p<0.0001

ConclusionsConclusions

Among a contemporary cohort of patients with Among a contemporary cohort of patients with NSTEACS, recurrent ischemia is commonNSTEACS, recurrent ischemia is common

Recurrent ischemia as detected on cECG is Recurrent ischemia as detected on cECG is strongly associated with death and recurrent MI in strongly associated with death and recurrent MI in the months after ACSthe months after ACS

Ischemia on cECG is a sensitive method to detect Ischemia on cECG is a sensitive method to detect myocardial perfusion after PCImyocardial perfusion after PCI

This relationship is consistent even in patients at This relationship is consistent even in patients at different clinical risk and in patients who undergo different clinical risk and in patients who undergo an early invasive management strategyan early invasive management strategy