PathophysiologyPathophysiology of ACSof ACS

1.4 MM

Non-ST-segment

elevation ACS

0.6 MM

ST-segment elevation MI

~ 2.0 MM patients admitted

to CCU or telemetry annually

NSTEMI NSTEMI vsvs STEMISTEMI

VANQWISHVANQWISH Boden et al N Engl J Med 1998;338:1785-1792

920 patients randomized to either “invasive” or “conservative” management, defined as medical therapy and noninvasive testing, with subsequent invasive management if indicated by the development of spontaneous or inducible ischemia, within 72 hours of the onset of a non– Q-wave infarction.ResultsThe number of patients who died at hospital discharge was significantly higher in the invasive-strategy group (36 vs. 15 patients, P=0.004), Overall mortality during follow-up did not differ significantly.ConclusionsMost patients with non–Q-wave MI do not benefit from routine, earlyinvasive management consisting of coronary angiography and revascularization.

FRISC II FRISC II –– Outcome at 1 YearOutcome at 1 Year

Lancet 2000;356:9-16

N= 2,457 Swedish ACS patients N= 2,457 Swedish ACS patients

conservative

invasive

Platelet adhesion

Platelet aggregation

Adhesive proteinsfibrinogenvWF

GPIIb/IIIa inhibitors

Roffi

et al. Eur Heart J 2002;23,1441–1448

N= 29,570 pts in 6 randomized, double-blind placebo-controlled trials of GPIIb/IIIa antagonists in the management of ACS

diabetics

2006;295:1531-1538

N=2,022 high risk ACS patients (unstable angina with EKG abnormalities or troponin elevation)

The primary end point was a composite of death, myocardialinfarction, or urgent target vessel revascularization

N=2,022 high risk ACS patients (unstable angina with EKG abnormalities or troponin elevation)

The primary end point was a composite of death, myocardialinfarction, or urgent target vessel revascularization

Oral AntiOral Anti--platelet Agents platelet Agents –– Sites of ActionSites of Action

GP IIb/IIIa inhibitor

CAPRIE CAPRIE -- Primary Endpoints*Primary Endpoints*

Months of FollowMonths of Follow--UpUp

Cum

ulat

ive

Even

t Rat

e (%

)C

umul

ativ

e Ev

ent R

ate

(%) 5.83%5.83%

ClopidogrelClopidogrel

AspirinAspirin

5.33%5.33%

8.7% Overall Risk Reduction

p=0.045

00

44

88

1212

1616

00 33 66 99 1212 1515 1818 2121 2424 2727 3030 3333 3636

** MI, Ischemic Stroke, or Vascular Death

N= 19,185 patients with atherosclerotic disease

0.00

0.01

0.02

0.03

0.04

0.05

0.06

Cum

ulat

ive

Haz

ard

Rat

e

Clopidogrel Clopidogrel + ASA*+ ASA*

1010 2020 3030

Placebo Placebo + ASA*+ ASA*

Days of FollowDays of Follow--UpUp00

PP = 0.003= 0.003N = 12,562N = 12,562

* In addition to other standard therapies.

The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

MI/Stroke/CV Death Within 30 DaysMI/Stroke/CV Death Within 30 Days

21%21%Relative RiskRelative Risk

ReductionReduction

Placebo+ ASA*

Clopidogr el

+ ASA*

Major Bleeding by ASA DoseMajor Bleeding by ASA Dose

<100 mg 2.6%

2.0%

100-200 mg 3.5% 2.3%

>200 mg 4.9% 4.0%

ASA Dose

COMMIT: Effect of Clopidogrel COMMIT: Effect of Clopidogrel on Death in Hospitalon Death in Hospital

Time (d Since Randomization [≤28 d)

Placebo + ASA: 1846 deaths (8.1%)Clopidogrel + ASA: 1728 deaths (7.5%)

7% (SE3) relative risk reduction (2P=.03)

Mor

talit

y(%

)

0

7

14

21

28

7

6

5

4

3

2

1

0

Adapted with permission from COMMIT Collaborative Group.

Lancet. 2005;366:1607-1621.

CLARITYCLARITY––TIMI 28: Primary EndpointTIMI 28: Primary Endpoint Occluded Artery (or Death/MI Through Angio/HD)Occluded Artery (or Death/MI Through Angio/HD)

PlaceboClopidogrel

P=.001

Odds Ratio: 0.64 (95% CI, 0.53-0.76)

1.00.4 0.6 0.8 1.2 1.6Clopidogrel

BetterPlaceboBetter

n=1752 n=1739

36%Odds Reduction

15.0

21.7

Occ

lude

d A

rter

y or

Dea

th/M

I (%

)

0

5

10

15

20

25

Sabatine MS et al N Engl J Med 2005;352:1179-1189

COMMIT: Effects of COMMIT: Effects of metoprololmetoprolol on deathon death

Days since randomisation

% dead

Metoprolol: 1776 deaths (7.7%)

Placebo: 1798 deaths (7.8%)

1% (SE 3) relative risk reduction (2P=0.7)

COMMIT: Effects of metoprolol on cardiogenic shock by Killip class

Metoprolol Placebo Odds ratio & 95% CIMetop. better Placebo better

BaselineKillip class (22,927) (22,922)

I 611 487(3.5%) (2.8%)

II 362 296(7.9%) (6.5%)

III 155 100(16.2%) (10.4%)

ALL 1141 888(5.0%) (3.9%)-29% SE 5

(2P < 0.00001)

0.4 0.7 1.0 1.3 1.6 1.9

Enhanced Platelet Enhanced Platelet Activation on UFHActivation on UFH

Unstable angina patientsSamples drawn before and after heparin infusionLight transmission aggregometry

Maximum (max) platelet aggregation in PRP from volunteers after adding saline, UFH, enoxaparin, or argatroban

Xiao and Theroux Circulation 1998;97:251-256

(0.625 μM)

Should we inhibit thrombin directly or Should we inhibit thrombin directly or indirectly?indirectly?

Indirect Inhibition

Direct Inhibition

Anti-Xa:Anti-IIa ratioBivalent versus univalent

Heparin binding site

Fibrin/ogenbinding site

Active site

Hirudin Argatroban

REPLACEREPLACE--2 Trial Design2 Trial Design

Bivalirudin vs

Heparin + GP IIb/IIIa During PCIBivalirudin vs

Heparin + GP IIb/IIIa During PCI

Randomization -

double blind, triple dummyRandomization -

double blind, triple dummy

N ~ 6000 Patients: Urgent or Elective PCI N ~ 6000 Patients: Urgent or Elective PCI

Heparin65 U/kg initial bolus

Planned GP IIb/IIIa(abciximab or eptifibatide)

Heparin65 U/kg initial bolus

Planned GP IIb/IIIa(abciximab or eptifibatide)

Bivalirudin0.75 mg/kg initial bolus,

1.75 mg/kg-hr during PCI

Provisional GP IIb/IIIa(abciximab or eptifibatide)

Bivalirudin0.75 mg/kg initial bolus,

1.75 mg/kg-hr during PCI

Provisional GP IIb/IIIa(abciximab or eptifibatide)

abciximab: 0.25 mg/kg bolus, 0.125 abciximab: 0.25 mg/kg bolus, 0.125 μμg/kgg/kg--min (max 10 min (max 10 μμg/min) x 12 hrsg/min) x 12 hrseptifibatideeptifibatide: 180 : 180 μμg/kg double bolus, 2.0 g/kg double bolus, 2.0 μμg/kgg/kg--min x 18min x 18--24 hrs24 hrs

••

““Quadruple EndpointQuadruple Endpoint””

at 30 Daysat 30 Days

••

target ACT>

225 sec

Primary Quadruple EndpointPrimary Quadruple Endpoint

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

11

1.11.1

Heparin + GP IIb/IIIaHeparin + GP IIb/IIIanonnon--inferiorityinferiority

boundary = 0.92boundary = 0.92

HeparinHeparinsuperioritysuperiorityboundaryboundary

Odds Ratio & 95% CIOdds Ratio & 95% CI

Heparin Heparin BetterBetter

BivalirudinBivalirudinBetterBetter

0.82

Heparin+GP IIb/IIIa(n=3008)

Heparin+GP IIb/IIIa(n=3008)

Bivalirudin

(n=2994)

Bivalirudin

(n=2994)

00

22

44

66

88

1010

1212Death, MI, URev, Maj Bld (%)Death, MI, URev, Maj Bld (%)

10.010.09.29.2

Odds Ratio = 0.917(0.772 - 1.089)

p = 0.32

21

Prospective, Randomized Comparison of Prospective, Randomized Comparison of Heparin Plus IIb/IIIa Inhibition and Heparin Plus IIb/IIIa Inhibition and Bivalirudin With or Without IIb/IIIa Bivalirudin With or Without IIb/IIIa

Inhibition in Patients with Acute Coronary Inhibition in Patients with Acute Coronary SyndromesSyndromes

Moderate-high risk

ACS

Study Design – First RandomizationStudy Design – First Randomization

Ang

iogr

aphy

with

in 7

2h

Aspirin in allClopidogrel

dosing and timingper local practice

Aspirin in allClopidogrel

dosing and timingper local practice

UFH orEnoxaparin+ GP IIb/IIIa

Bivalirudin+ GP IIb/IIIa

BivalirudinAlone

R*

*Stratified by pre-angiography thienopyridine use or administration*Stratified by pre-angiography thienopyridine use or administration

Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800)

Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800)

ACUITY Design. Stone GW et al. AHJ 2004;148:764–75ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

Medicalmanagement

PCI

CABG

ACUITY EnrollmentACUITY Enrollment

USA (246)USA (246)

Canada (26)Canada (26)

(17)

Australia(17)

Australia

(25) Spain(25) Spain

(8) France(8) France(12) UK(12) UK

(4) Norway(4) Norway

Finland (3)Finland (3)Poland (1)Poland (1)Germany (66)Germany (66)

Austria (4)Austria (4)

(4) Netherlands(4) Netherlands(5) Belgium(5) Belgium

Italy (15)Italy (15)

Sweden (6)Sweden (6)

(4) New Zealand(4) New Zealand

(5) Denmark(5) Denmark

13,819 pts randomized at 448 centers in 17 countries13,819 pts randomized at 448 centers in 17 countries

Primary Endpoint Measures (ITT)Primary Endpoint Measures (ITT)

11.7%

7.3%5.7%

3.0%

10.1%7.8%

Net clinicaloutcome

Ischemiccomposite

Major bleeding

30 d

ay e

vent

s (%

)

UFH/Enoxaparin+GPI (N=4603) Bivalirudin alone (N=4612)

UFH/Enoxaparin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin Alone

PNI

<0.0001PSup

= 0.015PNI

= 0.011PSup

= 0.32PNI

<0.0001PSup

<0.0001

0 1 2

Net Clinical Outcome CompositeNet Clinical Outcome CompositeUFH/Enoxaparin + IIb/IIIa vs. Bivalirudin AloneUFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone

Men (n=6444)Women (n=2771)

Diabetes (n=2585)No diabetes (n=6630)

CrCl

≥60 (n=6993)

CrCl

<60 (n=1644)

Age <65 (n=5051)Age ≥65 (n=4164)

Risk ratio±95% CI

Risk ratio±95% CI

BivalAlone

UFH/Enox+ IIb/IIIa

7.8%12.9%

US (n=5224)

OUS (n=3991)

10.6%9.5%

8.9%16.1%

10.8%9.8%

9.5%11.6%

9.2%14.7%

11.8%11.5%

10.4%16.8%

13.7%10.9%

10.9%13.5%

P Pint

0.86 (0.71-1.03)0.88 (0.75-1.02)

0.90 (0.77-1.05)0.82 (0.68-0.98)

0.86 (0.74-0.99)0.96 (0.77-1.19)

0.79 (0.64-0.97)0.90 (0.78-1.04)

0.87 (0.75-1.00)0.86 (0.70-1.04)

0.090.09

0.160.03

0.030.71

0.020.16

0.050.12

0.89

0.47

0.43

0.28

0.91

RR (95% CI)

Bivalirudin alone betterBivalirudin alone better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa better

0 1 2

Net Clinical Outcome CompositeNet Clinical Outcome CompositeUFH/Enoxaparin + IIb/IIIa vs. Bivalirudin AloneUFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone

Yes (n=3197)No (n=6008)

Low (0-2) (n=1291)Intermed

(3-4) (n=4407)High (5-7) (n=2449)

Elevated (n=5368)Normal (n=3841)

Risk ratio±95% CI

Risk ratio±95% CI

BivalAlone

UFH/Enox+ IIb/IIIa

9.2%11.3%

12.2%11.1%

P Pint

0.76 (0.65-0.89)1.02 (0.86-1.21)

12.2%7.1%

13.3%9.4%

0.92 (0.80-1.06)0.75 (0.61-0.93)

0.230.01

<0.0010.83

0.35

0.02

0.18

13.0%8.6%

13.7%10.6%

0.96 (0.80-1.14)0.81 (0.69-0.95)

0.610.01 0.42

Biomarkers (CK/Trop)

ST Deviation

TIMI Risk Score

Pre Thienopyridine

6.4% 10.2% 0.63 (0.43-0.91) 0.019.4% 10.2% 0.92 (0.77-1.10) 0.34

13.9% 15.2% 0.92 (0.76-1.11) 0.36

Yes (n=5192)No (n=4023)

RR (95% CI)

Bivalirudin alone betterBivalirudin alone better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa better

Moderate-high risk

ACS(n=13,819)

Study Design – Second RandomizationStudy Design – Second RandomizationModerate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819)

Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819)

ACUITY Design. Stone GW et al. AHJ 2004;148:764–75ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

Aspirin in allClopidogrel

dosing and timingper local practice

Aspirin in allClopidogrel

dosing and timingper local practice

BivalirudinAlone

(n=4,612)

UFH or EnoxaparinUFH or EnoxaparinRoutine upstream

GPI in all ptsGPI started in

CCL for PCI onlyR

BivalirudinBivalirudin

RRoutine upstream

GPI in all ptsGPI started in

CCL for PCI only

UFH

, Enoxaparin,or Bivalirudin

UFH

, Enoxaparin,or Bivalirudin

Routine upstreamGPI in all pts

(4,605)

Deferred GPIfor PCI only

(n=4,602)

VS.VS.

Days from Randomization

Ischemic Composite EndpointIschemic Composite Endpoint

0

5

10

15

0 5 10 15 20 25 30 35

Estimate P(log rank)7.1%0.147.9%

Bivalirudin alone (N=4612) 0.287.8%

Upstream IIb/IIIa vs. Selective IIb/IIIa vs. Bivalirudin alone Upstream IIb/IIIa vs. Selective IIb/IIIa vs. Bivalirudin alone C

umul

ativ

e Ev

ents

(%) Routine Upstream IIb/IIIa (N=4605)

Deferred PCI IIb/IIIa (n=4602)

Days from Randomization

Major Bleeding EndpointMajor Bleeding Endpoint

0

5

10

15

0 5 10 15 20 25 30 35

Estimate P(log rank)6.1%0.0094.9%

Bivalirudin alone (N=4612) <0.0013.0%

Upstream IIb/IIIa vs. Selective IIb/IIIa vs. Bivalirudin alone Upstream IIb/IIIa vs. Selective IIb/IIIa vs. Bivalirudin alone C

umul

ativ

e Ev

ents

(%)

Routine Upstream IIb/IIIa (N=4605)Deferred PCI IIb/IIIa (n=4602)

1

3.7 4

6.4

0

2

4

6

8

ST Elevation Myocardial Infarction (STEMI)ST Elevation Myocardial Infarction (STEMI)

Relationship Between Time to ReperfusionRelationship Between Time to Reperfusion and Mortality: GUSTOand Mortality: GUSTO--IIbIIb

Berger et al. Circulation 1999;100:14

30-daymortality

(%)

< 60 61 –

75 76 –

90 > 91 N: 104 109 76 140

p=0.001

Time to PTCA (minutes)

0

20

40

60

80

100

Wavefront Theory of Myocardial Loss

0

20

40

60

80

100

Reimer et al Circulation 1977;56:786-94

40 min 3h 6h 24h 96h 0 3h 6h 24hDuration of occlusion Time post-occlusion

Tran

smur

al ne

crosis

(%)

Myoc

ardia

l viab

ility (

%)

ASA ASA vsvs Placebo in ISISPlacebo in ISIS--II: Odds of Vascular DeathII: Odds of Vascular Death

Modified from: ISIS-2 Lancet 1988 Aug 13;2(8607):349-60

0.5

1

1.5

Odds ratio and 95% CI

ASA better Placebo better

Astrological Gemini/Libra (n=1442)Birthsign All Others (n=7157)

Prior MI YesNo

Diabetic YesNo

Sex MaleFemale

Age <6060-6970+

Systolic BP <100100-149150-175

Heart Rate <6060-99100+

EKG BBBIMIAMIST↓

ALL PATIENTS (9.4 vs

11.8% mortality) 23% ↓

“When in a trial with a clearly positive result many subgroups are considered, false negative results in some particular subgroups must be expected… It is clear that the best estimate of the real effect is given by the overall results derived from all subgroups combined.”

• Play of chance• Unrecognized randomization error • True effect

10.0%

6.7% 7.2%7.6%

4.8%

2.9%

0%

2%

4%

6%

8%

10%

12%

Death Death (excl shock) Reinfarction

Even

t rat

e

Lysis PCI

19 Randomized Trials of PCI 19 Randomized Trials of PCI vsvs LysisLysis

p=.0019p=.0019 p=.0053p=.0053 p<.0001p<.0001

Keeley, Grines; Lancet 2003Keeley, Grines; Lancet 2003

N = 5,066N = 5,066

1.3%

2.2%

0.08%

0.8%

0%

1%

2%

3%

Hemorrhagic stroke Total stroke

Even

t rat

e

Lysis PCI

P<0.0001P<0.0001 p=0.0002p=0.0002

Keeley, Grines; in pressKeeley, Grines; in press

N = 5,066N = 5,066

19 Randomized Trials of PCI 19 Randomized Trials of PCI vsvs

LysisLysis

STST-- elevation MIelevation MI(n=1,900)(n=1,900)

RandomizeRandomize

PCI (+ stent)PCI (+ stent)100 mg accelerated t100 mg accelerated t--PAPA

DANAMIDANAMI--2: Patient Flow2: Patient Flow

100 US miles

DANAMIDANAMI--22

DENMARKDENMARK

5.4 mill. inhabitants5.4 mill. inhabitants

5 PCI centers5 PCI centers

24 referral hospitals24 referral hospitals

62% of the Danish 62% of the Danish populationpopulation

Transport distanceTransport distanceup to 95 US miles up to 95 US miles (mean 35 miles)(mean 35 miles)

14%

8%

0%

4%

8%

12%

16%

Dea

th /

MI /

Str

oke

(%)

Lytic Primary PCI

P=0.0003 P=0.002Combined Transfer Sites

P=0.048Non-Transfer Sites

DANAMIDANAMI--2: Primary Results2: Primary Results

RRR 45%

Lytic Primary PCI Lytic Primary PCI

14%

9%

0%

4%

8%

12%

16%

12%

7%

0%

4%

8%

12%

16%RRR 40%

RRR 45%

5.9

2.2

3.7

5.7

0%

2%

4%

6%

8%

10%

<2 hr (n=460) >2 hr (n=374)30

-d M

orta

lity

(%)

Prehosp t-PAPCI

5.9

2.2

3.7

5.7

0%

2%

4%

6%

8%

10%

<2 hr (n=460) >2 hr (n=374)30

-d M

orta

lity

(%)

Prehosp t-PAPCI

15.3

7.46.0

7.3

0%

5%

10%

15%

20%

<3 hr (n=551) >3 hr (n=299)

30-d

Mor

talit

y (%

)

Lytic (STK)Transfer for PCI

Early Presenting Patients: Early Presenting Patients: Primary PCI vs FibrinolyticsPrimary PCI vs Fibrinolytics

P=.058 P=.47

CAPTIMCAPTIM

P<.02

PRAGUEPRAGUE--22

Widimsky P, et al. Eur Heart J. 2003;24(1):94-104. Steg PG, et al. Circulation. 2003;108(23):2851-2856.

Gersh, Stone, White, Holmes JAMA 2005;293:979-986

Eisenhower CheneyYear: 1955 2000

Therapy: Morphine Angioplasty/StentHeparin HeparinWarfarin AspirinAtropine Abciximab

Clopidogrelβ-BlockerStatin

Bed Rest: 7 Weeks < 2 Days

Expected Mortality: 30% < 5%

The Evolution of Optimal MyocardialThe Evolution of Optimal Myocardial Infarction Therapy 1955Infarction Therapy 1955--20002000