james j. ferguson, md the evolving standard of care for acute coronary syndromes 2006

James J. Ferguson, MD

James J. Ferguson, MD

The Evolving Standard of Care for Acute Coronary

Syndromes2006

TIMI 8

BAT

GUSTO IIA

OASIS Pilot

TIMI 7

CURE

CAPRIE

CREDO

ISAR-REACT

EPICEPILOG

CAPTURE

TARGET

GUSTO IVRESTORE

IMPACT 2

ESPRIT

ACE

ISAR-SWEET

EPISTENT

PURSUIT

PRISM PRISM-PLUS

REPLACE 2

OASIS 2

GUSTO IIB

HELVETICA

FRISC

FRIC

RITA 3

A to Z

INTERACT

SYNERGY

CADILLAC

TACTICS

ESSENCE

FRAXIS

FRISC 2

FRISC 2ACUTE 2

TIMI 11B

PROTECT

How do we sort out this mess ?


Syndromes2006

Evolutionary

perspectives

Evolving physiology

Evolving data

Evolving messages

Putting it together


Syndromes2006

Geological Time Scale

ACS Time Scale

Reduce demand

Treat the thrombus

Harmonize therapies

Open the vessel

Antithrombotic EpochAntithrombotic Epoch

Interventional Epoch

Interventional Epoch

Synergistic EpochSynergistic Epoch

Palliative EpochPalliative Epoch

Mechanistic Epoch

Mechanistic Epoch

Understand the biology

Evolutionary

perspectives

Evolving physiology

Evolving data

Evolving messages

Putting it together


Syndromes2006

DETERMINANTS OFRupture

ThrombosisHealing

Fibrous tissueAtheromatous material(lipid-rich)

Thrombus

Plaque hemorrhageMacrophageSmooth muscle cell

Luminal factors

Extra-luminal factors

Systemic factors

Luminal factors

Extra-luminal factors

Systemic factors

UNSTABLE PLAQUE

STABLE PLAQUE

MYOCARDIAL INFARCTION

Inflammation and repair

Core size

Capthickness

“Vulnerable” Plaque and

Acute Coronary Syndromes

Rupture

Thrombosis

Occlusion

Reduce thrombus burden

Limit thrombus progression

Promote healing / homeostasis

Open the occluded vessel

Limit the extent of the damage

Rx UA

Rx MI

ProthrombinProthrombin

Thrombin

FibrinogenFibrinogen

Fibrin Fibrin monomermonomer

Tissue FactorTissue Factor

VIIaVIIa

VIIVII

VIIa/TFVIIa/TF

IXIX IXaIXa

XX

XaXa

Fibrin Fibrin polymerpolymer

Crosslinked Fibrin

VV

VaVa

VIIIVIII

VIIIaVIIIaXIXI XIaXIa

XIIXII XIIaXIIa

PK, PK, HKHK

HKHK

XIIIXIII XIIIaXIIIa

CaCa++ ++

PLPLCaCa++ ++

PLPL

Coagulation

Question:

What do we really need to know about coagulation?

Answer:

How to treat it when it happens.

How to prevent it in the first place.

Question:

What do we really need to know about coagulation?

Answer:

How to treat it when it happens.

How to prevent it in the first place.

Coagulation

Platelet Activation

Thrombus

Injury

Platelet Aggregation

Thrombin Generation

Thrombin Activity

Coagulation

Platelet Activation

Thrombus

Injury

Platelet Aggregation

Thrombin Generation

Thrombin Activity

Aspirin

Ticlopidine

Clopidogrel

IIb/IIIa blockers

Heparin

LMW heparin

Xa inhibitors

LMW heparin

Heparin

AntithrombinsFibrinolytic Rx

Evolutionary

perspectives

Evolving physiology

Evolving data

Evolving messages

Putting it together


Syndromes2006

1990 1993 1996 1999 2002 2005

AbciximabEptifibatide

Tirofiban

P-S stent DE stent

Clopidogrel Clopidogrel ACS

Bivalirudin

DesirudinLepirudin

Argatroban

Enox ACS Dalt ACSEnoxaparin Dalteparin

UA / NSTEMI Trials

Thrombin InhibitorsThrombin Inhibitors HELVETICAHELVETICAERAERA

TIMI 8TIMI 8

BAT(original)

BAT(original)

GUSTO IIA GUSTO IIA

REPLACE 2REPLACE 2REDUCEREDUCE OASIS 2 OASIS 2

BAT(revised)

BAT(revised)

OASIS PilotOASIS Pilot

TIMI 7TIMI 7 GUSTO IIB GUSTO IIB

PROTECTPROTECT

LMW HeparinsLMW HeparinsFRICFRIC

ESSENCEESSENCE

FRISCFRISCACUTE 2 ACUTE 2

FRAXISFRAXIS

TIMI 11BTIMI 11B

INTERACT INTERACT

A to Z A to Z

RITA 3 RITA 3

FRISC 2FRISC 2SYNERGYSYNERGY

PROTECTPROTECT

ThienopyridinesThienopyridines ISARISARISAR-REACTISAR-REACT

CURECURECLASSICSCLASSICSCAPRIECAPRIE CREDOCREDO

STARSFANTASTIC

MATTIS

STARSFANTASTIC

MATTIS ISAR-SWEETISAR-SWEET

ARMYDA 2ARMYDA 2

ISAR-REACTISAR-REACTGP IIb/IIIa antagonistsGP IIb/IIIa antagonists EPICEPIC EPILOGEPILOG

EPISTENTEPISTENTCAPTURECAPTURE

TARGETTARGET CADILLACCADILLAC

GUSTO IVGUSTO IV

RESTORERESTORE

PRISMPRISMTACTICSTACTICSIMPACT 2IMPACT 2

ESPRITESPRITPURSUITPURSUIT

PRISM-PLUSPRISM-PLUS

ISAR-SWEETISAR-SWEET

ACEACE

PROTECTPROTECT

ISAR-COOLISAR-COOL

Interventional IssuesInterventional Issues

RITA 3RITA 3Wallstent restenosisWallstent restenosis

TAXUS IV TAXUS IV TACTICSTACTICS

SIRIUS SIRIUS RAVEL RAVEL FRISC 2FRISC 2STRESS

BENESTENT

STRESS

BENESTENTICTUSICTUS

ISAR-COOLISAR-COOL

ISAR-REACT 2ISAR-REACT 2

CHARISMACHARISMA

ACUITYACUITY

[ OASIS 5 ][ OASIS 5 ]

Medical Rx

No Cath

Cath PCI

Surgery

Medical Rx

Delayed surgery

Medical Rx

No disease

Delayed PCI

Time

Admission Cath PCI DischargeSurgery

UA/NSTEMI Management

Medical Rx

No Cath

Cath PCI

Surgery

Medical Rx

Delayed surgery

Medical Rx

No disease

Delayed PCI

Time


Patient X


Medical Rx

No Cath

Cath PCI

Surgery

Medical Rx

Delayed surgery

Medical Rx

No disease

Delayed PCI

Time


(82 %)

(18 %)

(52 %)

40 % < 48 hrs

12 % > 48 hrs

(12 %)

63 % < 48 hrs

19 % > 48 hrs

CRUSADERegistry

10/05-9/05n=35,897

Medical Rx

Patient X


ISAR - COOL

PROTECTCURECURE

ClopidogrelClopidogrel

Invasive StrategyInvasive Strategy LMW HeparinLMW Heparin

IIb/IIIa antagonistsIIb/IIIa antagonists

FRISC II

TACTICS / TIMI 18

RITA 3

ICTUS

FRISC II

TACTICS / TIMI 18

RITA 3

ICTUS

Important DataImportant Data UA / NSTEMI

INTERACT

A to Z

SYNERGY

INTERACT

A to Z

SYNERGY

OASIS 5

ISAR-REACT 2

ACUITY

ICTUS

OASIS 5

ISAR-REACT 2

ACUITY

ICTUS

Very Recent Data

Very Recent Data

UA / NSTEMI

OASIS 5OASIS 5 OASIS 5 InvestigatorsN Engl J Med. 2006;354: 1464-76

Patients w/ NSTE ACS

Chest pain < 24 hours2/3:

Age > 60ST-segment ∆

↑ cardiac markers

ASA, clopidogrel, IIb/IIIa, planned cath

per local practice

ExcludeAge < 21

Contraindication to enoxHemorrhagic stroke < 12

moCreat > 3 mg/dL (265

umol/L) Randomize

n = 20,000

Fondaparinux2.5 mg sc qd

Enoxaparin 1 mg/kg sc bid

PCI < 6 h: IV fondaparinux 2.5 mg w/o IIb/IIIa, 0 w/

IIb/IIIaPCI > 6h: IV fondaparinux 5 mg w/o IIb/IIIa, 2.5 mg w/

IIb/IIIa Primary Efficacy Death, MI, refractory ischemia at 9 days

Safety Major bleeding at 9 daysRisk/benefit Death, MI, refractory ischemia and major

bleeding at 9 days Secondary Above and each component separately at day 30 and 6 months Hypothesis: First test non-inferiority, then test superiority

PCI < 6 h: no UFHPCI > 6h: IV UFH

100 U/kg w/o IIb/IIIa60 U/kg w/ IIb/IIIa

Outcomes


In-hospital procedures at 9 Days

Cath Lab No Cath Lab

Centers (n) 420 (73%) 156 (27%)

Patients (n) 14,028 (70%) 6050 (30%)

Angiography 73.2% 27.7%

PCI 39.6% 12.5%

CABG 6.8% 1.8%

Revascularization 46.1% 14.1%

Mean duration of therapy: Enoxaparin 5.2 + 2.3 days Fondaparinux 5.4 + 2.4 days

Abciximab(n=1,012)

Abciximab(n=1,012)

Placebo(n=1,010)Placebo(n=1,010)

Endpoints:Primary Endpoint: Composite of death, MI, and urgent TVR due to myocardial

ischemia within 30 daysSecondary Endpoint: In-hospital major and minor bleeding

Endpoints:Primary Endpoint: Composite of death, MI, and urgent TVR due to myocardial

ischemia within 30 daysSecondary Endpoint: In-hospital major and minor bleeding

ISAR-REACT 2: Trial Design

Clopidogrel(Pre-treatment high-dose 600 mg loading dose for at least 2 hour pre-procedure, 2 x 75

mg/d through discharge, 75 mg/d for 4 weeks)

Clopidogrel(Pre-treatment high-dose 600 mg loading dose for at least 2 hour pre-procedure, 2 x 75

mg/d through discharge, 75 mg/d for 4 weeks)

↑ troponin T or new ST ↓Transient (<20 min) ST ↑ of > 0.1 mVNew BBB

↑ troponin T or new ST ↓Transient (<20 min) ST ↑ of > 0.1 mVNew BBB

Significant lesion in native vessel or bypass graftAmenable to and requiring PCI

Significant lesion in native vessel or bypass graftAmenable to and requiring PCI

2,022 patients with ACS and new angina episode within past 48 hours

Kastrati A, et al. JAMA. 2006; 295: 1531-8

ISAR-REACT 2: Primary EndpointPrimary Endpoint

Death, MI, or urgent TVR in 30 daysPrimary EndpointBy Troponin Status

p = .02 p = .98p = .03


ISAR-REACT 2: Bleeding

•There was no difference between the abciximab and placebo groups in in-hospital major and minor bleeding (p=NS for both).

•There was one intracranial bleed in each group.

•2.5% of patients received transfusions in the abciximab group compared with 2.0% in the placebo group (RR 1.25)

In-hospital Major and Minor Bleeding (%)P=NS


Moderate-high risk

ACS

ACUITY

An

gio

gra

ph

y w

ith

in 7

2h

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

Medicalmanagement

PCI

CABG

Endpoints: Death, MI, and unplanned revascularization for ischemia (30 days and 1 year); major bleeding (30-days); composite of the above (30-days)

Stone G. American College of Cardiology 2006 Scientific Sessions; March 12, 2006; Atlanta, GA.

ASA in allclopidogrel

dosing and timingper local practice

UFH orEnoxaparin+ GP IIb/IIIa

Bivalirudin+ GP IIb/IIIa

BivalirudinAlone

R

Moderate-high risk

ACS

ACUITY

An

gio

gra

ph

y w

ith

in 7

2h


Medicalmanagement

PCI

CABG



ASA in allclopidogrel


UFH orEnoxaparin+ GP IIb/IIIa

Bivalirudin+ GP IIb/IIIa

BivalirudinAlone

R

Ischemic Composite

BleedingNet Clinical Outcome

7.3 % 5.7 % 11.7 %

7.7 % 5.3 % 11.8 %

7.8 % 3.0 % 10.1 %

Moderate-high risk

ACS(n=13,819)

ACUITY Second Randomization – GP IIb/IIIa Inhibitor Timing


Aspirin in allClopidogrel


BivalirudinAlone

(n=4,612)

UFH or Enoxaparin

Bivalirudin

Routine upstream GPI in all pts

GPI started in CCL for PCI only

UF

H, E

no

xa

pa

rin,

or B

ivaliru

din

Routine upstreamGPI in all pts

(4,605)

Deferred GPIfor PCI only

(n=4,602)

VS





R

R

BivalirudinAlone

(n=4,612)

Moderate-high risk

ACS(n=13,819)

ACUITY Second Randomization – GP IIb/IIIa Inhibitor Timing


Aspirin in allClopidogrel


BivalirudinAlone

(n=4,612)

UFH or Enoxaparin

Bivalirudin



UF

H, E

no

xa

pa

rin,

or B

ivaliru

din

Routine upstreamGPI in all pts

(4,605)

Deferred GPIfor PCI only

(n=4,602)

VS





R

R

Ischemic Composite

BleedingNet Clinical Outcome

7.1 % 6.1 % 11.7

7.9 % 4.9 % 11.7 %

7.8 % 3.0 % 10.1 %Bivalirudin

Alone(n=4,612)

Mehta SR, et al. JAMA. 2005;293:2908-2917.

Routine vs Selective Invasive StrategyRoutine vs Selective Invasive Strategy:Summary of Odds Ratios for All Major OutcomesSummary of Odds Ratios for All Major Outcomes

No./Total (%)

Outcome Routine Selective Odds Ratio (95% CI) P Value

Randomization to Hospital Discharge

Death 82/4608 (1.8) 51/4604 (1.1) 1.60 (1.14 – 2.25) .007

Nonfatal MI 171/4608 (3.7) 139/4604 (3.0) 1.24 (0.99 – 1.56) .07

Death or MI 238/4608 (5.2) 177/4604 (3.8) 1.36 (1.12 – 1.66) .002

After Hospital Discharge to End of Follow-up

Death 172/4526 (3.8) 223/4552 (4.9) 0.76 (0.62 – 0.94) .01

Nonfatal MI 164/4370 (3.8) 294/4430 (6.6) 0.56 (0.46 – 0.67) <.001

Death or MI 323/4370 (7.4) 486/4430 (11.0) 0.64 (0.56 – 0.75) <.001

Randomization to End of Follow-up

Death 254/4608 (5.5) 274/4604 (6.0) 0.92 (0.77 – 1.09) .33

Nonfatal MI 335/4608 (7.3) 433/4604 (9.4) 0.75 (0.65 – 0.88) <.001

Death or MI 561/4608 (12.2) 663/4604 (14.4) 0.82 (0.72 – 0.93) .001

Routine vs Selective Invasive Strategies in ACS

Adapted from Mehta S, et al. JAMA. 2005;293;2908-2917.

Composite of Death or Myocardial InfarctionNo./Total (%)

Source Routine Invasive

Selective Invasive

TIMI IIIB 86/740 (11.6) 101/733 (13.8)

VANQWISH 152/462 (32.9) 139/458 (30.3)

MATE 16/111 (14.4) 11/90 (12.2)

FRISC II 127/1222 (10.4) 174/1235 (14.1)

TACTICS 81/1114 (7.3) 105/1106 (9.5)

VINO 4/64 (6.3) 15/67 (22.4)

RITA 3 95/895 (10.6) 118/915 (12.9)

Total 561/4608 (12.2) 663/4604 (14.4)

0.1 1.0 10

Odds Ratio (95% CI)

FavorsRoutineInvasive

FavorsSelectiveInvasive

OR - 0.8295% CI, 0.72-0.93

P < 0.001

ICTUS N Engl J Med 2005; 353: 1095-1104

•1200 ACS patients•Presenting within 1 day of onset of chest pain•42 Dutch hospitals (12 were high-volume PCI centers)•↑ Troponin T (≥ 0.03 μg/L)•Either ECG evidence of ischemia or documented Hx CAD•Randomized

Early invasive (n=604) Angio within 24-48 hours PCI within 48 hours, CABG as soon as possibleSelective invasive (n=596) Angio for refractory angina, provocable

ischemia

Primary Endpoint:

Death / MI / rehospitalization at 1 year

Early Invasive

Selective Invasive

Death 2.2 % 2.0 %

MI 14.6 % 9.4 %

Rehospitalization

7.0 % 10.9 %

Total 21.7 % 20.4 %

ICTUS N Engl J Med 2005; 353: 1095-1104

22 .7 %

21.2 %

[ RR 1.07, 95 % CI 0.87 - 1.33; p=0.33 ]

ICTUS N Engl J Med 2005; 353: 1095-1104

Median time to PCI23 hours (25th to 75th percentile, 15 to 44) with early invasive Rx283 hours (25th to 75th percentile, 142 to 647) with selective invasive Rx

ICTUS N Engl J Med 2005; 353: 1095-1104

All-Cause Mortality

Bavry et al. J Am Coll Cardiol 2006; 48: 1319-25

Even after ICTUS ...Even after ICTUS ...

All-cause mortality as a function of time of angio and extent of revascularization

Bavry et al. J Am Coll Cardiol 2006; 48: 1319-25

Even after ICTUS ...Even after ICTUS ...

Optimize supply / demand Optimize supply / demand

AcuteAcute

Treat underlying atherosclerosis

Prevent recurrent events

Stabilize the plaques

Enhance endothelial function

Chronic anti-thrombotic Rx

Treat underlying atherosclerosis

Prevent recurrent events

Stabilize the plaques

Enhance endothelial function

Chronic anti-thrombotic Rx

Long - termLong - termStatins

ASA

Clopidogrel

ASA / Clopidogrel

Warfarin

Risk factor ↓

Other things not to forgetOther things not to forget

BP control

Glucose control

Smoking cessation

ACE inhibitors

And don’t

forget . . .

O2Nitrates

β-blockers

Evolutionary

perspectives

Evolving physiology

Evolving data

Evolving messages

Putting it together


Syndromes2006

Lessons LearnedLessons Learned

Invasive is better than conservative in high and medium risk patientsFRISC II

TACTICS / TIMI 18RITA 3?? ICTUS ??

UA / NSTEMIUA / NSTEMI


Invasive is better than conservative in high and medium risk patientsAntiplatelet therapy is important

Clopidogrel is beneficialIIb/IIIa blockers are beneficialEarlier is better in high risk“Standard” is more than ASA




Antithrombin therapy is importantEnoxaparin - SYNERGY

Bivalirudin - ACUITYFondaparinux - OASIS 5“Standard” moving beyond UFHChallenges of multiple management pathways




Interaction among agentsInteraction with treatment strategies

Antithrombin therapy is importantHow you put them together is important




Antithrombin therapy is importantHow you put them together is importantLong term therapy is important

Statins ACE InhibitorsAntiplatelet Rx Antithrombotic Rx


Evolutionary

perspectives

Evolving physiology

Evolving data

Evolving messages

Putting it together


Syndromes2006

ASA

IIb/IIIa antagonists

1995 1998

EPISTENT

PURSUIT

2001

ESPRIT

GUSTO 4

2004

ISAR REACT

Clopidogrel CURE

2000

Anti-platelet agents

2006

1997 1999

UFH

LMWH TIMI 11B

2004

SYNERGY

Bivalirudin

2003

REPLACE 2

2001

Anti-thrombotic agents

2006

1992 1995 1998 2001 2004 2007

ISAR REACT 2

Fondaparinux

ACUITY

ACUITY

ACUITY

? ? ?OASIS 5

Our Evolving Anticoagulant Armamentarium

The predictive value of a diagnostic test

is a function not only of sensitivity and specificity,

but also the prevalence of the disease

in the population being tested.

The predictive value of a diagnostic test

is a function not only of sensitivity and specificity,

but also the prevalence of the disease

in the population being tested.

Bayes’ Theorem

Stuff you do works best

in people who really need it.

Stuff you do works best

in people who really need it.

Bubba’s Theorem

AgeAge

(+) Biomarkers(+) Biomarkers

(+) ST-segment (+) ST-segment ΔΔss

DiabetesDiabetes

Refractory symptomsRefractory symptoms

Acute Risk StratifiersAcute Risk Stratifiers

Extent of damageExtent of damageEF, CK, CKMB,

troponinEF, CK, CKMB,

troponin

Extent of homeostatic derangement

Extent of homeostatic derangement

CRP, CD40L, BNP, IL-6, Fibrinogen, P-selectin

CRP, CD40L, BNP, IL-6, Fibrinogen, P-selectin

Extent of diseaseExtent of diseaseEF, DMEF, DM

Evolutionary

perspectives

Evolving physiology

Evolving data

Evolving messages

Putting it together


Syndromes2006

Evolutionary

perspectives

Evolving physiology

Evolving data

Evolving messages

Putting it together

Therapeutic epochsBuilding on what has gone

beforeChanging itAdding to it

Evolutionary

perspectives

Evolving physiology

Evolving data

Evolving messages

Putting it together

Plaque ruptureHomeostatic forcesDynamic balance

Multiple interlocking mechanisms

Evolutionary

perspectives

Evolving physiology

Evolving data

Evolving messages

Putting it together

OASIS 5, ISAR-REACT 2, ACUITYICTUS

Stay tuned ... more to come

Evolutionary

perspectives

Evolving physiology

Evolving data

Evolving messages

Putting it together

Open vesselsKeep them open

Adjunctive therapy importantPerfusion rather than

patency

Evolutionary

perspectives

Evolving physiology

Evolving data

Evolving messages

Putting it together

Look at the big pictureEvaluate the data yourself

Risk stratification is keyDon’t just do ... think

james j. ferguson, md the evolving standard of care for acute coronary syndromes 2006

Documents

investigatorsn engl

w iibiiia primaryefficacydeath

hospital major

days fondaparinux

minor bleeding p

w iibiiiapci

refractory ischemia

planned cath