Empiric Management of ACS With GP IIb/IIIa Platelet Receptor Blockers

Empiric Management of ACS Empiric Management of ACS With GP IIb/IIIa Platelet With GP IIb/IIIa Platelet

Receptor BlockersReceptor Blockers

Current Challenges in the Current Challenges in the Management of ACSManagement of ACS

Death/MI at 30 days 8% to 16% in heparin/aspirin arms of various studies

Recurrent/refractory ischemia associated with reduced survival

Risk stratification/identification of medium/high-risk patient– Rest pain, post-MI– Recurrent ischemia– ST changes on ECG– Prior aspirin use– Serum markers

Implementing new treatment strategies using GP IIb/IIIa platelet blockers in medium- to high-risk ACS patients

Safety and cost of new agents

Downstream Downstream embolizationembolization

DETERMINANTS OF DETERMINANTS OF THROMBOSIS THROMBOSIS - Local factors- Local factors- Systemic factors- Systemic factors

UNSTABLE CORONARYUNSTABLE CORONARY ARTERY DISEASEARTERY DISEASE

RecanalizationRecanalization

LysisLysis

Remodeling

Remodeling

DYNAMIC

Lysis/

Repair

Lysis/

Repair

Cap disruptionCap disruption- Vulnerability- Vulnerability- Triggers- Triggers

VULNERABLE PLAQUEVULNERABLE PLAQUE

Fibrous capFibrous cap

Inflammation and repairInflammation and repair

Core sizeCore size

Lipid-rich coreLipid-rich core

Thr

ombo

lysi

s Throm

bosis

Fibrous tissue

Atheromatous material(lipid-rich)

Thrombus

Plaque hemorrhage

Macrophage

Smooth muscle cell

Théroux P, Fuster V. Théroux P, Fuster V. CirculationCirculation. 1998;97:1195-1206.. 1998;97:1195-1206.

CapCapthicknessthickness

LumenLumen

Determinants of Plaque VulnerabilityDeterminants of Plaque Vulnerability

Late Prognosis of Inhospital Refractory Late Prognosis of Inhospital Refractory Ischemia in Non-ST Segment Elevation ACSIschemia in Non-ST Segment Elevation ACS

No ischemiaNo ischemia

Non-refractory recurrent ischemiaNon-refractory recurrent ischemia

Refractory recurrent ischemia*Refractory recurrent ischemia*

Cu

mu

lativ

e S

urvi

val

Cu

mu

lativ

e S

urvi

val

1.001.00

.95.95

.90.90

.85.85

.80.80

.75.75

.70.706060 120120 180180 240240 300300 36036000

* * PP<0.03 vs. no ischemia.<0.03 vs. no ischemia.

Armstrong PW et al. Armstrong PW et al. Circulation.Circulation. 1998;98:1860-1868. 1998;98:1860-1868.

DaysDays

Prognostic Significance of Rest Pain in Prognostic Significance of Rest Pain in Primary UA and Postinfarction AnginaPrimary UA and Postinfarction Angina

0

5

10

15

20

25

30

0

5

10

15

20

25

30

4.24.2

18.418.4

1.41.40.00.0

10.910.9

26.326.3

7.37.3

0.00.0

Rest Pain Rest Pain <48 h<48 h

n=1091n=1091

Rest Pain Rest Pain <48 h<48 h

No Rest PainNo Rest Pain

n=261n=261

No Rest PainNo Rest Pain

Cannon CP et al. Cannon CP et al. Circulation.Circulation. 1995;92:I-19. 1995;92:I-19.

Death/MI at 42 DaysDeath/MI at 42 Days Death/MI at 1 YearDeath/MI at 1 Year

Dea

th/M

I, %

of

Pat

ient

sD

eath

/MI,

% o

f P

atie

nts

Dea

th/M

I, %

of

Pat

ient

s D

eath

/MI,

% o

f P

atie

nts

UA Patients

Post-MI Patients

Prognostic Value of ST-Segment Depression During Prognostic Value of ST-Segment Depression During Chest Pain in Patients With Suspected UA or NQWMIChest Pain in Patients With Suspected UA or NQWMI

DaysDays

1.01.0

0.90.9

0.80.8

00 1010 2020 3030 4040 5050 6060 7070 8080 9090

Sur

viva

lS

urvi

val

PP<0.001<0.001

Normal ECG without changesNormal ECG without changesAbnormal ST-T ECG without changesAbnormal ST-T ECG without changes STST STST

López de Sá E et al. López de Sá E et al. J Am Coll Cardiol.J Am Coll Cardiol. 1998;31(suppl A):79A. 1998;31(suppl A):79A.

ACS: Prior Aspirin Use in PURSUITACS: Prior Aspirin Use in PURSUIT

Death/MI (30 d)Death/MI (30 d)

N=10,948N=10,948 Risk Ratio and 95% CIRisk Ratio and 95% CI PlaceboPlacebo EptifibatideEptifibatide

No Prior AspirinNo Prior Aspirin 36.4%36.4% 12.9%12.9% 13.1%13.1%

Prior AspirinPrior Aspirin 63.6%63.6% 17.3%17.3% 14.9%14.9%

EptifibatideEptifibatideBetterBetter

EptifibatideEptifibatideWorseWorse

00 0.50.5 1.01.0 1.51.5 22

Alexander JH et al. Alexander JH et al. J Am Coll Cardiol.J Am Coll Cardiol. 1998;31(suppl A):93A. 1998;31(suppl A):93A.

CK-MB Levels As Predictors CK-MB Levels As Predictors of Mortality in PURSUITof Mortality in PURSUIT

0

2

4

6

8

10

12

0-1 >1-2 >2-3 >3-5 >5-10 >10

30-Day 6-Month

Mo

rta

lity

(%)

Mo

rta

lity

(%)

Alexander JH et al. Alexander JH et al. Circulation. Circulation. 1998;98(suppl):I-629.1998;98(suppl):I-629.

Maximal CK-MB (xULN)Maximal CK-MB (xULN)

ACS: Possible Link Between Platelets and ACS: Possible Link Between Platelets and Troponin and Benefit of GP IIb/IIIa InhibitionTroponin and Benefit of GP IIb/IIIa Inhibition

Atherosclerotic coronaryAtherosclerotic coronary

Plaque rupture/erosion/fissurePlaque rupture/erosion/fissure

Platelet thrombusPlatelet thrombus

EmbolizationEmbolization

Microvascular platelet aggregationMicrovascular platelet aggregation

NecrosisNecrosis

Troponin Troponin ++

GP IIb/IIIa GP IIb/IIIa inhibitor inhibitor

GP IIb/IIIa GP IIb/IIIa inhibitor inhibitor

Courtesy of Eric J. Topol, MD.Courtesy of Eric J. Topol, MD.

Relation of Troponin Status to Thrombus Relation of Troponin Status to Thrombus Resolution With GP IIb/IIIa Inhibition in CAPTUREResolution With GP IIb/IIIa Inhibition in CAPTURE

Hamm CW et al. Hamm CW et al. Circulation.Circulation. 1998;98(suppl I):I-492. 1998;98(suppl I):I-492.

0

2

4

6

8

10

12

Angio Pre-Rx With Abciximab

During PCI With Abciximab

% W

ith V

isib

le T

hro

mb

us

% W

ith V

isib

le T

hro

mb

us

4.1%

2.8%

11.2%

5.9%

TnT NegTnT Neg TnT PosTnT Pos

Relation of Troponin Status to Preventing Relation of Troponin Status to Preventing Need for Premature PTCA in CAPTURE Need for Premature PTCA in CAPTURE

Heeschen C et al. Heeschen C et al. Circulation.Circulation. 1998;98(suppl):I-358. 1998;98(suppl):I-358.

0

1

2

3

4

5

6

7

8Placebo

Abciximab

% R

equ

irin

g P

rem

atu

re P

TC

A%

Req

uiri

ng

Pre

ma

ture

PT

CA

1.4%1.8%

6.8%

2.0%

RR=61%RR=61%PP<0.01<0.01

TnT neg(n=625)

TnT pos(n=201)

Tro

pon

in I

(ng

/mL

)T

ropo

nin

I (n

g/m

L)

0

6

12

18

Heparin (n=52)

Tirofiban + Heparin (n=53)

TnI Levels in UA/NQWMI Patients TnI Levels in UA/NQWMI Patients Treated With Tirofiban: PRISM-PLUSTreated With Tirofiban: PRISM-PLUS

Baseline LevelsBaseline Levels Peak LevelsPeak Levels

Hahn SS et al. Hahn SS et al. J Am Coll Cardiol.J Am Coll Cardiol. 1998;31(suppl A):229A. 1998;31(suppl A):229A.

3.1

5.2

15.5

1.6

P=NS

P=0.017

ACS: A Change in Mind-SetACS: A Change in Mind-Set

When should short-acting GP IIb/IIIa platelet inhibition (tirofiban or eptifibatide) be added to aspirin and heparin Rx?

+

Topol EJ. Topol EJ. J Invasive Cardiol. J Invasive Cardiol. 1998;10(suppl D):2D-7D.1998;10(suppl D):2D-7D.

Troponin, CK-MB, ST , post-MI, rest pain, prior aspirin use, recurrent ischemia

Risk Stratification in ACSRisk Stratification in ACSST Elevation

MI

Spectrum of Chest Pain Syndromes

Clinical FindingClinical Finding

ECGECG

Serum MarkersSerum Markers

RiskRiskAssessmentAssessment

NoncardiacChest Pain

StableAngina

UnstableAngina

Non-STElevation MI

Rest Pain, Post-MIRest Pain, Post-MI

Low riskLow risk Medium-to-high riskMedium-to-high risk High riskHigh risk

Thrombolysis,Thrombolysis,Primary PCIPrimary PCI

Aggressive antithrombotic + Aggressive antithrombotic + antiplatelet therapyantiplatelet therapyDischargeDischarge

NegativeNegative PositivePositive

Diagnostic Diagnostic Rule out MI/ACS pathwayRule out MI/ACS pathway

NegativeNegative ST-T wave changesST-T wave changes ST elevationST elevation++

++

Nonrest, Subacute PainNonrest, Subacute Pain

NegativeNegative PositivePositive

GP IIb/IIIa Receptor Blockers: GP IIb/IIIa Receptor Blockers: UA/NQWMI TrialsUA/NQWMI Trials

PARAGON Lamifiban 2282 2 x 2 Death/MI1 & 5 g/kg/min Factorial design within 30 d

PRISM Tirofiban 3232 T vs h Death/MI/refractory0.6 g/kg/min 30 min B + I to ischemia within 48 h+ 0.15 g/kg/min PTT 2x control

PRISM-PLUS Tirofiban 1915 T vs h Death/MI/refractory0.6 g/kg/min 30 min B + I to ischemia within 7 d+ 0.15 g/kg/min PTT 2x control vs 0.4 g/kg/min 30 min T + h + 0.1 g/kg/min

PURSUIT Eptifibatide 10,948 At Death/MI180 g/kg bolus + 2 g/kg/min physician’s within 30 dor 1.3 g/kg/min discretion

TrialTrial AgentAgent NN Heparin Regimen Heparin Regimen

The PARAGON Investigators. The PARAGON Investigators. Circulation.Circulation. 1998;97:2386-2395. 1998;97:2386-2395.

The PRISM Study Investigators. The PRISM Study Investigators. N Engl J Med.N Engl J Med. 1998;338:1498-1505. 1998;338:1498-1505.

The PRISM-PLUS Study Investigators. The PRISM-PLUS Study Investigators. N Engl J Med.N Engl J Med. 1998;338:1488-1497. 1998;338:1488-1497.

The PURSUIT Trial Investigators. The PURSUIT Trial Investigators. N Engl J Med.N Engl J Med. 1998;339:436-443. 1998;339:436-443.

Primary Endpoint Primary Endpoint

Slide #15 Notes ContinuedSlide #15 Notes Continued

GP IIb/IIIa Receptor Blockers in GP IIb/IIIa Receptor Blockers in UA/NQWMI: Death or MI at 30 DaysUA/NQWMI: Death or MI at 30 Days

Odds Ratio Odds Ratio and CIand CI

NN GP IIb/IIIaGP IIb/IIIa ControlControlReduction ±Reduction ±

SDSD

The PARAGON Investigators. The PARAGON Investigators. Circulation.Circulation. 1998;97:2386-2395. 1998;97:2386-2395.The PRISM Study Investigators. The PRISM Study Investigators. N Engl J Med.N Engl J Med. 1998;338:1498-1505. 1998;338:1498-1505.The PRISM-PLUS Study Investigators. The PRISM-PLUS Study Investigators. N Engl J Med.N Engl J Med. 1998;338:1488-1497. 1998;338:1488-1497.The PURSUIT Trial Investigators. The PURSUIT Trial Investigators. N Engl J Med.N Engl J Med. 1998;339:436-443. 1998;339:436-443.

PARAGON A withlow-dose lamifiban 1513 10.6% 11.7% 11% 15

1526 12.0% 11.7% -2% 16

PRISM (tirofiban alone)

3232 5.8% 7.1% 19% 13

PRISM-PLUS(tirofiban + heparin)

1570 8.7% 11.9% 30% 14

PURSUIT(eptifibatide heparin)

9461 14.2% 15.7% 11% 5

high-dose lamifiban

0.00.0 1.01.00.50.5 1.51.5 2.02.0

Slide #16 Notes ContinuedSlide #16 Notes Continued

11.79.2

13.6 13

0

5

10

15

20

25

The PRISM-PLUS Study Investigators. The PRISM-PLUS Study Investigators. N Engl J Med.N Engl J Med. 1998;338:1488-1497. 1998;338:1488-1497.

Peterson JG et al. Peterson JG et al. Circulation. Circulation. 1998;98:I-360.1998;98:I-360.

PRISM-PLUSPRISM-PLUS(n=695)(n=695)

PURSUITPURSUIT(n=882)(n=882)

Dea

th o

r M

I, 3

0 D

ays

(%)

Dea

th o

r M

I, 3

0 D

ays

(%)

HeparinHeparin Tirofiban/ Tirofiban/ no Heparinno Heparin

PlaceboPlacebo Eptifibatide/ Eptifibatide/ no Heparinno Heparin

Interaction of Heparin and GP IIb/IIIa Interaction of Heparin and GP IIb/IIIa Platelet InhibitorsPlatelet Inhibitors

19% 41%

GP IIb/IIIa Inhibition in PRISM-PLUS: GP IIb/IIIa Inhibition in PRISM-PLUS: MI/Death Event Reductions at 2, 7, and 30 MI/Death Event Reductions at 2, 7, and 30 DaysDays

The PRISM-PLUS Study Investigators. The PRISM-PLUS Study Investigators. N Engl J MedN Engl J Med. 1998;338:1488-1497.. 1998;338:1488-1497.

2 Days2 Days 7 Days7 Days

RR=30%RR=30%PP=0.03=0.03

30 Days30 Days

RR=43%RR=43%PP=0.006=0.006

8.3

4.9

11.9

8.7

Pat

ient

s (%

)P

atie

nts

(%) RR=66%RR=66%

PP=0.01=0.01

2.6

0.9

Heparin (n=797)


0

5

10

15

GP IIb/IIIa Inhibition in PRISM-PLUS: GP IIb/IIIa Inhibition in PRISM-PLUS: Composite Endpoint at 2, 7, and 30 DaysComposite Endpoint at 2, 7, and 30 Days

0

5

10

15

20

25

PP=0.073=0.073

RR=22%RR=22%PP=0.029=0.029

2 Days 7 Days 30 Days


7.85.7

22.3

18.5

Pat

ient

s (%

)P

atie

nts

(%)

Heparin (n=797)


RR=32%RR=32%PP=0.004=0.004

17.9

12.9

DayDay

Sustained Effect of GP IIb/IIIa Inhibition: Sustained Effect of GP IIb/IIIa Inhibition: PRISM-PLUS Composite Endpoint at 180 DaysPRISM-PLUS Composite Endpoint at 180 Days


5

10

15

20

25

With

End

poi

nt (

%)

With

End

poi

nt (

%)

HeparinHeparin

Tirofiban + HeparinTirofiban + Heparin

= -5.0%, RR=32%, P=0.004

0 30 60 90 120 150 1807

= -3.8%, RR=22%, P=0.029

= -4.4%, RR=19%, P=0.02

30

35

GP IIb/IIIa Inhibition: Comparative Rates of Death or GP IIb/IIIa Inhibition: Comparative Rates of Death or MI at 30 Days for 3 Strategies in PRISM-PLUSMI at 30 Days for 3 Strategies in PRISM-PLUS

Heparin

Tirofiban + Heparin 20

15

5

0

10

Medical RxMedical Rx PTCAPTCA CABGCABG

10.1

7.8

13.1

8.8

16.8

12.2

RR=25%RR=25%(95% CI=0.46-1.23)(95% CI=0.46-1.23)

RR=34%RR=34%(95% CI=0.38-1.14)(95% CI=0.38-1.14)

RR=30%RR=30%(95% CI=0.40-1.0)(95% CI=0.40-1.0)

% D

eath

/MI

(30

Day

s)%

Dea

th/M

I (3

0 D

ays)

Barr et al. Barr et al. Circulation.Circulation. 1998;98:I-504. 1998;98:I-504.

16.7 15.6

11.614.5

0

5

10

15

20

25

Heparin Eptifibatide + Heparin

RR=31% RR=31%

PP=0.23=0.23

RR=7% RR=7%

PP=0.01=0.01


% D

eath

or

MI

(30

Day

s)%

Dea

th o

r M

I (3

0 D

ays)

Early PCIEarly PCI(Within 72 h After Randomization)(Within 72 h After Randomization)

Med Rx, Late PCI, CABGMed Rx, Late PCI, CABG

PURSUIT: Effect of GP IIb/IIIa Inhibition PURSUIT: Effect of GP IIb/IIIa Inhibition in Patients Undergoing Early PCIin Patients Undergoing Early PCI

PRISM-PLUS: Combined MI and Death During PRISM-PLUS: Combined MI and Death During Initial 48 Hours in All Patients and Postprocedure Initial 48 Hours in All Patients and Postprocedure in Patients Undergoing PTCAin Patients Undergoing PTCA

2 4 14 21 287

0.12

0.08

0.04

0.00

Heparin OnlyHeparin Only

RR=44%RR=44%

475 Patients Undergoing PTCA475 Patients Undergoing PTCA

Heparin OnlyHeparin OnlyTirofiban + HeparinTirofiban + Heparin

RR=66%RR=66%

All 1570 Patients EvaluatedAll 1570 Patients Evaluated

HoursHours DaysDays

Drug InfusionDrug InfusionPTCAPTCA

Pro

babi

lity

of D

eath

or

MI

Pro

babi

lity

of D

eath

or

MI



6 300 12 18 24 36 42 48

0.12

0.08

0.04

0.00

= -6.2%

0 30 60 90 120 150 180DayDay

4

8

12

16

20

24

28

32

% W

ith E

ndpo

int

% W

ith E

ndpo

int

HeparinHeparin


= -6.5%RR=45%

RR=27%

The PRISM-PLUS Study Investigators. The PRISM-PLUS Study Investigators. N Engl J MedN Engl J Med. 1998;338:1488-1497. . 1998;338:1488-1497. Barr et al. Barr et al. Circulation.Circulation. 1998;98:I-504. 1998;98:I-504.

Effect of GP IIb/IIIa Inhibition in Patients Undergoing Effect of GP IIb/IIIa Inhibition in Patients Undergoing PTCA: PRISM-PLUS Composite EndpointPTCA: PRISM-PLUS Composite Endpoint

PRISM-PLUS: Selected Subgroup Benefits PRISM-PLUS: Selected Subgroup Benefits With GP IIb/IIIa Inhibition: Composite Endpoint (7 Days)With GP IIb/IIIa Inhibition: Composite Endpoint (7 Days)

0.1 1 10

Risk Ratio (95% CI)Risk Ratio (95% CI)

Age< 65 y65-74 y75 y

Gender WomenMen

Prior heparin YesNo

Prior aspirin YesNo

Country USCanadaOther

Presentation NQWMIUAP

Diabetes YesNo

0.5 5


PRISM-PLUS: MI/Death Outcomes PRISM-PLUS: MI/Death Outcomes in Patients With Diabetesin Patients With Diabetes

Heparin (n=193)

Tirofiban + Heparin(n=169)

% P

atie

nts

% P

atie

nts

9.3%

1.2%

PP=0.004=0.004

15.5%

4.7%

PP=0.002=0.002 19.2%

11.2%

PP=0.044=0.044

Day 7 Day 30 Day 180

5

0

15

10

20

Théroux P et al. Théroux P et al. Circulation. Circulation. 1998;98:I-359.1998;98:I-359.

0.79 (0.69-0.91)

1.10 (0.91-1.34)

0.78 (0.66-0.93)

0.98 (0.84-1.13)

0.90 (0.75-1.08)

0.96 (0.78-1.17)

0.81 (0.66-0.99)

0.87 (0.76-1.00)

0.96 (0.77-1.19)

0.5 1 1.5EptifibatideEptifibatideBetterBetter

EptifibatideEptifibatideBetterBetter

PlaceboPlaceboBetterBetter

PlaceboPlaceboBetterBetter

High weight

Medium weight

Low weight

65 or older

Under 65

Women

Men

No diabetes

Diabetes


PURSUIT: Subgroup Analysis for PURSUIT: Subgroup Analysis for Death or MI at 30 DaysDeath or MI at 30 Days

Odds Ratio (CI)Odds Ratio (CI)

Major Bleeding (TIMI)Intracranial bleeding

Minor Bleeding (TIMI)

Transfusions (All Blood Products)

Platelets 90,000/mm3

1.4% (11)0.0%

10.5%

4.0%

1.9%

0.8% (6)0.0%

8.0%

2.8%

0.8%

Tirofiban + HeparinTirofiban + Heparinn=773n=773

HeparinHeparinn=797n=797

PRISM-PLUS: Hematologic ComplicationsPRISM-PLUS: Hematologic Complications

The PRISM-PLUS Study Investigators. The PRISM-PLUS Study Investigators. N Engl J MedN Engl J Med. 1998;338:1488-1497.. 1998;338:1488-1497.AGGRASTATAGGRASTAT®® package insert. package insert.

PP Value Value

NSNS

NS

NS

NS

GP IIb/IIIa Platelet Inhibition in Transfer GP IIb/IIIa Platelet Inhibition in Transfer Patients With UA/NQWMI: PRISM-PLUSPatients With UA/NQWMI: PRISM-PLUS

Are the safety and efficacy of GP IIb/IIIa inhibitors dependent on the setting in which patients are treated: community hospitals vs. tertiary care centers?

What is the safety and efficacy of GP IIb/IIIa inhibitors in patients requiring transfer?

Théroux P et al. Théroux P et al. Eur Heart J. Eur Heart J. 1998;19(suppl):50. Abstract.1998;19(suppl):50. Abstract.

PRISM-PLUS Transfer Patients: PRISM-PLUS Transfer Patients: Baseline CharacteristicsBaseline Characteristics

CommunityCommunity TransferredTransferred TertiaryTertiaryHospital Hospital Subgroup Subgroup Group Group

CharacteristicCharacteristic (n=322)(n=322) (n=228)(n=228) (n=512) (n=512)

Age (y) 62 12 61 12 63 11

Men 66% 71% 67%

Antecedent CAD 57% 54% 68%

ECG ischemia 93% 93% 93%

Presentation

UA 50% 47% 61%

NQWMI 50% 53% 39%


PRISM-PLUS Transfer Patients: PRISM-PLUS Transfer Patients: Clinical Status Prior to Transfer*Clinical Status Prior to Transfer*

CommunityCommunity TransferredTransferred TertiaryTertiaryHospital Hospital Subgroup Subgroup Group Group

EndpointEndpoint (n=322)(n=322) (n=228)(n=228) (n=512) (n=512)

Composite 8.4% 7.4% 8.0%

Death 0% 0% 0.2%

MI 2.8% 1.8% 2.0%

Death/MI 2.8% 1.8% 2.2%

Refractory ischemia 5.9% 6.1% 6.8%

* Event rates at 48 hours after randomization (regardless of treatment allocation).* Event rates at 48 hours after randomization (regardless of treatment allocation).


PRISM-PLUS Transfer Patients: Efficacy of PRISM-PLUS Transfer Patients: Efficacy of Tirofiban by Admitting Hospital—Death/MITirofiban by Admitting Hospital—Death/MI

0

5

10

15

20

Heparin Alone

Tirofiban + Heparin

3.9*

10.8

2.7

10.39.1

6.47.1*

13.812.0

5.4

9.7

14.0

10.3*

17.4

14.116.3

8.1

15.4

7 7 DaysDays

30 30 DaysDays

180 180 DaysDays

Community HospitalCommunity Hospital

% P

atie

nts

% P

atie

nts

* * PP<0.04 vs. heparin.<0.04 vs. heparin.

PP values for transfer subgroup not calculated as this group was defined by postrandomization events. values for transfer subgroup not calculated as this group was defined by postrandomization events.


7 7 DaysDays

30 30 DaysDays

180 180 DaysDays

TransferTransfer

7 7 DaysDays

30 30 DaysDays

180 180 DaysDays

TertiaryTertiary

PRISM-PLUS Transfer Patients: Efficacy of Tirofiban PRISM-PLUS Transfer Patients: Efficacy of Tirofiban by Admitting Hospital—Composite Endpointby Admitting Hospital—Composite Endpoint

0

5

10

15

20

25

30

35

40Heparin Alone

Tirofiban + Heparin

12.9*

21.6

10.8

21.4 20.416.516.2

23.926.4

18.122.2

25.427.1

33.5 33.936.7

23.4

30.8

% P

atie

nts

% P

atie

nts

**PP<0.04 vs. heparin.<0.04 vs. heparin.

PP values for transfer subgroup not calculated as this group was defined by postrandomization events. values for transfer subgroup not calculated as this group was defined by postrandomization events.


7 7 DaysDays

30 30 DaysDays

180 180 DaysDays

Community HospitalCommunity Hospital

7 7 DaysDays

30 30 DaysDays

180 180 DaysDays

TransferTransfer

7 7 DaysDays

30 30 DaysDays

180 180 DaysDays

TertiaryTertiary

T/HT/H HH T/H T/H H H T/H T/H HHEndpointEndpoint (n=155)(n=155) (n=167)(n=167) (n=111)(n=111) (n=117)(n=117) (n=248)(n=248) (n=264)(n=264)

PRISM-PLUS Transfer Patients: PRISM-PLUS Transfer Patients: Incidence of BleedingIncidence of Bleeding

CommunityCommunity TransferredTransferred TertiaryTertiaryHospitalHospital Subgroup Subgroup GroupGroup

TIMI major 1.9% 0.6% 2.7% 0.8% 1.2% 1.1% bleeding

TIMI minor 10.3% 13.8% 10.8% 17.9% 14.1% 9.8% bleeding

PRBC Txn 5.2% 2.4% 4.5 % 3.4% 4.4% 3.0%

None of the differences achieved statistical significance.None of the differences achieved statistical significance.

Note: The duration of study drug infusion in transfer patients was longer than in the overall Note: The duration of study drug infusion in transfer patients was longer than in the overall community hospital group and tertiary hospital group (80.5 ± 14.3 h vs. 71.8 ± 16.7 h community hospital group and tertiary hospital group (80.5 ± 14.3 h vs. 71.8 ± 16.7 h and 75.6 ± 17.7 h, respectively).and 75.6 ± 17.7 h, respectively).


PRISM-PLUS Transfer Patients: PRISM-PLUS Transfer Patients: ConclusionsConclusions

Use of GP IIb/IIIa inhibitor tirofiban improved outcomes in UA/NQWMI patients admitted to hospitals without catheterization or revascularization facilities as well as in those admitted to tertiary hospitals

Transfer of patients who were on tirofiban + heparin did not appear to alter bleeding risk and was generally safe and well tolerated


Effects of GP IIb/IIIa Inhibition on Effects of GP IIb/IIIa Inhibition on Angiographic Thrombus and TIMI Flow: Angiographic Thrombus and TIMI Flow: PRISM-PLUS Angiographic SubstudyPRISM-PLUS Angiographic Substudy

Objective: Determine effect of tirofiban on angiographically apparent thrombus

Films prior to hour 97 analyzed by blinded core laboratory

1230 films readable and analyzed (608 in tirofiban + heparin group; 622 in heparin group)

Zhao X-Q. Zhao X-Q. Circulation.Circulation. 1999; in press. 1999; in press.

PRISM-PLUS: Intracoronary Thrombus As a PRISM-PLUS: Intracoronary Thrombus As a Predictor of Clinical Outcomes in UA/NQWMIPredictor of Clinical Outcomes in UA/NQWMI

Thrombus (n=643)

No Thrombus (n=784)

% P

atie

nts

With

Eve

nt%

Pat

ient

s W

ith E

vent

19%

10%

4%

12%

6%

9%

5

0

15

10

20

Odds ratioOdds ratio 2.132.13 2.042.04 1.971.97 2.002.00 2.362.36PP value value <0.001<0.001 <0.001<0.001 0.0020.002 0.0020.002 0.0050.005

Composite Ref Ischemia MI DeathMI/Death

9%

5%

2%

5%

Events at 30 DaysEvents at 30 Days

Zhao X-Q et al. Zhao X-Q et al. CirculationCirculation. 1998;98:I-492.. 1998;98:I-492.

PRISM-PLUS: GP IIb/IIIa Receptor PRISM-PLUS: GP IIb/IIIa Receptor Inhibition and Thrombus GradeInhibition and Thrombus Grade


0

10

20

30

40

50

Cu

mu

lativ

e %

Cu

mu

lativ

e %

Heparin(n=622)


Possible

Small

Moderate

OverallOdds Ratio:

0.77P=0.022

17.1%24.1%

Possible

Small

Moderate

LargeRecent Occlusion

Large

Recent Occlusion

PRISM-PLUS: TIMI Flow As a Predictor PRISM-PLUS: TIMI Flow As a Predictor of Clinical Outcomes in UA/NQWMIof Clinical Outcomes in UA/NQWMI

Hazard Hazard ratioratio 1.69 1.69 1.491.49 1.641.64 1.391.39PP value value <0.001<0.001 0.040.04 0.0030.003 0.170.17

TIMI 0-2 (n=298)

TIMI 3 (n=1095)

Pat

ient

s W

ith E

vent

(%

)P

atie

nts

With

Eve

nt (

%) 27%

17%

6%

17%

5

0

15

10

20

Composite Ref Ischemia MIMI/Death

8%

12%

8%11%

25

30

Events at 30 DaysEvents at 30 Days

Zhao X-Q et al. Zhao X-Q et al. CirculationCirculation. 1998;98:I-359.. 1998;98:I-359.

PRISM-PLUS: GP IIb/IIIa Receptor PRISM-PLUS: GP IIb/IIIa Receptor Inhibition and TIMI FlowInhibition and TIMI Flow


0

5

10

15

20

25

Cu

mu

lativ

e %

Cu

mu

lativ

e %

MinimalPerfusion(TIMI 1)


Heparin(n=580)

TotalOcclusion

(TIMI 0)

PartialPerfusion(TIMI 2)

TotalOcclusion

(TIMI 0)

PartialPerfusion(TIMI 2)

OverallOverallOdds Ratio:Odds Ratio:

0.650.65

PP=0.002=0.00218.1%

25.5%Minimal

Perfusion(TIMI 1)

PRISM-PLUS: Angiographic Substudy PRISM-PLUS: Angiographic Substudy ConclusionsConclusions

TIMI flow and thrombus grade showed strong correlations with the clinical outcomes of MI, death, and refractory ischemia in ACS patients in PRISM-PLUS

48 hours of tirofiban + heparin produced significant improvements in TIMI flow and thrombus grade in UA/NQWMI

These observations suggest a mechanism by which tirofiban + heparin may have improved outcomes in PRISM-PLUS


Cost-Effectiveness of GP IIb/IIIa Inhibitor Cost-Effectiveness of GP IIb/IIIa Inhibitor Therapy in ACSTherapy in ACSCost-Effectiveness of GP IIb/IIIa Inhibitor Cost-Effectiveness of GP IIb/IIIa Inhibitor Therapy in ACSTherapy in ACS

Only significant differences were counted (MI reductions in PRISM-PLUS and PURSUIT)

Assume last effect carried forward

No indirect costs were included

No discount in medication costs

72-hour infusion

Other costs were negligible or would be presented in both groups

Rittenhouse BE. In: Spilker B, ed. Rittenhouse BE. In: Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd ed. 1996:1093-1103. 2nd ed. 1996:1093-1103.

The PRISM-PLUS Investigators. The PRISM-PLUS Investigators. N Engl J MedN Engl J Med. 1998;338:1488-1497.. 1998;338:1488-1497.

Tirofiban +Tirofiban +ParameterParameter HeparinHeparin Heparin Heparin $ $

Treated with GP IIb/IIIa 773 0

Additional medication, $/patient $1,050 0 812,000

Reduction in MIs 18 – (508,000)

Increase in adverse events 0 – 0

Net expense: $304,000

Rittenhouse BE. In: Spilker B, ed. Rittenhouse BE. In: Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd ed. 1996:1093-1103. 2nd ed. 1996:1093-1103.The PRISM-PLUS Investigators. The PRISM-PLUS Investigators. N Engl J MedN Engl J Med. 1998;338:1488-1497.. 1998;338:1488-1497.

An FFS Economic Model Based on An FFS Economic Model Based on 6-Month Data: PRISM-PLUS6-Month Data: PRISM-PLUS

An MCO Economic Model Based on An MCO Economic Model Based on 6-Month Data: PRISM-PLUS6-Month Data: PRISM-PLUS

Tirofiban +Tirofiban +ParameterParameter HeparinHeparin Heparin Heparin $$


Additional medication, $/patient $1,050 0 812,000


Increase in adverse events 0 – 0

Net expense: $668,000

Rittenhouse BE. In: Spilker B, ed. Rittenhouse BE. In: Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd ed. 1996:1093-1103. 2nd ed. 1996:1093-1103.The PRISM-PLUS Investigators. The PRISM-PLUS Investigators. N Engl J MedN Engl J Med. 1998;338:1488-1497.. 1998;338:1488-1497.

Cost-Effectiveness of GP IIb/IIIa Regression Cost-Effectiveness of GP IIb/IIIa Regression Analysis: PRISM-PLUS DataAnalysis: PRISM-PLUS DataCost-Effectiveness of GP IIb/IIIa Regression Cost-Effectiveness of GP IIb/IIIa Regression Analysis: PRISM-PLUS DataAnalysis: PRISM-PLUS Data

In the FFS model: $16,900 cost per event saved

In the MCO model: $37,100 cost per event saved

Rittenhouse BE. In: Spilker B, ed. Rittenhouse BE. In: Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd ed. 1996:1093-1103.2nd ed. 1996:1093-1103.


An FFS Economic Model Based on An FFS Economic Model Based on 1-Month Data: PURSUIT1-Month Data: PURSUITAn FFS Economic Model Based on An FFS Economic Model Based on 1-Month Data: PURSUIT1-Month Data: PURSUIT

Eptifibatide +Eptifibatide +ParameterParameter HeparinHeparin Heparin Heparin $$


Additional medication, $/patient $1,355 0 6,398,000

Reduction in MIs 61 – (1,721,000)

Increase in adverse events 151 – 341,000

Net expense: $5,018,000Rittenhouse BE. In: Spilker B, ed. Rittenhouse BE. In: Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd ed. 1996:1093-1103.2nd ed. 1996:1093-1103.The PURSUIT Trial Investigators. The PURSUIT Trial Investigators. N Engl J Med.N Engl J Med. 1998;339:436-443. 1998;339:436-443.

An MCO Economic Model Based on An MCO Economic Model Based on 1-Month Data: PURSUIT1-Month Data: PURSUITAn MCO Economic Model Based on An MCO Economic Model Based on 1-Month Data: PURSUIT1-Month Data: PURSUIT

Eptifibatide +Eptifibatide +ParameterParameter HeparinHeparin Heparin Heparin $$


Additional medication, $/patient $1,355 0 6,398,000


Increase in adverse events 136 – 147,000

Net expense: $6,066,000Rittenhouse BE. In: Spilker B, ed. Rittenhouse BE. In: Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd ed. 1996:1093-1103.2nd ed. 1996:1093-1103.The PURSUIT Trial Investigators. The PURSUIT Trial Investigators. N Engl J Med.N Engl J Med. 1998;339:436-443. 1998;339:436-443.

Cost-Effectiveness of GP IIb/IIIa Cost-Effectiveness of GP IIb/IIIa Regression Analysis: PURSUIT DataRegression Analysis: PURSUIT DataCost-Effectiveness of GP IIb/IIIa Cost-Effectiveness of GP IIb/IIIa Regression Analysis: PURSUIT DataRegression Analysis: PURSUIT Data

In the FFS model: $82,300 cost per event saved

In the MCO model:

$99,400 cost per event saved

Rittenhouse BE. In: Spilker B, ed. Rittenhouse BE. In: Spilker B, ed. Quality of Life and Pharmacoeconomics in Clinical Trials. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd ed. 1996:1093-1103.2nd ed. 1996:1093-1103.The PURSUIT Trial Investigators. The PURSUIT Trial Investigators. N Engl J Med.N Engl J Med. 1998;339:436-443. 1998;339:436-443.

Therapeutic Options for ACSTherapeutic Options for ACS

Unstable Angina/Non-ST Unstable Angina/Non-ST MI MI

Empiric GP IIb/IIIa Empiric GP IIb/IIIa in ER/CCUin ER/CCU

Traditional Rx Traditional Rx Cath Lab ± GP IIb/IIIaCath Lab ± GP IIb/IIIa

Cath LabCath Lab

Topol EJ. Topol EJ. J Invasive Cardiol. J Invasive Cardiol. 1998;10:(suppl D):2D-7D.1998;10:(suppl D):2D-7D.

Empiric Management of ACS: Empiric Management of ACS: ConclusionsConclusions

ACS: Medium- to high-risk patient = positive troponin, CK-MB, ST, post-MI, rest pain, recurrent ischemia, prior aspirin use

GP IIb/IIIa inhibition with either eptifibatide or tirofiban significantly improves outcomes in the medium- to high-risk patient

Magnitude of benefit of tirofiban has been shown to be similar in

– All treatment strategies: PCI, medical management, CABG

– All patient subgroups

– Community hospital, transferred patients, tertiary care setting

Data strongly support empiric use of GP IIb/IIIa inhibitors in ACS


Barr E et al. Barr E et al. CirculationCirculation. 1998;98:I-504.. 1998;98:I-504.Théroux P et al. Théroux P et al. Eur Heart J. Eur Heart J. 1998;19(suppl):50. Abstract. 1998;19(suppl):50. Abstract.

Documents

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