TACTICS- TIMI 18TACTICS- TIMI 18

Treat Angina with AggrastatTreat Angina with AggrastatTMTM and Determine Cost of Therapy and Determine Cost of Therapy

with an with an Invasive or Conservative Strategy Invasive or Conservative Strategy

Unstable Angina and Non-Q Wave MIUnstable Angina and Non-Q Wave MI

Center of spectrum of acute coronary syndromesCenter of spectrum of acute coronary syndromes

2-2.5 million hospital admissions /year worldwide 2-2.5 million hospital admissions /year worldwide

ASA, heparin, beta-blockers beneficialASA, heparin, beta-blockers beneficial

Tirofiban (AggrastatTirofiban (AggrastatTMTM) dramatic benefit) dramatic benefit

Invasive vs. Consvative strategy ???? Invasive vs. Consvative strategy ????

BackgroundBackground

Unstable angina and non-Q wave MIUnstable angina and non-Q wave MI

Center of spectrum of acute coronary Center of spectrum of acute coronary syndromessyndromes

890,000 hospital admissions per year in U.S. 890,000 hospital admissions per year in U.S.

ASA, heparin, beta-blockers beneficialASA, heparin, beta-blockers beneficial

Tirofiban (AggrastatTirofiban (AggrastatTMTM) dramatic benefit) dramatic benefit

Invasive vs. Consvative strategy ???? Invasive vs. Consvative strategy ????

BackgroundBackground

Initial Medical Management:Initial Medical Management:

ASA 160-325 mgASA 160-325 mg daily for all patients with UA daily for all patients with UA (except if ongoing major or life-threatening (except if ongoing major or life-threatening hemorrhage, recent GI bleed, or ASA hemorrhage, recent GI bleed, or ASA hypersensitivity)hypersensitivity)

IV HeparinIV Heparin for intermediate or high-risk UA (i.e., for intermediate or high-risk UA (i.e., prior CAD, rest pain, ECG changes, or age >65)prior CAD, rest pain, ECG changes, or age >65)

Beta-blockersBeta-blockers for all patients in the absence of for all patients in the absence of contraindications (e.g., bradycardia, hypotension, contraindications (e.g., bradycardia, hypotension, AV block, asthma, severe LV dysfunction with CHF AV block, asthma, severe LV dysfunction with CHF or shock, signif. COPD)or shock, signif. COPD)

RecommendationsRecommendationsAHCPR Unstable Angina GuidelineAHCPR Unstable Angina Guideline

Braunwald, E., et al. Circulation 1994;90:613-22.

Initial Medical Management (con’t):Initial Medical Management (con’t):

NitratesNitrates: Use for patients with ongoing ischemia : Use for patients with ongoing ischemia and use IV for high-risk patients. Switch to oral and use IV for high-risk patients. Switch to oral when stablewhen stable

Calcium antagonists:Calcium antagonists: May be May be used to control used to control angina if already on beta-blocker and nitrates, or if angina if already on beta-blocker and nitrates, or if unable to tolerate beta-blockers (e.g. severe unable to tolerate beta-blockers (e.g. severe COPD). Use heart-rate lowering CaCOPD). Use heart-rate lowering Ca++ blocker. blocker. Avoid in CHF or low EF.Avoid in CHF or low EF.

No thrombolysisNo thrombolysis: Shown to : Shown to increaseincrease subsequent subsequent MI in TIMI IIIB trial in patients with unstable anginaMI in TIMI IIIB trial in patients with unstable angina

RecommendationsRecommendationsAHCPR Unstable Angina GuidelineAHCPR Unstable Angina Guideline

Braunwald, E., et al. Circulation 1994;90:613-22.

Cholesterol Lowering Post MICholesterol Lowering Post MI

01

02

03

0

150 170 190 210 230 250

Total Cholesterol (mean)

CH

D E

ve

nts

(%

)

4S

CARE

Cholesterol loweringCholesterol lowering: Check lipids <24 hours, : Check lipids <24 hours, treat as needed. CARE trial indicates benefit for treat as needed. CARE trial indicates benefit for patients with LDL >125 mg/dl.patients with LDL >125 mg/dl.

Low Molecular Weight HeparinLow Molecular Weight Heparin: At least as : At least as effective as IV heparin. ESSENCE trial: 16% better effective as IV heparin. ESSENCE trial: 16% better than IV heparin (Death, MI, recurrent angina)than IV heparin (Death, MI, recurrent angina)

IIb/IIIa inhibitionIIb/IIIa inhibition: Tirofiban lead to a 34% : Tirofiban lead to a 34% reduction in death, MI, refarctory angina at 7 days reduction in death, MI, refarctory angina at 7 days in PRISM-PLUS. At 30 days, tirofiban (Aggrastatin PRISM-PLUS. At 30 days, tirofiban (AggrastatTMTM) ) lead to a 31% redution in death or MI. In PRISM, lead to a 31% redution in death or MI. In PRISM, there was a 36% reduction in composite endpoint there was a 36% reduction in composite endpoint at 48 hours.at 48 hours.Eptifibatide (IntegrilinEptifibatide (IntegrilinTMTM) lead to an 11% reduction ) lead to an 11% reduction in death or MI at 30 days in PURSUIT.in death or MI at 30 days in PURSUIT.

Updating - 1997Updating - 1997AHCPR Unstable Angina GuidelineAHCPR Unstable Angina Guideline

Early invasive strategy - Cath in all patients Early invasive strategy - Cath in all patients between 18-48 hours. Revascularization when between 18-48 hours. Revascularization when feasible based on anatomy: PTCA for 1 or 2 VD, feasible based on anatomy: PTCA for 1 or 2 VD, CABG for 3VDCABG for 3VD

Early conservative strategy - catheterization if Early conservative strategy - catheterization if patient had recurrent ischemia at rest or on patient had recurrent ischemia at rest or on testing:testing:

Recurrent ischemia at rest with ECG changesRecurrent ischemia at rest with ECG changes Recurrent MIRecurrent MI Positive ETT / Thallium at HD or 6 weeksPositive ETT / Thallium at HD or 6 weeks Positive ST segment Holter (>20 mins)Positive ST segment Holter (>20 mins)

Invasive vs. ConservativeInvasive vs. ConservativeTIMI IIIBTIMI IIIBCirculation 1994;89:1545-56Circulation 1994;89:1545-56

TIMI IIIB - One Year TIMI IIIB - One Year ResultsResults

0

4

8

12

16

0 7 14 21 28 35 42 49

Weeks

% o

f P

atie

nts

0

20

40

60

80

0 7 14 21 28 35 42 49

Weeks

% o

f Pat

ient

s

Death or MI Death or MI PTCA or CABGPTCA or CABG

P=<0.001P=<0.001P=NSP=NS

Anderson HV et al., JACC 1995;26:1643-1650.Anderson HV et al., JACC 1995;26:1643-1650.

12.2%12.2%10.8%10.8%

64%64%58%58%

Early ConservativeEarly Conservative

Early InvasiveEarly Invasive

Early InvasiveEarly Invasive

Early ConservativeEarly Conservative

TIMI IIIB - Primary Results to 42 daysTIMI IIIB - Primary Results to 42 days

InvasiveInvasive Conserv. Conserv. P valueP value

No. PtsNo. Pts 740 740 733 733

Death (%)Death (%) 2.4 2.4 2.5 2.5 NSNS

MI (%)MI (%) 5.1 5.1 5.7 5.7 NSNS

D/MI/+ETT (%)D/MI/+ETT (%) 16.2 16.2 18.1 18.1 NSNS

Rehosp Angina (%) 7.8Rehosp Angina (%) 7.8 14.1 14.1 <0.001<0.001

D/MI/Rehosp (%)D/MI/Rehosp (%) 15 15 22 22 0.0070.007

LOS (days)LOS (days) 10.2 10.2 10.9 10.9 <0.001<0.001

# Days rehosp# Days rehosp 365 365 930 930 <0.001<0.001

Circulation 1994;89:1545-56Circulation 1994;89:1545-56

No. PtsNo. Pts

Death or MI (%)Death or MI (%)

Death (%)Death (%)

MI (%)MI (%)

Death < HD (%)Death < HD (%)

Death > HD (%)Death > HD (%)

464622

29.29.99

17.17.33

12.12.66

4.54.5

12.12.88

InvasiveInvasive

458 458

26.926.9

12.912.9

14.014.0

1.31.3

11.611.6

Conserv.Conserv.

0.350.35

0.040.04

NSNS

0.0070.007

NSNS

P valueP value

VANQWISH TrialVANQWISH Trial

VA Hosptials Study: Management post Non-Q wave MIVA Hosptials Study: Management post Non-Q wave MI

Medical and interventional magagement of Medical and interventional magagement of unstable angina markedly improved in last 5 yrs unstable angina markedly improved in last 5 yrs ( ASA, heparin, stents, operator exper.)( ASA, heparin, stents, operator exper.)

Tirofiban improves: Tirofiban improves: Medical management of unstable angina Medical management of unstable angina (PRISM, PRISM-PLUS) (PRISM, PRISM-PLUS) Outcome following PTCA (RESTORE)Outcome following PTCA (RESTORE)

With current optimal management With current optimal management Which is better and more cost-effective -> Invasive Which is better and more cost-effective -> Invasive vs. Consvative strategy ? vs. Consvative strategy ?

Study RationaleStudy Rationale

TIMI IIIB: Troponin I vs. 42 Day Mortality TIMI IIIB: Troponin I vs. 42 Day Mortality

0-<0.40-<0.4 0.4-<1.00.4-<1.0 1.0-<2.01.0-<2.0 2.0-<5.02.0-<5.0 5.0-<9.05.0-<9.0 > 9.0> 9.0001122334455667788

Dea

th b

y 42

Day

s (%

)D

eath

by

42 D

ays

(%)

cTnI at Baseline (ng/ml)cTnI at Baseline (ng/ml)

1.01.01.71.7

3.43.4 3.73.7

6.06.0

7.57.5

Risk RatioRisk Ratio 6.26.2 7.87.83.53.5 3.93.91.01.0 1.81.8

831831 174174 148148 134134 5050 6767

p<0.001p<0.001

Antman et al. NEJM 1996;335: 1342-9.Antman et al. NEJM 1996;335: 1342-9.

Troponin T and I: associated with risk of death Troponin T and I: associated with risk of death

TACTICS-TIMI 18 tests “Troponin Hypothesis” TACTICS-TIMI 18 tests “Troponin Hypothesis” The troponins will be useful in determining the The troponins will be useful in determining the best treatment strategy (invasive vs. best treatment strategy (invasive vs. conservative)conservative)

Which is better - T or I?Which is better - T or I?

TACTICS-TIMI 18 will be first large comparison TACTICS-TIMI 18 will be first large comparison

Additional ObjectivesAdditional Objectives

Troponin HypothesisTroponin HypothesisTroponin HypothesisTroponin Hypothesis