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TACTICS-TIMI 18. T reat Angina with A ggrastat + Determine C ost of T herapy with an I nvasive or C onservative S trategy TIMI 18. As presented by Dr. Cannon at AHA 2000. Background and Hypothesis. Unstable angina and non-ST elevation MI: 1.3 million admissions/yr in U.S.A.

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slide1

TACTICS-TIMI 18

Treat Angina with Aggrastat + Determine Cost of Therapy with anInvasive or Conservative Strategy TIMI 18

As presented by Dr. Cannon at AHA 2000.

slide2

Background and Hypothesis

  • Unstable angina and non-ST elevation MI: 1.3 million admissions/yr in U.S.A.
  • Treatment strategies:
    • Invasive (INV): routine early cath and revasc
    • Conservative (CONS): stress test  if +, cath
  • Prior trials - mixed results
  • Current era - improved medical Rx and PCI: use of GP IIb/IIIa inhibitors, stents
  • 1o Hypothesis: INV strategy will be superior
slide3

TIMI IIIB Study Background and Goal

  • Assess optimal management of unstable angina and non-Q wave MI: Invasive vs. Conservative strategy
      • Invasive:
      • Coronary angiography within 18- 48 hours and revascularization as appropriate
      • Conservative:
      • Initial medical management and coronary angiography / revascularization only for recurrent ischemia

TIMI IIIB Investigators: Circulation 1994;89:1545-56

timi iiib protocol
TIMI IIIBProtocol

1473 Patients with Unstable Angina / NQWMI

ASA, IV Heparin, Beta-blockers, Nitrates, Ca++ blockers

Randomize

Early Conservative:

ST segment Holter

ETT Thallium Pre-D/C

Cath/PTCA if +ischemia

Early Invasive:

Cath 18-48 h

PTCA/CABG prn

ETT 6 weeks

Primary Endpoint:

Death, MI,

Positive ETT - 6 weeks

Circulation 1994;89:1545-56

Follow-up 1 year

slide5

TIMI IIIB

Invasive vs. Conservative

Early invasive strategy-

Cath in all patients between 18-48 hours. Revascularization when feasible based on anatomy:

  • PTCA for 1 or 2 VD
  • CABG for 3VD
  • Early conservative strategy-
  • Cath if patient had recurrent ischemia at rest or on testing:
    • Recurrent ischemia at rest with ECG changes
    • Recurrent MI
    • Positive ETT or Thallium
    • Positive ST segment holter

TIMI IIIB Investigators: Circulation 1994;89:1545-56

slide6

TIMI IIIB Primary Results to 42 days

TIMI IIIB Investigators: Circulation 1994;89:1545-56

Cannon, C. et. al. Unpublished data

slide7

TIMI IIIB One Year Results

Death or MI

Early Conservative

12.2%

10.8%

Early Invasive

P=NS

Weeks

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

slide8

TIMI IIIB One Year Results

PTCA or CABG

Early Invasive

64%

58%

Early Conservative

% of Patients

P=<0.001

Weeks

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

slide9

VANQWISH Trial

VA Hospitals Study: Management post Non-Q wave MI

Combined Endpoint

Death Rates

Non-fatal MI Rates

Conservative

15

15

25

p=0.05

p=0.025

Invasive

20

10

10

15

Percent

p=0.004

p=0.007

10

5

5

5

0

0

0

Discharge 12 mo

Discharge 12 mo

Discharge 12 mo

Boden WE: Presented at the ACC Scientific Sessions 1997, Anaheim CA

slide10

Surgical

Medical

P value

n=237

12%

29%

46%

0.44

NS

0.04

Mortality

2 years

8 years

Subgroup Refractory

angina+Low EF

VA Unstable Angina Cooperative Study

CABG vs. Medical Therapy for Unstable Angina

n=231

10%

28%

13%

Luchi et al NEJM 1987;316:977-84; Sharma et al. Circulation 1991;84:III-260-7.

slide11

RITA-2 Trial

PTCA vs. Medical Management of 1018 Stabilized Angina Patients

Presence of

2+ Angina

PTCA

Medical

P value

No. Pts

Death or MI

Death

Non-fatal MI

504

6.3%

2.2%

4.2%

514

3.3%

1.4%

1.9%

0.02

0.32

0.04

PTCA

Medical

40

30

%

20

10

0

3 mo. 2 yr

RITA-2 Trial Participants: Lancet 1997;350:461-8.

slide12

TIMI IIIB

1 year

VANQWISH

1 year

MATE

2 years

FRISC II

6 months

Prior Trials: Invasive vs. Conservative

P=0.025

24.0%

P=0.6

18.6%

P=0.42

P=0.031

14%

12.2%

12.1%

12%

10.8%

9.4%

N=1473

N=920

N=201

N=2457

In-hospital Procedures

Cath 98% 57% 96% 48% 100% 58% 96% 10%

Revasc 60% 40% 44% 33% 60% 37% 71% 9%

comparison to prior trials
Comparison to Prior Trials

TIMI 3 VANQWISH FRISC II TACTICS- TIMI 18

INV

Stents No No Yes Yes

GP IIb/IIIa No No No Yes

Cath Timing 24 hrs 2-4 days 4 days 24 hrs

CONS

ETT Nuclear Nuc./Echo ECG Nuc/Echo

ST  criteria 1mm 1mm 3mm 1mm

In-hosp Cath 57% 24% 10% 50%

Result Early INV INV < Del. INV Early INV

=Select. CONS > Very ? Select.

INV CONSINV

slide15

AHCPR Unstable Angina Guideline

Recommendations

Cardiac Catheterization / Revascularization:

“This guideline proposes two alternative definitive treatment strategies termed “early invasive” and “early conservative”.

“Randomized trial data did not support inherent superiority of either strategy based on medical outcomes.(TIMI IIIB) The decision about which strategy to pursue for a given patient should be based on the patient’s estimated risk, available facilities, and patient preference.”

AHCPR Guideline 1994

slide16

AHCPR Unstable Angina Guideline

Recommendations

  • Cardiac Catheterization / Revascularization:
    • Early invasive strategy - cath in all patients OR
    • Early conservative strategy - catheterization if patient had a high-risk indicator:
      • Persistent or recurrent ischemia
      • Positive ETT / nuclear imaging scan
      • CHF or LV dysfunction (EF < 50%)
      • Prior PTCA or CABG
      • Malignant ventricular arrhythmias
  • CABG recommended if:
    • Left Main > 50% or 3 VD and LV dysfunction

Braunwald E. et al. Circulation 1994;90:613-622

trial organization

Trial Organization

TIMI Study Group Christopher Cannon, MD

Brigham and Women’s Hosp. Eugene Braunwald, MD

Carolyn McCabe, BS

Economic Data Coordination William Weintraub, MD

Emory University Claudine Jurkovitz, MD, MPH

Elizabeth Mahoney, ScD

Sponsor - Merck: Laura Demopoulos, MD

Peter DiBattiste, MD

Debbie Robertson, RD MS

Paul DeLucca, Ph.D.

Data Center- Quintiles Josh Davis

Serum Marker Core Lab Nader Rifai, Ph.D.

Angiographic Core Lab C. Michael Gibson, MD

eligibility criteria
Eligibility Criteria
  • INCLUSION CRITERIA:
    • Accelerating pattern, prolonged or recurrent anginal pain at rest or minimal effort <24 hrs
    • At least 1 of the following:
      • Ischemic ECG changes
      • Elevated cardiac markers (local)
      • History: MI, CAD, PCI, CABG
  • MAJOR EXCLUSION CRITERIA:
    • Age < 18 years
    • Acute STEMI or thrombolytic < 24h
    • Increased bleeding risk (Hx.  Plts, GI bleed)
    • Killip Class III or IV
slide20

TACTICS-TIMI 18 Study Design

PCI/ CABG

Early

Invasive

Angio

Medical Rx

UA/

NSTEMI

ASA, Hep,Tirofiban

Endpoints

Early

Conservative

Baseline

Troponin

Medical Rx

ETT

+ischemia

Chest pain

Cath/ PCI/ CABG

Randomize

-24 hrs

Hour

0

6 mos

4- 48 108

hrs hrs

treatment strategies
Early invasive strategy

Cath between 4 and 48 hours

Revasc if suitable anatomy

Early conservative or “selective invasive” strategy Catheterization if:

Refractory angina (>10m rest CP, + ECG ’s)

Hemodynamic instability

+ ETT (ST >1mm,  BP, multiple defects, +Echo)

New MI or Rehospitalization for UA

CCS Class III or IV angina and + ETT

Treatment Strategies
statistics
1o Endpoint: Death, MI, Rehosp for ACS to 6 mos (100% CEC; MI:CK-MB>ULN, >3xULN p PCI)

Power: Invasive strategy will be superior80% power to detect a 25% diff.

Sample size: 1720, planned recalculation on blinded data after 50% patients: 2220 patients

Troponin hypothesis: added benefit in Tn + Pts

Follow-up: 99% complete

Analyses: ITT

Statistics
baseline characteristics
Baseline Characteristics

INVCONS

62 62

44 43

65 67

77 78

68 66

28 27

39 38

48 47

38 37

56 53

N = 2220

%

%

Age (years)

Age > 65

Male

White

Prior ASA

Diabetes

ST ’s

ECG ’s

NSTEMI

TnT >0.01 ng/ml

protocol implementation
Protocol Implementation

Cath/ Revasc - Initial Hosp (%)

CONSINV

Cath* 51 97

PCI 24 41

CABG** 13 19

Any Revasc 36 60 Revasc6 mos. 44 61

*Duration tirofiban

pre-cath (mean):

INV: 24 h

**30-day

post-CABG

mortality

= 3.6%

slide25

19.4%

15.9%

O.R 0.78

95% CI (0.62, 0.97)

p=0.025

CONS

INV

Primary Endpoint

Death, MI, Rehosp for ACS at 6 Months

20

16

% Patients

12

8

4

0

0

1

2

3

4

5

6

Time (months)

cardiac events at 30 days

INV (%)

1114

7.4

4.7

2.2

3.1

3.4

Cardiac Events at 30 Days

CONS (%)

OR

P value

No. Pts

1o Endpoint

Death/MI

Death

MI

Rehosp ACS

1106

10.5

7.0

1.6

5.8

5.5

0.67

0.65

1.40

0.51

0.61

0.009

0.02

0. 29

0.002

0.018

cardiac events at 6 months
Cardiac Events at 6 Months

CONS (%)

INV (%)

OR

P value

No. Pts

1o Endpoint

Death/MI

Death

MI

Rehosp ACS

1106

19.4

9.5

3.5

6.9

13.7

1114

15.9

7.3

3.3

4.8

11.0

0.78

0.74

0.93

0.67

0.78

0.025

<0.05

0.74

0.029

0.054

subgroups primary endpoint

0 0.5 1 1.5

Subgroups: Primary Endpoint

Death, MI, Rehosp ACS at 6 Months

CONS INV

(%) (%)

19.4 15.3

19.6 17.0

17.8 14.9

21.7 17.1

27.7 20.1

16.4 14.2

26.3 16.4

15.3 15.6

19.4 15.9

1O Endpoint %Pts

Men (66%)

Women (34%)

Age < 65 yrs (57%)

Age > 65 yrs (43%)

Diabetes (28%)

No diabetes (72%)

ST  * (38%)

No ST  (62%)

Total Population

*Interaction P=0.006

others P=NS

INV Better

CONS Better

slide29

Troponin T: 1oEP at 6 months

Death, MI, Rehosp ACS at 6 Months

CONS

INV

*

OR=0.52

*p<0.001

Interaction

P<0.001

p=NS

(%)

N=414

N=396

N=463

N=495

TnT cut point = 0.01 ng/ml (54% of Pts TnT +)

slide30

TIMI UA Risk Score: 1oEP at 6 mos

OR=0.55

CI (0.33, 0.91)

CONS

INV

OR=0.75

CI (0.57, 1.00)

Death/MI/ACS Rehosp (%)

TIMI Risk Score

% of Pts: 25% 60% 15%

additional outcomes 6 months

CONS (%)

1106

10.3

49.4

0.5

3.3

(1.3)

6

8.3

Additional Outcomes - 6 Months

INV (%)

OR

P value

No. Pts

Rec. UA + ECG

Rec. UA - ECG

Stroke

Major bleed (TIMI Major)

Init. LOS (median,

mean, days)

1114

6.3

32.3

0.5

5.5

(1.9)

5

7.4

0.58

0.49

1.0

1.6

1.5

-

0.001

<0.001

NS

0.01

NS

<0.001

comparison to prior trials1
Comparison to Prior Trials

TIMI 3 VANQWISH FRISC II TACTICS- TIMI 18

INV

Stents No No Yes Yes

GP IIb/IIIa No No No Yes

Cath Timing 24 hrs 2-4 days 4 days 24 hrs

CONS

ETT Nuclear Nuc./Echo ECG Nuc/Echo

ST  criteria 1mm 1mm 3mm 1mm

In-hosp Cath 57% 24% 10% 50%

Result Early INV INV < Del. INV Early INV

=Select. CONS > Very ? Select.

INV CONSINV

tactics timi 18 conclusions
Pts with UA/NSTEMI (+ ECG/+ markers/CAD), “upstream” Rx with GP IIb/IIIa inhibitor tirofiban

Early invasive strategy results in significant reduction in major cardiac events (Death/MI/ Rehosp for ACS)

“Troponin hypothesis” confirmed: Tn useful in choosing strategy,  benefit of INV if Tn +

TIMI Risk Score:

Intermediate- and high-risk Pts: INV superior

Low risk Pts: INVandCONSequal

TACTICS-TIMI 18: Conclusions
tactics timi 18 conclusions1
Possible mechanisms:

Benefit of earlyINV - prevents events compared with “wait and see” approach

Upstream tirofiban improved INV strategy

Results of TACTICS-TIMI 18 suggest need to

Update ACC/AHA UA/NSTEMI Guidelines

Change clinical management of UA/NSTEMI:broader use of an early invasive strategy with GP IIb/IIIa inhibition

EQOL being analyzed: W. Weintraub – ACC 2001

TACTICS-TIMI 18: Conclusions