Download - The TIMI Trials 1984 - 1999 Brigham and Women’s Hospital Harvard Medical School Boston, MA P ART I.R ESULTS OF TIMI 1 - TIMI 17 P ART II.T RIAL D ESIGNS.

The TIMI TrialsThe TIMI Trials1984 - 19991984 - 1999

Brigham and Women’s Hospital

Harvard Medical School

Boston, MA

PART I. RESULTS OF TIMI 1 - TIMI 17PART II. TRIAL DESIGNS FOR TIMI 18-24

IV Heparin

Baseline Angio

Patient with Acute ST Elevation MI Patient with Acute ST Elevation MI << 6 hours 6 hours

t-PA 80 mg / 3 hrs

Streptokinase1.5 MU / 60 mins

Angio 10, 20, 30, 45, 60, 75, 90 Mins

Double-blindDouble-blind

TIMI 1TIMI 1 Protocol Design

6270

3143

Reperfusion ofoccluded arteries

Patency at90 minutes

0

20

40

60

80

% o

f P

atie

nts

t-PA

SK

*P<0.001

**

TIMI Study Group N Engl J Med 1985;312:397- 401

TIMI 1TIMI 1 Primary Outcome

Comparison of t-PA and Streptokinase

TIMI 1TIMI 1Impact of 90 Minute Patency on Mortality

0 8 16 24 32 40 48

Weeks from Randomization

0

5

10

15

20

Mo

r tal

ity

(%)

Patent (N=161)

Occluded (N=128)

Open Artery Theory

Dalen, et. al. Am J Cardiol 1988; 62:179-85

TIMI Grade Flow Scoring System

Monitoring ReperfusionTIMI 1TIMI 1

TIMI 0 Complete occlusion

TIMI 1 Penetration of obstruction by contrast but no distal perfusion

TIMI 2 Perfusion of entire artery

but delayed flow

TIMI 3 Full perfusion, normal flow

10.6

7

4.7

0

2

4

6

8

10

12

14

TIMI 0/1 TIMI 2 TIMI 3

Flygenring BP et al. JACC 1991;17:275

Mortality at 42 Days

P < 0.005

IV t-PARandomize

6 week ETT / RVG

Immediate Invasive:Cath 2 hrs

N=195

Acute MI < 4 hours onset

Primary Endpoint:Pre-D/C EF

Follow-up 1 year

Delayed Invasive:

Cath 18-48 hrsN=194

Pre-D/C Angio and RVG

TIMI IIATIMI IIA Protocol Design

Conservative:Cath if +ETT or

ischemiaN=197

TIMI IIATIMI IIA Immediate PTCA vs. Delayed Invasive vs. Conservative Strategy post Thrombolysis

Management Strategy

TIMI IIA Invest. JAMA 1988;260:2849. Rogers, et al. Circulation 1990;81:1457-76

81 84 86

0

20

40

60

80

100

2 h 18 - 24 h Cons.

12.8

8.8

11.7

0

2

4

6

8

10

12

14

2 h 18 - 24 h Cons.

Patency at Discharge (%) Death or MI by 6 weeks (%)

IV t-PAHeparin, ASA Randomize

Pre-D/C ETT / RVG

Acute MI < 4 hours onsetAcute MI < 4 hours onset

Conservative::Cath if +ETT or

ischemia

Primary Endpoint:Death or MI

Follow-up 1 year

Invasive:Cath 18-48 hrs

Revasc if feasible

6 week ETT / RVG

TIMI IIBTIMI IIB Protocol Design

TIMI Study Group. NEJM 1989;320:618. Williams DO, Circulation 1992;85:533-42.

PTCA or CABG to 1 Year

0 7 14 21 28 35 42 52

Weeks

0

20

40

60

80

% o

f P

ati e

nts

Invasive

Conservative

0 7 14 21 28 35 42 52

Weeks

0

5

10

15

20

% o

f P

ati e

nts

P=NS

15.2%14.7%

Conservative

Invasive

*P<0.001

Death or MI to 1 Year

72.2%

35.5%*

TIMI IIBTIMI IIBConservative vs. Delayed Invasive

Management Strategy

1000 Pts

370 Caths saved400 PTCAs saved

$3,200,000 saved

With no difference in outcomeWilliams DO, et al. Circulation

1992;85:533-42.

$3000 per Cath$4000 per PTCA

TIMI IIBTIMI IIBCost Implications of Invasive Strategy

Management Strategy

14.7

72.2

98

15.2

35.545.2

0

20

40

60

80

100

120

'Death/MI PTCA orCABG

Cath

Invasive Conservative

Roberts et al. Circulation 1991;83:422-37.

TIMI IIBTIMI IIBIV Beta-Blockade Following Thrombolysis

Adjunctive Therapy

4.5

2.3

0

1

2

3

4

5

6

Late Beta-blocker

IV Beta-blocker

21.2

15.4

0

5

10

15

20

25

30

Late Beta-blocker

IV Beta-blocker

Reinfarction (%) Recurrent Ischemia (%)

P = 0.02 P = 0.005

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

Randomize

Angio 18-36 hrs

t-PA0.8 mg/kg over 90 mins

391 Patients with Unstable Angina / NQWMI391 Patients with Unstable Angina / NQWMI

Placebo

Primary Endpoint:Death, MI,Positive ETT 6 weeks Follow-up 6 weeks Circulation 1993;87:38-52

Baseline AngioAngio Exclusion: no CAD or LMain

TIMI IIIATIMI IIIA Protocol Design

Apparent thrombus35%

Possible thrombus30%

No thrombus35%

Improvement in Culprit Lesion: 25% t-PA vs. 19% placebo p=NS

TIMI IIIA Investigators. Circulation 1993;87:38-52.

TIMI IIIATIMI IIIAEffects of tPA on Coronary Lesions

Primary Results

BASELINE ANGIORAPHY:

ANGIORAPHY AFTER tPA:

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

Randomize

ETT 6 weeks

Early Invasive:Cath 18-48 h

PTCA/CABG prn

1473 Patients with Unstable Angina / NQWMI1473 Patients with Unstable Angina / NQWMI

Early Conservative:

ST Holter, ETT Thallium Cath/PTCA if +ischemia

1o Endpoint Inv-Cons:Death, MI,Positive ETT - 6 weeks

Follow-up 1 yearCirculation 1994;89:1545-56

2x2 Factorial:2x2 Factorial:t-PA vs. Placebot-PA vs. Placebo

1o Endpoint t-PA:Death, MI, Rec Isch,+ ETT, Thallium or ST Holter

TIMI IIIBTIMI IIIB Protocol Design

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

TIMI IIIBTIMI IIIB

tPA vs. Placebo in Non-ST Elevation ACSPrimary Results

54.2 55.5

0

10

20

30

40

50

60

70

80

tPA Placebo

8.8

6.2

0

2

4

6

8

10

12

tPA Placebo

0.55

00

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

tPA Placebo

Composite Endpoint Death or MI ICH

% o

f P

atie

nts

P = NS P = 0.05 P = 0.05

Events at 42dEvents at 42d InvasiveInvasive ConservativeConservative pp valuevalueNo. Pts 740 733Death (%) 2.4 2.5 NSMI (%) 5.1 5.7 NSD/MI/+ETT (%) 16.2 18.1 NS

Rehosp Angina (%) 7.8 14.1 <0.001D/MI/Rehosp (%) 15 22 0.007LOS (days) 10.2 10.9 <0.001# Days rehosp 365 930 <0.001

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

TIMI IIIBTIMI IIIB

Early Invasive vs. Conservative Strategy

Primary Results

• All consecutive patients admitted with unstable angina were screened.

• Inclusion Criteria: Ischemic pain >5 mins within 96 hrs with unstable pattern: At rest, accelerating, post MI

• Exclusion Criteria: Non-ischemic pain, ST elevation, admitted for revascularization procedure

• Patients in specific subgroups defined by gender, race and age were randomly selected for detailed evaluation and follow-up at 6 weeks and 1 year.

TIMI IIITIMI III RREGISTRYEGISTRY Protocol Design

2.6 3.6

11

0.8

6.6

22.9

1.63.7

6.8

1.63.7

8.2

In-Hospital 6 Weeks 1 Year0

5

10

15

20

25

% o

f P

ati e

nts

ST deviation >0.1 mV LBBB Tw change No ECG changes_

Stone PH, TIMI III Registry Study Group. JAMA 1996;275:1104-1112.Cannon CP et al for ECG Substudy Investigators. JACC 1997;30:133-40.

TIMI IIITIMI III RREGISTRYEGISTRY

Admission ECG as a prognostic indicator

Risk Stratification

Death or MI

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

0 1 2 3 4 5

No CKMB Elev

All Patients

No CKMB Elev

All Patients

No CKMB Elev

All Patients

Mortality at 42 Days (%)

TnI < 0.4 ng/mlTnI > 0.4 ng/ml

Enrolled 0-6 hrs

Enrolled 6-24 hrs

Enrolled 0-24 hrs

P<0.001

P <0.05

P <0.05

P<0.001

TIMI IIIBTIMI IIIBcTnI to Predict Risk of Mortality in ACS

Risk Stratification

Pt. with AMI < 6 hrs

Heparin, ASA

90 min Angio

18-36 hr AngioMIBI scan

RVG, MIBI scanFollow-up 6 wks, 1 yr

tPA Combination APSAC


Unsatisfactory Outcome One Year Mortality

Cannon CP, et al., TIMI 4 Investigators J Am Coll Cardiol 1994;24:1602-10

0 30 60 90 120150180210240270300330 365

Days from Randomization

0.7

0.8

0.9

1

Su

rviv

al

(% o

f P

ts)

t-PA

Comb.

APSAC

*p=0.07t-PA vs. APSAC

p=0.13t-PA vs. Comb.

TIMI 4TIMI 4Benefit of front-loaded tPA

Primary Results

42

52.456.7

0

20

40

60

80

tPA APSAC Comb.

% o

f P

atie

nts

*P = 0.06

*

Pt. with AMI < 6 hrsPt. with AMI < 6 hrs

Day 5-6: RVG, MIBI scan

4 Ascending Hirudin Doses:0.15 B, 0.05 IV0.1 B, 0.1 IV0.3 B, 0.1 IV0.6 B, 0.2 IV

5000 U Bolus,1000 U/h IVAPTT 65-90 secs


Heparin Hirudin

ASA, tPA

F/U 6 Weeks, 1 yr

90 min angio

18-36 hr angioMIBI Scan

6557

0

20

40

60

80

1.6

6.7

0

3

6

9

62

49

0

20

40

60

80

TIMI 5TIMI 5Hirudin vs. Heparin: Angiographic Results

Primary Results

Heparin N = 84

HirudinN = 162

Heparin N = 79

HirudinN = 157

Heparin N = 60

HirudinN = 123

TIMI 3 Flow at 90’TIMI 3 Flow at 90’ and 18-36 h

Reocclusion

Cannon CP, et al. J Am Coll Cardiol 1994;23:993-1003.

Pt. with AMI < 6 hrs

Day 5-6: RVG, MIBI scan

3 Ascending Hirudin Doses:0.15 B, 0.05 IV0.3 B, 0.1 IV0.6 B, 0.2 IV

5000 U Bolus,1000 U/h IVAPTT 65-90 secs


Heparin Hirudin

ASA, SK

F/U 6 Weeks

TIMI 6TIMI 6Heparin vs. Hirudin and stability of APTT

Adjunctive Therapy

25

61.5

72.7 74.1

0

20

40

60

80

100

Heparin 0.15/0.05 0.3/0.1 0.6/0.2

% o

f P

atie

nts

wit

h st

able

AP

TT

Hirudin Dose

Lee VL et al. for the TIMI 6 Investigators. Am J Cardiol 1995;75:7-13.

APTT range 30 seconds*p < 0.001

*

ASA

Randomize

30 Day Follow-up

Hirulog0.25 mg/kg/h

Patient with Unstable AnginaPatient with Unstable Angina

Hirulog0.5 mg/kg/h

Hirulog1.0 mg/kg/h

Hirulog0.02 mg/kg/h


TIMI 7TIMI 7Hirulog in Unstable Angina

Primary Results

10

12.5

3.2

5.2

0

2

4

6

8

10

12

14

16

18

Hospital Discharge Six Weeks

Dea

th o

r M

I (%

Pat

ien

ts)

Low Dose (0.02 mg/kg/hr)

Higher Doses (0.25-1.0 mg/kg/hr)

Fuchs, Cannon for the TIMI 7 Investigators Circulation 92 : 727, 1995

P = 0.008

P = 0.009

UA/NQMI < 24 hrsUA/NQMI < 24 hrs

Primary EndpointPrimary Endpoint: Death or MI: Death or MI

ASAASA

HirulogHirulog

Followup: 30 daysFollowup: 30 days

HeparinHeparin ( (aPTT 50-70s)aPTT 50-70s)


Pt. with AMI Pt. with AMI << 12 hrs 12 hrsPt. with AMI Pt. with AMI << 12 hrs 12 hrs

Thrombolytic Therapy (accel tPA or SK)Thrombolytic Therapy (accel tPA or SK)Thrombolytic Therapy (accel tPA or SK)Thrombolytic Therapy (accel tPA or SK)

Death, MI, Death, MI,

CHF/ShockCHF/Shock 30 days F/U30 days F/U

HEPARIN HEPARIN Bolus 5000 UBolus 5000 UInf 1000 U/hInf 1000 U/h

1300 u/h >80kg1300 u/h >80kg

HIRUDINHIRUDIN Bolus 0.6 Bolus 0.6

mg/kgmg/kg Inf 0.2 mg/kg/h Inf 0.2 mg/kg/h

Major BleedingMajor Bleeding

ASAASA

96 H Rx96 H Rx

aPTT 60-aPTT 60-90 s90 s

TIMI 9ATIMI 9A Protocol Design

Pt. with AMI < 12 hrsPt. with AMI < 12 hrsPt. with AMI < 12 hrsPt. with AMI < 12 hrs

Sample Size =3000 pts (Power 90%, Sample Size =3000 pts (Power 90%, .05, 25% Rx effect).05, 25% Rx effect)

Thrombolytic Therapy (accel tPA or SK)Thrombolytic Therapy (accel tPA or SK)Thrombolytic Therapy (accel tPA or SK)Thrombolytic Therapy (accel tPA or SK)

Death, MI, CHF/ShockDeath, MI, CHF/Shock 30 days30 days

HEPARIN HEPARIN Bolus 5000 UBolus 5000 UInf 1000 U/hInf 1000 U/h

HIRUDINHIRUDIN Bolus 0.1 Bolus 0.1

mg/kgmg/kg Inf 0.1 mg/kg/h Inf 0.1 mg/kg/h

Major BleedingMajor Bleeding

ASAASA

96 H Rx96 H Rx

aPTT 55-aPTT 55-85 s85 s

Protocol DesignTIMITIMI 9B9B

00 55 1010 1515 2020 2525 303000

22

44

66

88

1010

1212

1414

HIRUDINHIRUDIN

HEPARINHEPARIN

UNSATISFACTORY OUTCOMEUNSATISFACTORY OUTCOME

DEATH + REINFARCTIONDEATH + REINFARCTION

%%PtsPts

Days post randomizationDays post randomization

p=NSp=NS

12.912.9

11.911.9

9.79.7

9.59.5

TIMITIMI 9B9B

E. Antman for The TIMI 9B Investigators Circulation 1996;94: 911.

Primary ResultsHirudin vs. Heparin with tPA for MI

TIMI 9TIMI 9Influence of Heparin/Hirudin Dosing

Safety Observations

0

2

4

6

8

10

12

14

16

Heparin Hirudin Heparin Hirudin

Per

cent

age

of P

atie

nts

Major Hemorrhage:InstrumentationSpontaneousICH

Antman et al. Circulation 1994 and 1996

Major Hemorrhage:

TIMI 9A (N=713) TIMI 9B (N = 2929)

65%

25%

10%

60%

31%

9%

Thrombolysis Non-reperfusion Primary PTCA

TIMI 9TIMI 9 RREGISTRYEGISTRY

Initial Management Strategy in AMI

Critical Pathways

All Patients Pts presenting 12 hrs

Cannon CP et al. J Am Coll Cardiol 1995;231-232A.

TIMITIMI 9B9B Risk Stratification

Prediction of Mortality at 30 Days

• Age > 70, • Prior MI• Anterior MI, • Atrial fibrillation• Rales• Hypotension and HR• Female gender • Diabetes

1.62.9

7.4

16

22.3

0

5

10

15

20

25

0 1 2 3 >4Number Risk Factors

Mo

rtal

ity

- 30

Day

s (%

)

P<0.001

% Pts: 26% 37% 24% 10% 3%

Cannon CP et al. JACC 1999;33(Suppl. A):396A.

Hillis et al. TIMI 2

TIMI 10ATIMI 10A Protocol Design

TNK- tPA Bolus

ASA + IV Heparin

(APTT 55-85)

Follow-up Hosp. Discharge to 30 days

Pt. with Acute MI < 12hPt. with Acute MI < 12h

End Points:PharmacokineticsCoagulation parametersTIMI grade 3 flow at 90'TIMI frame countMajor hemorrhageAllergic Events

8 Ascending TNK-tPA Doses:5, 7.5, 10, 15, 20, 30, 40, 50 mg

Cannon CP et al. Circulation 1995;92:I-415.

TIMI 10ATIMI 10ATIMI Flow Grade at 90 Minutes

Primary Results

60

40

17

29

59 5764

80 40 66

42

2924

22

40

0

20

40

60

80

100

5 mg 7.5 mg 10 mg 15 mg 20 mg 30 mg 40 mg 50 mg

Pat

ien

ts (

%)

TIMI 3 TIMI 2

Cannon CP, TIMI 10A Investigators. Circulation 1997;95:351-6

TNK-tPA Dose

ASA, IV Heparin

Randomize

30 Day Follow-up

TNK-tPA 30mg

Patient with Acute ST Elevation MI < 12 hours Patient with Acute ST Elevation MI < 12 hours

TNK-tPA 40mg

TNK-tPA 50mg*

t-PA100 mg

Angio 60, 75, 90 Mins

*Stopped early*Stopped earlyReplaced with 40 mgReplaced with 40 mg

TIMI 10BTIMI 10B Protocol Design

TIMI 10BTIMI 10BTIMI Flow Grade at 90 Minutes

Primary Results

6355

63 66

1922 16

22

0

20

40

60

80

100

tPA TNK 30 mg TNK 40 mg TNK 50 mg

TIMI 3 TIMI 2

Cannon CP for the TIMI 10B Investigators. Circulation 1998;98:2805-14

*

77%77% 79%79%88%88%

82%82%

N = 311 304 146 76

ASA, IV Heparin

Randomize

30 Day Follow-up

TNK-tPA 30mg

Patient with Acute ST Elevation MI < 12 hours Patient with Acute ST Elevation MI < 12 hours

TNK-tPA 40mg

TNK-tPA 50mg*

*Stopped early*Stopped earlyReplaced with 40 mgReplaced with 40 mg

ASSENT IASSENT I Protocol Design

1.5

0.5

1.0

0 0 0

0.94

0.62

1.5

Total Stroke ICH Ischemic Stroke

% o

f P

atie

nts

30 mg TNK, n=1,705 40 mg TNK, n=1,457 50 mg TNK, n=73

ASSENT IASSENT I Primary ResultsIncidence of Stroke at 30 Days

Van de Werf F, Cannon CP for the ASSENT 1 Investigators Am Heart J 1999;137:786-91

2.8

2.11.8

0.80.71.1

0.0

1.0

2.0

3.0

TNK 30 tPA Either

% o

f P

atie

nts

Pre Post

p = 0.046

p = 0.4

p = 0.01

Giugliano RP, Circ 1997;96:I-535 (abstract)

TIMI 10B/ASSENT ITIMI 10B/ASSENT IICH Pre/post Reduction in Heparin

Adjunctive Therapy

Dose 2

N=309

Dose 1

N=320

IV BolusIV Bolus IV BolusIV Bolus Wgt AdjWgt AdjWgt AdjWgt Adj Fixed DoseFixed DoseFixed DoseFixed Dose

30 mg30 mg

30 mg30 mg

1.25 mg/kg1.25 mg/kg

Q 12 h (2-8d)Q 12 h (2-8d)

1.0 mg/kg1.0 mg/kg

Q 12 h (2-8d)Q 12 h (2-8d)

< 65 kg< 65 kg >> 65 kg 65 kg

40 mg40 mg 60 mg60 mg

Q12 hQ12 h

40 mg40 mg 60 mg60 mg

Q12 hQ12 h

Total Rx Period = 14 days

< 65 kg< 65 kg >> 65 kg 65 kg

Hospital Phase Home Rx

TIMI 11AProtocol Design

N=3211.25 mg/kg

Instrumented

Spontaneous

6.5%

1.9%

T3B Hep + Plac

N=735

3.2%

N=3091.0 mg/kg

0

2

4

6

8

10

Dose Tier 1 Dose Tier 2

%

TIMI 11 A Investigators. JACC 29: 1474,1997

TIMI 11APrimary Results

Incidence of Major Hemorrhage thru 14 days

p = 0.006

0.4%0.3%

5.8%5.6%

0

1

2

3

4

5

6

7

All Patients Rapid cTnT Neg

p = 0.001

Mor

tali

ty a

t 1

4 D

ays

(%)

<1.55 mg/dL>=1.55 mg/dL

CRP Concentration

N = 437 N = 346

TIMI 11ARisk Stratification

Baseline C-reactive Protein and Mortality

Morrow et al. JACC 1998;31:1460-5

ENOXENOX Bolus 30 mg IVBolus 30 mg IV1.0 mg / kg Q12h1.0 mg / kg Q12h

Pt. with UA/NQMI Pt. with UA/NQMI << 24 h 24 h

Primary Endpoint:

UFH UFH >> 3 days 3 daysBolus 70 U / kgBolus 70 U / kg

INF 15 U / kg / hINF 15 U / kg / h

Major BleedingSerious AEs

ASAASA

aPTT 1.5-2.5 x aPTT 1.5-2.5 x controlcontrol

Hosp DC Hosp DC (or 8 days)(or 8 days)

TIMI 11BProtocol Design

Death, MI, Urgent Revascularization

Acute Phase Protocol

22

44

66

88

1010

1212

1414

1616

1818

2020

00 22 44 66 88 1010 1212 1414

P=0.029RRR 15 %

UFHUFHENOXENOX 16.7 %16.7 %

14.2 %14.2 %%

Days

14.5 %14.5 %

12.4 %12.4 %

P=0.048RRR 15 %

TIMI 11BPrimary Results

Death/MI/Urgent Revascularization at 14 Days

E. Antman for The TIMI 11B Investigators Circulation 1999.

0

1

2

3

4

5

6

7

8

9

0 8 16 24 32 40 48 56 64 72

% P

ts

UFHUFHENOXENOX

5.2 %5.2 %

4.2 %4.2 % RRR 18%RRR 18%P=0.20P=0.20

7.3 %7.3 %

5.5 %5.5 %

RRR 24%RRR 24%P=0.02P=0.02

ESSENCEESSENCE

TIMI 11 BTIMI 11 B

Hours from Randomization

Efficacy ResultsDeath/MI/Urgent Revasc. Early Rx Phase

TIMI 11B


Efficacy ResultsTIMI 11B

- ESSENCE Meta-Analysis- ESSENCE Meta-Analysis

OVERALL

ESSENCE

TIMI 11B

OVERALL

ESSENCE

TIMI 11B

OVERALL

ESSENCE

TIMI 11B

0.5 1 2

Day

8

14

43

0.6 0.7 0.8 0.9Odds RatioEnox Better UFH Better

OR % p

0.77(0.62-0.95)

23 0.02

0.79(0.65-0.96)

21 0.02

0.82(0.69-0.97)

18 0.02

N

7081

7081

7081

3910

3910

3910

3171

3171

3171

UFH(%)

Enox (%)

5.3 4.1

6.5 5.2

8.6 7.1

Death/MI

Antman E, Cohen M for The TIMI 11B & ESSENCE Investigators Circulation 1999.

Pt. with UA/NQMI < 24 h

Death, MI, Severe Rec Isch Requiring Urgent Revasc

Acute = Day 8UFH iv > 72 hUFH iv > 72 h

Major Bleeding Serious AEs

ASA

ENOX iv-b,scENOX iv-b,sc

Placebo scPlacebo sc ENOX scENOX sc Chronic = Day 43

TIMI 11BProtocol Design

DaysDays

0

2

4

6

8

10

12

14

16

18

20

0 4 8 12 16 20 24 28 32 36 40 44

P=0.048P=0.048RRR 12 %RRR 12 %

UFHUFHENOXENOX

19.7 %19.7 %

17.3 %17.3 %

%%

TIMI 11BPrimary Results: Chronic Phase

Death/MI/Urgent Revascularization at 43 Days


TIMI 11BEfficacy Results

Efficacy of Enoxaparin Stratified by Baseline Risk

0.5 1 2

High(N=593)

Inter(N=1645)

Low(N=1672)

UFH(%)

ENOX(%)

OR (95 CI)

Favors ENOX

Favors UFHO.R.

29.6 0.78 (0.55,1.13)24.8

20.5 17.9

15.0 14.1

0.85 (0.66,1.08)

0.94 (0.72,1.23)

22

15

6

%

P=0.079 trend

Day 43 Death/MI/UR at 43 DaysDeath/MI/UR at 43 Days

Holper E. AHA 1998

TIMI 11BEfficacy Results

Efficacy of Enoxaparin Stratified by Rx Strategy

6.17.1

0

2

4

6

8

10

UFH ENOX

%

8.8

7

0

2

4

6

8

10

UFH ENOX

7.6 7.9

0

2

4

6

8

10

UFH ENOX

Med Rx

Guzman ESC 1999

PCI CABG

OR (95 CI) 0.85 (0.62,1.16) 0.77 (0.45,1.31) 1.04 (0.55,1.95)

1286 265 275 396 3741314

D/MI/UR

15 pts/dose

1o End Point:

% Inhibition of ADP-induced Plt aggregation

Plt. Aggreg. / PK samples0, 2, 4, 6, 9, 24, 36 h

Follow-up visit Day 7Phone Contact Day 14, 21

Sibrafiban3 mg bid

Sibrafiban5 mg qd

Sibrafiban5 mg bid

Sibrafiban10 mg qd

Additional Doses:7 mg bid15 mg qd10 mg bid

Plt. Aggreg. / PK samples0, 2, 4, 6, 9, 24 h

Cannon et al. Circulation 1998;97:340

Protocol DesignTIMI 12TIMI 12

Patients 1-7 days post-ACS

0

0.2

0.4

0.6

0.8

1

1.2

0 20 40 60 80 100

Peak % Inhibition of ADP-induced Aggregation (Day 1)

3 mg bid

5 mg bid

10 mg bid

7 mg bid

Minor or Major Bleeding (% of Pts)

R2=0.95

Cannon CP et al Circulation 1998;97:340-9

Primary ResultsTIMI 12TIMI 12 Platelet Inhibition and Bleeding Risk

3 mg bid3 mg bid5 mg bid5 mg bid7 mg bid7 mg bid10 mg bid10 mg bid

00

2525

5050

7575

100100

00 66 1212 2424

Mea

n %

in

hib

itio

n (

AD

P)

Mea

n %

in

hib

itio

n (

AD

P)

00 66 1212 2424 3636

D1D1 D28D28

Hours post-doseHours post-doseCannon et al. Circulation 1998;97:340

Primary ResultsTIMI 12TIMI 12 Inhibition of Platelet Aggregation by Dose Grp

ST , lytic eligible, < 12 h

Group I

tPA < 100 mg

Group II

dose tPA

Group III

dose SK

Group IV

No lytic

Angio (90 min) , In Hospital Events, 30 day F/U

No Abciximab Abx: bolus 0.25 mg/kg inf 0.125 g/kg/min x 12 h

STD Heparin (70 U/kg ; 15 U/kg/h)

Low Dose Heparin (60 U/kg ; 7 U/kg/h)

ASA

TIMI 14

vs

Group V

rPA 10+10U

Group VI

dose rPAvs

4540

5863

5749

62

74

0

20

40

60

80

100

100 mg bolus bolus + 30 mininfusion

bolus + 60 mininfusion

% o

f P

atie

nts

60 Min 90 Min

TIMI 14Primary Results

Speed and Extent of Thrombolysis: TIMI 3 Flow

Antman et al. Circulation 1999;99:2720

tPAtPA tPA + AbciximabtPA + Abciximab 2 Trend, p < 0.0022 Trend, p < 0.002

Normal Normal Flow Flow

cTFC < 28cTFC < 28

tPA 100 mg 36tPA 100 mg 36

tPA 50 (15b/35inf) + Abx tPA 50 (15b/35inf) + Abx 2828

Abx 100Abx 100

SK + Abx 45SK + Abx 45

cTFCcTFC Median Median

P=0.005P=0.005

%

Pat

ien

ts%

Pat

ien

ts

0101020203030404050506060707080809090

100100

0Corrected TIMI Frame Count

20 40 60 80 100

TIMI 14Efficacy Results

TIMI Frame Count at 90 Min

Antman et al. Circulation 1999;99:2720

ControlFull Dose Lytic:rPA 10 + 10 U

Reduced Dose Lytic

rPA

Angio (90 min) , In Hospital Events, 30 day F/U

No Abciximab Abx : bolus 0.25 mg/kg inf 0.125 g/kg/min x 12 h

Low Dose Heparin (60 U/kg ; 7 U/kg/h)

Very Low Dose Heparin (30 U/kg ; 4 U/kg/h)

ST Elevation, Lytic Eligible, < 12 hASA

No Abciximab

STD Heparin (70 U/kg ; 15 U/kg/h)

TIMI 14Protocol Design- rPA Phase - rPA Phase

TIMI 14Risk Stratification

ST Resolution and Mortality in Patients with Patent IRA

0.5

4.8

0

1

2

3

4

5

6M

ort

alit

y (%

)

STRES 70% STRES < 70%

P = 0.01

de Lemos et al for the TIMI 14 Investigators. Am J Cardiol, 1999

TIMI 14Risk Stratification

ST Resolution and TIMI Flow Grade

0%

20%

40%

60%

80%

100%

% o

f P

atie

nts

TIMI 0/1TIMI 2TIMI 3

TIMI 3 Flow: p < 0.001 for trendTIMI 3 Flow: p < 0.001 for trend

STRES STRES 30% 30% STRES 30-70%STRES 30-70% STRES STRES 70% 70%

de Lemos et al for the TIMI 14 Investigators. Am J Cardiol, 1999

TIMI 14Treatment Effects

Effect of Abciximab on ST Resolution

0%

20%

40%

60%

80%

100%

tPA Comb tPA Comb tPA Comb

% o

f P

ati

en

ts

> 70%30 - 70%< 30%

All PatientsAll Patients Patent IRAPatent IRA TIMI 3 FlowTIMI 3 Flow

P < 0.001P < 0.001 P < 0.001P < 0.001 P < 0.001P < 0.001

N 125 221 102 191 80 151

de Lemos et al for the TIMI 14 Investigators. Circulation, 1999

45/0.645/0.6 60/0.860/0.8

ACS within 0-48hACS within 0-48h

30/0.430/0.4

AspirinAspirinHeparin (opt)Heparin (opt)

OtherOtherDosesDoses 60/0.560/0.5 75/0.275/0.2 75/0.475/0.4 90/0.290/0.2100/0.5100/0.5120/0.4120/0.4

Bolus/Infusion (g/kg) (g/kg/m)

for 24-96 h PK/PD at 0, 20m, 1-4hPK/PD at 0, 20m, 1-4hQD, pre-stop, 2-4h &QD, pre-stop, 2-4h &

8-24h post stop8-24h post stop

Clinical f/u at 14dClinical f/u at 14d

Protocol DesignTIMI 15ATIMI 15A

0

20

40

60

80

100

120

1-4h 24h 48-96h Pre-stop 2-4h post 8-16hpost

17-24hpost

% IP

A

0.80 ug/kg/min : N=13

0.60 ug/kg/min : N=12

0.50 ug/kg/min : N=20

0.40 ug/kg/min : N=34

0.20 ug/kg/min : N=10

Only 1 specimen for each pt 8-24h post drugOnly 1 specimen for each pt 8-24h post drug

Primary ResultsTIMI 15ATIMI 15AMean Inhibition of Platelet Aggregation

Giugliano ACC 1998

TIMI 15B Protocol DesignIV Oral IIb/IIIa Inibitor in ACS

Unstable Anginaor non-STE-MI

(0 - 72 hrs)

Klerval 175 BIDpo x 4wks

Klerval 200 BIDpo x 4 wks

Klerval 150 TIDpo x 4 wks

IV Klerval 100 ug/kg bolus0.50 ug/kg/min infusion

for 24-96 hrs

Placebo BIDpo x 4 wks

Placebo TIDpo x 4 wks

IV PlaceboBolus + infusion

for 24-96 h

RANDOMIZE

AspirinPanel 1: Heparin (opt)

Panel 2: Enoxaparin

STE-MI(no lytic)(0 - 72 hrs)

STE-MI(with lytic)

(6-72 hrs)

ASA 150-162 mg daily

Patient with Unstable Coronary Syndrome <72 hours

OrbofibanOrbofiban50 mg BID50 mg BID

Orbo 50 mg BID x 30 daysOrbo 50 mg BID x 30 daysthen Orbo 30 mg BIDthen Orbo 30 mg BID

Placebo Placebo BIDBID

IV heparin, other med, Cath, PTCR, and CABG at the discretion of the treating physician

Follow-up visits Day 14, Day 30

Follow-up visit every 3 months

Primary endpoint through follow-up

(Avg. 1 yr, min. 6 mos)

Randomize 1:1:1

Protocol Design

No. PtsNo. Pts

Composite

(%)

Death

MI

Urg revasc

Rehosp

Stroke

PlaceboPlacebo

20.3

3.1

5.5

8.0

11.3

0.9

Orbo Orbo

50/30*50/30*

20.2

4.4

5.1

6.1

12.1

1.1

OrboOrbo

50/5050/50

20.1

4.1

5.4

6.1

11.2

1.1

P valuesP valuesEach Dose Each Dose vs. Placebovs. Placebo

Data as of Jun 10 1999

NS

0.002 / 0.03

NS

0.001 / 0.003

NS

NS

*Orbofiban 50mg bid x 30 days, then 30mg bid

Primary ResultsClinical Events Through 300 Days

Time (days)0 50 100 150 200 250 300

05

10

15

20

25

30 % Patients with primary endpoint

placebo50-30 mg50-50 mg

F/U pl v. 50-30: p=0.14pl v. 50-50: p=0.02

30d pl v. 50-30: p=0.73pl v. 50-50: p=0.08

Data as of Jun 10 1999

Primary ResultsPatients PCI on Study Drug

Cannon et al. AHA 1999

00

2525

5050

7575

100100

00 6h6h 12h12h 24h24h

% i

nh

ibit

ion

(A

DP

)%

in

hib

itio

n (

AD

P)

36h36h

IV infusion:IV infusion:(Eptifibatide 180 ug/kg (Eptifibatide 180 ug/kg

+ 2.0 ug/kg/min)+ 2.0 ug/kg/min)(mean +/- Std. Dev) (mean +/- Std. Dev)

N=48N=48

IntravenousIntravenous OralOral

Data on File, COR/Key Ferguson et al JACC 1998;31:185A (abstract)

00

5050

100100

0h0h 6h6h 0h 0h 6h 6h

8080

Oral :Oral :(Orbofiban (Orbofiban 50 mg BID)50 mg BID)

= Mean= Mean

PharmacodynamicsIV vs. Oral GP IIb/IIIa Inhibition

Orbofiban: minimal benefit with small excess in mortality

Major bleeding (3.5%) and thrombocytopenia (0.6%) rates higher than placebo (2%, 0%) but acceptable

Need to optimize dosing strategy of oral IIb/IIIa inhibitors

Peaks/troughs in % inhibition seen

Low blood levels at trough -> ? Proaggregatory effects

High blood levels in some Pts -> ? increased events

30% benefit in PCI patients on study drug

Other trials ongoing with other agents + trial designs

Clinical Implications

ST Elev MI ST Elev MI << 6 h 6 h

Primary EndpointPrimary Endpoint: All Cause Mortality (30 days): All Cause Mortality (30 days)

ASA

accel tPAaccel tPA<< 100 mg/90 min 100 mg/90 min

Heparin (aPTT 50-70s)

2 : 1lanoteplase lanoteplase 120 KU/kg120 KU/kg

Followup: 30 days, 6 months, 12 monthsFollowup: 30 days, 6 months, 12 months

Protocol Design

Time (days)

% P

ati

ents

02

46

0 5 10 15 20 25 30

nPA

tPA

24hr Mortality

tPA: 2.49%

nPA: 2.39%

30 Day Mortality

tPA: 6.60%

nPA: 6.77%

Primary ResultsLanoteplase vs tPA: 30 Day Mortality

Neuhaus KL. ACC 1999

N = 15, 078

0.5 0.75 1 1.25 1.5nPA Better tPA Better

Relative Risk & 95% CI for 30 day event rates

Severe CHF

Recurrent MI

Urgent Revasc (in-hosp)

Death + MI

Death + MI + Severe CHF

Death + MI + Severe HF+ non-fatal stroke

Efficacy ResultsLanoteplase vs tPA: Secondary Endpoints

Neuhaus KL. ACC 1999

2.4%

6.7%

3.0%

7.3%

2.7%

10.1%

1.8%

5.6%

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

24 Hours 30 Days

% p

atie

nts

West. EuropeEast. EuropeLatin AmericaNorth America

8882 2894 407 2873 8882 2894 407 2873N

Giugliano R. EHJ 1999;20:519 (abstract)

Practice PatternsMortality by Geographic Region

24 Hours 30 Days

37.040.0

24.021.0 20.0

17.0

0

10

20

30

40

50

In-hosp 30 Day

% o

f P

ati

en

ts

24h cath Day cath No cath

P < 0.0001P < 0.0001 P < 0.0001P < 0.0001

Llevadot J. EHJ 1999;20:356 (abstract)

Practice PatternsRevascularization Rates & Cath Lab Availability

In-HospitalIn-Hospital 30 Day30 Day

10.6

6.3 6.6

11.4

7.0

11.2

0

2

4

6

8

10

12

14

All cause Death Death + MI

% o

f P

atie

nts

24h cath Day cath No cath

P = NSP = NS

P = NSP = NS

Llevadot J. EHJ 1999;20:356 (abstract)

Practice PatternsDeath/MI at 30 Days and Cath Lab Availability

All Cause MortalityAll Cause Mortality Death or MIDeath or MI