How the TIMI Trials Have Improved Clinical Practice in ... fileAn Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School How the TIMI Trials Have

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

How the TIMI Trials Have

Improved Clinical Practice

in Cardiology

David A. Morrow, MD, MPH

Director, Levine Cardiac Intensive Care Unit

Senior Investigator, TIMI Study Group

Cardiovascular Division, Brigham & Women’s Hospital

Professor of Medicine

Harvard Medical School, Boston, MA



TIMI Investigators

Eugene Braunwald, MD

Founding Chairman Marc S. Sabatine, MD, MPH

Chairman

Elliott M. Antman, MD

Deepak L. Bhatt, MD, MPH

Christopher P. Cannon, MD

Robert P. Giugliano, MD, SM

Stephen D. Wiviott, MD

David A. Morrow, MD, MPH

Jessica L. Mega, MD, MPH

Benjamin M. Scirica, MD, MPH

Marc P. Bonaca, MD, MPH

Michelle O’Donoghue, MD, MPH

Christian T. Ruff, MD, MPH

Erin Bohula May, MD, D.Phil

TIMI Study Group

Founded in 1984

Risk factors

Pre-clinical Disease

Stable Disease

Unstable Syndrome

Disease Complications

Atherothrombosis

Arrhythmia

Heart failure

DIA

GN

OS

IS &

RIS

K A

SS

ES

SM

EN

T

TH

ER

AP

EU

TIC

SE

LE

CT

ION



Clinical Trials: Comprehensive Approach to Move Medicine Forward

1. Primary and Secondary Objectives

– Test the primary hypothesis

– Evaluate safety and efficacy of the

intervention

2. Provide new mechanistic insights

3. Break new ground in understanding the

epidemiology and natural history

4. Refine risk stratification and

therapeutic selection

Thrombosis of epicardial coronary artery……

……….the cause of STEMI

Thrombin

Fibrin

Platelets

Antithrombins Lytic

Rx

Antiplatelet Rx

Myocardial

Oxygen

Demand



62 70

31 43

Reperfusion of

occluded arteries

Patency at

90 minutes

0

20

40

60

80

% o

f P

atients

t-PA

SK

*P<0.001

* *

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

TIMI 1: tPA vs Streptokinase

for STEMI



Impact of 90 Minute Patency on Mortality

0 8 16 24 32 40 48

Weeks from Randomization

0

5

10

15

20 Patent (N=161)

Occluded (N=128)

Dalen JE, Am J Cardiol 1988; 62:179-85

TIMI 1: Open Artery Theory



TIMI 2: Initial Management of STEMI

-blockers

TIMI 2B Roberts et al. Circulation 1991;83:422-37.

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

Enoxaparin vs. UFH for STEMI

Rx w/ fibrinolytic: Death or MI

0

3

6

9

12

15

0 5 10 15 20 25 30

Pri

mary

En

d P

oin

t (%

)

ENOX up to 8d

UFH up to 48 hr

Relative Risk

0.83 (0.77 to 0.90)

P<0.0001, NNT 48

Days

9.9%

12.0%

Antman for ExTRACT-TIMI 25 Investigators. NEJM 2006; 354:1477-1488

7.5

4.5

6.9

3.0

0

1

2

3

4

5

6

7

8

Death Nonfatal MI

8% 33%

N=20,500 STEMI Symptoms < 6 h

Eligible to receive lytic

Fibrinolytic choice by M

/ESC 2005/Antman Antithromb STEMI ESC 05.ppt#15. Maintenance%20of%20%20Double%20Blind

Adding Clopidogrel to Thrombolysis

Reduction in rates of Occluded Infarct-related

Artery and Recurrent CV events

15.0

21.7

0

5

10

15

20

25

Clopidogrel Placebo

P<0.0001

n=1752 n=1739

36%

Odds Reduction

Oc

clu

de

d A

rte

ry o

r D

ea

th/M

I (

%)

Sabatine et al. N Engl J Med. 2005;352:1179-1189.

Days

En

d P

oin

t (%

) Clopidogrel

Placebo

0 5 10 15 30 20 25

P=.03

20%

15

10

5

0

CV Death, MI, UR (%)

0 1 2 3 4 5 6 Time (months)

0

4

8

12

16

20

% P

atients

CONS

INV

O.R 0.78

95% CI (0.62, 0.97)

p=0.025

19.4%

15.9%

Early Invasive vs. Conservative Rx

Death, MI, Rehosp for ACS at 6 Months

Cannon CP

NEJM 2001



TIMI Risk Score: Rx Interaction LMWH vs. UFH - TIMI 11B

4.7 8.3

13.2

19.9

26.2

40.9

3.5 8.6

14.1 14.9 20

28.8

0

10

20

30

40

50

0/1 2 3 4 5 6/7

D/M

I/U

rg R

evasc b

y 1

4 d

(%

)

Number of Risk Factors

UFH

C

c2

Slope

0.65

P <0.001

0.61

P <0.001

39% lower, P=0.01

ENOX

Antman et al. JAMA 2000; 284: 835



Relationship Between Troponin & Risk

1 1.7

3.4 3.7

6

7.5

0

1

2

3

4

5

6

7

8

<0.4 <1.0 <2.0 <5.0 <9.0 >=9.0

% (

%)

Cardiac Troponin I

Antman et al. NEJM 1996; 335: 1342

P<0.001

Mortality TIMI 11B (%)

4.3

16.2

6.67.4

0

5

10

15

20

cTnI - cTnI +

(%

)

CONS

INV

Targeting Invasive Management Death, MI, Rehosp ACS

OR=0.41 *p< 0.001

p=NS

Morrow DA

JAMA 2001

11.8

20.3

12.8

16.1

19.5

30.6

0

5

10

15

20

25

30

35

Low 0-2 Mod 3-4 High 5-7

TIMI Risk Score

OR=0.75 (0.57, 1.00)

OR=0.55 (0.33, 0.91)

Cannon CP

NEJM 2001

Troponin TIMI Risk Score

Prognostic Use of a More Sensitive Current Generation Assay

Results

5.6

13.8 13.515.0

0

2

4

6

8

10

12

14

16

< 0.04 0.04 - <0.1 0.1 - <1.5 >= 1.5

Baseline cTnI ug/L

Death

or

MI (%

)

Adj HR 2.4 (1.7 – 3.6) p < 0.001

Adj HR 3.0 (2.3 – 4.0) p < 0.001

Adj HR 2.6 (2.0 – 3.4) p < 0.001

Referent

1589 319 1002 1603

1 year outcomes in 4,513 pts with NSTEACS

Bonaca et al. JACC 2010; 55: 2118 - 2124

Not

Done

Current Generation cTnI (ng/ml)

2%

12%

24%

Not

Done

Nano-cTnI (ng/ml)

96% 100% 100%

8 104

14

0

10

20

30

40

50

60

70

80

90

100

0 hours 2 hours 8 hours 24 hours

Perc

en

t w

ith

Po

sit

ive c

Tn

I R

esu

lt (

%)

=>0.1 0.07-0.1 0.04-0.07

Detection of cTnI in Patients with

Unstable Angina

Wilson S et al. Am Heart J 2009 (In press)



Time (days)

0 50 100 150 200 250 300

0

2

4

6

8

10

Mo

rta

lity,

Pe

rce

nt

Quartile 4

Quartile 2

Quartile 3

Quartile 1

B-type Natriuretic Peptide (BNP)

and Mortality

deLemos et al. NEJM 2001; 345:1014-1021

Independent of age, Killip class,

HR, BP, DM, anterior MI

P < 0.001



Multimarker Approach: cTnI, CRP, & BNP

TACTICS-TIMI 18

12.1

5.7

13

0

2

4

6

8

10

12

14

0 1 2 3

# of Elevated Markers

30

-Da

y M

ort

ality

Ris

k (

%)

Sabatine et al. Circulation 2002; 105: 1760.

P=0.0001

31% 44% 20% 6%

1.0 10 0.1

Age

Diabetes

Prior MI

Prior CHF

ST deviation

0 biomarkers elevated

1 biomarker elevated



Lower risk Higher risk

Lipid-filled plaque

Ruptured plaque with thrombus

Early atherothrombosis

1 2

3

4

5

Adapted with permission from Libby P. Sci Am. 2002;286:46-55.

Atherothrombosis: An Interaction Between

Lipids, Inflammation, and Thrombosis

32.630.8

64.5*74.8*

69.3*

4.9

20.331.8

0

10

20

30

40

50

60

70

80

90

100

0 4 8 12 16 20 24

Prasugrel 60 mg

*P<0.0001 vs clopidogrel

IPA

(%; 20 mM ADP)

Hours

Wiviott SD et al. Circulation. 2007;16:2923-32.

Clopidogrel 600 mg

PRINCIPLE-TIMI 44: Inhibition of platelet

aggregation with loading dose

Prasugrel vs. Clopidogrel

in pts with PCI for ACS

Wiviott et al. New Engl J Med

2007;357:2001-2015

Montalescot et al. Lancet

2009;373:723-31

0

5

10

15

0 30 60 90 180 270 360 450 0

5

10

15

0 30 60 90 180 270 360 450

Days

CV

De

ath

, M

I, S

tro

ke

(%)

12.1

9.9

Prasugrel

Clopidogrel

HR 0.81; P<0.001

12.4

HR 0.79; P=0.02

10.0

Clopidogrel

Prasugrel

STEMI All ACS

Days

TIMI Major (non-CABG) Bleed

HR 1.32 (1.03-1.68)

TIMI Major (non-CABG) Bleed

HR 1.11 (0.70-1.77)

n=3534

Net Clinical Outcome Bleeding Risk Subgroups

(Post-hoc Analysis)

OVERALL

>=60 kg

< 60 kg

< 75

>=75

No

Yes

0.5 1 2

Prior

Stroke / TIA

Age

Wgt

Risk (%)

+ 54

-16

-1

-16

+3

-14

-13

Prasugrel Better Clopidogrel Better HR

Pint = 0.006

Pint = 0.18

Pint = 0.36

Wiviott SD et al NEJM 357: 2001, 2007

Rate of Myocardial Infarction

According to Clinical Scenario

Scirica BM et al. ACC 2012, Chicago, March 24, 2012

Bleeding

GUSTO Mod/Sev at 3 yrs

4.2 v. 2.5%, HR 1.66, p<0.001

Vorapaxar in Stable Atherosclerosis

CV Death, MI, or Stroke

0%

2%

4%

6%

8%

10%

12%

0 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080

Ev

en

t R

ate

(%

)

Days since randomization

9.3%

10.5%

Hazard Ratio 0.87

p < 0.001

N = 26449 with prior MI, stroke, PAD

Mean f/u: 2.5 years Placebo

Vorapaxar

Morrow et al. NEJM 2012; 366: 1404-1413

Stroke 1.03 (0.85, 1.25)

PAD 0.94 (0.78, 1.14)

MI 0.80 (0.72, 0.89)

Qualifying Athero 0.058

4883

3787

17779

Limb Vascular Efficacy

Hospitalization for

Acute Limb Ischemia Pre-specified, adjudicated

2.3%

3.9%

Hazard Ratio 0.58

95% CI 0.39 to 0.86

p = 0.006

Placebo

Vorapaxar

N = 3767

Days from randomization

Peripheral

Revascularization Prespecified, Investigator

18.4%

22.2%

Hazard Ratio 0.84;

95% CI 0.73 to 0.97

p = 0.017

Bonaca et al. Circulation 2012



Months from Randomization

Ticagrelor 60 mg

HR 0.84 (95% CI 0.74 – 0.95)

P=0.004

CV

De

ath

, M

I, o

r S

tro

ke (

%)

3 6 9 12 0 15 18 21 24 27 30 33 36

Ticagrelor 90 mg

HR 0.85 (95% CI 0.75 – 0.96)

P=0.008

Placebo (9.0%)

Ticagrelor 90 (7.8%) Ticagrelor 60 (7.8%)

Primary Endpoint

6

5

4

3

10

9

8

7

2

1

0

N = 21,162

Median follow-up 33 months



Primary

prevention trials

Secondary

prevention trials

50 70 110 130 150 170 190 90 210

% P

ati

en

ts w

ith

CH

D E

ven

t

LDL-C achieved mg/dL

CARE-Rx

4S-Rx

LIPID-PL

4S-PL

CARE-PL

LIPID-Rx

AFCAPS-Rx

WOSCOPS-Rx

WOSCOPS-PL

AFCAPS-PL

25

20

15

10

5

0

ASCOT-PL

ASCOT-Rx

HPS-Rx

HPS-PL

HPS

LRC-PL LRC-Rx

POSCH-PL

POSCH-Rx

Non statin trials

Statin trials

TNT-80A

TNT-10A

Ballantyne CM. Am J Cardiol. 1998;82:737-743.

O’Keefe JH, et al, J Am Coll Cardiol. 2004;43:2142-2146.

Effect of Lowering LDL Cholesterol

on Coronary Heart Disease (CHD) Events

PL = placebo

Rx = active treatment

Intensive vs. Standard Statin: LDL Changes (Post-ACS)

Median LDL-C (Q1, Q3)

95 (79, 113)

62 (50, 79) LDL-C

(mg/dL)

20

40

60

80

100

120

Rand. 30 Days 4 Mos. 8 Mos. 16 Mos. Final

Pravastatin 40 mg

Atorvastatin 80 mg 49%

21%

P<0.001

<24h

Cannon CP, et al. N Engl J Med. 2004;350:1495-1504.

Intensive vs. Standard Statin Therapy: All-Cause Death or Major CV Events

0 3 18 21 24 27 30 6 9 12 15

%

With

Event

Months of Follow-up

Pravastatin 40 mg (26.3%)

Atorvastatin 80 mg (22.4%)

16% RR

(P= 0.005)

30

25

20

15

10

5

0

Cannon CP, et al. N Engl J Med. 2004;350:1495-1504.

LDL-C and Lipid Changes

1 Yr Mean LDL-C TC TG HDL hsCRP

Simva 69.9 145.1 137.1 48.1 3.8

EZ/Simva 53.2 125.8 120.4 48.7 3.3

Δ in mg/dL -16.7 -19.3 -16.7 +0.6 -0.5

Median Time avg

69.5 vs. 53.7 mg/dL

Simva — 22.2%

1704 events

EZ/Simva — 20.4%

1544 events

HR 0.90 CI (0.84, 0.97)

p=0.003

NNT= 56

CV Death, Non-fatal MI, or Non-fatal Stroke

7-year event rates



AMG 145 Q2W Dose Response: % Change in LDL-C Through 12 Wks

p < 0.0001 for weeks 2-12 for each dose vs placebo

Study Drug

Administration

Placebo Q2W (n = 78) AMG145 70 mg Q2W (n = 79)

AMG145 105 mg Q2W (n = 79) AMG145 140 mg Q2W (n = 78)

Baseline Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 –100

–90

–80

–70

–60

–50

–40

–30

–20

–10

0

10

Mea

n %

Ch

an

ge

fro

m B

ase

line in

Ca

lcu

late

d L

DL-C

number of patients

79 79

78

78

78 76

77

74

77 76

76

77

75 77

77

78

76 73

75

76

76 77

76

77

76 74

73

74

LDL-C calculated

using Friedewald

Giugliano RP et al. and Sabatine MS. Lancet 2012;380:2007-2017.

Generation of Hypotheses for New

Directions in Clinical Investigation

0

2

4

6

8

10

0 24 48 72 96 120 144 168

Hours from randomization

Incid

ence o

f V

T >

8 b

eats

(%

)

RANOLAZINE

PLACEBO

RR 0.63

95%CI 0.52,

0.76

p<0.001

RR 0.67

p=0.008

RR 0.65

p<0.001

8.3%

5.3%

Scirica BM et al. Circulation 2007

First Occurrence of VT >7 beats % Change in HbA1c in DM

M4

N = 707 Ranolazine

N = 770 Placebo

M8

N = 535

N = 598

M16

N = 112

N = 122

<0.001 P-value <0.001 = 0.13

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0 4 8 12 16

Month of Follow-up

-0.64

LS Mean baseline (Ran) 7.5%



Impact on Practice Guidelines

I IIa IIb III

Prasugrel at the time of PCI in patients at medium or high risk

Early invasive strategy in patients who have an elevated risk for clinical events

High-intensity statin

Conservative strategy in women with low-risk features

Enoxaparin in patients managed either invasively or conservatively

Prasugrel should be given as early as possible or at time of primary PCI

Fibrinolytic therapy (fibrin-specific agents preferred)

Clopidogrel in patients receiving fibrinolytic therapy

Enoxaparin in patients receiving fibrinolytic therapy

Beta-blockers

ST

EM

I U

A/N

ST

EM

I

ACCF/AHA Guidelines for STEMI (2013) and UA/NSTEMI (2014)

Ongoing …

How the TIMI Trials Have Improved Clinical Practice in ... fileAn Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School How the TIMI Trials Have

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