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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
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
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
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
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
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
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
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
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
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
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
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
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
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
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
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)
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
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
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
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
2 biomarkers elevated
3 biomarkers 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
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
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
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
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
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
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%
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
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 …