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Intra Coronary AdjunctivE Tenecteplase During
Primary PCI for STEMI:
A Randomized, Open-Label, Placebo Controlled Pilot Study To Evaluate The
Feasibility And Safety Of Low-Dose Intracoronary Tenecteplase vs. IC
Saline Placebo Administered as Adjunctive Therapy To Aspirin, Clopidogrel,
And Glycoprotein IIb/IIIa Inhibition During Primary PCI For STEMI.
Varun Kumar, M.B.B.S.; Lakshmi Gopalakrishnan, M.B.B.S.; Priyamvada Singh,
M.B.B.S.; Jianping Guo; Samer Kazziha, M.D.; Chandan Devireddy, M.D.; Duane
Pinto, M.D. M.P.H; J. Jeffrey Marshall, M.D.; George Stouffer, M.D.; Kreton
Mavromatis, M.D.; Laura Grip; Eugene Braunwald, M.D.; and C. Michael Gibson
M.S., M.D. on behalf of the ICE T TIMI 49 Investigators
An Investigator Initiated Trial Funded by a Research Grant from Genentech Inc.
BACKGROUND
Distal Embolization During Primary PCI
Embolization During Diagnostic
Angiography
Distal Vessel Cut Off and Stain of
Myocardium Despite Excellent Result
Upstream in Coronary Artery
The Goal is to Restore Both Normal Epicardial &
Normal Myocardial Blood Flow
p = 0.05
7.0%
3.7%
n = 487
n = 328
Epicardial TIMI Grade 3 Flow
Epicardial TIMI Grade 2 / 1 / 0 Flow
7.5%
5 way p = 0.007
5.4%
4.7%
2.9%
0.7%
n = 136
Myocardial
Perfusion
Grade 3
n = 34
Myocardial
Perfusion
Grade 2
n = 279
Myocardial
Perfusion
Grades 0/1
n = 64
Myocardial
Perfusion
Grade 3
n = 226
Myocardial
Perfusion
Grades 2/1/0
Gibson et al, Circulation 2000
GOAL
Evaluate the feasibility and safety of
low-dose IC tenecteplase (TNK)
administration as adjunctive therapy to
aspirin, clopidogrel, and glycoprotein
IIb/IIIa inhibition during primary PCI
(PPCI).
TRIAL ORGANIZATION
Trial Leadership: TIMI Study Group
Chairman: Eugene Braunwald; Principal Investigator: C. Michael Gibson
Project Director: Laura Grip; Statistician: Satishkumar Mohanavelu
Data Safety Monitoring Board
Jeffrey J. Popma, M.D.
Enrolling Sites
Principal Investigator
Research Coordinator
Number of Patients
Dr. Samer Kazziha
Elias Boueiri
n=13
Dr. Chandan Devireddy
Joanna Duncan
n=11
Dr. Duane Pinto
Jenifer Kaufman
n=6
Dr. J. Jeffrey Marshall
Ki-Ling Suen
n=5
Dr. George Stouffer
Carl Schuler
n=3
Dr. Kreton Mavromatis
Pamela Hyde
n=2
STEMI < 6 hours for 1° PCI
UFH
Glycoprotein IIb/IIIa inhibitor
ASA 160-325 mg
Clopidogrel 300-600 mg
TIMI 0/1 Flow in Culprit Artery
R
Advance wire and balloon without crossing lesion or withdrawing wire
Study Drug - IC tenecteplase
4 mg bolus
Study Drug - IC saline
4 mL bolus
2 min
2 min
Angiography of culprit artery to assess percent stenosis, thrombus burden,
epicardial flow and myocardial perfusion
Check ACT (200-225 sec)
UFH if necessary
PCI
Advance wire and balloon across lesion
Study Drug - IC tenecteplase
4 mg bolus
Study Drug - IC saline
4 mL bolus
2 min
2 min
Angiography of culprit artery to assess epicardial flow and myocardial
perfusion
PRIMARY EFFICACY ENDPOINT:
Quantitative Coronary Analysis
Primary Endpoint:
The percent diameter stenosis of the culprit artery following the first
administration of tenecteplase bolus vs placebo.
85%
93%
SECONDARY EFFICACY ENDPOINTS
• Secondary:
– Corrected TIMI Frame Count (CTFC)
– Rate of restoring patency following IC
bolus
– Rates of
Grade
TIMI
Myocardial
Perfusion
– Change in thrombus grade following first
tenecteplase bolus
SAFETY ENDPOINTS
- TIMI Major bleeding
- TIMI Minor bleeding
- TIMI Significant bleeding
- Stroke through 30 days
- ICH through 30 days
- Cardiac arrhythmias
BASELINE CHARACTERISTICS
IC
Tenecteplase
N = 18
Placebo
N = 16
P-Value
Age, mean (SD)
54.0 (±7.5)
55.9 (±9.3)
NS
Sex, male
14 (77.8%)
13 (81.3%)
NS
Prior PCI
3 (16.7%)
2 (12.5%)
NS
Diabetes
2 (11.1%)
3 (18.8%)
NS
12 (66.7%)
6 (35.5%)
NS
Prior MI
3 (16.7%)
1 (6.3%)
NS
Hyperlipidemia
9 (50.0%)
6 (37.5%)
NS
Prior angina
3 (18.8%)
7 (41.2%)
NS
Smoker within
past year
12 (75.0%)
10 (55.6%)
NS
Hypertension
PRIMARY EFFICACY END POINT:
PERCENT DIAMETER STENOSIS OF THE CULPRIT LESION AFTER
FIRST ADMINISTRATION OF STUDY DRUG AND OTHER SECONDARY
ENDPOINTS
IC Tenecteplase
N = 18
Placebo
N = 16
P-Value
Percent
Diameter
Stenosis, (SD)
89.5% (±12.5)
93.7% (±10.5)
NS
Change in
Percent
Stenosis, (SD)
-6.4% (±9.4)
-1.9% (±4.4)
NS
CTFC
100.0
(60.0,100.0)
100.0
(100.0,100.0)
NS
TFG 2/3
9 (50.0%)
4 (25.0%)
NS
TMPG 2/3
4 (25.0%)
2 (14.3%)
NS
Decrease in
Thrombus
Grade
8 (44.4%)
2 (12.5%)
0.041
POST-PCI ANGIOGRAPHIC CHARACTERISTICS
(BEFORE SECOND BOLUS)
CTFC
CTFC <14
TFG 2/3
TMPG 2/3
IC Tenecteplase
N = 18
Placebo
N = 16
P-Value
26.00 (21.0,33.0)
16.00 (12.0,24.0)
0.050
1 (8.3%)
5 (38.5%)
0.087
15 (100.0%)
15 (100.0%)
NS
8 (61.5%)
10 (71.4%)
NS
POST-PCI CORRECTED TIMI FRAME COUNT BY
TREATMENT GROUP (Cumulative Distribution Function)
% Patients with CTFC < X axis
100%
IC Placebo
Median 16
90%
80%
70%
60%
IC Tenecteplase
Median 26
p=0.05
50%
40%
30%
20%
10%
0%
0
10
20
30
40
50
60
CTFC Frames
70
80
90
100
POST-SECOND BOLUS ANGIOGRAPHIC
CHARACTERISTICS
IC Tenecteplase
N = 18
Placebo
N = 16
P-Value
29.0 (23.0,43.0)
20.0 (14.0,30.0)
NS
2 (12.5%)
1 (7.69%)
NS
TFG 2/3
16 (94.1%)
15 (100.0%)
NS
TMPG 2/3
9 (56.3%)
11 (73.3%)
NS
CTFC
CTFC <14
SAFETY: BLEEDING
IC Tenecteplase
N = 18
Placebo
N = 16
P-Value
TIMI Major Bleeds
0.0% (0)
0.0% (0)
N/A
TIMI Minor Bleeds
27.8% (5)
6.3% (1)
0.180
TIMI Minimal Bleeds
22.2% (4)
12.5% (2)
0.660
TIMI Major or Minor Bleeds
27.8% (5)
6.3% (1)
0.180
Transfusion of PRBC
5.6% (1)
0.0% (0)
1.000
Thrombocytopenia
0.0% (0)
26.7% (4)
0.033
Stroke
0.0% (0)
0.0% (0)
N/A
Intracranial Hemorrhage (ICH)
0.0% (0)
0.0% (0)
N/A
LIMITATIONS
• Small sample size limits definitive
conclusions regarding efficacy and safety
• Time needed for study drug to act when
administered via intra-coronary route was
assumed to be within two minutes
CONCLUSIONS
• Compared with IC placebo, IC TNK
administration did not improve the pre-PCI
percent stenosis, but did improve pre-PCI
thrombus burden.
• There was more post-PCI hyperemia
following placebo administration, perhaps
reflecting greater distal embolization.