1. 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.

2. 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

3. The Goal is to Restore Both Normal Epicardial & Normal Myocardial Blood Flow
7.0%
3.7%
Mortality (%)
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%
Mortality (%)
2.9%
0.7%
n = 64
n = 226
n = 136
n = 34
n = 279
Myocardial
Perfusion
Grade 3
Myocardial
Perfusion
Grade 2
Myocardial
Perfusion
Grades 0/1
Myocardial
Perfusion
Grade 3
Myocardial
Perfusion
Grades 2/1/0
Gibson et al, Circulation 2000 3

4. 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).

5. 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

6. STEMI < 6 hours for 1° PCI
ASA mg
Clopidogrel mg
UFH
Glycoprotein IIb/IIIa inhibitor
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 ( 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

7. 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%

8. SECONDARY EFFICACY ENDPOINTS
Corrected TIMI Frame Count (CTFC)
Rate of restoring patency following IC bolus
Rates of TIMI Myocardial Perfusion Grade
Change in thrombus grade following first tenecteplase bolus

9. SAFETY ENDPOINTS - TIMI Major bleeding - TIMI Minor bleeding
- TIMI Significant bleeding
- Stroke through 30 days
- ICH through 30 days
- Cardiac arrhythmias

10. 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%)
Prior PCI
3 (16.7%)
2 (12.5%)
Diabetes
2 (11.1%)
3 (18.8%)
Hypertension
12 (66.7%)
6 (35.5%)
Prior MI
1 (6.3%)
Hyperlipidemia
9 (50.0%)
6 (37.5%)
Prior angina
7 (41.2%)
Smoker within past year
12 (75.0%)
10 (55.6%)

11. 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)
CTFC
100.0 (60.0,100.0)
100.0 (100.0,100.0)
TFG 2/3
9 (50.0%)
4 (25.0%)
TMPG 2/3
2 (14.3%)
Decrease in Thrombus Grade
8 (44.4%)
2 (12.5%)
0.041

12. POST-PCI ANGIOGRAPHIC CHARACTERISTICS
(BEFORE SECOND BOLUS)
IC Tenecteplase
N = 18
Placebo
N = 16
P-Value
CTFC
26.00 (21.0,33.0)
16.00 (12.0,24.0)
0.050
CTFC <14
1 (8.3%)
5 (38.5%)
0.087
TFG 2/3
15 (100.0%) NS
TMPG 2/3
8 (61.5%)
10 (71.4%)

13. % Patients with CTFC < X axis
POST-PCI CORRECTED TIMI FRAME COUNT BY TREATMENT GROUP (Cumulative Distribution Function)
p=0.05
% Patients with CTFC < X axis
CTFC Frames

14. POST-SECOND BOLUS ANGIOGRAPHIC CHARACTERISTICS
IC Tenecteplase
N = 18
Placebo
N = 16
P-Value
CTFC
29.0 (23.0,43.0)
20.0 (14.0,30.0) NS
CTFC <14
2 (12.5%)
1 (7.69%)
TFG 2/3
16 (94.1%)
15 (100.0%)
TMPG 2/3
9 (56.3%)
11 (73.3%)

15. SAFETY: BLEEDING IC Tenecteplase N = 18 Placebo N = 16 P-Value
TIMI Major Bleeds
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
Transfusion of PRBC
5.6% (1)
1.000
Thrombocytopenia
26.7% (4)
0.033
Stroke
Intracranial Hemorrhage (ICH)

16. 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

17. 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.