Transcript JUPITER I Study

Advanced Angioplasty 2004
JANUS: the next generation of DES
Daniela Trabattoni, MD
Centro Cardiologico Monzino, IRCCS
Institute of Cardiology
University of Milan
Italy
Drug Eluting Stent Technologies STATE OF THE ART
Presently available drug eluting stents are characterized by surfaces
integrally coated with:
- polymer matrices containing the drug
- drugs directly linked to the stent surface
- ceramic coatings embedding the drug
Vessel wall
Integral coating
Stent strut
cross section
Blood
They proved to be effective, but also showed
potential limitations
DES with integral coating: POTENTIAL LIMITATIONS
1) Relatively low drug loading capability
2) Unselected drug release
3) Significant amount of drug lost in the blood stream
4) Potential suboptimal biocompatibility of the surface
(at the end of release)
5) Potentially delayed endothelialization
6) Limitations in Direct Stenting approach
CARBOSTENT JANUS DRUG-RELEASING MECHANISM
 Deep sculpturing on the outer stent surface contains and
releases the drug only toward the vessel wall (no drug is lost
into the blood stream)
 Stable non thrombogenic surface toward the blood
Smooth muscle cells
VESSEL WALL
Endothelial cells
BLOOD
STENT STRUT
CROSS SECTION
Carbofilm™ Coated
Surface
Drug-releasing
Sculpture
JANUS Carbostent Distinctive Features
1) Relatively high drug loading capability
2) Targeted drug release
3) No drug lost in the blood stream
4) Carbofilm™ coated surface superior bio- and
hemocompatibility
5) Un-hindered endothelialization
6) Suitable for direct stenting approach
Tacrolimus – FK 506
Streptomyces Tsukubaensis
Tacrolimus (FK 506)
Fujisawa Pharmaceutical Co.
(Japan)
A macrolide antibiotic
produced by Streptomyces
Tsukubaensis
Tacrolimus is the active ingredient of two pharmaceutical products
registered in all the main countries of the world: the
immunosuppressant Prograf®, used in the treatment of patients
after kidney or liver transplantation, and Protopic®, a drug used in
the treatment of atopic dermatitis
Tacrolimus (FK506)
• Tacrolimus binds to FK binding protein (FKBP12)
• Tacrolimus-FKB12 complex inhibits cytoplasmic phosphatase calcineurin, which
activates transcription factor NFAT (after dephosphorilation, NAFT translocates
into the nucleus and activates several cytokine genes involved in immune
response and inflammation)
• By inhibition of calcineurin, Tacrolimus
has an inhibitory effect on the expression
of pro-inflammatory cytokynes (IL-2, IL-3,
IL-4, IL-5, IFN, Gm-CSF and TNF),
which leads to reduced immune response
and inflammation
• Tacrolimus-FKB12 complex has also an
antiproliferative effect on vascular
SMCs by affecting the expression
of cell cycle proteins
C. Matter - TCT 2002
C. Matter - TCT 2002
RABBIT STUDY
Release Kinetic
 Tacrolimus concentration in the
iliac artery tissue reached its
maximum few days after
implantation
Tacrolimus concentration in the vessel tissue
ng/mg
1000
 This peak corresponds to that of
the vessel inflammatory response
100
10
0
5
10
15
Days
20
25
30
 A steady tissue concentration
was present over the following
weeks
One month after stent implantation, about 50% of Tacrolimus was
released
Tacrolimus concentration in the blood was always below the HPLC
sensitivity threshold, confirming that no drug was released into the
blood stream
Endothelialization at 15 Days
(SEM- pig coronary arteries)
JANUS
TECNIC
JANUS
TECNIC
In Vivo Animal Evaluation
Pig Coronary Arteries at 28 Days
CONTROL STENT
Prox
JANUS CARBOSTENT
Mid
Dist
Non injury model (1.1 : 1)
Animal Study: 28-day results
Non Injury model
Neointimal Area (mm2)
1,50
Neointimal Thickness (mm)
0,15
 = 32%
 = 24%
1,00
]
0,10
1.02
]
0.09
]
0.78
]
0.06
0,05
0,50
0,00
0,00
Tecnic
Janus
Tecnic
Janus
Injury Model (pig coronary arteries) at 90 days
CONTROL STENT
Prox
JANUS CARBOSTENT
Mid
Dist
Overstretch model (1.3:1)
Animal Study: 90-day results
Injury model
Neointimal Area (mm2)
 = 71%
2,00
Neointimal Thickness (mm)
 = 58%
0,20
]
]
1.71
0,10
0.13
1,00
]
0.06
]
0.49
0,00
0,00
Tecnic
Janus
Tecnic
Janus
Janus Carbostent Clinical Investigation
JUPITER I Study Design
 Phase
Clinical registry
50 patients
 Phase
Clinical evaluation
randomized 1:1
multicenter
double blind
Investig. & Core-Lab
JANUS
TECNIC
Follow-up at
1, 6, 12 and
24 months
 100 patients
• 1 month: Clinical
 100 patients
• 6 months: Clinical,
angiographic and IVUS
• 12 months: Clinical
• 24 months: Clinical
Interim analysis at 1 month
“Safety” evaluation
Clinical, angiographic
and IVUS follow-up at
6 months
Clinical follow-up
at 12 and 24
months
JUPITER I Study: Principal Investigators
1. Antonio Bartorelli, MD
Centro Cardiologico Monzino (Milano)
2. David Antoniucci, MD
Ospedale Careggi (Firenze)
3. Giancarlo Piovaccari /Andrea Santarelli, MD
Ospedale degli Infermi (Rimini)
4. Gianbattista Danzi, MD
Poliambulanza Hospital (Brescia)
5. Alberto Benassi, MD
Hesperia Hospital Modena (Modena)
6. Roberto Serdoz, MD
Ospedale San Pietro FBF (Roma)
Inclusion Criteria
( phase)
The JUPITER I study
Angiographic criteria:
• De-novo coronary lesions in native vessels
• Lesion located in target vessel with a diameter 3 and 4 mm
• Target lesion length 12 mm
• The stented target vessel segment must be 3 mm longer than
•
•
•
•
the target lesion
Target lesion with a %DS  50% and <100% (TIMI I)
< Two target vessels for each patient
One target lesion for each target coronary vessel
One Janus stent only (15 mm x 3.0-3.5 mm) for each target
lesion
Exclusion Criteria
( phase)
Clinical
•
•
•
•
Oral anticoagulation
unrelated to stent procedure
Contraindication / allergy to
aspirin, ticlopidine or
clopidogrel
Depressed LV function
(EF< 40%)
AMI
The JUPITER I study
Anatomic
•
•
•
•
•
•
Bifurcation lesions
Lesions located in the only
remaining vessel or LM
Grafts
CTO
Massive thrombus
Heavily calcified lesions
Clinical investigation – JUPITER I ( Phase)
Status @ November 2003
Enrolled patients: 50 - Implanted stents: 58
30
25
20
26
15
14
10
3
5
1
6
0
0
Monzino (MI)
Careggi (FI)
Fatebenefratelli
(RM)
Poliambulanza
(BS)
Hesperia (MO)
Ospedale degli
Infermi (RM)
The JUPITER I study
Patient Characteristics
N° patients
 Male gender
 Age (years)
 Diabetes

50
72.9%
63.9 ± 9.0
22.9%
ID
NID
10.4%
12.5%
Cholesterol
 Previous MI
45.8%
31.2%
•
•

The JUPITER I study
Antithrombotic Therapy

Pretreatment with aspirin (325 mg/day or 500 mg i.v.)

Heparin bolus to mantain the ACT > 300 seconds
throughout the procedure

Aspirin (325 mg/day) + Clopidogrel loading dose
followed by 75 mg/day for 2 months
The JUPITER I study
Acute Angiographic Results
Pre
Post
RVD (mm)
3.16 + 0.42
3.34 + 0.37
MLD (mm)
0.93 + 0.50
3.15 + 0.36
71.17 + 17.63
5.40 + 5.05
DS (%)
Lesion length (mm) 9.91 + 1.97
Acute gain (mm)
2.24 + 0.62
Clinical Results
Acute (50 pts)
Angiographic Success
Stent Thrombosis
Death
Q-wave MI
non-Q wave MI
Angina
(Urgent) CABG
TL Re-PTCA
100%
0%
0%
0%
0%
0%
0%
0%
The JUPITER I study
3-mos (50 pts) 6-mos (24pts)
0%
2.1% (1)*
0%
0%
2.1% (1)**
0%
2.1% (1)**
0%
0%
0%
0%
0%
0%
2.5%
* Non cardiac death, due to cancer
** Unscheduled angiography for recurrent angina that revealed distal edge restenosis ( postdilation with a balloon longer
than the stent)
CONCLUSIONS (I)
•
Animal studies with Tacrolimus-eluting Janus Carbostent:
- Peak drug concentration in the vascular tissue within the first few
days, followed by steady concentration over the following month
- No drug released into the blood stream
- No thrombotic events in spite of a reduced antiplatelet treatment
(ASA for 7 days only)
- Good endothelialization after 7 days, completed after 15 days
- Reduction of neointimal area and thickness in either non-injury and
injury porcine model at 28 and 90 days without any sign of toxicity
CONCLUSIONS (II)
•
Clinical study with Tacrolimus-eluting Janus Carbostent:
- In the  phase of the Jupiter I study, implantation of the
Tacrolimus-eluting Janus Carbostent™ was associated with 100%
procedural and clinical success
- TLR @ 6 mos was 2.5% in the first 24 pts. Six-mos angio/IVUS
is still ongoing in the remaining -phase pts.
- The randomized -phase of the Jupiter I study is ongoing to assess
the efficacy of Janus Carbostent™ compared to the no-drugreleasing Tecnic Carbostent ™
JANUS PROJECT – EVALUATION PLAN
IN VITRO
I N VITRO
PHARMACOKINETIC
HUMAN SMC
PROLIFERATION
& MIGRATION
RABBIT SMC
PROLIFERATION
& MIGRATION
SHORT-TERM IN VIVO
PHARMACOKINETIC
RABBIT
STUDY
LONG-TERM IN VIVO
PHARMACOKINETIC
PIG
STUDY
CLINICAL
INVESTIGATION
NEOINTIMAL
PROLIFERATION
SCULPTURE FILLED
WITH ONE DRUG
(Tacrolimus)
AND NO POLYMER
LONGITUDINAL DOSE DISTRIBUTION
Variable dose distribution along the longitudinal axis of the stent
can be achieved filling the sculptures with different amount of drug
(Dose level)
Homogeneous distribution
Two levels distribution
Three levels distribution
LONGITUDINAL DRUG / DOSE DISTRIBUTION
Suitable amount of different drugs can be loaded selectively along
the longitudinal axis of the stent to provide synergic therapeutic effects
(Dose level)
Homogeneous distribution
of two different drugs
Two different drugs in
two different areas
Three levels distribution
MECHANICAL IMPACT OF SCULPTURES
ON THE STENT STRUCTURE
The sculpture impact on stent structural resistance has been
carefully evaluated with the Finite Element Analysis, and thoroughly
verified by means of severe collapse and endurance tests.
Stress Level
Color Scale
No sculpture is located
in the red/orange areas,
where higher stress is reached
In vitro release kinetics
Effect of the drug/polymer ratio
200
Relased Amount ( mg)
150
100
Tacrolimus
Tacrolimus/PMMA ratio 2:1
Tacrolimus/PMMA ratio 1:2
50
0
0
20
40
60
Time (h)
80
100
120
In Vivo Animal Evaluation
Pig Coronary Arteries at 28 Days
S 79.15 RCA MID
Cell colonization filling the stent sculpture (arrow)