DrugEluting Stents: Clinical Implications of Drug Differentiation

1
Drug-Eluting Stents Clinical Implications of
Drug Differentiation

• Campbell Rogers, MD
• Director, Cardiac Catheterization Laboratory
• Associate Professor of Medicine
• Brigham and Womens Hospital
• Harvard Medical School
• Boston, Massachusetts

2
Differential Events Leading to In-Stent
Restenosis
1
Fraction of Maximal Response
0
Time
Platelet Deposition
Leukocyte recruitment
VSMC migration / proliferation
Matrix deposition
3
Differential Effects ofDES System Elements
Stent Platform
Polymer Drug Carrier
Drug
4
Cell Cycle Inhibition
Sirolimus Everolimus ABT-578
S
X
G0
G1
G2
Cell cycle
Resting
Cell division
M
5
Macrolide Antibiotics

• Sirolimus

• Cell-cycle regulating
• Antiproliferative
• Antimigratory
• Immunomodulatory
• Similarities
• Significant human systemic experience in
  prevention of allograft rejection
• Mechanisms of action to prevent in-stent
  restenosis
• Differences
• Systemic bioavailability
• Local retention (lipophilicity, transport, etc)

6
Rapamycin Analogs
EVEROLIMUS
SIROLIMUS
ABT-578
N
N
N
N
N
N
7
Mechanism of Cell Proliferation
8
----limus Inhibition of Cell Proliferation
----LIMUS
----LIMUS
9
Sirolimus
Paclitaxel

• Paclitaxel
• Isolated from bark and needles of Pacific yew
  tree
• Chemotherapeutic agent, administered with
  solubilizing agent Cremophor
• Antitumor activity(ovarian, NSC lung, breast)
• Doses used systemically approximately 1000-fold
  higher than stent-based doses

10
Cell Cycle Inhibition
Sirolimus Everolimus ABT-578
S
X
G0
G1
G2
Cell cycle
Resting
Cell division
X
M
Paclitaxel
11
Mechanism of Action
Alters microtubule dynamics involved in cell
division

• Binds to microtubules
• Stabilizes microtubule structure
• Forms bundles and multiple asters
• Inhibits cell division, motility, shape change,
  and alters inflammatory cell function

12
Clinical Implicationsof Drug Differentiation
Cytostatic
Cytotoxic
Tumor-Growth Delay
Tumor Regression
Control
Control
Tumor Size
Tumor Size
Increasing dosesof new agent
Increasing dosesof new agent
Time
Time
Tolcher A. Oncologist. 2001 6 Suppl 340-44.
13
How Else to Categorize?

• Vascular toxicity rather than cytotoxicity
• Late incomplete apposition
• Medial thinning
• Aneurysm/rupture
• Delayed re-endothelialization

Vasculo-toxic effects in pig coronaries 90 days
High dose, fast release
Low dose, slow release
Rogers C et al. Circ. 2000.
14
Coating Differentiation
Metals
Molecular coatings
Ceramics
Polymers
15
Surface Drug Coatings
16
Matrix Release
17
Erosive Matrix Release
Erosive release

• Issues
• Rate of release
• Rate of degradation
• Toxic products
• Emboli flaking

Erosion then release
18
Top Coat
19
In-Vivo Kinetics of Sirolimus Releasefrom
Polymer Coated Stents
In-Vivo Sirolimus Release
Topcoat
1.2
1.0
Stent
Fast Formulation
0.8
0.6
Fraction Released
Basecoat
0.4
0.2
Slow Formulation
0.0
-0.2
0
5
10
15
20
Time (days)
20
Stent Differentiation
21
Hwang et al, Circulation. 2001.
22
Symmetry ofStent Expansion
Hwang et al, Circulation. 2001.
23
Closed Cell Design
24
Open Cell Design
25
Closed Cell vs Open Cell Stents
Open Cell
Closed Cell
26
Stent Overlap
27
Safety with OverlappingTaxus MR Stents
Controln61
P value
TAXUS MRn63
NA
0
0
Stent Thrombosis
1.00
1
Aneurysms (acquired)
0
0.21
5 (7.9)
1 (1.6)
30-day MACE
Dawkins, Keith D. TAXUS VI.Presented at The
Annual Paris Course on Revascularization May
2528, 2004 Paris, France.
28
Low Repeat Revascularization RatesFollowing
Drug-Eluting Stent Implantationin De Novo
Bifurcation Lesions
Treatment with SES period 04/02-04/03
Treatment with PES period 03/03-09/03
MACE
100
60
55
90
48
CYPHER n123
38
40
Percent ()
80
28
27
27
Percent ()
18
TAXUS n71
20
14
8
70
4
0
60
P0.03
Crush
Crush
Culotte
Culotte
T stent
T stent
Kissing Balloon post
Kissing balloon post
Kissing stent
Kissing stent
0
3
6
9
Stenting technique
Follow-up (months)
Both the SES and PES used for de novo
bifurcation lesions demonstrate a low rate of
target vessel revascularization (TVR). Ensuring
complete lesion coverage with drug-eluting stents
may further reduce restenosis, particularly at
the ostium of the side branch
Hoye A, Lemos PA, Tanabe K, et al.Presented at
American College of Cardiology 53rd Annual
Scientific Session March 710, 2004 New
Orleans, LA.
29
Deep Injury and Tissue Responses after Stent
Implantation
1.2
0.8
INTIMA (mm2)
0.4
0
0.6
0.4
0.2
0
INJURY SCORE
Rogers and Edelman. Circulation. 1995.
30
Flow Patterns at Bifurcations May Alter Drug
Release and Deposition
Richter et al. J Clin Invest. 2004.
31
Main Branch only
32
4
3
2
1
Distal
Proximal
33
Clinical Implicationsof DES Differentiation

• Bifurcations
• Overlapping stents
• Multivessel treatment
• ISR TAXUS III MACE 29, TVR 22 Cypher Confli
  cting registry results
• AMI Taxus 100 patients, 4 SAT in 30 d (ACC
  2004) Cypher 183 pts, 0 SAT in 30 d (JACC
  2004)
• SVGs No data
• Left Main Cypher 16 TVR (Columbo)