Clinical Group

1
Clinical Group

• Rebecca Kurnik
• Kelly Martens
• Acknowledgements
• Roshni Aggarwal
• Joshua Aronson
• Yiuka Leung
• Christiana Obiaya

2
Coronary Heart Disease

• Arteries narrow, heart deprived of oxygen
• Chronic CHD vs. Acute CHD
• Atherosclerosis
• Cholesterol, Blood Pressure, Smoking
• 3 categories of treatment
• Medication
• CABG (bypass surgery)
• PTCA (angioplasty)

Topol, Texbook of Interventional Cardiology, 4th
ed. American Heart Association Interview with Dr.
Peter Kurnik, M.D.
3
Medication and CABG

• Medication
• Preventative/Chronic CHD drugs
• -Aspirin, ACE inhibitors, cholesterol reducers,
  beta blockers
• Drugs following Heart Attack - tPA

• CABG
• Procedure conduit (saphenous vein), sternum cut,
  Cold potassium cardioplegia, CPB machine,
  cannulation, heparin
• Positive relieve angina, low restenosis
• Negative hospitalization, long recovery,
  complications
• Minimally Invasive CABG

http//www.madsci.com/manu/ches_thr.htm40 www.ada
m.com www.cincinnatichildrens.org Current
Controlled Trials in Cardiovascular Medicine
4
Angioplasty

• Before catheterization, angiography
• Procedure catheter, wire, balloon
• Overnight stay, some angina
• Restenosis, Abrupt Closure

• Anti-platelet- aspirin, Plavix, GPIIb/IIIa
• Anti-coagulant-heparin, coumadin

5
Restenosis

• The re-closing of an artery treated for
  atherosclerosis
• Occurs in 15-20 of stents and 33-50 of
  angioplasties

• Mechanism of Restenosis
• Arterial Injury
• Immune Response
• SMC Proliferation
• Migration of SMCs
• Initmal Proliferation
• Healing

cross section of an artery
http//www.biocompatibles.co.uk/drugdelivery/html/
Approaches.htm
http//www.fightcoronarydisease.com/resten/resten_
01.asp
6
What is a stent?

• Medical device used for the treatment of coronary
  artery disease
• Metal or plastic cylindrical lattice
• Ideal Characteristics
• Stents vs. Angioplasty (1994)
• Stents less restenosis (19, vs 35),
• fewer clinical events
• Angioplasty better small/long arteries,
• bifurcations
• Stent vs Surgery (2001)
• Stents more repeat procedures,
• more adverse effects, more restenosis

Cordis Corporation
Coronary and Peripheral Intervention Key
Applications
Goldberg et al. NEJM331496, 1994 Serruys,
Patrick W, et al. NEJM v. 341, 2001.
7
Does Design Make a Difference?

• Influences angiographic restenosis and
• clinical events
• Stent geometry
• Metallic surface area
• Strut Thickness
• Surface properties
• Manufacture technique

8
The Geometric Influence

• Designs coiled, slotted tube, corrugated-ring,
  uniform cell

JOSTENTS GFX stent

• Slotted Tube vs. Coiled
• 2002 study compared coil stents vs. tube stents
• Results Area of lumen was significantly larger
  in the tube stents
• Conclusions Tube stents induce less negative
  remodeling and undergo less recoil.

Coron Artery Dis 2002 Sep13305-12
9
Open-Cell vs. Tube Stents
Palmaz-Schatz
IntraStent

• 2002 clinical study
• Limitations of Palmaz-Schatz rigid,
  foreshortening, poor conformability, balloon
  rupture
• Compared IntraStent with Palmaz-Schatz
• Conclusions open-cell designs foreshorten less,
  better conformability, less likely to cause
  balloon rupture
• There is a higher percent recoil and intimal
  tissue growth in open-cell designs.

Catheter Cardiovasc Interv 2002 Jul56400-9.
10
Influence of Strut Thickness
Guidants ACS Rx Multilink
Cordis Bx Velocity

• 2003 ISAR-STEREO-2 Trial
• Compared ACS Rx Multilink (50 microm) to Bx
  Velocity (140 microm)
• Results Rate of restenosis was 17.9 for
  Multilink and 31.4 for Bx Velocity.
• Conclusion Stents with thinner struts induce
  less angiographic and clinical restenosis than
  thicker-strut stents.

J Am Coll Cardiol. 2003 Apr 16411289-92.
11

• Stent Deployment
• Self-Expanding (10) and Balloon-Expandable (90)
• Self-Expanding
• Constrained by sheath or temperature (Nitinol)
• Chronic, continuous outward force
• Does not allow multiple expansion to adjust stent
  diameter

Constrained by Membrane Sheath
Temperature
12
Balloon Expandable

• Mounted onto high-pressure, low-compliance
  balloon.
• Advantage over Self-expanding stents
• Allows repeated balloon inflations
• Minimize damage to blood vessel
• Pre-crimp balloon onto stent

13
Delivery System Zipper Platform

• Over-the-wire
• Rapid-exchange
• Zipper platform

OTW RX Zipper
? ? ? Short wire
? ? ? Wire exchange
? ? ? Cont. wire support
Zipper delivery is a platform with the benefits
of over-the-wire and rapid-exchange
platforms. -Martin B. Leon, M.D., at
Transcatheter Cardiovascular Therapeutics (TCT)
conference
www.medtronic.com
14
Intravascular Ultrasound (IVUS-Guiding)

• Sound waves reflected back by the artery wall.
• Provides information about arterial composition

Cholesterol

• Calcium

• Helps physician to fully but not over expand
  stent
• Reduces arterial injury
• Reduces restenosis

MUSIC(1998,Eur Heart Jr), AVID, CRUISE
(19992000,Circulation)
15
Distal Filter Devices

• Mechanism
• Guidewire with collapsed filter extended through
  lesion
• Nitinol filter deployed
• Interventional procedure carried out
• Filter collapsed, guidewire withdrawn

SAPPHIRE Trial
Primary endpoint results Primary endpoint results Primary endpoint results
Component Stenting with filter device Surgery w/o filter device
30-day death 0.6 2.2
30-day stroke 3.8 5.3
30-day MI 2.6 7.3
Conclusion Filter devices reduce 30-day MACE by
50 compared to surgery without filters.
http//www.medscape.com/viewarticle/445125
16
Stent Complication Thrombosis

• Thrombosis the formation of a solid blood clot
  in an artery
• Rates of occurrence 1.8 within 72 hrs 8.8
  within 30 days
• Highest risk 2 weeks after stent implantation

Normal artery Thrombosed artery
Treatment Anti-platelet/coagulant therapy
Scheller et al., 2001
17
Drug-eluting Stents (DES)

• Conventional drug delivery
• Leads to variations in dosage throughout the day
• Patients may forget to take doses
• Controlled release
• Constant, effective drug concentration
• Minimize patient error
• DES utilize a polymer degradation system
• Polymer coating on stent breaks down at a
  determined rate, releasing drug

18
Characteristics of an Ideal Drug

• Anti-thrombotic - Reduce platelet adhesion and
  fibrin binding
• Anti-inflammatory - Inhibit the bodys immune
  response to the stent
• Anti-proliferative - Intercept cell growth
  signaling pathways
• A promoter of healing - Stimulate endothelial
  cell growth
• Harmless to normal cells

19
Choice of Drug Rapamycin (Sirolimus)

• Macrocyclic Lactone
• C51H79NO13
• Soluble in Organic Solvents
• Can be synthesized
• Rapamycin is active metabolite
• Marketed in the US by
  Wyeth Pharmaceuticals as Rapamune

• Inhibits inflammation, smooth muscle cell
  proliferation, and
• smooth muscle cell migration

www.wyeth.com
20
Clinical Study SIRIUS (Cypher Stent)
Clinical Events (Out-of-Hospital to 9 months)
Sirolimus N533 Control N525
Death 0.8 0.6
MI (All) 0.6 1.7
Q-wave 0.4 0.4
Non Q-wave 0.2 1.3
Target Lesion Revasc. 3.9 16.6
Target Vessel Revasc. 3.2 4.8
MACE 4.9 17.7
Target Vessel Failure 6.4 19.6
Sirolimus is effective in practice in preventing
in-stent restenosis
Cordis Corporation
21
Other Possible Drugs for use in DES

• Paclitaxel
• First used as anti-cancer drug
• Inhibits restenosis by blocking cell cycle
  progression
• Reduced restenosis rates from 17.9-36.9 to
  0.8-6.4
• Paclitaxel only targets cell division, while
  rapamycin targets
• cell division and immuno-regulation
• Everolimus ABT-578
• Rapamycin analogues
• Inhibit cell proliferation and smooth muscle
  cell migration
• 24-47 increase in lumen area
• Positive, but preliminary results
• Less tested in humans than rapamycin

bostonscientific.com Honda et al. Robert S.
Schwarz, M.D.
22
Future Possibilities

• Tetrathiomolybdate (TTM) Hypothesized targets
  based on porcine model inflammation, cell
  proliferation, migration of the SMCs, improves
  re-endothelialization
• Growth Factors Cause accelerated endothelial
  regrowth, minimize endothelial dysfunction, and
  interfere with intimal growth
• Radioactive Stents Radiation could inhibit
  cell proliferation, inhibiting restenosis
• Stents and Cancer Use DES to target drugs to
  tumor sites

Mandinov et al., unpublished data
Van Belle, et. al., B. Alberts,
Handbook of Coronary Stents Serruys, P.W., Ed.
Martin Dunitz Ltd. London, 2002 Laird, J.R. et
al. Circulation 1996, 93, 529-536
23
Recommendations

• Structure Corrugated-ring stent
• Delivery Pre-crimped Balloon-expandable, Zipper
  platform
• Filter Devices
• Drug Rapamycin, include heparin in polymer

24
Thank you Clinical Group

• Professor Essigmann
• Professor Langer
• TA - Jyoti Agarwal
• Ken Nesmith
• Monica Morrison
• Luis Abrishamian-Garcia
• Colin Champ

• Jonathan King
• Sean Liu
• Georgette Charles
• Adriana Tajonar
• Pamela Chang
• Mike Batty
• Gayani Tillekeranti
• Bonny Lee

25
Mechanism of Sirolimus

• Binds to FKBP-12, then complex binds to and
  inactivates mTOR
• (mammalian target of rapamycin)
• Inhibits activation of p70 S6 kinase and protein
  translation