Drugeluting Stents for Management of Instent Restenosis

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Drug-eluting Stents for Management of Instent
Restenosis

• Adel Zaki
• Cairo University

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From PTCA to Stent-mania

• In USA over 150,000 persons had a new stent in
  1999. Not known in 2002 and 2003.
• Stenting any or all coronary narrowing in 70 of
  all patients who under went PCI.
• PCI Stent deployment.

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The Ideal StentWhat stent to use to prevent ISR?

• many believe that all stents are created equal
  in terms of preventing restenosis.
• stents (profile, deliverability, visibility, the
  ease with which equipment can be advanced beyond
  them, access into side branches).
• the choice of stent influences the restenosis
  rate.

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ISR in Letrature.From single proximal stent to
Stent every coronary!!

• Long coronary lesions (gt20 mm) ADVANCE Study
  Final Results of the Additional Value of NIR
  Stents for Treatment of Long Coronary
  Lesions.No reduction in major adverse cardiac
  events (MACE) at 9 months. Serruys PW, et al (J
  Am Coll Cardiol 2002
• Small coronary arteries (lt3 mm) stenting have a
  lower in-hospital complication rate but higher
  ISR than large coronaries.
• Stenting chronic occlusions The SICCO-study
  (Stenting in Chronic Coronary Occlusion).
• Uprotected LMCA stenting.
• Stenting bifurcation lesions stent placement on
  the side branch and on the parent branch provides
  no advantage!!

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To Avoid ISR
(J Am Coll Cardiol 200240102133)

• Types of stents.
• The average coronary lesion.
• Lesions situated on a curve (gt90)
• Ostial lesions.
• Bifurcational lesions.
• Lesions located at the left main stem.
• Calcified lesions.
• Chronic total occlusions.
• Vessels smaller than 3.0 mm in diameter.
• Saphenous vein grafts.
• Special situations.
• Drug-eluting stents.

Sorin beStent Multilink
BxVelocity
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Mechanism of ISR

• Restenosis occurs in coronary artery stents
  because vascular smooth-muscle cells migrate from
  the media of the vessel wall into the lumen of
  the stent and proliferate. It is termed
  neointimal (NI) proliferation, with reduction
  in the luminal diameter of stented vessels in
  about 30.

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ISR

• A disease replacing another disease
• Incidence varies from 10-50.
• This disease has a clinical picture or
  reappearance of manifestation of CHD,
  angiographic findings or types of ISR and
  multiple experimental and in vivo management
  techniques.

Types of ISR I) Focal (lt10 mm length), it has
been further subdivided into types IA to
ID based on the site of focal ISR in
relation to the stent.II) Diffuse (ISR gt10 mm
within the stent. III) Proliferative ISR gt10 mm
extending outside the stent.IV) Occlusive ISR.
Type. Mehran R, et al. Circulation. 1999.
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Treatments of ISR

• Mechanical treatments. PTCA redilatation showed
  that the gained in-stent lumen is due to 44
  stent expansion and 56 compression of NI tissue
  in the stent and re-ISR is 20-30 for type I and
  II, and 50-83 for type III and IV (Mehran R, et
  al Am J Cardiol 19967861822).
• Directional coronary atherectomy is not
  recommended for increased morbidity due to stent
  strut fracture and disruption

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• Rotational atherectomy was not recommended after
  ARTIST-trial (Angioplasty Versus Rotational
  Atherectomy for Treatment of In-Stent Restenosis)
  results. High restenosis rate up to 65.
  (Harrington RA, J Am Coll Cardiol 199525
  16939).
• The cutting balloon (CBA) and re-stenting
  restenosis rate 20.
• Brachytherapy ISR outside-stent stenosis as
  edge effect or what simulate the candy
  wrapper. Albiero R, et al, Circulation. 2000.A
  6 to 12 mCi by radioactive stent implantation had
  a higher ISR after 1 yr.

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Causes of In-stent Restenosis

• lesion characteristics (i.e., vessel size, lesion
  length, stenosis severity, calcification,
  thrombus).
• procedural characteristics (i.e., final luminal
  diameter, acute gain, treatment length).
• clinical characteristics (i.e., diabetes, perhaps
  renal insufficiency)
• stent type.

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How to Treat ISR?

• NI proliferation due to stent metals substance
  Köster,et al, (Lancet 2000 356 1895-97), found
  that patients with allergic patch-test reactions
  to nickel and molybdenum had a higher frequency
  of ISR.
• Using Titaniumnitrideoxide (TiNOX) to cover
  stainless steel stent and to renders the stent
  surface biologically inert.

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• Heparin-coated stents or standard PTCA is more
  effective and was described as a more costly
  stent (Alt E,et al, Circulation. 2000). Similar
  results with hirudin and the prostacyclin
  analogue iloprost on experimental pigs.
• Enoxaparin inhibit smooth muscle cell
  proliferation in experimental models. Kiesz RS,
  et al, (Circulation. 200110326-31.).

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Sirolimus (rapamycin) and SES.

• A potent immunosuppressive agent used for the
  prophylaxis of renal transplant rejection (in
  1999). It induces cell-cycle arrest in the late
  G1 phase and inhibits the proliferation of human
  smooth muscle cells in vitro. Marx SO,et al. Circ
  Res 1995.
• Two lines of research
• Can systemic sirolimus therapy could inhibit
  stenosis after PTCA ?
• Stent slow release coating with sirolimus.

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Paclitaxel (Taxol)

• Antiproliferative agent was used for treatment of
  cancer by blocking the cell cycle
• Paclitaxel inhibits cell processes that are
  dependent on microtubule turnover.

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Early OutcomeRapamycin-Eluting Stent
EvaluatedAt Rotterdam Cardiology Hospital
(RESEARCH) Registry

• (J Am Coll Cardiol 20034120939)
• The safety of SES is currently unknown.
• 198 SES with 301 bare stents
• Stent thrombosis in 0.5 SES patients and 1.7 of
  the control patients.
• 30-day MACE rate was similar.

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RAVEL-studyRandomized Study with the
Sirolimus-Eluting Bx Velocity Balloon-Expandable
Stent

• ISR droped from 26.6 to 0.
• At follow up to one year, the overall rate of
  major adverse cardiac events (MACE) was 5.8 in
  the sirolimus-stent group and 28.8 in the
  standard-stent group

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A RANDOMIZED COMPARISON OF A SIROLIMUS-ELUTING
STENT WITH A STANDARD STENT FOR CORONARY
REVASCULARIZATION Morice MC, et al. (N Engl J Med
20023461773-80.)
The trial included 238 patients at 19
center. In-stent late luminal loss at six
months. ISR 0 to 26.6
Cumulative Frequency of ISR Immediately and at 6
m in SES and in Standard Stents.
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Sirolimus-Eluting Stent for Treatment of Complex
In-Stent Restenosis. The First Clinical
Experience.Degertekin M, et al. J Am Coll
Cardiol 2003.

• SES in 16 pt. with recurrent ISR (100) 4
  brachytherapy and 3 totally occluded
• A 18 mm Bx VELOCITY, (n 26).
• QCA 3D-IVUS at 6 m.
• One died and 3 pt (3/15 30) had restenosis
  (one in-stent and two in-lesion).

CX
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SIRIUS Sirolimus-Eluting Stents versus Standard
Stents in Patients with Stenosis in a Native
Coronary Artery. Moses JW, et al.N Engl J Med
20033491315-23.

• A recent trial on 1058-patient.
• Complex coronary disease diabetes composed 26.
  longer lesions (mean, 14.4 mm). small vessels
  (mean, 2.80 mm).
• Total ISR was 3.2 in SES, as compared with 35.4
  those with standard stents.
• Patients with diabetes composed 26. ISR occurred
  in 18 in the SES and 51 in standard stents.

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A Paclitaxel-Eluting Stent for the Preventionof
Coronary Restenosis. Park, SJ. N Engl J Med
20033481537-45.

• Three centers, 177 pt, follow-up for 6 m.
• Low dose, 1.3 µg per square millimeter, or high
  dose, 3.1 µg.
• Event-free survival was 98 in low dose and 100
  in the high-dose.
• A dose-dependent reduction in the volume of NI
  proliferation.

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J Am Coll Cardiol 200342141520.

• Contrast media adhere to the coronary vessel
  wall for some seconds after injection.
• Exprimental on pigs.

Do we need a stent ?
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Directions for the Future (QA)

• How long drug eluting stents will act? All
  studies are less than 1 yr. Can ISR occur after
  longer periods?
• Safety What are their effects on normal
  coronaries?
• Other material for coating Immunosuppressive-
  Sirolimus and antiproliferative-Taxol. Do we
  need Antiplatelets, anti-inflamatory?

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• Can these drugs work without eluting stents, IV,
  systemic or intracoronary ?
• Is ISR- NI-proliferationa new disease?
  atherosclerotic disease?Immune
  disease?Malignant disease?
• Rule of cell transplantation and gene therapy.
  Will we see drug-eluting-stem cells?

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Thank U.