Drug Eluting Stents: Should we be worried

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Drug Eluting Stents Should we be worried
Siberia

• Renu VirmaniMD
• Armed Forces Institute of Pathology
• WashingtonDC

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Faculty Disclosure Declaration

• Grant Research Support - Medtronic Guidant
  Cordis Corp W.L. Gore Amersham Health -GE
  Takeda Atrium Medical Corporation Invatec ev3
  diaDexus Topspin Medical Technology Ltd/Boston
  Scientific Novartis Paracor Medical Inc.
• Consultant - Medtronic Guidant Abbott W.L.
  Gore Terumo Topspin Cryovascular Bard
  Volcano.
• Major Stock Shareholder - None
• Other Financial or Material Support - None

Renu Virmani M.D.
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Drug-Eluting Stents Comprise a Three-Component
System
Drug loaded directly without an intervening
polymer
Ideal Stent design
Drug
Polymer (erodable/ non-erodable)
Drug (lipophylic) binds to tissues better than
to blood Cytostatic and allows
endothelialization while suppressing smooth
muscle cell proliferation and migration
Polymer that does not induce inflammation but
allows rapid release followed by slow release of
drug over a long period
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Lessons From Preclinical Studies of DES
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Forest plot Comparing all-cause Mortality rate in
DES and for BMS
Odds Ratio (95 CI)
Trial RAVEL STRUS C-SIRUS E-SIRUS Pooled Paclitaxe
l polymeric TAXUS I TAXUS II TAXUS
IV Pooled Paclitaxel non-polymeric ASPECT ALUTES
DELIVER PATENCY Pooled Total
DES n/N 2/120 5/533 0/50 2/175 9/878 0/31 0/260 9
/662 9/953 1/117 1/152 5/517 0/25 7/810 25/2641

BMS n/N 2/118 3525 0/50 1/177 6/870 0/30 2/263 7/
662 9/945 0/58 038 5/512 1/6 6/634 21/2449
0.98 (0.14 to 7.20) 1.55 (0.40 to 7.34) 1.00
(0.00 to 690) 1.70 (0.22 to 25.5) 1.15 (0.45 to
3.06) 0.97 (0.00 to 668) 0.20 (0.00 to
1.99) 1.25 (0.47 to 3.50) 0.66 (0.00 to
8.32) 151 (0.08 to 1391) 0.76 (0.04 to
663) 0.99 (0.28 to 3.44) 0.35 (0.00 to 6.45) 0.89
(0.26 to 2.67) 1.11 (0.61 to 2.06)
The two trial reported only cardiac
mortality Babapulle MN et al. Lancet 14 Aug 2004
0.01 0.1 1.0 10.0
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Pathology of Drug Eluting Stents in Humans

• Paclitaxel (TAXUSTM)
• Sirolimus (CYPHERTM)

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F.D.A. Seeks Reports of Stent Problems The New
York Times April 23 2004
Balloon stuck on the stent (Taxus Express2)
Dr. William Campbell
Circumferential calcification
54-year-old M had PCI-LAD for AMI. Subsequently
had repeat Cath- long RCA lesion a long TAXUS
stent was placed but there was incomplete
deployment of the stent various balloons
catheters were used one of the balloons got
stuck.
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Taxus Stent Thrombosis - 41 days
Proximal to stent
LAD3
LAD1
LAD3
th
th
th
LAD3
LAD3






47-year-old M with anterior MI on angiography
had 100 LAD (3 vessel disease) had angioplasty
and TAXUS stent placement in the LAD 41 days
prior to death
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Taxus Stent Acute Chronic Inflammation
40-year-old female with AMI (LAD TAXUS) 3 days
prior to SD
A
LAD
LD
LAD1
Intima
Media
Adventitia
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Cypher stents with Subacute Occlusive Thrombosis
Cypher stents with Mild Non-occlusive Thrombus
Diffuse disease 51 year old had documented
vasospasm and had diffuse narrowing. This
patient had an abnormal Thalium scan (5 months)
found to have severe narrowing of proximal LAD
received a BioDivYsio stent presents 5 months
later with UAP has in-stent restenosis receives
brachytherapy and Cypher stent in the mid LAD
presents 9 days later with CP -50 to 70
narrowing of proximal LAD S7 stent placed
patient admitted 2 months later with CP
catheterization slow flow to LAD ballooned
arrests and dies after by-pass surgery. At
autopsy diffuse disease.
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Cypher with Hypersensitivity Reaction
Cypher with Minimal Neointima late after Stenting
Cypher with Restenosis
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CypherTM Stent in Left Circumflex and Left
Anterior Descending Coronary Arteries and
BiodivYsio Stent in Left Diagonal
LAD/LD
LCx
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Subacute Stent Thrombosis - 7 days
LAD
LD
A
B
Thrombus
CD
A
C
LAD
Thrombus
Thrombus
D
B
LD
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Causes of subacute thrombosis -CYPHER

• Polymer peeling off the stent during deployment
• Under expansion of the stent
• Small stent used in a larger vessel-cracking of
  polymer
• Drug
• Inappropriate location chosen for stent
  -bifurcation crush technique

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CYPHER Proximal and Distal Stent Sections
Virmani R el al. Circulation 2004
Th
Eosinophils (Luna stain)
Chronic Inflammation
T-Lymphocytes (UCHL)
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Causes of Adventitial Medial and Intimal
Inflammation (eosinophils) limited to the area
of the Stent Hypersensitivity reaction to
drug v Hypersensitivity reaction to
polymer Part of atherosclerosis
Infection
Adverse side effects to Sirolimus mostly limited
to bone-marrow suppression hypercholesterolemia
and triglyceridemia. Other reported
side-effects include hypocalemia hyperglycemia
diarrhea and abnormal liver function tests.
Hypersensitivity has been reported in one
patient following Sirolimus.
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Granulomatous reaction seen in CYPHER Stents
Implanted for 28 and 90 days in Pig Coronary
Arteries
Cypher
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Pathologic and Morphometric Findings at
Overlapping TAXUS and CYPHER DES Stents in Rabbit
Iliac Arteries

• TAXUS and CYPHER stents induce inflammation
  (especially eosinophilic) with fibrin deposition
  and delayed endothelialization at 28 days
  however the changes are more marked in TAXUS
  than CYPHER stents/
• At 90-days there is greater progression of
  neointimal formation with persistence of
  inflammation in TAXUS than CYPHER
• Medial cell loss is greater in TAXUS than CYPHER
• Clinically overlapping sites will result in
  greater late loss and TVR with TAXUS than CYPHER
  stents - Careful follow-up gt18 months is required

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Are DES as good as the Clinicians claim they are
Conclusions

• Preclinical data would suggest that currently
  used polymers on DES stents are proinflammatory
  thrombogenic at overlapping sites and even
  induce a hypersensitivity reaction in animals
  (pigs and rabbits) more so with TAXUS than
  CYPHER.
• Human studies have shown that DES stents may
  cause an increase in thrombosis may be a result
  of inappropriate use of the DES stent or
  premature withdrawal of anticoagulant therapy or
  polymer/drug effects.
• In sensitive patients DES may induce a
  hypersensitivity reaction and late thrombosis.

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Acknowledgments

• Frank Kolodgie Ph.D.
• Andrew Farb M.D.
• Allen Burke M.D.
• Eduardo Acampado. DVM.
• Robert Kutz M.S.
• Deena Weber M.S.
• You-hui Liang M.D.
• Hedwig Avallone
• Lila Adams