Drug Eluting Stents

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Drug Eluting Stents
Cypher stent, Cordis

• Resident Grand Rounds
• Tania Chao
• October 7, 2003

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Background

• Since the advent of angioplasty in 1977 and
  subsequently stenting in 1993, the field of
  percutaneous intervention has been plagued by the
  problem of restenosis.

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Background..

• Rates of in-stent restenosis are reported to be
  10 59 in patients after PTCI
• In select patients with simple lesions, stenosis
  rates may be 10 20.
• In diabetic patients, small caliber vessels, and
  saphenous vein grafts, stenosis rates may be up
  to 59.

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Pathophysiology of Restenosis
Robbins Pathologic Basis of Disease, 6th ed.
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Pathophysiology of Restenosis..

• Elastic Recoil
• Reorganization of Thrombus
• Negative Remodeling
• Neointimal Proliferation
• Inflammation

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Reorganization of Thrombus
Exposure to subintimal surfaces cause fibrin and
platelet aggregation.
Bennett et al.
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Negative Remodeling
Injury to the adventitia results in collagen
synthesis and overall shrinkage of the vessel.

• From UptoDate Online

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Neointimal Hyperplasia
Schwartz RS et al.

• Smooth muscle cell proliferation and migration
• Major cause of in-stent stenosis

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Sirolimus

• Sirolimus (rapamycin) Immunosuppressant
• - Increases intracellular receptor p27kip which
  inhibits cell cycle progression

Marx SO et al
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Paclitaxel

• Antimitotic Drug extracted from the Pacific Yew
  tree found in the Northwestern US and Canada
• Stabilizes microtubules to disrupt cell cycle
• Prevent smooth muscle proliferation

GW Stone, tctmd.com
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Definitions

• In-stent luminal late loss minimal luminal
  diameter (MLD) immediately after procedure MLD
  at follow up
• Restenosis defined as greater than 50 stenosis
  at follow-up
• Target lesion in stent zone
• Target vessel in stent zone 5 mm proximal and
  distal
• Target vessel failure (TVF) cardiac death, MI,
  revascularization of target vessel
• Major adverse cardiac events (MACE) death, MI,
  revascularization

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RAVEL
Randomized study with the sirolimus-eluting Bx
VELocity balloon expandable stent

• First randomized double-blind study to compare
  sirolimus-eluting stents to bare metal stents
• 238 patients were randomized to receive sirolimus
  stents or standard metal stents.
• Primary endpoints in-stent luminal late loss by
  angiography
• Secondary endpoints percentage of ISS of luminal
  diameter, rate of restenosis
• Clinical endpoints Major cardiac events
  cardiac death, MI, revascularization

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RAVEL Inclusion Criteria

• Stable or unstable angina or silent ischemia
• Single primary target lesion in native coronary
  artery
• 2.5 3.5 mm in diameter
• Able to be covered by an 18 mm stent
• 51-99 stenosis
• TIMI flow rate of 1 or greater

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RAVEL Exclusion Criteria

• Acute myocardial infarction
• Stenosis of left main that was unprotected
• Ostial lesion
• LVEF
• Thrombus within target lesion
• Intolerance of aspirin or plavix

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RAVEL Patient characteristics
120 patients randomized to sirolimus stents and
118 randomized to standard
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RAVEL Results
Angiographic results at 6 months
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RAVEL Results
Frequency of Restenosis
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RAVEL Results
MACE rates at 1 year

• Death
• Myocardial infarction
• Revascularization

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RAVEL Results
Event Free Survival
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RAVEL Conclusions

• The sirolimus stent resulted in significant
  decreases in all angiographic parameters.
• There was a significant decrease in need for
  revascularization at 1 year (17.8 vs. 0.8)
• There was no difference in complication rates.
• This results in a NNT of 4.4 patients to prevent
  one revascularization at 1 year.

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TAXUS IV
The pivotal, prospective, Randomized Trial of the
Slow-rate Release Polymer-based Paclitaxel-Eluting
TAXUS stent

• Large scale multi-center trial to compare
  paclitaxel-coated stents to bare metal stents
• 1326 patients were randomized to receive TAXUS
  stents or standard metal stents.
• Primary Endpoints MACE rates at 1,4,9 months and
  yearly for 5 years.
• Angiography and IVUS were performed on a subset
  of patients at 9 months.

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TAXUS IV Inclusion Criteria

• Single primary target lesion in native coronary
  artery
• 2.5 3.75 mm in diameter
• Lesion lengths 10 28 mm

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TAXUS IV Exclusion Criteria

• Prior PTCI in target vessel in 9 months
• Acute myocardial infarction (In last 72 hours)
• Planned use of cutting balloon
• Prior or planned use of brachytherapy
• Ostial lesion, bifurcation, TIMI 0 or 1 flow,
  thrombus in vessel or excessive vessel tortuousity

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TAXUS IV Results

• 662 patients were randomized to the TAXUS stent,
  652 patients were randomized to control stents.
• Baseline patient and target lesion
  characteristics were similar between the two
  groups.

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TAXUS IV Results
Angiography Results on subset of 559 patients at
9 months
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TAXUS IV Results

• Clinical Results
• 9 month MACE

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TAXUS IV
Decrease in need for revascularization across all
vessel sizes and lesion lengths
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TAXUS IV
Subset analysis Significant decrease in Need
for TLR in all groups except diabetics on insulin
and vessel diameters greater than 3 mm.
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TAXUS IV Conclusions

• This study showed that the TAXUS stent
  significantly decreased the need for
  revascularization and is safe in a broader
  population than previously studied. This study
  included multiple stent placement and longer
  lesion lengths (up to 28 mm, previously up to 18
  mm)
• The RR for revascularization was 0.39 with a NNT
  of 13.7 to prevent one revascularization at 9
  months.

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SIRIUS
Sirolimus-Eluting Stents versus Standard Stents
in Patients with Stenosis in a Native Coronary
Artery October 2, 2003

• Large-scale multi-center study to compare
  sirolimus-eluting stents to bare metal stents
• 1058 patients were randomized to receive
  sirolimus stents or standard metal stents.
• Primary endpoints Failure of target vessel
  death from cardiac causes, MI, repeat
  revascularization. Clinical follow-up at 1, 3,
  6, 9 months, every year up to 5 years
• Secondary endpoints IVUS and angiography results
  at 8 months

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SIRIUS Inclusion Criteria

• Stable or unstable angina or signs of MI
• Single primary target lesion in native coronary
  artery
• 2.5 3.5 mm in diameter
• 15 30 mm in length
• 51-99 stenosis
• TIMI flow rate of 1 or greater

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SIRIUS Exclusion Criteria

• Recent MI (
• Unprotected left main disease
• Ostial lesions or bifurcations
• TIMI 0 Flow (total occlusion)
• Angiographic evidence of thrombus
• Calcified lesions that could not be predilated
• EF

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SIRIUS Results
533 patients were randomized to sirolimus stents
and 525 to the standard stents. Baseline
patient characteristics and target lesion
characteristics were well matched between the 2
groups An average of 1.4 stents were placed with
28 receiving overlapping stents.
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SIRIUS Results
Results of Angiography at 8 months
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SIRIUS Results
Clinical Outcomes at 9 months
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SIRIUS Results
Event free survival in Sirolimus vs. Standard
stents up to 9 months.
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SIRIUS Results

• Subgroup Analysis
• 26 of the studied population had diabetes.
• Restenosis in Diabetics 17.6 with sirolimus,
  50.5 with standard
• TLR in Diabetics 6.9 with sirolimus, 22.3 in
  standard

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SIRIUS Conclusions

• This study evaluated a higher risk population
  than previous studies. 27 required overlapping
  stents, 41.6 had multi-vessel disease, and
  target lesions were longer (14.4 mm compared to
  9.58 mm in RAVEL).
• There was a significant decrease in the TLR in
  all subgroups analyzed, with a 91 decrease in
  the rate of restenosis overall, 75 decrease in
  the overall TLR and a 62 decrease in MACE rates.

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Available Stents

• The CYPHER sirolimus-eluting stent is currently
  the only commercially available stent. It was
  approved by the FDA on April 24, 2003.
• The TAXUS paclitaxel-eluting stent is to be
  submitted this month for approval (already
  available in Europe, Australia, South America).

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Conclusions
Reduction 70 36 64 61 95
75
NNT 15 17 8
14 4.4 8
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Conclusions

• The use of drug-eluting stents has resulted in a
  dramatic decrease in the rates of in-stent
  stenosis and need for revascularization.
• Current use is limited by cost (3,195/stent) and
  availability. Initial cost offset by decreased
  need for revascularization?
• Studies need to compare drug-eluting stents to
  CABG for multi-vessel disease and brachytherapy
  for in-stent stenosis

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Conclusions..

• Populations not studied chronic total
  occlusions, bifurcations, saphenous vein grafts,
  left main disease, acute myocardial infarction
• Plavix 3 or 6 months
• There is no difference in mortality between drug
  eluting stents and bare metal stents.