Use of Drug Eluting Stents for InStent Restenosis: Are We There Yet

1
Use of Drug Eluting Stents for In-Stent
Restenosis Are We There Yet?

• Jose Diez, M.D.
• Robert Smith, M.D.
• Cardiac Catheterization Conference
• March 23, 2004

2
Outline

• Case presentation with LHC results
• Traditional approaches for dealing with in-stent
  restenosis
• Cutting Balloon Angioplasty (CBA)
• Brachytherapy
• PTCA
• Bare Metal Stent
• Drug eluting stents for in-stent restenosis
• Conclusions

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Case Presentation
JD is a 72 yo AAF with h/o CAD s/p stenting to
RCA and LAD in 10/03 who was referred for
elective LHC after describing a history of
progressive SOB and chest pain. She described
the chest pain as precordial, pressure like, and
similar to previous episodes of angina. Her
chest pain was typically less than a few minutes,
relieved with SL NTG, and occurred sometimes with
exertion and sometimes at rest. It was usually
associated with SOB. She first experienced the
chest pain approximately 2 months after stent
placement (12/03) and underwent a negative stress
echo at that time. In 2/04, she was evaluated
and discharged from the ER for similar episodes
of chest pain with SOB. Subsequently, an
adenosine cardiolyte stress test was negative for
ischemia. Because of persistence of her
symptoms, she was referred for LHC.
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Past Medical History

• CAD s/p STEMI in 10/03 with stent to culprit RCA
  lesion (Medtronic Zipper) and stent to LAD
  (Cypher)
• Exercise stress echo 12/03 negative for ischemia.
  Pt exercised for 7 minutes
• Adenosine cardiolyte stress test 2/04 negative
  for ischemia
• TTE 2000 showed moderate AI, concentric LVH, mild
  MR
• HTN for gt 10 years
• Type II DM on oral hypoglycemics
• Hyperlipidemia
• PVD
• Cerebrovascular disease s/p left CEA and 60
  lesion in the right internal CA (h/o TIAs)
• Obstructive Sleep Apnea on home CPAP

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Medications

• Plavix 75mg PO QD
• ASA 81mg PO QD
• Lopressor 50mg PO BID
• Lisinopril 40mg PO QD
• Atorvastatin 80mg PO QHS

6
Social History

• Retired Nurse
• Denies h/o cigarette smoking
• Denies EtOH
• Denies drug use
• Lives with daughter
• Husband is deceased

7
Family History

• Father died of congestive heart failure
• Also significant for DM, HTN

8
Physical Exam

• 152/88 52 14 36.0 SaO2 97
• Gen NAD, symptom free
• Neck Right Carotid Bruit, No JVD
• CV nlS1S2, 2/6 HSM apex ? axilla
• Chest clear
• Abd NABS, NT, ND
• Ext no edema

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Labs

• Na 133
• K 4.1
• Cl 101
• CO2 29
• Glu 172
• BUN 11
• Cr 0.6
• Ca 1.8
• Mg 1.8
• Tn lt0.04
• Myo 22
• CK 68

• WBC 6.6
• Hgb 12.5
• Hct 36.5
• MCV 87.5
• Plt 221
• PTT 26
• INR 1.02

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ECG

• NSR with q waves in the inferior leads

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Restenosis

• Occurs in 30-40 of patients by 6 months after
  PTCA
• Occurs in 20-30 of patients by 6 months after
  PTCA with stenting 1,2
• Restenosis is thought secondary to combination of
  vessel wall remodeling and neointimal hyperplasia
  with smooth muscle cell and matrix proliferation
• Elastic recoil and thrombosis may also play a
  role
• 1Fischman et al., N Engl J Med 1994331496-501
• 2Serruys et al., N Engl J Med 1994331489-495

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ISR Available Therapies

• Cutting Balloon Angioplasty (CBA)
• Angioplasty
• Brachytherapy
• Stent within Stent
• Bare Metal Stents
• Drug Eluting Stents

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Cutting Balloon Angioplasty

• The cutting balloon is a device with 3-4
  longitudinal atherotome blades mounted on the
  outer surface of the device
• It produces longitudinal incisions in a target
  lesion resulting in more effective dilatation of
  the lesion
• Keeps the balloon from moving proximally or
  distally during inflation
• May help facilitate extrusion of in-stent
  hyperplasia through the stent struts

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Cutting Balloon
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Cutting Balloon Angioplasty for ISR

• In a 2001 study, CBA was compared to rotational
  atherectomy, PTCA, or restenting in a study of
  684 patients with ISR1
• At angiographic f/u, CBA was associated with less
  lumen loss than that seen with atherectomy and
  stent
• This corresponded to a 6 month restenosis rate of
  20 for CBA, 36 for atherectomy, and 41 for
  restenting
• At 11 month follow up, there was no difference in
  the incidence death, MI, or bypass surgery
• 1Adamian et al. J Am Coll Cardiol 2001
  Sep38(3)672-9

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Brachytherapy for ISR

• Intracoronary brachytherapy reduces vessel wall
  remodeling and causes a reduction in the
  proliferation of the neointima
• The SCRIPPS Trial1 was a double blind randomized
  trial that compared gamma irradiation to placebo
  for treatment of ISR (n55). Follow up was
  performed at 6 months, 3 years, and 5 years
• 23 of patients had recurrent stenosis at
  angiographic follow up
• 1Grise et al., Circulation. 105(23)2737-2740,
  June 11, 2002

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SCRIPPS Trial 5 Year F/U
18
SCRIPPS Trial TLR
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SCRIPPS Trial Event Free Survival
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PTCA for ISR

• In a 1998 study, PTCA was performed in 52
  patients presenting with ISR 1
• Initial angiographic success rate was 100
• At 6 month follow up, angiographic restenosis
  rate was 54
• 18 patients (35) had TVR
• No patients died
• Conclusions PTCA for ISR is safe but has a high
  rate of recurrent stenosis
• 1Eltchaninoff et al., J Am Coll Cardiol 1998
  Oct32(4) 980-984

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Repeat Stenting for ISR

• In a study from 2000, 65 patients underwent
  repeat stenting as treatment for ISR 1
• Angiographic success was obtained in all patients
• 3 patients had acute adverse events (1 death, 2
  NQWMIs)
• During follow up (17/- 11 months), TVR was
  required in 14
• Angiographic follow up (mean of 9 months) showed
  ISR in 30
• 1Alfonso et al., Am J Cardiol 2000 Feb
  185(3)327-32

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Repeat Stenting vs. PTCA

• Addressed in the RIBS trial1 (compared repeat
  stenting to PTCA alone in 450 patients)
• Restenosis rate and event free survival at 6
  months were similar in the two groups
• Among patients with a target vessel diameter gt or
  equal to 3mm, stenting was associated with a
  significantly lower restenosis rate (27 vs. 49
  for PTCA) at 6 months
• 1Alfonso et al., J Am Coll Cardiol 2003 Sep
  342(5)796-805

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Repeat Stenting vs. PTCA

• In vessels gt or equal to 3mm, patients who were
  restented had better event free one year survival
  (84 vs. 62)
• There was an almost significant trend toward
  worse outcomes with re-stenting when the vessel
  diameter was less than 3mm

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Summary of Restenosis Rates

• Brachytherapy 12 at 6 months and 23 at 5 years
• CBA 20 at 6 months
• PTCA 54 at 6 months, 49 at 6 months
• Bare Metal Stents 41 at 6 months, 30 at 9
  months, 27 at 6 months

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Drug Eluting Stents for ISR

• The efficacy of Sirolimus Eluting Stents has been
  evaluated in 2 small, noncomparative trials 1,2
• The efficacy of Paclitaxel eluting stents has
  also been evaluated in a single noncomparative
  trial 3
• 1Degertekin et al., J Am Coll Cardiol 2003 Jan
  1541(2)184-9
• 2Sousa et al., Circulation 2003 10724
• 3Tanabe et al., Circulation 2003 Feb 4107(4)
  559-564

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Drug Eluting Stents for ISR

• In an initial series of 25 patients with ISR in
  whom a SES was implanted, all vessels were patent
  at 1 year and only one patient developed ISR
  within the newer stent 1
• Exclusion criteria for this study included
  lesions in SVGs, patients who had undergone
  previous brachytherapy to the target vessel, and
  lesions greater than 36mm in length
• No ostial lesions were treated in this study
• 1Sousa et al., Circulation 2003 10724

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Drug Eluting Stents for ISR

• Post procedure angiography and IVUS was performed
  at 4 and 12 months
• All patients were free of angina after 1 year
• There were no repeat revascularizations, stent
  thromboses, or major clinical events (CVA, MI,
  Death) after 1 year
• On 4 month angiographic follow up, lumen diameter
  was unchanged in 50 of patients, and slightly
  greater in some patients

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Drug Eluting Stents for ISR

• There was a slight but significant decrease in
  mean lumen diameter between 4 and 12 months
  (angiographic late loss averaged 0.07mm at 4
  months and 0.36mm at 12 months)
• Volume obstruction by IVUS was 0.81 at 4 months
  and 1.76 at 12 months
• No patients had ISR at 4 months and 1 patient had
  ISR at 1 year
• All stents were properly deployed

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Drug Eluting Stents for ISR

• In a second report1, 16 patients with severe,
  recurrent ISR in a native coronary vessel
  received a SES (average lesion length 18.4mm)
• Patients with objective evidence of ischemia were
  excluded
• 4 patients has total occlusions pre-procedure
  and 3 others had received brachytherapy
• Quantitative angiographic and IVUS follow up was
  performed at 4 months and clinical follow up at 9
  months
• 1Degertekin et al., J Am Coll Cardiol 2003 Jan
  1541(2)184-9

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Drug Eluting Stents for ISR

• At 4 month follow up, one patient had died and
  three patients had angiographic evidence of
  restenosis (18.8)
• Late lumen loss averaged 0.21mm and volume
  obstruction of the stent by IVUS was 1.1
• At 9 months clinical follow up, 3 patients had
  experienced major adverse events (2 deaths and 1
  MI)

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Drug Eluting Stents for ISR

• The TAXUS III Trial1 evaluated paclitaxel eluting
  stents for treatment of ISR
• This was a noncomparative 2 center study that
  evaluated 28 patients with ISR
• Inclusion criteria were lesions lt or to 30mm,
  50-99 stenosis, and vessel diameter 3.0 to 3.5mm
• Exclusion criteria were AMI, LVEF lt30, CVA
  within 6 months, SCr gt1.7, and contraindication
  to antiplatelet therapy
• 1Tanabe et al., Circulation 2003 Feb 4107(4)
  559-564

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Drug Eluting Stents for ISR

• There was no subacute stent thrombosis
• 25 of 28 patients completed angiographic follow
  up at 6 months
• 4 patients had angiographic evidence of
  restenosis (16)
• One of these patients had total occlusion of a
  lesion previously treated with a gold coated
  stent (he was asymptomatic)
• One patient had ISR in a bare metal stent used to
  treat a dissection at the end of a PES
• Two patients has ISR in gaps between sequential
  PESs
• The mean lumen late loss was 0.54mm

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Drug Eluting Stents for ISR

• The major adverse cardiac event rate was 29 (8
  patients)
• This included 1 NQWMI, 1 CABG, and 5 TLRs
• 1 patient with ISR of bare metal stent and 2
  patients with stenoses of gaps between PESs
• 2 patients without angiographic restenosis
  underwent TLR as result of IVUS assessment at
  follow up (1 incomplete apposition and 1
  insufficient expansion of the stent

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Conclusions

• Treating ISR is a major challenge facing
  interventional cardiologists
• With traditional treatments (PTCA, CBA,
  re-stenting), restenosis develops in 30-80 of
  patients
• Prior to drug eluting stents, the best therapy
  was intravascular brachytherapy (23 restenosis
  in the SCRIPPS trial)
• Early studies indicate that drug eluting stents
  may prove effective for treating in-stent
  restenosis

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Conclusions

• Between all DES studies, there was no subacute
  thrombosis
• Between all studies, there were only 4 compelling
  cases of ISR within a DES
• When the DESs were properly deployed, there were
  only 6 adverse cardiac events between the studies
• Sirolimus eluting stents and paclitaxel eluting
  stents both appear to be effective for treating
  ISR
• Early data indicates that DESs are superior than
  traditional methods for treating ISR
• Are we there yet? Maybe