An Update on the Safety and Efficacy of Drug Eluting Stents

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An Update on theSafety and Efficacy of Drug
Eluting Stents

• Annual Cardiovascular Conference
• Lake Louise, March 2008
• Eric A. Cohen MD, FRCPC
• Sunnybrook Health Sciences Centre

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Disclosures

• Advisory boards and/or speakers honoraria
• Medtronic
• Abbott Vascular
• Boston Scientific
• Research support
• Medtronic
• Abbott Vascular
• Boston Scientific
• Cordis / JJ

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Old school
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Really old school
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New school
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Restenosis The Achilles Heel of PCI

• Angiographic restenosis
• 30-40 with balloon angioplasty
• 15-20 with bare stents
• Restenotic tissue (intimal thickening) primarily
  smooth muscle cells and extra-cellular matrix

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Coronary stenting provided reliable procedural
results
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Why we need something better thanbare metal
stents . . .
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Formidable technical challengesStent, drug,
polymer, delivery system
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October 21, 2006 Doctors Rethink Widespread Use
of Heart Stents
 

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Stent thrombosis is not a new problem . .

• METHODS. From March 1986 to January 1988, we
  implanted 117 self-expanding, stainless-steel
  endovascular stents . . . The mortality after one
  year was 7.6 percent (8 patients).
• RESULTS. Complete occlusion occurred in 27 stents
  in 25 patients (24 percent) 21 within the first
  14 days after implantation.
• Serruys PW, Strauss BH, et al. NEJM, 1991

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Supporting Data

• Drug eluting stents are effective at lowering the
  need for repeat intervention.
• Current drug-eluting stents are associated with a
  small incremental risk of late thrombosis .
• The risk of late thrombosis varies with patient,
  lesion, and procedural factors.
• Stent thrombosis frequently results in myocardial
  infarction or death. Repeat interventions can
  also lead to adverse outcomes, but much less
  often.
• Stopping antiplatelet therapy markedly increases
  the risk of late thrombosis, but it is not known
  whether very long-term (or indefinite) dual
  therapy is necessary or beneficial.

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3-Year Freedom from Target Lesion
Revascularization Multiple Stent Patients, TAXUS
II, IV, V, VI
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Freedom From MACE to 2 Years
12 mos.
9 mos.
Plt0.0001
91.5
89.4
85.3
84.9
79.8
75.1
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Supporting Data

• Drug eluting stents are effective at lowering the
  need for repeat intervention.
• Current drug-eluting stents are associated with a
  small incremental risk of late thrombosis.
• The risk of late thrombosis varies with patient,
  lesion, and procedural factors.
• Stent thrombosis frequently results in myocardial
  infarction or death. Repeat interventions can
  also lead to adverse outcomes, but much less
  often.
• Stopping antiplatelet therapy markedly increases
  the risk of late thrombosis, but it is not known
  whether very long-term (or indefinite) dual
  therapy is necessary or beneficial.

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Temporal sequence of reendothelialization in BMS
and DES
Luscher, TF et al. Circulation 20071151051-1058
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DES reduce neointima formation but may increase
stent thrombogenicity
Luscher, TF et al. Circulation 20071151051-1058
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Cumulative Incidence of Stent Thrombosis at 4
Years, According to Definitions Used in Trial
Protocol
Mauri L et al. N Engl J Med 20073561020-1029
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Supporting Data

• Drug eluting stents are effective at lowering the
  need for repeat intervention.
• Current drug-eluting stents are associated with a
  small incremental risk of late thrombosis.
• The risk of late thrombosis varies with patient,
  lesion, and procedural factors.
• Stent thrombosis frequently results in myocardial
  infarction or death. Repeat interventions can
  also lead to adverse outcomes, but much less
  often.
• Stopping antiplatelet therapy markedly increases
  the risk of late thrombosis, but it is not known
  whether very long-term (or indefinite) dual
  therapy is necessary or beneficial.

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Frequency of stent thrombosis

• Rate of excess stent thrombosis between year 1
  and 4 among pts with DES approx 1 per 500 pt
  years
• What happens after year 4 ???

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Off-label vs On-label use of DES

• When used off-label . . .
• Very long lesions
• Multiple overlapping stents
• Bifurcation lesions
• Acute MI
• Treatment of bare-metal in-stent restenosis
• Etc
• . . . DES are associated with higher rate of
  stent thrombosis
• The same is true for bare metal stents

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The hazard of off-label use is not restricted to
DES
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Hazard ratios for on-label and off-label usage

• Pre post cohort study
• 1164 consecutive BMS treated pts (before DES
  introduced) vs 1285 consecutive DES pts
• 2 year follow-up
• 40 clopidogrel use at 2 years in both groups

Applegate RJ et al. J Am Coll Cardiol 2008
51607-614.
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Supporting Data

• Drug eluting stents are effective at lowering the
  need for repeat intervention.
• Current drug-eluting stents are associated with a
  small incremental risk of late thrombosis.
• The risk of late thrombosis varies with patient,
  lesion, and procedural factors.
• Stent thrombosis frequently results in myocardial
  infarction or death. Repeat interventions can
  also lead to adverse outcomes, but much less
  often.
• Stopping antiplatelet therapy markedly increases
  the risk of late thrombosis, but it is not known
  whether very long-term (or indefinite) dual
  therapy is necessary or beneficial.

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Clinical Outcomes in Patients afterDefinite or
Probable Stent Thrombosis
Mauri L et al. N Engl J Med 20073561020-1029
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• A large reduction in a phenomenon with moderate
  clinical risk (restenosis) may be offset by a
  small increase in a phenomenon with high clinical
  risk (stent thrombosis).
• Stone et al, NEJM March 2007

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Network meta-analysis
Entries represent the point estimate and (worst
case boundary of the 95 confidence window) NNT
/ NNH number needed to treat or harm over 4
years
Lancet, Sept 2007
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Swedish Registry20,000 patients stented in
2003/04
Lagerqvist B et al. N Engl J Med
20073561009-1019
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ESTROFA Registry (Spain) de la Torre-Hernández
JM et al, J Am Coll Cardiol. 200851986-90

• 23,500 patients treated with DES in Spain
• Angiographically documented stent thrombosis at 3
  years in 2 (301 cases)
• 152 late (62 very late gt1 year).
• No differences between stent types
• Independent predictors of stent thrombosis
• subacute diabetes, renal failure, ACS, STEMI,
  and LAD stenting
• late STEMI, LAD stenting, stent length
• Mortality at 1-year post stent thrombosis 16

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Massachusetts Registry Two-year outcomes

• 2003 - 2005
• gt17,000 pts 65 treated with DES
• 28 diabetic 24 STEMI

Mauri L. AHA 2007
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Observational propensity-adjusted analysis
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Myocardial infarction
5.7
5.2
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Death
4.3
5.5
6.1
7.8
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Supporting Data

• Drug eluting stents are effective at lowering the
  need for repeat intervention.
• Current drug-eluting stents are associated with a
  small incremental risk of late thrombosis.
• The risk of late thrombosis varies with patient,
  lesion, and procedural factors.
• Stent thrombosis frequently results in myocardial
  infarction or death. Repeat interventions can
  also lead to adverse outcomes, but much less
  often.
• Stopping antiplatelet therapy markedly increases
  the risk of late thrombosis, but it is not known
  whether very long-term (or indefinite) dual
  therapy is necessary or beneficial.

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Endeavor Safety Analysis
Cardiac Death and MI to 1080 Days (cumulative
incidence)
10
8
6.6
6
Cumulative Incidenceof Cardiac Death or MI
4
3.5
2
0
0
90
180
270
360
450
540
630
720
810
900
990
1080
Time after Initial Procedure (days)
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Bioabsorbable stents

• Ormiston J, Serruys PW, Regar E, et al. A
  bioabsorbable everolimus-eluting coronary stent
  system for patients with single de-novo coronary
  artery lesions (ABSORB) a prospective open-label
  trial. Lancet 2008 371899-907.
• Di Mario C, Ferrante G. Biodegradable
  drug-eluting stents promises and pitfalls.
  Lancet 2008 371873-874.
• At one year . . . .
• the anti-restenotic effect appears durable,
  although not perfect (approx 12)
• late loss is comparable to TAXUS but higher than
  everolimus on a permanent metal stent
• concerns about loss of scaffolding integrity
  based on IVUS and OCT

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Some perspective on the appropriate role and
impact of DES
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TVR
7.4
10.7
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Stratified TVR ratesDIABETES
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Stratified TVR rates NON-DIABETICS
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Recommendations CAIC / CCS

• Limit use of DES to patients at high risk for
  repeat intervention.
• Extended duration dual antiplatelet therapy may
  be of value for selected patients. Provincial
  drug plans should reimburse accordingly.
  Administrative barriers must be minimized.
• In all cases . . . the interventional
  cardiologist and the patient must have an
  explicit discussion about the known and potential
  risks and benefits of drug-eluting stents.  The
  patient's willingness and ability to take
  anti-platelet medications over an extended period
  should be considered in determining their
  suitability for DES.

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DES have not solved the problem of
re-intervention in extensive disease
Hannan et al, NEJM 2008
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There is still a role for CABG . . .
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To put this in perspective . . .

• We do need something better than BMS for
  certain patients
• Stent thrombosis isnt a new issue either with
  DES or BMS
• More similarity than difference in currently
  available DES too early to conclude whether
  newer stents offer an advantage
• For now, DES should be used selectively
• Better technology will eventually solve this
  problem (and probably reveal new issues)

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• Long-term clinical outcomes with
  sirolimus-eluting coronary stents five-year
  results of the RAVEL trial.
• Morice MC, Serruys PW, Barragan P, Bode C, Van Es
  GA, Stoll HP, Snead D, Mauri L, Cutlip DE, Sousa
  E.
• J Am Coll Cardiol. 2007 Oct 250(14)1299-304.
  Epub 2007 Sep 17.
• Institut Cardiovasculaire Paris Sud, Massy,
  France. mc.morice_at_icps.com.fr
• OBJECTIVES This study examined the clinical
  outcomes at 5 years in RAVEL (A Randomized
  Comparison of a Sirolimus-Eluting Stent With a
  Standard Stent for Coronary Revascularization),
  the first controlled trial of drug-eluting
  stents. BACKGROUND The 6-month rate of
  angiographic coronary restenosis has been
  markedly lowered by sirolimus-eluting stents
  (SES). The long-term performance of drug-eluting
  stents, however, is under close scrutiny.
  METHODS The trial included 238 patients (mean
  age 60.7 /- 10.4 years, 76 men) with a single,
  de novo native coronary artery lesion, randomly
  assigned to treatment with SES versus bare-metal
  stents (BMS). Rates of major adverse cardiac
  events (MACE), defined as all-cause mortality,
  myocardial infarction, and percutaneous or
  surgical revascularization up to 5 years of
  follow-up, and rates of stent thrombosis were
  compared between the 2 treatment groups. RESULTS
  Complete datasets were available in 92.5 of
  patients treated with SES and 89.1 of patients
  assigned to BMS. The 1-, 3-, and 5-year rates of
  survival free from target lesion
  revascularization (TLR) were, respectively,
  99.2, 93.8, and 89.7 in the SES group versus
  75.9, 75.0, and 74.0 in the control group (p lt
  0.001 log-rank). Rates of all MACE at 5 years
  were 25.8 in patients treated with SES versus
  35.2 in patients assigned to BMS (p 0.03
  log-rank). Rates of stent thrombosis, per
  protocol or by the Academic Research Consortium
  definitions, were similar in both groups.
  CONCLUSIONS The 5-year rate of TLR associated
  with SES was significantly lower than that with
  BMS. There was no apparent adverse effect
  associated with the use of SES, although the
  trial was not powered to examine uncommon
  complications.