Why are drug-eluting stents safer than bare-metal stents?

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Why are drug-eluting stents safer than
bare-metal stents?

• Giuseppe Biondi Zoccai, MD
• Sapienza University of Rome, Rome, Italy
• METCARDIO, Ospedaletti, Italy
• giuseppe.biondizoccai_at_uniroma1.it

10th International Cardiology Congress Patras
4-6 May 2012
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LEARNING GOALS

• Current paradigm
• Why could drug-eluting stents possibly be safer
  than bare-metal stents?
• The case for network meta-analyses
• Stent thrombosis with drug-eluting versus
  bare-metal stents evidence from a network
  meta-analysis
• Paradigm shift

3
LEARNING GOALS

• Current paradigm
• Why could drug-eluting stents possibly be safer
  than bare-metal stents?
• The case for network meta-analyses
• Stent thrombosis with drug-eluting versus
  bare-metal stents evidence from a network
  meta-analysis
• Paradigm shift

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WHAT IS STENT THROMBOSIS?
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INCIDENCE OF STENT THROMBOSIS
very late
total
acute
subacute
late
at a median folllow-up of 18 months DAscenzo
et al, Int J Cardiol 2012
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PREDICTORS OF STENT THROMBOSIS
number of studies confirming the independent
role of the predictor DAscenzo et al, Int J
Cardiol 2012
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IMPACT OF STENT THROMBOSIS
Chechi et al, J Am Coll Cardiol 2008
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2006 ANNUS HORRIBILIS FOR DRUG-ELUTING STENTS
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2006 ANNUS HORRIBILIS FOR DRUG-ELUTING STENTS
Nordmann et al, Eur Heart J 2006 Camenzind,
ESC/WCC 2006 Bavry et al, Am J Med 2006
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LEARNING GOALS

• Current paradigm
• Why could drug-eluting stents possibly be safer
  than bare-metal stents?
• The case for network meta-analyses
• Stent thrombosis with drug-eluting versus
  bare-metal stents evidence from a network
  meta-analysis
• Paradigm shift

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POTENTIAL OF EVEROLIMUS-ELUTING STENTS
Verheye et al, J Am Coll Cardiol 2007
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POTENTIAL OF EVEROLIMUS-ELUTING STENTS
Kolandaivelu et al, Circulation 2011
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RISK OF STENT THROMBOSIS WITH EVEROLIMUS-ELUTING
VERSUS BARE-METAL STENTS
Kaiser et al, New Engl J Med 2010
Sabate, ESC 2011
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POTENTIAL OF ZOTAROIMUS-ELUTING STENTS
Guagliumi et al, J Am Coll Cardiol Intv 2010
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LEARNING GOALS

• Current paradigm
• Why could drug-eluting stents possibly be safer
  than bare-metal stents?
• The case for network meta-analyses
• Stent thrombosis with drug-eluting versus
  bare-metal stents evidence from a network
  meta-analysis
• Paradigm shift

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META-ANALYSES

• I like to think of the meta-analytic process as
  similar to being in a helicopter.
• On the ground individual trees are visible with
  high resolution.
• This resolution diminishes as the helicopter
  rises, and in its place we begin to see patterns
  not visible from the ground.
• Ingram Olkin

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SYSTEMATIC REVIEW AND META-ANALYSES

• What is a systematic review?
• A systematic appraisal of the methodological
  quality, clinical relevance and consistency of
  published evidence on a specific clinical topic
  in order to provide clear suggestions for a
  specific healthcare problem
• What is a meta-analysis?
• A quantitative synthesis that, preserving the
  identity of individual studies, tries to provide
  an estimate of the overall effect of an
  intervention, exposure, or diagnostic strategy

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ARGUABLY THE MOST IMPORTANT META-ANALYSIS EVER.
Antman et al, JAMA 1992
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SHOWING DISCREPANCIES AMONG EVIDENCE AND EXPERTS
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STANDARD (PAIR-WISE) META-ANALYSES
Point estimate
95 confidence interval
Inconsistency
P for effect
P for heterogeneity
Summary estimate
Hsia et al, Ann Surg 2008
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INDIRECT AND NETWORKMETA-ANALYSES
Biondi-Zoccai et al, HSR Proceedings 2011
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PARALLEL HIERARCHY OF CLINICAL RESEARCH
Biondi-Zoccai et al, HSR Proceedings 2011
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LEARNING GOALS

• Current paradigm
• Why could drug-eluting stents possibly be safer
  than bare-metal stents?
• The case for network meta-analyses
• Stent thrombosis with drug-eluting versus
  bare-metal stents evidence from a network
  meta-analysis
• Paradigm shift

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NETWORK META-ANALYSIS OF STENT THROMBOSIS
Palmerini, Biondi-Zoccai et al, Lancet 2012
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GOAL

• We aimed to perform direct, indirect and combined
  (i.e. network) meta-analyses of the risk of stent
  thrombosis with all FDA approved coronary stents
• Bare-metal stents (BMS) Cobalt-chromium
  everolimus-eluting stents (CoCr-EES) Endeavor
  zotarolimus-eluting stents (End-ZES)
  Paclitaxel-eluting stents (PES)
  Platinum-chromium everolimus-eluting stents
  (PtCr-EES) Resolute zotarolimus-eluting stents
  (Res-ZES) Sirolimus-eluting stents (SES)

Palmerini, Biondi-Zoccai et al, Lancet 2012
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SEARCH AND SELECTION

• Randomized trials of FDA approved coronary stents
  reporting on stent thrombosis according to the
  Academic Research Consortium (ARC) definitions
  were searched in multiple databases (including
  MEDLINE/PubMed).
• Authors and experts were queried for additional
  data and insights on other potentially pertinent
  studies.

Palmerini, Biondi-Zoccai et al, Lancet 2012
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END-POINTS

• Primary end-point
• 1-year definite stent thrombosis
• Secondary end-points
• Definite stent thrombosis occurring before 30
  days, after 30 days, and within 2 years
• Definite or probable stent thrombosis (at the
  above time points)
• Death, cardiac death and myocardial infarction
  within 2 years

Palmerini, Biondi-Zoccai et al, Lancet 2012
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ANALYSIS

• Direct (pair-wise) meta-analyses were performed
  with a random-effect method computing odds ratios
  (OR) with 95 confidence intervals (95CI).
• Indirect and network meta-analyses were performed
  with a random-effect method within a Bayesian
  hierarchical framework, also computing OR and
  95CI.

Palmerini, Biondi-Zoccai et al, Lancet 2012
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ANALYSIS

• Small study effects were appraised by funnel plot
  inspection.
• Statistical consistency in pair-wise and network
  analyses was appraised with I2.
• Sensitivity analyses were conducted using a
  fixed-effect method and restricted to several
  subgroups of interest.
• RevMan and WinBUGS were used for computations.

Palmerini, Biondi-Zoccai et al, Lancet 2012
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REVIEW PROFILE
2602 potentially relevant articles
FDA approved stents (BMS, SES, PES,
End-ZES, Res-ZES, CoCr-EES,
PtCr-EES) 49 RCTs 50,844 pts
2441 excluded 2117 not a comparison of DES 324
post-hoc, subgroup, follow-up, or pooled
analyses
Review of title and abstract
161 articles needing full review
112 excluded 84 not an RCT 13 DES not FDA
approved 11 no ARC definition 4 DES pooled
Full-text review
49 RCTs meeting criteria
Palmerini, Biondi-Zoccai et al, Lancet 2012
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EVIDENCE NETWORK
9 studies
PES
BMS
4 studies
9 studies
8 studies
1 study
5 studies
2 studies
6 studies
End-ZES
SES
6 studies
CoCr-EES
1 study
2 studies
Res-ZES
PtCr-EES
Palmerini, Biondi-Zoccai et al, Lancet 2012
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1-YEAR DEFINITE STENT THROMBOSIS
Palmerini, Biondi-Zoccai et al, Lancet 2012
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30-DAY DEFINITE STENT THROMBOSIS
Odds Ratio 95
CoCr-EES vs BMS CoCr-EES vs PES CoCr-EES vs
SESCoCr-EES vs End-ZES CoCr-EES vs
Res-ZES PtCr-EES vs BMS PtCr-EES vs PES PtCr-EES
vs End-ZES PtCr-EES vs Res-ZES SES vs BMS
0.21 (0.11-0.42) 0.27 (0.14-0.51) 0.40
(0.21-0.79) 0.22 (0.09-0.54) 0.07
(0.00-0.46) 0.06 (0.00-0.68) 0.07
(0.00-0.83) 0.06 (0.00-0.73) 0.02
(0.00-0.43) 0.54 (0.30-0.90)
10
1
0.1
0.01
Favors Stent 2
Favors Stent 1
Palmerini, Biondi-Zoccai et al, Lancet 2012
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30-DAY TO 1-YEAR DEFINITE STENT THROMBOSIS
Odds Ratio 95
CoCr-EES vs BMS CoCr-EES vs PES CoCr-EES vs
End-ZES End-ZES vs SES
0.27 (0.08-0.74) 0.24 (0.08-0.62) 0.13
(0.02-0.56) 4.06 (1.11-18.5)
100
1
0.1
10
0.01
Favors Stent 1
Favors Stent 2
Palmerini, Biondi-Zoccai et al, Lancet 2012
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2-YEAR DEFINITE STENT THROMBOSIS
Palmerini, Biondi-Zoccai et al, Lancet 2012
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OTHER RESULTS FOR DEFINITE STENT THROMBOSIS
Palmerini, Biondi-Zoccai et al, Lancet 2012
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OTHER RESULTS FOR DEFINITE STENT THROMBOSIS
Palmerini, Biondi-Zoccai et al, Lancet 2012
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OTHER RESULTS FOR DEFINITE OR PROBABLE STENT
THROMBOSIS
Palmerini, Biondi-Zoccai et al, Lancet 2012
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STATISTICAL CONSISTENCY
Statistical inconsistency (I2) 0 for both
comparisons
Palmerini, Biondi-Zoccai et al, Lancet 2012
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WHAT ABOUT DEATH OR MYOCARDIAL INFARCTION?

• CoCr-EES were also associated with a
  significantly lower risk of myocardial infarction
  (OR0.61 0.47-0.79).
• These differences were supported by favorable
  trends for all cause death (OR0.83 0.65-1.03)
  and cardiac death (OR0.82 0.58-1.13).

Palmerini, Biondi-Zoccai et al, Lancet 2012
41
LEARNING GOALS

• Current paradigm
• Why could drug-eluting stents possibly be safer
  than bare-metal stents?
• The case for network meta-analyses
• Stent thrombosis with drug-eluting versus
  bare-metal stents evidence from a network
  meta-analysis
• Paradigm shift

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IMPLICATIONS

• The largest and most comprehensive appraisal of
  the risk of stent thrombosis with di?erent types
  of coronary stents has the following
  implications
• CoCr-EES were associated with signi?cantly lower
  rates of 1-year and 2-year de?nite stent
  thrombosis than were BMS, a result not present
  with any other DES.

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IMPLICATIONS

• Decreases in stent thrombosis with CoCr-EES
  compared with BMS were apparent both early and
  late (occurring before 30 days and between 31
  days and 1 year).
• CoCr-EES were also associated with lower 1-year
  rates of de?nite stent thrombosis than were other
  1st and 2nd generation DES, including PES, SES,
  PC-ZES, and Re-ZES.
• These benefits were associated with lower rates
  of myocardial infarction.

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IS THIS A PARADIGM SHIFT?
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THE REPLY IS YOURS
IF I NEEDED A STENT TODAY, WHICH STENT SHOULD I
CHOOSE?
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Many thanks for your attentionFor these and
further slides on these topics please feel free
to visit the metcardio.org websitehttp//www.me
tcardio.org/slides.html
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DEFINITIONS OF STENT THROMBOSIS
Cutlip et al, Circulation 2007
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DEFINITIONS OF STENT THROMBOSIS
Cutlip et al, Circulation 2007
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DEFINITIONS OF STENT THROMBOSIS
Cutlip et al, Circulation 2007
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TIMING OF STENT THROMBOSIS
Cutlip et al, Circulation 2007