www.metcardio.org stent thrombosis: evidence from a network meta-analysis giuseppe biondi zoccai, md...
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Stent thrombosis: Stent thrombosis: evidence from a evidence from a
network meta-analysisnetwork meta-analysis
Giuseppe Biondi Zoccai, MDGiuseppe Biondi Zoccai, MDDepartment of Medico-Surgical Sciences and BiotechnologiesDepartment of Medico-Surgical Sciences and Biotechnologies
Sapienza University of RomeSapienza University of [email protected]@gmail.com
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LEARNING GOALS
• What is stent thrombosis (ST)?
• What are network meta-analyses (NMA)?
• NMA of ST– Goals
– Methods
– Results
– Implications
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LEARNING GOALS
• What is stent thrombosis (ST)?
• What are network meta-analyses (NMA)?
• NMA of ST– Goals
– Methods
– Results
– Implications
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WHAT IS STENT THROMBOSIS
D’Ascenzo et al, submitted
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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
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total acute subacute late very late
INCIDENCE OF DES THROMBOSIS
D’Ascenzo et al, Int J Cardiol 2012
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PREDICTORS OF STENT THROMBOSIS
D’Ascenzo et al, Int J Cardiol 2011
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IMPACT OF STENT THROMBOSIS
Chechi et al, J Am Coll Cardiol 2008
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LEARNING GOALS
• What is stent thrombosis (ST)?
• What are network meta-analyses (NMA)?
• NMA of ST– Goals
– Methods
– Results
– Implications
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FAMOUS QUOTES
“If I have seen further it is by standing on the shoulders of giants” Isaac Newton
“The great advances in science usually result from new tools rather than from new doctrines” Freeman Dyson
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FAMOUS QUOTES“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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BABY STEPS OF META-ANALYSIS• 1904 - Karl Pearson (UK): correlation between inoculation of
vaccine for typhoid fever and mortality across apparently conflicting studies
• 1931 – Leonard Tippet (UK): comparison of differences between and within farming techniques on agricultural yield adjusting for sample size across several studies
• 1937 – William Cochran (UK): combination of effect sizes across different studies of medical treatments
• 1970s – Robert Rosenthal and Gene Glass (USA), Archie Cochrane (UK): combination of effect sizes across different studies of, respectively, educational and psychological treatments
• 1980s – exponential development/use of meta-analytic methods
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MINIMAL GLOSSARY• Review: viewpoint on a subject quoting different primary authors
• Overview: as above
• Qualitative review: deliberately avoids a systematic approach
• Systematic review: deliberately uses a systematic approach to study
search, selection, abstraction, appraisal and pooling
• Quantitative review: uses quantitative methods to appraise or synthesize
data
• Meta-analysis: uses specific statistical methods for data pooling and/or
exploratory analysis
• Individual patient data meta-analysis: uses specific stastistical
methods for data pooling or subgroup exploration exploiting individual patient data
→ Our focus: systematic review + meta-analysis
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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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EBM HIERARCHY OF EVIDENCE1. N of 1 randomized controlled trial
2. Systematic reviews of homogeneous randomized trials
3. Single (large) randomized trial
4. Systematic review of homogeneous observational studies addressing patient-important outcomes
5. Single observational study addressing patient-important outcomes
6. Physiologic studies (eg blood pressure, cardiac output, exercise capacity, bone density, and so forth)
7. Unsystematic clinical observationsGuyatt and Rennie, Users’ guide to the medical literature, 2002
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PROS• Application to any clinical research question
• Systematic searches for clinical evidence
• Explicit and standardized methods for search and selection
of evidence sources
• Thorough appraisal of the internal validity of primary studies
• Quantitative synthesis with increased statistical power
• Increased external validity by appraising the effect of an
intervention (exposure) across different settings
• Test subgroup hypotheses (eg with patient-level reviews)
• Explore clinical and statistical heterogeneity
Lau et al, Lancet 1998
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REASONS FOR META-ANALYSIS FAILURE
• Duplicate efforts may lead to discordant results
• Funding or conflicts of interest may bias
• Studies/events might not be found
• Studies may be of low quality/internal validity
• Studies may be heterogeneous/inconsistent, ie “mixing
apples with oranges” provides unreal fruits
• Studies may not be relevant to current individual practice
• Selection based on publication may bias
• Analysis with highly sensitive but unrobust tests may biasLeLorier et al, New Engl J Med 1997; Lau et al, Lancet 1998;
Rosen, BMC BMC Health Services Research 2009
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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
www.metcardio.orgHsia et al, Ann Surg 2008
P for effect
Incosistency
P for heterogeneity
STANDARD (PAIR-WISE) META-ANALYSES
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INDIRECT AND NETWORKMETA-ANALYSES
Biondi-Zoccai et al, HSR Proceedings 2011
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PARALLEL HIERARCHY OF CLINICAL RESEARCH
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LEARNING GOALS
• What is stent thrombosis (ST)?
• What are network meta-analyses (NMA)?
• NMA of ST– Goals
– Methods
– Results
– Implications
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NETWORK META-ANALYSIS (NMA) OF STENT THROMBOSIS (ST)
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NMA OF ST: BACKGROUND
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NMA OF ST: GOALS
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LEARNING GOALS
• What is stent thrombosis (ST)?
• What are network meta-analyses (NMA)?
• NMA of ST– Goals
– Methods
– Results
– Implications
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NMA OF ST: DESIGN
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NMA OF ST: DESIGN
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NMA OF ST: SEARCH AND SELECTION
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NMA OF ST: ANALYSIS
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NMA OF ST: ANALYSIS
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LEARNING GOALS
• What is stent thrombosis (ST)?
• What are network meta-analyses (NMA)?
• NMA of ST– Goals
– Methods
– Results
– Implications
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NMA OF ST: PROFILE
FDAapproved
stents(BMS, SES, PES, End-ZES, Res-ZES, CoCr-EES, PtCr-EES)
49 RCTs
50,844 pts
2602 potentially relevant articles
2441 excluded2117 not a comparison of DES324 post-hoc, subgroup, follow-up, or pooled analyses
Review of titleand abstract
161 articles needing full review
112 excluded84 not an RCT13 DES not FDA approved11 no ARC definition4 DES pooled
Full-textreview
49 articles meeting criteria
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NMA OF ST: NETWORK9 studies9 studies
PESPESBMSBMS
SESSESEnd-ZESEnd-ZES
Res-ZESRes-ZES Pt-Cr-EESPt-Cr-EES
CoCr-EESCoCr-EES
1 study
1 study
8 studies
8 studies1 st
udy
1 st
udy
4 studies
4 studies 9 studies
9 studies
6 studies6 studies
6 studies6 studies
2 st
udies
2 st
udies
2 studies
2 studies 5 st
udie
s
5 st
udie
s
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NMA OF ST: RESULTS
Odds Ratio [95%]30-day definite stent thrombosis
CoCr-EES vs BMS
CoCr-EES vs PES
CoCr-EES vs SES
CoCr-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)
Favors Stent 1
1010.10.01
Favors Stent 2
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NMA OF ST: RESULTS
Odds Ratio[95%]30d – 1yr definite stent thrombosis
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 (1.11-18.54)
Favors Stent 1
1001010.10.01
Favors Stent 2
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NMA OF ST: RESULTS
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NMA OF ST: RESULTS
Odds Ratio [95%]2-year definite stent thrombosis
CoCr-EES vs BMS
CoCr-EES vs PES
0.35 (0.17-0.69)
0.34 (0.19-0.62)
Favors Stent 1
1010.10.01
Favors Stent 2
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NMA OF ST: RESULTS
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NMA OF ST: RESULTS
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NMA OF ST: RESULTS
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NMA OF ST: RESULTS
IV = inverse varianceIV = inverse varianceSE = standard errorSE = standard error
Odds Ratio IVRandom, 95% CI
1010.10.001
Favors CoCr-EESFavors BMS
WeightSELog (odds ratio)
Definite stent thrombosisDirect estimateIndirect estimateTotal (95% CI)Test for overall effect Z=4.82 (p<0.00001)
Definite or probable thrombosisDirect estimateIndirect estimateTotal (95% CI)Test for overall effect Z=4.48 (p<0.00001)
-1.427-1.421
-0.968-1.122
0.5190.359
0.3770.304
32.4%67.6%
100.00%
39.4%60.6%
100.00%
0.24 (0.09-0.66)0.24 (0.12-0.49)0.24 (0.14-0.43)
0.38 (0.18-0.80)0.33 (0.18-0.53)0.35 (0.22-0.55)
Statistical inconsistency (I2): 0% for both comparisons
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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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LEARNING GOALS
• What is stent thrombosis (ST)?
• What are network meta-analyses (NMA)?
• NMA of ST– Goals
– Methods
– Results
– Implications
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IMPLICATIONS• The largest and most comprehensive study
comparing the rates of ARC definite and definite or probable stent thrombosis between different types of DES and between DES and BMS has the following implications:– CoCr-EES were associated with significantly
lower rates of 1-year and 2-year definite stent thrombosis than were BMS, a result not present with other DES.
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IMPLICATIONS– The reduction in stent thrombosis with
CoCr-EES compared with BMS was apparent both early and late (occurring before 30 days and between 31 days and 1 year).
– CoCr-EES were also associated with significantly lower 1-year rates of definite stent thrombosis than were other first and second generation DES, including PES, SES, PC-ZES, and Re-ZES.
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IS THIS A PARADIGM SHIFT?
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THE REPLY IS YOURS…
IF YOU NEEDED A STENT TODAY, WHICH STENT WOULD YOU CHOOSE?
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