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Giuseppe Biondi-Zoccai, MDSapienza University of Rome, Latina, Italy
[email protected]@gmail.com
Stent thrombosis: the meta-analytic view
Why should you listen to me?
MEDLINE/PubMed queried on July 30, 2014 for “stent AND thrombosis AND (zoccai OR biondi-zoccai)”
Why should you listen to me?
MEDLINE/PubMed queried on July 30, 2014 for “meta-analysis AND (zoccai OR biondi-zoccai)”
METCARDIO, since 2003
Network Meta-Analysis: Evidence Synthesis with Mixed Treatment Comparison
Learning milestones
• Scope of the problem• Stent thrombosis• Meta-analysis• Incidence and impact• Predictors• Prevention and treatment
Learning milestones
• Scope of the problem• Stent thrombosis• Meta-analysis• Incidence and impact• Predictors• Prevention and treatment
Flashback to 2006: the death/MI/thrombosis iceberg
Unavoidability of meta-analysis
MEDLINE/PubMed queried on July 30, 2014 for “stent AND thrombosis”
Unavoidability of meta-analysis
MEDLINE/PubMed queried on July 30, 2014 for “stent AND thrombosis”
Unavoidability of meta-analysis
MEDLINE/PubMed queried on July 30, 2014 for “stent AND thrombosis AND meta-analysis”
Learning milestones
• Scope of the problem• Stent thrombosis• Meta-analysis• Incidence and impact• Predictors• Prevention and treatment
What is stent thrombosis?
Schuchman, New Engl J Med 2006
Unprecedented and unpredictable
Gupta et al, J Invasive Cardiol 2004
Failing stents: thrombosis vs restenosis
Schuchman, New Engl J Med 2006
Camenzind et al, Circulation 2007
Trade-off: thrombosis vs restenosis?
Another clinical conundrum
BLEEDING
THROMBOSIS
Mechanisms of thrombosis: Virchow's triad
BLOOD FLOW
VESSEL
Mechanisms of stent thrombosis
PATIENT FACTORS
LESION FACTORS
PROCEDURAL & MEDICAL
RX FACTORS
History of stent thrombosis:30-day rates from 1991 to 2006
16
3,51,4 0,8 0,6 1,5 0,9 1,6 1
02468
1012141618
PS - 1991 STRESS -1995
Colombo -1995
ISAR -1996
STARS -1997
Moussa -1999
Cutlip -2001
Wenaweser - 2005
Moreno -2006
Acu
te a
nd s
ubac
ute
sten
t th
rom
bosi
s (%
)
What is stent thrombosis?• Acute occlusion of a previously patent stent.• It is a clinical syndrome (it presents with acute
coronary syndrome or sudden death – if silent it cannot be defined stent thrombosis).
• It is not due to restenosis (i.e. there was no progressively severe restenosis with final occlusion).
• It is not due to new plaque rupture at distant site, but it may be mistaken with in-stent neo-atherosclerosis and thrombosis.
Academic Research Consortium definitions• Definite stent thrombosis:
– Clinical syndrome (ACS or AMI)– And:
• angiographic evidence of thrombus or occlusion• or pathologic evidence of acute thrombosis
• Probable stent thrombosis:– Unexplained death < 30 days– or target vessel AMI without angiographic confirmation of
thrombosis or other identified culprit lesion
• Possible stent thrombosis:– Unexplained death after 30 days
Cutilip et al, Circulation 2007
Timing of stent thrombosis
Type Occurrence* IncidenceAcute ST† ≤1 day +Subacute
ST† 2-30 days +++
Late ST 2-12 months ++Very late
ST>1 year ++
*after PCI†defined together as early STCutilip et al, Circulation 2007
Learning milestones
• Scope of the problem• Stent thrombosis• Meta-analysis• Incidence and impact• Predictors• Prevention and treatment
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
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
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 educational, psychological and medical treatments.
• 1980s – Exponential development/use of meta-analytic methods thanks to the availability of advanced scholarly databases and computing systems.
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 observations
Guyatt G and Rennie D, Users’ Guide to the Medical Literature, 2002
Parallel hierarchy of clinical research
Biondi-Zoccai et al, HSR Proceedings 2011
Minimal glossary• Review: viewpoint on a subject quoting different primary authors
• 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 key goal: systematic review (± meta-analysis)
Biondi-Zoccai et al, Network Meta-Analysis: Evidence Synthesis with Mixed Treatment Comparison 2014
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.
Biondi-Zoccai et al, Network Meta-Analysis: Evidence Synthesis with Mixed Treatment Comparison 2014
Indirect and network meta-analyses
• An adjusted indirect comparison meta-analysis exploit several randomized trials sharing a common comparator to generate an interaction indirect effect estimate.
• Network meta-analyses (also called mixed treatment comparisons) combine estimates from direct and indirect meta-analyses to provide more precise effect estimates.
Biondi-Zoccai et al, Network Meta-Analysis: Evidence Synthesis with Mixed Treatment Comparison 2014
Biondi-Zoccai et al, Minerva Cardioangiol 2008
TREATMENT A
TREATMENT B
TREATMENT C
TREATMENT C
OR (A vs C)
OR (B vs C)
OR (A vs B)
ln ORa-b = ln ORa-c – ln ORb-c
var (ln ORa-b) = var (ln ORa-c) – var (ln ORb-c)
Rationale of indirect/network meta-analyses
Patients
randomized
to
treatment B
vs
treatment C
Patients
randomized
to
treatment A
vs
treatment C
Small theoretical overlap between patients
randomized to A vs C and to B vs C
↓UNADJUSTED INDIRECT META-ANALYSIS
OF A VS B LIKELY UNRELIABLE
(multivariable methods recommended)
Patients
randomized
to
treatment A
vs
treatment C
Large theoretical overlap between patients
randomized to A vs C and to B vs C
↓
UNADJUSTED INDIRECT META-ANALYSIS
OF A VS B LIKELY RELIABLE
Patients
randomized
to
treatment B
vs
treatment C
Rationale of indirect/network meta-analyses
Biondi-Zoccai et al, Minerva Cardioangiol 2008
Arguably the most important meta-analysis ever….
Antman et al, JAMA 1992
…showing discrepancies among evidence and experts
Pros of meta-analysis• 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
A rather successful pairwise meta-analysis of randomized trials
Agostoni et al, J Am Coll Cardiol 2003
Cons of meta-analysis• 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 bias
LeLorier et al, New Engl J Med 1997; Lau et al, Lancet 1998; Rosen, BMC BMC Health Services Research 2009
Appraising a meta-analysis: AMSTAR
Shea et al, BMC Med Res Methodol 2007
Shea et al, BMC Med Res Methodol 2007
Appraising a meta-analysis: AMSTAR
Rules of thumb to appraise a meta-analysis
• The three rules of thumb to decide whether a
meta-analysis can be trusted are:
– Were the included studies all based on proper
randomization or were observational estimates
adjusted for confounders?
– Were the included studies clinically and
statistically homogeneous?
– Are there at least 100 events in any of the two
treatment groups for the end-point of interest?
Learning milestones
• Scope of the problem• Stent thrombosis• Meta-analysis• Incidence and impact• Predictors• Prevention and treatment
Incidence of stent thrombosis
Bangalore et al, Circulation 2012
Incidence of stent thrombosis*
*median rate (per 1000 patient-years of follow-up): a 9.85 per 1000 patient-years rate equals a 0.985% yearly incidence
Bangalore et al, Circulation 2012
Comprehensive systematic review on incidence and predictors of stent thrombosis
D’Ascenzo et al, Int J Cardiol 2013
Incidence of stent thrombosis*
*at a median folllow-up of 22 months, with 95% DES penetration
D’Ascenzo et al, Int J Cardiol 2013
Incidence of DES thrombosis*
*at a median folllow-up of 22 months
D’Ascenzo et al, Int J Cardiol 2013
Prognosis of definite stent thrombosis
Kohn et al, PLoS ONE 2013
Prognosis of definite stent thrombosis
Kohn et al, PLoS ONE 2013
Learning milestones
• Scope of the problem• Stent thrombosis• Meta-analysis• Incidence and impact• Predictors• Prevention and treatment
Impact of diabetes mellitus (DM)
Qin et al, PLoS ONE 2013
Impact of stent length
Moreno et al, J Am Coll Cardiol 2005
Impact of CYP2C19 polymorphism in those receiving clopidogrel
Qin et al, PLoS ONE 2013
Most common predictors of definite or probable stent thrombosis*
• appraised in ≥5 studies and proven independently and significantly associated with ST in ≥50% cohorts; ATD=antiplatelet therapy discontinuation
D’Ascenzo et al, Int J Cardiol 2013
Most powerful predictors of definite or probable stent thrombosis*
*associated with a relative estimate of risk >5.0 or <0.2 for stent thrombosis
D’Ascenzo et al, Int J Cardiol 2013
Synthesis of predictors* of stent thrombosis
*predictors present in ≥10% of included studies
D’Ascenzo et al, Int J Cardiol 2013
Learning milestones
• Scope of the problem• Stent thrombosis• Meta-analysis• Incidence and impact• Predictors• Prevention and treatment
Impact of bivalirudin
Nairooz et al, Am J Cardiol 2014
Impact of prolonged DAPT
Liu et al, J Cardiovasc Pharmacol 2014
Benefits of high-dose clopidogrel
Chen et al, PLoS ONE 2013
Impact of cilostazol
Zhou et al, Exp Ther Med 2013
DAT=dual antiplatelet therapy; TAT=triple antiplatelet therapy
Impact of novel antiplatelet agents
Biondi-Zoccai et al, Int J Cardiol 2011
Impact of novel antiplatelet agents
Biondi-Zoccai et al, Int J Cardiol 2011
Impact of oral anticoagulants
Saheb et al, Chin Med J (Engl) 2013
DAPT=dual antiplatelet therapy; TT=triple antiplatelet therapy (including oral anticoagulant)
Impact of novel oral anticoagulants
Komocsi et al, Arch Intern Med 2012
Benefits of intravascular ultrasound
Ahn et al, Am J Cardiol 2014
Impact of drug-eluting balloons
Frolich et al, BMC Medicine 2013
Impact of complex bifurcation stenting
Zimarino et al, J Am Coll Cardiol Intv 2013
Superiority of EES vs other DES and BMS
Palmerini et al, Lancet 2012
Review 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 RCTs meeting criteria
Palmerini et al, Lancet 2012
Evidence network9 studies
PESBMS
SESEnd-ZES
Res-ZES PtCr-EES
CoCr-EES
1 study
8 studies1 st
udy
4 studies 9 studies
6 studies
6 studies
2 st
udies
2 studies 5 st
udie
s
Palmerini et al, Lancet 2012
1-year definite stent thrombosis
Odds Ratio[95%]
CoCr-EES vs BMS
CoCr-EES vs PES
CoCr-EES vs SES
CoCr-EES vs Res-ZES
CoCr-EES vs End-ZES
SES vs BMS
End-ZES vs SES
0.23 (0.13-0.41)
0.28 (0.16-0.48)
0.41 (0.24-0.70)
0.14 (0.03-0.47)
0.21 (0.10-0.44)
0.57 (0.36-0.88)
1.92 (1.07-3.90)
Favors Stent 1 Favors Stent 2
1010.10.01
Palmerini et al, Lancet 2012
30-day definite stent thrombosis
Odds Ratio [95%]CoCr-EES vs BMSCoCr-EES vs PESCoCr-EES vs SESCoCr-EES vs End-ZESCoCr-EES vs Res-ZESPtCr-EES vs BMSPtCr-EES vs PESPtCr-EES vs End-ZESPtCr-EES vs Res-ZESSES 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
Palmerini et al, Lancet 2012
Statistical consistency
IV = inverse varianceSE = 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
Palmerini et al, Lancet 2012
What about death or MI?
• CoCr-EES were also associated with a significantly lower risk of myocardial infarction (OR=0.61 [0.47-0.79]).
• These differences were supported by favorable trends for all cause death (OR=0.83 [0.65-1.03]) and cardiac death (OR=0.82 [0.58-1.13]).
Palmerini et al, Lancet 2012
Superiority of EES in STEMI as well
Palmerini et al, J Am Coll Cardiol 2013
Superiority of EES vs BES as well
Palmerini et al, J Am Coll Cardiol 2014
Take home messages
Take home messages• Stent thrombosis is a very important event, despite its
slowly decreasing incidence.• Meta-analysis represents a unique tool to navigate the
scholarly literature maze on stent thrombosis.• The meta-analytic take at stent thrombosis suggests that
several patient, lesion, and treatment predictors of stent thrombosis can be envisioned, which may have only limited individual precision, but still hold true at a more collective level.
• We anticipate that stent thrombosis will become again important in the approaching bioresorbable vascular scaffold era.
• Accordingly, researchers and clinicians must all remain aware of the subtleties of stent thrombosis.
Many thanks for your attention!
For any query:[email protected]
For these slides:http://www.metcardio.org/ppts
/2014/Biondi-Zoccai_VCU_2014_Stent_thrombosis.pptx
For similar slides:http://www.metcardio.org/slides.html