giuseppe biondi-zoccai, md sapienza university of rome, latina, italy...

Giuseppe Biondi-Zoccai, MDSapienza University of Rome, Latina, Italy

giuseppe.biondizocca@uniroma1.itgbiondizoccai@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:giuseppe.biondizoccai@uniroma1.it

gbiondizoccai@gmail.com

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