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Stent thrombosis : the meta-analytic view

Stent thrombosis : the meta-analytic view. Giuseppe Biondi-Zoccai , MD Sapienza University of Rome, Latina, Italy giuseppe.biondizocca@uniroma1.it gbiondizoccai@gmail.com. Why should you listen to me?.

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Stent thrombosis : the meta-analytic view

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  1. Stentthrombosis: the meta-analyticview Giuseppe Biondi-Zoccai, MD Sapienza University of Rome, Latina, Italy giuseppe.biondizocca@uniroma1.it gbiondizoccai@gmail.com

  2. Why should you listen to me? MEDLINE/PubMed queried on July 30, 2014 for “stent AND thrombosis AND (zoccai OR biondi-zoccai)”

  3. Why should you listen to me? MEDLINE/PubMed queried on July 30, 2014 for “meta-analysis AND (zoccai OR biondi-zoccai)”

  4. METCARDIO, since 2003

  5. Network Meta-Analysis: Evidence Synthesis with Mixed Treatment Comparison

  6. Learningmilestones • Scope of the problem • Stentthrombosis • Meta-analysis • Incidence and impact • Predictors • Prevention and treatment

  7. Learningmilestones • Scope of the problem • Stentthrombosis • Meta-analysis • Incidence and impact • Predictors • Prevention and treatment

  8. Flashback to 2006: the death/MI/thrombosis iceberg

  9. Unavoidability of meta-analysis MEDLINE/PubMed queried on July 30, 2014 for “stent AND thrombosis”

  10. Unavoidability of meta-analysis MEDLINE/PubMed queried on July 30, 2014 for “stent AND thrombosis”

  11. Unavoidability of meta-analysis MEDLINE/PubMed queried on July 30, 2014 for “stent AND thrombosis AND meta-analysis”

  12. Learningmilestones • Scope of the problem • Stentthrombosis • Meta-analysis • Incidence and impact • Predictors • Prevention and treatment

  13. Whatisstentthrombosis? Schuchman, New Engl J Med 2006

  14. Unprecedented and unpredictable Guptaet al, J Invasive Cardiol 2004

  15. Failing stents: thrombosis vs restenosis Schuchman, New Engl J Med 2006

  16. Trade-off: thrombosis vs restenosis? Camenzindet al, Circulation 2007

  17. Another clinical conundrum BLEEDING THROMBOSIS

  18. Mechanisms of thrombosis: Virchow's triad BLOOD FLOW VESSEL

  19. Mechanisms of stent thrombosis PATIENT FACTORS LESION FACTORS PROCEDURAL & MEDICAL RX FACTORS

  20. History of stent thrombosis:30-day ratesfrom 1991 to 2006

  21. Whatisstent 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.

  22. Academic Research Consortiumdefinitions • Definite stent thrombosis: • Clinical syndrome (ACS or AMI) • And: • angiographic evidence of thrombus or occlusion • or pathologicevidenceof 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 Cutilipetal, Circulation 2007

  23. Timing of stent thrombosis Cutilipetal, Circulation 2007

  24. Learningmilestones • Scope of the problem • Stentthrombosis • Meta-analysis • Incidence and impact • Predictors • Prevention and treatment

  25. 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

  26. 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

  27. Baby steps of meta-analysis • 1904 - Karl Pearson (UK):correlationbetweeninoculationof vaccine fortyphoidfeverand mortalityacrossapparentlyconflictingstudies. • 1931 – Leonard Tippet (UK):comparisonofdifferencesbetween and withinfarmingtechniqueson agriculturalyieldadjustingfor sample sizeacrossseveralstudies. • 1937 – William Cochran (UK):combinationofeffectsizesacrossdifferentstudiesofmedicaltreatments. • 1970s – Robert Rosenthal and Gene Glass (USA), ArchieCochrane (UK):combinationofeffectsizesacrossdifferentstudiesofeducational, psychological and medicaltreatments. • 1980s – Exponentialdevelopment/useofmeta-analyticmethodsthanksto the availabilityofadvancedscholarlydatabasesand computingsystems.

  28. EBM hierarchy of evidence • N of 1 randomized controlled trial • Systematic reviews of homogeneous randomized trials • Single (large) randomized trial • Systematic review of homogeneous observational studies addressing patient-important outcomes • Single observational study addressing patient-important outcomes • Physiologic studies (eg blood pressure, cardiac output, exercise capacity, bone density, and so forth) • Unsystematic clinical observations GuyattG and Rennie D, Users’ Guide to the MedicalLiterature, 2002

  29. Parallelhierarchyofclinicalresearch Biondi-Zoccaiet al, HSR Proceedings 2011

  30. Minimal glossary • Review: viewpoint on a subjectquotingdifferentprimaryauthors • Qualitative review: deliberatelyavoids a systematicapproach • Systematicreview: deliberatelyuses a systematicapproachtostudysearch, selection, abstraction, appraisal and pooling • Quantitative review: uses quantitative methodstoappraise or synthesize data • Meta-analysis: usesspecificstatisticalmethodsfor data pooling and/or exploratoryanalysis • Individualpatient data meta-analysis: usesspecificstastisticalmethodsfor data pooling or subgroupexplorationexploitingindividualpatient data →Our key goal:systematicreview (± meta-analysis) Biondi-Zoccaiet al, Network Meta-Analysis: EvidenceSynthesiswithMixed Treatment Comparison 2014

  31. Systematic review and meta-analyses • Whatis a systematicreview? • A systematicappraisalof the methodologicalquality, clinicalrelevance and consistencyofpublishedevidence on a specificclinicaltopic in ordertoprovideclearsuggestionsfor a specifichealthcareproblem. • Whatis a meta-analysis? • A quantitative synthesisthat, preserving the identityofindividualstudies, triestoprovidean estimate of the overalleffectofanintervention, exposure, or diagnosticstrategy. Biondi-Zoccaiet al, Network Meta-Analysis: EvidenceSynthesiswithMixed Treatment Comparison 2014

  32. Indirect and network meta-analyses • An adjustedindirectcomparisonmeta-analysisexploit severalrandomizedtrialssharing a common comparatorto generate aninteractionindirecteffectestimate. • Network meta-analyses(alsocalledmixed treatment comparisons) combine estimatesfromdirect and indirectmeta-analysestoprovide more precise effectestimates. Biondi-Zoccaiet al, Network Meta-Analysis: EvidenceSynthesiswithMixed Treatment Comparison 2014

  33. Rationaleofindirect/network meta-analyses OR (A vs C) TREATMENT A TREATMENT C ln ORa-b = ln ORa-c – ln ORb-c OR (A vs B) var (ln ORa-b) = var (ln ORa-c) – var (ln ORb-c) TREATMENT B TREATMENT C OR (B vs C) Biondi-Zoccaiet al, Minerva Cardioangiol 2008

  34. Rationaleofindirect/network meta-analyses Patientsrandomizedto treatment A vs treatment C Patients randomized to treatment B vs treatment C Patients randomized to treatment A vs treatment C Patientsrandomizedto treatment B 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 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) Biondi-Zoccaiet al, Minerva Cardioangiol 2008

  35. Arguably the mostimportantmeta-analysisever…. Antmanet al, JAMA 1992

  36. …showingdiscrepanciesamongevidence and experts

  37. Prosofmeta-analysis • Applicationtoanyclinicalresearchquestion • Systematicsearchesforclinicalevidence • Explicit and standardizedmethodsforsearch and selectionofevidencesources • Thoroughappraisalof the internalvalidityofprimarystudies • Quantitative synthesiswithincreasedstatisticalpower • Increasedexternalvaliditybyappraising the effectofanintervention (exposure) acrossdifferentsettings • Test subgrouphypotheses (egwithpatient-levelreviews) • Exploreclinical and statisticalheterogeneity Lauet al, Lancet 1998

  38. A rathersuccessful pairwise meta-analysisofrandomizedtrials Agostoni et al, J Am Coll Cardiol 2003

  39. Consofmeta-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 LeLorieret al, New Engl J Med 1997; Lauet al, Lancet 1998; Rosen, BMC BMC Health Services Research 2009

  40. Appraising a meta-analysis: AMSTAR Sheaetal, BMC MedResMethodol 2007

  41. Appraising a meta-analysis: AMSTAR Sheaetal, BMC MedResMethodol 2007

  42. Rulesofthumbtoappraise a meta-analysis • The threerulesofthumbto decide whether a meta-analysis can betrusted are: • Were the includedstudiesallbased on properrandomization or wereobservationalestimatesadjustedforconfounders? • Were the includedstudiesclinically and statisticallyhomogeneous? • Are thereat least 100 eventsin anyof the two treatment groupsfor the end-pointof interest?

  43. Learningmilestones • Scope of the problem • Stentthrombosis • Meta-analysis • Incidence and impact • Predictors • Prevention and treatment

  44. Incidence of stent thrombosis Bangalore et al, Circulation 2012

  45. Incidence of stent thrombosis* *median rate (per 1000 patient-yearsof follow-up): a 9.85 per 1000 patient-years rate equals a 0.985% yearlyincidence Bangalore et al, Circulation 2012

  46. Comprehensivesystematicreview on incidence and predictorsofstentthrombosis • D’Ascenzoet al, Int J Cardiol 2013

  47. Incidenceofstentthrombosis* *ata medianfolllow-upof22 months, with 95% DES penetration D’Ascenzoet al, Int J Cardiol 2013

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