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Giuseppe Biondi Zoccai, MD Division of Cardiology, University of Turin, Turin, Italy

What matters in the eyes of interventional cardiologists i.e. tips to effectively analyze data and get credibility in the cardiologist’s eye. Giuseppe Biondi Zoccai, MD Division of Cardiology, University of Turin, Turin, Italy. Learning goals. Scope of the problem

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Giuseppe Biondi Zoccai, MD Division of Cardiology, University of Turin, Turin, Italy

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  1. What matters in the eyes of interventional cardiologists i.e. tips to effectively analyze data and get credibility in the cardiologist’s eye Giuseppe Biondi Zoccai, MD Division of Cardiology, University of Turin, Turin, Italy

  2. Learning goals • Scope of the problem • Key definitions and clinical end-points • Surrogate end-points • Case studies on SPIRIT III and COMPARE

  3. Scope of the problem: barrierstocredibleinteractionwithICs

  4. Scope of the problem - 1: defense

  5. Scope of the problem - 2: distrust

  6. Scope of the problem - 3: time

  7. Your MUST DOs • Identifyyourmessage • Identify the type of IC facingyou • Tailoryourpresentationaccordingyourmessage and the IC facingyou • Avoidpitfalls in data presentation/interpretation • Emphasizepointsthat show yourknowledge and credibilitywhileleaving the IC amplemarginforinterpretation and comment • Makesureyoumakegooduse of definitions and end-points

  8. Your MUST DO NOTs • Forgetting your final goal/message • Reach the IC unprepared and without thorough knowledge of the topic of interest • Switching from topic to topic • Using the same approach with all ICs • Letting the IC dominate you from beginning to end • Patronizing the IC

  9. Learning goals • Scope of the problem • Key definitions and clinical end-points • Surrogate end-points • Case studies on SPIRIT III and COMPARE

  10. Definitions • Definitionsmayrelate or nottoend-points (i.e. clinical events or key biologicvariables) • Definitionsmaybearbitrary (i.e. based on conventions) or based on scientific data • Key definitionsshouldbewellknown, butshouldnotbepresented just to show thatyou are knowledgeable • Rather, theyshouldsupportyourcredibilityand reassure the IC thathe/sheisspeakingwith a crediblepeer

  11. End-points • End-points are key clinical (e.g. death) or biologic (e.g. ejectionfraction) responsevariables • End-points are usedtoappraisewhether the studyhasmetitsobjectives • Usuallyonlyoneprimaryend-pointispresent per study • Other (secondary) end-points are commonlyreported, buttheirstrengthifdiscordantwith the primaryoneisratherlimited

  12. Death • Death is the most important safety end-point • Given its low incidence, only very large studies (>10,000 pts) can appraise changes in death rate • Causes of death can be used to distinguish subtypes: • All cause death • Non-cardiac death • Cardiac death

  13. Academic Research Consortium Cutlip et al, Circ 2007

  14. Death Cutlip et al, Circ 2007

  15. Myocardial infarction • Myocardialinfarction (i.e. myocardialischemicnecrosis) is a key safetyend-point • However, its impact on prognosishighlydepend on the chosencut-off (e.g. >1 time the upper limit of normal vs. >3 vs. >5) • Severaldefinitions of spontaneous vs. peri-proceduralmyocardialinfarction are available • Yet, anyinfarctionleadingto creatinine kinase-myocardial/brain (CK-MB) peaklevels >5 times the upper limit of normalisconsideredlarge

  16. Myocardial infarction Thygesen et al, JACC 2007

  17. Myocardial infarction Thygesen et al, JACC 2007

  18. Thygesen et al, JACC 2007

  19. Myocardial infarction Thygesen et al, JACC 2007

  20. Target lesion revascularization • Target lesionrevascularization (TLR) is a key efficacyend-point in clinical trials of coronarydevices • Itisdefinedasrepeatcoronaryrevascularizationinvolving the previouslytreatedsegmentor the proximal or distal 5 mm edges • Itsexternalvaliditydepends a lot on the distinctionbetweenclinicallydriven vs. angiographically driven TLR (whererisk of oculostenotic reflex is high)

  21. Target vessel revascularization • Target vessel revascularization (TVR) is a key efficacy clinical end-pointin trials of coronarydevices • Itisdefinedasanyrepeatrevascularizationinvolving the same vessel whichhaspreviouslytreated at study entry • Itusuallyincludes TLR (thusbeingcomposed of TLR and non-TL-TVR) • Itisalso prone toinflation due to routine angiographic follow-up

  22. Repeat revascularization Cutlip et al, Circ 2007

  23. Stent thrombosis • Stent thrombosisis a key safety clinical end-point • Its impact on prognosisishowevervariable, depending on patientcharacteristics (e.g. priorleftventricularejectionfraction), lesioncharacteristics (e.g. location), and timelytreatment • The AcademicResearchConsortiumhasrecentlyenabled a commonlyagreedupon set of definitionsfor stent thrombosis, accordingto timing and likelihood

  24. Definite stent thrombosis Cutlip et al, Circ 2007

  25. Probable or possible stent thrombosis Cutlip et al, Circ 2007

  26. Timing of stent thrombosis Cutlip et al, Circ 2007

  27. Target lesion/vessel failure • Failureevents are a ratherrecentdevelopmentin coronary stent trials • Target lesionfailure (TLF) isusuallydefinedas a composite end-point of cardiacdeath, myocardialinfarctionnotclearlyattributabletoothersegmentsthan the target lesion, or TLR • Target lesionfailure (TVF) isusuallydefinedas a composite end-point of cardiacdeath, myocardialinfarctionnotclearlyattributabletoothersegmentsthan the target vessel, or TVR

  28. Major adverse cardiac events • Major adverse cardiacevents (MACE) are a key safety clinical end-pointin mostcoronarytrials • They are usuallydefinedas the composite of death, non-fatalmyocardialinfarction, or TVR • In othercasesTLRisincluded in the definition in place of TVR • In fewcases, strokeisalsoincluded, leadingto the composite end-point of major adverse cerebro-cardiovascularevents (MACCE)

  29. Hierarchy in composite end-points • Individualoutcomes of composite end-points can beindividually and separatelycounted or hierarchicallycounted, depending on the aim of the study • Forinstance, the outlook of a patienthaving a MACE because of fatalmyocardialinfarction, maybesummarized in 2 differentways: • non-hierarchical fashion -> MACE=yes, death=yes, myocardialinfarction=yes • hierarchical fashion -> MACE=yes, death=yes, myocardialinfarction=no

  30. Patient vs. lesion focus Cutlip et al, Circ 2007

  31. Stroke • Strokeisusuallyconsideredonly a secondarysafetyend-point • Itis a neurologiceventusually due tobrain ischemia or hemorrhage • Stroke can bedefinedasanypermanentneurologic deficitleadingtoclinicallyevidentneurologicobjectiveimpairment or subjectivedysfunction • Strokeshouldbedistinguishedfromtransientischemicattack (TIA, lasting <24 h), and reversibleischemicneurologic deficit (RIND, alsoreversiblebutlasting >24 h)

  32. Bleeding • Bleedingis a key clinical safetyend-pointin mostrecentcardiovasculartrials • Itisusuallydistinguished in major/severe (e.g. fatal, life-threatening or requiringsurgicalintervention), minor/mild (creatingsubstantialimpairmentbutnot major/severe), and minimal (neither major/severe or minor/mild) • Severalclassifications are available, suchas ACUITY, GUSTO, TIMI

  33. Other events/end-points • Repeat hospitalizations • For any cause • For angina • For heart failure • Multiple/recurrent events • Quality of life • EuroQOL • Minnesota Angina Score

  34. Risk of event inflation • Systematicangiographic follow-up in asymptomaticpatientsalmostdoubles the rate of binaryangiographic restenosis and TLR • As TLR increases due toangio follow-up, similarincreases in TVR and MACE • Thus, anystudywith routine angiographic follow-up maybeconsideredby the wary IC lessreliable and over-optimisticif a clinical differenceisfound

  35. Learning goals • Scope of the problem • Key definitions and clinical end-points • Surrogate end-points • Case studies on SPIRIT III and COMPARE

  36. Surrogate end-points • A surrogate end-pointisanend-pointwhichhasno direct clinical relevancefor the patient • Its purpose is to predict treatment benefits that would be measured by clinical endpoints, decrease study size/duration, and reduce exposure to ineffective treatments • Examples include blood pressure, cholesterol, HIV viral load, ejection fraction, and late loss • Correlation of surrogates and clinical end-points is not sufficient: treatment differences in the surrogate should be associated with treatment differences in the clinical endpoint

  37. Qualitative coronary angiography • Qualitative coronary angiography uses qualitative/categorical features to describe a coronary lesion • Examples include: • Thrombolysis in Myocardial Infarction flow, • American College of Cardiology/American Heart Association lesion type, • dissection type • extent of calcification

  38. Quantitative coronary angiography • Quantitative coronaryangiography (QCA) quantitativelymeasurescoronaryfeatures • Ithelps in the comparison of procedural and follow-up results of several PCI devices • The mostimportant data gainedfrom QCA are: • Reference vessel diameter (RVD) • Minimum lumen diameter (MLD) • Diameter stenosis (DS) • Binaryangiographic restenosis (BR or BAR) • Late lumen loss (LLL)

  39. Quantitative coronary angiography Garrone et al, JIC 2009

  40. Quantitative coronary angiography Vermeersch et al, JACC 2006

  41. Case study: late loss Biondi-Zoccai et al, EI 2008

  42. Case study: late loss Mauri et al, AHA 2005

  43. Case study: late loss Agostoni et al, AJC 2006

  44. Case study: late loss Rivero et al, EI 2008

  45. Intravascular ultrasound • Intravascular ultrasound (IVUS) isaninvasive imagingmodalityusedratherfrequentlyin coronarytrials • IVUS hassatisfactoryspatial and volumetricresolution(>QCA) and vessel penetration • Itthus can quantitatein-stenthyperplasiaand early/late stent apposition • TypicalIVUS-based surrogate end-points include: neointimal area, neointimal volume, neointimal volume area, and neointimal volume thickness

  46. Intravascular ultrasound Biondi-Zoccai et al, MCA 2005

  47. Optical coherence tomography • Opticalcoherencetomography (OCT) is a novel invasive imagingmethod, stillrarelyusedfor surrogate imagingend-points in coronarytrials • OCT hassuperiorspatialresolution(>IVUS, >>>QCA), butithaslimitedpenetrationcapability • OCT has a role and will play a evengreaterrole in the future toappraise vessel responsetodrug-elutingstents (butstill no endothelialcells)

  48. Optical coherence tomography Guagliumi et al, CCI 2008

  49. Fractional flow reserve • Fractional flow reserve (FFR) isuncommonlyusedas a surrogate end-point in clinical trials, butitsusemightbecome more frequent • FFR represents the ratio of bloodpressuredistalto the target stenosis/aorticbloodpressure • FFR<0.75-0.80indicates a functionallysignificant stenosis, irrespective of angiographicseverity

  50. Fractional flow reserve

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