www.metcardio.org 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
Giuseppe Biondi Zoccai, MD Division of Cardiology, University of Turin, Turin, Italy
Jan 31, 2016
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 - PowerPoint PPT Presentation
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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, MDDivision of Cardiology,
University of Turin, Turin, Italy
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Learning goals
• Scope of the problem
• Key definitions and clinical end-points
• Surrogate end-points
• Case studies on SPIRIT III and COMPARE
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Scope of the problem: barriers to credible interaction with ICs
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Scope of the problem - 1: defense
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Scope of the problem - 2: distrust
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Scope of the problem - 3: time
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Your MUST DOs• Identify your message• Identify the type of IC facing you• Tailor your presentation according your message
and the IC facing you• Avoid pitfalls in data presentation/interpretation• Emphasize points that show your knowledge and
credibility while leaving the IC ample margin for interpretation and comment
• Make sure you make good use of definitions and end-points
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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
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Learning goals
• Scope of the problem
• Key definitions and clinical end-points
• Surrogate end-points
• Case studies on SPIRIT III and COMPARE
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Definitions• Definitions may relate or not to end-points
(i.e. clinical events or key biologic variables)• Definitions may be arbitrary (i.e. based on
conventions) or based on scientific data• Key definitions should be well known, but
should not be presented just to show that you are knowledgeable
• Rather, they should support your credibility and reassure the IC that he/she is speaking with a credible peer
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End-points• End-points are key clinical (e.g. death) or
biologic (e.g. ejection fraction) response variables
• End-points are used to appraise whether the study has met its objectives
• Usually only one primary end-point is present per study
• Other (secondary) end-points are commonly reported, but their strength if discordant with the primary one is rather limited
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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
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Academic Research Consortium
Cutlip et al, Circ 2007
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Death
Cutlip et al, Circ 2007
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Myocardial infarction
• Myocardial infarction (i.e. myocardial ischemic necrosis) is a key safety end-point
• However, its impact on prognosis highly depend on the chosen cut-off (e.g. >1 time the upper limit of normal vs. >3 vs. >5)
• Several definitions of spontaneous vs. peri-procedural myocardial infarction are available
• Yet, any infarction leading to creatinine kinase-myocardial/brain (CK-MB) peak levels >5 times the upper limit of normal is considered large
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Myocardial infarction
Thygesen et al, JACC 2007
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Myocardial infarction
Thygesen et al, JACC 2007
www.metcardio.orgThygesen et al, JACC 2007
www.metcardio.orgThygesen et al, JACC 2007
Myocardial infarction
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Target lesion revascularization• Target lesion revascularization (TLR) is a key
efficacy end-point in clinical trials of coronary devices
• It is defined as repeat coronary revascularization involving the previously treated segment or the proximal or distal 5 mm edges
• Its external validity depends a lot on the distinction between clinically driven vs. angiographically driven TLR (where risk of oculostenotic reflex is high)
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Target vessel revascularization
• Target vessel revascularization (TVR) is a key efficacy clinical end-point in trials of coronary devices
• It is defined as any repeat revascularization involving the same vessel which has previously treated at study entry
• It usually includes TLR (thus being composed of TLR and non-TL-TVR)
• It is also prone to inflation due to routine angiographic follow-up
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Repeat revascularization
Cutlip et al, Circ 2007
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Stent thrombosis• Stent thrombosis is a key safety clinical end-
point• Its impact on prognosis is however variable,
depending on patient characteristics (e.g. prior left ventricular ejection fraction), lesion characteristics (e.g. location), and timely treatment
• The Academic Research Consortium has recently enabled a commonly agreed upon set of definitions for stent thrombosis, according to timing and likelihood
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Definite stent thrombosis
Cutlip et al, Circ 2007
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Probable or possible stent thrombosis
Cutlip et al, Circ 2007
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Timing of stent thrombosis
Cutlip et al, Circ 2007
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Target lesion/vessel failure
• Failure events are a rather recent development in coronary stent trials
• Target lesion failure (TLF) is usually defined as a composite end-point of cardiac death, myocardial infarction not clearly attributable to other segments than the target lesion, or TLR
• Target lesion failure (TVF) is usually defined as a composite end-point of cardiac death, myocardial infarction not clearly attributable to other segments than the target vessel, or TVR
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Major adverse cardiac events• Major adverse cardiac events (MACE) are a key
safety clinical end-point in most coronary trials• They are usually defined as the composite of
death, non-fatal myocardial infarction, or TVR• In other cases TLR is included in the definition in
place of TVR• In few cases, stroke is also included, leading to
the composite end-point of major adverse cerebro-cardiovascular events (MACCE)
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Hierarchy in composite end-points• Individual outcomes of composite end-points can
be individually and separately counted or hierarchically counted, depending on the aim of the study
• For instance, the outlook of a patient having a MACE because of fatal myocardial infarction, may be summarized in 2 different ways:– non-hierarchical fashion -> MACE=yes, death=yes,
myocardial infarction=yes– hierarchical fashion -> MACE=yes, death=yes,
myocardial infarction=no
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Patient vs. lesion focus
Cutlip et al, Circ 2007
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Stroke• Stroke is usually considered only a secondary
safety end-point• It is a neurologic event usually due to brain
ischemia or hemorrhage• Stroke can be defined as any permanent
neurologic deficit leading to clinically evident neurologic objective impairment or subjective dysfunction
• Stroke should be distinguished from transient ischemic attack (TIA, lasting <24 h), and reversible ischemic neurologic deficit (RIND, also reversible but lasting >24 h)
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Bleeding
• Bleeding is a key clinical safety end-point in most recent cardiovascular trials
• It is usually distinguished in major/severe (e.g. fatal, life-threatening or requiring surgical intervention), minor/mild (creating substantial impairment but not major/severe), and minimal (neither major/severe or minor/mild)
• Several classifications are available, such as ACUITY, GUSTO, TIMI
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Other events/end-points
• Repeat hospitalizations– For any cause– For angina– For heart failure
• Multiple/recurrent events• Quality of life– EuroQOL– Minnesota Angina Score
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Risk of event inflation
• Systematic angiographic follow-up in asymptomatic patients almost doubles the rate of binary angiographic restenosis and TLR
• As TLR increases due to angio follow-up, similar increases in TVR and MACE
• Thus, any study with routine angiographic follow-up may be considered by the wary IC less reliable and over-optimistic if a clinical difference is found
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Learning goals
• Scope of the problem
• Key definitions and clinical end-points
• Surrogate end-points
• Case studies on SPIRIT III and COMPARE
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Surrogate end-points•A surrogate end-point is an end-point which has
no direct clinical relevance for 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
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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
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Quantitative coronary angiography• Quantitative coronary angiography (QCA)
quantitatively measures coronary features• It helps in the comparison of procedural and
follow-up results of several PCI devices• The most important data gained from QCA
are:– Reference vessel diameter (RVD)– Minimum lumen diameter (MLD)– Diameter stenosis (DS)– Binary angiographic restenosis (BR or BAR)– Late lumen loss (LLL)
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Quantitative coronary angiography
Garrone et al, JIC 2009
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Quantitative coronary angiography
Vermeersch et al, JACC 2006
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Case study: late loss
Biondi-Zoccai et al, EI 2008
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Case study: late loss
Mauri et al, AHA 2005
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Case study: late loss
Agostoni et al, AJC 2006
www.metcardio.orgRivero et al, EI 2008
Case study: late loss
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Intravascular ultrasound
• Intravascular ultrasound (IVUS) is an invasive imaging modality used rather frequently in coronary trials
• IVUS has satisfactory spatial and volumetric resolution (>QCA) and vessel penetration
• It thus can quantitate in-stent hyperplasia and early/late stent apposition
• Typical IVUS-based surrogate end-points include: neointimal area, neointimal volume, neointimal volume area, and neointimal volume thickness
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Intravascular ultrasound
Biondi-Zoccai et al, MCA 2005
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Optical coherence tomography• Optical coherence tomography (OCT) is a
novel invasive imaging method, still rarely used for surrogate imaging end-points in coronary trials
• OCT has superior spatial resolution (>IVUS, >>>QCA), but it has limited penetration capability
• OCT has a role and will play a even greater role in the future to appraise vessel response to drug-eluting stents (but still no endothelial cells)
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Optical coherence tomography
Guagliumi et al, CCI 2008
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Fractional flow reserve
• Fractional flow reserve (FFR) is uncommonly used as a surrogate end-point in clinical trials, but its use might become more frequent
• FFR represents the ratio of blood pressure distal to the target stenosis/aortic blood pressure
• FFR<0.75-0.80 indicates a functionally significant stenosis, irrespective of angiographic severity
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Fractional flow reserve
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Learning goals
• Scope of the problem
• Key definitions and clinical end-points
• Surrogate end-points
• Case studies on SPIRIT III and COMPARE
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The SPIRIT III trial
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The SPIRIT III trial
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The SPIRIT III trial
Don’t forget the importance of adequate randomization!
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The SPIRIT III trial
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The SPIRIT III trial
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The SPIRIT III trial
Primary end-point: in-segment late loss at 240 days
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The SPIRIT III trial
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The SPIRIT III trial
Key scondary end-point: TVF, defined as cardiac death, myocardial infarction, or
ischemia-driven TVR at 270 days
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The SPIRIT III trial
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The SPIRIT III trial
Never emphasize too much subgroup analyses: the IC almost never trust them
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The COMPARE trial
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The COMPARE trial
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The COMPARE trial
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The COMPARE trial
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The COMPARE trial
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The COMPARE trial
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The COMPARE trial
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The COMPARE trial
Primary end-point: composite of all-cause mortality, non-fatal myocardial infarction, and TVR within 12 months
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The COMPARE trial
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The SPIRIT IV trial
still under review
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Other usueful tips and tricks• Emphasize, when the case is appropriate: – randomized vs. non-randomized design– single center vs. multicenter setting– superiority vs. non-inferiority design– company vs. spontaneous/independent funding– selective vs. universal inclusion criteria– short-term vs. long-term follow-up– surrogate (e.g. imaging) vs. clinical primary end-
point– adequate vs. inadequate sample size and power– preliminary presentation vs. full-text publication
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Questions
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Take home messages
• Facts and critical interpretation of them are both important for all interventional cardiologists
• A thorough understanding of key definitions, end-points, clinical outcomes and surrogate end-points is pivotal to effectively communicate with interventional cardiologists
• Thus, study thoroughly educational materials already available to you, and continue to educate yourself and keep updating your knowledge base
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Thank you for your attention
For these and further slides on these topics feel free to visit the metcardio.org website:http://www.metcardio.org/slides.html
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