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

What matters in the eyes of ICs i.e. tips to analyze in an effective and impactful way data and to get credibility in the IC’s eyesi.e. tips to effectively analyze
data and get credibility in
the cardiologist’s eye
Giuseppe Biondi Zoccai, MD
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Surrogate end-points
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Scope of the problem: barriers to credible interaction with ICs
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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
Surrogate end-points
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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
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Death
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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
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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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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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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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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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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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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Surrogate end-points
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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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Examples include:
American College of Cardiology/American Heart Association lesion type,
dissection type
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)
Late lumen loss (LLL)
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Case study: late loss
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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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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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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Surrogate end-points
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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
Never emphasize too much subgroup analyses: the IC almost never trust them
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Emphasize, when the case is appropriate:
randomized vs. non-randomized design
superiority vs. non-inferiority design
company vs. spontaneous/independent funding
short-term vs. long-term follow-up
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
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