1. Intravascular Diagnostics: Do They Really Matter?
Sergio Waxman, M.D.
CRT, February 25, 2013
Associate Director, Cardiac Catheterization Lab
Director, Interventional Cardiology Training Program
Director, Interventional Cardiovascular Research
Professor of Medicine, Tufts University School of Medicine

2. Sergio Waxman, MD Consulting: InfraReDx, Inc.
Stocks, Stock Options, other ownership interest: AngioLight

3. Why IVDx Technologies? Known limitations of angiography to define CAD
Diagnostic advantages for adjunct use of IVDx technologies…
Provide physiologic information (e.g., Fractional Flow Reserve [FFR])
Provide structural information such as lumen narrowing, plaque burden, lesion borders, remodeling (e.g., Intravascular ultrasound [IVUS], OCT)
Provide information re. plaque composition such as calcification, LCP, inflammation (e.g. VH-IVUS, OCT, NIRS)
Potential benefits of adjunct use of IVDx technologies…
Optimize treatment based on additional information
Improve patient outcomes
Why should we use IVDx technologies? I don’t need to tell this audience about the limitations of angiography to define CAD, however it is our most commonly used tool. We have heard about the diagnostic advantages of … Nevertheless, the promise of benefit for the extra step of using these devices has not yet been realized, or at least not been proved.

4. Current Paradigm for Diagnosing and Treating CAD
Treatment is the same regardless of plaque morphology or extent of disease and is currently guided by angio”steno”graphy
Stent/DAPT/statin
Area of most severe angiographic stenosis
TCFA
Stable lesion
Ruptured plaque
Diffuse vs focal disease
Let’s review our current paradigm of diagnosing and treating CAD. It is all based on angiostenography regardless of plaque morphology or extent of disease.

5. A New Diagnostic and Therapeutic Paradigm?
Plaque Dx:
- Physiology
- Structure
- Composition =
Lesion Tailored Therapy
Optimize PCI Result
Improve Patient Outcomes
 Costs/  Quality
Yet IVDx are used in <10% of PCI cases
Perhaps we are entering a new paradigm in which plaque information can be used to …
We need to look for evidence that justifies higher use of IVDx

6. Potential Applications of IVDx
Key areas for IVDX studies:
Plaque morphology (VP) [IVUS, OCT, NIRS]
Diagnostic lesion assessment (to treat or not to treat) [FFR, IVUS, OCT, NIRS]
Pre-intervention imaging (planning )[IVUS, OCT, NIRS]
Post-intervention optimization (fine tuning) [FFR, IVUS, OCT]
Complication evaluation [IVUS, OCT]
Restenosis evaluation [IVUS, OCT]
Stent thrombosis evaluation [IVUS, OCT]
Stent coverage [IVUS, OCT]
These are some of the potential applications of IVDx

7. Adoption of IVDX: Finding the Right Application
Cost/Benefit =
Units of benefit/cost
Threshold of acceptance/rejection
Benefit
Cost
Benefit
Cost
Let me share a mental exercise to understand which applications may be worth pursuing first. In this model, we can assess the costs and benefits of using a technology for a certain application
Benefit: Improved Clinical Outcome + Cost Savings
Cost: Risk to patient + Ease of use + Ease of interpretation + $$

8. Adoption of IVDX: Finding the Right Application
Units of benefit/cost
Threshold of acceptance/rejection
Benefit
Cost
Benefit
Cost
Benefit: Improved Clinical Outcome + Cost Savings
Cost: Risk to patient + Ease of use + Ease of interpretation + $$

9. Patients with ACS undergoing PCI
Analytical Framework for Assessing Utility of IVDX in Clinical Practice
Patients with ACS undergoing PCI
These investigators set a framework for assessing utility of using IVDx in addition to angiography and rated the evidence from existing studies to answer a few key questions.
*Therapeutic decision-making outcomes include: 1) Change in the decision if stenting is needed; 2) Change in the number or the type of stents; 3) Change in the decision for reintervention
Modified from:
Raman G, Ip S, et al. IVDx Procedures and Imaging Techniques vs Angiography Alone: A Comparative Effectiveness Review. Draft Document, AHRQ/HHS May 2012

10. Rating the Strength of Evidence of Available Studies for Each Key Question
Strength of evidence based on 4 domains:
- Risk of bias - Directness
- Consistency - Precision
High ●●●
Further research is very unlikely to change the confidence in the estimate of effect.
Moderate ●●○
Further research may change the confidence in the estimate of effect and may change the estimate.
Low ●○○
Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate.
Insufficient ○○○
Evidence either is unavailable or does not permit estimation of an effect.
Rating the Strength of Evidence From the CER
Throughout this slide set, strength of evidence ratings are assigned to findings of the report. Strength of evidence is typically assigned to reviews of medical treatments after assessing four domains: risk of bias, consistency, directness, and precision. Although these categories were developed for assessing the strength of treatment studies, the domains apply also to studies of prevalence and screening. Available evidence for each KQ was assessed for each of these four domains; the domains were combined qualitatively to develop the strength of evidence for each KQ.
Reference:
Uhlig K, Balk EM, Patel K, et al. Self-Measured Blood Pressure Monitoring. Comparative Effectiveness Review No. XX (Prepared by Tufts Evidence-based Practice Center under Contract No. HHSA I). Rockville, MD: Agency for Healthcare Research and Quality; XXXX AHRQ Publication No. XXXXX.
Key words: methods, comparative effectiveness, systematic review, strength of evidence
Alt Text:
The strength of evidence pertaining to each Key Question of the CER is classified into four broad categories or grades:
High: High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect.
Moderate: Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate.
Low: Low confidence that the evidence reflects the true effect. Further research is likely to change our confidence in the estimate of effect and is likely to change the estimate.
Insufficient: Evidence is either unavailable or does not permit estimation of an effect.
Raman G, Ip S, et al. IVDx Procedures and Imaging Techniques vs Angiography Alone: A Comparative Effectiveness Review. Draft Document, AHRQ/HHS May 2012

11. Key Question 1
What is the impact of using IVDx and angiography in deciding whether a coronary lesion requires intervention – when compared to angiography alone
Strength of evidence is moderate that supports the use of FFR + angiography vs. angiography alone (1 RCT and 2 non-randomized studies)
Aids in deciding whether and which lesions to stent
Lower risk of death or myocardial infarction (MI) or Major Adverse Cardiac Events (MACE)
Lower resource utilization in the short-term
Strength of evidence is insufficient for assessing:
Quantitative coronary angiogram and stent-related outcomes
Short-term patient-centered outcomes
Techniques other than FFR
This is an overview and does not cover each outcome.
Raman G, Ip S, et al. IVDx Procedures and Imaging Techniques vs Angiography Alone: A Comparative Effectiveness Review. Draft Document, AHRQ/HHS May 2012

12. Key Question 2
For patients undergoing PCI, what is the impact of using IVDx and angiography to guide stent placement (either immediately prior to or during the procedure)—when compared to angiography alone
Strength of evidence is moderate that supports the use of IVUS + angiography vs. angiography alone (9 RCTs and 17 non-randomized studies)
Decreases target vessel revascularization
Decreases stent restenosis
Aids in optimizing stent placement
Increases short-term resource utilization
No significant difference in mortality, MI and MACE
No significant difference in quantitative coronary angiogram
Strength of evidence is insufficient that supports the use of FFR (1 high-risk of bias non-randomized study)
Strength of evidence is insufficient for all other techniques (no studies)
This is an overview and does not cover each outcome.
Raman G, Ip S, et al. IVDx Procedures and Imaging Techniques vs Angiography Alone: A Comparative Effectiveness Review. Draft Document, AHRQ/HHS May 2012

13. Meta-analyses of Observational and Randomized IVUS Studies During PCI
TV Revascularization –medium term
Myocardial Infarction –medium term
Mortality –medium term

14. Can Use of IVUS During PCI Improve Outcomes? ADAPT-DES IVUS Sub-Study
IVUS Use and Definite/Probable ST at 1 Yr
IVUS Use and Spontaneous MI (not ST) at 1Yr
Witzenbichler B, Maehara A, Weisz G, et al. ADAPT-DES Study, TCT 2012

15. How Did IVUS Change the Procedure?
ADAPT-DES IVUS Sub-Study
Witzenbichler B, Maehara A, Weisz G, et al. ADAPT-DES Study, TCT 2012

16. Can Use of OCT During PCI Improve Outcomes
Can Use of OCT During PCI Improve Outcomes? CLI-OPCI Study: Angio vs Angio+OCT
Findings in OCT-Guided Group
Clinical Results: Angio vs Angio+OCT Groups
Non-randomized, consecutive pts, 1:1 matching with randomly selected pts
OCT Group: Longer stents, more overlapping stents, larger balloons, more DES
OCT use not associated with any major complication
Prati F, et al. CLI-OPCI, EuroInt 2012

17. Key Question 3
For patients having just undergone a PCI, what is the impact of using IVDx and angiography to evaluate the success of stent placement immediately after the procedure—when compared to angiography alone
Strength of evidence is insufficient that examined this comparison
(2 IVUS studies with high risk of bias)
No significant difference in short- or long-term quantitative coronary angiogram results
No significant difference in the incidence of restenosis
Strength of evidence is insufficient for all other techniques
This is an overview and does not cover each outcome.
Raman G, Ip S, et al. IVDx Procedures and Imaging Techniques vs Angiography Alone: A Comparative Effectiveness Review. Draft Document, AHRQ/HHS May 2012

18. How can we adopt IVDx in clinical practice
How can we adopt IVDx in clinical practice? Findings associated with outcomes
Application
FFR
IVUS
OCT
NIRS
Ischemia detection
<0.80
<3-4 mm2
<2 mm2 NA
Deferred PCI
>0.80
Endpoint of stenting
>0.94
>9 mm2 (>6 mm2), full apposition, >80% ref. area
Suboptimal PCI
Stent CSA, edge stenosis (edge lumen CSA <4 mm2, plaque burden >70%), stent expansion <70%
Edge dissection, stent malapposition, underexpansion, thrombus, residual edge stenosis (MLA <4mm2)
LCP at margin of stent
PCI strategy
Dense calcium, necrotic core (VH)
Dense calcium
Circumferential LCP, high LCBI
VP detection (non-culprit disease)
Plaque burden >70%, MLA <4mm2, VH-TCFA
OCT-TCFA
LCP ?
So if the evidence is not there yet, how can we move forward?

19. Key Factors for Adoption of IVDx
Clinical
Useful applications with measurable benefits (associated with specific treatments, improvement in outcomes)
Safety
Technical
Ease of use (plug-and-play systems, miniaturization)
Image interpretation (automated quantitation)
Co-registration with angiogram (integration of information, roadmap)
Financial
Low costs
Reimbursement

20. Summary and Conclusions
Use of IVDx beyond angiography alone provides additional information regarding plaque physiology, morphology, and composition that can potentially impact patient outcomes. However, evidence supporting their routine use is not available. Clinical adoption of IVDx may center around practical applications (helping make the decision to treat with PCI, or to guide and optimize PCI procedures). There is moderate strength evidence that supports use of FFR to make decision to treat a lesion and of IVUS during PCI to improve mid-term outcomes. Evidence gap for all other devices and applications (although new data are emerging from non-RCT’s). Directed RCT’s need to be performed to answer the question of whether IVDx matter beyond angiography alone. The time is ripe… (technologies are mature, pay-for-quality models, evidence-based medicine).

22. Key Question 4
How do different IVDx techniques compare to each other in their effects on therapeutic decision making, intermediate outcomes, and patient- centered outcomes?
Strength of evidence is insufficient that examined this comparison
(1 FFR vs. IVUS non-randomized study with high risk of bias)
No significant difference in MACE at 1 yr
Strength of evidence is insufficient for other techniques (no available studies)
This is an overview and does not cover each outcome.
Raman G, Ip S, et al. IVDx Procedures and Imaging Techniques vs Angiography Alone: A Comparative Effectiveness Review. Draft Document, AHRQ/HHS May 2012

23. Key Question 1 Evidence Gaps Based on the Findings
What is the impact of using IVDx and angiography in deciding whether a coronary lesion requires intervention – when compared to angiography alone
Data on FFR-guided vs. Angiography-only-guided PCI in women and in patients with left main disease and acute MI
FFR data on comparing patients with low angina score given aggressive medical therapy instead of PCI vs. PCI guided by IVDx techniques
FFR data on <30 day outcomes
Comparative studies using other IVDx techniques besides FFR with angiography to address Key Question 1
This is an overview and does not cover each outcome.
Raman G, Ip S, et al. IVDx Procedures and Imaging Techniques vs Angiography Alone: A Comparative Effectiveness Review. Draft Document, AHRQ/HHS May 2012

24. Key Question 2 Evidence Gaps Based on the Findings
For patients undergoing PCI, what is the impact of using IVDx and angiography to guide the stent placement (either immediately prior to or during the procedure)—when compared to angiography alone
More recent data on IVUS comparative studies
Data on the use of newer types of stents deployed using IVUS
Long-term data using IVUS
Comparative data on other IVDx techniques besides IVUS
This is an overview and does not cover each outcome.
Raman G, Ip S, et al. IVDx Procedures and Imaging Techniques vs Angiography Alone: A Comparative Effectiveness Review. Draft Document, AHRQ/HHS May 2012

25. Key Questions 3 and 4 Evidence Gaps Based on the Findings
For patients having just undergone a PCI, what is the impact of using IVDx and angiography to evaluate the success of stent placement immediately after the procedure—when compared to angiography alone
How do different IVDx techniques compare to each other in their effects on therapeutic decision making, intermediate outcomes, and patient- centered outcomes?
Comparative data on all IVDx techniques
This is an overview and does not cover each outcome.
Raman G, Ip S, et al. IVDx Procedures and Imaging Techniques vs Angiography Alone: A Comparative Effectiveness Review. Draft Document, AHRQ/HHS May 2012

26. Key Question 2 (continued)
For patients undergoing PCI, what is the impact of using IVDx and angiography to guide the stent placement (either immediately prior to or during the procedure)—when compared to angiography alone
Strength of evidence is insufficient that supports the use of FFR (1 high-risk of bias non-randomized study)
Favorable changes in minimal lumen diameter and % diameter stenosis
No significant difference in long-term all–cause mortality
Strength of evidence is insufficient for all other techniques (no studies)
This is an overview and does not cover each outcome.
Raman G, Ip S, et al. IVDx Procedures and Imaging Techniques vs Angiography Alone: A Comparative Effectiveness Review. Draft Document, AHRQ/HHS May 2012

27. Impact of IVUS Imaging on Early and Late Outcomes Following PCI With DES: A Sub-Study of the MATRIX Registry
Impact on procedure:
Less predilatation 54% vs 70% p<0.01
More postdilatation 42% vs 34% p<0.01
Larger final stent diam 3.1 mm vs 3.0 mm p<0.01
Claessen BE, Mehran R, Mintz G et al. JACC Intv 2011;4:974-81