1 Justin Davies, MBBS, PhD Interventional Cardiologist Hammersmith Hospital, Imperial College London CRT, 2017
2 Disclosure Statement of Financial InterestWithin the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Company Grant/Research Support Consulting Fees/Honoraria Royalty Income Intellectual Property Rights Volcano Philips
3 Ongoing studies using iFR and FFRStudy Countries Patients Endpoint summary Status SYNTAX II1 The Netherlands, Poland, Spain, United Kingdom, Latvia 451 PCI with modern DES in 3VD—applying SYNTAX score II, iFR®/FFR and IVUS guidance to optimize DES Complete PROSPECT II2 Sweden, Denmark, Norway 900 IVUS & NIRS (blinded) performed in culprit vessel(s) Successful PCI of all intended lesions by angiogram and FFR/iFR® Recruiting MITNEC3 Canada 450 Diagnostic yield of non-invasive tests vs FFR Performance of iFR® vs FFR vs non-invasive tests ORBITA4 UK Estimated enrollment 200 Impact of PCI on QoL metrics vs OMT alone Ability of ‘Functional Gain’ to predict QoL gains J-DEFINE5 Japan Estimated enrollment 500 Practical use and events using ‘hybrid’ iFR®/FFR Mismatch of non-invasive and angio w/ FFR/ IFR® Active, but not recruiting DEFINE-FLAIR6 Europe, Asia, North America, Africa Estimated enrollment 2500 Non-inferiority of iFR® vs FFR (stable, UA, ACS) Safety deferral of non-culprit during primary PCI Awaiting results Q1 2017 iFR SWEDEHEART7 Denmark, Iceland, Sweden Estimated enrollment 2000 Predictive value of post-PCI iFR on outcomes DEFINE FLOW8 Netherlands Estimated enrollment 450 Natural history of physiology (pressure and flow) Outcomes of CFR and FFR quadrants (MACE) Enrolling by invitation only DEFINE Dx9 US, EU 2000 Appropriateness of patients with high risk factors to bypass nuclear and proceed to cath w/FFR Protocol development DEFINE PAD9 US 300 Ability of FFR to predict event rates following PAD stenting and atherectomy 10 prospective studies including >10,000 patients enrolling with iFR There is already 5000 patients enrolled in DEFINE-FLAIR, iFR-SWEDEHEART, and SYNTAX II 1. SYNTAX II. Accessed December ; 2. PROSPECT II, available at: https://clinicaltrials.gov/ct2/show/NCT Accessed December 8, 2016; 3. MITNEC. https://clinicaltrials.gov/ct2/show/NCT Accessed December 8, 2016; 4. ORBITA. https://clinicaltrials.gov/ct2/show/NCT Accessed December 2016; 5. J-DEFINE. https://clinicaltrials.gov/ct2/show/NCT Accessed December 8, 2016; 6. DEFINE-FLAIR. https://clinicaltrials.gov/ct2/show/NCT ?term=DEFINE+FLAIR&rank=1. December 8, 2016; 7. iFR SWEDEHEART. https://clinicaltrials.gov/ct2/show/NCT ?term=ifr+swedeheart&rank=1. Accessed December 8, 2016; 8. DEFINE FLOW. https://clinicaltrials.gov/ct2/show/NCT ?term=define+flow&rank=1. Accessed December 8, 2016; 9. Philips data on file
4 iFR modality Definition:Instantaneous pressure ratio, across a stenosis during the wave-free period, when resistance is naturally constant and minimised in the cardiac cycle 120 Pressure (mm Hg) 300 400 700 800 Time (ms) 200 100 70 500 600 900 Pa Pd Wave-free period This shows the phase in the cardiac cycle, in diastole where the heart has stopped contracting and relaxing and the aorta has been stretched open as more blood has moved into it than can move out during systole. The aorta recoils and you have passive perfusion down the coronary artery so it’s a good time to look at the physiology in the artery and the relationship between pressure and flow across the stenosis as the measurement is stable because the heart is not contracting or relaxing at any given time. iFR, instant wave-free ratio
5 Potential benefits of using iFRImprove patient experience1,2 Avoid off-label use of adenosine in USA Time savings 1 Costs savings 1 Avoid rare but serious complications 1 Under assessment in (1) DEFINE-FLAIR, (2) iFR-SwedeHeart studies
6 iFR provides simple and easy co-registration of physiology with anatomy
7 Translating iFR from a research tool into clinical practiceEvidence against the ‘gold standard’ Commercially available All of these components are needed to bring a research tool into clinical practice. It needs to safe and easily adopted into cath labs. Safe and cost-effective Clinical outcomes
8 What we know about iFR: Vasodilators do not improve physiological diagnostic accuracyHere you can see a comparison of the accuracy of FFR (with adenosine) and iFR (without adenosine) using various reference standards in five different studies. Up until the first study (CLARIFY – this is covered later on in the day), it was believed that you could only obtain a very accurate reading during hyperaemia, but CLARIFY showed that this was not true. All five of these studies show that there is no significant clinical disadvantage in using iFR versus FFR and in some cases iFR is significantly better than FFR. CFR, Coronary Flow Reserve; HSR, Hyperaemic Stenosis Resistance; ROC, receiver-operating characteristic; PET, positron emission tomography; SPECT, single-photon emission computed tomography 4. Sen S et al. J Am Coll Cardiol. 2013;62:566; 5. Petraco R et al. Circ. Int. 2014;7: ; 6. de Waard G et al. J Am Coll Cardiol. 2014;63:A1692. 1. Van de Hoef TP et al. Circ Cardiovasc Interv. 2012;5:508-14; 2. Sen S et al. J Am Coll Cardiol. 2013;61: ; 3. Van de Hoef TP et al. EuroIntervention. 2015;11:914-25;
9 Why are we still using adenosine for physiological assessment?
10 Adenosine, a significant barrier to FFR adoption“If only adenosine were not so : difficult to mix, costly, time consuming, uncomfortable for the patient, and (rarely) potentially dangerous…. FFR would be easier to perform and therefore would be used more often” M Kern, On the search for an “easy” FFR: Submaximal hyperemia and NTG-induced translesional pressure drop (Pd/Pa-NTG), Cathet. Cardiovasc. Intervent. February 1, 2016
11 Leadership Team Javier Escaned Co-Principal InvestigatorClinico San Carlos, Madrid Justin Davies Co-Principal Investigator Imperial College, London
12 Leadership Team Patrick Serruys Manesh Patel Co-Chairman Co-ChairmanImperial College, London Manesh Patel Co-Chairman DCRI, Duke
13 DEFINE-FLAIR: Study designFFR >0.8 Defer PCI FFR ≤0.8 Perform PCI FFR-guided PCI iFR ≤0.89 iFR >0.89 Intermediate lesion requiring physiological assessment In ACS : intermediate non-culprit lesion N=2500, 1:1 Randomisation iFR-guided PCI 30 day, 1-, 2- and 5-year follow-up Primary endpoint to be reported at 1-year Key trial information Investigator-initiated and -led study 49 sites across 17 countries Estimated enrollment: up to 2500 Follow-up: 5 years Status: Completed enrolment Primary endpoint completion: Dec 2016 Primary Results: March 2017 Narrowing of coronary arteries interferes with blood flow and can cause chest pain. But patients may have more than one narrowing and studies have shown that not all narrowings need to be treated. To identify the narrowings that need treating cardiologists sometimes quantify the extent of the narrowing by measuring FFR, the ratio of the pressure in the aorta to the pressure downstream of the narrowing. This technique requires the administration of drugs that add cost and time to the procedure and in some countries are simply unavailable. As a result despite the clear health and healthcare costs benefits of FFR its use is limited to less than 5% of procedure. We have developed a new technique called the instantaneous wave-free ratio (iFR) that does not require the administration of drugs for its accurate assessment. It has been approved for use in this indication. This is the first physiology study that is truly global and the study design is very rigorous. Patients in the study arms only undergo either FFR or iFR, not both procedures to prevent inadvertent bias in the study. So far, clinicians involved in the study have adhered to the protocol very well. DEFINE FLAIR. https://clinicaltrials.gov/ct2/show/NCT Accessed December 8, 2016.
14 Global Reach of DEFINE-FLAIR17 Countries 49 Centers
15 DEFINE-FLAIR: Study hypotheses and aimsIn patients with coronary stenoses suitable for physiological assessment with FFR, the decision to perform coronary revascularisation based on iFR measurements is: Non-inferior to FFR in terms of safety and efficacy Superior to FFR in terms of cost-effectiveness Aim Comparison of clinical outcomes of patients whose treatment has been guided by iFR vs those whose treatment has been guided by FFR If both study hypotheses are confirmed iFR could be used in a similar manner to FFR for the assessment of physiological stenosis severity iFR could lead to improved healthcare cost efficiencies DEFINE FLAIR. https://clinicaltrials.gov/ct2/show/NCT Accessed December 8, 2016.
16 DEFINE-FLAIR: EndpointsPrimary outcome Major adverse cardiac events* in the iFR and FFR groups at year 1 Secondary endpoints Death (all cause) at 30 days, 1, 2 and 5 years Death (cardiovascular) at 30 days, 1, 2 and 5 years MI at 30 days, 1, 2 and 5 years Repeat revascularisation by PCI or CABG at 30 days, 1, 2 and 5 years Costs associated with iFR or FFR guidance Quality of life in patients included in the iFR or FFR guidance groups By the primary endpoint completion, we should have over 7000 lesions included, with same sort of numbers recruited as FAME. *Major adverse cardiovascular events, defined as a combined endpoint of death, non-fatal myocardial infarction, or unplanned revascularisation. CABG, coronary artery bypass graft; MI, myocardial infarction. DEFINE FLAIR. https://clinicaltrials.gov/ct2/show/NCT Accessed December 8, 2016.
17 Study Design – Key FeaturesStrategy study Robust non-inferiority design Margin similar to Noble/Excel/Syntax Similar inclusion and exclusion to FAME/FAME2 Clinically relevant patient distributions (70- 80% in “critical intermediate zone”)
18 Study Design – Key FeaturesBlinding (patients/follow-up teams) Core lab analysis of physiological screenshots Monitoring 100% sites Independent international clinical events committee
19 iFR Swedeheart: Study designFFR >0.8 Defer PCI FFR ≤0.8 Perform PCI FFR-guided PCI iFR ≤0.89 iFR >0.89 Intermediate lesion requiring physiological assessment In ACS : intermediate non-culprit lesion N=2000, 1:1 Randomisation iFR-guided PCI 1–5 year follow-up Key trial information Location: Denmark, Iceland and Sweden Estimated enrollment: ~2000 Follow-up: 5 years Primary endpoint completion: Dec 2016 This study is conducted in Scandinavian countries. The design is similar to that of DEFINE-FLAIR, as the aim and rationale of this study. iFR Swedeheart. https://clinicaltrials.gov/ct2/show/NCT Accessed December 8,
20 Number of patients in the physiology-guided groupDEFINE-FLAIR + iFR SWEDEHEART Largest combined prospective clinical outcomes dataset Number of patients in the physiology-guided group + A huge number of data on patients guided by physiology will be generated with both SwedeHeart and DEFINE-FLAIR 1 2 3 4 5 4,5 1. Bech G et al. Circulation. 2001;103: ; 2. Torino P et al. J Am Coll Cardiol. 2010;55: ; 3. De Bruyne B et al. N Engl J Med. 2014;371: ; 4. iFR SWEDEHEART. https://clinicaltrials.gov/ct2/show/NCT ?term=ifr+swedeheart&rank=1. Accessed Dec 8, 2016; 5. DEFINE-FLAIR. https://clinicaltrials.gov/ct2/show/NCT ?term=DEFINE+FLAIR&rank=1. Dec 8, 2016
21 Main Arena (Hall D) Washington DC 18th March, 11am
22 Late Breaking Clinical Trial PresentationsMain Arena (Hall D) Washington DC 18th March, 11am
23 Increased awareness and uptake of iFR technologyThe great IFR vs. FFR debate: why sometimes “the wait and see approach” is the best tactic as the best pragmatic solution will always emerge and become established Patrick W. Serruys, Editor-in-Chief iFR used in >4,200 labs around the world (as of Jan 2017) Serruys PW. EuroIntervention. 2013;9:11-3