From rest to hyperemia How much flow is

From rest to hyperemia How much flow is enough? Nils Johnson MD, MS, FACC, FESC Associate Professor of Medicine Weatherhead Distinguished Chair of Heart Disease Division of Cardiology, Department of Medicine and the Weatherhead PET Imaging Center Mc. Govern Medical School at UTHealth (Houston) Memorial Hermann Hospital – Texas Medical Center United States of America Weatherhead PET Imaging Center

Disclosure Statement of Financial Interest Within the past 12+ months, Nils Johnson has had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship • Grant/research support (to institution) • Licensing and associated consulting (to institution) • Support for educational meetings/training Organizations (alphabetical) • St Jude Medical (for CONTRAST study) • Volcano/Philips (for DEFINE-FLOW study) • Boston Scientific (for smart-minimum FFR algorithm) • Various, including academic and industry (honoraria/fees donated to institution) • PET software 510(k) from FDA • K 113754 (cfr. Quant, 2011) (application by Lance Gould, to institution) • K 143664 (Heart. See, 2014) • K 171303 (Heart. See update, 2017) • Patent pending (USPTO serial number 62/597, 134) • SAVI and ∆P/Q methods

Pyramid of diagnostic accuracy 100% = gold standard 50% = coin flip Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25; 9(8): 757 -67. (Based on Figure 1)

Angiogram <70% accuracy Frame from 1 st ever selective coronary angiogram Mason Sones, October 30, 1958, Cleveland Clinic 4, 086 lesions with QCA Compared to FFR≤ 0. 8 • 50%DS threshold – 0. 64 AUC top = Ryan TJ, JACC. 1998 Mar 15; 31(4 Suppl B): 89 B-96 B. (Figure 1) bottom = Toth G, Eur Heart J. 2014 Oct 21; 35(40): 2831 -8 (Figure 1 A)

Pyramid of diagnostic accuracy 100% = gold standard 65% ≈ angiogram alone Sones, 1958 50% = coin flip

Resting physiology

Pyramid of diagnostic accuracy 100% = gold standard Grüntzig, 1979 80% ≈ rest physiology (Pd/Pa or i. FR) 65% ≈ angiogram alone Sones, 1958 50% = coin flip

i. FR in new AUC Patel MR, JACC. 2017 May 2; 69(17): 2212 -2241. (Title and scenario 3)

FDA approved rest Pd/Pa URL http: //www. accessdata. fda. gov/cdrh_docs/pdf 17/K 172182. pdf, accessed February 22, 2018 (Excerpts with emphasis)

Pd/Pa and i. FR perform the same Agreement with FFR (%) 100% = FFR with adenosine 90% 80% i. FR Pd/Pa p=1. 00 p=0. 78 70% 60% 50% RESOLVE ADVISE 2 n=1, 593 n=690 VERIFY 2 CONTRAST n=257 n=763 RESOLVE = Jeremias A, JACC. 2014 Apr 8; 63(13): 1253 -61 ADVISE 2 = Escaned J, JACC Cardiovasc Interv. 2015 May; 8(6): 824 -33 and 834 -6 VERIFY 2 = Hennigan B, Circ Cardiovasc Interv. 2016; 9(11). pii: e 004016. CONTRAST = Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25; 9(8): 757 -67 Key conclusions • Pd/Pa ≈ i. FR • 3, 300+ lesions • multiple studies • Volcano i. FR

Bhatt DL, NEJM. 2017 May 11; 376(19): 1879 -1881.

i. FR negative, “do not perform PCI” Rest Treadmill 59 year-old man with 40 -80% prox LAD lesion Composite of slides presented by Pijls NH, TCT lecture on September 14, 2014 Bhatt DL, NEJM. 2017 May 11; 376(19): 1879 -1881. (Figure 1 subset) right, top = Davies JE, NEJM. 2017 May 11; 376(19): 1824 -1834. right, bottom = Go tberg M, NEJM. 2017 May 11; 376(19): 1813 -1823. Pd/Pa = 0. 96 i. FR = 0. 97 normal ECG +ECG

Rest missed cause for angina! Rest Treadmill Rest 59 year-old man with 40 -80% prox LAD lesion and no rest symptoms but classic angina Stress normal ECG +ECG no defect LAD defect Pd/Pa = 0. 96 i. FR = 0. 97 FFR = 0. 73 Composite of slides presented by Pijls NH, TCT lecture on September 14, 2014

PCI instead of OMT helped patient i. FR 0. 96 FFR 0. 73 Focal No drift Rest Treadmill +ECG After PCI -ECG Rest Stress After PCI FFR 0. 99 normal ECG After PCI Composite of slides presented by Pijls NH, TCT lecture on September 14, 2014 no defect LAD normal

Multi-test, pre/post validation of FFR – “composite information from sequentially performed noninvasive tests has a diagnostic accuracy of almost 100%” • FFR<0. 75 – all 21 had 1+ test positive (often 2 or 3) – all positive tests return to normal – all FFR increased to >0. 75 after PCI Pijls NH, N Engl J Med. 1996 Jun 27; 334(26): 1703 -8 (Figure 2 and quotes from text with emphasis added)

Did high stress forces cause rupture? Intermediate prox LAD lesion treated medically Returned with STEMI at prox LAD site i. FR = 0. 97 FFR = 0. 76 Ng M, EPIC lecture on October 14, 2017, in Sydney, Australia. (Composite of slides)

Accuracy versus FFR and rest disagree more in LM/LAD Sensitivity Specificity Kobayashi Y, JACC Cardiovasc Interv. 2016 Dec 12; 9(23): 2390 -2399. (Figure 1 for i. FR and Pd/Pa with axis

i. FR trials suggest higher death/MI • • Clinical case Negative i. FR 0. 97 Positive FFR 0. 76 Medically treated Later STEMI Subject-level meta-analysis (Euro. PCR) • CV death = higher for i. FR (HR 1. 52, p=0. 30) • Nonfatal MI = higher for i. FR (HR 1. 19, p=0. 45) Study-level meta-analysis (Circulation) • Death or MI = higher for i. FR (HR 1. 30, p=0. 09) Ng M, EPIC lecture on October 14, 2017, in Sydney, Australia. (Composite of slides) Euro. PCR = Escaned J, Euro. PCR lecture on May 16, 2017. (Slide 13 results) Circulation = Berry C, Circulation. 2017 Dec 12; 136(24): 2389 -2391. (Results from table)

Pyramid of diagnostic accuracy 100% = gold standard 95+% ≈ FFR hyperemia Grüntzig, 1979 80% ≈ rest physiology (Pd/Pa or i. FR) 65% ≈ angiogram alone Sones, 1958 50% = coin flip

Vasodilators in human physiology • • • contrast medium (1974, Gould KL, Am J Cardiology) dipyridamole (1978, Gould KL, Am J Cardiology) coronary occlusion (1984, Marcus ML, NEJM) papaverine (1986, Wilson RF, Circulation) adenosine (1990, Wilson RF, Circulation) ATP (2003, De Bruyne B, Circulation) nitroprusside (2004, Kern MJ, Circulation) nicorandil (2006, Kang JC, Int J Cardiology) regadenoson (2011, Nair PK, JACC Interventions )

Contrast: always ready, fast, cheap produces hyperemia! URL https: //www. nghs. com/cardiac-catheterization-lab, accessed February 22, 2018 (annotated).

1959 paper on contrast hyperemia 70 kg * (0. 025 to 0. 25 cc/kg) = 1. 8 to 18 cc ≈ 10 cc of IC contrast gave 60% increase in flow Guzman SV, Am Heart J. 1959 Oct; 58(4): 597 -607 (taken from results, page 602)

CONTRAST protocol: example Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25; 9(8): 757 -67. (Figure 2)

CONTRAST example: summary • Rest – Pd/Pa = 0. 93 and 0. 92 – i. FR = 0. 91 and 0. 91 • IC contrast – c. FFR = 0. 77 and 0. 76 • IC adenosine – FFR = 0. 69 and 0. 69 • IV adenosine – FFR = 0. 68 and 0. 69 • Drift check – 1. 01 at guide Both Pd/Pa and i. FR miss low FFR, but contrast FFR gets it right!

CONTRAST: diagnostic accuracy contrast = 85. 8% accuracy i. FR = 79. 9% accuracy Pd/Pa = 78. 5% accuracy superior accuracy (p<0. 001) Optimal binary cutoff for contrast FFR ≤ 0. 83 (accuracy >84% for 0. 83 -0. 85) Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25; 9(8): 757 -67. (Figure 4, left)

c. FFR better than resting physiology 1. 0 = FFR with adenosine 90% 87% 80% p<0. 001 p<0. 0001 c. FFR Pd/Pa 70% 60% 50% CONTRAST MEMENTO Kanaji n=763 n=1026 n=91 CONTRAST = Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25; 9(8): 757 -67. MEMENTO = Leone AM, Euro. Intervention. 2016 Aug 20; 12(6): 708 -15. Kanaji = Kanaji Y, Int J Cardiol. 2016 Jan 1; 202: 207 -13. Area under ROC curve Accuracy (%) 100% = FFR with adenosine p<0. 001 0. 9 p<0. 001 c. FFR Pd/Pa 0. 8 0. 7 0. 6 0. 5 CONTRAST MEMENTO Kanaji

Limitations of contrast FFR (c. FFR) • Contrast hyperemia too short for pull-back tracings – Applies to IC adenosine too – Can perform serial IC bolus measurements • No data collected on contrast-induced nephropathy – Average dose 8 m. L of IC contrast for single vessel – Used to document pressure wire position anyway – Clinical impact negligible

Details on contrast injections Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25; 9(8): 757 -67. (Table 1, selected rows)

Does type of contrast matter? “c. FFR best independent of osmolality which had no significant impact” Nishi T, Circ Cardiovasc Interv. 2017 Oct; 10(10). pii: e 004985. (Figure 5)

Does amount of contrast matter? (<8 cc) (≥ 8 cc) “c. FFR best independent of injected volume which had no significant impact” Nishi T, Circ Cardiovasc Interv. 2017 Oct; 10(10). pii: e 004985. (Figure 6 with volume annotations)

Practical algorithm Pd/Pa ≤ 0. 8 PCI reasonable Based on discussion with Keith Oldroyd, March 27, 2016. >0. 8

Practical algorithm Pd/Pa ≤ 0. 8 >0. 8 PCI reasonable (10% of lesions) • less information about depth of ischemia! • pullback less sensitive (smaller pressure jumps) Approximate percentages from CONTRAST

Practical algorithm Pd/Pa ≤ 0. 8 PCI reasonable (10% of lesions) >0. 8 contrast FFR ≤ 0. 8 >0. 8 PCI reasonable (20% of lesions) • • maintains 100% accuracy streamlines physiologic evaluation

Practical algorithm Pd/Pa ≤ 0. 8 PCI reasonable (10% of lesions) >0. 8 contrast FFR ≤ 0. 8 PCI reasonable (20% of lesions) >0. 8 adenosine FFR ≤ 0. 8 >0. 8 PCI reasonable (20% of lesions) medical therapy (50% of lesions)

Pyramid of diagnostic accuracy Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25; 9(8): 757 -67. (Figure 1)