Long-term outcomes with physiology

Increased risk of MI with medical treatment

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
McGovern 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 Organizations (alphabetical)

• Grant/research support • St Jude Medical (for CONTRAST study)
(to institution) • Volcano/Philips (for DEFINE-FLOW study)

• Licensing and associated consulting • Boston Scientific

(to institution) (for smart-minimum FFR algorithm)

• Support for educational meetings/training • Various, including academic and industry

(honoraria/fees donated to institution)

• PET software 510(k) from FDA • K113754 (cfrQuant, 2011)

(application by Lance Gould, to institution) • K143664 (HeartSee, 2014)
• K171303 (HeartSee update, 2017)

• Patent pending • SAVI and ∆P/Q methods

(USPTO serial number 62/597,134)
 The PCI skeptics (nihilists?)

Ornish D, Redberg RF. NEJM. 2019 Jan 3;380(1):103-104. (Excerpts with emphasis)
 Anecdote or clue?

Baseline Follow-up
• Negative iFR 0.97 • Ostial LAD occluded
• Positive FFR 0.76 • Presented as STEMI
• Medically treated
Ng M, EPIC lecture on October 14, 2017, in Sydney, Australia. (Composite of slides)
 Has there been a hint so far?

FAME 2
9.6% vs 13.4%
(n = 43 vs 59)

PRIMULTI
3.7% vs 6.4%
(n = 11 vs 38)
Compare-Acute
6% vs 8%
(n = 20 vs 25)
FAME 2 = Xaplanteris P, NEJM. 2018 Jul 19;379(3):250-259. (Table 2 excerpt)
PRIMULTI = Engstrøm T, Lancet. 2015 Aug 15;386(9994):665-71. (Table 3 excerpt)
CompareAcute = Smits PC, NEJM. 2017 Mar 30;376(13):1234-1244. (Table 3 excerpt)
 Increase sample size by “pooling”

combined N = 2400 subjects

mean follow-up 35 months
Zimmermann FM, EHJ. 2019 Jan 7;40(2):180-186. (Figure 1)
 FFR stable = pooling valid

101 patients with ACS 50 patients with STEMI 73 patients with STEMI
STEMI in 75% 66 non-culprit lesions FFR acute = 0.88 ± 0.07
FFR acute = 0.77 ± 0.13 FFR acute = 0.82 ± 0.07 FFR late = 0.86 ± 0.09
FFR late = 0.77 ± 0.13 FFR late = 0.82 ± 0.08 (measured 1 month later)
(measured 35 days later) (measured 5-8 days later) Only 5 changed >0.8 to <0.75
Only 2 changed >0.8 to <0.75

Animal model
left = Ntalianis A, JACC Cardiovasc Interv. 2010 Dec;3(12):1274-81. (Figure 1 with annotations)
middle = Musto C, Am Heart J. 2017 Nov;193:63-69. (Figure 1B and results from Table 2) microsphere emboli
right = van der Hoeven NW, JAMA Cardiol. 2019 Jul 3. [Epub ahead of print] (Figure 1E) FFR/IMR stable in LCx (non-culprit)
bottom = Lee JM, JACC Cardiovasc Interv. 2018 Apr 23;11(8):717-24. (Figure 2) FFR/IMR unstable in LAD (culprit)
 Reduction in CV death + MI

absolute risk
OMT 16.4%
FFR 10.7%
number needed to treat = 18

Zimmermann FM, EHJ. 2019 Jan 7;40(2):180-186. (Figure 2 plus results)

 Benefit driven by MI and not death

Myocardial infarction
• 8.5% FFR
• 13.4% OMT

Zimmermann FM, EHJ. 2019 Jan 7;40(2):180-186. (Table 1)

 Important subgroup messages

1.Supports pooling of these RCT’s

2.FFR negative lesions dilute benefit

Zimmermann FM, EHJ. 2019 Jan 7;40(2):180-186. (Figure 3 portion)

 FFR associates with plaque risk
3+ high-risk
plaque features

3+

2
1

0 high-risk
plaque features

Lee JM, JACC. 2019 May 21;73(19):2413-2424. (Figure 1 and part of Central Illustration plus annotations)
 iFR < FFR for plaque vulnerability
positive
remodeling
low
attenuation
plaque predict 1+ of
• positive remodeling
• low attenuation plaque
• spotty calcification
• napkin ring sign

Driessen RS, JACC Cardiovasc Imaging. 2019 Aug 8. [Epub ahead of print] (annotated Figure 1 and modified Central Illustration)
 Why do we see this association?

∆P does not depend

on plaque composition

Kern MJ, JACC. 2010 Jan 19;55(3):173-85. (Figure 2 inset)

 Why do we see this association?

initially we see no
association between
∆P ∆P and vulnerability

∆P does not depend

on plaque composition plaque vulnerability

Kern MJ, JACC. 2010 Jan 19;55(3):173-85. (Figure 2 inset)

 Why do we see this association?

low gradient and

no vulnerability
remains stable
∆P
stable

∆P does not depend

on plaque composition plaque vulnerability

Kern MJ, JACC. 2010 Jan 19;55(3):173-85. (Figure 2 inset)

 Why do we see this association?
• intraplaque hemorrhage
• silent rupture/heal
• other mechanisms…
increases ∆P and
vulnerable features

∆P
stable
growth #1

∆P does not depend

on plaque composition plaque vulnerability

inset top = Virmani R, Arterioscler Thromb Vasc Biol. 2005 Oct;25(10):2054-61. (Figure 2A-D)
inset mid = Bentzon JF, Circ Res. 2014 Jun 6;114(12):1852-66. (Figure 3)
Kern MJ, JACC. 2010 Jan 19;55(3):173-85. (Figure 2 inset)
 Why do we see this association?
finally association
has developed for
and so on…
∆P and vulnerability

∆P
growth #2
stable
growth #1

∆P does not depend

on plaque composition plaque vulnerability

Kern MJ, JACC. 2010 Jan 19;55(3):173-85. (Figure 2 inset)

 Low FFR plaque <-> vulnerable plaque
FFR≤0.72
FFR=0.73-0.79
FFR=0.80-0.87
FFR≥0.88
Low FFR lesion
Vulnerable features
Exposed to mechanical stress

left, top = Driessen RS, JACC. 2018 Feb 6;71(5):499-509. (Central Illustration)
left, bottom = Lee JM, JACC Cardiovasc Imaging. 2019 Jun;12(6):1032-43. (Figure 2)
right = Matsuo Y, JACC Cardiovasc Imaging. 2019 Jun;12(6):1103-5. (Figure 1 portion with custom legend)
 Vulnerable plaque = rupture risk

Low FFR lesion Natural history leads

Vulnerable features to plaque rupture
Exposed to mechanical stress

left = Driessen RS, JACC. 2018 Feb 6;71(5):499-509. (Central Illustration)

middle = Lee JM, JACC Cardiovasc Imaging. 2019 Jun;12(6):1032-43. (Figure 4A)
 Unifying hypothesis

Low FFR lesion Natural history leads PCI stabilizes lesion

Vulnerable features to plaque rupture At short-term cost
Exposed to mechanical stress But long-term benefit

left = Driessen RS, JACC. 2018 Feb 6;71(5):499-509. (Central Illustration)

middle = Lee JM, JACC Cardiovasc Imaging. 2019 Jun;12(6):1032-43. (Figure 4A)
right = Zimmermann FM, EHJ. 2019 Jan 7;40(2):180-186. (Figure 2)
 COMPLETE: PCI for stable lesions

• non-culprit noted at STEMI

• %DS≥70%
• or %DS 50-69% and FFR≤0.8
• outcome = CV death + MI
Mehta SR, NEJM. 2019 Sep 1. [Epub ahead of print] (Title and Figure 1A)
 COMPLETE: MI was only effect

COMPLETE EHJ meta-analysis

MI 0.68 (95%CI 0.53-0.86) 0.70 (95%CI 0.51-0.97)
CV death 0.93 (95%CI 0.65-1.32) 1.04 (95%CI 0.58-1.78)

Mehta SR, NEJM. 2019 Sep 1. [Epub ahead of print] (Portion of Table 3)
 COMPLETE: driven by “worse” lesions

likely FFR(+)
likely FFR(-)

Fewer stents but same result if FFR instead of %DS?

Mehta SR, NEJM. 2019 Sep 1. [Epub ahead of print] (Portion Figure 2)
 PCI benefit even without symptoms?!
• post-hoc substudy
• 98 subjects in FAME 2
• asymptomatic but FFR≤0.80
• 5-year follow-up
• myocardial infarction
FFR+, no symptoms, MT  PCI vs medical therapy
 HR 0.13 (95%CI 0.03-0.57)
• significant interaction
 larger benefit of PCI
FFR+, no symptoms, PCI without symptoms

Fournier S, JACC. 2019 Sep 24;74(12):1642-1644. (Figure 1A with curve annotations)

 “Together, these new data support a
less restrictive indication for
revascularization in [chronic coronary
syndromes] when PCI is restricted to
angiographic stenoses on large vessels
EHJ meta-analysis
causing a significant intracoronary
pressure gradient.”

Knuuti J, EHJ. 2019 Aug 31 [Epub ahead of print] (Excerpts and quote from section 3.4)