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Role of FFR-Guided PCI in Patients with Stable CAD
William F. Fearon, MDProfessor of MedicineDirector, Interventional CardiologyStanford University School of Medicine
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Conflicts of Interest
n Research grants from Medtronic and Abbott Vascular
n Consulting with HeartFlow and CathWorks
n Research and salary support from National Institutes of Health: R61/R33 HL139929 (PI)
n Interventional Cardiologist!!
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November 2, 2017
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Brown DL and Redberg RF. Lancet 2018;391:3-4.
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Surgery for Blocked Arteries Is Often Unwarranted, Researchers FindDrug therapy alone may save lives as effectively as bypass orstenting procedures, a large federal study showed.
November 16, 2019
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COURAGE: Aim
n To determine whether the addition of PCI to optimal medical therapy, when used as an initial management strategy, further reduces the risk of death or nonfatal MI in patients with stable CAD, compared with optimal medical therapy alone.
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COURAGE: Results2,287 stable patients with 1, 2, or 3 vessel CAD randomized to optimal medical therapy or PCI
Boden, et al. New Engl J Med 2007;356:1503-16.
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Degree of Ischemia in COURAGE
Shaw, et al. Circulation 2008;117:1283-91.
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Hachamovitch, et al. Circulation 2003;107:2900-06.
Importance of Myocardial IschemiaWith greater degrees of ischemia, there is a survival benefit for PCI
P<0.001
10% IschemicMyocardium
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Why didn’t COURAGE show a benefit with PCI?n It did not included patients with
significant myocardial ischemia
n PCI was not optimal (No DES, incomplete revascularization)
n PCI was not guided by Fractional Flow Reserve (FFR)
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Fractional Flow ReserveDistal
Pressure (Pd)
Proximal Pressure (Pa)
FFR = Pd / Paduring maximal flow
Pd
Pa
Pd / Pa = 60 / 100FFR = 0.60
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Tonino, et al.J Am Coll Cardiol 2010;55:2816-21.
1329 lesions in the FFR-guided arm of FAME
~35%
~20%
Limitation of Angiography
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DEFER Trial 15 Year Follow-Up
Zimmermann, et al. Eur Heart J 2015;36:3182-8
181 patients with intermediate lesions and FFR≥0.75 randomized to deferral or performance of PCI
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Safety of Deferring PCI Based on FFR
Adapted from: Muller, et al. JACC Cardiovasc Interv 2011;4:1175-82
5 year follow-up of 564 intermediate proximal LAD lesions deferred because FFR≥0.80
No Known CADModerate Prox LAD, FFR≥0.80
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New Engl J Med 2009;360:213-24.
FAME 1 Study: One Year Outcomes
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8.7 9.511.1
18.3
1.8
5.7 6.5 7.3
13.2
0
5
10
15
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Death MI RepeatRevasc
Death/MI MACE
Angio-Guided FFR-Guided
p=0.02p=0.04
%
~40% ¯
~35% ¯ ~30% ¯~35% ¯
~30% ¯
1,005 patients with multivessel CAD randomized to FFR or Angio-guided PCI
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FFR-Guided
Angio-Guided
730 days4.5%
Pijls, et al. J Am Coll Cardiol 2010;56:177-184
FAME Study: Two Year OutcomesDeath/MI was significantly reduced from 12.9% to 8.4% (p=0.02)
Survival Free of MACE
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FAME: Economic Evaluation
Circulation 2010;122:2545-50.
Bootstrap Analysis
FFR-guided PCI saved >$2,000 per patient at one year compared to Angio-guided PCI
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FAME 2
Death and MI in the COURAGE study
Boden et al., New Engl J Med 2007;356:1503-16.
Implications of FAME
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FAME 2: Design
n Hypothesis:q Optimal medical therapy plus FFR-guided PCI
with current generation drug-eluting stents improves outcomes compared to optimal medical therapy alone in patients with stable coronary artery disease.
De Bruyne, et al. New Engl J Med 2012;367:991-1001
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FAME 2Stable CAD patients scheduled for 1, 2 or 3 vessel DES-PCI
N = 1220
FFR in all target lesions
When all FFR > 0.80 (n=332)
MT
At least 1 stenosiswith FFR ≤ 0.80 (n=888)
Randomization 1:1
PCI + MT MT
Primary Endpoint: Death, MI or Urgent Revascularization at 2 Yr
Registry
50% randomly assigned to FU27%
Randomized Trial
73%
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Primary Endpoint: Death, MI, Urgent Revasc
0
5
10
15
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25
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Cum
ulat
ive
inci
denc
e (%
)
166 156 145 133 117 106 93 74 64 52 41 25 13Registry447 414 388 351 308 277 243 212 175 155 117 92 53PCI+MT441 414 370 322 283 253 220 192 162 127 100 70 37MT
No. at risk
0 1 2 3 4 5 6 7 8 9 10 11 12Months after randomization
MT vs. Registry: HR 4.32 (1.75-10.7); p<0.001PCI+MT vs. Registry: HR 1.29 (0.49-3.39); p=0.61PCI+MT vs. MT: HR 0.32 (0.19-0.53); p<0.001
De Bruyne, et al. New Engl J Med 2012;367:991-1001
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FAME 2: Clinical OutcomesThree Year Rate of Death, MI, or Urgent Revascularization
Circulation 2018;137:480-487.
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FAME 2: Clinical OutcomesThree Year Rate of Death, MI, or Urgent Revascularization
Randomized trial N=888 P value Registry N=332Event PCI+MT=447 MT=441 With FU=166
MACE 10.1% 22% <0.001 12.7%
Death 2.7% 3.6% 0.43 3.0%
Myocardial Infarction (MI) 6.3% 7.7% 0.41 6.6%
Death or MI 8.3% 10.4% 0.28 9.0%
Urgent Revascularization 4.3% 17.2% <0.001 6.6%
Circulation 2018;137:480-487.
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FAME 2: Clinical Outcomes% of Patients with Class II-IV Angina at each Time Point
Circulation 2018;137:480-487.
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FAME 2: Cost-Effectiveness
At three years, the ICER for PCI was $1,600/QALY. Circulation 2018;137:480-487.
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Relationship between FFR and MACE607 medically treated patients in FAME 2
Barbato, et al. J Am Coll Cardiol 2016;68:2247-55.
FFR=0.87-1.0
FFR=0.64-0.77
FFR=0.78-0.86
FFR≤0.63
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FAME 2: Five Year Follow-UpFive Year Rate of Spontaneous Myocardial Infarction
Xaplanteris, et al. New Engl J Med 2018;379:250-59.
P=0.04
Medical Therapy
PCI
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Meta-Analysis of FFR-Guided PCI2,400 patients with stable (or stabilized) CAD from 3 randomized trials comparing FFR-guided PCI with medical therapy
Zimmermann, et al. Eur Heart J 2019;40:180-186.
Dea
th o
r MI
Death or MI
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ORBITA Trialn 200 patients with single vessel stenosis
>70% and with stable angina n All patients received 6 weeks of medical
optimization and then assessment of exercise capacity and angina
n Patients then randomized to PCI versus sham PCI
n At 6 weeks had repeat assessment of exercise capacity and angina
Al-Lamee R, et al. Lancet 2018;391:31-40.
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ORBITA Trial
Al-Lamee R, et al. Lancet 2018;391:31-40.
Primary endpoint: change in exercise time at 6 weeks post procedure
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ORBITA TrialPercentage of patients free of patient-reported angina
Al-Lamee R, et al. Circulation 2018;138:1780-92.
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ORBITA TrialRelationship of difference in SAQ QOL score and FFR
Al-Lamee R, et al. Circulation 2018;138:1780-92.
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FFR Predicts Quality of Life891 stable patients treated medically or with PCI in FAME 1 and FAME 2
Nishi T, et al. Circulation 2018;138:1797-1804.
-0.06
-0.04
-0.02
0
0.02
0.04
0.06
0.08
0.1
0.12
Reference Upper Middle LowerMea
n ch
ange
in E
Q5D
fro
m b
asel
ine
to 1
mon
th
(FFR>0.80) (FFR≤0.50)(FFR 0.80–0.70) (FFR 0.69–0.51)
P for trend <0.001 (overall)
Medical Treatment
PCI
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FFR Predicts Quality of Life706 stable patients treated with PCI in FAME 1 and FAME 2
Nishi T, et al. Circulation 2018;138:1797-1804.
Mea
n ch
ange
in E
Q5D
fro
m b
asel
ine
to 1
yea
r
-0.02
0
0.02
0.04
0.06
0.08
0.1
0.12
Lower Middle Upper(Delta FFR≥0.33)(Delta FFR≤0.18) (Delta FFR 0.19–0.32)
P for trend = 0.009
Delta FFR = Post PCI FFR – Pre PCI FFR
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ISCHEMIA Trial
Hochman, et al. AHA 2019
In patients with stable CAD and at least moderate ischemia on a stress test, is there a benefit to adding coronary angiography, and if feasible, revascularization to optimal medical therapy alone?
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ISCHEMIA TrialStable Patient
Moderate or severe ischemia(determined by site; read by core lab)
CCTA not required, e.g., eGFR 30 to <60 or coronary anatomy previously defined
Blinded CCTA
Core lab anatomy eligible?
RANDOMIZE
Screen failure
INVASIVE StrategyOMT + Cath +
Optimal Revascularization
CONSERVATIVE Strategy OMT alone
Cath reserved for OMT failure
NO
YES
Hochman, et al. AHA 2019
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ISCHEMIA Trial
Hochman, et al. AHA 2019
Inclusion Criteria• Age ≥21 years• Moderate or severe ischemia*
• Nuclear ≥10% LV ischemia (summed difference score ≥7)• Echo ≥3 segments stress-induced moderate or severe
hypokinesis, or akinesis• CMR
• Perfusion: ≥12% myocardium ischemic, and/or• Wall motion: ≥3/16 segments with stress-induced severe
hypokinesis or akinesis• Exercise Tolerance Testing (ETT) >1.5mm ST depression in >2 leads
or >2mm ST depression in single lead at <7 METS, with angina
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ISCHEMIA Trial
Hochman, et al. AHA 2019
Major Exclusion Criteria •NYHA Class III-IV HF•Unacceptable angina despite medical therapy•EF < 35%•ACS within 2 months•PCI or CABG within 1 year •eGFR <30 mL/min or on dialysis
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ISCHEMIA Trial
Hochman, et al. AHA 2019
CCTA Eligibility CriteriaInclusion Criteria• ≥50% stenosis in a major epicardial vessel (stress imaging
participants)• ≥70% stenosis in a proximal or mid vessel (ETT participants)
Major Exclusion Criteria • ≥50% stenosis in unprotected left main
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ISCHEMIA Trial
Hochman, et al. AHA 2019
Primary Endpoint:n Time to CV death, MI, hospitalization for unstable angina, heart
failure or resuscitated cardiac arrest
Major Secondary Endpoints:n Time to CV death or MIn Quality of Life
Other Endpoints include:n All-Cause Deathn Net clinical benefit (stroke added to primary endpoint)n Components of primary endpoint
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ISCHEMIA Trial
Hochman, et al. AHA 2019
Characteristic Total INV CON
Baseline Inducible Ischemia*
Severe 54% 53% 55%
Moderate 33% 34% 32%
Mild/None 12% 12% 12%
Uninterpretable 1% 1% 1%
Core lab adjudicated degree of ischemia on non-invasive testing
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ISCHEMIA Trial
Hochman, et al. AHA 2019
Cardiac Catheterization Revascularization
12%
95% 96%
9%
28%
76%79% 80%
23%
7%
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ISCHEMIA Trial
Hochman, et al. AHA 2019
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ISCHEMIA Trial
Hochman, et al. AHA 2019
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ISCHEMIA Trial
Hochman, et al. AHA 2019
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ISCHEMIA Trial
Hochman, et al. AHA 2019
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ISCHEMIA Trial
Hochman, et al. AHA 2019
Procedural Myocardial Infarction
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ISCHEMIA Trial
Hochman, et al. AHA 2019
Spontaneous Myocardial Infarction
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ISCHEMIA Trial
Hochman, et al. AHA 2019
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ISCHEMIA Trial
Spertus, et al. AHA 2019
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ISCHEMIA Trial
Hochman, et al. JAMA Card 2019;4:273-86.
Baseline angina frequency in randomized patients in ISCHEMIA
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ISCHEMIA Trial
Hochman, et al. AHA 2019
Pre-specified subgroup analyses for interaction on the primary endpoint
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Asymptomatic Patients in FAME 2
Asymptomatic and Med Rx
Symptomatic and Med Rx
Symptomatic and PCIAsymptomatic and PCI
Asymptomatic patients treated medically had significantly higher death/MI
Fournier, et al. J Am Coll Cardiol 2019;74:1642-44.
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Asymptomatic Patients in FAME 2Asymptomatic patients treated medically had significantly higher death/MI
Fournier, et al. J Am Coll Cardiol 2019;74:1642-44.
p = 0.022
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Impact of PCI in Stable CADISCHEMIA FAME 2No ∆ Mortality No ∆ Mortality
↓ Spontaneous MI ↓ Spontaneous MI
↓ Hosp. for unstable ↓ Hosp. for urgentangina revascularization
↓ Angina at 3 years ↓ Angina at 3 years
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Spectrum of Stable CAD
Scheidt: Basic Electrocardiography; 1986Adapted from: Frank H. Netter, M.D.
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Approach to Stable CAD
n Initial attempt at controlling symptoms with medical therapy alone.
n If the patient cannot tolerate medical therapy, has refractory symptoms, or prefers to avoid medications, an initial approach with FFR-guided revascularization is reasonable.
n Longer term follow-up from ISCHEMIA and substudy analyses will further inform practice.
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