Utilization and Outcomes of Measuring Fractional Flow Reserve in Patients With Stable Ischemic Heart Disease

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 75, NO. 4, 2020

ª 2020 THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION. PUBLISHED BY ELSEVIER. ALL RIGHTS RESERVED.

Utilization and Outcomes of Measuring Fractional Flow Reserve in Patients With Stable Ischemic Heart Disease Rushi V. Parikh, MD,a Grace Liu, MSC,b Mary E. Plomondon, PHD,b Thomas S.G. Sehested, MD,c Mark A. Hlatky, MD,d Stephen W. Waldo, MD,b,e William F. Fearon, MDf

ABSTRACT BACKGROUND The use and clinical outcomes of fractional flow reserve (FFR) measurement in patients with stable ischemic heart disease (SIHD) are uncertain, as prior studies have been based on selected populations. OBJECTIVES This study sought to evaluate contemporary, real-world patterns of FFR use and its effect on outcomes among unselected patients with SIHD and angiographically intermediate stenoses. METHODS The authors used data from the Veterans Affairs Clinical Assessment, Reporting, and Tracking (CART) Program to analyze patients who underwent coronary angiography between January 1, 2009, and September 30, 2017, and had SIHD with angiographically intermediate disease (40% to 69% diameter stenosis on visual inspection). The authors documented trends in FFR utilization and evaluated predictors using generalized mixed models. They applied Cox proportional hazards models to determine the association between an FFR-guided revascularization strategy and all-cause mortality at 1 year. RESULTS A total of 17,989 patients at 66 sites were included. The rate of FFR use gradually increased from 14.8% to 18.5% among all patients with intermediate lesions, and from 44% to 75% among patients who underwent percutaneous coronary intervention. One-year mortality was 2.8% in the FFR group and 5.9% in the angiography-only group (p < 0.0001). After adjustment for patient, site-level, and procedural factors, FFR-guided revascularization was associated with a 43% lower risk of mortality at 1 year compared with angiography-only revascularization (hazard ratio: 0.57; 95% confidence interval: 0.45 to 0.71; p < 0.0001). CONCLUSIONS In patients with SIHD and angiographically intermediate stenoses, use of FFR has slowly risen, and was associated with significantly lower 1-year mortality. (J Am Coll Cardiol 2020;75:409–19) © 2020 the American College of Cardiology Foundation. Published by Elsevier. All rights reserved.

F

ractional flow reserve (FFR) is a validated

controlled trials, conducted predominantly in pa-

method to assess the functional significance

tients with stable ischemic heart disease (SIHD),

of epicardial coronary stenoses using coronary

have established the clinical utility of measuring

pressure

wire

measurements

(1,2).

Randomized

FFR

to

guide

coronary

revascularization

of

From the aDivision of Cardiology, University of California, Los Angeles, Los Angeles, California; bRocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado; cDepartment of Cardiology, Copenhagen University Hospital, Herlev and Gentofte, Denmark; dDepartment of Health Research and Policy, Department of Medicine, Stanford University School of Medicine, Listen to this manuscript’s

Stanford, California; eSection of Cardiology, University of Colorado School of Medicine, Aurora, Colorado; and the fDivision of

audio summary by

Cardiovascular Medicine and Stanford Cardiovascular Institute, Veterans Affairs Palo Alto Health Care System and Stanford

Editor-in-Chief

University School of Medicine, Stanford, California. The views expressed in this article are those of the authors and do not

Dr. Valentin Fuster on

necessarily reflect the position or policy of the Department of Veterans Affairs or the United States Government. This material is

JACC.org.

the result of work supported with resources and the use of facilities at the Rocky Mountain Regional VA Medical Center. Dr. Waldo has received unrelated research funding to the Denver Research Institute from Abiomed, Cardiovascular Systems Inc., and Merck Pharmaceuticals. Dr. Hlatky has received research funding from HeartFlow. Dr. Fearon has received research support from Abbott Vascular and Medtronic; and has minor stock options with HeartFlow. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received July 11, 2019; revised manuscript received October 2, 2019, accepted October 21, 2019.

ISSN 0735-1097/$36.00

https://doi.org/10.1016/j.jacc.2019.10.060

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JACC VOL. 75, NO. 4, 2020 FEBRUARY 4, 2020:409–19

FFR in Patients With Stable Ischemic Heart Disease

ABBREVIATIONS

angiographically intermediate stenoses. The

AND ACRONYMS

DEFER (Deferral Versus Performance of PCI

tions of the NCDR CathPCI Registry database (10,11).

of Non-Ischemia-Producing Stenoses) trial

Mortality data were obtained from the VA Vital Status

demonstrated the safety of deferring revas-

File, which extracts data from several VA and non-VA

cularization of stenoses with FFR values in

sources; of note, these data are not subclassified into

the nonischemic range (FFR >0.75) (3). The

cardiovascular or noncardiovascular mortality. This

FAME (Fractional Flow Reserve versus Angi-

study was approved by the Colorado Multiple In-

ography for Multivessel Evaluation) and

stitutions Review Board with a waiver of the

FAME 2 trials subsequently reported reduced

requirement to obtain informed consent.

major cardiovascular events when percuta-

STUDY POPULATION. The study population con-

neous

was

sisted of all patients who underwent coronary angi-

reserved for stenoses with FFR values in the

ography at a PCI-capable VA cardiac catheterization

ACS = acute coronary syndrome

CAD = coronary artery disease CI = confidence interval FFR = fractional flow reserve HR = hazard ratio NCDR = National Cardiovascular Data Registry

OR = odds ratio PCI = percutaneous coronary

coronary

intervention

(PCI)

ischemic zone (FFR #0.80) compared with

intervention

data elements comply with the standardized defini-

laboratory between January 1, 2009, and September

either angiography-only PCI (4,5) or medical

30, 2017, and had angiographically intermediate ste-

therapy alone (4,5). The latest American Col-

noses (defined as a 40% to 69% diameter stenosis on

lege of Cardiology/American Heart Associa-

visual inspection by the operator performing the

Clinical Assessment, Reporting,

tion

and Tracking Program

recommendation

SIHD = stable ischemic heart disease

VA CART = Veterans Affairs

guidelines

have for

given

a

Class

Ia

coronary angiogram), regardless of whether or not

revascularization

of

they

ultimately

underwent

PCI.

Patients

with

functionally significant stenoses, and a Class IIa

concomitant

recommendation for the use of FFR to assess interme-

chronic total occlusions and/or presenting with acute

diate stenoses (6,7).

coronary syndrome (ACS) were excluded from the

severe

stenoses

($70%)

including

primary analyses because before 2018 the VA CART

SEE PAGE 420

Program lacked the granularity to reliably link an FFR Adoption

of

an

FFR-guided

revascularization

measurement to a particular lesion. In addition, pa-

strategy in patients with SIHD and angiographically

tients were excluded if they had a prior coronary ar-

intermediate stenoses who undergo PCI rose from 8%

tery bypass grafting. If a patient underwent multiple

in 2009 to nearly 31% in 2014 in data from the Na-

coronary angiograms during the time frame, only the

tional Cardiovascular Data Registry (NCDR) CathPCI

first angiogram (i.e., index angiogram) was used in

Registry-based study (8), but these data do not cap-

the analyses.

ture patients who had a PCI deferred based on a nonischemic FFR value. More importantly, the published NCDR registry data did not address predictors of FFR-guided revascularization nor its effect on clinical outcomes. In the present report, we used data from the national Department of Veterans Affairs (VA) Clinical Assessment, Reporting, and Tracking (CART) Program to fill these evidence gaps by performing a contemporary, real-world analysis of temporal patterns and predictors of FFR utilization, and evaluating

its

impact

on

clinical

outcomes

among

unselected patients with angiographically intermediate coronary stenoses and SIHD.

DEFINITIONS AND OUTCOMES. FFR-guided PCI was

defined as PCI immediately following FFR measurement or in a staged procedure (i.e., nonurgent PCI of the interrogated stenosis within 30 days of the index coronary angiogram). A high-volume site was defined as one with greater than the median annual hospital volume

of

coronary

angiograms.

The

primary

endpoint was all-cause mortality at 1 year. Secondary endpoints included myocardial infarction, repeat revascularization,

stroke,

and

the

composite

endpoint of all-cause mortality, myocardial infarction, and repeat revascularization at 1 year. Myocardial infarction data were obtained based on standard

METHODS

International

Classification

of

Diseases-9th/10th

STUDY SAMPLE. Data for this study were derived

as

from the VA CART Program, a national quality and

excluding staged PCI (a 30-day window post–index

safety program for invasive cardiac procedures per-

angiogram was instituted to avoid counting staged

formed throughout the VA Healthcare System. Stan-

PCIs as repeat revascularizations).

dardized patient and procedural data from all VA

STATISTICAL ANALYSIS. FFR data were aggregated

cardiac catheterization laboratories are captured by a

by year and stratified by PCI, hospital volume, and

clinical software application that is embedded within

hospital site status to explore temporal trends and

the electronic health record, which links these data

variation in FFR utilization. Patient demographic and

with longitudinal clinical outcomes (9). The VA CART

clinical characteristics, as well as site-level factors,

Revision codes. Repeat revascularization was defined any

urgent

or

nonurgent

revascularization

Parikh et al.

JACC VOL. 75, NO. 4, 2020 FEBRUARY 4, 2020:409–19

were compared between FFR and angiography-only groups. To test the differences between the 2

T A B L E 1 Baseline Patient, Site-Level, and Procedural Characteristics

Overall (N ¼ 17,989)

groups, we used chi-square test for categorical variables and Mann-Whitney Wilcoxon nonparametric test for continuous variables. Missing values were

FFR (n ¼ 2,967, 16.5%)

Angiography-Only (n ¼ 15,022, 83.5%)

Patient factors Age, yrs

imputed using the Markov chain Monte Carlo multiple

Male

imputation method, under the assumption that all

Race

65.8  8.9

65  8.4

66  8.9

17,481 (97.2)

2,866 (96.6)

14,615 (97.3)

covariates had a joint multivariate normal distribu-

White

14,553 (80.9)

2,474 (83.4)

12,079 (80.4)

tion, with 15 imputations conducted based on

Black

3,065 (17.0)

426 (14.4)

2,639 (17.6)

maximum percentage of missingness (12). General-

Other

371 (2.1)

67 (2.3)

304 (2.0)

Hypertension

16,062 (89.3)

2,631 (88.7)

13,431 (89.4)

Hyperlipidemia

15,452 (85.9)

2,582 (87.0)

12,870 (85.7)

Diabetes

8,025 (44.6)

1,294 (43.6)

6,731 (44.8)

Tobacco use (current or former)

11,609 (64.5)

1,873 (63.1)

9,736 (64.8)

ized mixed models with random hospital intercept and logit link, including all patient, site-level, and procedural covariates listed in Table 1, were used to determine predictors of FFR use. All continuous

Family history of CAD

2,735 (15.2)

543 (18.3)

2,192 (14.6)

covariates were standardized to compare the relative

Prior MI

3,970 (22.1)

686 (23.1)

3,284 (21.9)

predictive strength of different covariates. Categorical

Prior PCI

4,302 (23.9)

838 (28.2)

3,464 (23.1)

covariates were not standardized to allow for com-

Prior heart failure

1,462 (8.1)

141 (4.8)

1,321 (8.8)

parison of odds ratios (ORs) at a clinically meaningful

Peripheral arterial disease

2,919 (16.2)

382 (12.9)

2,537 (16.9)

Cerebrovascular disease

2,694 (15.0)

408 (13.8)

2,286 (15.2)

Chronic kidney disease

3,531 (19.6)

468 (15.8)

3,063 (20.4)

scale. These logistic regression data are presented as ordered ORs with 95% confidence intervals (CIs). Site-

608 (3.4)

76 (2.6)

532 (3.5)

level variation in FFR utilization also was estimated

Body mass index, kg/m2

30.6  6.2

30.9  6.0

30.6  6.3

using a median OR. Time-to-event outcomes were

LVEF, %

52.6  14.2

54.2  13.0

52.3  14.4

analyzed using log-rank tests and Kaplan-Meier

Stress test

curves stratified by an FFR-guided revascularization

Positive

4,449 (25.7)

676 (23.9)

3,773 (26.0)

strategy. Multiple Cox proportional hazards models

Negative/equivocal

2,253 (13.0)

358 (12.6)

1895 (13.1)

adjusting for all covariates listed in Table 1 were used

None

10,619 (61.3)

1,800 (63.5)

8,819 (60.9)

17,498 (97.3)

2,890 (97.4)

14,608 (97.2)

to determine whether or not an FFR-guided revascularization strategy was independently associated with

Currently on dialysis

Site-level factors Academic affiliation Hospital volume

clinical outcomes. Site-level frailties were included in

High

13,380 (74.4)

2,189 (73.8)

11,191 (74.5)

the models to account for clustering by site. Given

Low

4,609 (25.6)

778 (26.2)

3,831 (25.5)

4,961 (33.0)

that all-cause mortality is a competing risk for

Procedural factors

myocardial infarction, stroke, and repeat revascular-

Extent of CAD

ization, a cause-specific hazard ratio (HR) for each of

3-vessel/left main

6,006 (33.4)

1,045 (35.2)

these secondary endpoints was first estimated by

2-vessel

5,693 (31.6)

939 (31.6)

4,754 (31.6)

1-vessel

6,290 (35)

983 (33.1)

5,307 (35.3)

treating

mortality

411

FFR in Patients With Stable Ischemic Heart Disease

as

censoring.

Subsequent

competing risk analyses were then carried out by

Values are mean  SD or n (%). Missing data: LVEF (14%), Stress test (3.7%), BMI (0.8%).

estimating a subdistribution HR. Cox proportional

CAD ¼ coronary artery disease; FFR ¼ fractional flow reserve; LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial infarction; PCI ¼ percutaneous coronary intervention.

hazards data are presented as HR with 95% CI. Statistical analyses were performed by CART Program analytic center using SAS version 9.4 (SAS Institute,

coronary artery disease (CAD) in the setting of SIHD.

Inc., Cary, North Carolina). A p value <0.05 was

FFR was used in 2,967 (16.5%) of these patients,

considered statistically significant.

whereas the remaining 15,022 (83.5%) underwent

RESULTS

level, and procedural characteristics stratified by use

angiography only (Figure 1). Baseline patient, siteof FFR were largely balanced between those with and STUDY POPULATION. Between January 1, 2009, and

without FFR, with modest (<5%) absolute differences

September 30, 2017, 104,708 patients with at least 1

(Table 1). Compared with patients in the angiography-

angiographically intermediate stenosis underwent

only group, those in the FFR group had higher rates of

coronary angiography at 1 of 66 PCI-capable VA sites.

prior PCI (28.2% vs. 23.1%) and lower rates of prior

After excluding 81,947 patients with concomitant

heart failure (4.8% vs. 8.8%), peripheral arterial dis-

severe stenoses, 2,552 presenting with ACS, and 2,220

ease (12.9% vs. 16.9%), and chronic kidney disease

patients with a prior coronary artery bypass grafting,

(15.8% vs. 20.4%). The differences between the

the final study population consisted of 17,989 pa-

groups were minimal with respect to stress test sta-

tients with angiographically intermediate native

tus, academic affiliation (only 2 of 66 sites were not

412

Parikh et al.

JACC VOL. 75, NO. 4, 2020 FEBRUARY 4, 2020:409–19

FFR in Patients With Stable Ischemic Heart Disease

F I G U R E 1 Study Design

Total number of patients undergoing coronary angiography at 66 FFR/PCI capable VA cardiac catheterization laboratories from January 1, 2009 to September 30, 2017 with at least 1 angiographically-intermediate stenosis (N = 104,708)

Concomitant severe stenosis (N = 81,947) ACS (N = 2,552) History of CABG (N = 2,220) Final SIHD cohort for analysis (N = 17,989)

Angiography-only revascularization (N = 15,022)

FFR-guided revascularization (N = 2,967)

ACS ¼ acute coronary syndrome; CABG ¼ coronary artery bypass grafting; FFR ¼ fractional flow reserve; PCI ¼ percutaneous coronary intervention; SIHD ¼ stable ischemic heart disease.

academically

affiliated),

and

extent

of

CAD

low-volume sites, although adoption of FFR at highvolume sites appears to be increasing (Figure 2).

on angiography. TEMPORAL PATTERNS AND PREDICTORS OF FFR

However, there was significant site-level variation in

UTILIZATION. Overall, use of FFR in patients with

the use of FFR (median OR: 3.56; 95% CI: 2.7 to 4.4)

angiographically intermediate stenoses and SIHD rose

after adjustment for all of the patient, site-level, and

from 14.8% in 2009 to 18.5% in 2017. This upward

procedural factors listed in Table 2 (Figure 3).

trend was consistent and magnified among the subset

Following

of patients undergoing PCI, increasing from 44% in

predictors of increased FFR utilization included prior

multivariate

adjustment,

independent

2009 to 75% in 2017 (Central Illustration) (the annu-

PCI (OR: 1.30), family history of CAD (OR: 1.18), more

alized raw data are provided in Online Table 1). The

extensive CAD (OR: 1.13), and higher left ventricular

percentage of patients who underwent FFR without

ejection fraction (OR: 1.08), whereas independent

subsequent PCI or coronary artery bypass grafting

predictors of decreased FFR utilization included prior

(i.e.,

heart failure (OR: 0.58), peripheral arterial disease

nonischemic

FFR)

was

82%

overall,

and

remained relatively unchanged from 2009 to 2017

(OR: 0.80), and older age (OR: 0.91) (Table 2).

(Online Table 2). The deferred revascularization rate

FFR-GUIDED REVASCULARIZATION STRATEGY AND

among those who underwent angiography only was

CLINICAL OUTCOMES. Revascularization occurred in

higher (96%) and similarly remained stable over time.

537 patients in the FFR group (487 PCI, 50 coronary

The median hospital volume of coronary angio-

artery bypass grafting) and 631 patients in the

grams was 241 (interquartile range: 134 to 365), and

angiography-only group (331 PCI, 300 coronary artery

the median hospital rate of FFR use was 11.3%

bypass grafting). Notably, only 186 (29.5%) of those

(interquartile range: 8.1% to 21.3%). FFR utilization

patients who underwent angiography-only revascu-

did

larization had documented ischemia with a positive

not

appreciably

differ

between

high-

and

Parikh et al.

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FFR in Patients With Stable Ischemic Heart Disease

C ENTR AL I LL U STRA T I O N Fractional Flow Reserve–Guided Revascularization of Angiographically Intermediate Coronary Stenoses in Stable Ischemic Heart Disease: Temporal Trends and Impact on 1-Year All-Cause Mortality

80 PCI 70

FFR Utilization (%)

60

50

40

30 All-Comers 20

10 2009

2010

2011

2012

2013 Year

2014

2015

2016

2017

All-Cause Mortality Event Probability

0.08 0.06 0.04 0.02 0.00 0

120

240 Days

Number at risk 15,022 2,967

14,154 2,809 Angio-Only

360 Logrank p < 0.0001

13,372 2,679

12,710 2,534 FFR

Parikh, R.V. et al. J Am Coll Cardiol. 2020;75(4):409–19.

The utilization of a fractional flow reserve (FFR)-guided revascularization strategy in patients with angiographically intermediate stenoses and stable ischemic heart disease has steadily increased from 2009 to 2017. In particular, the rate of adoption in the percutaneous coronary intervention (PCI) arena has reached 75%. Furthermore, an FFR-guided revascularization strategy is associated with significantly lower all-cause mortality at 1 year compared with an angiography (Angio)-only revascularization strategy.

413

Parikh et al.

414

JACC VOL. 75, NO. 4, 2020 FEBRUARY 4, 2020:409–19

FFR in Patients With Stable Ischemic Heart Disease

lower rate of drug-eluting stent implantation and

F I G U R E 2 Temporal Patterns of FFR Utilization Stratified by

higher rate of angioplasty only (Online Table 3). Statin

Hospital Volume

and beta-blocker use at 90 days was similar between the groups regardless of revascularization status,

25

although nearly half of the patients who underwent FFR Utilization (%)

High Volume

revascularization

20

were

not

taking

a

statin

(Online Table 4). Overall, 89.9% of the cohort completed 1-year follow-up, and the rate of all-cause mortality was

15

lower among those who underwent revascularization

Low Volume

compared with those who did not (4.4% vs. 5.5%). The primary endpoint of all-cause mortality at 1 year

10

(Central Illustration) was 2.8% of patients in the FFR group and 5.9% of patients in the angiography-only 5

group (log-rank p < 0.0001), which corresponds to a

2009 2010 2011 2012 2013 2014 2015 2016 2017 Year

52.5% relative risk reduction and 3.1% absolute risk reduction

with an FFR-guided revascularization

strategy. There were no significant differences in The rate of FFR use was similar between high- and low-volume sites,

cumulative event-free rates for the secondary end-

although adoption of FFR at high-volume sites appears to be gradually

points of myocardial infarction, repeat revasculari-

increasing. FFR ¼ fractional flow reserve.

zation, and stroke at 1 year, whereas the composite outcome of all-cause mortality, myocardial infarction, and repeat revascularization at 1 year occurred

stress test. Among the PCI cohort, 68% received drug-

less frequently in the FFR group (6.8% vs. 9.3%, log-

eluting stents, 9.5% received bare metal stents, 22.1%

rank p < 0.0001) (Figure 4). In multiple Cox regres-

received angioplasty only, and 0.40% received both

sion adjusted analyses, an FFR-guided revasculari-

drug-eluting and bare metal stents; compared with

zation strategy was associated with a 43% lower risk

the FFR group, the angiography-only group had a

of all-cause mortality at 1 year (HR: 0.57; CI: 0.45 to 0.71; p < 0.0001) compared with an angiography-only revascularization strategy. The risk of myocardial

T A B L E 2 Predictors of FFR Utilization

infarction, repeat revascularization, and stroke at 1

Prior heart failure

OR

Multivariate 95% CI

p Value

0.58

0.47–0.70

<0.0001

year was similar between the groups, whereas the risk of the composite endpoint of all-cause mortality, myocardial infarction, and repeat revascularization at

Academic affiliation

0.69

0.18–2.65

0.59

Peripheral arterial disease

0.80

0.70–0.91

0.0006

1 year (HR: 0.80; CI: 0.69 to 0.93; p ¼ 0.004) was

Chronic kidney disease

0.89

0.79–1.01

0.07

significantly lower in the FFR group than the

Currently on dialysis

0.91

0.69–1.21

0.52

angiography-only group (Table 3). Of note, these

Age, per 8.9-yr increase

0.91

0.87–0.96

0.0001

cause-specific HRs were very similar to the sub-

Male

0.92

0.72–1.17

0.50

Tobacco use, current or former

0.94

0.86–1.03

0.22

Diabetes

0.98

0.90–1.08

0.72

Hypertension

1.01

0.87–1.16

0.94

stenoses and/or presenting with ACS yielded consistent outcome data (Online Table 5).

distribution HRs. Last, a secondary analysis including patients with concomitant angiographically severe

Cerebrovascular disease

1.01

0.89–1.15

0.87

Body mass index (per 6.2-U increase)

1.02

0.97–1.07

0.47

Prior MI

1.02

0.90–1.15

0.75

Race, white vs. not white

1.05

0.93–1.19

0.41

Stress study, none/negative/equivocal vs. positive

1.07

0.96–1.18

0.23

Hyperlipidemia

1.08

0.95–1.23

0.26

LVEF, per 14.2% increase

1.08

1.03–1.14

0.004

Extent of CAD, 3-vessel/left main vs. 1- or 2-vessel

1.13

1.03–1.23

0.01

stenoses and SIHD demonstrates the following: 1) that

DISCUSSION This contemporary VA CART registry-based study of 17,989 patients with angiographically intermediate

Hospital volume, per 166-angiogram increase

1.15

0.90–1.46

0.26

utilization of an FFR-guided revascularization strat-

Family history of CAD

1.18

1.05–1.33

0.005

egy increased slowly between 2009 and 2017, but rose

Prior PCI

1.30

1.16–1.46

<0.0001

more quickly among patients undergoing PCI; and 2) after adjusting for differences in patient, site-level,

OR for continuous variables are per increase by 1 SD. CI ¼ confidence interval; OR ¼ odds ratio; other abbreviations as in Table 1.

and procedural factors, an FFR-guided revascularization strategy was associated with a significantly

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FFR in Patients With Stable Ischemic Heart Disease

F I G U R E 3 Site-Level Variation in Use of FFR

Hospital FFR Utilization (%)

100

80

60

40

20

0 2009

2010

2011

2012

2013 Year

2014

2015

2016

2017

There is significant site-level variation in fractional flow reserve (FFR) utilization. The median rate and range of FFR use by site increased from 2009 to 2013, but has remained relatively stable thereafter. Upper edge of box ¼ 75th percentile; lower edge of box ¼ 25th percentile; line inside box ¼ 50th percentile (median); diamond ¼ mean; upper whisker ¼ maximum value below 1.5 times of interquartile range (IQR) above 75th percentile; lower whisker ¼ minimum value above 1.5 times IQR below 25th percentile; circle ¼ extreme values beyond 1.5 (IQR) above 75th percentile or below 25th percentile.

lower risk of all-cause mortality at 1 year compared

similar but 2-fold higher upward trend in FFR-guided

with an angiography-only revascularization strategy

PCI in the VA Healthcare System during that time

(Central Illustration). The current study expands on

period: from 44% in 2009 up to 62% in 2014, and ul-

the published NCDR data by capturing the entire

timately reaching 75% in 2017. Potential hypotheses

spectrum of patients undergoing FFR to direct

for the more widespread adoption of FFR observed in

revascularization of angiographically intermediate

this VA-based study is the greater degree of site aca-

stenoses in SIHD (i.e., regardless of whether PCI was

demic affiliation compared with the NCDR study (97%

performed or deferred) spanning from the publication

vs. 48%) and the lack of fee-for-service reimburse-

of FAME to present day and by evaluating predictors

ment in the VA. Compared with the PCI cohort, the

of FFR use and its association with hard clinical

rise in FFR use among all-comers with angiographic-

outcomes. Furthermore, these robust, real-world,

ally intermediate stenoses and SIHD in our study was

observational data provide further support for the

more modest (14.8% in 2009 to 18.5% in 2017), high-

adoption of an FFR-guided revascularization strategy

lighting that FFR remains underused. However, these

in patients with angiographically intermediate ste-

data are likely exaggerated by the limitation of the VA

noses and SIHD.

CART Program in being unable to restrict all-comers

TEMPORAL TRENDS IN FFR UTILIZATION. To the

to those with anatomically and clinically relevant

best of our knowledge, the present study provides

angiographically intermediate lesions based on vessel

the most comprehensive and contemporary data on

size, lesion appearance and location, and symptom-

real-world FFR utilization to guide revascularization

atology. Thus, the PCI cohort may be a more accurate

of angiographically intermediate stenoses in SIHD. A

and relevant barometer for overall FFR utilization

prior NCDR CathPCI Registry-based study of nearly

over time.

400,000 patients at 766 sites with SIHD and angio-

Similar to FAME, the present registry-based study

graphically intermediate stenosis, all of whom un-

demonstrated that an FFR-guided revascularization

derwent PCI, reported a gradual rise in FFR use, from

strategy

8% in 2009 to nearly 31% in 2014 (8). We observed a

angiography-only strategy. The rate of deferred

resulted

in

less

overall

PCI

than

an

415

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FFR in Patients With Stable Ischemic Heart Disease

F I G U R E 4 Association of FFR-Guided Revascularization With Secondary Clinical Endpoints

Event Probability

MI

Repeat Revascularization

0.06

0.06

0.04

0.04

0.02

0.02

0.00

0.00 0

120

240

360

0

120

240

360

Logrank p = 0.37

Logrank p = 0.33

Number at risk

Number at risk

15,022

14,106

13,297

12,604

15,022

13,877

13,005

12,270

2,967

2,798

2,665

2,515

2,967

2,737

2,598

2,432

240

360

Composite Outcome Event Probability

416

Stroke

0.09

0.09

0.06

0.06

0.03

0.03 0.00

0.00 120

0

240

360

120

0

Days

Days Logrank p < 0.0001

Number at risk

Logrank p = 0.06 Number at risk

15,022

13,849

12,965

12,227

15,022

14,112

13,296

12,614

2,967

2,731

2,589

2,423

2,967

2,806

2,671

2,523

Angio-Only

FFR

Kaplan-Meier analysis demonstrated no significant differences between the fractional flow reserve (FFR) and angiography (Angio)-only groups in eventfree survival at 1 year with respect to the secondary endpoints of myocardial infarction (MI), repeat revascularization, and stroke. However, the composite endpoint of all-cause mortality, MI, and repeat revascularization occurred significantly less frequently in the FFR group.

revascularization (i.e., nonischemic FFR) in this

although

study was 82% overall, and did not appreciably

fee-for-service and almost entirely academically

change from 2009 to 2017. In contrast, the rate of

affiliated, we still detected significant site-level vari-

nonischemic FFR reported in FAME was 37%. This

ation in FFR. This important finding suggests that the

implied variation in operator use of FFR between the

main reason for FFR underutilization in the contem-

real-world and randomized controlled trial setting is

porary era is operator belief regarding the utility of

likely explained by the substantial difference in the

coronary physiology, and that revised reimbursement

severity of stenoses interrogated. None of the steno-

policies and additional education/training may not

ses in our study were angiographically severe ($70%),

have a meaningful impact on FFR adoption.

the

VA

Health

Care

System

is

not

whereas nearly 59% of the stenoses in FAME were

We also found that prior PCI, 3-vessel/left main

angiographically severe due to the trial protocol,

CAD, family history of CAD, younger age, absence of

and hence much more likely to fall in the ischemic

heart failure, higher left ventricular ejection frac-

FFR range.

tion, and absence of peripheral arterial disease were

PREDICTORS OF FFR USE. After adjustment for all

independent predictors of FFR utilization. Unsur-

patient,

prisingly, these findings suggest that operators elect

site-level,

and

procedural

factors,

and

Parikh et al.

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FFR in Patients With Stable Ischemic Heart Disease

T A B L E 3 Association of FFR-Guided Revascularization With Clinical Outcomes at 1 Year

FFR (n ¼ 2,967)

Angiography-Only (n ¼ 15,022)

82 (2.8)

890 (5.9)

Univariate

Multivariate

HR (95% CI)

p Value

HR (95% CI)

p Value

Primary endpoint All-cause mortality

0.46 (0.37–0.58) <0.0001 0.57 (0.45–0.71) <0.0001

Secondary endpoints MI

19 (0.64)

Repeat revascularization Composite of all-cause mortality, MI, and repeat revascularization Stroke

111 (0.79)

112 (3.8)

510 (3.4)

203 (6.8)

1,403 (9.3)

13 (0.44)

112 (0.75)

0.80 (0.49–1.30)

0.37

0.77 (0.47–1.27)

1.11 (0.90–1.36)

0.33

1.04 (0.84–1.28)

0.31 0.74

0.73 (0.63–0.85) <0.0001 0.80 (0.69–0.93)

0.004

0.58 (0.33–1.03)

0.19

0.06

0.68 (0.38–1.21)

Values are n (%) unless otherwise indicated. HRs are adjusted for all covariates listed in Table 1. HR ¼ hazard ratio; other abbreviations as in Tables 1 and 2.

to measure FFR in younger patients lacking signif-

In contrast to our registry-based data, FAME did

icant comorbidities who have more extensive CAD.

not report a statistically significant survival benefit

However,

of

with FFR-guided revascularization, although it did

documented ischemia on stress testing did not

demonstrate similar relative and absolute risk re-

predict the use of FFR in angiographically inter-

ductions in all-cause mortality at 1 year to our study

mediate SIHD. Indeed, only 29.5% of patients who

(52% vs. 58% and 3.1% vs. 1.2%, respectively). More

underwent angiography-only revascularization had

recently, a patient-level meta-analysis of 3 random-

a preceding positive stress test. Although angio-

ized controlled trials (FAME 2, DANAMI-3-PRIMULTI

graphic lesion appearance and/or findings from

[Complete Revascularization Versus Treatment of

intravascular imaging or other physiologic modal-

the Culprit Lesion Only in Patients with ST-segment

ities may have justified a portion of the in-

Elevation Myocardial Infarction and Multivessel Dis-

terventions, these data highlight that potentially

ease], and COMPARE-ACUTE [Comparison Between

somewhat

unexpectedly,

the

lack

inappropriate revascularization remains a major

FFR Guided Revascularization Versus Conventional

issue in the current era.

Strategy in Acute STEMI Patients With MVD])

FFR-GUIDED REVASCULARIZATION AND OUTCOMES.

comparing FFR-directed revascularization with med-

Our large sample of 17,989 patients with angio-

ical therapy in 2,400 patients with stable coronary

graphically intermediate stenoses and SIHD, coupled

stenoses reported significantly lower myocardial

with complete prospective follow-up, allowed us to

infarction in the FFR arm (8.5% vs. 13.4%, HR: 0.70;

evaluate the impact of an FFR revascularization

CI: 0.51 to 0.97; p ¼ 0.03), but found no difference in

strategy on 1-year clinical outcomes. Following

all-cause or cardiac mortality (13). However, as evi-

adjustment for patient, site-level, and procedural

denced by the increased mortality rate and the more

factors, we found that an FFR-directed approach was

than 10-fold higher rate of myocardial infarction in

associated with a 43% lower rate of all-cause mor-

the meta-analysis (albeit over longer-term follow-up),

tality at 1 year compared with an angiography-only

these discordant findings likely reflect a few funda-

approach in SIHD. However, myocardial infarction,

mental differences in the study cohorts. Our study

repeat revascularization, and stroke occurred at

only involved patients with SIHD and angiographic-

similar rates between the groups. A number of factors

ally intermediate disease, whereas the meta-analysis

may explain the lower all-cause mortality in the FFR

captured a higher-risk population that included both

group compared with the angiography-only group

patients with SIHD (37%) and stable nonculprit ste-

despite

noses

no

significant

difference

in

myocardial

in

the

setting

of

ST-segment

elevation

infarction: 1) significant site-level variation in FFR

myocardial infarction (63%) regardless of angio-

utilization; 2) residual confounding by unaccounted-

graphic severity (FAME 2, 58% angiographically se-

for differences between the groups, such as operator

vere; nonculprit stenosis severity not reported in the

variation in adoption of an FFR-guided revasculari-

other 2 trials). In addition, our cohort had a sub-

zation strategy; and 3) underpowered to detect a

stantially lower burden of ischemia (18% with FFR-

difference in myocardial infarction given the very low

positive stenoses) than that of the meta-analysis

number of myocardial infarctions in both groups at 1-

(FAME

year follow-up.

COMPARE-ACUTE, 51%) (13).

2,

100%;

DANAMI-3-PRIMULTI,

69%;

417

418

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FFR in Patients With Stable Ischemic Heart Disease

with

regarding the technical performance of FFR (e.g.,

concomitant angiographically severe stenoses and/or

Last,

although

we

excluded

wire position in the interrogated vessel, dose and

ACS from our primary analysis because of limitations

route of adenosine) were not reliably available.

concerning the granularity of the lesion-specific FFR

Fourth, the outcome analyses were restricted to a 1-

data, a secondary analysis including these patients

year follow-up period. We chose the 1-year time

demonstrated consistent outcome results. Thus, our

point to eliminate censoring and because prior

data may extend to the ACS population and supports

studies have shown that deferred coronary stenoses

FFR-guided

angio-

with an FFR >0.80 treated with optimal medical

graphically intermediate stenoses irrespective of pa-

therapy have an excellent prognosis and low event

revascularization

patients

strategy

of

tient presentation.

rate even out to 15 years (17). Finally, owing to the FFR-GUIDED

demographic makeup of the VA patient population,

REVASCULARIZATION. We anticipate the progres-

our cohort was predominantly male and may be less

sive rise in the adoption of an FFR-guided revas-

generalizable to nonveteran populations, although

cularization strategy to continue in the future.

the reasonably large proportion of black patients

FUTURE

DIRECTIONS

IN

First, the heightened focus on appropriate use

provides important data for this previously under-

criteria for PCI with respect to reimbursement in-

studied group.

centives in the coming years may lead to greater use of FFR in patients with angiographically inter-

CONCLUSIONS

mediate SIHD and reduce the amount of potentially inappropriate angiography-only PCI without docu-

Adoption of an FFR-guided revascularization strat-

mented

a

egy in patients with SIHD and angiographically in-

number of recent trials have reported encouraging

termediate coronary stenoses has slowly increased

data regarding the

benefit of an FFR-directed

from 2009 to 2017, and is associated with a signifi-

approach for revascularization of nonculprit steno-

cant reduction in all-cause mortality at 1 year

ses across the spectrum of ACS; the application of

compared with an angiography-only revasculariza-

FFR in this domain is expected to be included by

tion strategy.

ischemia

on

stress

testing.

Second,

the next set of updated ACS guidelines (14–16). coronary

ADDRESS FOR CORRESPONDENCE: Dr. William F.

physiologic indices such as nonhyperemic pressure

Fearon, Division of Cardiovascular Medicine, Veter-

ratios, angiography-derived FFR, and computed

ans Affairs Palo Alto Health Care System and Stanford

tomography–derived FFR will likely increase the

University, 300 Pasteur Drive, Room H2103, Palo Alto,

Finally,

the

emergence

of

alternative

overall utilization of coronary physiology to direct

California 94035. E-mail: [email protected] OR

revascularization. Future registry-based studies ac-

[email protected].

counting for all physiologic modalities are war-

@StephenWaldoMD, @wfearonmd.

Twitter:

@rushiparikh11,

ranted to accurately quantify the landscape of coronary physiology-guided revascularization. STUDY LIMITATIONS. First, although we adjusted

for known patient, site-level, and procedural confounders, the data are observational in nature, and inherently subject to residual confounding. For

PERSPECTIVES COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: In patients with SIHD and

example, angiographic severity of coronary stenoses

coronary stenosis of intermediate angiographic severity,

was assessed by the operator rather than by core

revascularization guided by measurement of FFR is

laboratory adjudication; as such, operator reporting

associated with a lower risk of 1-year mortality compared

variability, particularly with respect to stenoses

with guidance by angiographic assessment alone.

interrogated with FFR, is a major unmeasured confounder. Second, as described previously, the data lacked granularity to differentiate between a number of important factors, including cardiovascular versus noncardiovascular mortality, which precluded further mechanistic analysis of the survival

benefit

observed

with

FFR.

Third,

data

TRANSLATIONAL OUTLOOK: Future studies should quantify the adoption of physiologically guided coronary revascularization and assess the alignment of these data with appropriate use criteria, and reimbursement policy.

Parikh et al.

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FFR in Patients With Stable Ischemic Heart Disease

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A PP END IX For supplemental tables, please see the online version of this paper.

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