Received: 8 May 2017
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Revised: 18 June 2017
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Accepted: 4 August 2017
DOI: 10.1002/ccd.27302
ORIGINAL STUDIES
Fractional flow reserve versus angiography guided percutaneous coronary intervention: An updated systematic review Tariq Enezate, MD1
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Jad Omran, MD2
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Ashraf S. Al-Dadah, MD3 |
Martin Alpert, MD1 | Christopher J. White, MD4 | Mazen Abu-Fadel, MD5 | Herbert Aronow, MD6 | Mauricio Cohen, MD7
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Frank Aguirre, MD3 |
Mitul Patel, MD2 | Ehtisham Mahmud, MD2 1 Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, Missouri
Abstract Objectives: To compare outcomes of fractional flow reserve (FFR) to angiography (ANGIO) guided
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Division of Cardiovascular, University of California at San Diego, Sulpizio Cardiovascular Center, La Jolla, California 3
percutaneous coronary intervention (PCI). Background: The results of a recent randomized controlled trial reported unfavorable effects of
Section of Cardiovascular Disease, Prairie Cardiovascular Consultant, Springfield, Illinois
routine measurement of FFR, thereby questioning its validity in improving clinical outcomes.
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queried from January, 2000 through December, 2016 and studies comparing FFR and ANGIO
Department of Cardiology, Ochsner Medical Center, New Orleans, Louisiana 5
Section of Cardiovascular Disease, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 6
Division of Cardiovascular Medicine, Rhode Island and Miriam Hospitals, Providence, Rhode Island 7
School of Medicine, University of Miami Hospital, Miami, Florida
Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were guided PCI were included. Clinical endpoints assessed during hospitalization and at follow-up (>9 months) included: myocardial infarction (MI), major adverse cardiovascular events (MACE), target lesion revascularization (TLR), and all-cause mortality. Additional endpoints included number of PCIs performed, procedure cost, procedure time, contrast volume, and fluoroscopy time. Results: A total of 51,350 patients (age 65 years, 73% male) were included from 11 studies. The use of FFR was associated with significantly lower likelihood of MI during hospitalization (OR 0.54, 95% CI: 0.39 to 0.75, P 5 0.0003) and at follow-up (OR 0.53, 95% CI: 0.40 to 0.70,
Correspondence Tariq Enezate, MD, Room CE-306, University of Missouri/Health Sciences Center, 5 Hospital Drive, Columbia, MO 65201, USA. Email:
[email protected]
P 5 0.00001). Similarly, FFR-PCI was associated with lower in-hospital MACE (OR 0.51, 95% CI: 0.37 to 0.70, P 5 0.0001) and follow-up MACE (OR 0.63, 95% CI: 0.47 to 0.86, P 5 0.004). In-hospital TLR was lower in the FFR-PCI group (OR 0.62, 95% CI: 0.40 to 0.97, P 5 0.04), but not at follow-up (OR 0.83, 95% CI: 0.50 to 1.37, P 5 0.46). There was no difference of in-hospital (OR 0.58, 95% CI: 0.31 to 1.09, P 5 0.09) or follow-up all-cause mortality (OR 0.84, 95%CI: 0.59 to 1.20, P 5 0.34). FFR-PCI was associated with significantly less PCI (OR 0.04, 95% CI: 0.01 to 0.15, P 5 0.00001) with lower procedure cost (Mean Difference 24.27, 95% CI: 26.61 to 21.92, P 5 0.0004). However, no difference in procedure time (Mean Difference 0.79, 95% CI: 22.41 to 3.99, P 5 0.63), contrast use (Mean Difference 28.28, 95% CI: 224.25 to 7.68, P 5 0.31) or fluoroscopy time (Mean Difference 0.38, 95% CI: 22.54 to 3.31, P 5 0.80) was observed. Conclusions: FFR-PCI as compared to ANGIO-PCI is associated with lower in-hospital and followup MI and MACE rates. Although, in-hospital TLR was lower in the FFR-PCI group, this benefit was not present after 9 months. FFR-PCI group was also associated with less PCI and lower procedure costs with no effect on procedure time, contrast volume or fluoroscopy time.
Catheter Cardiovasc Interv. 2017;1–10.
wileyonlinelibrary.com/journal/ccd
C 2017 Wiley Periodicals, Inc. V
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KEYWORDS
coronary stenosis, fractional flow reserve, hemodynamic assessment, percutaneous coronary intervention
1 | INTRODUCTION
defined as a repeated PCI or coronary artery bypass graft surgery
Percutaneous coronary intervention (PCI) is currently indicated for
posite endpoint of all-cause death, nonfatal MI, TRL, and stroke
flow-limiting coronary lesions associated with myocardial ischemia
[6,13,14].
involving the target vessel [4,6,15–18]. MACE was defined as the com-
when guideline-directed medical therapy is expected to have suboptimal outcomes and/or fails to control ischemic symptoms [1]. Angiography (ANGIO) alone is limited by both intraobserver and interobserver variability and inability to determine the hemodynamic significance of intermediate coronary lesions (40–70% stenosis range) [2,3]. FFR is a validated tool that is used to assess the hemodynamic significance of intermediate lesions facilitating decision making for intervention [2]. The benefit of FFR guided PCI (FFR-PCI) over ANGIO guided PCI (ANGIO-PCI) has been established in several studies [4–9]. However, a recent trial has suggested that routine FFR evaluation was associated with adverse effects including higher mortality, thereby questioning the routine use of FFR to improve clinical outcomes [10]. Due to these disparities, we performed a systematic review and meta-analysis to compare clinical and procedural outcomes with both strategies.
2 | METHODS The study was performed in accordance with the recommendations of the Cochrane collaboration and is reported in accordance with those set forth by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [11]. The aim of this meta-analysis
2.2 | Information sources and search methods A comprehensive literature search was conducted through the electronic databases MEDLINETM, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) from January 2000 through December 2016 for abstracts using various combinations of the terms: fractional flow reserve (FFR) guided revascularization, ANGIO-guided revascularization, intermediate coronary lesions, hemodynamic assessment, and revascularization outcomes. We included studies that were double-armed comparing FFR to ANGIO-PCI groups, and studies reporting at least a portion of the endpoints of interest. We excluded single armed studies, studies of left main coronary artery disease and studies that did not report endpoints of interest. Two reviewers (TE, JO) identified studies eligible for further review by performing a screen of abstracts and titles. If a study met the inclusion criteria, the manuscript was obtained and reviewed. In addition, bibliographic references of identified randomized clinical trials and review articles were reviewed.
2.3 | Study identification
was to compare outcomes associated with FFR versus ANGIO-PCI in
The previously described data sources were searched for possible stud-
patients with ischemic heart disease.
ies irrespective of dates of publications. The search was limited to English-language literature. We included original papers irrespective of
2.1 | Study endpoints and definitions The primary endpoints were myocardial infarction (MI), major adverse cardiovascular events (MACE), target lesion revascularization (TLR) and all-cause mortality at in-hospital and follow-up ( 9 months). Secondary endpoints included the number of PCIs performed, the procedure cost, the procedure time, the volume of contrast used and fluoroscopy time for each strategy. PCI-related MI was defined based on Universal Myocardial Infarc-
randomization. The initial search identified 200 citations. A total of 160 citations were excluded by reviewing the abstract/title. Of the final 40 studies, we identified 11 original papers that fulfilled the criteria for inclusion (Supporting Information Figure S1).
2.4 | Data collection and extraction Two independent reviewers (TE, JO) extracted data from the included studies by using pre-specified data elements. Data were abstracted on
tion Definition Document as cardiac biomarker increase of more than
patients’ demographics and baseline characteristics, study design, sam-
three times the 99th percentile upper reference limit in two or more
ple size, aim of each study, value of FFR used, target lesion type, clini-
blood samples with/without electrocardiographic ischemic changes
cal setting and type of endpoint measures when available.
(i.e., MI type 4a) [6,12–17]. Follow up MI was defined as (two out of
One review author extracted the data from included studies and a
three criteria): prolonged chest pain 20 min, elevated biomarkers lev-
second author verified the extracted data. The numbers of events in
els (serum creatine kinase or troponin) over two-fold higher than the
each study were extracted when available. Table 1 depicts patients’
upper reference range and ST-T segment changes or new Q waves on
baseline characteristics, demographics, studies type and type of target
serial electrocardiogram indicative of myocardial damage [18]. TLR was
lesions and clinical settings of each study [4–7,10,14,16–20].
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T AB LE 1
Studies characteristics, FFR values, clinical setting, and patients’ demographics
Study/author
Year
Type
FFR value
Koo
2008
Prospective/ nonrandomized
0.75
FAME/Pijls
FAMOUS/Layland
FUTURE/Rioufol
DKCRUSH-VI/Chen
Wongpraparut
DEFER-DES/Park
Frohlich
Di Serafino
Li
Puymirat
3
2010
2014
2016
2015
2005
2015
2014
2013
2013
2012
Prospective/ randomized
Prospective/ randomized
Prospective/ randomized
Prospective/ randomized
Prospective/ nonrandomized
Prospective/randomized
Retrospective/ observational
Retrospective/ observational
Retrospective/ observational
Retrospective/ observational
0.8
0.8
0.8
0.8
0.75
0.75
NA
0.8
0.75–0.80
0.8
Target lesion/ setting
Follow-up (month)
Group
No. of patients
Mean age
Male %
Side branch of bifurcation lesions
9
FFR
110
62
68
ANGIO
110
63
70
FFR
509
65
75
ANGIO
496
64
73
FFR
176
62
76
ANGIO
174
62
73
FFR
465
65
86
ANGIO
469
66
82
FFR
160
65
76
ANGIO
160
65
73
FFR
57
58
75
ANGIO
80
62
79
FFR
114
62
69
ANGIO
115
63
72
FFR
2,767
64
74
ANGIO
37,090
66
74
FFR
65
69
77
ANGIO
158
71
77
FFR
1,090
66
70
ANGIO
6,268
68
63
FFR
222
72
58
ANGIO
495
72
68
Native multivessel disease
NSTEMI
12
Multivessel stable disease
Side branch of bifurcation lesions
Multivessel stable disease
Stable native disease
Stable and unstable disease
stable and unstable bypass graft disease
Stable and unstable disease
Stable and unstable native small vessel disease
2.5 | Risk of bias assessment Methodological quality was defined as the control of bias assessed through the reported methods in each individual study using the Cochrane risk of bias tool [21] to assess quality of randomized trials.
24
12
12
30
60
39
46
51
40
attrition bias due to incomplete follow-up/early termination of one study (Supporting Information Tables S1 and S2).
2.6 | Statistical analysis and data synthesis
The Newcastle-Ottawa Scale (NOS) [22] was used to assess the quality
From the abstracted data, the odds ratio (OR) using the inverse var-
of observational studies. Two reviewers (JO, TE) independently
iance method for each study outcome to allow for pooling of similar
assessed each study quality by examining risk of bias tool components.
outcomes was calculated. The average effects for the outcomes and
Funnel plot test showed no evidence of publication bias by showing
95% confidence intervals (CI) were obtained using a random effects
symmetrical distribution of the studies (Supporting Information Figure
model, as described by DerSimonian [21].
S2). There was a possibility of performance and detection bias due to
To assess heterogeneity of treatment effect among trials, we used
nonblinding in two studies, there also was risk of selection bias due to
the I2 statistic method. The I2 statistic represents the proportion of het-
nonrandomization in two studies and there was possible limited
erogeneity of treatment effect across trials that were not attributable
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F I G U R E 1 The measure of effect of FFR on MI in each study were plotted using OR and 95% CI on a forest plot. The overall results showing lower MI in (i.e., favors) FFR group during hospitalization (A) and at follow-up (B) [Color figure can be viewed at wileyonlinelibrary. com]
to chance or random error. Hence, a value of 50% or more reflects sig-
0.39 to 0.75, P 5 0.0003) and at follow-up (OR 0.53, 95% CI: 0.40 to
nificant heterogeneity that is due to real differences in study popula-
0.70, P 5 0.00001, Figure 1A,B). FFR-PCI was associated with lower in-hospital MACE (OR 0.51,
tions, protocols, interventions, and outcomes [21]. The P-value threshold for statistical significance was set at 0.8) at the time of the initial
ciated with improved long-term survival, although the incidence of in-
catheterization (i.e., hemodynamically insignificant, but anatomically
hospital mortality and procedural complications were lower in the
vulnerable for rupture) [6].
FFR group [19]. The authors concluded that a survival benefit from a
The use of FFR for the evaluation of the hemodynamic significance
diagnostic FFR procedure was hard to prove, particularly in stable
of intermediate coronary lesions in patients with stable ischemic heart
ischemic heart disease in which PCI has not demonstrated clear sur-
disease has been endorsed by American College of Cardiology/Ameri-
vival benefit when compared to medical therapy. The authors also
can Heart Association (ACC/AHA) as well as European Society of Car-
concluded that the benefits of FFR reported from other studies were
diology in their 2015 guidelines [24–26].
mainly related to fewer adverse events (mainly MI, TLR) and from the
These recommendations are supported by several early studies
stent sparing effect of FFR (which can explain lower procedural com-
including DEFER (FFR to Determine the Appropriateness of Angio-
plications in the FFR group) rather than mortality benefits. However,
plasty in Moderate Coronary Stenosis), FAME (FFR versus ANGIO for
these studies were not powered to detect difference in survival rates
Guiding PCI) and FAME-2 (FFR–Guided PCI versus Medical Therapy in
[5,8,9,19].
Stable Coronary Disease) trials, all of which have proven safety and
The recently published FUTURE (Functional Testing Underlying
showed superior outcomes of FFR-PCI compared with ANGIO-PCI or
Revascularization) trial does question the benefit of FFR-PCI given the
best medical therapy alone [5,8,9].
lack of improvement in MI, MACE, or TLR at one year. This study was
FFR utility has been demonstrated in several clinical settings,
halted prematurely due to excess all-cause mortality at one year in
including stable native coronary artery disease, multivessel coronary
the FFR-PCI group (4%) in comparison to the ANGIO-PCI group (2%,
Mean procedure time. The measure of effect of FFR on the mean procedure time in each study were plotted using OR and 95% CI on a forest plot. The overall results showing no significant difference between FFR and ANGIO groups regarding procedure time [Color figure can be viewed at wileyonlinelibrary.com]
FIGURE 7
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Average contrast volume use per procedure. The measure of effect of FFR on the average contrast volume used in each study were plotted using OR and 95% CI on a forest plot. The overall results showing no significant difference between FFR and ANGIO groups regarding the contrast volume used during the procedure [Color figure can be viewed at wileyonlinelibrary.com]
FIGURE 8
P 5