Prevalence and Prognostic Relevance of
Modifying Anatomical Features Influencing
the Measurement of Fractional Flow Reserve in Complex Situations in Daily Practice
Sebastian Barth1*, Sebastian Kerber1, Michael Zacher2 and Martina Hautmann1
1RHÖNKLINIKUM Campus Bad Neustadt/Saale, Department of Cardiology, Bad Neustadt/Saale, Germany
2RHÖNKLINIKUM Campus Bad Neustadt/Saale, Department of Medical Documentation, Bad Neustadt/Saale, Germany
Submission: December 13, 2022; Published: January 05, 2023
*Corresponding author: Sebastian Barth, Department of Cardiology RHÖNKLINIKUM Campus Bad Neustadt Von-Guttenberg-Str. 11D - 97616 Bad Neustadt a. d. Saale, Germany
How to cite this article: Sebastian B, Sebastian K, Michael Z, Martina H. Prevalence and Prognostic Relevance of Modifying Anatomical Features Influencing the
Measurement of Fractional Flow Reserve in Complex Situations in Daily Practice. J Cardiol & Cardiovasc Ther. 2023; 18(1): 555980. DOI: 10.19080/JOCCT.2023.18.555980
Fractional low reserve (FFR)-guided percutaneous coronary intervention (PCI) has been shown to reduce the need for PCI and to improve clinical outcome. Several anatomical features and hemodynamic parameters are well known to influence FFR determination. We evaluated the prevalence and prognostic impact of modifying anatomical features influencing the FFR- measurement on survival, myocardial infarction and the need of recurrent coronary revascularization.
For 232 patients undergoing cardiac catheterization with FFR-measurement 2014 in our institute, a match partner (without FFR-measurement) could be found by using the propensity score method. The factors influencing the FFR measurement were categorized and determined for each patient.
The majority of patients (90.6% with and 90.5% without FFR) had at least one modifying factor. The number of implanted stents (FFR: n=114 vs. no FFR: n=181, p=0.006), stented vessels (FFR: n=79 vs. no FFR: n=112, p=0.015), and total stent length (FFR: 2134mm vs. no FFR: 3162mm, p=0.029) were higher in the group without FFR-measurement. During follow-up of 42.9 ± 10.5 months patients with FFR- measurement had less frequent myocardial infarctions (FFR: n=0 vs. no FFR: n=10, p=0.001) and Redo- PCI´s (FFR: n=21 vs. no FFR: n=47, p=0.007). There was no difference between the mortality rates of the two groups (HR 0.781, 95% CI 0.463-1.318).
FFR-guided PCI is not associated with increased long-term mortality and leads to a significantly lower incidence of myocardial infarction even in complex situations. FFR-guided PCI results in less re- interventions and reduces the number and length of implanted stents.
Functional assessment of the coronary stenoses during invasive coronary angiography using intracoronary pressure guidewires has become an indispensable tool in daily practice. The impact of measuring the fractional flow reserve (FFR) in the decision-making of stenoses with a luminal diameter reduction of 50- 90% has been demonstrated in several studies [1-3]. FFR-guided percutaneous coronary intervention (PCI) has been shown to reduce the need for PCI and to improve clinical outcome . Furthermore, this method has proven to be cost-effective . These demonstrated beneficial effects have resulted in this method being highly recommended in the current guidelines of the European Society of Cardiology (ESC) 2018 . Nevertheless,
several hemodynamic factors, the size of the perfusion territory,
the minimal lumen diameter and lesion length as well as
microvascular dysfunction and diseases that led to an increased
myocardial mass due to a diffuse scarring of the myocardium
by fibrous transformation are well known to influence FFR
determination. For this reason, patients with such the FFRmeasurement
influencing factors were excluded from large,
randomized trials like DEFER, FAME and FAME 2 [3,7,8]. Despite
clear evidence, many interventional cardiologists continue to rely
on the visual assessment of diameter stenosis severity alone, rather
than performing FFR . Potential reasons include the uncertainty
about the interpretation of FFR measurements, particularly in
complex situations . This finding is also confirmed by the
results of the prospective ALKK (Arbeitsgemeinschaft Leitende
Kardiologische Krankenhausärzte) coronary angiography and PCI
registry of data of 38 hospitals from 2010 to 2013. Overall, FFR
was performed in only 3.2% of coronary angiographies, whereas
in real-world scenarios use has a wide range from 0.1 to 8.8% .
The aim of our analysis was to evaluate the prevalence of these
modifying anatomical features influencing the FFR-measurement
in patients who underwent cardiac catheterization in our institute
and whether these factors negatively affect the well known
benefits of FFR measurement on survival, myocardial infarction
or the need of recurrent percutaneous coronary interventions
(PCI) and coronary artery bypass grafting (CABG).
Out of 233 patients undergoing cardiac catheterization
with FFR-measurement 2014 in our institute, a match partner
(cardiac catheterization without FFR-measurement in 2014)
could be found for 232/3.462 patients by using the propensity
score method. The 232 patients with FFR measurement represent
the study population, and the matched patients (without FFR
measurement) the control collective.
The indication for coronary catheterization included acute
coronary syndrome, persistent angina despite medication,
dyspnea at rest or exertion or markedly positive stress test. In the
rare case of acute coronary syndrome (ACS), FFR measurement
was conducted in a non-culprit lesion vessel.
The FFR is defined as the ratio between distal coronary
pressure and aortic pressure, both measured simultaneously
at maximal hyperemia. Distal coronary pressure was measured
with a coronary pressure guidewire (Volcano Verrata Pressure
Wire®,Volcano, San Diego, CA 92130 USA). Maximal hyperemia
was induced by intravenous adenosine, administered at 140 g/
kg/min via a central vein. Hyperemic pullback recordings were performed in case of diffuse diseased arteries to discriminate focal from diffuse disease. In the FFR group, an FFR ≤0.75 of a
particular stenosis was considered as functionally significant and
was revascularized with either a stent or a bypass. Percutaneous
coronary intervention (PCI) was performed with drug eluting
stents (DES) and/or bare metal stents (BMS).
Datasets of 2014 of our patients were retrieved from the ALKK
coronary angiography and PCI registry, including information
about medical history, indication for the procedure, the procedure
itself and complications until hospital discharge. All data, obtained
using the standardized questionnaires of the ALKK registry, were
analyzed centrally at the Karl Ludwig Neuhaus Datenzentrum in
Ludwigshafen, Germany. Additionally, further metrics (i.e. invasive
measurements, perfusion territory, microvascular dysfunction,
etc.) were retrieved from electronic patient records at the time
of catheterization and re-evaluation of the recorded cardiac
catheterization at our institute. All variables were documented in
a categorical fashion.
Obstructive diameter stenosis was defined as the presence
of coronary stenosis equal to or greater than 50%. A patient
was considered to be hypertensive if he or she had received
such a diagnosis on the basis of persistently elevated systemic
blood pressure greater than 140/90 mmHg. A patient was
considered to have diabetes in case of increased levels of plasma
glucose >200mg/dl after two hours in oral glucose tolerance
test, after fasting or elevated glycated hemoglobin (A1C). The
cardiovascular risk factor cigarette smoking was divided into
three categories: smoker (smoking during the last two month),
former smoker (smoker who quit smoking at least one month
ago) and non smoker. Patients who have stopped smoking more
than 20 years ago were not considered to have smoking as a risk
factors. Family history was defined as coronary heart disease or
stroke in first- or second-degree relatives under the age of 65
(females) and 55 (males). All patients gave informed consent, and
the ALKK registry has been approved by the ethics committee of
the Landesärztekammer Rheinland-Pfalz in Mainz, Germany.
The factors influencing the FFR measurement were divided
into seven groups: (1) elevated left ventricular end diastolic
pressure, (2) endothelial dysfunction, (3) serial epicardial
stenoses, (4) branch steal, (5) decreased myocardial mass by
fibrous transformation, (6) previous myocardial infarction and
(7) small perfusion territory. An elevated left ventricular pressure
(1) was defined as >12mmHg in invasive measurement. Under
the heading endothelial dysfunction (2) of the coronary artery
examined with FFR, a diffuse atherosclerotic disease, a slow
flow-phenomenon (TIMI 2) and prior stents were subsumed.
The category branch steal (4) included a multi vessel disease (three vessel disease), abundant collaterals and bypassed vessels. Diseases that led to an increased myocardial mass due to a diffuse
scarring of the myocardium by fibrous transformation due to
pressure or volume loading have been summarized under point
5. These included a dilated cardiomyopathy with pronounced
structural dilatation (LVEDD >56mm, LVESD >35mm), a severe
impaired left ventricular function (LVEF <30%) and a left
ventricular hypertrophy of >12mm.
Quantitative variables were expressed as mean ± standard
deviation. Qualitative data (nominal or ordinal scale) were given
as frequencies and rates. For comparison between subgroups,
the classical chi-square- test or Kruskal-Wallis test were used.
P-values of a two-tailed test of 0.05 or less were considered
significant. Data analysis of the ALKK registry was performed
using SAS statistical analysis software, version 9.3 (SAS Institute,
Inc., Cary, North Carolina. U.S.A.), and of the Cardiovascular Center
Bad Neustadt/Saale using IBM SPSS Statistics for Windows,
Version 24.0. Armonk, NY: IBM Corp.
We used nearest neighbor propensity-score matching to
ensure that the two patient-groups, with and without FFR, were
comparable in terms of patient characteristics. The propensityscore
was estimated by the use of all listed variables in Figure 1
[12-14]. Based on the calculated score, every patient of the group
with FFR was matched to the closest patient of the group without
FFR. Furthermore, the propensity-score’s tolerable deviation of
each match was defined in advance with a caliper (“maximum
distance”), therefore consequently excluding bad matches with
high differences. The caliper was set at 0.2 ∗ propensity-score’s
standard deviation, which reduced the difference between the
groups by >95% .
Mean patient age was 68±10 years (FFR) and 67±11 years (no
FFR). 67 out of 232 (28.9%) of the group with FFR-measurement
and 63 out of 232 (27.2%) without FFR-measurement were female.
The mean left ventricular ejection fraction (LVEF) was 56±13%
(FFR) and 57±12% (no FFR). 18 out of 232 (7.8%) in the FFRgroup
and 16 out of 232 (6.9%) without FFR-measurement had
an impaired LVEF of ≤30%. The two groups were homogeneous
with regard to previous cardiac catheterization (FFR: 65.1% vs.
no FFR: 65.1%), PCI (FFR: 47.0% vs. no FFR: 49.1%), history of
coronary artery bypass grafting (FFR: 7.8% vs. no FFR: 7.3%) and
myocardial infarction (FFR: 26.7% vs. no FFR: 21.6%). Further
patients characteristics are summarized in Table 1.
BMI body mass index, CAD coronary artery disease, CABG coronary artery bypass grafting, CCS Canadian Cardiovascular Society grading of angina pectoris, LVEF left ventricular ejection fraction, NYHA New York Heart Association, PCI percutaneous coronary intervention.
Both groups were homogenous for the prevalence of left
main stenosis (FFR: 5.6% vs. no FFR: 3.5%, p=0.264). In the vast
majority of procedures, drug-eluting stents were implanted in
both groups (FFR: 83.3%vs. no FFR: 82.9%, p=0.497). The number
of implanted stents (FFR: n=114 vs. no FFR: n=181, p=0.006),
total stent length (FFR: 2134mm vs. no FFR: 3162mm, p=0.029)
and the number of stented vessels (FFR: n=79 vs. no FFR: n=112,
p=0.015) were higher in the group without FFR-measurement.
During follow-up of 42.9 ± 10.5 months patients with FFRmeasurement
had less frequent myocardial infarctions (FFR: n=0
vs. no FFR: n=10, p=0.001) and Redo-PCI´s (FFR: n=21 vs. no FFR:
n=47, p=0.007). Further information is listed in Table 2.
The measurement of the FFR was associated less frequently
with a recommendation of PCI (FFR: n=57, 24.4% vs. no FFR:
n=92, 39.7%, p<0.001), while there was no difference regarding
the recommendation of surgical treatment between both groups
(with FFR 12.1% vs. without FFR 9.5%, p=0.387) (Table 3).
There were no differences in bleeding or puncture site
complications (FFR: n=5, 2.2% vs. no FFR: n=5, 2.2%, p=1.000).
Both groups had neither periprocedural complications rates
resulting in death (up to 36 hours after the procedure), non fatal
myocardial infarction nor stroke, MAC(C)E rates, rescue PCI or
59.8% of the patients, examined with an FFR-measurement,
and 59.4% of the patients without FFR- measurement had an elevated left ventricular end diastolic pressure as the most common confounding factor. The prevalence of the other
confounding factors is listed in descending order in Figure 2A.
9.4% of the patients with FFR-measurement and 9.5% of the
patients without FFR-measurement had no confounding factor,
while the vast majority (90.6% with FFR and 90.5% without FFR)
had at least one factor influencing the FFR-measurement. Four or
more factors were found in a fifth of the patients in both groups
There was no significant difference between the mortality
rates of the two groups (HR 0.781, 95% CI 0.463- 1.318). After
one year 15 deaths in the group without FFR-measurement
(survival rate 96.0 ± 0.01%) and 12 deaths in the group with
FFR-measurement (survival rate 96.9 ± 0.01%) were reported.
The four-year survival rate was 83.6 ± 0.03% (without FFR) and
84.8 ± 0.03% (with FFR). The Kaplan-Meier curves of all patients
(n=464) divided into both subgroups are shown in Figure 3.
According to the current European guidelines on myocardial
revascularization, the assessment of a functional relevance of
intermediate non-culprit stenoses represents the decisive gold
standard for determining the appropriate treatment strategy
. The potential benefit of revascularization depends on
the presence and extent of myocardial ischemia . These
recommendations are based mainly upon the results of the
DEFER, the FAME and FAME-2 trial [3,7,8]. In these studies,
however, there were numerous exclusion criteria. In the FAME
study, the excluded patient groups comprised the following:
patients with angiographically significant left main CAD, previous
coronary artery bypass surgery, recent history of STEMI, impaired
left ventricular function (<30%), left ventricular hypertrophy (>13mm), cardiogenic shock or extremely tortuous or calcified coronary arteries. In DEFER, patients with a total occlusion of
the target artery, acute Q-wave infarction, or unstable angina
documented by transient ST-segment abnormality as well as
patients with small-sized target arteries (reference diameter
<2.5mm) were excluded. Furthermore, the majority of the patients
in the DEFER study had a single stenosis of uncertain functional
severity in one single coronary artery. In daily practice, patients
in the catheterization laboratory more often have multivessel
disease, often with one or more angiographically severe stenoses
and comitant intermediate stenoses [15,16]. As demonstrated,
there are numerous factors that influence the FFR measurement.
Hyperaemia following maximum vasodilatation of the coronary
microvasculature through adenosine administration is required
for the assessment of a lesion-specific coronary ischemia. In
presence of microvascular dysfunction due to an endothelial
dysfunction, serial epicardial stenoses in a diffuse coronary artery
disease, a branch steal effect, an increased myocardial mass by
fibrous transformation as found in hypertrophic and/or dilated
cardiomyopathy and previous myocardial infarction, the extent of
achieved maximum hyperaemia will be less as compared to healthy
individuals. Uncertainty about data acquisition and interpretation
in these specific situations seem to be an explanation why the FFR
measurement is not widely used in clinical practice .
In our study, we deliberately included all patients in
whom an FFR measurement was performed in daily practice.
The proportion of patients who would have been excluded in
the FAME- and DEFER-study is more than half of our study
population. In particular, left ventricular hypertrophy with a
consecutive elevated left ventricular end diastolic pressure would
have excluded more than half of all our patients. More than twothirds
of our patients had at least two modifying anatomical
features influencing the FFR-measurement. In addition to these
large randomized trials, our investigation provides an important
statement in the treatment of patients with numerous factors
modifying the FFR-measurement in daily practice. Similar to the
results of large, randomized studies with highly selected patient
populations, FFR-guided PCI in our study population leads also to
a significantly lower incidence of myocardial infarction and is not
associated with increased long-term mortality. According to the large randomized trials DEFER, FAME and FAME 2, determination of the hemodynamic relevance of coronary artery stenoses with
FFR results in less re-interventions and reduces the number
and length of implanted stents even in complex situations. The
comorbidities and anatomical features do not influence the
result of the FFR measurement in the sense of false-negative
or false-positive, but rather the functional significance of the
angiographically evaluated epicardial stenosis, which is reflected
in the FFR measurement.
FFR-guided PCI is not associated with increased longterm
mortality and leads to a significantly lower event rate of
myocardial infarction even in complex situations. FFR-guided
PCI results in less re-interventions and reduces the number and
length of implanted stents as well.
Our observation is not a prospective, randomized trial.
The selection of lesions measured with FFR was based on the
operator´s visual interpretation of the angiogram together
with clinical parameters. It is well- known that there is a high
interobserver variability in assessing anatomic coronary stenosis
severity. Therefore, the defined study population and their matchpartners
are not representative of all patients undergoing invasive