JACC: CARDIOVASCULAR INTERVENTIONS
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
VOL. 8, NO. 6, 2015
ISSN 1936-8798/$36.00
PUBLISHED BY ELSEVIER INC.
Letter
TO THE EDITOR
The methodology and results of the ADVISE II
study, as well as the list of participating investigators
and centers, were reported elsewhere (3). Pd/Pa was
Diagnostic Accuracy of
Baseline Distal-to-Aortic
Pressure Ratio to Assess
Coronary Stenosis Severity
A Post-Hoc Analysis of the ADVISE II Study
calculated as the mean transstenotic pressure ratio
during baseline and was derived from the same cardiac beats used for iFR computation. Both indexes
were obtained from pressure recordings (a minimum
of 20 s) obtained after crossing the stenosis and
before starting the infusion of adenosine. FFR was
defined as the Pd/Pa ratio during stable hyperemia,
induced by intravenous infusion of adenosine at a
rate of 140/ m g/kg/min (3). A total of 919 intermediate
The demonstration that coronary revascularization on
the basis of functional rather than anatomic stenosis
assessment results in better patient outcomes has
stimulated the interest in fractional flow reserve (FFR)
and other physiological indexes (1). The instantaneous wave-free ratio (iFR), introduced in late 2011,
was developed to facilitate the functional assessment
of coronary stenoses by obviating the need for vasodilator drugs (2). The baseline distal coronary pressure
to aortic pressure (Pd/Pa) ratio (calculated as the mean
nonhyperemic transstenotic pressure ratio across
the whole cardiac cycle) has also been proposed as a
simpler index than FFR to estimate stenosis severity,
and a renewed interest in the diagnostic value of
the baseline Pd/Pa ratio has been generated by the
concept of iFR and studies such as RESOLVE (Multicenter Core Laboratory Comparison of the Instantaneous Wave-Free Ratio and Resting Pd/Pa With
Fractional Flow Reserve) (1). The ADVISE II (Adenosine Vasodilator Independent Stenosis Evaluation II)
study was a large, prospective, multicenter, core laboratory–based international study designed to determine the extent to which iFR accurately reflects FFR
(3). Because the RESOLVE study was reported after
the design and approval by ethical review boards of
ADVISE II, Pd/Pa analyses were not included as prespecified endpoints of the study. Despite this, the
SEE PAGE 824
coronary stenoses were investigated during baseline
and hyperemia. From these, 690 pressure recordings
(n ¼ 598) met core laboratory physiology criteria and
were included in this analysis. The median FFR was
0.84 (quartiles 1 and 3: 0.77 and 0.90). The scatterplot
of the baseline Pd/Pa and FFR relationship is shown
in the Figure 1A. Pd/Pa and FFR were strongly correlated (r ¼ 0.84, 95% confidence interval [CI]: 0.82 to
0.86, p < 0.001). Using FFR #0.80 as a cutoff to
define significant stenoses, receiver-operating characteristic (ROC) analysis identified 0.91 as the optimal
Pd/Pa cutoff, with an area under the ROC curve
(C statistic) of 0.90 (95% CI: 0.88 to 0.93, p < 0.001).
This 0.91 baseline Pd/Pa cutoff classified correctly
83.2% of total stenoses, with a sensitivity of 66.5%
and specificity of 92.5%. Figure 1B shows the ROC
curves of iFR and baseline Pd/Pa compared with
FFR #0.80. No significant difference between the
areas under the ROC iFR and baseline Pd/Pa curves
was documented (difference in C statistic, 0.00
[95% CI: 0.01 to 0.00], p ¼ 0.350). To achieve 90%
classification agreement with FFR, the minimal Pd/Pa
exclusion ranges below and above the optimal 0.91
cutoff were #0.89 (to predict FFR #0.80) and $0.94
(to predict FFR >0.80) and provided a percent
agreement of 90.4%. To achieve 95% classification
agreement with FFR, the minimal Pd/Pa exclusion
ranges below and above the same 0.91 cutoff
were #0.88 (to predict FFR #0.80) and $0.97 (to
predict FFR >0.80) and provided a percent agree-
ADVISE II investigators believe that the meticulously
ment of 95.5%. The proportion of patients and ste-
collected and analyzed data provide an opportunity to
noses free of adenosine by these hybrid Pd/Pa–FFR
investigate the diagnostic performance of Pd/Pa rela-
strategies amounted to 75.6% (95% CI: 71.9% to
tive to FFR. Accordingly, in this post-hoc analysis of
79.0%) and 78.4% (95% CI: 75.1% to 81.4%), respec-
the ADVISE II study, we report the diagnostic accuracy
tively, for a 90% classification agreement and to
of Pd/Pa compared with FFR, using the same meth-
47.0% (95% CI: 42.9% to 51.1%) and 51.4% (95% CI:
odology as for the iFR and FFR comparison.
47.6% to 55.2%), respectively, for a 95% classification
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 8, NO. 6, 2015
Echavarría-Pinto et al.
MAY 2015:834–6
Letter to the Editor
F I G U R E 1 Pd/Pa and FFR Relationship
(A) Scatterplot of the Pd/Pa and FFR relationship. (B) Receiver-operating characteristic curves of iFR and Pd/Pa compared with FFR #0.80.
CI ¼ confidence interval; FFR ¼ fractional flow reserve; IFR ¼ instantaneous wave-free ratio; Pd/Pa ¼ baseline distal coronary pressure to aortic
pressure.
agreement. Finally, even in the most conservative
of myocardial flow impairment; 2) Pd/Pa and FFR
scenario (100% agreement), 14% of stenosis with a
have a greater inherent association because they
baseline Pd/Pa <0.81 would not require hyperemic
both assess pressure throughout the cardiac cycle
stress for correct classification.
and not over a finite period of time in diastole; and
The design of the ADVISE II study offers several
3) FFR is used as the standard of reference. In this
methodological advantages over previous iFR versus
regard, 2 recent head-to-head comparisons of the
FFR comparisons that reduces the potential for bias
diagnostic accuracy of iFR, Pd/Pa, and FFR that used
and threats to statistical validity. These include the
as a reference standard nonpressure-derived tests of
following: 1) dedicated and prospectively defined
myocardial flow impairment (coronary flow reserve
data collection; 2) better data control; 3) additional
and single-photon emission computed tomography,
checks for data integrity and consistency; and
both with a wealth of supportive outcome data [4,5])
4) a level of clinical detail appropriate to address the
found a similar discrimination power for both resting
research question. Therefore, the ADVISE II study
(Pd/Pa, iFR) and hyperemic (FFR) indexes. Further
allows several strong conclusions to be drawn. First,
studies should address whether differences between
both baseline Pd/Pa and iFR are strongly correlated
resting and hyperemic indexes in terms of the iden-
with FFR. Second, at the extremes of the distribution
tification of revascularization targets are clinically
of values of both of these indexes, the probability of
relevant. Finally, the calculation of Pd/Pa in the
significant stenosis (FFR #0.80 at the low end) and
ADVISE II study slightly differs from that used in
nonsignificant stenosis (FFR >0.80, at the high end)
clinical practice because Pd/Pa was derived from
is very high. Indeed, both indexes could reach a
optimal beats selected by the iFR calculation algo-
100%
rithm. These, in addition to the demanding meth-
classification
agreement
at
the
low
end
(iFR <0.73, Pd/Pa <0.81), whereas only iFR reached a
odology
100% classification match at the high end (value of
analyses mandated in the ADVISE II study, might
in
the
catheterization
laboratory
and
1.0). These findings confirm that when FFR is used as
help explain why, in contrast, the RESOLVE study
a reference, a proportion of stenoses can be classified
could not find an upper boundary of baseline Pd/Pa
correctly without hyperemic stress, and that an in-
that predicted with $90% accuracy a negative FFR
verse relationship between diagnostic accuracy and
value.
reduction in adenosine use exists. In this interpre-
whether the larger spread of possible iFR values and
Further
clinical
studies
should
address
tation, however, the following has to be kept in
its more balanced sensitivity and specificity (3)
mind: 1) iFR, Pd/Pa, and FFR are intrinsically corre-
confers on this index a pragmatic value above the
lated because they all rely on pressure as a surrogate
Pd/Pa.
835
836
Echavarría-Pinto et al.
JACC: CARDIOVASCULAR INTERVENTIONS VOL. 8, NO. 6, 2015
MAY 2015:834–6
Letter to the Editor
Mauro Echavarría-Pinto, MD
Tim P. van de Hoef, MD
Hector M. Garcia-Garcia, MD, PhD
Ton de Vries, MA
Patrick W. Serruys, MD, PhD
Habib Samady, MD
Jan J. Piek, MD, PhD
Amir Lerman, MD
*Javier Escaned, MD, PhD
on behalf of the ADVISE II Study Group
*Hospital Clinico San Carlos
Cardiovascular Institute
28040 Madrid
Spain
E-mail: [email protected]
http://dx.doi.org/10.1016/j.jcin.2014.12.245
Please note: This work was funded by Volcano Corporation, San Diego, California. Dr. Echavarría-Pinto has served as a speaker at educational events
organized by Volcano Corporation and St. Jude Medical. Dr. Echavarría-Pinto
was funded with a clinical scholarship from the Fundación Interhospitalaria
Investigacion Cardiovascular, Madrid, Spain. Dr. Escaned is a consultant for and
a speaker at educational events organized by Volcano Corporation and St. Jude
Medical. Dr. van de Hoef has served as a speaker at educational events organized by Volcano Corporation, St. Jude Medical, and Boston Scientific. Dr.
Samady has received institutional research grants from Volcano Corporation, St.
Jude Medical, Abbott Vascular, Medtronic, Forrest Pharmaceuticals, Gilead, and
Toshiba. All other authors have reported that they have no relationships
relevant to the contents of this paper to disclose. (Adenosine Vasodilator
Independent Stenosis Evaluation II [ADVISE II]; NCT01740895).
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