JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 67, NO. 14, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jacc.2016.01.057
EDITORIAL COMMENT
Does Physiology Trump Anatomy as the
“Best Course” to Guide PCI Decision
Making and Outcomes?*
Anthony G. Nappi, MD,a William E. Boden, MDa,b
T
he treatment of coronary artery disease
of fractional flow reserve (FFR) has become the
(CAD) has been anatomically driven for a
primary invasive method used by angiographers to
half-century, particularly since the advent
assess the “functional” (or perhaps more accurately,
of percutaneous coronary intervention (PCI) almost
the “physiological”) significance of an intermediate-
40 years ago (1). Despite technological advances
grade coronary stenosis (e.g., a 50% to 70% dia-
in
both
coronary
revascularization
and
non-
meter reduction). The FFR, defined as the ratio of
revascularization treatment options, which includes
maximal blood flow across a coronary arterial stenosis
both therapeutic lifestyle intervention and aggressive,
relative to the blood flow in the vessel if the stenosis
multifaceted pharmacological secondary prevention—
were not present, has been well validated with
the combination of which is commonly referred
noninvasive stress tests to determine whether an
to as optimal medical therapy (OMT)—the overwhelm-
angiographic lesion would produce ischemia (2,3).
ingly favored clinical approach for CAD management
Furthermore, mounting clinical trials data have
continues to be “fixing all significant coronary
shown that the performance of a PCI may be safely
stenoses.” Although increasingly more sophisticated
deferred in coronary lesions that appear angiograph-
noninvasive imaging modalities are widely embraced
ically significant, but are not physiologically signifi-
and incorporated into routine clinical practice,
cant, as assessed by FFR (3–5).
the final common diagnostic pathway seems to inevi-
In the original FAME (Fractional Flow Reserve
tably lead to the cardiac catheterization laboratory
versus Angiography for Multivessel Evaluation) study
where the results of coronary angiography very
(5), patients with multivessel CAD were randomized
frequently “confirm” the anatomic presence of
to an anatomically guided PCI strategy based on
obstructive CAD—objective findings that most cardiol-
angiographic
ogists have difficulty ignoring—and that frequently
versus an FFR-guided strategy (FFR #0.80) (5). This
criteria
($50%
luminal
narrowing)
result in myocardial revascularization, most often
seminal study demonstrated a significant reduction
with ad hoc PCI.
in major adverse cardiac events (MACE) in the
Although the limitations of coronary angiography
patients randomized to FFR-guided PCI and high-
are well known, as is the difficulty of reliably asses-
lighted the importance of revascularization based on
sing coronary stenosis severity by visual estimation
the functional significance of coronary lesions.
alone, the use of a pressure wire and measurement
The study also re-emphasized the safety of treating
non–flow-limiting coronary stenoses that were not
ischemia producing, defined as an FFR >0.8, with
*Editorials published in the Journal of the American College of Cardiology
OMT, as cited in the preceding text. An additional
reflect the views of the authors and do not necessarily represent the
therapeutic dynamic, however, has evolved in the
views of JACC or the American College of Cardiology.
aftermath of the DEFER (Deferral Versus Performance
From the aDepartment of Medicine, Albany Medical Center, and Albany
of PTCA in Patients Without Documented Ischemia)
Medical College, Albany, New York; and the bDepartment of Medicine,
Samuel S. Stratton VA Medical Center, Albany, New York. Both authors
(4), FAME (5), and FAME-2 (6) trials—namely, does
have reported that they have no relationships relevant to the contents of
the use of a pressure wire to obtain FFR assess-
this paper to disclose.
ments in patients with obstructive CAD provide
Nappi and Boden
JACC VOL. 67, NO. 14, 2016
APRIL 12, 2016:1712–4
Physiology Trumps Anatomy for PCI
cardiologists with a more accurate and reliable inva-
guidance, the residual angiographic lesions, which
sive physiological tool that would potentially provide
were not functionally significant, did not appear to
clinicians with more powerful prognostic information
correlate with residual ischemia or predict a worse
that would derive from such a more selective revas-
long-term clinical outcome (10). In short, this analysis
cularization approach?
supported
A long-held belief among many practicing cardiologists has been that “angiographically complete”
the
physiological
appropriateness
of
functionally complete revascularization rather than
anatomically complete revascularization.
revascularization is associated with improved long-
The authors cite some obvious limitations of their
term outcomes after multivessel revascularization for
study: exclusion of recent (within 5 days) ST-segment
stable CAD as compared with “anatomically incom-
elevation myocardial infarction patients, absence of a
plete” revascularization, and this would appear to be
control arm, inclusion of a small portion of patients
well validated in recent comparative effectiveness
with functionally significant lesions that were left
trials that have shown the superiority of coronary ar-
untreated, and the caveat that such a post hoc
tery bypass graft (CABG) surgery versus PCI in patients
analysis
with extensive multivessel CAD, particularly among
generating. Additionally, the study participants in
diabetic patients and patients with left main stem CAD
FAME would generally be considered a low- to
(7–9). However, might this paradigm of “complete
intermediate-risk group on the basis of the degree of
anatomic revascularization” shift if it could be
angiographic disease at baseline (average baseline SS
demonstrated that a physiologically directed approach
of 14.4), and thus it remains unclear to what degree
should
only
be
considered
hypothesis
with FFR guidance could better identify which ste-
these findings can be generalized to higher-risk
notic coronary lesions should be targeted by PCI and
angiographic subsets with more extensive or com-
which could be safely avoided, particularly if these
plex CAD. Nevertheless, the authors could not
residual (but functionally insignificant) stenoses did
demonstrate that clinical outcomes at 1 and 2 years
not reflect residual ischemia or predict worse clinical
differed among the RSS and SRI subgroups, irre-
outcomes? In other words, could physiology trump
spective of the baseline SS stratification, which would
anatomy in our quest to discover the holy grail of
suggest the applicability of these results to the broader
which therapeutic approach to “complete revascular-
population of patients with more complex CAD.
ization” is both more effective and cost-effective?
SEE PAGE 1701
What are the clinical implications of these study
findings? Although RSS and SRI may not be routinely
used in clinical practice, the results of this post hoc
In this issue of the Journal, Kobayashi et al. (10)
analysis does further support the concept of a more
performed a post hoc analysis in which they calcu-
judicious approach to revascularization that is phys-
lated a residual SYNTAX score (RSS) and SYNTAX
iologically directed and selectively targeted to only
revascularization index (SRI) in the FFR-guided PCI
those coronary stenoses that are functionally signifi-
cohort of the aforementioned FAME trial. The authors
cant and ischemia producing, rather than a purely
then looked at 1- and 2-year MACE rates in patients
anatomic approach that seeks to revascularize all
subdivided into 4 separate quartiles based on these
stenotic coronary segments, regardless of whether
scores, and the burden of residual angiographic dis-
they are ischemia producing or not. Subjecting pa-
ease. The objective of their analysis was to clarify
tients with functionally insignificant coronary lesions
whether residual angiographic disease, which was
to anatomically directed PCI alone where there is not
ischemia producing, remained of prognostic impor-
compelling evidence that revascularization of such
tance after “functionally” complete revascularization
stenoses correlates prognostically with future events
was achieved.
could conceivably tilt the balance of PCI risk versus
The authors found that the patients with MACE
benefit toward the former.
had higher SYNTAX scores (SS) than patients without
How might these data inform clinical decision
MACE (17.3 7.3 vs. 13.9 7.1, p ¼ 0.001), whereas
making for revascularization? A common dilemma
they had similar RSS and SRI indices after PCI (RSS:
facing clinicians is to identify which mode of revas-
7.2 6.6 vs. 6.4 5.6, p ¼ 0.51 and SRI: 60.8 29.8%
cularization is best suited for a patient with multi-
vs. 54.3 32.9%, p ¼ 0.24), respectively (10). The
vessel CAD. For example, in the diabetic patient with
Kaplan-Meier analysis also showed a similar inci-
extensive, multivessel CAD, the superiority of surgi-
dence of MACE at 1 year with the RSS/SRI stratifica-
cal revascularization over multivessel PCI with drug-
tions (log-rank p ¼ 0.55 and p ¼ 0.54, respectively).
eluting stents in patients considered appropriate for
From these findings, the authors concluded that after
both forms of revascularization is believed to be due
functionally complete revascularization with FFR
to the more complete revascularization afforded by
1713
1714
Nappi and Boden
JACC VOL. 67, NO. 14, 2016
APRIL 12, 2016:1712–4
Physiology Trumps Anatomy for PCI
surgery in subjects with diffuse angiographic disease,
(NCT01471522) (12) will hopefully provide some clarity
based on the results of several recent trials (7–9).
because this study is designed and powered to eval-
The cardioprotective benefit of CABG is postulated to
uate the long-term superiority of revascularization of
result from bypass grafts to the mid-coronary vessels
choice (FFR-guided PCI or CABG surgery) plus OMT
that not only treat culprit lesions (even anatomically
versus a strategy of OMT alone for the composite
complex ones), but also afford prophylaxis against
endpoint of cardiovascular death or myocardial
new proximal disease, whereas stents treat only
infarction
suitable stenotic segments with little or no benefit
ischemia as assessed by stress imaging studies. Addi-
against native coronary disease progression (11). Yet,
tionally, the FAME-3 trial seeks to address a similar
in these 3 trials, revascularization by PCI was entirely
question in patients with 3-vessel CAD who are ran-
anatomically directed. There are likely subsets of
domized to an FFR-guided PCI approach with new-
diabetic patients with 3-vessel CAD in whom only 2 of
generation drug-eluting stents versus CABG surgery
the 3 coronaries display physiological flow limitation
(13), which will directly test physiologically directed
that may be appropriate for an FFR-guided 2-vessel
versus anatomically directed revascularization stra-
PCI rather than CABG, as would be traditionally rec-
tegies, respectively. Until these ongoing studies
ommended. Such a targeted, physiologically directed
conclude, clinicians will need to make individual
revascularization approach would, therefore, better
revascularization decisions based on currently avail-
inform individual clinical decisions regarding CABG
able trials data. Thus, the present analysis adds
or PCI. It would also potentially enable the clini-
importantly to our scientific evidence base that a
cian to feel more comfortable treating the residual
physiologically directed PCI approach to identifying
in
subjects
with
moderate-to-severe
stenotic (albeit functionally insignificant) CAD with
and treating only functionally significant coronary
OMT alone.
stenoses can lead to better clinical outcomes, and
Finally, do these findings provide insight into the
design and conduct of current trials? Whether revas-
defines for us a path forward to utilize PCI in a more
selective, safe, and cost-effective manner.
cularization plus OMT of ischemia-producing disease
is superior to OMT alone in a large population of
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
stable CAD patients remains unproven. The ongoing
William E. Boden, Samuel S. Stratton VA Medical
ISCHEMIA (International Study of Comparative Health
Center, 113 Holland Avenue, Albany, New York 12208.
Effectiveness with Medical and Invasive Approaches)
E-mail: [email protected].
REFERENCES
1. Grüntzig A. Transluminal dilatation of coronary
artery stenosis. Lancet 1978;1:263–5.
6. De Bruyne B, Fearon WF, Pijls NH, et al. Fractional flow reserve-guided PCI for stable coronary
11. Taggart DP. PCI or CABG in coronary artery
disease? Lancet 2009;373:1150–2.
2. Pijls NH, De Bruyne B, Peels K, et al. Measurement of fractional flow reserve to assess the
functional severity of coronary-artery stenosis.
N Engl J Med 1996;334:1703–8.
artery disease. N Engl J Med 2014;371:1208–17.
12. International Study of Comparative Health
7. Frye RL, August P, Brooks MM, et al.
A randomized trial of therapies for type 2 diabetes
and coronary artery disease. N Engl J Med 2009;
Effectiveness with Medical and Invasive
Approaches (ISCHEMIA). ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov/ct2/show/
NCT01471522. Accessed January 29, 2016.
3. Caymaz O, Fak AS, Tezcan H, et al. Correlation
of myocardial fractional flow reserve with
thallium-201 SPECT imaging in intermediate-
360:2503–15.
severity coronary artery lesions. J Invasive Cardiol 2000;12:345–50.
coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360:
961–72.
8. Serruys PW, Morice MC, Kappetein AP, et al.
Percutaneous coronary intervention versus
4. Pijls NH, van Schaardenburgh P, Manoharan G,
et al. Percutaneous coronary intervention of
9. Farkouh ME, Domanski M, Sleeper LA, et al.
functionally nonsignificant stenosis: 5-year
follow-up of the DEFER Study. J Am Coll Cardiol
2007;49:2105–11.
Strategies for multivessel revascularization in patients with diabetes. N Engl J Med 2012;367:
2375–84.
5. Tonino PA, De Bruyne B, Pijls NH, et al. Frac-
10. Kobayashi Y, Nam C-W, Tonino PAL, et al. The
tional flow reserve versus angiography for guiding
percutaneous coronary intervention. N Engl J Med
2009;360:213–24.
prognostic value of residual coronary stenoses
after functionally complete revascularization.
J Am Coll Cardiol 2016;67:1701–11.
13. Zimmermann FM, De Bruyne B, Pijls NH, et al.
Rationale and design of the Fractional Flow
Reserve versus Angiography for Multivessel Evaluation (FAME) 3 trial: a comparison of fractional
flow reserve-guided percutaneous coronary
intervention and coronary artery bypass graft
surgery in patients with multivessel coronary
artery disease. Am Heart J 2015;170:619–26.
KEY WORDS fractional flow reserve,
multivessel revascularization, residual SYNTAX
score, SYNTAX revascularization index