Cardiovascular Revascularization Medicine 11 (2010) 189 – 198

Review

Percutaneous coronary intervention for small vessel coronary

artery disease☆
Giuseppe Biondi-Zoccai a,⁎, Claudio Moretti a , Antonio Abbate b , Imad Sheiban a
Interventional Cardiology, Division of Cardiology, University of Turin, S. Giovanni Battista “Molinette” Hospital, 10126 Turin, Italy
a
b
Division of Cardiology/VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23298, USA
Received 25 December 2008; received in revised form 3 April 2009; accepted 6 April 2009

Abstract Symptomatic coronary artery disease may be commonly due to significant atherosclerotic disease
involving coronary vessels of relatively small caliber (i.e., with reference vessel diameter b2.75
mm). Whenever medical therapy fails and in other selected cases, revascularization by means of
percutaneous coronary intervention (PCI) or bypass surgery is indicated even for small vessel
coronary disease. However, despite the numerous developments and improvements in devices and
techniques, PCI of small coronary vessels is still fraught with a significant risk of midterm restenosis
after both balloon-only PCI and bare-metal stent implantation. Drug-eluting stents, especially those
associated with very low angiographic late lumen loss (b0.20 mm), appear to significantly improve
angiographic and clinical outcomes after PCI of small coronary vessels. The present article provides
a concise and updated review on percutaneous coronary revascularization in patients with
symptomatic small vessel coronary artery disease.
© 2010 Elsevier Inc. All rights reserved.

Keywords: Coronary artery disease; Drug-eluting stent; PTCA; Stent

1. Introduction artery disease or those stable subjects failing medical

Coronary artery disease remains a major cause of
morbidity and mortality worldwide despite the major
improvements in primary and secondary prevention
strategies. Whereas aggressive medical therapy is safe
and effective as an initial management approach in patients
with stable coronary artery disease [1], percutaneous
coronary intervention (PCI) or surgical revascularization
is clearly indicated in most patients with acute coronary
☆
Dr. Biondi-Zoccai has consulted for Boston Scientific, Cordis,
Genae, Invatec, Mediolanum Cardio Research, and Medtronic and has
lectured for Bristol Myers-Squibb, Medtronic, and Sanofi-Aventis.
⁎ Corresponding author. Interventional Cardiology, Division of Cardio-
logy, University of Turin, S. Giovanni Battista “Molinette” Hospital, Corso
Bramante 88-90, 10126 Turin, Italy. Fax: +39 0116967053.
E-mail address: gbiondizoccai@gmail.com (G. Biondi-Zoccai).
therapy [1–3].
Atherosclerotic coronary involvement extends often to
distal and small-caliber coronaries, such that as much as 20–
30% of patients undergoing PCI may have significant
disease in coronary segments whose diameter is relatively
small (e.g., b2.75 mm) [4]. In this setting, balloon-only PCI
or bare-metal stents (BMS) have proved only partially
effective, as early and midterm failures could occur in up to
50% of patients [5]. The recent development of drug-eluting
stents (DES) has, however, drastically changed the percuta-
neous management of small vessel coronary disease, thanks
to their potent antirestenotic effect and remarkable early and
midterm safety [6]. The aim of this article is to provide a
concise and updated review on current and future approaches
for percutaneous coronary revascularization in patients with
symptomatic small vessel coronary artery disease. This
review is based on a systematic PubMed search strategy,
whose details are available in the Appendix.

1553-8389/09/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.carrev.2009.04.007
190 G. Biondi-Zoccai et al. / Cardiovascular Revascularization Medicine 11 (2010) 189–198

2. Definition and prevalence restenosis [9,10] and thrombosis [11], in comparison to

Several definitions of small vessel coronary disease have
been proposed in the past. However, most recent studies on
the topic have identified an angiographic reference vessel
diameter equal or lower than 2.75 mm as the most
appropriate cutoff [7]. Thus, as a rule of thumb, it can be
stated that any coronary vessel amenable to percutaneous
treatment with a 2.75 mm or smaller device should be
considered as small. In addition, thanks to the market
approval and subsequent availability of DES with a
2.25-mm diameter, some authors have suggested the term
very small vessel coronary artery disease for those coronary
segments that are amenable to percutaneous treatment with
a 2.25-mm device.
Despite varying definitions in the literature, there is
universal agreement that small vessel coronary artery
disease is highly prevalent (up to 20–30% of patients
with symptomatic coronary artery disease) [4] and that
patients with diabetes mellitus or chronic renal failure are at
even higher risk of developing this specific type of coronary
artery disease [8]. The prognostic implications of small
coronary artery disease are also great, as a small reference
vessel diameter in the coronary segment undergoing
percutaneous PCI is significantly and directly associated
with an increased risk of adverse clinical events, including
larger reference vessel diameters.
A common conceptual framework is useful before a
detailed description of available approaches for the percu-
taneous revascularization of small vessel coronary artery
disease. Indeed, the goal of PCI is to improve the minimum
lumen diameter in a given target coronary segment, which
has a specific reference vessel diameter (roughly defined as
the average of the diameters of apparently normal segments
localized proximally and distally to the target segment).
Thus, the minimum lumen diameter increases significantly
after the procedure, yet decreases at follow-up, mainly
because of recoil and hyperplasia phenomena. Late lumen
loss is precisely the difference between the postprocedural
minimum lumen diameter and the follow-up minimum
lumen diameter, and ranges between 0.05 and 0.10 (for the
most effective DES) and 1.0 and 1.5 mm (for balloon-only
PCI) (Fig. 1) [12]. Whereas a low late loss is generally
beneficial, it appears even more important in small coronary
vessels (i.e., vessels with reference vessel diameter
≤2.75 mm) (Fig. 2). The statistical distribution of late loss
is non-Gaussian and bimodal, and this makes speculations
based only on late loss largely exploratory [13]. Nonetheless,
predicted binary restenosis rates can be built upon average
differences in late loss, even if they should be viewed with
caution (Fig. 3).

Fig. 1. Definition of late loss and pertinent statistical distribution modified from EuroIntervention 2008;4:29-32. Panel A shows the scheme of an artery before,
just after and long after PCI, with the definition of angiographic late lumen loss, as post-PCI MLD minus follow-up MLD. Panel B shows examples of frequency
distributions of continuous biological variables. Despite being commonly reported as following a Gaussian distribution (top), late loss has been presented in
some cases as distributed in a right-skewed fashion (middle), but the most appropriate distribution summarizing late loss values in real patients remains a bimodal
distribution (bottom). Conversely, patient age typically follows a Gaussian distribution (top) in clinical studies, and postprocedural peak cardiac enzyme levels
most commonly follow a right-skewed distribution (middle). MLD, minimum lumen diameter.
 G. Biondi-Zoccai et al. / Cardiovascular Revascularization Medicine 11 (2010) 189–198 191

Fig. 2. Porcine coronary artery specimens 28 days after stenting showing two typical late loss patterns: a stent characterized by minimal late loss (A) and a stent
characterized by more evident late loss (B). Metallic stent struts appear as white spots due to pathologic processing.

It should be thus stressed that not all small vessel coronary
lesions are born equal. Indeed, an extensively diseased
proximal left anterior descending lesion with negative
remodeling might appear having a reference vessel diameter
similar to that of a distal secondary branch of a posterolateral
artery; yet, the clinical relevance and management strategy
differ significantly. For instance, if there is a large amount of
myocardium at risk, efforts should be maximized to provide
the most appropriately sized and effective treatment [e.g., a
DES associated with low late loss, with lesion preparation
with appropriate pre-dilation, and stent size chosen based on
intravascular imaging such as intravascular ultrasound
(IVUS)]. Conversely, a small diameter coronary lesion
providing flow to a small portion of myocardium is often
not worth major therapeutic efforts and should be often better
served with conservative medical therapy only.
3. Role of medical therapy and bypass surgery
Before discussing in greater detail current PCI strategies
for small coronary artery disease, it is worth emphasizing that
a trial of aggressive medical therapy (i.e., antiplatelet agents,
beta-blockers, angiotensin-converting enzyme inhibitors,

Fig. 3. Modeling the impact of different late losses on follow-up binary angiographic restenosis after PCI in coronary segments with small (b2.75 mm), medium
(2.75–3.25 mm), and large (N3.25 mm) reference vessel diameter.
192 G. Biondi-Zoccai et al. / Cardiovascular Revascularization Medicine 11 (2010) 189–198
 G. Biondi-Zoccai et al. / Cardiovascular Revascularization Medicine 11 (2010) 189–198
and/or statins) is recommended in all patients with stable
coronary artery disease without high-risk features (e.g.,
unprotected left main disease), as PCI in this setting may
only provide a symptomatic benefit [1,3]. Conversely,
bypass surgery is still traditionally considered the first-line
revascularization means for diabetics with multivessel
disease or subjects with unprotected left main stenosis or
multivessel disease and concomitant significant left ven-
tricular systolic dysfunction [14]. Recommendations for
both medical therapy in low-risk stable patients and surgical
therapy for high-risk subjects hold true even in the presence
of small vessel coronary artery disease. However, in the
latter case, there should be an individualized appraisal of the
risk–benefit balance of surgical vs. percutaneous revascular-
ization, as bypass surgery is more likely to achieve
anatomically or functionally complete coronary revascular-
ization but at the expense of an increase in periprocedural
complications [15]. Moreover, coronary artery bypass
surgery in patients with small vessel disease is also
associated with an increase in late adverse clinical events
since small vessels provide poor distal runoff for the
aortocoronary grafts, a phenomenon which often results in
graft occlusion or malfunctioning.
Beyond standard medical therapy for the primary and
secondary prevention of coronary artery disease, there has
been recently a diffuse interest on systemic drug therapy for
the prevention of restenosis after PCI in both large and small
coronary arteries. Whereas promising data have been
occasionally reported for oral rapamycin [16], steroids
[17], and cilostazol [18], further clinical data are needed
before routinely recommending such treatments.
4. Role of balloon-only angioplasty
Balloon-only PCI has been the main percutaneous
revascularization approach in patients with small vessel
coronary artery disease for almost 2 decades. Since its
introduction, balloon-only PCI proved in fact relatively safe
and effective [19], at least in comparison to other more
aggressive technical approaches such as directional ather-
ectomy, rotational atherectomy, or laser-based interventions
[20]. Despite such favorable comparisons, binary restenosis
rates following balloon-only PCI of small coronary vessels
can reach 50–60%, thus determining angiographic and
clinical recurrence of small coronary disease in many
patients (Fig. 3) [5]. Nonetheless, a favorable midterm
outlook can be predicted whenever balloon-only PCI
achieves a satisfactory postprocedural angiographic result
(e.g., diameter stenosis b20%). Indeed, in such cases,
balloon-only PCI of small coronary vessels appears
noninferior even in comparison to BMS [5].
Fig. 4. Pooled analysis from selected randomized comparisons of stents for small vessel coronary disease focusing on binary angiographic restenosis (A) and
major adverse cardiac events (B).
193
5. Role of nonstent devices
Despite the disappointing results of nonballoon and
nonstent devices (such as directional, laser, or rotational
atherectomy) in coronary artery disease in general and in
small vessel disease in particular [20], several investigators
have attempted using other coronary devices, albeit with
inconclusive results. To date, only very selective usage of
cutting balloon, Fx MiniRail, or Angioscore can be envisaged
in either large or small vessel coronary artery disease [21,22].
6. Role of BMS
The introduction of bare-metal, balloon-expandable
stents led to major improvements in acute success of PCI
and also reduced significantly the risk of midterm rest-
enosis, at least in medium- and large-sized coronary arteries
[23,24]. Several energies were soon focused in the BMS
era on the identification of predictors of restenosis [25,26].
Hausleiter et al. [26] reported from a cohort of 3156
patients treated with BMS in small coronary arteries that
early adverse clinical outcomes were mainly predicted by
acute coronary syndrome at admission and left ventricular
ejection fraction, whereas binary restenosis at midterm
follow-up could vary between 30% and 55% and was
directly dependent on lesion length and total stent length.
Another major factor implicated in the risk of restenosis
was strut thickness and density, as stents with lower strut
thickness yielded less abundant neointimal hyperplasia
[27]. More poignantly, Kasaoka et al. [28] performed
extensive angiographic and IVUS analyses to identify risk
factors for restenosis after BMS implantation, disclosing
that total stent length, smaller reference lumen diameter and
smaller final minimum lumen diameter were strong
predictors of in-stent restenosis. In lesions with IVUS
guidance, IVUS stent lumen cross-sectional area was
actually an even better independent predictor than angio-
graphic measurements.
Thus, it was soon appreciated that small vessel coronary
artery disease was a more challenging subset for testing the
performance of coronary stents. Several randomized trials
comparing BMS and balloon-only PCI in small coronary
vessels were then conducted, with largely inconclusive
results. In 2005, Agostoni et al. [5] finally conducted an
extensive meta-analysis including 13 studies and 4383
patients, showing that BMS may have an overall beneficial
impact on binary restenosis (27.8% vs. 35.8% for balloon-
only PCI, P=.003) and target lesion revascularization (TLR)
(14.9% vs. 18.7%, P=.02). However, this benefit was
heterogeneous (P=.001), and further exploratory analyses
demonstrated that it was largely limited to studies in which
194 G. Biondi-Zoccai et al. / Cardiovascular Revascularization Medicine 11 (2010) 189–198
optimal balloon-only PCI (i.e., aimed at postprocedural
diameter stenosis b20%) was not systematically sought.
Most recent data on BMS have confirmed this compre-
hensive meta-analysis [29], even in the setting of acute ST-
segment-elevation acute myocardial infarction treated with
primary PCI [30].
7. Role of drug-eluting stents
The introduction of effective DES into clinical practice has
revolutionized PCI by providing a device that effectively
prevents restenosis in low-risk lesions and reduces signifi-
cantly its risk in more complex lesions, thus providing
clinically relevant benefits in terms of TLR and major adverse
cardiac events [31]. Whereas few studies have been focused
specifically on small coronary disease in the DES era, several
post hoc observations are also available, clarifying the exact
role of DES in this setting. Specifically, the Canadian Study of
the Sirolimus-Eluting Stent in the Treatment of Patients With
Long. De Novo Lesions in Small Native Coronary Arteries
(C-SIRIUS) trial showed that sirolimus-eluting stents
(Cypher, Cordis, Miami, FL, USA) reduced in such relatively
small vessel coronary lesions binary restenosis from 52% with
BMS to only 2% with sirolimus-eluting stents (Pb.001), with
obvious ensuing clinical benefits [32]. The only randomized
trial specifically focused to date on the comparison of DES vs.
BMS in truly small vessel coronary artery disease (reference
vessel diameter ≤2.75 mm as inclusion criteria but actually
2.17±0.26 mm in the BMS group and 2.22±0.29 mm in the
DES group), the Sirolimus-Eluting Stent and a Standard Stent
in the Prevention of Restenosis in Small Coronary Arteries
Trial (SES-SMART) study, further validated these observa-
tions. Specifically, among the 257 patients enrolled, BMS
were associated at midterm angiographic follow-up with a
binary in-segment restenosis rate of 53% vs. 10% after
sirolimus-eluting stent implantation (Pb.001) [7,33]. Similar
results were provided by sub-analyses of other trials or
registries on sirolimus-eluting stents, clearly establishing that
these devices are associated with very low late loss (ranging
between 0.05 and 0.20 mm) and, thus, can be a very effective
tool in small vessel coronary artery disease [34–37].
Paclitaxel-eluting stents (Taxus, Boston Scientific,
Natick, MA, USA) remain among the most effective first-
generation DES, as clearly demonstrated by the pivotal
dedicated trials [38,39]. However, these devices are
associated with a late loss averaging 0.30 mm, which
could potentially impact unfavorably on outcomes in very
small coronary arteries. Indeed, whereas paclitaxel-eluting
stents clearly outperform BMS in small vessels [40,41],
direct comparison to other DES associated with lower late
loss (e.g., sirolimus-eluting stents and everolimus-eluting
stents) suggests that superior outcomes in small coronary
arteries can be obtained with the latter devices rather than
with the former. These conclusions are largely based on
head-to-head randomized comparisons [37,42–45], also
confirmed in observational registries, including those
focusing on stents as small as 2.25 mm in diameter [46–50].
Other stents have been recently approved in Europe and/or
in the US, including zotarolimus-eluting stents [Endeavor and
Endeavor Resolute (both from Medtronic, Minneapolis, MN,
USA) which differ in polymer covering (phosphorylcholine
and BioLinx, respectively)] and everolimus-eluting stents
[Xience V (Abbott Vascular, Abbott Park, IL, USA), and
Promus (Boston Scientific] 51,52]. Interestingly, Endeavor is,
to date, among the DES with the highest associated late loss
(ranging between 0.50 and 0.70 mm) and, thus, it may appear
less appealing in patients with small vessel coronary artery
disease. This conclusion is based on the fact that, in small
vessels, even a mild increase in late loss may lead to increase in
binary restenosis (Fig. 3) and also on direct comparisons
between Endeavor and sirolimus-eluting stents [53].
Conversely, everolimus-eluting stents are associated with
very low late lumen loss (lower than 0.20 mm), making them
attractive alternatives to sirolimus-eluting stents, which have
conversely well-known limitations in stent/balloon platform
flexibility and deliverability. Indeed, there is already clear
randomized clinical proof that everolimus-eluting stents are
superior to BMS and to paclitaxel-eluting stents in general and,
thus, may have an even more favorable risk-benefit profile in
small vessel coronary artery disease (Fig. 4) [52,54,55].
Specifically, there is already evidence from the 1002-patient
SPIRIT III randomized trial that everolimus-eluting stents
reduce, in comparison to paclitaxel-eluting stents, late lumen
loss (0.16±0.41 vs. 0.30±0.53 mm, P=.002) and binary
angiographic restenosis in (2% vs. 6%, P=.06), as well as
major adverse cardiac events (6% vs. 10%, P=.02) [45].
Thus, as drug-eluting stents in general appear superior to
BMS, it appears that drug-eluting stents with low late lumen
loss may be preferable to drug-eluting stents with higher late
lumen loss in small coronary vessels. Indeed, thanks to the
current availability of drug-eluting stents associated with low
late lumen loss, interventionists aiming to perform PCI for
small and technically challenging coronary lesions have now
ample availability of devices with adequate antirestenotic
effects. Given an equivalent antirestenotic effect (i.e.,
similarly low late lumen loss), choice of a specific device
should then be based on other stent characteristics, including
deliverability, flexibility, and balloon inflation/deflation
properties, making everolimus-eluting stents one of the
most attractive alternatives currently available.
8. Role of imaging and fractional flow reserve
Intravascular ultrasound has provided seminal insights into
the mechanisms of PCI and has proved decisive to define the
current technique of stent implantation. In small vessels, IVUS
has also clearly demonstrated that coronary angiography often
mistakenly underestimate real reference vessel diameters,
especially in patients with diffuse disease such as diabetics [8].
Thus, IVUS is recommended whenever there is uncertainty on
 G. Biondi-Zoccai et al. / Cardiovascular Revascularization Medicine 11 (2010) 189–198
the exact reference vessel diameter of the target coronary
segment, as well as to optimize balloon-only PCI and/or
stenting [56,57]. Indeed, it is conceivable that IVUS can
significantly improve angiographic and clinical results after
BMS implantation [58]. Conversely, it is unclear whether
IVUS should be used routinely or more selectively in patients
with small vessel coronary disease undergoing DES implanta-
tion, as no pertinent controlled trials are yet available.
StentBoost (Philips) is a novel radiographic technique that
increases spatial resolution of the cineangiographic equip-
ment to more accurately appraise stent expansion. Whereas
few data are available on StentBoost to date, either in large or
small vessel PCI, this appears a promising and cost-effective
tool to appraise stent expansion in small vessels [59].
Coronary angiography still remains the most commonly
used tool to recognize and define small coronary artery
disease. However, identifying truly functionally significant
stenoses in this setting may be challenging if cardiologists
rely only on angiography or IVUS. Thus, usage of
fractional flow reserve (with a cutoff value of 0.75–0.80
after induction of maximal vasodilatation with adenosine)
is recommended in patients with angiographically inter-
mediate stenoses in small coronary vessels or whenever
there is no definite proof of correlation with symptoms or
signs of myocardial ischemia [60].
Finally, optical coherence tomography (OCT), thanks to
its superior spatial resolution in comparison to IVUS, will
surely play a relevant role in the future in the management of
patients with small coronary vessel disease. However, the
lower depth of penetration of OCT in comparison to IVUS
suggest that this novel imaging technology will complement
rather than substitute IVUS for the invasive management of
small coronary vessel disease.
9. Perspectives for the future
The quest for a completely safe and effective device for
PCI continues, and most energies are currently focused on
drug-eluting balloons and bioabsorbable stents. Whereas
data are still very limited, Scheller et al. [61] have shown that
a paclitaxel-eluting balloon can challenge effectively and
safely standard balloons and, possibly, DES, in the treatment
of BMS restenosis or peripheral artery disease.
Bioabsorbable stents hold the promise of effectively
treating significant coronary artery disease while “disappear-
ing” after months have passed since the PCI and the stent has
been absorbed by naturally occurring healing processes.
Despite the obvious attractive aspects of this concept, there
remains much room for improvement, as to date, available
bioabsorbable stents are still fraught with significant rates of
recoil and restenosis [62,63].
10. Clinical implications and conclusions
Small vessel coronary artery disease is a frequent
occurrence in patients with symptomatic coronary artery
195
disease. Despite the great technical evolution of PCI, the
optimal treatment of small coronary vessels by PCI is still
debated. Many technical approaches for percutaneous
revascularization of small coronary disease have been
proposed in the last decades; nevertheless, several inter-
ventionalists still support balloon-only PCI for small vessels,
thus avoiding stenting. This is mainly based on three key
points which also represent the typical challenges of PCI in
small vessels: (a) small vessels are often considered not
relevant clinically for the patients, thus not worthwhile a
stent; (b) high restenosis rate; and (c) difficult deliverability
of stents in small vessels.
The clinical relevance of small vessels should be
judged on clinical bases. Patients presenting with ischemic
symptoms or signs and concomitant small vessels disease
are clear candidates to PCI. Nevertheless, different sizes of
coronary vessels in different populations are also of
relevance (e.g., diabetic patients, females, Asian popula-
tions). Consequently, small vessels could be a primary
target in different patients, and improvement of results in
this subset of patients is warranted. However, restenosis
rates are not negligible even with the use of DES. This is
mainly due to the fact that even low late loss could
negatively affect long-term results given the small
coronary diameter. Technical difficulties in terms of
deliverability of the stents in these vessels represent
another challenging point: small size gives more friction
especially for the deliverability of long stents Moreover,
small vessels are often tortuous and lesions are located
distally and may be calcified.
All the above challenging points could be resolved with
appropriate technology: the “ideal” stent to treat small
vessels should be a DES (since angiographic results with
BMS remain unacceptable for the high restenosis rate) with a
low late loss, a stent platform with low strut thickness, and
high conformability to the vessel (thus preferably a cobalt
chromium platform). The advent of dedicated stents with
these characteristics will certainly improve procedural and
late results. Thus, more small coronary vessels shall be
stented safely and effectively than is currently thought and
more clinical benefits shall be given to those patients with
really small vessels as primary target for their disease.
Acknowledgments
This work is part of an ongoing senior investigator
program of the Meta-analysis and Evidence-based Medicine
Training in Cardiology (METCARDIO) group based in
Turin, Italy (http://www.metcardio.org).
Appendix
PubMed was searched on July 2, 2008, with the following
query: small AND coronary AND stent⁎ AND (randomized
controlled trial[pt] OR controlled clinical trial[pt] OR
196 G. Biondi-Zoccai et al. / Cardiovascular Revascularization Medicine 11 (2010) 189–198
randomized controlled trials[mh] OR random allocation[mh]
OR double-blind method[mh] OR single-blind method[mh]
OR clinical trial[pt] OR clinical trials[mh] OR (clinical trial
[tw] OR ((singl⁎[tw] OR doubl⁎[tw] OR trebl⁎[tw] OR
tripl⁎[tw]) AND (mask⁎[tw] OR blind[tw])) OR (latin square
[tw]) OR placebos[mh] OR placebo⁎[tw] OR random⁎[tw]
OR research design[mh:noexp] OR comparative study[tw]
OR follow-up studies[mh] OR prospective studies[mh] OR
cross-over studies[mh] OR control⁎[tw] OR prospectiv⁎[tw]
OR volunteer⁎[tw]) NOT (animal[mh] NOT human[mh])
NOT (comment[pt] OR editorial[pt] OR meta-analysis[pt]
OR practice-guideline[pt] OR review[pt])).
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