Curr Cardiol Rep (2016) 18: 35
DOI 10.1007/s11886-016-0710-4
ISCHEMIC HEART DISEASE (D MUKHERJEE, SECTION EDITOR)
Coronary Sinus Stent: Could It Help in Refractory
Chronic Stable Angina?
Wael ElMallah 1
Published online: 27 February 2016
# Springer Science+Business Media New York 2016
Abstract Refractory angina is a life-disabling disease, even
with the discovery of antianginal drugs and the advances in
revascularization surgically or percutaneously to improve
symptoms. Over the last decade a renewal of interest in an
old surgical modality of narrowing the coronary sinus has
evolved. Although the surgical procedure idea was born in
1940 it was overshadowed by the development of coronary
artery bypass graft and percutaneous interventions. Recently,
a percutaneous approach of reducing the coronary sinus size
has been developed and several clinical studies have been
reported in refractory angina patients. We review the history
of coronary sinus intervention, and explore coronary sinus
stent possible mechanism of action, device design, and the
clinical data supporting its use.
Keywords Coronary sinus intervention . Refractory angina .
Coronary sinus reducer stent
Introduction
Almost, two centuries lapsed between the first description of
the, coronary venous drainage by Adam Christian Thebesius
in 1703 [1], until the first reported coronary sinus intervention
(CSI) by Prat in 1893 [2]. The Prat experiment in hens proved
that heart nutrients can be provided through via retrograde
This article is part of the Topical Collection on Ischemic Heart Disease
* Wael ElMallah
wael.elmallah@ttuhsc.edu
1
Division of Cardiology, Department of Internal Medicine, Texas
Tech University Health Science Center, 4800 Alberta Avenue, El
Paso, TX 79905, USA
infusion through the coronary sinus, since coronary sinus re-
mains free of disease even when atherosclerosis is extensive.
Attempts since the 1940s to improve myocardial perfusion
through the coronary sinus were withered by the lack of clin-
ical significance or conflicting data and overshadowed by the
innovation in coronary artery revascularization techniques [3].
Refractory angina entails persistent symptoms in the presence
of objective evidence of ischemia despite maximally tolerated
medical therapy and with a consensus that revascularization,
either surgically or percutaneously, cannot be achieved [4].
Recently, interest in coronary sinus intervention as a path for
myocardial perfusion in refectory angina has been revived as
several trials reported favorable outcomes in refractory angina
cohorts [5]. Table 1 summarizes the different CSI modalities
[5, 6, 7].
History of Coronary Sinus Occlusive Therapy
The concept of coronary sinus occlusion was first reported in
1941, when Claude Becks described his first surgical proce-
dure of coronary sinus reduction to a diameter of 3 mm [3]. In
1948, Claude Becks described his second procedure of plac-
ing a vascular graft between the descending thoracic aorta and
the coronary sinus followed by ostial reconstruction of the
coronary sinus ostium [8]. Experimental as well as clinical
data in 200 patients with refractory angina documented a tem-
porary improvement in symptoms. However, excessive mor-
tality and severe derangements, such as myocardial hemor-
rhage and edema, coupled with a limited understanding of
the mechanisms resulted in abandoning this surgical approach
[9].
In 1984, PICSO, was developed [10]. The concept involves
inserting a balloon tipped catheter into the coronary sinus. The
balloon has a pressure sensor. The catheter is connected to a
35 Page 2 of 6
Table 1 Summary of coronary sinus intervention modalities
Occlusion of the coronary sinus blood flow
PICSO Pressure-controlled intermittent
coronary sinus occlusion
Neovasc Reducer (TM) Coronary sinus stent reducer
Retrograde reperfusion
Becks II procedure
Cardioplegia
PICVA Percutaneous in situ coronary
venous arterialization
SRP Synchronized retroperfusion
SSR Synchronized
Suction and retroperfusion
console controlling the whole system. The balloon is inflated
to occlude the coronary sinus over several heart beats and
once the coronary sinus pressure plateaus, it deflates the bal-
loon, terminating the obstructing to venous flow thus permit-
ting drainage of cardiac venous return. Over the last three
decades, abundant data has accumulated on myocardial sal-
vage in experimental ischemia, reperfusion injury, acute glob-
al ischemia, and heart failure. More recently, evidence regard-
ing PICSO use as adjuvant therapy during primary PCI has
been reported [11, 12].
Based on the same concept, the coronary sinus (CS)
Reducer (Neovasc Inc., Vancouver, B.C., Canada) was devel-
oped [13]. The balloon expandable stent reduces the size of
the coronary sinus to a 3 mm diameter with the objective of
treating patients with refractory angina. We are going to re-
view the design and current evidence in support for its use in
refractory angina patients.
CS Reducer Design
The CS Reducer is a stainless steel balloon-expandable stent.
It is deployed at 2-4 atmospheric pressures. At deployment
pressure, the stent assumes an hourglass shaped with a mid-
diameter of 3 mm and a 7-13 mm at both ends. The expansion
of the Reducer is asymmetric in such a way that the proximal
end expands more than the distal end, to accommodate the
tapering diameter of the coronary sinus. The mid stent
narrowing can be abolished if balloon inflation pressure is
increased to 8 bars, completely opening the mid segment of
the stent, which will then attain a tubular shape. The stent is
Curr Cardiol Rep (2016) 18: 35
Pressure controlled balloon occlusion of the coronary sinus over several
heart beats. The pressure wave redistributes blood from normally
perfused veins retrograde into the microcirculation of deprived
myocardium. Once, systolic pressure reaches a plateau, occlusion is
released, allowing sufficient drainage.
Permanent occlusion of the coronary sinus
Surgical graft shunting blood from the aorta into the coronary sinus, and
ligation of the coronary sinus to ensure delivery of arterial blood into
ischemic zones.
Retro infusion of cardioplegia during cardiac arrest in surgery.
Percutaneously redirecting arterial blood flow from the occluded,
offending artery into an adjacent coronary vein, thereby arterializing
the vein and providing retroperfusion to ischemic myocardium
Synchronized retroperfusion of arterial blood during diastole in settings
of myocardial infarction, through the coronary sinus.
Suctioning of blood followed by synchronized retroperfusion of arterial
blood during diastole through selective access of the local coronary vein
draining the ischemic area.
pre-mounted on over the wire balloon and is delivered through
an internal jugular approach. After performing a right heart
catherization and coronary sinus angiography, the Reducer is
deployed at 30 degree left anterior oblique angulation, 1-2 mm
from the coronary sinus ostium, avoiding any side branch oc-
clusion (Fig. 1). The patient is preloaded with dual antiplatelet
therapy and continued on treatment for 3-6 months [13].
Animal Studies
The evidence for potential benefits and possible pathways of
action was driven mainly from PICSO studies, while only one
animal study has investigated the CS Reducer safety and sug-
gested a possible mechanism of action.
Initially, the driving hypothesis beyond CSI, was that me-
chanical occlusion of the coronary sinus whether it is total
temporary or partial chronic occlusion, will result in redistri-
bution of flow within the venous compartment allowing
rertograde perfusion to the to deprived perfusion zones. The
occlusion of the coronary sinus will raise the coronary sinus
pressure resulting in a redistribution of venous blood and
plasma-dense fluid from normally perfused territories into
underperfused areas. Consequently, blood will be squeezed
into the microcirculation, reducing the areas of ischemia.
During temporal occlusion as seen in PICSO procedures, a
phase of washout follows the filling of the venous compart-
ment [14, 15]. A meta-analysis of seven experimental trials of
PICSO in 125 test animals documented an inverse relationship
between achieved coronary sinus systolic pressure, and dura-
tion of ischemia [16]. The analysis showed a significant
Curr Cardiol Rep (2016) 18: 35
Fig. 1 CS Reducer deployment in the coronary sinus. A, The left anterior
oblique angiography of the coronary sinus during deployment. B,
Diagram representing a posterior view of the balloon mounter CS
Reducer positioning from the internal jugular vein through the SVC
into the coronary sinus. CS = coronary sinus, IVC = inferior vena cava,
SVC = superior vena cava
reduction in infarct size of 29.3 % in the PICSO group com-
pared to the control group (p b 0.001; 95 % confidence inter-
val, 40.9 to 17.7). To explore the benefit of additional
retroperfusion of arterial blood during PICSO, dose depen-
dence data showed that the amount of blood retro-perfused
had an inverse correlation to salvage (r = 0.97; p b 0.004)
[10, 17]. So, the cyclic redistribution of venous blood into
the center of ischemia followed by washout, maintains basal
metabolism as well as vasodilation, collateral flow, and im-
proved perfusion to the border zone. The resulting increased
energy storage is thus the main factor of salvage in CSI [18].
In a pig model of reversible myocardial ischemia, implanta-
tion of the Reducer was associated with reduced mortality and
improved ischemic parameters [13]. Whether the same theory
will hold true for the CS Reducer stent remains to be seen
considering given that the occlusion is partial, chronic, and
not associated with a period of washout.
Early, histological data from Becks procedure, described
the formation of many vascular channels distal to the occluded
artery [8], which indicates neo-angiogenesis. Similar findings
were observed after 8 to 12 weeks of coronary sinus
narrowing by the CS Reducer in pigs, new macroscopic epi-
cardial as well intramyocardial blood vessels developed [13].
Page 3 of 6 35
It was later that Weigel et al. explained the cascade leading
from coronary sinus narrowing to neo-angiogenesis (Fig. 2)
[19]. Miyasaka et al. postulated that chronic rise in venous
pressure will result in mechano-transduction and activation
of endothelium [20]. In a pig model of myocardial ischemia,
Weigel et al., proved that PICSO resulted in a fourfold in-
crease of heme oxygenase-1 gene expression (HO-1) in the
infarct area (P < .001), and a 2.5-fold enhanced transcription of
vascular endothelial growth factor (VEGF) in the infarct
(P < .006), border (P < .002), and remote (P < .02) areas [19].
HO-1, an anti-atherosclerotic molecule also known to be in-
volved in vasodilation, and VEGF, are associated with a better
cardiac function in 4 week follow up after experimental in-
farction. This upregulation of pro-angiogenetic molecules has
been observed in remote zones as well as in border zones and
also to some extent in ischemic zones. It is noteworthy that
that VEGF/VEGF2 and their receptor proteins were markedly
upregulated in myocardial cells in the remote zone but not in
the coronary sinus blood during experimental coronary artery
occlusion in pigs [21].
The Safety of CS Reducer was tested in nonischemic pigs.
These pigs were observed for up to a year. The implantation
procedure had no short or long term complications. The mean
pressure gradient measured across the reducers was 3.71
1.75 mmHg immediately after implantation and 2.83
1.47 mmHg 6 months later [13].
Clinical Trials
The first in-man application of the CS Reducer was reported
in 2007; in a multi-center trial conducted between centers in
Germany, Israel, and India. In an open label use, 15 patients
with symptomatic CAD and refractory CCS class II to IV
angina, underwent CS Reducer implantation. Patients were
selected based on the presence of objective evidence of revers-
ible myocardial ischemia, determined by perfusion scan and/
or by dobutamine echocardiography, plus left ventricular ejec-
tion fraction >25 %. Exclusion criteria included patients with
an acute MI in the prior 3 months, revascularization in the
primary 7 months, severe arrhythmias, decompensated heart
failure, severe valvular heart disease, CS devices, mean atrial
pressure 15 mmHg or tricuspid valve replacement or repair.
The primary end point was device safety and the secondary
end point was technical success. In this small number of pa-
tients, the device met all primary and secondary endpoints. All
implantation procedures were completed successfully. All pa-
tients were discharged from the hospital 1 to 2 days later
without clinical complications. No major adverse cardiac
events had occurred during the periprocedural period or dur-
ing the follow up period of 10 to 12 months (mean follow-up
11 1.03 months). A postimplantation CT angiography anal-
ysis measured the mean diameters of the Reducers in the
35 Page 4 of 6
Fig. 2 Summary of the pathways
by which coronary sinus
intervention and particularly
PICSO exert their effect through
regeneration, myocardial
protection, and improvement in
myocardial perfusion. IL-
6 = Interleukin 6,
VEGF = vascular endothelial
growth factor, HO = heme
oxygenase
proximal segment at 11 2 mm, distal segment at 7.2 1 mm,
and mid segment at 3.0 0.2 mm. At 6 months, angina score
was lower in 12 of the 14 patients and remained constant in two.
The average CCS class for the 14 patients was 3.07 at baseline
and 1.64 at follow-up (p = 0.0001). Ischemic burden was not
changed on stress testing. For the whole group, the average
double product and exercise duration were unchanged 6 months
after implantation compared with baseline (18,675 at baseline
vs. 20,365 at 6 months [p = 0.18] and 7.08 at baseline vs. 6.79 at
6 months [p = 0.59], respectively). Dobutamine echocardiogra-
phy showed improvement in eight out of 13 patients, while
Thallium SPECT showed only improvement in four patients.
These results were maintained for three years [13].
To explore efficacy, 23 patients were recruited in an open
label design; 14 patients from Israel and nine patients from
Belgium. The same inclusion and exclusion criteria and study
design as the first in-man use trial. The Reducer implantation
was successful in 21 (91 %) patients. The procedure failed in
two patients due to an unsuitable CS anatomy but no
procedure-related complications were observed immediately
after the procedure and at one-year follow-up. Among the
remaining 21 patients the procedure was uneventful and no
procedure-related complications were observed during a mean
follow-up period of 11.4 5 months. The angina score de-
creased significantly 6 months following Reducer implanta-
tion from a mean of 3.35 0.6 to 2.0 1 (n = 20, p < 0.001).
Seventeen (85 %) patients reported relief of symptoms follow-
ing the procedure. Objectively, Exercise duration as well as
Curr Cardiol Rep (2016) 18: 35
time to ST depression were prolonged (3:16 1:48 vs. 5:16
1:14 min, p = 0.05, and 1:47 1:12 vs. 3:57 2 min,
p = 0.59, respectively). There was a trend to improvement in
METS and Duke Score (4 1.8 vs. 5 1.3 and 10.8 9 vs.
6.3 7, p = 0.17, respectively). Similarly, six months wall mo-
tion score index at stress improved significantly (1.9 0.4 vs.
1.4 0.4, p = 0.046), as well as ejection fraction during dobu-
tamine infusion increased significantly from 48.9 % to 55 %
(p < 0.04). Thallium SPECT, summed stress score and
summed difference score were both significantly reduced,
suggesting an improvement in the extent and severity of the
ischemic segments (21.5 10 vs.13.2 9, p = 0.01, and 11.1
6 vs. 4.7 4, p = 0.007, respectively). Criticism was directed
to the patient selection process. During the follow-up period
four patients underwent coronary angiography due to angina.
Two of these patients were treated by PCI for new coronary
lesions, one patient was referred to CABG for progression of
his disease, and one patient was treated medically. [22]
The Coronary Sinus Reducer for Treatment of Refractory
Angina (COSIRA) trial was designed to examine whether
the implantation of the coronary-sinus reducing device
could effectively improve refractory angina symptoms.
The trial was designed to overcome the shortcomings of
the previous designs. It randomized patients from 11 clin-
ical centers on double blinded design to the Reducer stent
versus the sham procedure. The selection of the patients
was more rigorous. A heart team approach decided on the
revascularization appropriateness. Only patients who were
Curr Cardiol Rep (2016) 18: 35
symptomatic after one month of maximum tolerable med-
ical treatment and Canadian Class III to IV angina were
selected. Also, the trial was overseen by an independent
coordinating center, a steering committee, a clinical events
committee, and a data and safety monitoring board. One
hundred and four patients with suitable coronary anatomy
were randomized in 1:1 ratio to CS Reducer implantations
versus a sham procedure. Successful implantation was
achieved in 50 of the 52 patients (96 %) assigned to the
treatment group. A venous valve in the coronary sinus was
the cause of failure in the remaining two patients as the
devices failed to cross the valves. Regarding efficacy, a
significant change was observed in anginal class, quality
of life, and mean exercise duration, but not in the angina
stability, or frequency. Of the patients in the treatment
group 35 % had an improvement for at least two CCS
classes compared to 15 % in the control group (P = 0.02).
The Reducer stent reduced the CCS class from a mean of
3.2 0.4 at baseline to 2.1 1.0 at 6 months of follow-up in
the treatment group, as compared with a reduction from
3.1 0.3 to 2.6 0.9 in the control group (P = 0.001). Of
the fifty patients, 71 % had an improvement of at least
one CCS class, as compared with 42 % (22 of 52) in the
control group (P = 0.003). Although, the Seattle Angina
Questionnaire total score was significantly higher in the
treatment group (17.6 points), as compared with 7.6 points
in the control group (P = 0.048), angina stability did not
significantly differ between the two groups (18.1 vs. 8.3
points, P = 0.16) as well the frequency of angina (15.3 vs.
11.0 points, P = 0.44). At 6 months of follow-up, the mean
exercise duration had improved by 59 seconds (13 %) in
the treatment group and by 4 seconds (1 %) in the control
group (P = 0.07). When assessing ischemia objectively
there was a trend toward improvement that did not reach
statistical significance. On repeat stress test at six months,
the mean time to ST segment depression was non signifi-
cantly higher at 49 seconds in the treatment group when
compared to 18 seconds in the control group (P = 0.41).
The dobutamine wall-motion index improved by 14 % in
the treatment group and by 8 % in the control group
(P = 0.20). Concerning safety, one case of periprocedural
mortality has been reported which was the first since the
device was used in humans. Adverse events did not differ
between the two arms (64 % in the mean treatment arm vs
69 % in the control arm, p = 0.68). There were three myo-
cardial infarctions and one death in the control group, and
there was one periprocedural myocardial infarction and no
deaths in the treatment group. CT angiography performed
only in 70 % of the treatment group but had no evidence of
device migration or occlusion in any of the patients. It was
concluded that the device was effective and safe [23, 24].
The device was approved for commercial use in 2013 (CE-
Mark). At Euro PCR 2015, the University of Medical Centre
Page 5 of 6 35
of Utrecht, reported their experience as a part of clinical care
looking at angina improvement. Twenty-three, patients with
objective evidence of myocardial ischemia and no option for
revascularization were treated with CS Reducer. Procedural
success; defined as the successful placement of the device in
the CS without any periprocedural adverse events, was 100 %.
After a median follow-up of 6 months there was a significant
improvement in CCS class. The average CCS class at baseline
was 3.35 0.49 and improved to 2.13 0.92 at follow-up
(P = <0.001). The majority of patients (78 %) experienced an
improvement of clinical symptoms. Of the cohort 39 % by one
CCS class, 35 % by two CCS classes, and 4 % by three CCS
classes. Nearly one fifth (22 %) of the patients had no clinical
improvement [25].
The data seem to be consistent. The CS Reducer is safe to
implant and improves the CCS angina class. What remains to
be seen is how the device exerts its action and whether it
improves objectively myocardial perfusion or not. Finally,
why, does 20 % to 30 % of the patients selected based on
the current protocol constantly fail to benefit from the device?
These questions dictate a need for a larger trial.
Conclusion
Although, the current data is limited by the lack of device
specific animal investigation explaining the mechanistic ef-
fect, the small number of patients enrolled in clinical and lack
of long-term follow up, nevertheless, continued use is clearly
supported by : 1) the encouraging outcomes in all reported
clinical evidences, 2) the safety profile of the device, 3) the
lack of any alternative to improve the quality of life in refrac-
tory angina patients, and 4) the ease of implantation of coro-
nary sinus stents. We need to refine the selection process and
identify further cohort characteristics that may either improve
or hinder the clinical benefit. Moreover, we need long term
follow up to explore how long the clinical benefit will last. It is
imperative to recognize that, these are not an alternative for
maximal medical treatment, life style modification or revas-
cularization procedure. Furthermore, the selection process for
these patients should be rigorous and may require a multidis-
ciplinary approach involving the primary care physicians, the
non-invasive cardiologists, interventional cardiologists, and
cardiothoracic surgeons in a heart team approach.
Compliance with Ethical Standards
Conflict of Interest Wael ElMallah declares that he has no conflict of
interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
35 Page 6 of 6
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