International Journal of Cardiology 209 (2016) 122–130

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International Journal of Cardiology

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Review

Coronary Sinus Reducer system™: A new therapeutic option in refractoryangina patients unsuitable for revascularization

Alfonso Ielasi ⁎, Maria Chiara Todaro, Giulietta Grigis, Maurizio TespiliCardiology Division, Bolognini Hospital Seriate, Seriate (BG), Italy

⁎ Corresponding author at: Cardiology Division, Bologn21, 24068 Seriate (BG), Italy.

http://dx.doi.org/10.1016/j.ijcard.2016.02.0180167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved

a b s t r a c t

a r t i c l e i n f o

Article history:Received 4 January 2016Accepted 1 February 2016Available online 3 February 2016

A challenge of modern cardiovascular medicine is to find new, effective treatments for patients with refractoryangina pectoris (RAP), a clinical condition characterized by severe angina despite optimal medical therapy and“no option” for a surgical or percutaneous revascularization. Although the relevant advance of both pharmaceu-tical and interventional treatments for patients affected by symptomatic coronary artery disease has greatlycontributed to prolong survival, the increasing number of patients experimenting persistent and invalidating an-gina symptoms, highlights that quality of life of these patients has not been equally improved. Clinical limitationsof the efficiency of conventional and relatively new approaches justify the search for new therapeutic options.In this review, we will focus on the epidemiology of RAP, and we will provide a brief update on the differentoptions actually available to these patients with particular interest to an innovative device that narrow thecoronary sinus: the Reducer system (Neovasc Inc., Richmond B.C., Canada). The efforts of present and future clin-ical studies will ultimately answer the question of whether this intriguing therapy is a suitable strategy for treat-ment of patients with RAP.

© 2016 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

Myocardial ischemia is the result of an imbalance between oxygendemand and supply. This condition is most commonly due to coronaryatherosclerosis, resulting in a critical narrowing of the vessels. Thera-peutic interventions may focus on reducing myocardial ischemicburden by improving oxygen supply through coronary flow increaseor redistribution from well oxygenated myocardium to ischemicregions of the myocardium, or alternatively by modulation of the maindeterminants of myocardial oxygen consumption: heart rate, left ven-tricular (LV) contractility and LV wall tension [1].

Conventional approaches to restore this balance between oxygensupply and demand focus on disruption of the underlying diseaseprocess through medications, life-style modifications or revasculariza-tion techniques, such as coronary artery bypass graft surgery (CABG)or percutaneous coronary interventions (PCI).

Although the relevant advance in both pharmacological and inter-ventional treatments for patients affected by coronary artery disease(CAD) has greatly contributed to prolong survival, the increasingnumber of patients experiencing persistent and invalidating anginasymptoms, highlights that quality of life of these patients has not beenequally improved.

ini Hospital Seriate, Via Paderno

.

The management of these refractory angina pectoris (RAP) patientsstill represents a challenging issue for cardiologists.

In this review,wewill focus on the epidemiology of RAP, andwewillprovide a brief update on the different treatment options actuallyavailable for these patients with particular interest to an innovativedevice that narrow the coronary sinus: the Reducer system (NeovascInc., Richmond B.C., Canada).

1.1. Epidemiology

Refractory angina is defined as CanadianCardiovascular Society class(CCS) III or IV angina, withmarked limitation in ordinary physical activ-ity or inability to perform ordinary physical activity without discomfort,with an objective evidence of myocardial ischemia, and persistence ofsymptoms despite optimal medical therapy, life style modification,and revascularization therapies [2].

RAP is a relatively common clinical problem. It is estimated thatthere are asmany as 525,000 angina patients in the EU andUS classifiedeach year as having no revascularization options. Additionally, there arewell over 500,000 other patientswhohave undergone revascularizationwith either PCI or CABGbut continue to suffer fromangina,which bringsthe total number of patients that could potentially benefit from newangina therapies to over 1 million annually [3–6] The Joint StudyGroup estimated the incidence of refractory angina between 5% and10% of patients undergoing cardiac catheterization [7].

Table 1Phenotype of patients unsuitable for revascularization.

Phenotype Characteristics

A. Suspected cardiac“X” syndrome

1. Normal coronary angiogram

• Objective evidence of myocardial ischemia in absenceof significant coronary epicardial stenosis;

• Possible microvascular dysfunction;• Natural history: prognosis not necessarily benign butlow mortality rate; [18–19]

2. Prior CABG

• Objective evidence of myocardial ischemia in presenceof normally functioning grafts;

• Potential microvascular dysfunction;• Mortality rate/year: 9.2%; [8]

B. CAD with limitedterritory at risk

1. Limited territory at risk with no prior CABG

• Significant epicardial (non-LAD single vessel CTO, sidebranch or distal) stenosis inducing angina but notsuitable for PCI and not associated with high risk fea-tures at non-invasive stratification;

• Mortality rate/year: 1.8%–2.4% (1- and 2-vessel diseasetreated medically); [20]

2. Limited territory at risk with prior CABG

1. Significant epicardial stenosis inducing angina but notsuitable for PCI and not enough severe to justify aredo-CABG (SVG occlusion or incomplete revasculari-zation at the time of CABG);

2. Mortality rate/year: 2.4%; [21]C. Diffuse CAD • Diffuse coronary atherosclerosis from proximal to

distal segments with small (b 1 mm) distal run-off;• May involve 3 coronary arteries simultaneously withpossible focal plaques but typically part of a diffuseprocess;

• Natural history unknown;D. “End-stage” CAD • Extreme CAD that combines stenosis in proximal

segments and a diffuse atherosclerosis of the distalbeds. A network of collateralsis typically visible inviable territories;

• Most frequently seen on patients with prior,degenerated CABG;

• Mortality rate/year: above 5% (ranging from 5.1% to33%); [22–24]

CAD: coronary artery disease; CABG: coronary artery bypass graft; LAD: left anteriordescending artery; CTO: chronic total occlusion.

123A. Ielasi et al. / International Journal of Cardiology 209 (2016) 122–130

1.2. Patients not suitable for myocardial revascularization

Due to the heterogeneity of CAD patterns, such as long diffuse CAD,multiple distal coronary stenoses, and or small coronary arteries and thepresence of multiple comorbidities, an increasing number of patientssuffering from RAP, are deemed not suitable for revascularization. Thedecision not to pursue further revascularization is difficult and variesdepending on patient-specific characteristics and available medicalexpertise [8]. Based on the definition proposed by Jolicoeur et al., apatient is deemed unsuitable for revascularization in the presence of aCAD due to one or several significant epicardial stenoses and/or to mi-crovascular dysfunction where PCI or bypass surgery cannot be reason-ably attempted or is not expected to improve myocardial perfusion [2].When appropriate, thediagnosis of CADunsuitable for revascularizationshould be based on a consensual agreement involving a specializedmedical team of at least an interventional cardiologist and a cardiacsurgeon. The decision, which be based on a recent angiogram, is tempo-rary and should be reassessed periodically due to the dynamic nature ofCAD [2]. Jolicoeur et al., grouped patients unsuitable for revasculariza-tion under 4 anatomo-pathological phenotypes based on readilyaccessible coronary angiographic features.

Phenotype A: suspected cardiac syndrome X.Phenotype B: CAD with a limited territory at risk.Phenotype C: Diffuse thread-like coronary atherosclerosis.Phenotype D: End-stage CAD (Table 1).In addition to anatomical features, non-anatomical characteristics

such as comorbidities (i.e. cancer, chronic obstructive pulmonarydisease, and chronic kidney disease), available local expertise, or proce-dural risk (i.e. old age) are important to give the “no-option” label inRAP patients.

1.3. Alternative therapies for RAP patients

The management of patients with chronic persistent, angina orangina equivalent symptoms impairing quality of daily life, despite op-timal medical therapy and multiple revascularization procedures, stillrepresents a challenging issue for cardiologists. For this reason, overthe last decades different pharmacological and non-pharmacologicaltreatment options have been suggested for patients suffering from angi-nal symptoms [9] (Tables 2 and 3).

A considerable number of therapeutic strategies have been investi-gated to treat RAP, such as transcutaneous electric nerve stimulation,spinal cord stimulation (SCS), left stellate ganglion blockade, endoscop-ic thoracoscopic sympathectomy, thoracic epidural anesthesia,enhanced external balloon counter pulsation (EECP), stem cell therapy,and, finally, myocardial laser revascularization by surgical transcutane-ous myocardial laser revascularization (TMR) or percutaneous myocar-dial revascularization (PMR) technique. Even if the initial experienceswith most of these therapies were encouraging, placebo-controlledtrials have then shown onlymodest improvements in exercise treadmilltime and symptoms of angina. Each existing therapy has a limiteddegree of efficacy, and none of these approaches have become widely-utilized therapies [3–6]. Prominent placebo effects have obscuredresults from potentially innovative approaches and must be taken intoconsideration when discussing the beneficial effects of novel therapies.In the 2012 Canadian Cardiovascular Society (CCS) practice guidelinesfor the management of patients with RAP and in the 2013 Europeanguidelines for the management of stable CAD, all non-pharmacologicaloptions received a weak recommendation for use and none ofthese treatment options has routinely being used in clinical practice[7–10].

2. Coronary Sinus Reducer system

2.1. The device

The Reducer is a balloon-expandable hourglass shaped stainlesssteel device, laser cut into a pre-specified geometric pattern with flexi-ble longitudinal struts and no welding points.

The Reducer Balloon Catheter (Fig. 1) is an over the wire uniquehourglass shaped balloon catheter. The proximal and distal portions ofthe balloon have differing diameters to conform to the tapered typicalconfiguration of the CS. Two radiopaque markers, located on thecatheter shaft, mark the location of the crimped Reducer on the deploy-ment balloon. A third marker located just proximally to the balloon isused to assist the operator to visualize when the balloon section of thecatheter is completely outside the tip of the guide catheter.

The Reducer is implanted percutaneously in the CS through the rightinternal jugular vein (IJV) approach.

Once implanted using inflation pressures between 2 to 6 bars, the CSReducermay achieve a diameter of 3mm at its mid portion, while it canreach diameters of 9.0 and 14.0 mm at its distal and proximal ends,respectively. In case it is necessary to remove the narrowing from theCS (i.e. dislodgment with necessity to implant a second device), ballooninflation to a diameter of 6–8mmwill the narrow center of the Reducer,which will then attain a tubular shape.

Table 2Novel pharmacological therapeutic option for patients suffering refractory angina.

Pharmacologicalagents

Mechanism of action Anti-ischemic effect Clinical outcome Evidences of literature

Vasodilators Nicorandil Opening of mitochondrialATP-sensitive potassiumchannels (KATP)

Coronary artery dilatation;Cardio-protective affect

Combined end point of CVdeath, nonfatal MI, andhospital admission for cardiacchest pain

IONA Trial [25]

Arginine Nitric-oxide-mediated,endothelium-dependentvasodilatation

Increase of coronary bloodflow

No Trials available

Fasudil andHydroxyfasudil

Inhibition of Rho kinaseenzyme which reducesvascular smooth musclesensitization to calcium

Maintain coronaryvasodilatation and preventvasospasm

Anti-ischemic, but noantianginal, effects with orwithout concomitantanti-anginal medication.

No Trials available

Oxygen sparingagents

Ivabradine Blocks If channels;Regulates Alfa adrenergicmediated coronaryvasoconstriction

Intrinsic chronotropic effect onsinoatrial node;Coronary artery flowdistribution

Increase in TET ASSOCIATE Trial [26]24% reduction in CV death andhospitalization for MI or heartfailure

BEAUTIFUL Trial [27]

Ranolazine Inhibits late inward of Sodiumcurrent and prevents Calciumover-load

Reduces diastolic tension;Improves regional coronaryblood flow in areas ofmyocardial ischemia;May partially inhibitmitochondrial fatty-acidoxidation

Improvement of TET andischemic threshold

ERICA Trial [28]

Increase treadmill exercisecapacity;Reduction of angina and NTuse

CARISA Trial [29]

Reduce angina frequency andsublingual NT use in patientswith type 2 diabetes mellitusand chronic SA

TERISA Trial [30]

Allopurinol Inhibition of xanthine oxidase Reduces oxidative stress;Increasesendothelium-dependentvasodilatation

Prolongs time to both chestpain and ST- segmentdepression;No clinical outcome

Effect of high-dose allopurinolon exercise in patients withchronic stable angina Trial [31]

Trimetazidine Inhibition of mitochondriallong-chain 3-ketoacyl-CoAthiolase, an important enzymefor the β-oxidation of fattyacids;Increase of glucose oxidation

Oxygen sparing andenhancement of energyefficiency in ischemicmyocytes

Improves time to ST-segmentdepression compared withplacebo and weekly anginafrequency

TRIMPOL II Trial [32]

Perhexiline Inhibits carnitine-palmitoyltransferase 1 and 2,which transfer free fatty acidfrom the cytosol intomitochondria

Oxygen sparing Improves exercise-tolerance A double-blindplacebo-controlled clinicaltrial of a novel antianginalagent [33]

CV: cardiovascular; MI: myocardial infarction; TET: total exercise time; SA: stable angina; NT: nitroglycerin.

124 A. Ielasi et al. / International Journal of Cardiology 209 (2016) 122–130

The device was designed to establish, after the complete endotheli-alization of the struts (within at least 6 weeks after implantation) acontrolled narrowing of the CS which is the final pathway of the cardiacvenous drainage [11].

The CS narrowing should be associated with a subsequent redistri-bution of collateral bloodflow fromnon-ischemic to ischemic territoriesof the myocardium inducing a reduction of the extent of the ischemiaand the relief of angina symptoms [11].

2.2. The implantation procedure

The CS Reducer is implanted within the CS through the right IJV.

1. Under local anesthesia, the IJV access is gained (usually echo-guided) and a 9F sheath is positioned in place.

2. A 6F Multipurpose catheter is advanced into the right atrium inorder to assess the intra-cavitary pressures. In case of mean rightatrial pressure less than 15 mm Hg there is indication to proceedwith the device implantation.

3. The Multipurpose catheter is then advanced towards the ostium ofthe CS (30° left anterior oblique view) and once it is engaged thecatheter is gently placed as distally as possible in the CS and avenography is performed.

4. Using the CS angiography the optimal location for Reducer implan-tation is chosen. The best site of implantation is usually about 2 cm

distal to the CS ostium, where the CS diameter is about 7–14 mm,avoiding side branches.

5. Bonemarkers are chosen as landmarks for the device implantation.6. A 0.035 in. wire is advanced within the multipurpose and then left

distally into the CS while the catheter is removed.7. The CS Reducer system is advanced over the wire within a 9F guid-

ing catheter into the CS.8. The guiding catheter with the Reducer is advanced into the CS.

When the Reducer is located within the site chosen for implanta-tion, the guiding catheter is gently withdrawn exposing theReducer in the landing zone previously identified.

9. The Reducer is implanted by inflating the balloon up to 4–6 atm for30–60 s.

10. After implantation, in order to avoid device displacement, theballoon is completely deflated and the guiding catheter re-advanced up to the narrowed segment of the device to favor aprotected balloon retrieval (Fig. 2).

Theoretical complications related to the CS Reducer implantationcould be:

1. CS dissection during catheter or wire manipulations (usuallyconservatively managed with echo monitoring to exclude cardiactamponade).

2. Immediate or late device migration (more probable in case ofimplantation in a smaller or larger than recommended CS).

3. Cardiac tamponade due to CS rupture.

Table 3Novel non-pharmacological therapeutic options for refractory angina.

Non-pharmacologicalagent

Mechanism of action Anti-ischemic effect Clinical outcome Evidences ofliterature

Non-invasivetreatments

Enhanced externalcounterpulsation (EECP)

Utilizes three sets of pneumaticcuffs around the lowerextremities, which inflate duringdiastole and deflate in systole

In diastole: increase coronaryblood flow; In systole: reduceafter-load and increase venousreturn

Increase time toexercise-inducedST-depression; Reduce anginafrequency

MUST-EECP Trial [34]

Extracorporealshockwave therapy(ESWT)

Brief, high-amplitude acousticpressure pulses are delivered totissues in order to exert a focalmechanical stress

Local shear stress, promotes insitu expression ofchemo-attractants, such asstromal cell-derived factor 1,VEGF, and NO

Increase the mean 6-minwalking test distance at 12months; Improve CCS anginaand SAQ scores

Wang, Y. et al. [35]

Improve LVEF at 4 months andfunctional class combinedwith bone-marrow-derivedcell therapy

CELLWAVE Trial [36]

Invasivetreatments

Chronic total occlusionsPCI

Revascularization of chronic totalocclusion in patients stillsymptomatic for angina and notsuitable for CABG

Improve coronary flow in still vitalischemic myocardial areas

Reduction in cardiac death, MIand re-hospitalization at 1year vs. MT

IRCTO Registry [37]

Percutaneous narrowingof the coronary sinus(Reducer™)

Stainless steel,balloon-expandable,hourglass-shaped device thatcreates a controlled narrowing ofthe coronary sinus

Induces a trans-sinusal pressuregradient, responsible forblood-flow redistribution toischemic sub-endocardial regions

Improve Angina score;Improve CCS; Improvestress-induced ST-segmentdepression; Reduce extent andseverity of ischemic burden atstress test

COSIRA Trial [17]

Therapeuticangiogenesis

Intracoronary VEGF andFGF

The use of protein growth factors,gene therapy, or stem-cell therapyenhance the natural process ofangiogenesis

Promote revascularization Improve angina and Qol VIVA Trial [38]

Intracoronary deliveryof an Ad5FGF

Improve angina; Improveexercise capacity in high-riskpatients (CCS III–IV)

AGENT [39] AGENT-2[40] AGENT 3 andAGENT 4 [41]

Intracoronarytransplantation ofbone-marrow CD34+cells

Reduce mortality over 6–12months; Improve CCS; Reduceweekly angina count

RENEW study [42]

Trans-endocardialinjection of CD133+cells

Improvement in anginaepisodes per month andangina functional class

PROGENITOR Trial[43]

Neuromodulation Spinal-cord stimulation(SCS)

A multipolar electrode issurgically positioned in theepidural space between the C7and T4 and linked to aprogrammable pulse generatorpromoting the release ofγ-aminobutyric acid.

Chemical, mechanical, or electricalmeans to interrupt a pain signalanywhere in the transmissionpathway from the periphery tothe brainAnalgesic effect reducessympathetic afference responsiblefor vasoconstriction.

Reduce angina frequency andnitrate consumption

Eddicks S [44] LanzaGA [45]

No difference with controlgroup

STARTSTIM [46]

Subcutaneous electricalnerve stimulation(SENS)

Multipolar electrodes aresubcutaneously implanted in theparasternal area and tunneled to apulse generator located in theupper abdomen.

Reduce angina frequency andnitrate consumption

No trials availableBuiten M [47]

Cardiac sympathectomy Temporary sympathectomy bystellate ganglion blockade

Anecdotal success in patientswith angina

No studies available

Transmyocardial laserrevascularization(TMLR)

Performed epicardially duringCABG or endocardially via apercutaneous approach (PTMLR)

PTMLR improved exercisetolerance in patients with CCSclass III angina.

PACIFIC Trial [48]DIRECT Trial [49]

No difference with placebo

SAQ: Seattle angina questionnaire; LVEF: left ventricular ejection fraction; Qol: quality of life. VEGF: vascular endothelial growth factor; NO: nitric oxide; CCS: Canadian CardiovascularSociety; FGF: fibroblast growth factor; Ad5FGF: adenovirus encoding FGF5; MT: medical therapy; MI: myocardial infarction; PCI: percutaneous coronary intervention.

125A. Ielasi et al. / International Journal of Cardiology 209 (2016) 122–130

However up to nownomajor complicationswere reported during orafter CS Reducer implantation.

2.3. Coronary sinus narrowing: back to the future

The first experimental evidence that support the CS narrowing inpatients with CAD has been shown by a cardiac surgeon in 1955 [12].

Beck et al. initially demonstrated in a dog model of acute coronaryartery ligation that the partial narrowing of the CS is associated with areduction in the infarct size and mortality by a doubled degree of retro-grade backflow from the distal stump of the occluded coronary artery.So CS narrowing may force the oxygenized arterial blood into under-perfused myocardial segments reducing the extent of the ischemiaand the angina symptoms.

In humans, Beck treated his patients with disabling angina by openchest surgery creating a 60–70% narrowing of the CS to achieve a3 mm residual lumen diameter (“Beck Procedure”).

A comparative study of 185 patients at the Cleveland Clinic showedthat long-term mortality in the group of patients treated as per Beck'sprocedure to be significantly lower, at 13%, than the 30% mortalityrate observed in the control group. Furthermore, in the surgical group,90%of patients reported complete or significant relief of their symptomsas measured by reduction of pain and need for medication [13].

These pre-clinical and clinical studies demonstrated that the successof the CS narrowing procedure was likely driven by elevated CS pres-sure, which triggered protective mechanisms that improved perfusionof ischemic territories of the myocardium.

The success of CABG and then of PCI asmechanical revascularizationoptions decreased the interest in the surgical ligation of CS but

Fig. 1. The Neovasc Coronary Sinus (CS) Reducer System. A. The hourglass shaped stainless steel Reducer device. B. The proximal and distal segments of the balloon have differingdiameters to conform to the taper typically encountered in the CS. C. Reducer system crimped on the balloon before and during (D) deployment.

126 A. Ielasi et al. / International Journal of Cardiology 209 (2016) 122–130

the current rise in patients with RAP creates an opportunity toreconsider this approach when the patients are unsuitable forrevascularization.

2.4. Theoretical pathophysiological mechanism of action of the CS Reducersystem

The suggested anti-ischemic effect of the CS Reducer is based on thehypothesis described by Camici et al. [14], according to which, in anormal heart, during exercise there is a sympathetically mediated con-striction of subepicardial vessels which leads to a preferential bloodflow towards the subendocardial capillaries. In patients with obstruc-tive CAD this physiologic compensatory mechanism is dysfunctional

Fig. 2. CS Reducer implantation. A. Coronary sinus angiography showing no anatomical contrcatheter is removed. C. Pre-mounted CS Reducer system advancement over the wire withinadvanced up to the landing zone previously identified. E. CS Reducer implantation (inflating tadvanced up to the narrowed segment of the device to favor a protected balloon retrieval.

[14]. In addition, in the presence of ischemia, impaired contractilityand elevated left ventricle end-diastolic pressure (LVEDP) exert anexternal pressure on the subendocardial capillaries which furtherincreases the resistance to flow to the subendocardium, leading to a vi-cious cycle of worsening subendocardial ischemia. Elevated CS pressurecausing backwards pressure elevation in the venules and capillaries willresult in a slight dilatation of the capillaries' diameter and a significantreduction of the resistance to flow. As a consequence of the reductionin subendocardial capillary resistance, the normal subepicardial to sub-endocardial blood flow ratio will be restored [15]. The result of thisprocess is an enhancement of blood flow to the ischaemic subendocar-dial layers of the myocardium, which will improve contraction, reduceLVEDP and lead to symptoms relief.

aindication to Reducer implantation. B. A 0.035″ wire is left distally into the CS while thea 6F guiding catheter into the CS. D. Pull-back of the guiding catheter while the devicehe balloon up to 6 atm for 30–60 s). F. The balloon deflated and the guiding catheter re-

Fig. 3. Theoretical mechanism of action of the reducer system. A. During exercise there is a sympathetically mediated constriction of subepicardial vessels which leads to a preferentialblood flow towards the subendocardial capillaries. B: in patients with obstructive coronary artery disease this physiologic compensatory mechanism is dysfunctional leading to avicious cycle of worsening subendocardial ischemia. C: Elevated CS pressure causing backwards pressure elevation in the venules and capillaries will result in a slight dilatation of thecapillaries' diameter and a significant reduction of the resistance to flow. As a consequence of the reduction in sub-endocardial capillary resistance, the normal sub-epicardial to sub-endocardial blood flow ratio will be restored.

127A. Ielasi et al. / International Journal of Cardiology 209 (2016) 122–130

In order to examine the validity of the presumed mechanism ofaction of the CS Reducer, a set of preclinical experiments and a first-in-man safety study were initially conducted (Fig. 3).

2.5. CS Reducer: pre-clinical and clinical evidences

In 2007, Banai et al. reported thefirst-in-man experiencewith the CSReducer in an open-label, multicenter, non-randomized, prospectivestudy. Fifteen patients unsuitable for myocardial revascularization(“no option” patients) were electively treated with the CS Reducer im-plantation. All patients enrolled had left ventricular ejection fraction≥30% and refractory angina (CCS class II to IV) despite optimal medicaltherapy with an objective evidence of reversible myocardial ischemia.

Clinical evaluation, dobutamine echocardiography, thallium single-photon emission computed tomography (SPECT), and administrationof the Seattle Angina Questionnaire for assessing quality of life andangina classwere performed before and at 6-months after implantation.All procedures were completed successfully with any peri-proceduraland/or at follow-up device-related adverse events. Angina scoreimproved in 12 of 14 patients, average CCS score was 3.07 at baselineand 1.64 at follow-up (n = 14, p b 0.0001); stress-induced ST-segment depression was reduced in 6 of 9 patients and was eliminatedin 2 of these 6 (p= 0.047). The extent and severity of myocardial ische-mia by dobutamine echocardiography and by SPECT was reduced (p=0.004 [n=13] and p=0.042 [n=10], respectively) [11]. In 2014 a twoCenters (Tel Aviv and Antwerpen) experience provided further evi-dence regarding the efficacy of the CS Reducer as a therapeutic strategyfor “no option” patients suffering from RA. Konigstein et al. reported asuccessful device implantation in 21 of 23 eligible patients (91%), at

both centers. The procedure failed in two patients due to an unsuitableCS anatomy. No device-related adverse effects were observed duringthe procedure or the follow-up period. CCS score diminished from amean of 3.3 at baseline to 2.0 at six months (n= 20, p b 0.01), exerciseduration was prolonged from 3:16 min to 5:16 min (n = 8, p = 0.05).Thallium SPECT summed stress score and summed difference scorewere both reduced (n = 9, 21.5 ± 10 vs.13.2 ± 9, p = 0.01, and11.1 ± 6 vs. 4.7 ± 4, p = 0.007, respectively). Wall motion scoreindex at peak dobutamine infusion was also significantly improved(n= 8, 1.9 ± 0.4 vs. 1.4 ± 0.4, p = 0.046) [16]. Based on these encour-aging result the randomized sham-control COSIRA (Coronary SinusReducer for Treatment of Refractory Angina) trial was designed inorder to address the concern regarding the possible placebo effect,and hopefully further support the preliminary observations.

The results of the COSIRA trial were published on February 2015[17]. A total of 104 patients with CCS class III or IV angina and myocar-dial ischemia, who were not candidates for revascularization, wererandomized to implantation of the device (treatment group) or to asham procedure (control group). The primary end point was the pro-portion of patients with an improvement of at least two CCS anginaclasses at 6 months.

The devicewas successfully implanted in 50 of the 52 patients (96%)randomly assigned to the treatment group. In 2 patients, the implanta-tion failed owing to a venous valve in the coronary sinus that could notbe crossed with the device.

A total of 35% of the patients in the treatment group (18 of 52patients), as compared with 15% of those in the control group (8 of52), had an improvement of at least two CCS angina classes at 6 months(p=0.02). The devicewas also associatedwith improvement of at least

Table 4Clinical studies on refractory angina patients treated with the reducer system.

Clinical study Inclusion criteria Number of patients End-points Results p

Banai et al. [11]Prospective, Open-Label,Multicenter, Safety andFeasibilityFirst-in-Man Study

Proven CAD, and refractoryangina despite optimalmedical therapy

15 Primary end-point: Safety:absence of any MACE relatedto the procedure (death, MI,perforation of the CS, CSocclusion, or need for urgentdilatation of the Reducerduring 6 months of follow-up).

Secondary end-point:technical success. Successfuldelivery and deployment ofthe Reducer in the CS

Reduction of averageCCS class for 14 patients(3.07 vs. 1.64)

b0.001

Reduction of Stress-induced STsegment in 6 of 9 patients andeliminated in 2 of these 6

0.047

Reduction of the extent andseverity of myocardialischemia by dobutamineechocardiography and bythallium SPECT

0.0040.042

Konigstein et al. [16] Severe angina pectoris (CCSclass II-IV) despite optimalmedical therapy

Objective evidence ofmyocardial ischemia EF ≥25%,No option for surgical orpercutaneous coronaryrevascularization

23 selected21 successfully implanted(2 failed for unsuitable CSanatomy)

Ischemic burden reduction at6-months follow-up,evaluated by means ofobjective parameters

TreadmillCCS class decreased from amean of 3.35 ± 0.6 to 2.0 ± 1.Exercise duration increased3:16± 1:48 vs. 5:16± 1:14min.

Time to ST depression prolonged(1:47± 1:12 vs. 3:57 ± 2min)

METS increased(4 ± 1.8 vs. 5 ± 1.3).

Duke Score was improved(−10.8± 9 vs.−6.3± 7).

b0.0010.050.590.170.17

Dobutamine stress testWMSI at rest remainedunchanged(1.5 ± 0.3 vs. 1.3 ± 0.4).

0.4

WMSI at stress improvedsignificantly (1.9 ± 0.4 vs. 1.4 ±0.4).

0.046

Thallium SPECTSRS remained unchanged (9.7 ±7 vs. 8.4 ± 10, p = 0.23).

0.01

SSS and SDS were bothsignificantly reduced, (21.5 ±10 vs.13.2 ± 9, and 11.1 ± 6vs. 4.7 ± 4).

0.007

COSIRA Trial [17]

Multicenter, randomized,double blind trial

104 randomized toReducer implantation(treatment group) vs.a sham procedure(control group)

Primary end-point: proportionof patients with animprovement of at least twoCCS angina classes at 6 months

Improvement of atleast two CCS and one CCSangina class in 35% and 71% ofthe patients in the treatmentgroup vs. 15% and 42% of thosein the control group

0.020.003

SAQ improved in thetreatment group vs. controlgroup (on a 100-point scale,17.6 vs. 7.6 points).

0.03

CCS: Canadian Cardiovascular Society; CS: coronary sinus; EF: ejection fraction; METS: metabolic equivalents; WMSI: wall motion score index; SRS: summed rest score; SSS: summedstress score; SDS: summed difference score; SAQ: Seattle angina questionnaire; SPECT: single photon emission computerized tomography.

128 A. Ielasi et al. / International Journal of Cardiology 209 (2016) 122–130

one CCS angina class in 71% of the patients in the treatment group(37 of 52 patients), as compared with 42% of those in the controlgroup (22 of 52) (p = 0.003). Quality of life as assessed with theuse of the Seattle Angina Questionnaire was significantly improvedin the treatment group, as compared with the control group(improvement on a 100-point scale, 17.6 vs. 7.6 points; p = 0.03).There were no significant between-group differences in improve-ment in exercise time or in the mean change in the wall-motionindex as assessed by means of dobutamine echocardiography [17].Despite the relatively small sample of this clinical trial, the resultsconfirmed that the CS Reducer system may serve the growing pro-portion of patients that remains symptomatic despite maximalanti-anginal therapy.

However, even if the concept of amechanical treatment of refractoryangina is intriguing, more informative clinical studies are needed toconfirm the role of such device in clinical practice (Table 4).

For this reason, the post marketing REDUCER-I study is currentlyenrolling patients. This is an observational multi-center, multi-country, three-arm study (Arm 1: patients prospectively enrolled inthe REDUCER-I study; Arm 2: patients previously implanted in the Re-ducer [treatment arm] of the COSIRA study; Arm 3: patients in whomthe Reducer was implanted under CE Mark [unrelated to the COSIRAstudy], prior to enrollment in the REDUCER-I study). It is planned toenroll up to 400 subjects at up to 40 investigational centers in order toassess the clinical outcomes at 6 months through 5 years post Reducerimplant.

Primary end-points of the study are: 1) Angina symptoms (CCSgrade) improvement; 2) Device and/or procedure related peri-procedural Serious Adverse Events (SAEs) defined as a composite ofdeath, myocardial infarction (MI), cardiac tamponade, clinically-drivenre-dilation of a Reducer, life threatening arrhythmias (ventriculartachycardia [VT] or ventricular fibrillation [VF]), and respiratory failure

129A. Ielasi et al. / International Journal of Cardiology 209 (2016) 122–130

through 30 days post-implant; 3) Major Adverse Cardiac Events(MACE): a composite of cardiac death, major stroke, and MI through30 days post implant.

2.6. Our experience and future directions

From March 2015 to December 2015, five consecutive patientsaffected by RAP despite optimal medical therapy, were selected for CSReducer implantation in our Center. All patients satisfied the clinical in-clusion criteria (refractory angina defined as CCS class II to IV despitemedical therapy not amenable to or at high risk for CABG or PCI andwith left ventricular ejection fraction ≥30%) for CS Reducer therapyand showed an extended inducible myocardial ischemia territory of atfunctional stress tests (treadmill test and/or exercise SPECT). Beforethe procedure, all patients completed the Seattle Angina Questionnairefor quality of life evaluation, underwent a sixminuteswalking test and acomprehensive trans-thoracic echocardiography including a detailedevaluation of systolic and diastolic function with estimation of LV fillingpressure. CS Reducer implantation was successfully performed in allpatients without intra-operative and/or early post-procedural compli-cation. Chest X-ray and echocardiography to rule out pericardial effu-sion, were performed one day after the procedure and patients wereregularly dismissed at home asymptomatic the day after the procedure.

Although It is still early to draw any conclusions considering our rel-atively short follow-up period, from preliminary clinical evaluation, itemerges that patients are all experimenting a significant improvementof quality of life, with a marked reduction of weekly angina rate and ni-troglycerin assumption. According to our protocol for RAP treated withReducer implantation, a complete follow-up including evaluation of theangina score, stress test, 6 min walking test and echocardiography withspecial attention to diastolic functionwill be performed every 6monthsin order to verify the eventual persistent benefit after the implantationof this promising device in our RAP patients.

3. Conclusions

A multidisciplinary approach is often needed for the optimaltreatment of patients with RAP. In addition to physical rehabilitation,drug optimization, and aggressive risk-factor modification, amultidisci-plinary team can offer advanced options customized to a patient's pro-file. The CS Reducer might represent in well selected patients, a noveland promising therapeutic approach for the treatment of RAP. Selectionof potential candidates represents themost important step in thewholemanagement of this special subset of patients. Since on a correct selec-tion of patients depends most part of the successful clinical outcome ofthe procedure, when performed by experienced operators.

Conflict of interest statement

The authors report no relationships that could be construed as aconflict of interest.

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