Giannini F

Montone RA

Niccoli G

Russo M

English

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Full Terms & Conditions of access and use can be found athttps://www.tandfonline.com/action/journalInformation?journalCode=ierd20Expert Review of Medical DevicesISSN: 1743-4440 (Print) 1745-2422 (Online) Journal homepage: https://www.tandfonline.com/loi/ierd20The coronary sinus Reducer device for refractorychronic angina: rationale, clinical evidence andfuture perspectivesRocco A. Montone, Michele Russo, Francesco Giannini & Giampaolo NiccoliTo cite this article: Rocco A. Montone, Michele Russo, Francesco Giannini & Giampaolo Niccoli(2018) The coronary sinus Reducer device for refractory chronic angina: rationale, clinicalevidence and future perspectives, Expert Review of Medical Devices, 15:9, 611-613, DOI:10.1080/17434440.2018.1511422To link to this article:  https://doi.org/10.1080/17434440.2018.1511422Published online: 04 Sep 2018.Submit your article to this journal Article views: 1018View related articles View Crossmark dataEDITORIALThe coronary sinus Reducer device for refractory chronic angina: rationale, clinicalevidence and future perspectivesRocco A. Montonea, Michele Russoa, Francesco Gianninib and Giampaolo NiccoliaaDepartment of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; bUnit of CardiovascularInterventions, IRCCS San Raffaele Scientific Institute, Milan, ItalyARTICLE HISTORY Received 23 May 2018; Accepted 9 August 2018KEYWORDS Angina pectoris; coronary sinus; microvascular angina; quality-of-life; refractory angina1. IntroductionIn the last decades, the widespread use of percutaneous coron-ary intervention (PCI) with drug-eluting stent (DES) implantationand the introduction of novel anti-ischemic drugs representedmajor steps forward for the treatment of coronary artery disease(CAD). However, despite these improvements refractory anginaremains an important healthy problem [1]. Indeed, it has beenestimated that there are >500,000 Canadians and up to 1.8million Americans living with refractory angina [1]. Moreover,clinical trials and registries clearly demonstrated that 20–30%of patients undergoing percutaneous or surgical revasculariza-tion might continue to experience persistence of angina despitea successful revascularization [2]. Thus, each year, as many as525,000 patients develop refractory angina in continental Europeand in the USA [3], and an additional 500,000 who undergoeither PCI or coronary bypass surgery continue to suffer fromangina, which means that an additional 1 million patients couldbenefit annually from new targeted therapies [4].According to the 2013 ESC Guidelines on Stable coronaryartery disease (CAD), refractory angina is defined as a ‘chroniccondition caused by clinically established reversible myocar-dial ischemia in the presence of CAD, which cannot be ade-quately controlled by a combination of medical therapy,angioplasty and coronary artery bypass graft’ [3]. Refractoryangina represents a very disabling condition, which deter-mines a very poor quality of life. It has also an importantclinical impact on public health resources determining alarge number of hospitalizations and exceeding instrumentalexaminations.Current guidelines recommend the introduction of an opti-mized medical therapy with ß-blockers, calcium-channel blockersor nitrates as first-line approach, and ivabradine, ranolazine, nicor-andil or trimetazidine as second-line [3]. In addition, in case offailure of medical therapy alone, the use of non-pharmacologicalapproaches, such as enhanced external balloon counterpulsation(EECP), spinal-cord stimulation (SCS) and transcutaneous electricnerve stimulation (TENS) [3] may be considered. However none ofthese devices has become a standard of care, and despite theirinitial promise, many trials demonstrated only modestimprovements in exercise capacity and in angina relief [5]. Thus,new treatments for refractory angina are needed.2. History and rationale of coronary sinus intervention.From Claude Beck to coronary sinus ReducerThe hypothesis that an increased coronary sinus pressurecould have antianginal effects was proposed by ClaudeSchaeffer Beck, a pioneer American cardiac surgeon, that in1950’s and 1960’s obtained a significant relief of angina symp-toms in patients suffering from severe disabling angina, byperforming a 60–70% narrowing of coronary sinus [6]. Othersurgeons confirmed his results in the next years stimulatingthe research on devices able to update Beck’s hypothesis onnew technologies. The physiological mechanism behind theantianginal effect of coronary sinus intervention is that coron-ary sinus increasing pressure provides a direct retrogradeaccess route to ischemic myocardium for blood flow. Indeed,in patients with epicardial coronary disease there is a dysfunc-tion in normal physiological compensatory mechanism ofblood redistribution from subepicardial layers to subendocar-dial ones during stress. In this condition the normal ratiobetween subendocardial and subepicardial blood flow isaltered, in favor of second one, so that subendocardium per-fusion is compromised during stress, causing angina symp-toms [7]. It has been supposed that an increased pression inthe coronary venous system could determine a vasodilatationof the arterioles, reducing resistances in the subendocardiumvessels and favoring a blood redistribution from subepicardiallayers to subendocardium, with a reduction of subendocar-dium ischemia and, consequently, angina symptoms [7,8].Keeping in mind this pathophysiological background, theCoronary Sinus Reducer (Figure 1) is a balloon-expandable stain-less steel mesh, pre-mounted on an hourglass shaped ballooncatheter, that represents a modern percutaneous approach toincrease coronary sinus venous pressure creating a narrowing inthe coronary sinus (CS) lumen [9]. The narrowing within the CS,and consequently the pressure gradient in the narrowed centralpart of the device, are not achieved in the acute peri-proceduralphase, but are established 4–6 weeks after implantation, whenCONTACT Rocco A. Montone rocco.montone@gmail.com Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario A.Gemelli IRCCS, L.go A. Gemelli, 8, 00168 Rome, ItalyEXPERT REVIEW OF MEDICAL DEVICES2018, VOL. 15, NO. 9, 611–613https://doi.org/10.1080/17434440.2018.1511422© 2018 Informa UK Limited, trading as Taylor & Francis Groupthe metal mesh will be covered by tissue in-growth generatedfrom oversizing of the wide ends of the device (causing injury-induced tissue proliferation) [7]. Procedure is performed via rightinternal jugular vein and represents a quite safe procedure.Acute complication related to CS Reducer implantation may beCS perforation or dissection, device migration, CS thrombosis [7].3. Clinical evidencePreclinical studies demonstrated safety and efficacy of CSReducer implantation in mice [9], opening the avenue fordevice implantation in humans. Banai et al. conducted asmall prospective multicentre first-in-man study to evaluatethe safety and feasibility of the Coronary Sinus Reducer in 15patients with severe refractory angina and reversible ischemia[10]. In this study they demonstrated, after 6 months and thenafter 3 years from CS Reducer implantation, that its use is safeand effective in reducing angina and ischemia. Konigstein et alconfirmed these results in an open-label trial involving 23patients with refractory angina treated with CS Reducer [11].In this study no adverse event were reported at discharge andat 6 months from implantation. Efficacy was demonstratedwith a reduction in Canadian Cardiovascular Society (CCS)angina class, a prolongation in exercise duration and a reduc-tion of ischemia (evaluated with thallium SPECT).Actually, the most largest study evaluating CS reducer isCOSIRA trial, a randomized double-blind sham-controlled trialenrolling 104 patients with severe refractory angina and evi-dence of myocardial ischemia [12]. Primary end point was theimprovement of CCS angina class at 6 month after implantation.In this trial, the device was successfully implanted in 50 of the 52patients (96%). Quality of life improved in the treatment group,with 35% of patients having an improvement of at least two CCSclasses when compared to 15% in the control group, and with animprovement of at least one CCS angina class in 71% of patientsin the device-group, as compared with 42% of those in thecontrol group. About safety, only one case of periproceduralmyocardial infarction was registered in the treatment group.Moreover, this trial showed a trend for ischemia reduction inthe device-group, although this end point did not reach statis-tical significance. Abawy et Al. [13] confirmed the COSIRA trialresults in a real-world study, showing safety and effective of CSReducer in CCS angina class improvement (achieved in 70% ofpatients). Recently, Giannini et al, in a single-center experience,enrolled 50 patients with refractory angina and documentedmyocardial ischemia undergoing to CS Reducer implantation.Of interest, they demonstrated an improvement of at least oneCCS angina class in 80% of patients, an improvement in quality oflife, 6-min walking test distance, without any device-relatedadverse events during the procedure or at follow-up [14].4. Future perspectivesDespite these interesting results, data reveal that 15–30% ofpatients do not gain clinical benefit from CS Reducer implanta-tion. The reason is currently unknown. However, the presence ofalternative venous drainage systems to the CS could explain thisphenomenon. Themeasurement of difference between coronarysinuswedgepressure and right atrial pressurehas beenproposedas a predictor of alternative venous drainage systems, suggestinga reduced benefit deriving from CS reducer implantation [15].Coronary sinusabcFigure 1. A: Diaphragmatic face of the heart. In evidence the coronary sinus. B: The typical hourglass shape of coronary sinus Reducer; C: Coronary sinus reducermounted on the delivery balloon.612 R. A. MONTONE ET AL.CS Reducer received the CE mark and is currentlyimplanted in European countries, but it is not still approvedfor marketing in the United States by the FDA. In the futuremore information will be obtained about safety and effective-ness of CS Reducer implantation by the COSIRA-II pivotal trial.This study is a multicentre, double-blinded sham-controlledrandomized trial, enrolling 380 patients in North America inorder to get the FDA approval for marketing of the device inthe United States [16]. In Europe, a large observational post-market study, the REDUCER-1 (NCT02710435), aiming at enrol-ling up to 400 patients with refractory angina, is providingencouraging preliminary results (with 115 patients enrolled),indicating that 81% of patients experienced an improvementof at least one CCS angina class after 6 months [16]. Completeresults will be important in order to confirm these data.In conclusion, in patients with chronic angina, refractory tomedical therapies, CS Reducer demonstrated to be effective inabout 70–80% of patients in reducing symptoms of angina,myocardial ischemia and improving quality of life and it iscandidate to become the standard of care for these patients.Identifying the target population that can get benefit from CSimplantation will be the next purpose. Further studies areneeded to solve these open issues.FundingThis paper was not funded.Declaration of interestThe authors have no relevant affiliations or financial involvement with anyorganization or entity with a financial interest in or financial conflict withthe subject matter or materials discussed in the manuscript. This includesemployment, consultancies, honoraria, stock ownership or options, experttestimony, grants or patents received or pending, or royalties.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or otherrelationships to disclose.ReferencesPapers of special note have been highlighted as either of interest (•) or ofconsiderable interest (••) to readers.1. McGillion M, Arthur HM, Cook A, et al. Management of patientswith refractory angina: canadian cardiovascular society/canadianpain society joint guidelines. Can J Cardiol. 2012;28(2 Suppl.):S20–S41.2. Niccoli G, Montone RA, Lanza GA, et al. Angina after percutaneouscoronary intervention: the need for precision medicine. Int JCardiol. 2017;248:14–19.3. Montalescot G, Sechtem U, Achenbach S, et al. ESC guidelines onthe management of stable coronary artery disease: the task forceon the management of stable coronary artery disease of theEuropean society of cardiology. Eur Heart J. 2013;34:2949–3003.4. Mannheimer C, Camici P, Chester MR, et al. The problem of chronicrefractory angina; report from the ESC joint study group on thetreatment of refractory angina. Eur Heart J. 2002;23:355–370.5. Giannini F, Aurelio A, Jabbour RJ, et al. The coronary sinus reducer:clinical evidence and technical aspects. Expert Rev Cardiovasc Ther.2017;15:47–58.6. Beck CS, Leighninger DS. Scientific basis for the surgical treatmentof coronary artery disease. J Am Med Assoc. 1955;159:1264–1271.7. Konigstein M, Giannini F, Banai S. The Reducer device in patientswith angina pectoris: mechanisms, indications, and perspectives.Eur Heart J. 2018;39:925–933.8. Ido A, Hasebe N, Matsuhashi H, et al. Coronary sinus occlusionenhances coronary collateral flow and reduces subendocardialischemia. Am J Physiol Heart Circ Physiol. 2001;280:H1361–H1367.9. Banai S, Ben-Muvhar S, Tsehori J, et al. Transcatheter coronary sinusnarrowing with the Neovasc Reducer - an alternative treatmentapproach for patients with disabling angina who are not candi-dates for revascularization procedures - a preclinical study. Abstractpresentation at the 2004 annual conference of the Israel HeartSociety.10. Banai S, Ben Muvhar S, Parikh KH, et al. Coronary sinus reducerstent for the treatment of chronic refractory angina pectoris: aprospective, open-label, multicenter, safety feasibility first-in-manstudy. J Am Coll Cardiol. 2007;49:1783–1789.• Coronary sinus Reducer first in-man implantation study.11. Konigstein M, Meyten N, Verheye S, et al. Transcatheter treatmentfor refractory angina with the coronary sinus Reducer.EuroIntervention. 2014;9:1158–1164.12. Verheye S, Jolicoeu R, Behan MW, et al. Efficacy of a device tonarrow the coronary sinus in refractory angina. N Engl J Med.2015;372:519–527.•• COSIRA trial the first randomized double-blind trial evaluatingCoronary Sinus Reducer.13. Abawi M, Nijhoff F, Doevendans PA, et al. Safety and efficacy of adevice to narrow the coronary sinus for the treatment of refractoryangina: a single-centre real-world experience. Neth Heart J. 2016;24(9):544–551.14. Giannini F, Baldetti L, Ponticelli F, et al. Coronary sinus Reducerimplantation for the treatment of chronic refractory angina: asingle-center experience. JACC Cardiovasc Interv. 2018 Apr 23;11(8):784–792.15. Baldetti L, Colombo A, Banai S, et al. Coronary sinus reducernon-responders: insights and perspectives. EuroIntervention.2018;13:1667–1669.16. Verheye S. REDUCER-1 post-market study and US IDE. Washington(DC): TCT Congress; 2017 Oct 30.EXPERT REVIEW OF MEDICAL DEVICES 613

The coronary sinus Reducer device for refractory chronic angina: rationale, clinical evidence and future perspectives

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The coronary sinus Reducer device for refractory chronic angina: rationale, clinical evidence and future perspectives

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