The Coronary Sinus Reducer Stent for the Treatment of Refractory Angina Pectoris

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The Coronary Sinus Reducer Stent for the Treatment of Refractory Angina Pectoris

Corresponding author: Dr. Yoav Paz, University, Tel Aviv Sourasky medical center,Tel Aviv, Israel, Tel: +972527360340; Email: pazyoav@bezegint.net

Abstract

As long as life expectancy of patients with atherosclerotic coronary artery disease is increasing the group of patients that remain suffering from chronic and refractory angina pectoris despite the use of multiple therapeutic modalities is also growing and more patients remain severely disabled due to refractory anginal symptoms. This group of patients is sometimes called “non-op- tion” patients and obviously need an innovative option. The current review introduces an emerging innovation for the treatment of these “non-option” patients who continue to suffer from disabling symptoms despite optimal medical therapy namely: the Neovasc coronary sinus reducer stent (CSRS).

Keywords: Ischemic Heart Disease; Refractory Angina Pectoris; Coronary Sinus; Beck Operation; Coronary Sinus Reducer Stent; Upside-Down Strategy; Neovasc

Abbreviations

CSRS: Coronary Sinus Reducer Stent; CAD: Coronary Artery Disease;

PCI: Percutaneous Coronary Interventions; CABG: Coronary Artery Bypass Grafting; EECP: Enhanced External Counter Pulsation; RAP: Refractory Angina Pectoris;

CS: Coronary Sinus;

CCS: Canadian Cardiovascular Society

Introduction

Angina pectoris is chest pain or discomfort due to myocardial ischemia that occurs when the demand for oxygenated blood exceeds the supply. The main cause for such imbalance is en- hanced atherosclerosis of the coronary arteries-coronary ar- tery disease (CAD). Anginal symptoms are not only disabling and frightening but also associated with increased morbidity and mortality therefore has high social impact also that needs effective medical management.

Current approach

Multiple interventions are available, some still under research for the relief of anginal symptoms, starting with lifestyle mod- ifications, wide range of medications, percutaneous coronary interventions (PCI), coronary artery bypass grafting (CABG), spinal cord stimulation, percutaneous myocardial laser revas- cularization, transmyocardial laser revascularization, autolo- gous (CD34+) stem cells interventions, intramyocardial bone marrow stem cells injection and enhanced external counter pulsation therapy (EECP) [1-6].

Despite this wide range of therapeutic strategies there are still many patients who remain severely disabled due to refractory anginal symptoms, creating a unique “non-option” group of pa- tients suffering from refractory angina pectoris (RAP), mostly relatively young persons with impaired systolic left ventricular function that experience poor quality of life [7-9].

Current estimates indicate that 850,000-1,000,000 patients in the United States suffer from RAP [10-14]. Taking into consid- eration that these “non-option” group of patients really needs an innovative option in the mid-1990s Dr. Shinfeld and Dr. Paz (cardiac surgeons) initiated an unusual, novel approach to support the ischemic myocardium. Dr. Shinfeld and Dr. Paz suggested the catheterization of the coronary veins instead of catheterizing the atherosclerotic coronary arteries and reduc- tion of the coronary sinus (CS) diameter instead of expanding a narrowed coronary artery, therefore they called it ‘‘the up- side-down strategy”.

The Coronary Sinus Reducer Stent

With the assistance of mechanical engineers the two cardiac surgeons designed and manufactured a unique stainless steel balloon expandable stent with a simple and specific delivery system that is inserted through a peripheral vein using a per- cutaneous transvenous approach. The stent is mounted on a folded balloon attached to the distal end of the catheter deliv- ery system.

Implantation process

Under local anesthesia the stent on its delivery system is in- serted into the internal jugular vein and advanced under flu- oroscopic guidance into the CS which is the final pathway of most of the coronary perfusion blood flow [figure 1A].

Figure 1. Implantation process – schematic illustration.

Reprinted from EuroIntervention 2014, 9(10), Konigstein et al, Tran- scatheter treatment for refractory angina with the Coronary Sinus Re- ducer. Eurointervention 2014, 9(10): 1158-1164. Copyright (2014), with permission from Europa Digital & Publishing

After the achievement of a good position in the CS the balloon is inflated and the stent that was inserted as a cylinder chang- es its shape to hourglass shaped stent with neck diameter of 3 mm [Figure 1B, 2], decreasing the CS effective diameter for blood flow to less than 3 mm, increasing the CS pressure,

increasing the coronary venous pressure and reducing the coronary blood outflow. Therefore the inventors gave this unique device the name of Coronary Sinus Reducer Stent (CSRS) [15-22].

Figure 2. The coronary sinus Reducer on the dedicated balloon and delivery system.

Reprinted from EuroIntervention 2014, 9(10), Konigstein et al, Transcatheter treatment for refractory angina with the Coronary Si- nus Reducer. Eurointervention 2014, 9(10): 1158-1164. Copyright (2014), with permission from Europa Digital & Publishing

As a safety maneuver the balloon can be inflated to supranor- mal pressure that opens the reducer completely to its wide diameter cylindrical shape without a neck.

The main idea behind the CSRS

The main idea behind the upside-down strategy was to re- build a retrograde coronary pressure that was attenuated by the atherosclerotic disease. In a preliminary nonischemic pig model the mean CS pressure was elevated from 7.0 mmHg to 24.6 mmHg after CSRS deployment. Further studies in non- ischemic pig model were devoted to macroscopic and histolog- ic investigations of the treated hearts, especially to see if any structural or histological damage like infarct had occurred to the treated hearts after CSRS implantation. While looking for such damage these studies revealed that 8 to12 weeks of cor- onary sinus narrowing ended up with macroscopic epicardi- al and intramyocardial new blood vessels-neovascularization [Figure 3]. Histopathlogic analysis described these findings as: “Significant proliferation of small-medium size vessels, con- taining smooth muscle, representing coronary collaterals was evident almost in all specimens, representing various myocar- dial anatomical areas, including specimens from anterior and mid-posterior wall. Most significant proliferation was evident at the peri-coronary sinus specimens, including anterior and posterior specimens”.

According to the unpredicted neovascularization findings af- ter the implantation of the CSRS in non-ischemic pig model the inventors created the name “Neovasc” for this special novel CSRS.

Figure 3. Histopathologic finding (x400)

On those days, the cascade leading from coronary sinus nar- rowing to new macroscopic epicardial and intramyocardial blood vessels was not clear enough however some explana- tions were suggested. The study by Guenter Weigel and col- leagues sheds some light on this subject by favoring the neo- angiogenesis explanation that is triggered by some kind of increased coronary sinus pressure [23].

The CSRS and Back operations

Some people make a mistake and compare the Neovasc CSRS to Beck procedure (Beck operation). Beck procedure has al- most nothing in common with the Neovasc CSRS. Dr Claude Beck has described in the 1940s two types of coronary sinus interventions [24-26]. Beck I procedure consisted of external surgical narrowing the coronary sinus, abrading both epicar- dium and inner pericardium (some kind of neurectomy that was in those days a therapy for RAP), spilling of powdered as- bestos and 5% aqueous trichloracetic acid on the epicardium, and placement of mediastinal fat over the treated epicardium. Beck II procedure consisted of a vascular graft between the de- scending aorta and the coronary sinus followed by operative external constriction of the CS ostium a few weeks later. Both procedures needed thoracotomy and have very little in com- mon with the Neovasc CSRS.

In 2000 and before the progression to ischemic pig model Dr. Tsehori joined to the inventors and the mechanical engi- neers in order to cooperate with economical forces. Between 2000-2002 fine tuning of the device was made beside many experiments in ischemic pig model that strengthened the up- side-down concept and reinforced the idea that the CSRS has the ability to build retrograde coronary perfusion pressure and the proliferation of small-medium size coronary blood vessels.

The “Neovasc” team was led by these three cardiac surgeons until the end of 2002.

Human studies

The first human study of the CSRS was started in 2004 [27]. This was a prospective, open-label, multicenter, safety feasibil- ity study. The Neovasc CSRS was percutaneously implanted in 15 patients who had RAP despite optimal medical treatment. Two patients had class IV Canadian Cardiovascular Society (CCS), 12 had class III CCS and one had class II CCS. Six patients underwent previous PCIs, 4 patients had suffered acute myo- cardial infarction and 3 underwent a previous CABG operation. Mean follow-up was 11 1.03 months.

No procedural related complications were observed. All pa- tients were discharged from hospital 1–2 days after CSRS im- plantation. No major adverse cardiac events were reported during the follow-up period. Six months after implantation of the Neovasc CSRS most of the patients had improved their CCS scores compared to baseline (3.07 vs 1.64; P <0.0001). Improvements were also observed for stress-induced ST-seg- ment depression and for the extent and severity of myocardial ischemia, as shown by either dobutamine echocardiography or thallium single-photon emission computed tomography.

These improvements were maintained at 3 years after CSRS implementation [28]. In 2014 Konigstein et al had reported six-month follow-up clinical results of 23 patient that were treated with the CSRS due to RAP in two medical centers (CCS class II-IV) despite optimal medical therapy [29]. All patients had angiographic evidence of severe obstructive CAD, ejection fraction ≥25% and were non-candidates for CABG or PCI, 83% of these patients had a history of acute myocardial infarction, and 74% had a history of CABG surgery.

In this report failure to implant a CSRS occurred in two patients because of unsuitable anatomy of the CS. One patient was lost to follow-up for the six-month evaluation. No device-re- lated adverse effects were observed during the procedure or the six-month follow-up period. CCS score diminished from a mean of 3.3 at baseline to 2.0 at six months (n=20, p<0.01. Thallium SPECT summed stress score and summed difference score were both reduced (n=9, 21.5±10 vs.13.2±9, p=0.01, and 11.1±6 vs. 4.7±4, p=0.007, respectively). Wall motion score index at peak dobutamine infusion was also significantly im- proved (n=8, 1.9±0.4 vs. 1.4±0.4, p=0.046).

The Coronary Sinus Reducer for Treatment of Refractory An- gina (COSIRA) study was a phase 2, multicenter, randomized, double-blind, sham-controlled clinical trial to test the safety and efficacy of the CSRS [30]. The trial was conducted at 11 clinical centers and was sponsored by Neovasc. In this study 104 patients with CCS class III or IV angina pectoris who were not candidates for other method of revascularization were

randomly assigned to implantation of the device (treatment group) or to a sham procedure (control group). The primary end point was the proportion of patients with an improvement of at least two CCS angina classes at 6 months. 52 patients were assigned to the treatment group and 52 to the control group. Thirty five percents of the patients in the treatment group, as compared with only 15% of those in the control group had an improvement of at least 2 CCS angina classes at 6 months (P = 0.02). CSRS implantation was associated with improvement of at least 1 CCS angina class in 71% of the patients in the treat- ment group. Seattle Angina Questionnaire was used to assess the patients’ quality of life. Quality of life improvement was significantly higher improved in the treatment group as com- pared with the control group (improvement on a 100-point scale, 17.6 vs. 7.6 points; P = 0.03). In the treatment group 1 patient had had a myocardial infarction at 6 months while at the same time 1 patient had died and 3 had had a myocardial infarction in the control group.

In 2016 Abawi et al. provided further evidence regarding the efficacy of the CSRS as a therapeutic strategy for “no option” patients suffering from RAP [31]. In this report 23 patients un- derwent CSRS implantation (91.3% had previous CABG, 82.6% had previous PCI, 47.8% had previous myocardial infarction, 52.2% of those patients were suffering of diabetes mellitus).

The safety endpoint if this trial was defined as the successful delivery of the first device in the proper location and without any device-related adverse events. This endpoint was met in all 23 patients.

The efficacy in this trial was defined as any reduction in CCS. After a median follow-up of 9 (8–14) months this efficacy was reached in 17 patients (74%). The mean CCS class was reduced from 3.4±0.6 at baseline to 2.1±1.0 at follow-up (p < 0.001), 8 patients (34.8%) improved by 1 CCS class, 7 (30.4%) by 2

CCS classes and 2 (8.7%) by 3 CCS classes. One patient died 4 months after implantation because of progressive heart failure that wasn’t associated with the CSRS implantation.

Also in 2016 Lelasi et al. reported of 5 patients suffering of RAP with CCS II – IV despite optimal medical therapy not amena- ble to or at high risk for CABG or PCI and with left ventricular ejection fraction ≥30% [32]. These 5 patients were selected for CSRS implantation.

CSRS implantation was successfully performed in all these 5 patients without intra-operative and/or early post-procedural complication. Lelasi et al. reported that in their relatively short follow-up period all 5 patients are experimenting a significant improvement in quality of life, with a marked reduction of weekly angina rate and nitroglycerin consumption.

In November 2011 Neovasc Inc. had announced that the CE mark was received for its Reducer™ [33]. This mean that the Reducer conforms to the applicable European Directive, it al-

lows the product to be marketed for the treatment of patients in all member states of the European Union, the European Eco- nomic Area and Switzerland.

Summary

Further evaluation of CSRS has to be done but these findings suggest that the Neovasc CSRS may be a safe, feasible, comfort- able, and effective option for many patients suffering of CAD especially for dose with RAP where other alternatives are lack.

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