Transcatheter treatment for refractory angina with the coronary sinus Reducer

Abstract

Aims: To evaluate the clinical efficacy of the coronary sinus (CS) Reducer in attenuating angina severity in patients suffering from severe refractory angina.

Methods and results: Patients with refractory angina, objective evidence of myocardial ischaemia and no option for revascularisation were treated with CS Reducer implantation at two medical centres. Six-month follow-up evaluation consisted of clinical assessment of angina severity. Objective assessment of ischaemia at six-month follow-up was performed in one of the two centres. Successful CS Reducer implantation was achieved in 21 of 23 eligible patients, at both centres. No device-related adverse effects were observed during the procedure or the follow-up period. Canadian Cardiovascular Society (CCS) score diminished from a mean of 3.3 at baseline to 2.0 at six months (n=20, p<0.01), exercise duration was prolonged from 3:16 to 5:16 min (min:sec; n=8, p=0.05). 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 improved (n=8, 1.9±0.4 vs. 1.4±0.4, p=0.046).

Conclusions: CS Reducer implantation was safe and resulted in significant improvement of angina class. The results of the ongoing randomised sham-control trial will address the concern regarding the possible placebo effect, and hopefully further support our encouraging observations.

Introduction

Refractory angina pectoris is a major clinical challenge in contemporary cardiovascular medicine1. Alongside the remarkable progress in therapeutic strategies intended for patients with coronary artery disease (CAD), a growing number of patients who suffer from severe and diffuse CAD not amenable for revascularisation continue to experience severe debilitating angina despite optimal medical therapy. These patients are often labelled as “no option” patients. Controversy remains regarding the incidence and prevalence of refractory angina. Data derived from cardiac catheterisation laboratory registries showed that 6-12% of patients referred to angiography with evidence of ischaemia were ineligible for traditional revascularisation2-5. This rate would imply 100,000 to 200,000 new patients identified per year in the USA6.

Despite the disabling symptoms, recent studies have shown that the life expectancy of patients with refractory angina is not significantly inferior to that of other patients with stable/chronic ischaemic heart disease6. It is therefore now well accepted that the goal of therapy should mostly be directed at improving these patients’ quality of life rather than extending their lifespan.

The coronary sinus (CS) Reducer™ (Neovasc Inc., Vancouver, B.C., Canada) has emerged as a therapeutic strategy for patients with refractory angina pectoris7. The Reducer is a stainless steel, balloon-expandable, hourglass-shaped stent, designed to be implanted in the CS to create a controlled narrowing of the lumen, leading to increase in coronary venous pressure (Figure 1). By elevating backward pressure and dilating subendocardial capillaries the Reducer reduces resistance to flow and restores to normal the endocardial/epicardial blood-flow ratio which is pathologically impaired in the ischaemic myocardium.

Figure 1. The coronary sinus Reducer on the dedicated balloon and delivery system.

Following preclinical experiments which demonstrated ischaemia attenuation six weeks after CS Reducer implantation in a porcine model of myocardial ischaemia (Figure 2), the first-in-man study proved the safety and feasibility of the CS Reducer7. The CS Reducer is an approved device-based therapy for refractory angina in Europe.

Figure 2. Contrast perfusion dobutamine echo performed in 2 pigs with reversible myocardial ischaemia of the left circumflex coronary artery territory. Left panels: baseline contrast perfusion echo at peak dobutamine infusion showing large area of ischaemia (filling defect) in the lateral wall of the left ventricle of the 2 pigs. Right panels: 6 weeks after CS Reducer implantation, contrast perfusion echo at peak dobutamine infusion and a higher heart rate demonstrate marked improvement in myocardial ischaemia in both pigs.

We describe here the clinical follow-up results from two clinical centres of CS Reducer implantation in patients treated for refractory angina. In these two medical centres the Reducer is used for the treatment of patients suffering from severe angina pectoris with objective evidence of myocardial ischaemia who are non-candidates for surgical or percutaneous coronary revascularisation.

Methods

We report here the results of the six-month clinical follow-up of the first 23 patients treated with CS Reducer implantation in two medical centres: Antwerp Cardiovascular Center ZNA Middelheim, Antwerp, Belgium, and Tel Aviv Medical Center, Tel Aviv, Israel. All participants signed a written informed consent for the treatment which has the approval of the institutional ethics committee of the Tel Aviv Medical Center, and of the Middelheim Cardiovascular Center.

PATIENT SELECTION

Patients suffering from coronary artery disease and severe angina pectoris (CCS class II-IV) despite optimal medical therapy, with objective evidence of myocardial ischaemia and ejection fraction ≥25%, who were non-candidates for surgical or percutaneous coronary revascularisation, were eligible for CS Reducer implantation.

All patients had angiographic evidence of severe obstructive coronary artery disease not suitable for revascularisation.

Excluded were patients with: 1) recent (within three months) myocardial infarction, 2) recent (within six months) PCI or CABG, 3) life-threatening rhythm disorders or any rhythm disorders that would require placement of an internal defibrillator and/or pacemaker, 4) decompensated heart failure, 5) severe valvular heart disease, 6) pacemaker or other CS electrode, 7) patients who had undergone tricuspid valve replacement or repair, and 8) patients with mean right atrial pressure higher than 15 mmHg.

THE DEVICE

The CS Reducer is a stainless steel balloon-expandable, hourglass-shaped stent, designed to be introduced into the CS through the right internal jugular vein. A few weeks following implantation the Reducer is covered by tissue, and only then does the Reducer establish a controlled narrowing of the CS. The diameter at its mid portion is 3 mm, and it can reach a diameter of 7-13 mm at both ends, using inflation pressure of 2 to 4 bars. 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 PROCEDURE

Patients were pretreated with aspirin and clopidogrel for a week prior to the procedure. Under local anaesthesia a 6 Fr diagnostic multipurpose or AL1 catheter was introduced into the CS through the right internal jugular vein under fluoroscopic guidance. Right atrial pressure was measured and was followed by angiography of the CS in 30 degrees left anterior oblique angulation. The optimal site for implantation was determined according to the vessel diameters and in order to avoid side branch bifurcation. CS diameters were determined by quantitative coronary angiography (QCA). The diagnostic catheter was then replaced (over the wire) with a preshaped 9 Fr guiding catheter, and IV heparin was administered. The Reducer, which comes preloaded on the balloon, was then introduced over the wire in the guiding catheter into the CS, positioned at the desired site, and implanted by inflating the delivery balloon to achieve slight oversizing. The desired implantation site is about 1-2 cm from the CS ostium. Post-implantation angiography was performed to ensure appropriate implantation, patency, and appropriate reduction of the lumen’s diameter (Figure 3).

Figure 3. Schematic illustration describing the implantation process of the CS Reducer.

SCREENING AND FOLLOW-UP EVALUATION

All patients underwent a full clinical assessment, with determination of CCS class before implantation.

Objective screening evaluation consisted of one or more of the following: a treadmill stress test, a radionuclide perfusion study and/or a dobutamine echocardiography before implantation of the Reducer.

Follow-up evaluation consisted of clinical evaluation for CCS class determination at one and six months following CS Reducer implantation for all patients.

The evaluation of objective parameters at six months was performed only in one centre and the analysis of the objective measures of ischaemia was performed only for patients with available data both at baseline and at six-month follow-up.

TREADMILL EXERCISE TEST

The parameters that were inserted into the analysis were: total exercise duration, time to ST depression, METS and Duke Score.

ECHO DOBUTAMINE

A 16-segment quantitative analysis was used. The wall motion of each segment at rest and during peak dobutamine infusion was graded according to a score (1 - normal, 2 - hypokinetic, 3 - akinetic, 4 - dyskinetic, 5 - aneurysmatic)8. The summed wall motion scores of myocardial segments divided by the number of segments was defined as wall motion score index (WMSI). Baseline and six-month WMSI at rest and stress were compared.

RADIONUCLIDE PERFUSION SCAN

A 17-segment model of the left ventricle (LV) and a five-point semi-quantitative perfusion score (0 - normal to 4 - absent) were used.

The following semi-quantitative parameters of perfusion abnormalities were calculated: 1) summed rest score (SRS), calculated as the sum of the individual segment scores on the rest scan, 2) summed stress score (SSS), calculated as the sum of the individual segment scores on the stress scan, and 3) summed difference score (SDS), calculated as the difference between the SSS and the SRS and indicative of the composite of the extent and severity of ischaemia9. The SSS, SRS and SDS of all patients at baseline and six months following the procedure were compared.

STATISTICAL ANALYSIS

All data were displayed as mean (±standard deviation) for continuous variables, and as the number (percentage) of patients in each group for categorical variables. The Wilcoxon test was used to evaluate the statistical significance between baseline and six-month parameters. All of the analyses were considered significant at a two-tailed p-value of <0.05. The SPSS statistical package was used to perform all statistical evaluation (SPSS, Chicago, IL, USA).

Results

Twenty-three patients were selected for the treatment, 14 in Tel Aviv, and nine in Antwerp. Failure to implant a Reducer occurred in two patients due to unsuitable anatomy of the CS. One patient was lost to follow-up for the six-month evaluation. Therefore, the final analysis for CCS class was performed on 20 patients. Baseline clinical characteristics of the patients are shown in Table 1. Mean age was 71.4±9.8 years (range 52-88; male 70%). The study population was characterised by a high prevalence of cardiovascular risk factors including hypertension, dyslipidaemia and diabetes mellitus in 78%, 87% and 56.5% of patients, respectively. A history of myocardial infarction was present in 83% of patients, and 17 (74%) patients had a history of CABG surgery.

SUCCESS RATE AND SAFETY OF THE PROCEDURE

The Reducer implantation was successful in 21 (91%) patients. As mentioned before, the procedure failed in two patients due to an unsuitable CS anatomy. In these two patients no procedure-related complications were observed immediately after the procedure and at one-year follow-up. One of these two patients died a year after the procedure following a prolonged hospitalisation due to heart failure. 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 (median 12, CI: 6-30). One patient was lost to follow-up for the six-month evaluation, but was alive and feeling well as per telephone conversation. 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.

CCS CLASS

Angina score expressed by CCS class decreased significantly six months following Reducer implantation from a mean of 3.35±0.6 to 2.0±1 (n=20, p<0.001). Seventeen (85%) patients reported relief of symptoms following the procedure (Figure 4). Clinical improvement was, in most cases, reported starting a few weeks following the procedure, and maintained at one-year follow-up.

Figure 4. CCS class of all registry patients at baseline and 6 months following CS Reducer implantation.