This was a prospective, single-arm, non-blinded registry of 51 consecutive patients referred for Reducer implantation, of whom 26 underwent the procedure and entered the analysis, between May 2017 and July 2019 in two Portuguese tertiary centers.

Inclusion criteria were angina (at least Canadian Cardiovascular Society [CCS] class 2) despite maximally tolerated pharmacological therapy and not amenable for revascularization, and ischemia documented by myocardial stress single-photon emission computed tomography (SPECT) or myocardial stress magnetic resonance imaging (MRI) attributable to the left coronary artery regardless of the presence of obstructive epicardial CAD.

Exclusion criteria were ischemia related exclusively to the right coronary artery, severely depressed left ventricular ejection fraction (LVEF) (<35%), symptoms predominantly of heart failure, presence of a cardiac resynchronization therapy device, recent acute coronary syndrome (<3 months), recent revascularization (<6 months), right heart disease, severe valvular heart disease, mean right atrial pressure >15 mmHg, or any other clinical context that would preclude clinical benefit or antithrombotic therapy.

Each patient with RA who was referred for Reducer implantation by their attending cardiologist was assessed by one of the study investigators regarding their eligibility for the procedure, namely the existence of revascularization targets and candidacy for alternative procedures like percutaneous coronary intervention (PCI) for chronic total occlusions; documented ischemia in the left coronary artery territory by SPECT, cardiac MRI or stress echocardiography; and whether antianginal therapy was titrated to its maximum tolerated dose and metabolic risk factors were controlled.

Briefly, right atrial pressure measurement and CS retrograde venography were performed to assess hemodynamic and anatomical suitability for Reducer implantation, using a multipurpose catheter via the right internal jugular vein. The device was then implanted, under 5000 U of unfractionated heparin, through a 9 F delivery guide catheter over a 0.035″ wire at the proximal portion of the CS (2–3 cm distal to the ostium, avoiding collaterals), with an intentional overexpansion of 10–20%. A final venography was performed to assess device position and complications. A detailed description of the procedure can be found elsewhere.9,10,14

Dual antiplatelet therapy with aspirin and clopidogrel was recommended for at least one month, and ideally six months. If oral anticoagulant therapy was prescribed, additional clopidogrel was mandated for one month.

All data regarding the procedure, in-hospital outcomes and follow-up were recorded in a dedicated database. All patients had at least one pre-implantation consultation with optimization of pharmacological therapy followed by clinical reassessment on the day of the procedure, at one month post procedure (by telephone) and at three and six months (in person). Symptomatic status and therapeutic appropriateness were assessed at each appointment.

The primary safety endpoint was successful implantation of the Reducer device at the intended site in the CS without complications. Secondary safety endpoints were periprocedural and six-month procedure- or device-related complications including device success (defined as successful implantation at the intended site), CS perforation, CS dissection, cardiac tamponade, migration, arrhythmias, vascular complications, myocardial infarction and death.

The primary efficacy endpoint was CCS class change, and the secondary endpoints were improvement in QoL assessed by score on the short version of the Seattle Angina Questionnaire (SAQ-7) and reduction in pharmacological antianginal therapy between baseline and six months after the procedure.

Categorical variables were expressed as proportions and compared using the chi-square test. Normality of continuous variables was assessed by the Shapiro-Wilk test. Continuous variables with normal distribution were expressed as mean±standard deviation and compared using the paired-samples t test, while non-normally distributed variables were expressed as median [interquartile range] and compared using the Wilcoxon signed test. All comparisons are between baseline and six-month follow-up.

A p-value <0.05 was considered statistically significant. IBM SPSS Statistics version 21 was used for the statistical analysis.

Fifty-one consecutive patients with angina considered to be refractory were assessed as possible candidates for Reducer device implantation. Of this initial cohort, eight patients had symptomatic control after optimization of medical treatment, two underwent percutaneous revascularization, five had ischemia limited to the right coronary artery, five refused to proceed, two were considered to have significant comorbidity that would preclude clinical benefit, one died and two suffered an acute coronary syndrome while waiting for the procedure. A total of 26 patients thus proceeded to Reducer implantation and were analyzed (Figure 1).

Figure 1.

Study population selection. CCS: Canadian Cardiovascular Society; PCI: percutaneous coronary intervention; RCA: right coronary artery; SAQ-7: short version of the Seattle Angina Questionnaire.

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Detailed baseline population characteristics are described in Table 1. The mean age was 71±7 years and 20 (77%) were male. Obstructive CAD judged not amenable to further revascularization was present in 23 (88%) patients and three patients had microvascular angina (defined by the presence of anginal symptoms and reversible ischemia on stress SPECT and MRI in the absence of angiographically significant CAD). All patients with obstructive CAD (n=23) had already had at least one coronary intervention: 18 (69%) had previous PCI, 16 (62%) had previous coronary artery bypass graft surgery (CABG), and 12 (46%) had both. The main reasons precluding coronary revascularization in this population (most patients had more than one reason for no further revascularization) were chronic total occlusions (54%), long diffuse CAD (58%), multiple coronary tandem lesions (54%), poor distal targets (39%), last remaining patent coronary artery (23%), and microvascular disease (12%).

CAD risk factors were highly prevalent and did not differ between patients with obstructive CAD and microvascular disease. Eight patients (31%) had moderate-to-severe chronic kidney disease (glomerular filtration rate 15–60 ml/min/1.73 m2), 16 (62%) had a history of previous myocardial infarction and median LVEF was 55% [44–66%].

Mean baseline CCS class was 2.7±0.47, with 18 (69%) in CCS 2 and eight (31%) in CCS 3.

The mean baseline SAQ-7 scores were 50.3±15.2 points for physical limitation, 55.3±21.4 for angina frequency, and 34.2±23.2 for quality-of-life domains. The mean baseline modified SAQ-7 score in both centers was 46.6±18.0.

All patients were treated with statins and at least one antiplatelet drug. The mean number of anti-ischemic drugs at baseline was 3.3±1.1. Twenty-three patients (88.4%) were on beta-blockers, 18 (69.2%) on calcium channel blockers, six (23.1%) on nicorandil, 12 (46.2%) on ranolazin, 17 (65.4%) on long-acting nitrates, and five (19.2%) on ivabradin.

The right jugular vein was used as the access site in all patients. The median duration of the procedure was 58 [46–95] min and mean balloon inflation pressure was 4.1±0.9 atm. Twenty-four (92.3%) were discharged on the same day. Median fluoroscopy time was 17.8±11.1 min and median radiation dose was 1918.3±4021.7 mGy.

The primary safety outcome of successful device deployment at the intended site without complications was achieved in 23 patients (88.5%), with two unsuccessful attempts and one isolated procedure-related complication. The unsuccessful implantations were due to one failure to cannulate the CS and one device migration. In the former, a challenging CS anatomy prevented selective engagement despite the use of several catheters and techniques.

Regarding the secondary safety outcomes, device success was achieved in 24 patients (92.3%). There were two complications: one device migration to the superior vena cava after full stent expansion, requiring surgical retrieval; and one wire-related perforation of a distal branch of the CS with cardiac tamponade requiring pericardiocentesis. These patients were discharged at 24 h and 48 h, respectively, with an otherwise uneventful hospital stay.

The mean follow-up was 22.9±8.3 months, all patients having completed six-month follow-up. The two patients in whom implantation failed remained under maximally tolerated antianginal therapy and were referred to a cardiac rehabilitation program. No symptomatic improvement was noted thereafter. The following results refer to the 24 patients in whom implantation was successful.

Mean CCS class improvement was 1.3±0.2, from 2.7±0.5 to 1.4±0.9 (p<0.001). Eighteen patients (75%) showed improvement of at least one CCS class, 10 (42%) presented a reduction of two CCS classes and in six (25%) patients the CCS class remained unchanged (Figure 2). All scales of the SAQ-7 showed a significant improvement after Reducer implantation. The physical limitation score improved from 50.3 to 70.6 (p=0.001), the angina frequency score improved from 55.3 to 64.4 (p=0.005), and the QoL score improved from 34.2 to 54.4 (p=0.006). This translated into a mean SAQ-7 summary score improvement from 46.6 to 63.2 (p<0.001) (Figure 3).

Figure 2.

Changes in Canadian Cardiovascular Society Angina class after Reducer implantation.

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Figure 3.

Changes in Seattle Angina Questionnaire score after Reducer implantation.

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Thirteen patients (54%) discontinued or had the dose reduced of at least one anti-ischemic drug. The mean number of anti-ischemic drugs fell from 3.4±1.1 to 2.9±1.2 (p=0.010) (Figure 4).

Figure 4.

Changes in the number of antianginal drugs per patient during follow-up.

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During the six-month post-procedure time frame, none of the patients suffered any major cardiovascular event.

Our study suffers from the inherent limitations of a single-arm, open-label study assessing subjective endpoints, prone to bias from both investigators and patients regarding reporting and interpretation of symptoms, especially in a setting in which the placebo effect can be as high as 40%.10 Nevertheless, our findings were very similar to the results of the treatment arm of the COSIRA trial and other observational data, suggesting a consistent effect. The small sample size may to some extent have limited the power of the statistical analysis (due to type II error), nevertheless given the magnitude of the differences in the endpoints between baseline and follow-up this seems unlikely. The lack of functional capacity assessment and of echocardiographic and objective quantification of ischemia are two other limitations worth mentioning, as other studies have documented reductions in ischemic territories and improvements in cardiopulmonary fitness and LVEF after Reducer implantation.23–27 As depression is commonly present in CAD patients, a depression assessment questionnaire should have been used, as this comorbidity may affect treatment response.28 Finally, there is a lack of data regarding the best antithrombotic therapy modality after Reducer device implantation and whether this could influence clinical outcomes.