Author + information
- Received December 9, 2014
- Revision received March 25, 2015
- Accepted April 9, 2015
- Published online July 1, 2015.
- Jason H. Rogers, MD∗∗ (, )
- Martyn Thomas, MD†,
- Marie-Claude Morice, MD‡,
- Inga Narbute, MD§,
- Milana Zabunova, MD§,
- Thomas Hovasse, MD‡,
- Mathieu Poupineau, MD‖,
- Ainars Rudzitis, MD§,
- Ginta Kamzola, MD§,
- Ligita Zvaigzne, MD§,
- Samantha Greene, BA¶ and
- Andrejs Erglis, MD§
- ∗Division of Cardiovascular Medicine, University of California, Davis Medical Center, Sacramento, California
- †Guy’s and St Thomas’ Hospital, London, United Kingdom
- ‡Générale de Santé, Institut Cardiovasculaire Paris Sud, Massy, France
- §Latvian Centre of Cardiology, Pauls Stradins Clinical University Hospital, Riga, Latvia
- ‖Cardiology Department, Centre Hospitalier Prive, Claude Galien, Quincy Sous-Senart, France
- ¶MVRx Inc., Belmont, California
- ↵∗Reprint requests and correspondence:
Dr. Jason H. Rogers, Division of Cardiovascular Medicine, University of California, Davis Medical Center, 4860 Y Street, Suite 2820, Sacramento, California 95817.
Objectives MAVERIC (Mitral Valve Repair Clinical Trial) reports the safety and efficacy of the ARTO system in patients with symptomatic heart failure and functional mitral regurgitation (FMR).
Background The ARTO system percutaneously modifies the mitral annulus to improve leaflet coaptation in FMR.
Methods The MAVERIC trial is a prospective, nonrandomized first-in-human study. Key inclusion criteria were systolic heart failure New York Heart Association functional classes II to IV, FMR grade ≥2+, left ventricular (LV) ejection fraction ≤40%, LV end-diastolic diameter >50 mm and ≤75 mm. Exclusion criteria were clinical variables that precluded feasibility of the ARTO procedure. Primary outcomes were safety (30-day major adverse events) and efficacy (MR reduction, LV volumes, and functional status).
Results Eleven patients received the ARTO system, and there were no procedural adverse events. From baseline to 30 days, there were meaningful improvements. Effective regurgitant orifice area decreased from 30.3 ± 11.1 mm2 to 13.5 ± 7.1 mm2 and regurgitant volumes from 45.4 ± 15.0 ml to 19.5 ± 10.2 ml. LV end-systolic volume index improved from 77.5 ± 24.3 ml/m2 to 68.5 ± 21.4 ml/m2, and LV end-diastolic volume index 118.7 ± 28.6 ml/m2 to 103.9 ± 21.2 ml/m2. Mitral annular anteroposterior diameter decreased from 45.0 ± 3.3 mm to 38.7 ± 3.0 mm. Functional status was 81.8% New York Heart Association functional class III/IV improving to 54.6% functional class I/II. At 30 days, there were 2 adverse events: 1 pericardial effusion requiring surgical drainage; and 1 asymptomatic device dislodgement.
Conclusions The ARTO system is a novel transcatheter device that can be used safely with meaningful efficacy in the treatment of FMR. (Mitral Valve Repair Clinical Trial [MAVERIC]; NCT02302872)
- coronary sinus
- functional mitral regurgitation
- heart failure
- mitral annulus
- transcatheter mitral valve repair
Percutaneous treatment of functional mitral regurgitation (FMR) is an important therapeutic target and remains an unmet clinical need in the field of adult structural heart disease. Mitral regurgitation (MR) can arise from abnormalities of the valve itself (primary MR), but more commonly, it is a consequence of underlying ischemic or nonischemic left ventricular (LV) dysfunction, which results in restricted leaflet motion and inadequate leaflet coaptation (functional or secondary MR). Moderate-to-severe MR is present in up to 74% of inpatients and 45% of outpatients with systolic heart failure, and the presence of FMR is associated with a higher mortality rate than for patients without FMR (1). Despite the use of guideline-directed medical therapy for systolic heart failure, quality of life and survival remain poor in patients with concomitant FMR (2). Small randomized clinical trials of patients with ischemic MR undergoing coronary artery bypass surgery with and without MR correction have shown improved LV remodelling and functional capacity in the MR correction group (3,4). However, many patients with moderate-to-severe FMR have significant comorbidities and are not routinely offered surgery in clinical practice (5).
Percutaneous therapies have the potential to allow treatment of FMR in patients who are not currently offered surgery. Although other transcatheter technologies currently exist, there remain concerns with technical complexity, safety, and efficacy. The ARTO (MVRx Inc., Belmont, California) system is a catheter-based system designed to treat FMR. The mechanism of the device consists of a suture that connects interatrial-septal and coronary sinus anchors. This suture is tensioned in order to shorten the anteroposterior (AP) diameter of the mitral annulus, thereby improving mitral leaflet coaptation and reducing FMR. We previously reported that this system was effective in ameliorating FMR in an ovine tachycardia model, and we subsequently performed successful temporary transcatheter implantation in 2 patients before planned mitral valve surgery (6,7). In this paper, we report the first-in-human 30-day primary outcome measures of safety and efficacy for 11 patients treated with the latest generation of the ARTO device.
Patients were enrolled at a single institution (Pauls Stradins Clinical University Hospital, Riga, Latvia) between October 2013 and May 2014. A local heart team consisting of a cardiologist, cardiac surgeon, and heart failure specialist evaluated all patients, and they were deemed to be at high surgical risk due to underlying comorbidities and would not be offered surgery as part of routine clinical care. All patients provided informed consent and the MAVERIC (Mitral Valve Repair Clinical Trial) protocol was approved by the institutional ethics committee.
Key inclusion criteria for the trial included the following: age 21 to 85 years, inclusive; New York Heart Association functional classes II to IV systolic heart failure of any etiology; FMR grade ≥2+; LV ejection fraction ≤40%; LV end-diastolic diameter >50 mm and ≤75 mm; and transseptal puncture feasibility. Key exclusion criteria consisted of the following: femoral or internal jugular vein unable to accommodate a 16-F introducer sheath; structural abnormality of the mitral valve (e.g., flail, prolapse, or leaflet calcification); significant mitral annular calcification; hemodynamic instability (systolic pressure <90 mm Hg without afterload reduction, cardiogenic shock, need for inotropic support or intra-aortic balloon pump); previous mitral valve surgery or valvuloplasty or any currently implanted prosthetic valve or ventricular assist device; history of rheumatic heart disease; any atrial septal defect or patent foramen ovale associated with clinical symptoms; any atrial septal aneurysm; serum creatinine >2.5 mg/dl or dialysis dependence; platelet count <100 × 103 cells/mm3; any active infection, endocarditis, or intracardiac thrombus; percutaneous coronary intervention or surgery anticipated within the 6-month follow-up period following the investigational procedure; life expectancy <1 year.
The primary safety outcome was the major adverse event rate at 30 days post-procedure. Major adverse events were defined as stroke, myocardial infarction, death, any device-related surgery, and any events (even if unforeseen in the study planning) that the events committee might consider major. The primary efficacy outcome was FMR grade and change from baseline to 30 days evaluated by 2-dimensional transthoracic echocardiogram. Other evaluations obtained included functional status, left ventricular volume and function indices, and procedural details. Follow-up to 3 years post-procedure is planned. Successful device placement was defined as successful delivery of the device including retrieval of all catheters and no procedural device-related major adverse events. Procedure time was defined as the time from first guidewire introduction to last catheter removal.
All echocardiographic and clinical data were monitored and analyzed by an independent core laboratory (Cardiovascular European Research Centre, Massy, France). Echocardiographic grading of MR severity at baseline and follow-up was performed in accordance with current American Society of Echocardiographic guidelines, and MR was graded on a traditional 0 to 4+ scale (8). Because FMR differs from primary MR in that the parameters of effective regurgitant orifice area (EROA) ≥20 mm2 and regurgitant volume ≥30 ml identify significant FMR because of their prognostic value, these indices were included in the results summary (9). Computed tomography (CT) scans were also performed at baseline and in follow-up to assess for patency of the great coronary sinus and device appearance.
Procedure and device description
All 11 procedures were carried out by the same team of interventional cardiologists, imaging specialists, and anesthesiologists. The procedures were carried out under general anesthesia with transesophageal echocardiographic (TEE) guidance. The procedure has been described in detail previously (6,7). Briefly, 1 interventionalist worked from the right internal jugular vein using a 16-F sheath and the other from the right femoral vein using a 16-F sheath. A magnetic catheter (MagneCath, MVRx Inc.) was placed in the coronary sinus (CS) from the right internal jugular vein. A standard transseptal puncture in the anterior mid-fossa was performed by the femoral operator under TEE guidance and a second MagneCath was placed in the left atrium (LA). The 2 MagneCaths were manipulated and linked magnetically posteriorly in the LA behind the posterior mitral leaflet. A small puncturing wire was then advanced from the CS into the LA MagneCath and externalized to create a continuous loop wire from the right internal jugular vein to the right femoral vein. Through a series of wire and catheter exchanges, a 3-cm CS anchor (T-Bar, MVRx Inc.) was then placed in the coronary sinus and connected to an atrial septal anchor by a suture of adjustable length. This suture was then adjusted in length in order to shorten the AP diameter of the mitral annulus until significant reduction was seen in the mitral regurgitation as assessed by TEE. The suture was then “locked” and cut, allowing removal of the delivery system via the femoral vein and jugular vein. The procedure is illustrated in Figure 1. A single loading dose of clopidogrel was given on the day of the study procedure following treatment, then 75-mg orally daily for a minimum of 3 months. Aspirin 75 to 100 mg was given daily post-procedure at the investigator’s discretion for up to 6 months following the study procedure. Heparin was given during the procedure to maintain a therapeutic activated clotting time of 250 to 300 s.
Continuous variables are expressed as mean ± SD. Statistical comparisons are not reported due to the small number of patients in this study. The authors had full access to the data and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Eleven patients were enrolled and 10 had ≥3+ FMR at enrolment, 1 had 2+ FMR, and all were symptomatic despite guideline-directed medical therapy. Demographics and baseline characteristics of the patients are shown in Table 1. Patients were predominantly male (80%) and had a mean age of 60 years. Despite the high surgical risk of these patients as determined by a heart team, the logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) (6.5 ± 4.6%) and Society of Thoracic Surgeons score (5.0 ± 3.7%) were intermediate, indicating in a similar way to the transcatheter aortic valve replacement population that this score does not always adequately reflect the risk as assessed by a heart team. Forty-six percent of patients had revascularization before the procedure (27% percutaneous coronary intervention and 18% coronary artery bypass graft). These patients were symptomatic, with 81.8% being New York Heart Association functional class III/IV, and there was a mean baseline B-type natriuretic peptide level of 753.8 ng/l. No patient had a biventricular pacemaker as none met the current guideline recommendations for this therapy based on QRS duration, ejection fraction, and presence of sinus rhythm (10). Procedural times shown in Figure 2 favorably decreased during this first-in-human experience. A case example is shown in Figure 3. Safety and efficacy at 30 days are shown in Tables 2 and 3⇓⇓ and Figure 4. No procedural safety events occurred in any patient. At 30 days, MR grade, LV volumes, mitral annular dimensions, and functional status all improved. Pre-procedure FMR was 90% grades 3 to 4+, improving to 82% grades 1 to 2+ at 30 days. EROA by proximal isovelocity surface area at baseline to 30 days decreased from 30.3 ± 11.1 to 13.5 ± 7.1 mm2, and regurgitant volumes decreased from 45.4 ± 15.0 to 19.5 ± 10.2 ml. LV end-systolic volume index decreased from 77.5 ± 24.3 ml/m2 to 68.5 ± 21.4 ml/m2 and LV end-diastolic volume index from 118.7 ± 28.6 ml/m2 to 103.9 ± 21.2 ml/m2. Vena contracta improved from 6.2 ± 1.4 mm at baseline to 3.0 ± 1.1 mm at 30 days. Mitral annular AP diameter decreased from 45.0 ± 3.3 mm to 38.7 ± 3.0 mm. Functional status was 81.8% New York Heart Association functional class III/IV and 18.2% functional class I/II at baseline improving to 45.5% functional class III/IV and 54.6% functional class I/II. Pulmonary artery systolic pressures as determined by echocardiography improved from 44 ± 14 mm Hg at baseline (n = 8) to 34 ± 10 mm Hg at 30 days (n = 9).
Antiplatelet therapy was recommended, but not mandated, before and after the procedure at the treating physician’s discretion. Warfarin was not given unless the patient had another indication for anticoagulation, such as atrial fibrillation. The pre-procedural anticoagulation was 18% (2 of 11) on warfarin, 9% (1 of 11) on warfarin + aspirin, 45% (5 of 11) on single antiplatelet (aspirin or clopidogrel) therapy, 18% (2 of 11) on dual antiplatelet therapy, 1 with no antiplatelet or anticoagulant agent. The post-procedural regimen was 45% (5 of 11) on warfarin alone, 45% (5 of 11) on warfarin + clopidogrel, 9% (1 of 11) on dual antiplatelet therapy.
There were 2 adverse events in follow-up. In 1 subject, an asymptomatic posterior pericardial effusion was noted 5 days after the procedure, which became large by day 15 and was associated with dyspnea. The patient was on warfarin post-procedure due to a history of atrial fibrillation. Attempts to percutaneously drain the effusion were not successful, and the patient underwent successful surgical drainage of the effusion by a subxiphoid approach without recurrence. In another patient, the CS T-Bar was found to have dislocated from the great cardiac vein (GCV) into the left atrium. This dislocation was asymptomatic and detected on routine follow-up CT scan performed on day 35 post-procedure. TEE showed no defect or shunt from the LA to CS. The patient underwent successful elective surgical mitral valve replacement on post-procedure day 65—all tissue in the LA was well healed with no evidence of erosion or damage. All other 9 subjects had no adverse events at 30 days, and CT scans showed the device to be intact and the CS patent in these subjects.
This first-in-human study has demonstrated that the ARTO transcatheter mitral valve repair system can be safely placed in high-risk patients with systolic heart failure and FMR. These patients were symptomatic despite guideline-directed medical therapy and revascularization where appropriate. The procedure has a favorable learning curve in this small series and is performed primarily with fluoroscopic guidance. There were no procedural adverse events. The procedure is performed entirely at the atrial level; therefore, patients remain hemodynamically stable and there is no tendency for ventricular arrhythmias. No conduction disturbances were seen in this series. Although the true efficacy of the device will be proven during longer-term follow-up, there was markedly reduced FMR at 30 days. All echocardiographic measures of FMR including American Society of Echocardiographic grade, regurgitant volume, vena contracta, and EROA showed a meaningful immediate improvement at the conclusion of the procedure and at 1-month follow-up. This is in contrast to other CS devices where efficacy may not be seen acutely, but only after time (11).
The ARTO procedure is more similar in concept to indirect annuloplasty than to direct annuloplasty as there are no anchor elements directly attached to the mitral annulus. It is known that the CS travels on average 5 to 10 mm above the plane of the mitral annulus (12). The movement of the mitral annulus in the ARTO procedure occurs by distraction of tissue in the atrium above the annulus, which is then transmitted to annular tissue. In general, the transseptal puncture was targeted more anteriorly in a low-to-middle location in the fossa ovalis to allow a more horizontal and AP suture vector. Although the suture angle is not parallel to the true AP diameter of the mitral annulus, it does exert a force vector in the AP direction that results in shortening of the AP diameter. The angle of the suture is ∼20° to 30° posterior to a true AP orientation. The details of this force vector have been previously published (7). The degree of AP diameter reduction achieved with the ARTO device is more than reported with any other indirect transcatheter annuloplasty approach to date. There was some minor loss of efficacy between the post-procedure and 30-day values for MR quantification. As there are no major structural changes seen with the device at 30 days, the mechanism is likely related to tissue remodeling around the device and to the small number of patients treated in this series. The system should not develop slack because the septal and coronary sinus anchors are rigid and the suture material and lock are inelastic.
The 2 adverse events between days 1 and 30 may be mitigated in the future. The posterior pericardial effusion is likely to have been caused by guidewire manipulation within the LA, possibly causing a very small perforation of the LA appendage. An angled guidewire was used in this series to help direct the LA MagneCath, and in future procedures, a J-tipped wire will be used. Increased operator experience and the use of a deflectable guide catheter may also minimize this complication in the future. Migration of the coronary sinus T-Bar anchor into the LA is a potential complication of this procedure. This occurred asymptomatically in 1 patient with no immediate clinical sequelae. The mechanism of migration may be related to the fact that the T-Bar has a shorter rigid central portion and flexible ends. This problem may be minimized in the future by avoiding excess tension on the atrial/CS wall during delivery. The required tension placed on the suture has been measured experimentally in an ovine model to be ∼147 g (7). The tension placed on the suture in a human is likely greater, but it is difficult to quantify. Theoretically, increased tension could result in device migration, but in this series, all patients were tensioned to a similar degree. Therefore, correlating the degree of tension with risk in this series is not possible. No occurrence of compression of the circumflex coronary artery was seen in this study. Coronary artery compression (which has been observed with other CS devices) was avoided with the ARTO device in 2 ways. First, careful pre-procedural CT scan can demonstrate the 3-dimensional relationship between the coronary sinus and the circumflex coronary artery, allowing some pre-procedural planning with regard to placement of the CS anchor, although no patient was excluded pre-procedure for concern of coronary compression. Second, as the suture is tensioned at the end of this procedure, a simultaneous coronary angiogram is performed to exclude coronary artery compression. If at any point, coronary artery compression or other untoward effect is seen, the entire device can be removed before final deployment and the procedure discontinued, although this was not necessary in this series.
Previous pathophysiological studies have demonstrated that an increase in AP mitral annular diameter is the common final pathway in the development of FMR (13), and that shortening this dimension is critical to alleviating MR. The surgical approach to FMR generally involves placement of a rigid circumferential annuloplasty ring directly on the mitral annulus with a goal of reduction in mitral annular AP diameter of at least 20% (14). A number of predictors for recurrent MR after restrictive annuloplasty have been identified, including LV end-diastolic diameter >65 mm (15), posterior leaflet angle ≥45° (16), and mitral valve coaptation depth ≥11 mm (17). The effect of these parameters on the success of percutaneous therapies is yet to be elucidated. Of note, the ARTO system achieves a 14% reduction in AP diameter at 30 days in this trial, which far exceeds that achieved by other currently available CS-based indirect annuloplasty devices. Although no patients in this series required cardiac resynchronization therapy, we do not believe that a CS lead would preclude performance of the ARTO procedure, because CS leads are small (4-F to 6-F) and the CS diameter in heart failure patients is large. Other percutaneous techniques for the treatment of FMR include edge-to-edge repair with the MitraClip (Abbott, Menlo Park, California). This device has been applied successfully to FMR in the setting of end-stage systolic heart failure, but it does not result in a meaningful reduction of mitral annular diameter, which may lead to decreased durability over time, especially in patients with very large annuli or ventricles (18). Despite the potential advantages of a direct annular approach, the development and adoption of percutaneous direct annuloplasty has lagged behind other approaches, largely owing to the technical challenges of catheter delivery and positioning. Much discussion has taken place recently on the relative merits of transcatheter mitral valve repair versus replacement and the reduction of MR (as generally achieved by transcatheter repair) as compared with the elimination of MR (as aimed for with transcatheter replacement). Although a surgical trial of repair versus replacement demonstrated equipoise between the 2 therapies in mid-term follow-up (19), the decision of transcatheter repair versus replacement may well depend on patient clinical characteristics and the relative risk of the procedure. The current transcatheter replacement devices appear to carry a high procedural risk, and it is likely that the procedural risk will be higher with replacement than repair for some time to come. The patients in this series treated with the ARTO device were at high risk with a mean LV ejection fraction of 37.5%, and all had been turned down for cardiac surgery. This group may therefore be particularly suited to transcatheter repair. The reduction in FMR in this series appears favorable compared with that reported with other transcatheter repair devices. Importantly, for FMR, an EROA ≥20 mm2 and regurgitant volume ≥30 ml has been shown to correlate with worse clinical outcomes, and the mean EROA (13.5 ± 7.1 mm2) and RV (19.5 ± 10.2 ml) achieved in this series was well below these target values (9).
This is a small, nonrandomized, nonblinded observational study. Because of the innovative nature of the technology and some variability in echocardiographic windows, echocardiographic parameters were not measurable in every patient at every time point. However, paired interpretable data were used for comparisons, and all echocardiographic assessments were performed by an independent core lab. Given the small numbers in this study, the strength of any statistical comparison is limited and therefore not reported.
This first-in-human study of the ARTO transcatheter mitral valve repair system demonstrates that the procedure can be safely performed with a favorable learning curve. There is strong evidence of device efficacy with clinically meaningful reductions in MR. These initial data are extremely promising, especially in terms of safety, and larger studies with longer-term follow-up are planned to confirm sustained reduction of MR and improvement in functional status of the patients.
WHAT IS KNOWN? Patients with systolic heart failure often have coexistent FMR.
WHAT IS NEW? Although surgical correction of FMR has been shown in some studies to improve quality of life and reduce LV size, surgery is not routinely performed in clinical practice because of patient comorbidities and perceived surgical risk. Consequently, there is significant interest in developing minimally invasive transcatheter methods of correcting FMR. In this study, we safely treated 11 patients with the novel ARTO system, with meaningful reductions in FMR and improved functional status.
WHAT IS NEXT? Further investigations with larger randomized trials addressing the impact of transcatheter FMR correction as compared with medical or surgical therapy are needed.
Dr. Rogers is a consultant to MVRx, Inc. Ms. Greene is consultant for MVRx, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- coronary sinus
- computed tomography
- effective regurgitant orifice area
- functional mitral regurgitation
- great cardiac vein
- left atrium
- left ventricle
- mitral regurgitation
- transesophageal echocardiographic
- Received December 9, 2014.
- Revision received March 25, 2015.
- Accepted April 9, 2015.
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