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Safety and performance of a novel transventricular beating heart mitral valve repair system: 1-year outcomes

Safety and performance of a novel transventricular beating heart mitral valve repair system:... Abstract OBJECTIVES Open in new tabDownload slide Open in new tabDownload slide The objective of this study was to evaluate the safety and performance of a novel, beating heart procedure that enables echocardiographic-guided beating heart implantation of expanded polytetrafluoroethylene (ePTFE) artificial cords on the posterior mitral leaflet of patients with degenerative mitral regurgitation. METHODS Two prospective multicentre studies enrolled 13 (first-in-human) and 52 subjects, respectively. Patients were treated with the HARPOON beating heart mitral valve repair system. The primary (30-day) end point was successful implantation of cord(s) with mitral regurgitation reduction to ≤moderate. An independent core laboratory analysed echocardiograms. RESULTS Of 65 patients enrolled, 62 (95%) achieved technical success, 2 patients required conversion to open surgery and 1 procedure was terminated. The primary end point was met in 59/65 (91%) patients. Among the 62 treated patients, the mean procedural time was 2.1 ± 0.5 h. Through discharge, there were no deaths, strokes or renal failure events. At 1 year, 2 of the 62 patients died (3%) and 8 (13%) others required reoperations. At 1 year, 98% of the patients with HARPOON cords were in New York Heart Association class I or II, and mitral regurgitation was none/trace in 52% (n = 27), mild in 23% (n = 12), moderate in 23% (n = 12) and severe in 2% (n = 1). Favourable cardiac remodelling outcomes at 1 year included decreased end-diastolic left ventricular volume (153 ± 41 to 119 ± 28 ml) and diameter (53 ± 5 to 47 ± 6 mm), and the mean transmitral gradient was 1.4 ± 0.7 mmHg. CONCLUSIONS This initial clinical experience with the HARPOON beating heart mitral valve repair system demonstrates encouraging early safety and performance. Clinical registration numbers NCT02432196 and NCT02768870. Echocardiography, Mitral regurgitation, Surgery, Valvuloplasty INTRODUCTION Degenerative mitral valve disease with chordal elongation and/or rupture and leaflet prolapse is the most common indication for mitral valve operation. Outcomes with conventional surgical treatment are limited by variable repair rates owing to differences in individual centre volumes and the relatively high volumes required for a given surgeon to achieve proficiency in mitral valve repair [1–3]. Although excellent durability of conventional surgical mitral valve repair is reported in multiple single-centre retrospective series [4, 5], there are few core laboratory-adjudicated series providing late mitral regurgitation (MR) recurrence rates, and several retrospectives [6] and prospective core lab-adjudicated surgical series have reported significant rates of early recurrent MR [7]. Conventional mitral valve surgery is invasive and associated with morbidity related to cardiopulmonary bypass, cardioplegic cardiac arrest, aortic cross-clamping and cannulation, atriotomy and current incisions. An alternative and less-invasive procedure to artificial cordal mitral valve repair was first introduced clinically in 2009 by Speziali et al.[8], and stable 5-year results have been reported using this approach [9]. The HARPOON beating heart mitral valve repair system (HARPOON System; Edwards Lifesciences, Irvine, CA, USA) was developed to enable surgeons to anchor expanded polytetrafluoroethylene (ePTFE) cords transventricularly on prolapsed mitral valve leaflets on the beating heart under transoesophageal echocardiographic image guidance. Implanted cord length is titrated on the beating heart to optimize the repair [10, 11]. We report 1-year outcomes of all patients treated with the HARPOON System to date. MATERIALS AND METHODS This study reports procedural and 1-year outcomes of all patients that have been implanted with artificial ePTFE cords using the HARPOON System. This includes 13 patients enrolled in 2 centres in the prospective early feasibility study between February 2015 and February 2016 [11], and 52 subsequent patients enrolled in the TRACER (Mitral TransApical NeoCordal Echo-Guided Repair) trial, a prospective, non-randomized multicentre study performed at 6 European centres between March 2016 and November 2017. The study protocol was approved by the responsible national authority of each country and the ethics committee at each institution. All participating patients provided informed consent. Serious adverse events were site-reported and adjudicated by an independent clinical events committee. The authors had full access to the data and are responsible for the completeness and accuracy of the reported data and analyses. Results through 2 April 2019 are reported here. Study patients Patients with severe degenerative MR as a result of isolated posterior leaflet prolapse were considered for enrollment. Anatomic and clinical screening for enrollment was determined by a central eligibility committee that consisted of an experienced mitral valve surgeon (J.S.G.) and echocardiographer (M.N.D.A.). The primary anatomic inclusion criterion focused on the tissue: gap ratio, defined as the ratio of the height/length of the prolapsing segment of the posterior leaflet to the gap between the coaptation surface of the anterior leaflet and the hinge point of the base of the posterior leaflet (measured at peak systole; Fig. 1). Figure 1: Open in new tabDownload slide Tissue-to-gap ratio. Figure 1: Open in new tabDownload slide Tissue-to-gap ratio. In general, patients with a tissue: gap ratio of 1.5:1 or more were considered to have adequate posterior leaflet tissue to allow sufficient coaptation and effective abrogation of MR after mitral valve repair with the HARPOON System. During screening examination, centres were encouraged to perform ‘pan-through’ studies in the four-chamber and long-axis transoesophageal echocardiographic views, and the smallest measured tissue: gap ratio was used as a key criterion for eligibility. Centres were also encouraged to provide full-volume 3-dimensional transoesophageal echocardiography (TOE) data, which was imported into TomTec (TomTec imaging systems, TomTec USA, Chicago, IL, USA) for further analyses and preoperative target planning. The use of the TomTec system allowed the ‘on-axis’ determination of the tissue: gap ratio. Exclusion criteria included anterior leaflet prolapse (defined as the excursion of the free edge of the anterior leaflet above the plane of the annulus during peak systole), severe mitral annular calcification, the presence of multiple or complex colour Doppler jets and significant tricuspid or aortic valvular disease. Additional exclusion criteria included functional MR, a Society of Thoracic Surgeons (STS) predicted risk of mortality of >8% (for repair), severe pulmonary hypertension (>70 mmHg) or severe left ventricular (LV) dysfunction. Full inclusion and exclusion criteria for both trials are available at: https://clinicaltrials.gov/ct2/show/NCT02432196 (early feasibility study) and at https://clinicaltrials.gov/ct2/show/NCT02768870 (TRACER). All patients had class I or IIa indications for operative intervention [12]. The HARPOON beating heart mitral valve repair system The HARPOON System includes a dedicated haemostatic introducer and a delivery system. The 12-Fr (inner diameter) introducer has a haemostatic valve that allows bloodless insertion and withdrawal of multiple delivery systems during the procedure. The delivery system is a single-use, preloaded 9-Fr (3 mm) external diameter rigid shafted instrument that has an atraumatic end effector at the distal end designed to stabilize the device on the underside of the mitral leaflet at the targeted implantation site. Once the desired location is ascertained using TOE and the leaflet is stabilized by the end effector, the surgeon actuates the device and extends a 21-gauge needle with a prewrapped ePTFE double-helical knot (50 winds) across the leaflet. The needle is withdrawn, and the knot is automatically formed, anchoring the ePTFE cordal pair to the leaflet. The procedure The HARPOON procedure has been previously described [10, 11]. In brief, the procedure is performed under general anaesthesia with a single lumen endotracheal tube. Crucial for procedural success is teamwork between the transoesophageal echocardiographer and the surgeon. A large monitor positioned directly in front of the surgeon (on the patient’s right side) is used to display the echocardiographic images and facilitates effective HARPOON procedures. Transthoracic surface echocardiography is helpful to identify the optimal incision location, most frequently the (left) 5th intercostal space. The desired ventricular access point is 2–4 cm basal from the true apex of the heart and between the left anterior descending coronary artery and the diagonal branches. If possible, a non-rib-spreading incision is performed, and visualization is enhanced with the use of a soft tissue retractor. The pericardium is opened, and the desired entrance site is confirmed on TOE imaging with finger indentation of the ventricular wall. Two pairs of pledgeted 3–0 monofilament horizontal mattress sutures are placed, and the introducer is inserted under TOE guidance using a 0.035″ guidewire. Intravenous heparin is administered before introducer insertion and activated clotting time of ≥350 s is maintained throughout the procedure. The delivery system is inserted through the introducer and directed using echocardiographic guidance to the underside of the prolapsed leaflet segment, taking care to avoid traversing the native chordae tendineae supporting the anterior leaflet. Optimal imaging includes simultaneous (xPlane) bicommissural and long-axis views. Targeting goals include placement of ePTFE knots close to the free edge of the mitral valve leaflet and spaced 3–5 mm apart across the free edge of the prolapsed segment. Knots are placed sequentially from lateral to medial, and assessment of knot position is ascertained with 3-dimensional ‘surgeons view’ TOE imaging following the placement of each knot. A minimum of 3 cordal pairs/knots is recommended to distribute the load among the cordal pairs. A new delivery system is used for each knot, and after implantation, the 2 ePTFE strands associated with each knot are exteriorized through the introducer. Once knot implantation is complete, the introducer is removed, and the purse-strings tied. All ePTFE strands are then passed separately through a large stiff felt pledget, and then through a tourniquet. The length of the implanted ePTFE cords is then titrated under echo guidance to achieve optimal coaptation. Finally, the cords are fixed with a shodded clamp and each pair tied individually. Aspirin (325 mg) is administered postoperatively and daily thereafter. Primary performance and safety end points Technical success was defined as leaving the operating room with ≥1 ePTFE artificial cords in place. The primary performance end point was successful implantation of ≥1 ePTFE cord on the prolapsed leaflet with a reduction of MR to ≤ moderate after the procedure and after 30 days. Various postoperative safety end points were monitored over the observational period. Renal failure was defined as a new requirement for dialysis (receiving renal replacement therapy) or an increase in the creatinine level to more than 3× baseline. Echocardiographic analyses Preprocedural, intraprocedural and postoperative echocardiograms were performed by the sites and securely transmitted to an independent core laboratory (Massachusetts General Hospital, Boston, MA, USA) for anonymized and standardized evaluation. MR severity was graded as none/trace, mild, moderate or severe using integrative criteria specified by the American Society of Echocardiography and European Society of Cardiology [13]. LV dimensions and volumes and left atrial volumes (biplane area length) were measured according to established guidelines [14]. The mitral annular area was calculated as π × (one-half of the mitral annular dimension in the parasternal long-axis view) × (one-half of the mitral annular dimension in the apical two-chamber view) using the elliptical assumption for the mitral annulus [15]. Follow-up Enrolled patients were scheduled for treatment with the HARPOON System following baseline clinical and echocardiographic evaluation, then underwent clinical and echocardiographic evaluation at discharge, 30 days, 6 months and 1 year. Clinical evaluation at baseline and 1 year included New York Heart Association (NYHA) heart failure classification. Additional follow-up results are not yet complete. Continuous variables are represented as mean ± standard deviation, and sometimes with (minimum–maximum). Comparisons of echocardiographic measures between baseline and 1 year were made with paired t-tests, with significant differences declared if P-value <0.05. Exact 95% confidence intervals (CIs) are reported. RESULTS Patient characteristics From February 2015 through November 2017, 65 patients were enrolled in the early feasibility study and TRACER trials at 6 centres in 3 countries. All eligible implanted patients completed a 1-year clinical and/or echocardiographic follow-up as of the 2 April 2019 data lock for this report. The patient age of the implanted cohort was 61 ± 12 years, and the mean STS and EuroSCORE II operative risk scores were 0.6 ± 0.6% and 1.2 ± 1.1%, respectively. Study population characteristics are shown in Table 1. Table 1: Baseline characteristics Factor . . Age (years) 61.0 ± 12.2 (39–89) Female gender 24% (15/62) NYHA class  I 41% (24/59)  II 41% (24/59)  III 19% (11/59)  IV 0% (0/59) STS risk of mortality 0.6±0.6% (0.2–3.5) EuroSCORE II 1.2±1.1% (0.5–5.1) LVEF 69.2±5.8% (48–81) Factor . . Age (years) 61.0 ± 12.2 (39–89) Female gender 24% (15/62) NYHA class  I 41% (24/59)  II 41% (24/59)  III 19% (11/59)  IV 0% (0/59) STS risk of mortality 0.6±0.6% (0.2–3.5) EuroSCORE II 1.2±1.1% (0.5–5.1) LVEF 69.2±5.8% (48–81) LVEF: left ventricular ejection fraction; NYHA: New York Heart Association; STS: Society of Thoracic Surgeons. Open in new tab Table 1: Baseline characteristics Factor . . Age (years) 61.0 ± 12.2 (39–89) Female gender 24% (15/62) NYHA class  I 41% (24/59)  II 41% (24/59)  III 19% (11/59)  IV 0% (0/59) STS risk of mortality 0.6±0.6% (0.2–3.5) EuroSCORE II 1.2±1.1% (0.5–5.1) LVEF 69.2±5.8% (48–81) Factor . . Age (years) 61.0 ± 12.2 (39–89) Female gender 24% (15/62) NYHA class  I 41% (24/59)  II 41% (24/59)  III 19% (11/59)  IV 0% (0/59) STS risk of mortality 0.6±0.6% (0.2–3.5) EuroSCORE II 1.2±1.1% (0.5–5.1) LVEF 69.2±5.8% (48–81) LVEF: left ventricular ejection fraction; NYHA: New York Heart Association; STS: Society of Thoracic Surgeons. Open in new tab Primary performance end point Technical success was achieved in 62 of the 65 enrolled patients (95%). In 1 of the 3 patients that did not achieve technical success, the HARPOON System introducer was placed and intracavitary LV pressures of 260 mmHg were measured, in association with LV outflow tract obstruction. It was decided to terminate the procedure; the introducer was removed, and the patient subsequently consented for interval conventional myectomy and mitral valve repair. Two patients required intraoperative conversion to conventional mitral valve repair, as their HARPOON ePTFE knots were deployed in the prolapsed leaflet but not in the intended locations due to suboptimal echocardiographic equipment and poor visualization. The knots were not associated with leaflet damage and in both cases, conventional mitral valve repair (using ePTFE cords) was successful, with none/trace MR recorded at hospital discharge. Among the 62 patients achieving technical success, an average of 4.1 ± 1.0 (1–7) pairs of ePTFE cords was implanted and the MR grade at discharge of the 58 patients with evaluable echocardiograms was none/trace in 74% (43/58), mild in 21% (12/58), moderate in 3% (2/58) and severe in 2% (1/58). The primary performance end point was met in 59 of the 65 patients enrolled (91%; 95% CI 81–97%). MR severity at 30 days among 60 patients with evaluable echocardiograms was none/trace in 62% (37/60), mild in 23% (14/60), moderate in 13% (8/60) and severe in 2% (1/60). The average procedure time was 126 ± 36 (72–222) min. The amount of time the introducer was in the LV averaged 42 ± 18 (18–126) min. The average intraoperative blood loss was 272 ± 182 (50–949) ml. Early safety end points The mean postoperative hospital length of stay was 6.0 ± 2.1 (3–15) days. Through discharge, there were no events of death, stroke, transient ischaemic attack, renal failure, reintubation (measured in 49 TRACER patients) or blood transfusions. One patient died on postoperative day (POD) 13. After effective implantation of 4 cords and discharge on POD 7 [on oral anticoagulation for atrial fibrillation (AF)], an echocardiogram on POD 9 demonstrated normal LV and mitral valve function, no MR, and trace pericardial effusion. On POD 13, progressive hypotension was followed by an asystolic arrest and resuscitation was unsuccessful. An autopsy showed that the artificial cords were intact on both the mitral leaflet and the ventricular surface. There was 2 l of blood in the left chest with no blood in the pericardium. One patient required reoperation on POD 27 as a result of severe MR caused by methicillin-sensitive Staphylococcus aureus (MSSA) infective endocarditis. This patient had an unrecognized baseline dental infection and elevated white blood cell count. At reoperation, vegetation and perforation of the posterior leaflet were found; a mechanical valve was implanted, and the patient was discharged in good condition. One patient was readmitted with angina and diagnosed with myocardial infarction on POD 5. The patient was discharged the next day, and subsequent echocardiograms demonstrated normal ventricular function; the patient completed a 1-year follow-up. New postoperative AF was identified in 18% [9] of the 50 patients without baseline AF, which resolved in 8 of these patients at 30 days. Among 12 patients with preoperative AF, 58% (7/12) were in normal sinus rhythm at 30 days and 82% (9/11) at 1 year. One-year safety end points Through 1 year of follow-up, 1 additional patient died, 1 patient experienced a stroke and no patients experienced renal failure or endocarditis. The patient's death occurred at home on POD 214 from unknown causes; an autopsy was not authorized. The stroke occurred on POD 349, was non-disabling, and was adjudicated as not related to either the study device or the procedure. There were 8/62 (13%) reoperations in the first year (0.87 freedom from event rate, 95% CI 0.78–0.95). In addition to the previously described patient with early infective endocarditis, 1 patient underwent a recurrent operation (POD 279) for reprolapse (the ventricular free wall below the pledget at the entrance site had invaginated, allowing the posterior MV leaflet to prolapse). On the reanalysis of the baseline imaging, this patient had a small tissue: gap ratio and a very large absolute gap between the tip of the anterior leaflet and the base of the posterior leaflet. One patient underwent reoperation at 8 months and was found to have a ruptured ePTFE cord within a few millimetres of the leaflet. This patient was the sole subject that had only one ePTFE cordal pair inserted at the original procedure. Three patients had recurrent severe MR on the basis of ruptured ePTFE cords, at 211, 253 and 352 days after the operation. In 1 case a non-shodded sharp clamp was used to stabilize the cords during knot tying on the epicardial pledget, and in the other 2 all cords were ruptured within the myocardium, a few millimetres from the pledget. In the remaining 2 patients, causes of recurrent MR were multifactorial and included unrecognized and untreated anterior leaflet prolapse, native anterior chordal rupture, an untied ePTFE knot at the apex and poor imaging and targeting. At reoperation, the mitral valve was re-repaired in 6/8 cases (75%), and was replaced in 2 cases (one due to extensive leaflet destruction from endocarditis, and the other because of poor visualization). In all 8 reoperative cases, the mitral leaflets were intact and the ePTFE knot anchors well-incorporated into the leaflet tissue. All patients left the hospital with no MR and in good condition. Mitral regurgitation reduction and clinical status MR severity before the procedure and at discharge, 30 days, 6 months and 12 months is shown in Figs 2 and 3. At hospital discharge, 95% of patients had ≤mild MR. We observed a progression of MR between discharge and 30 days, with moderate MR in 13% of patients and severe MR in 2%. At 1 year, among all 52 patients alive and with HARPOON cord(s), MR was ≤mild in 75%, moderate in 23% and severe in 1 patient (2%). A representative follow-up echocardiogram is included as a Video 1. Figure 2: Open in new tabDownload slide Severity of mitral regurgitation (including reoperations). Figure 2: Open in new tabDownload slide Severity of mitral regurgitation (including reoperations). Figure 3: Open in new tabDownload slide Severity of mitral regurgitation (exclusive of reoperations). Figure 3: Open in new tabDownload slide Severity of mitral regurgitation (exclusive of reoperations). NYHA functional status from baseline to 1 year is outlined in Fig. 4; 98% (47/48) of patients with HARPOON cord(s) were in NYHA functional class I or II at 1 year. Figure 4: Open in new tabDownload slide NYHA class. NYHA: New York Heart Association. Figure 4: Open in new tabDownload slide NYHA class. NYHA: New York Heart Association. Video 1: Transthoracic apical 4-chamber view of a patient 30 months after HARPOON repair. Video 1: Transthoracic apical 4-chamber view of a patient 30 months after HARPOON repair. Close Echocardiographic variables and reverse remodelling We observed favourable reverse LV and left atrial remodelling from baseline to 1 year (Table 2). LV end-diastolic volume was decreased by 22% (P < 0.001) and LV end-diastolic diameter was decreased by 11% (P < 0.001). Anterior-to-posterior mitral annular dimension was decreased by 11% (P < 0.001). The mean transmitral gradient was 1.3 ± 0.5 mmHg at 30 days (n = 51) and 1.4 ± 0.7 mmHg at 1 year (n = 47). Table 2: Cardiac remodelling . Baseline . Discharge . 30 days . 1 year . P-valuea . LVEDD (mm) 53 ± 5 49 ± 6 49 ± 5 47 ± 6 <0.001 LVEF (%) 69 ± 6 58 ± 8 61 ± 5 63 ± 6 <0.001 LVEDV (ml) 153 ± 41 129 ± 37 120 ± 28 119 ± 28 <0.001 MV annular anterior–posterior diameter (mm) 34 ± 5 32 ± 5 32 ± 5 31 ± 5 <0.001 Mean MV gradient (mmHg) NA 1.3 ± 0.6 1.3 ± 0.5 1.4 ± 0.7 NA . Baseline . Discharge . 30 days . 1 year . P-valuea . LVEDD (mm) 53 ± 5 49 ± 6 49 ± 5 47 ± 6 <0.001 LVEF (%) 69 ± 6 58 ± 8 61 ± 5 63 ± 6 <0.001 LVEDV (ml) 153 ± 41 129 ± 37 120 ± 28 119 ± 28 <0.001 MV annular anterior–posterior diameter (mm) 34 ± 5 32 ± 5 32 ± 5 31 ± 5 <0.001 Mean MV gradient (mmHg) NA 1.3 ± 0.6 1.3 ± 0.5 1.4 ± 0.7 NA a P-values: baseline versus 1 year. LVEDD: left ventricular end-diastolic diameter; LVEDV: left ventricular end-diastolic volume; LVEF: left ventricular ejection fraction; MV: mitral valve; NA: not applicable. Open in new tab Table 2: Cardiac remodelling . Baseline . Discharge . 30 days . 1 year . P-valuea . LVEDD (mm) 53 ± 5 49 ± 6 49 ± 5 47 ± 6 <0.001 LVEF (%) 69 ± 6 58 ± 8 61 ± 5 63 ± 6 <0.001 LVEDV (ml) 153 ± 41 129 ± 37 120 ± 28 119 ± 28 <0.001 MV annular anterior–posterior diameter (mm) 34 ± 5 32 ± 5 32 ± 5 31 ± 5 <0.001 Mean MV gradient (mmHg) NA 1.3 ± 0.6 1.3 ± 0.5 1.4 ± 0.7 NA . Baseline . Discharge . 30 days . 1 year . P-valuea . LVEDD (mm) 53 ± 5 49 ± 6 49 ± 5 47 ± 6 <0.001 LVEF (%) 69 ± 6 58 ± 8 61 ± 5 63 ± 6 <0.001 LVEDV (ml) 153 ± 41 129 ± 37 120 ± 28 119 ± 28 <0.001 MV annular anterior–posterior diameter (mm) 34 ± 5 32 ± 5 32 ± 5 31 ± 5 <0.001 Mean MV gradient (mmHg) NA 1.3 ± 0.6 1.3 ± 0.5 1.4 ± 0.7 NA a P-values: baseline versus 1 year. LVEDD: left ventricular end-diastolic diameter; LVEDV: left ventricular end-diastolic volume; LVEF: left ventricular ejection fraction; MV: mitral valve; NA: not applicable. Open in new tab DISCUSSION This initial global clinical experience with the HARPOON System demonstrated efficient, safe, and predictable initial procedural MR reduction and favourable cardiac remodelling and patient functional status despite a degree of recurrent MR and 1-year reoperation rates. Treatment with the HARPOON System was very safe in-hospital, with no mortality and no patients requiring reintubation or blood transfusion. No patient required a mitral valve replacement at the index procedure. We found that the procedure was simple and straightforward to teach and learn, and reproducible across 6 diverse centres and teams. Nearly all patients left the operating room with insignificant MR, and we were able to accomplish the procedure in many cases with a non-rib spreading approach. With a mean total procedure time of just over 2 h, the procedure was efficient compared to the nearly 4 h required for conventional mitral valve repair [16]. A key advantage of this approach is that artificial cordal length may be titrated on the loaded, beating heart, something that is not possible on an arrested heart during conventional on-pump operations. The knot anchors are low profile and leave a minimal footprint on the mitral leaflets, which preserve the option for future mitral valve repair. The repair rate for degenerative disease in North America based on the STS Adult Cardiac Surgery Database is 80% [2] and in the New York state database 67% [1]. In contrast, this experience demonstrates that mitral valve repair was achieved acutely in all anatomically suitable patients that had ePTFE cords successfully implanted (95%, 62/65) with the HARPOON System. At 1-year follow-up, 75% of patients in this experience had ≤mild MR and 13% required reoperation. These outcomes are not as favourable as some retrospective institutionally reported outcomes from centres of excellence, which report 5-year freedom from recurrent MR of 90% [5, 17, 18]. By contrast, other retrospective single-centres and 1 core laboratory-adjudicated multicentre report significant rates of early MR recurrence and reoperation. In 1 large series of patients (n = 2575) with degenerative mitral regurgitation (DMR) isolated posterior leaflet repair, 11% of patients developed ≥moderate MR 2 weeks after operation [6]. Similarly, the surgical arm (n = 80) of EVEREST II reported 24% of patients with moderate or greater MR at 1 year [7]. Two predominant factors contributed to late recurrent moderate and severe MR. These included ePTFE cordal rupture and reprolapse. Posterior leaflet reprolapse was most commonly observed between discharge and 30 days. Possible mechanisms underlying this phenomenon include LV remodelling and/or migration of cords through the myocardium with associated relative elongation of the cords. While we observed immediate intraoperative resolution of MR and remodelling upon tensioning of implanted ePTFE cords, there was minimal remodelling between discharge and 30 days. An alternative hypothesis is that the cords may transit the myocardium intra-ventricularly perpendicular to the LV wall and then are angled sharply towards the mitral valve where they emerge from the myocardium; cord tension may lead to cord migration through the relatively soft myocardium in a direction that decreases the acute angle at the endocardium and results in relative elongation of the cords. As this phenomenon of early relative cordal elongation was identified, surgeons felt the need to over-tension the posterior leaflet in anticipation of relative reprolapse in the first weeks after implantation. We have not observed substantial rates of reprolapse after the first month or two. Further study is required to elucidate the mechanism(s) and strategies to prevent this phenomenon. Cordal rupture was responsible for severe recurrent MR and reoperation in 4 patients. In 1 case, only a single cord during the HARPOON procedure was implanted and rupture was likely related to excess stress on this cord. In another case, a non-shodded clamp was used to stabilize the ePTFE cords on the myocardial pledget and is thought to have precipitated cordal rupture adjacent to the pledget. In the other 2 cases, all 4 and 6 cords were ruptured within the myocardium, a few millimetres from the pledget. Additional contributing factors to recurrent MR included native anterior chordal rupture, imaging and targeting difficulties and 1 cord becoming untied at the epicardial pledget. As our experience with the HARPOON procedure progressed, our patient selection and procedural technique undoubtedly improved. Key learnings included that 1 vendor’s TOE system had robust ultrasound artifact suppression which compromised visualization of the HARPOON device tip. This was associated with early conversions as well as suboptimal ePTFE knot targeting on leaflets and recurrent MR. We refined our targeting and now require ≥3 knots in all patients. The HARPOON procedure achieved favourable LV remodelling that was sustained through 1 year. This included stable reduction of the mitral annular anterior–posterior dimension, negligible transmitral gradients and LV volume and function improvements that are similar to values observed after conventional surgical mitral valve repair [19, 20]. Despite a significant rate of reoperations in this initial clinical experience, overall patient survival at 1 year among patients undergoing the HARPOON procedure was 97%, and among surviving patients, 98% were in NYHA class I or II, and 97% (58/60) had functioning mitral valve repairs. CONCLUSIONS In conclusion, this initial mitral valve repair experience with the HARPOON System was associated with an excellent safety profile, a high rate of technical procedural success, and efficacious core laboratory-confirmed MR reduction at hospital discharge. We observed modest recurrent MR which was associated with a variety of patient selection and procedural execution issues. This initial experience highlights the potential of the HARPOON beating heart mitral valve repair system as a minimally invasive procedure for the surgical treatment of severe degenerative MR, and we are optimistic that these early learnings will inform future use of this system and drive improved results. Studies of greater duration and with a broader set of operators will be required to determine the long-term durability of HARPOON beating heart mitral valve repair. Acknowledgement The authors acknowledge the contributions of Neil Moat, MBBS. Funding This work was supported by the HARPOON Medical and Edwards Lifesciences. Conflict of interest: James S. Gammie is a consultant to Edwards Lifesciences, is the founder of Protaryx Medical and was the founder of HARPOON Medical. Michael N. D’Ambra, Andrzej Gackowski, Piotr Szymanski, Steve Livesey, Alison Duncan, Rashmi Yadav, Paolo Denti and Krzysztof Bartus are consultants to Edwards Lifesciences. Michele DeBonis is a consultant for Abbott Laboratories and Medtronic. Rashmi Yadav is a member of Medtronic Independent Physician Quality Panel. All other authors declared no conflict of interest. Author contributions James S. Gammie: Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Software; Supervision; Validation; Visualization; Writing—original draft; Writing—review & editing. Krzysztof Bartus: Investigation; Writing—review & editing. Andrzej Gackowski: Investigation; Writing—review & editing. Piotr Szymanski: Investigation; Writing—review & editing. Agata Bilewska: Investigation; Writing—review & editing. Mariusz Kusmierczyk: Investigation; Writing—review & editing. Boguslaw Kapelak: Investigation; Writing—review & editing. Jolanta Rzucidlo-Resil: Investigation; Writing—review & editing. Alison Duncan: Investigation; Writing—review & editing. Rashmi Yadav: Investigation; Writing—review & editing. Steve Livesey: Investigation; Writing—review & editing. Paul Diprose: Investigation; Writing—review & editing. Gino Gerosa: Investigation; Writing—review & editing. Augusto D’Onofrio: Investigation; Writing—review & editing. Demetrio Pittarello: Investigation; Writing—review & editing. Paolo Denti: Investigation; Writing—review & editing. Giovanni La Canna: Investigation; Writing—review & editing. Michele De Bonis: Investigation; Writing—review & editing. Ottavio Alfieri: Investigation; Writing—review & editing. Judy Hung: Investigation; Writing—review & editing. Piotr Kolsut: Investigation; Writing—review & editing. Michael N. D’Ambra: Investigation; Writing—review & editing. Reviewer information European Journal of Cardio-Thoracic Surgery thanks Raimund A. Erbel, Francesco Onorati, David Schibilsky and the other, anonymous reviewer(s) for their contribution to the peer review process of this article. REFERENCES 1 Chikwe J , Toyoda N , Anyanwu AC , Itagaki S , Egorova NN , Boateng P et al. Relation of mitral valve surgery volume to repair rate, durability, and survival . J Am Coll Cardiol 2017 ; 69 : 2397 – 406 . Google Scholar Crossref Search ADS WorldCat 2 Gammie JS , Chikwe J , Badhwar V , Thibault DP , Vemulapalli S , Thourani VH et al. Isolated mitral valve surgery: the Society of Thoracic Surgeons adult cardiac surgery database analysis . Ann Thorac Surg 2018 ; 106 : 716 – 27 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Holzhey DM , Seeburger J , Misfeld M , Borger MA , Mohr FW. 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Robotic repair of posterior mitral valve prolapse versus conventional approaches: potential realized . J Thorac Cardiovasc Surg 2011 ; 141 : 72 – 80.e1–4 . Google Scholar Crossref Search ADS PubMed WorldCat 17 Suri RM , Taggarse A , Burkhart HM , Daly RC , Mauermann W , Nishimura RA et al. Robotic mitral valve repair for simple and complex degenerative disease: midterm clinical and echocardiographic quality outcomes . Circulation 2015 ; 132 : 1961 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat 18 Lawrie GM , Zoghbi W , Little S , Shah D , Ben-Zekry Z , Earle N et al. One hundred percent reparability of degenerative mitral regurgitation: intermediate-term results of a dynamic engineered approach . Ann Thorac Surg 2016 ; 101 : 576 – 84 . Google Scholar Crossref Search ADS PubMed WorldCat 19 Suri RM , Schaff HV , Dearani JA , Sundt TM , Daly RC , Mullany CJ et al. Recovery of left ventricular function after surgical correction of mitral regurgitation caused by leaflet prolapse . J Thorac Cardiovasc Surg 2009 ; 137 : 1071 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat 20 Pandis D , Grapsa J , Athanasiou T , Punjabi P , Nihoyannopoulos P. Left ventricular remodeling and mitral valve surgery: prospective study with real-time 3-dimensional echocardiography and speckle tracking . J Thorac Cardiovasc Surg 2011 ; 142 : 641 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat ABBREVIATIONS AF Atrial fibrillation CIs Confidence intervals LV Left ventricular MR Mitral regurgitation NYHA New York Heart Association POD Postoperative day STS Society of Thoracic Surgeons TOE Transoesophageal echocardiography TRACER Mitral TransApical NeoCordal Echo-Guided Repair © The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. 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Safety and performance of a novel transventricular beating heart mitral valve repair system: 1-year outcomes

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Oxford University Press
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© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
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1010-7940
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10.1093/ejcts/ezaa256
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Abstract

Abstract OBJECTIVES Open in new tabDownload slide Open in new tabDownload slide The objective of this study was to evaluate the safety and performance of a novel, beating heart procedure that enables echocardiographic-guided beating heart implantation of expanded polytetrafluoroethylene (ePTFE) artificial cords on the posterior mitral leaflet of patients with degenerative mitral regurgitation. METHODS Two prospective multicentre studies enrolled 13 (first-in-human) and 52 subjects, respectively. Patients were treated with the HARPOON beating heart mitral valve repair system. The primary (30-day) end point was successful implantation of cord(s) with mitral regurgitation reduction to ≤moderate. An independent core laboratory analysed echocardiograms. RESULTS Of 65 patients enrolled, 62 (95%) achieved technical success, 2 patients required conversion to open surgery and 1 procedure was terminated. The primary end point was met in 59/65 (91%) patients. Among the 62 treated patients, the mean procedural time was 2.1 ± 0.5 h. Through discharge, there were no deaths, strokes or renal failure events. At 1 year, 2 of the 62 patients died (3%) and 8 (13%) others required reoperations. At 1 year, 98% of the patients with HARPOON cords were in New York Heart Association class I or II, and mitral regurgitation was none/trace in 52% (n = 27), mild in 23% (n = 12), moderate in 23% (n = 12) and severe in 2% (n = 1). Favourable cardiac remodelling outcomes at 1 year included decreased end-diastolic left ventricular volume (153 ± 41 to 119 ± 28 ml) and diameter (53 ± 5 to 47 ± 6 mm), and the mean transmitral gradient was 1.4 ± 0.7 mmHg. CONCLUSIONS This initial clinical experience with the HARPOON beating heart mitral valve repair system demonstrates encouraging early safety and performance. Clinical registration numbers NCT02432196 and NCT02768870. Echocardiography, Mitral regurgitation, Surgery, Valvuloplasty INTRODUCTION Degenerative mitral valve disease with chordal elongation and/or rupture and leaflet prolapse is the most common indication for mitral valve operation. Outcomes with conventional surgical treatment are limited by variable repair rates owing to differences in individual centre volumes and the relatively high volumes required for a given surgeon to achieve proficiency in mitral valve repair [1–3]. Although excellent durability of conventional surgical mitral valve repair is reported in multiple single-centre retrospective series [4, 5], there are few core laboratory-adjudicated series providing late mitral regurgitation (MR) recurrence rates, and several retrospectives [6] and prospective core lab-adjudicated surgical series have reported significant rates of early recurrent MR [7]. Conventional mitral valve surgery is invasive and associated with morbidity related to cardiopulmonary bypass, cardioplegic cardiac arrest, aortic cross-clamping and cannulation, atriotomy and current incisions. An alternative and less-invasive procedure to artificial cordal mitral valve repair was first introduced clinically in 2009 by Speziali et al.[8], and stable 5-year results have been reported using this approach [9]. The HARPOON beating heart mitral valve repair system (HARPOON System; Edwards Lifesciences, Irvine, CA, USA) was developed to enable surgeons to anchor expanded polytetrafluoroethylene (ePTFE) cords transventricularly on prolapsed mitral valve leaflets on the beating heart under transoesophageal echocardiographic image guidance. Implanted cord length is titrated on the beating heart to optimize the repair [10, 11]. We report 1-year outcomes of all patients treated with the HARPOON System to date. MATERIALS AND METHODS This study reports procedural and 1-year outcomes of all patients that have been implanted with artificial ePTFE cords using the HARPOON System. This includes 13 patients enrolled in 2 centres in the prospective early feasibility study between February 2015 and February 2016 [11], and 52 subsequent patients enrolled in the TRACER (Mitral TransApical NeoCordal Echo-Guided Repair) trial, a prospective, non-randomized multicentre study performed at 6 European centres between March 2016 and November 2017. The study protocol was approved by the responsible national authority of each country and the ethics committee at each institution. All participating patients provided informed consent. Serious adverse events were site-reported and adjudicated by an independent clinical events committee. The authors had full access to the data and are responsible for the completeness and accuracy of the reported data and analyses. Results through 2 April 2019 are reported here. Study patients Patients with severe degenerative MR as a result of isolated posterior leaflet prolapse were considered for enrollment. Anatomic and clinical screening for enrollment was determined by a central eligibility committee that consisted of an experienced mitral valve surgeon (J.S.G.) and echocardiographer (M.N.D.A.). The primary anatomic inclusion criterion focused on the tissue: gap ratio, defined as the ratio of the height/length of the prolapsing segment of the posterior leaflet to the gap between the coaptation surface of the anterior leaflet and the hinge point of the base of the posterior leaflet (measured at peak systole; Fig. 1). Figure 1: Open in new tabDownload slide Tissue-to-gap ratio. Figure 1: Open in new tabDownload slide Tissue-to-gap ratio. In general, patients with a tissue: gap ratio of 1.5:1 or more were considered to have adequate posterior leaflet tissue to allow sufficient coaptation and effective abrogation of MR after mitral valve repair with the HARPOON System. During screening examination, centres were encouraged to perform ‘pan-through’ studies in the four-chamber and long-axis transoesophageal echocardiographic views, and the smallest measured tissue: gap ratio was used as a key criterion for eligibility. Centres were also encouraged to provide full-volume 3-dimensional transoesophageal echocardiography (TOE) data, which was imported into TomTec (TomTec imaging systems, TomTec USA, Chicago, IL, USA) for further analyses and preoperative target planning. The use of the TomTec system allowed the ‘on-axis’ determination of the tissue: gap ratio. Exclusion criteria included anterior leaflet prolapse (defined as the excursion of the free edge of the anterior leaflet above the plane of the annulus during peak systole), severe mitral annular calcification, the presence of multiple or complex colour Doppler jets and significant tricuspid or aortic valvular disease. Additional exclusion criteria included functional MR, a Society of Thoracic Surgeons (STS) predicted risk of mortality of >8% (for repair), severe pulmonary hypertension (>70 mmHg) or severe left ventricular (LV) dysfunction. Full inclusion and exclusion criteria for both trials are available at: https://clinicaltrials.gov/ct2/show/NCT02432196 (early feasibility study) and at https://clinicaltrials.gov/ct2/show/NCT02768870 (TRACER). All patients had class I or IIa indications for operative intervention [12]. The HARPOON beating heart mitral valve repair system The HARPOON System includes a dedicated haemostatic introducer and a delivery system. The 12-Fr (inner diameter) introducer has a haemostatic valve that allows bloodless insertion and withdrawal of multiple delivery systems during the procedure. The delivery system is a single-use, preloaded 9-Fr (3 mm) external diameter rigid shafted instrument that has an atraumatic end effector at the distal end designed to stabilize the device on the underside of the mitral leaflet at the targeted implantation site. Once the desired location is ascertained using TOE and the leaflet is stabilized by the end effector, the surgeon actuates the device and extends a 21-gauge needle with a prewrapped ePTFE double-helical knot (50 winds) across the leaflet. The needle is withdrawn, and the knot is automatically formed, anchoring the ePTFE cordal pair to the leaflet. The procedure The HARPOON procedure has been previously described [10, 11]. In brief, the procedure is performed under general anaesthesia with a single lumen endotracheal tube. Crucial for procedural success is teamwork between the transoesophageal echocardiographer and the surgeon. A large monitor positioned directly in front of the surgeon (on the patient’s right side) is used to display the echocardiographic images and facilitates effective HARPOON procedures. Transthoracic surface echocardiography is helpful to identify the optimal incision location, most frequently the (left) 5th intercostal space. The desired ventricular access point is 2–4 cm basal from the true apex of the heart and between the left anterior descending coronary artery and the diagonal branches. If possible, a non-rib-spreading incision is performed, and visualization is enhanced with the use of a soft tissue retractor. The pericardium is opened, and the desired entrance site is confirmed on TOE imaging with finger indentation of the ventricular wall. Two pairs of pledgeted 3–0 monofilament horizontal mattress sutures are placed, and the introducer is inserted under TOE guidance using a 0.035″ guidewire. Intravenous heparin is administered before introducer insertion and activated clotting time of ≥350 s is maintained throughout the procedure. The delivery system is inserted through the introducer and directed using echocardiographic guidance to the underside of the prolapsed leaflet segment, taking care to avoid traversing the native chordae tendineae supporting the anterior leaflet. Optimal imaging includes simultaneous (xPlane) bicommissural and long-axis views. Targeting goals include placement of ePTFE knots close to the free edge of the mitral valve leaflet and spaced 3–5 mm apart across the free edge of the prolapsed segment. Knots are placed sequentially from lateral to medial, and assessment of knot position is ascertained with 3-dimensional ‘surgeons view’ TOE imaging following the placement of each knot. A minimum of 3 cordal pairs/knots is recommended to distribute the load among the cordal pairs. A new delivery system is used for each knot, and after implantation, the 2 ePTFE strands associated with each knot are exteriorized through the introducer. Once knot implantation is complete, the introducer is removed, and the purse-strings tied. All ePTFE strands are then passed separately through a large stiff felt pledget, and then through a tourniquet. The length of the implanted ePTFE cords is then titrated under echo guidance to achieve optimal coaptation. Finally, the cords are fixed with a shodded clamp and each pair tied individually. Aspirin (325 mg) is administered postoperatively and daily thereafter. Primary performance and safety end points Technical success was defined as leaving the operating room with ≥1 ePTFE artificial cords in place. The primary performance end point was successful implantation of ≥1 ePTFE cord on the prolapsed leaflet with a reduction of MR to ≤ moderate after the procedure and after 30 days. Various postoperative safety end points were monitored over the observational period. Renal failure was defined as a new requirement for dialysis (receiving renal replacement therapy) or an increase in the creatinine level to more than 3× baseline. Echocardiographic analyses Preprocedural, intraprocedural and postoperative echocardiograms were performed by the sites and securely transmitted to an independent core laboratory (Massachusetts General Hospital, Boston, MA, USA) for anonymized and standardized evaluation. MR severity was graded as none/trace, mild, moderate or severe using integrative criteria specified by the American Society of Echocardiography and European Society of Cardiology [13]. LV dimensions and volumes and left atrial volumes (biplane area length) were measured according to established guidelines [14]. The mitral annular area was calculated as π × (one-half of the mitral annular dimension in the parasternal long-axis view) × (one-half of the mitral annular dimension in the apical two-chamber view) using the elliptical assumption for the mitral annulus [15]. Follow-up Enrolled patients were scheduled for treatment with the HARPOON System following baseline clinical and echocardiographic evaluation, then underwent clinical and echocardiographic evaluation at discharge, 30 days, 6 months and 1 year. Clinical evaluation at baseline and 1 year included New York Heart Association (NYHA) heart failure classification. Additional follow-up results are not yet complete. Continuous variables are represented as mean ± standard deviation, and sometimes with (minimum–maximum). Comparisons of echocardiographic measures between baseline and 1 year were made with paired t-tests, with significant differences declared if P-value <0.05. Exact 95% confidence intervals (CIs) are reported. RESULTS Patient characteristics From February 2015 through November 2017, 65 patients were enrolled in the early feasibility study and TRACER trials at 6 centres in 3 countries. All eligible implanted patients completed a 1-year clinical and/or echocardiographic follow-up as of the 2 April 2019 data lock for this report. The patient age of the implanted cohort was 61 ± 12 years, and the mean STS and EuroSCORE II operative risk scores were 0.6 ± 0.6% and 1.2 ± 1.1%, respectively. Study population characteristics are shown in Table 1. Table 1: Baseline characteristics Factor . . Age (years) 61.0 ± 12.2 (39–89) Female gender 24% (15/62) NYHA class  I 41% (24/59)  II 41% (24/59)  III 19% (11/59)  IV 0% (0/59) STS risk of mortality 0.6±0.6% (0.2–3.5) EuroSCORE II 1.2±1.1% (0.5–5.1) LVEF 69.2±5.8% (48–81) Factor . . Age (years) 61.0 ± 12.2 (39–89) Female gender 24% (15/62) NYHA class  I 41% (24/59)  II 41% (24/59)  III 19% (11/59)  IV 0% (0/59) STS risk of mortality 0.6±0.6% (0.2–3.5) EuroSCORE II 1.2±1.1% (0.5–5.1) LVEF 69.2±5.8% (48–81) LVEF: left ventricular ejection fraction; NYHA: New York Heart Association; STS: Society of Thoracic Surgeons. Open in new tab Table 1: Baseline characteristics Factor . . Age (years) 61.0 ± 12.2 (39–89) Female gender 24% (15/62) NYHA class  I 41% (24/59)  II 41% (24/59)  III 19% (11/59)  IV 0% (0/59) STS risk of mortality 0.6±0.6% (0.2–3.5) EuroSCORE II 1.2±1.1% (0.5–5.1) LVEF 69.2±5.8% (48–81) Factor . . Age (years) 61.0 ± 12.2 (39–89) Female gender 24% (15/62) NYHA class  I 41% (24/59)  II 41% (24/59)  III 19% (11/59)  IV 0% (0/59) STS risk of mortality 0.6±0.6% (0.2–3.5) EuroSCORE II 1.2±1.1% (0.5–5.1) LVEF 69.2±5.8% (48–81) LVEF: left ventricular ejection fraction; NYHA: New York Heart Association; STS: Society of Thoracic Surgeons. Open in new tab Primary performance end point Technical success was achieved in 62 of the 65 enrolled patients (95%). In 1 of the 3 patients that did not achieve technical success, the HARPOON System introducer was placed and intracavitary LV pressures of 260 mmHg were measured, in association with LV outflow tract obstruction. It was decided to terminate the procedure; the introducer was removed, and the patient subsequently consented for interval conventional myectomy and mitral valve repair. Two patients required intraoperative conversion to conventional mitral valve repair, as their HARPOON ePTFE knots were deployed in the prolapsed leaflet but not in the intended locations due to suboptimal echocardiographic equipment and poor visualization. The knots were not associated with leaflet damage and in both cases, conventional mitral valve repair (using ePTFE cords) was successful, with none/trace MR recorded at hospital discharge. Among the 62 patients achieving technical success, an average of 4.1 ± 1.0 (1–7) pairs of ePTFE cords was implanted and the MR grade at discharge of the 58 patients with evaluable echocardiograms was none/trace in 74% (43/58), mild in 21% (12/58), moderate in 3% (2/58) and severe in 2% (1/58). The primary performance end point was met in 59 of the 65 patients enrolled (91%; 95% CI 81–97%). MR severity at 30 days among 60 patients with evaluable echocardiograms was none/trace in 62% (37/60), mild in 23% (14/60), moderate in 13% (8/60) and severe in 2% (1/60). The average procedure time was 126 ± 36 (72–222) min. The amount of time the introducer was in the LV averaged 42 ± 18 (18–126) min. The average intraoperative blood loss was 272 ± 182 (50–949) ml. Early safety end points The mean postoperative hospital length of stay was 6.0 ± 2.1 (3–15) days. Through discharge, there were no events of death, stroke, transient ischaemic attack, renal failure, reintubation (measured in 49 TRACER patients) or blood transfusions. One patient died on postoperative day (POD) 13. After effective implantation of 4 cords and discharge on POD 7 [on oral anticoagulation for atrial fibrillation (AF)], an echocardiogram on POD 9 demonstrated normal LV and mitral valve function, no MR, and trace pericardial effusion. On POD 13, progressive hypotension was followed by an asystolic arrest and resuscitation was unsuccessful. An autopsy showed that the artificial cords were intact on both the mitral leaflet and the ventricular surface. There was 2 l of blood in the left chest with no blood in the pericardium. One patient required reoperation on POD 27 as a result of severe MR caused by methicillin-sensitive Staphylococcus aureus (MSSA) infective endocarditis. This patient had an unrecognized baseline dental infection and elevated white blood cell count. At reoperation, vegetation and perforation of the posterior leaflet were found; a mechanical valve was implanted, and the patient was discharged in good condition. One patient was readmitted with angina and diagnosed with myocardial infarction on POD 5. The patient was discharged the next day, and subsequent echocardiograms demonstrated normal ventricular function; the patient completed a 1-year follow-up. New postoperative AF was identified in 18% [9] of the 50 patients without baseline AF, which resolved in 8 of these patients at 30 days. Among 12 patients with preoperative AF, 58% (7/12) were in normal sinus rhythm at 30 days and 82% (9/11) at 1 year. One-year safety end points Through 1 year of follow-up, 1 additional patient died, 1 patient experienced a stroke and no patients experienced renal failure or endocarditis. The patient's death occurred at home on POD 214 from unknown causes; an autopsy was not authorized. The stroke occurred on POD 349, was non-disabling, and was adjudicated as not related to either the study device or the procedure. There were 8/62 (13%) reoperations in the first year (0.87 freedom from event rate, 95% CI 0.78–0.95). In addition to the previously described patient with early infective endocarditis, 1 patient underwent a recurrent operation (POD 279) for reprolapse (the ventricular free wall below the pledget at the entrance site had invaginated, allowing the posterior MV leaflet to prolapse). On the reanalysis of the baseline imaging, this patient had a small tissue: gap ratio and a very large absolute gap between the tip of the anterior leaflet and the base of the posterior leaflet. One patient underwent reoperation at 8 months and was found to have a ruptured ePTFE cord within a few millimetres of the leaflet. This patient was the sole subject that had only one ePTFE cordal pair inserted at the original procedure. Three patients had recurrent severe MR on the basis of ruptured ePTFE cords, at 211, 253 and 352 days after the operation. In 1 case a non-shodded sharp clamp was used to stabilize the cords during knot tying on the epicardial pledget, and in the other 2 all cords were ruptured within the myocardium, a few millimetres from the pledget. In the remaining 2 patients, causes of recurrent MR were multifactorial and included unrecognized and untreated anterior leaflet prolapse, native anterior chordal rupture, an untied ePTFE knot at the apex and poor imaging and targeting. At reoperation, the mitral valve was re-repaired in 6/8 cases (75%), and was replaced in 2 cases (one due to extensive leaflet destruction from endocarditis, and the other because of poor visualization). In all 8 reoperative cases, the mitral leaflets were intact and the ePTFE knot anchors well-incorporated into the leaflet tissue. All patients left the hospital with no MR and in good condition. Mitral regurgitation reduction and clinical status MR severity before the procedure and at discharge, 30 days, 6 months and 12 months is shown in Figs 2 and 3. At hospital discharge, 95% of patients had ≤mild MR. We observed a progression of MR between discharge and 30 days, with moderate MR in 13% of patients and severe MR in 2%. At 1 year, among all 52 patients alive and with HARPOON cord(s), MR was ≤mild in 75%, moderate in 23% and severe in 1 patient (2%). A representative follow-up echocardiogram is included as a Video 1. Figure 2: Open in new tabDownload slide Severity of mitral regurgitation (including reoperations). Figure 2: Open in new tabDownload slide Severity of mitral regurgitation (including reoperations). Figure 3: Open in new tabDownload slide Severity of mitral regurgitation (exclusive of reoperations). Figure 3: Open in new tabDownload slide Severity of mitral regurgitation (exclusive of reoperations). NYHA functional status from baseline to 1 year is outlined in Fig. 4; 98% (47/48) of patients with HARPOON cord(s) were in NYHA functional class I or II at 1 year. Figure 4: Open in new tabDownload slide NYHA class. NYHA: New York Heart Association. Figure 4: Open in new tabDownload slide NYHA class. NYHA: New York Heart Association. Video 1: Transthoracic apical 4-chamber view of a patient 30 months after HARPOON repair. Video 1: Transthoracic apical 4-chamber view of a patient 30 months after HARPOON repair. Close Echocardiographic variables and reverse remodelling We observed favourable reverse LV and left atrial remodelling from baseline to 1 year (Table 2). LV end-diastolic volume was decreased by 22% (P < 0.001) and LV end-diastolic diameter was decreased by 11% (P < 0.001). Anterior-to-posterior mitral annular dimension was decreased by 11% (P < 0.001). The mean transmitral gradient was 1.3 ± 0.5 mmHg at 30 days (n = 51) and 1.4 ± 0.7 mmHg at 1 year (n = 47). Table 2: Cardiac remodelling . Baseline . Discharge . 30 days . 1 year . P-valuea . LVEDD (mm) 53 ± 5 49 ± 6 49 ± 5 47 ± 6 <0.001 LVEF (%) 69 ± 6 58 ± 8 61 ± 5 63 ± 6 <0.001 LVEDV (ml) 153 ± 41 129 ± 37 120 ± 28 119 ± 28 <0.001 MV annular anterior–posterior diameter (mm) 34 ± 5 32 ± 5 32 ± 5 31 ± 5 <0.001 Mean MV gradient (mmHg) NA 1.3 ± 0.6 1.3 ± 0.5 1.4 ± 0.7 NA . Baseline . Discharge . 30 days . 1 year . P-valuea . LVEDD (mm) 53 ± 5 49 ± 6 49 ± 5 47 ± 6 <0.001 LVEF (%) 69 ± 6 58 ± 8 61 ± 5 63 ± 6 <0.001 LVEDV (ml) 153 ± 41 129 ± 37 120 ± 28 119 ± 28 <0.001 MV annular anterior–posterior diameter (mm) 34 ± 5 32 ± 5 32 ± 5 31 ± 5 <0.001 Mean MV gradient (mmHg) NA 1.3 ± 0.6 1.3 ± 0.5 1.4 ± 0.7 NA a P-values: baseline versus 1 year. LVEDD: left ventricular end-diastolic diameter; LVEDV: left ventricular end-diastolic volume; LVEF: left ventricular ejection fraction; MV: mitral valve; NA: not applicable. Open in new tab Table 2: Cardiac remodelling . Baseline . Discharge . 30 days . 1 year . P-valuea . LVEDD (mm) 53 ± 5 49 ± 6 49 ± 5 47 ± 6 <0.001 LVEF (%) 69 ± 6 58 ± 8 61 ± 5 63 ± 6 <0.001 LVEDV (ml) 153 ± 41 129 ± 37 120 ± 28 119 ± 28 <0.001 MV annular anterior–posterior diameter (mm) 34 ± 5 32 ± 5 32 ± 5 31 ± 5 <0.001 Mean MV gradient (mmHg) NA 1.3 ± 0.6 1.3 ± 0.5 1.4 ± 0.7 NA . Baseline . Discharge . 30 days . 1 year . P-valuea . LVEDD (mm) 53 ± 5 49 ± 6 49 ± 5 47 ± 6 <0.001 LVEF (%) 69 ± 6 58 ± 8 61 ± 5 63 ± 6 <0.001 LVEDV (ml) 153 ± 41 129 ± 37 120 ± 28 119 ± 28 <0.001 MV annular anterior–posterior diameter (mm) 34 ± 5 32 ± 5 32 ± 5 31 ± 5 <0.001 Mean MV gradient (mmHg) NA 1.3 ± 0.6 1.3 ± 0.5 1.4 ± 0.7 NA a P-values: baseline versus 1 year. LVEDD: left ventricular end-diastolic diameter; LVEDV: left ventricular end-diastolic volume; LVEF: left ventricular ejection fraction; MV: mitral valve; NA: not applicable. Open in new tab DISCUSSION This initial global clinical experience with the HARPOON System demonstrated efficient, safe, and predictable initial procedural MR reduction and favourable cardiac remodelling and patient functional status despite a degree of recurrent MR and 1-year reoperation rates. Treatment with the HARPOON System was very safe in-hospital, with no mortality and no patients requiring reintubation or blood transfusion. No patient required a mitral valve replacement at the index procedure. We found that the procedure was simple and straightforward to teach and learn, and reproducible across 6 diverse centres and teams. Nearly all patients left the operating room with insignificant MR, and we were able to accomplish the procedure in many cases with a non-rib spreading approach. With a mean total procedure time of just over 2 h, the procedure was efficient compared to the nearly 4 h required for conventional mitral valve repair [16]. A key advantage of this approach is that artificial cordal length may be titrated on the loaded, beating heart, something that is not possible on an arrested heart during conventional on-pump operations. The knot anchors are low profile and leave a minimal footprint on the mitral leaflets, which preserve the option for future mitral valve repair. The repair rate for degenerative disease in North America based on the STS Adult Cardiac Surgery Database is 80% [2] and in the New York state database 67% [1]. In contrast, this experience demonstrates that mitral valve repair was achieved acutely in all anatomically suitable patients that had ePTFE cords successfully implanted (95%, 62/65) with the HARPOON System. At 1-year follow-up, 75% of patients in this experience had ≤mild MR and 13% required reoperation. These outcomes are not as favourable as some retrospective institutionally reported outcomes from centres of excellence, which report 5-year freedom from recurrent MR of 90% [5, 17, 18]. By contrast, other retrospective single-centres and 1 core laboratory-adjudicated multicentre report significant rates of early MR recurrence and reoperation. In 1 large series of patients (n = 2575) with degenerative mitral regurgitation (DMR) isolated posterior leaflet repair, 11% of patients developed ≥moderate MR 2 weeks after operation [6]. Similarly, the surgical arm (n = 80) of EVEREST II reported 24% of patients with moderate or greater MR at 1 year [7]. Two predominant factors contributed to late recurrent moderate and severe MR. These included ePTFE cordal rupture and reprolapse. Posterior leaflet reprolapse was most commonly observed between discharge and 30 days. Possible mechanisms underlying this phenomenon include LV remodelling and/or migration of cords through the myocardium with associated relative elongation of the cords. While we observed immediate intraoperative resolution of MR and remodelling upon tensioning of implanted ePTFE cords, there was minimal remodelling between discharge and 30 days. An alternative hypothesis is that the cords may transit the myocardium intra-ventricularly perpendicular to the LV wall and then are angled sharply towards the mitral valve where they emerge from the myocardium; cord tension may lead to cord migration through the relatively soft myocardium in a direction that decreases the acute angle at the endocardium and results in relative elongation of the cords. As this phenomenon of early relative cordal elongation was identified, surgeons felt the need to over-tension the posterior leaflet in anticipation of relative reprolapse in the first weeks after implantation. We have not observed substantial rates of reprolapse after the first month or two. Further study is required to elucidate the mechanism(s) and strategies to prevent this phenomenon. Cordal rupture was responsible for severe recurrent MR and reoperation in 4 patients. In 1 case, only a single cord during the HARPOON procedure was implanted and rupture was likely related to excess stress on this cord. In another case, a non-shodded clamp was used to stabilize the ePTFE cords on the myocardial pledget and is thought to have precipitated cordal rupture adjacent to the pledget. In the other 2 cases, all 4 and 6 cords were ruptured within the myocardium, a few millimetres from the pledget. Additional contributing factors to recurrent MR included native anterior chordal rupture, imaging and targeting difficulties and 1 cord becoming untied at the epicardial pledget. As our experience with the HARPOON procedure progressed, our patient selection and procedural technique undoubtedly improved. Key learnings included that 1 vendor’s TOE system had robust ultrasound artifact suppression which compromised visualization of the HARPOON device tip. This was associated with early conversions as well as suboptimal ePTFE knot targeting on leaflets and recurrent MR. We refined our targeting and now require ≥3 knots in all patients. The HARPOON procedure achieved favourable LV remodelling that was sustained through 1 year. This included stable reduction of the mitral annular anterior–posterior dimension, negligible transmitral gradients and LV volume and function improvements that are similar to values observed after conventional surgical mitral valve repair [19, 20]. Despite a significant rate of reoperations in this initial clinical experience, overall patient survival at 1 year among patients undergoing the HARPOON procedure was 97%, and among surviving patients, 98% were in NYHA class I or II, and 97% (58/60) had functioning mitral valve repairs. CONCLUSIONS In conclusion, this initial mitral valve repair experience with the HARPOON System was associated with an excellent safety profile, a high rate of technical procedural success, and efficacious core laboratory-confirmed MR reduction at hospital discharge. We observed modest recurrent MR which was associated with a variety of patient selection and procedural execution issues. This initial experience highlights the potential of the HARPOON beating heart mitral valve repair system as a minimally invasive procedure for the surgical treatment of severe degenerative MR, and we are optimistic that these early learnings will inform future use of this system and drive improved results. Studies of greater duration and with a broader set of operators will be required to determine the long-term durability of HARPOON beating heart mitral valve repair. Acknowledgement The authors acknowledge the contributions of Neil Moat, MBBS. Funding This work was supported by the HARPOON Medical and Edwards Lifesciences. Conflict of interest: James S. Gammie is a consultant to Edwards Lifesciences, is the founder of Protaryx Medical and was the founder of HARPOON Medical. Michael N. D’Ambra, Andrzej Gackowski, Piotr Szymanski, Steve Livesey, Alison Duncan, Rashmi Yadav, Paolo Denti and Krzysztof Bartus are consultants to Edwards Lifesciences. Michele DeBonis is a consultant for Abbott Laboratories and Medtronic. Rashmi Yadav is a member of Medtronic Independent Physician Quality Panel. All other authors declared no conflict of interest. Author contributions James S. Gammie: Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Software; Supervision; Validation; Visualization; Writing—original draft; Writing—review & editing. Krzysztof Bartus: Investigation; Writing—review & editing. Andrzej Gackowski: Investigation; Writing—review & editing. Piotr Szymanski: Investigation; Writing—review & editing. Agata Bilewska: Investigation; Writing—review & editing. Mariusz Kusmierczyk: Investigation; Writing—review & editing. Boguslaw Kapelak: Investigation; Writing—review & editing. Jolanta Rzucidlo-Resil: Investigation; Writing—review & editing. Alison Duncan: Investigation; Writing—review & editing. Rashmi Yadav: Investigation; Writing—review & editing. Steve Livesey: Investigation; Writing—review & editing. Paul Diprose: Investigation; Writing—review & editing. Gino Gerosa: Investigation; Writing—review & editing. Augusto D’Onofrio: Investigation; Writing—review & editing. Demetrio Pittarello: Investigation; Writing—review & editing. Paolo Denti: Investigation; Writing—review & editing. Giovanni La Canna: Investigation; Writing—review & editing. Michele De Bonis: Investigation; Writing—review & editing. Ottavio Alfieri: Investigation; Writing—review & editing. Judy Hung: Investigation; Writing—review & editing. 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European Journal of Cardio-Thoracic Surgery – Oxford University Press

Published: Jan 4, 2021

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