Abstract: Aims. To compare early device success, procedural success, and 30-day safety endpoint according to the new Mitral Valve Academic Research Consortium criteria (MVARC) in severe primary and secondary mitral regurgitation (MR) patients. Methods and Results. A total of 210 patients were enrolled; 105 patients with primary MR were compared with 105 patients with secondary MR. All patients were highly symptomatic (New York Heart Association III/IV 79.0% vs 87.6%). Decision for MitraClip therapy was done by the heart team. Patients were on optimal medical heart failure therapy. Preprocedural MR grade was 3.4 ± 0.5 in secondary MR vs 3.7 ± 0.4 in primary MR (P<.001). Device success according to MVARC was high in both groups (93.3% in secondary MR vs 94.3% in primary MR), treated with 1.4 ± 0.6 vs 1.3 ± 0.5 MitraClips (P=.14). Reduction of New York Heart Association class from baseline to 30-day follow-up was 1.7 ± 1.1 in secondary MR vs 2.2 ± 1.2 in primary MR (P<.01). Rate of MVARC minor vascular complications was low. Thirty-day safety endpoint according to MVARC criteria was low in both groups (4.8% in secondary MR vs 5.7% in primary MR (P=non-significant). Conclusion. Percutaneous mitral valve repair using the MitraClip device is safe and effective in patients with primary and secondary MR, with a high early device success rate and low 30-day safety endpoint according to the MVARC criteria.
J INVASIVE CARDIOL 2017;29(4):145-150.
Key words: mitral valve, regurgitation, percutaneous repair, MVARC
Surgical mitral valve repair is the preferred treatment option for mitral regurgitation (MR). However in patients at high surgical risk, it is associated with an increased perioperative mortality.1,2 The EVEREST (Endovascular Valve Edge-to-Edge REpair Study) trials3-5 demonstrated safety and efficacy of percutaneous mitral valve repair with the MitraClip device (Abbott Vascular) in patients who were good surgical candidates. Although achieving less reduction in MR compared with surgical repair, data on clinical outcomes were superior, demonstrating a lower rate of major cardiovascular events compared with surgical approach according to the study definitions. Long-term follow-up in EVEREST II3-5 demonstrated greater benefit compared with surgery in patients with secondary MR vs primary MR in this very early MitraClip experience.5-7 Standardized endpoint definitions are essential to ensure comparability between trials. Recently, corresponding to aortic valve therapies, the Mitral Valve Academic Research Consortium (MVARC) criteria8,9 have been defined. This is the first study comparing the outcome of MitraClip device implantation in primary MR vs secondary MR in a high-volume center implementing the standardized MVARC criteria.8,9
We prospectively enrolled 210 patients with severe symptomatic primary MR (n = 105) or secondary MR (n = 105), defined as MR grade ≥3+. Risk evaluation was based on surgical risk as defined by the Society of Thoracic Surgeons (STS) score, frailty, major organ system compromise, and procedure-related impediment. Percutaneous repair was decided by a heart team including cardiologists and heart surgeons. All patients underwent diagnostic evaluation with routine laboratory testing, medical history with current medication, New York Heart Association (NYHA) classification, electrocardiography (ECG), transthoracic echocardiogram (TTE), transesophageal echocardiography (TEE), and right and left heart catheterization. Echocardiography was done to evaluate the left atrium, left ventricular dimensions and function, MR grade and etiology, and to exclude thrombus in the heart chambers with special focus on the left atrial appendage. TEE was performed with a multiplane, phased-array 4-7 MHz TEE probe with a CX50 (Philips Medical Systems). Etiology and MR grade3 were assessed by TEE and TTE as previously described.10,11 An effective regurgitant orifice (ERO) was considered severe if >0.2 cm² in secondary MR and >0.4 cm² in primary MR. Patients with intracardial thrombus were not eligible for the procedure. Patients with impairment of leaflet coaptation due to left ventricular dilation, restricted leaflets, or annular dilation were considered to have secondary MR. Patients with mitral valve leaflet prolapse, flail leaflet, clefts, chordal and papillary muscle rupture were defined to have primary MR. The procedure was performed under general anesthesia in the catheterization laboratory, as described elsewhere.12-14 Femoral venous access closure was done with a figure-of-eight suture for 6 hours, followed by a compression bandage for 12 hours. Patients were on oral anticoagulation plus acetylsalicylic acid for 4 weeks post procedure or continuously anticoagulated when in atrial fibrillation. Written informed consent was obtained from all patients. The study was ethically approved by the ethics committee of the University of Ulm. Guidance and position of the device were controlled by fluoroscopy and by periprocedural TEE. Control TTE was performed before discharge and at 30-day follow-up. All patients received a postprocedural Holter-ECG and were monitored for 48 hours to document heart rhythm including new onset of atrial fibrillation. Technical success measured immediately post procedure was defined as absence of procedural mortality, successful delivery of the device, correct positioning, and freedom from emergency surgery or reintervention. Periprocedural complications, in-hospital clinical outcomes, and 30-day clinical outcomes were assessed. Bleeding events were defined according to the MVARC primary bleeding scale. Device success according to MVARC at 30 days was defined as the absence of procedural mortality or stroke, proper placement and positioning of the device, freedom from unplanned surgical or interventional procedure, continued safety and performance of the device without functional or structural failure, and reduction to MR ≤2+ without mitral stenosis.8,9 Procedural success was defined as device success and absence of death, stroke, life-threatening bleeding, and major vascular and cardiac complications. Patients were followed to assess their clinical history at scheduled outpatient controls. Safety endpoint at 30 days was defined according to MVARC criteria,8,9 including all-cause death, disabling and non-disabling stroke, and stage 2 and 3 acute kidney injury.
Statistical analysis. Categorical parameters are presented as counts and percentages and were compared by Pearson’s Chi-square test. Continuous variables are presented as mean ± standard deviation. Groups were compared with the two-sample t-test or Mann-Whitney U-test. The primary outcome measure was device success according to MVARC criteria and the secondary outcome measure was the safety endpoint at 30-day follow-up. A P-value <.05 was considered to be statistically significant. Statistical analysis was performed using Statistica release 7.1 (StatSoft).
Surgical risk was high as defined by STS risk score, frailty, major organ compromise, and procedure-related impediment. Mean age was significantly higher in primary MR patients vs secondary MR patients (79.3 ± 7.1 years vs 73.6 ± 10.3 years; P<.001). NYHA class III/IV was present in 87.6% vs 79% of patients, respectively. There were no significant differences in comorbidities except a higher rate of previous myocardial infarction in secondary vs primary MR (Table 1). Patients were on optimal medical heart failure therapy according to present guidelines. There was no significant difference in the presence of atrial fibrillation with 67.6% in secondary MR and 70.4% in primary MR patients. Echocardiography revealed significantly higher left ventricular end-systolic and end-diastolic diameters as well as a significantly lower left ventricular ejection fraction in functional MR patients (Table 2). Mean MR grade at baseline was higher in patients with primary MR (3.7 ± 0.4) vs patients with secondary MR (3.4 ± 0.5; P<.001).
Procedural outcomes. Technical success was similar in both groups, with 98.1% in primary MR and 98.1% in secondary MR (Table 3). There were 2 cases in each group where final clip placement was not possible. In 1 case in each group, the clip had to be retrieved because of severe mitral stenosis after placement in multiple locations. In 1 patient with primary MR, there was thrombus in the inferior vena cava. In another secondary MR patient, leaflet coaptation was not possible due to massive annular dilation. The number of implanted MitraClips was similar, with 1.4 ± 0.6 in the secondary MR group and 1.3 ± 0.5 in the primary MR group (P=.14). The rate of single clip placement was higher in primary MR patients. MR grade reduction to MR ≤2+ was achieved in 95.2% in secondary MR and 96.2% in primary MR. Mean pressure gradient (MPG) post procedure was significantly higher in degenerative valves (3.9 ± 1.4 mm Hg vs 3.1 ± 1.1 mm Hg; P<.01). There was 1 postprocedural partial clip detachment in a patient with primary MR, which was stabilized in a second procedure by the implantation of 2 additional clips. Overall periprocedural complication rate in this high-risk population was low and did not differ between patients with primary MR or secondary MR (Table 3). There was no clip embolization, pericardial effusion, conversion to surgery, or periprocedural death. No major bleedings or major vascular complications as defined by MVARC bleeding scale were noted. The rate of minor vascular complications was low (Table 3). There were mainly hematomas, 2 aneurysms, 1 arteriovenous fistula, and 1 need for surgical closure of the access site, none meeting the definition of major vascular complication criteria.
Clinical outcomes in-hospital and at 30-day clinical follow-up. In-hospital clinical outcomes were similar between both groups (Table 4). Device success at 30-day follow-up was high and similar, with 93.3% in secondary MR and 94.3% in primary MR. Procedural success was 87.8% in primary MR patients and 88.6% in secondary MR patients. Thirty-day safety endpoint according to MVARC criteria was low in secondary MR patients as well as in primary MR patients (4.8% vs 5.7%). There was 1 non-procedure related stroke (0.5%) after 4 days in an anticoagulated atrial fibrillation patient with secondary MR. There was no periprocedural death. Three patients (2.9%) with secondary MR and 4 patients (3.8%) with primary MR died within 30 days of follow-up. In the secondary MR group, 1 patient died in septic shock and 2 patients died in end-stage heart failure, with left ventricular ejection fractions of 18% and 10%. In the primary MR group, 1 patient died in urosepsis, 1 patient had a pulmonary embolism despite oral anticoagulation, and 1 patient died after aspiration in hypoxic respiratory failure and in renal failure denying hemofiltration. Clinical performance status according to NYHA class significantly improved in both groups (Figure 1). Mean NYHA class was 1.4 ± 1.1 in functional MR vs 1.1 ± 1.0 in primary MR (P=.01), with significantly higher reduction from baseline in primary MR patients (P<.01), who were actually more symptomatic at baseline (Figure 1).
We compared the outcomes of percutaneous mitral valve repair with the MitraClip device in 210 patients with primary MR vs secondary (severe) MR according to MVARC criteria. We were able to demonstrate that device success was high and the safety endpoint at 30-day follow-up was low according to MVARC, with no difference between patients with primary MR vs secondary MR.
The multicenter, randomized, EVEREST II trial15,16 included 184 patients treated with MitraClip. In this trial, patients with secondary MR derived greater benefit from the MitraClip procedure vs patients with primary MR. Data comparing outcomes in patients with primary MR vs secondary MR are limited since predominantly secondary MR patients were included in most studies. The multicenter European GRASP17 registry included 117 patients, with primary MR present in 28 patients (24%). In the GRASP registry, number of clips needed in primary MR patients was higher than in secondary MR patients, with no difference in the primary efficacy endpoint. In our experience including 210 patients, the number of clips in the primary MR and secondary MR groups was similar. In a large, single-center study by Braun et al,18 a total of 119 patients were studied with predominantly primary MR (n = 72; 61%). There was no difference in primary success, improvement in functional class, or event-free survival between groups. Reduction of MR grade to <2+ was more frequent (87.1%) in secondary MR patients than in primary MR patients (83.3%), with a numerically higher MR reduction in secondary MR. The ACCESS-EU trial,19 which comprised 576 patients, had only 20.6% with primary MR. Reduction to MR <2+ at discharge was higher in secondary MR patients and procedure time was longer when primary MR was treated. The MitraSwiss registry20 reported data of 74 patients undergoing MitraClip implantation in Switzerland including the first experiences. Primary MR was treated in 28 patients (38%). MR reduction to <2+ was more frequent in primary MR vs secondary MR patients. More than 1 clip was implanted in 43% of primary MR patients and 37% of secondary MR patients.
The Transcatheter Valve Treatment Sentinel Pilot registry21 included 628 patients in 25 centers, of which 176 patients (28%) had primary MR. Procedural success, MR reduction, and safety were similar in primary and secondary MR groups. The MitraClip Asian Pacific registry22 included 163 patients at eight sites in 5 countries, of which 75 patients (46%) had primary MR. Efficacy and safety were similar between groups, with an equal improvement in NYHA functional class. In this multicenter registry, number of clips needed in primary MR to achieve MR reduction was higher compared with patients with secondary MR. Duration of procedure was longer and there were more unsuccessful cases in primary MR patients, including partial clip detachment and difficult grasping of leaflets. In our experience with a large number of patients treated in a single center, there was no difference in number of clips between primary and secondary MR patients. In addition, MVARC-defined outcomes including technical success, device success, procedural success, and 30-day safety endpoint were similar.
Our patients were older than in the GRASP registry or EVEREST II trial. Patients with primary MR were even more symptomatic and had significantly higher grade of MR at baseline (3.7 ± 0.4 vs 3.4 ± 0.5; P<.001). Interestingly, we could demonstrate a significantly higher NYHA class reduction in patients with primary MR vs secondary MR patients. More patients with primary MR were in NYHA class I at 30-day follow-up, yet they were more symptomatic at baseline. The lower NYHA class is paralleled by a significantly higher MR grade reduction from baseline in primary MR vs secondary MR patients.
Secondary MR patients often also present with an impaired left ventricular ejection fraction involving the left ventricle and the left atrium in addition to severe MR. Left ventricular ejection fraction was more preserved in primary MR patients, which could explain the slightly better clinical outcomes after 30 days with similar postprocedural MR reduction. The primary clinical effectiveness endpoint of all-cause mortality was low in both groups. Device success and procedural success at 30-day follow-up as defined by MVARC criteria were high in both groups, with no difference between groups.
Study limitations. This is not a randomized controlled trial, but rather a large, single-center experience. Comparison of device success and procedural success as well as 30-day safety endpoint with so far published data is limited by the fact that we present the first study using the new MVARC criteria to define device success and procedural success at 30-day follow-up.
Percutaneous mitral valve repair using the MitraClip device is safe and effective in patients with primary and secondary MR, with a high early device success rate and low 30-day safety endpoint according to the MVARC criteria.
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From the Department of Internal Medicine II, Cardiology, University of Ulm, Ulm, Germany.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted September 13, 2016, provisional acceptance given December 5, 2016, final version accepted December 22, 2016.
Address for correspondence: Prof Dr Jochen Wöhrle, FESC, Department of Internal Medicine II, University of Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany. Email: email@example.com