Safety and Efficacy of Percutaneous Mitral Valve Repair Using the MitraClip® System in Patients with Diabetes Mellitus

Background Patients with diabetes mellitus show a negative outcome in percutaneous coronary intervention, aortic valve replacement and cardiac surgery. The impact of diabetes on patients undergoing treatment of severe mitral regurgitation (MR) using the MitraClip system is not known. We therefore sought to assess whether percutaneous mitral valve repair with the MitraClip system is safe and effective in patients with diabetes mellitus. Methods and Results We included 58 patients with severe and moderate-to-severe MR in an open-label observational single-center study. Ninteen patients were under oral medication or insulin therapy for type II diabetes mellitus. MitraClip devices were successfully implanted in all patients with diabetes and in 97.4% (n = 38) of patients without diabetes (p = 0.672). Periprocedural major cardiac adverse and cerebrovascular events (MACCE) occurred in 5.1% (n = 2) of patients without diabetes whereas patients with diabetes did not show any MACCE (p = 0.448). 30-day mortality was 1.7% (n = 1) with no case of death in the diabetes group. Short-term follow up of three months showed a significant improvement of NYHA class and quality of life evaluated by the Minnesota Living with Heart Failure Questionnaire in both groups, with no changes in the 6-minute walk test. Conclusions Mitral valve repair with the MitraClip system is safe and effective in patients with type II diabetes mellitus. Trial Registration MitraClip Registry NCT02033811


Introduction
Mitral valve regurgitation (MR) is the second common valvular heart disease and severely affects morbidity and mortality [1][2][3][4][5]. Surgical treatment for many years used to be the first line treatment for patients with severe symptomatic MR [6]. Percutaneous mitral valve repair (PMVR) with the MitraClip system, however, has emerged to an effective therapeutic alternative for patients who can not undergo surgery due to high surgical risk [7]. Many of the high-risk patients present with diabetes mellitus, which is known to worsen outcome in patients referred to percutaneous coronary intervention (PCI) [8][9][10][11][12], cardiac surgery [13][14][15] or transcatheter aortic valve replacement (TAVI) [16,17]. The impact of diabetes on treatment of MR using the MitraClip system is not known. We therefore sought to assess whether percutaneous mitral valve repair with the MitraClip system is safe and effective in patients with diabetes mellitus.

Methods
The protocol for this trial and supporting CONSORT checklist are available as supporting information; see Checklist S1 and Protocol S1.

Patient selection and study design
A total of 58 Patients with symptomatic severe or moderate-tosevere MR evaluated by trans-thoracic and trans-esophageal echocardiography who underwent PMVR with the MitraClip System at the Heart Center Duesseldorf were included in the study ( Figure 1). All patients were discussed in the institutional heart team and declined for surgical treatment due to high operative risk. Patients were included into our registry after informed written consent was obtained. The registry is registered at clinical trials (NCT02033811). In a sub-analysis of this registry, patients were grouped according to the presence of type II diabetes mellitus (oral medication or on insulin therapy). The objective of the study was to evaluate the safety and efficacy of the MitraClip procedure in patients with diabetes mellitus with a follow-up after 3 months. Study procedures were in accordance with the Declaration of Helsinki and the institutional Ethics Committee of the Heinrich-Heine University approved the study protocol.

Data collection and definitions
Collected data included patient characteristics, imaging findings, periprocedural in hospital data, laboratory results and follow up data up to three month after PMVR. Blood samples for biochemistry and hematology analysis results were taken before the procedure. Clinical outcome parameters for follow up after three months were NYHA classification, 6-minute walk test (6MWT), and quality of life measured by the Minnesota Living With Heart Failure Questionnaire (MLHF Q). Trans-thoracic echocardiography (TTE) was performed before the procedure and during follow up. Trans-esophageal echocardiography (TEE) was performed at baseline. Severity of mitral regurgitation was classified by TTE and TEE by measuring vena contracta (VC) and regurgitation volume. A severe mitral regurgitation was defined as a VC $0.7 cm and a regurgitation volume $60 ml [18,19].
In-hospital complications were reported for both groups. The definition of MACCE (major adverse cardiac and cerebrovascular event) included death, ST-elevation myocardial infarction, stroke and procedure related re-operation. A significant mitral stenosis after procedure was defined as a mean gradient .10 mmHg. Peripheral vascular complications were defined as minor vascular complication according to VARC II [38]. A major vascular complication was defined according to VARC II as overt bleeding either associated with a drop in hemoglobin level of at least 3.0 g/ dL or requiring transfusion of two or three units of whole blood, or causing hospitalization, or permanent injury, or requiring surgery and does not meet criteria of life-threatening or disabling bleeding.

Procedure
The MitraClip procedure was performed either in general anesthesia or deep sedation using TEE and fluoroscopy for guidance. The procedure and the MitraClip System have previously been described in detail [20,21]. After a femoral venous access and transseptal puncture, the system is positioned in the left atrium. The arms of the clip are aligned perpendicular to the long axis of the leaflet edges and the clip is advanced into the left ventricle. After grasping the leaflets and checking the leaflet insertion the clip is deployed and the system removed.

Statistical Analysis
Continuous data were expressed as mean 6 standard deviation (SD) and compared with the unpaired student's t-test or Mann-Whitney U test if not normally distributed. Normality was checked with the Kolmogorov-Smirnov test. Categorical variables were evaluated as percentage and compared with the x-square test or Fisher's exact test. Statistical analysis was performed with SPSS Statistics 22 (IBM) and Prism (GraphPad). A p-value ,0.05 was considered to be significant.

Results
We enrolled 58 patients with symptomatic severe and moderateto-severe MR. Nineteen patients (32.8%) presented with diabetes mellitus type II with either oral medication or insulin therapy.
Groups did not differ except for HbA1c and blood glucose levels. Baseline characteristics are summarized in Table 1.
At the time of follow up, significant improvement of NYHA class was seen in both groups from 3.160.6 to 2.260.5 (p,0.0001) in patients without diabetes and 3.260.6 to 2.260.5 (p,0.0001) in patients with diabetes. Quality of life measured by the MLHF Questionnaire was improved with a score reduction from 43615 to 36614 (p,0.0001) in non-diabetic patients and 45612 to 36611 (p,0.001) in patients with diabetes ( Figure 2). 6-MWT (2966121.6 m to 3006130.8 m; p = 0.743), left ventricular ejection fraction (45616% to 44613%; p = 0.660), and left ventricular end-diastolic diameter (59611 mm to 60612 mm; p = 0.163) did not change in patients without diabetes. In patients with diabetes 6-MWT (275690 m to 308611 m; p = 0.057), ejection fraction (37613% to 35613%; p = 0.455) and left ventricular end-diastolic diameter (61614 mm to 63611 mm; p = 0.243) were also unaffected. MR reduction $1 grade was observed in 65.8% (n = 25) of patients without diabetes and in all patients with diabetes ( Figure 3).

Discussion
The key findings of our study are: i) mitral valve repair with the MitraClip system is safe and effective in patients with diabetes mellitus. ii) This is associated with an improvement in functional status after three months follow up.
Patients with diabetes are at higher risk when undergoing PCI or cardiac surgery [8][9][10][11][12][13][14][15]. The underlying mechanisms are multifarious and involve an increased platelet activity, endothelial dysfunction [22,23], impaired wound healing, and a higher risk for infections caused by hyperglycemia [24,25]. Patients with diabetes moreover often present with comorbidities such as impaired renal function or coronary artery disease, which increase the surgical risk. PMVR with the MitraClip system has been shown to be safe and feasible and an alternative for surgical mitral valve repair in high-risk patients [7,20]. The role of diabetes in those patients, however, has not been investigated so far.
In our study population none of the diabetic patients died within 3 months follow-up. However, slightly higher mortality rates have been described [26][27][28]. These high mortality rates may reflect the morbidity of the patients who are referred to MitraClip procedure -sometimes as palliative therapy -and the importance of careful patient selection and risk stratification. Successful clip implantation was 100% in the diabetic group and 97.4% in the nondiabetic group. Overall complication rate was low in our study population, which has also been proved in other studies [29,30] and confirms the safety of the procedure. Diabetic patients did not present with a higher complication rate.
Previous studies have identified diabetes mellitus to be a risk factor for early and late mortality after surgical mitral valve repair [31,32,35]. Therefore it has been included in risk models like the Euroscore II or the STS score. Hospital mortality rates for mitral valve repair have been described from 1.5% to 6.5% [36,37]. Complications like deep sternal wound infection, stroke or acute renal failure after cardiac surgery are more likely in diabetic patients [33,34,35]. A less invasive treatment option like the MitraClip procedure in diabetic patients therefore seems to be an good alternative. Clinical outcome was improved after three months follow up in patients with diabetes and in non-diabetic patients. NYHA class was reduced and quality of life improved. These findings consist with other reports [26,28]. No improvement was observed in the 6-MWT in both groups, which may be due to the short-term follow up of three months in our study. In previous studies 6MWT was improved after 12 months [26,29]. Echocardiographic evaluation after three months showed a good result with an MR reduction $1 grade in 93.1% (n = 54) of the patients. All patients in the diabetes group did benefit from PMVR with an MR reduction $1 grade. There were no relevant changes in ejection fraction and LVEDD in our study population, which may be due to the short term period of follow up. Baseline ejection fraction was moderately to severely reduced in both groups and left ventricular end-diastolic diameter enlarged. Recovery might be seen after a longer period. In contrast, a previously published study reported a reduction of left ventricular end-diastolic volume after short-term follow up of 30 days and one year probably due to early reverse remodeling [28].
Our study has limitations. PMVR using the MitraClip system is safe and event rates are low. Therefore, a prospective randomized study with more patients and longer follow-up time is needed. Furthermore, patients should be classified concerning the duration of diabetes and diabetes-induced comorbidities.

Conclusion
We here show that the MitraClip procedure can be performed safely and effectively in patients with type II diabetes mellitus. Our short-term follow up shows an improvement in functional status in our patients with no negative influence on 3-month-mortality.

Supporting Information
Checklist S1 CONSORT Checklist.