Author + information
- Received February 1, 2018
- Revision received April 23, 2018
- Accepted May 1, 2018
- Published online June 18, 2018.
- Christian Besler, MDa,∗,
- Mathias Orban, MDb,c,∗,
- Karl-Philipp Rommel, MDa,∗,
- Daniel Braun, MDb,
- Mehul Patel, MDd,
- Christian Hagl, MDe,
- Michael Borger, MD, PhDf,
- Michael Nabauer, MDb,
- Steffen Massberg, MDb,c,
- Holger Thiele, MDa,
- Jörg Hausleiter, MDb,c,† and
- Philipp Lurz, MD, PhDa,†∗ ()
- aDepartment of Cardiology, Heart Center Leipzig – University Hospital, Leipzig, Germany
- bMedizinische Klinik und Poliklinik I, Klinikum der Universität München, Munich, Germany
- cMunich Heart Alliance, Partner Site German Center for Cardiovascular Disease (DZHK), Munich, Germany
- dDepartment of Cardiology, East Carolina University, Greenville, North Carolina
- eHerzchirurgische Klinik und Poliklinik, Klinikum der Universität München, Munich, Germany
- fDepartment of Cardiac Surgery, Heart Center Leipzig – University Hospital, Leipzig, Germany
- ↵∗Address for correspondence:
Dr. Philipp Lurz, Department of Internal Medicine/Cardiology, University of Leipzig – Heart Center, Strümpellstraße 39, 04289 Leipzig, Germany.
Objectives This study sought to investigate predictors of procedural success and clinical outcomes in patients with tricuspid regurgitation (TR) at increased surgical risk undergoing transcatheter tricuspid valve edge-to-edge repair (TTVR).
Background Recent data suggest TTVR using the edge-to-edge repair technique in patients at high surgical risk is feasible and improves functional status at short-term follow-up.
Methods TTVR was carried out in 117 patients with symptomatic TR (median age 79.0 years [interquartile range (IQR): 75.5 to 83.0 years], EuroSCORE II 6.3% [IQR: 4.1% to 10.8%], STS mortality score 5.3% [IQR: 2.9% to 7.1%]) at 2 centers in Germany between March 2016 and November 2017. Seventy-four patients had concomitant severe mitral regurgitation and underwent transcatheter edge-to-edge repair of both valves.
Results During TTVR, 185 and 34 clips were implanted at the anteroseptal and posteroseptal commissures, respectively. Procedural success (TR reduction ≥1) was achieved in 81% of patients. Median TR effective regurgitant orifice area was reduced from 0.5 to 0.2 cm2. After a median follow-up of 184 days (IQR: 106 to 363 days), 24 patients died and 21 patients were readmitted for heart failure. TTVR procedural success independently predicted the time free of death and admission for heart failure (hazard ratio: 0.20 [95% confidence interval: 0.08 to 0.48]; p < 0.01), irrespective of concomitant mitral regurgitation. Small TR coaptation gap size and a central/anteroseptal TR jet location independently predicted procedural success on multivariate analysis.
Conclusions Successful TR reduction by TTVR serves as a predictor for reduced mortality and heart failure hospitalization. TR coaptation gap and jet location may assist in decision making whether a patient is anatomically suited for TTVR.
- edge-to-edge repair
- heart failure
- right ventricle
- transcatheter therapy
- tricuspid regurgitation
- tricuspid valve
Tricuspid regurgitation (TR) either isolated or in combination with left-sided valvular heart disease is associated with an increased risk of heart failure (HF) hospitalization and cardiovascular mortality (1–3). Recent studies in elderly patients at high surgical risk undergoing transcatheter aortic valve replacement or interventional mitral valve repair have suggested that residual TR following repair of left-sided valvular heart disease remains associated with poor clinical outcome at mid-term follow-up (4–6). Several transcatheter devices are currently in pre-clinical and early clinical evaluation as potential novel treatment options for symptomatic TR in patients at increased risk for surgery (7). According to recent data from 106 patients enrolled in the multicenter TriValve registry, transcatheter tricuspid valve edge-to-edge repair (TTVR) (MitraClip, Abbott Vascular, Santa Clara, California) is so far the most common technique applied for interventional TR treatment (8). Preliminary evidence suggests that TTVR is safe and feasible, and associated with an improvement in New York Heart Association (NYHA) functional class and 6-min walking distance at short-term follow-up (9,10). Whether transcatheter treatment of TR translates to a reduction in objective clinical endpoints is not proven. In addition, clinical and echocardiographic characteristics of patients currently treated by interventional TR repair are rather heterogeneous, and predictors of procedural or clinical outcome remain to be elucidated. Therefore, the aim of the present study was to investigate whether reduction of TR by TTVR improves clinical outcome in terms of HF hospitalizations and mortality in patients deemed unsuitable for surgical treatment. In addition, the present study sought to identify potential predictors of TR reduction during the procedure and thereby address the question of which patients benefit the most from TTVR.
The retrospective analysis was conducted in 117 consecutive patients with symptomatic TR treated by TTVR at 2 tertiary care centers in Germany (Heart Center Leipzig–University Hospital, Leipzig, Germany, and the University Hospital of the Ludwig-Maximilians University, Munich, Germany) between March 2016 and November 2017. Seventy-four patients had concomitant severe mitral regurgitation (MR) and underwent combined transcatheter mitral and tricuspid valve edge-to-edge repair (TMTVR). All patients were referred with symptoms of right HF and were in NYHA functional class II to IV despite optimal medical therapy. Pre-procedural assessment included a comprehensive transthoracic and transesophageal echocardiography (TOE), evaluation of N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels (Cobas, Elecsys NT-proBNP II, Roche, Basel, Switzerland) and a 6-min walk test. Patients were discussed at the local heart team meeting and considered to be at high or prohibitive risk for surgery. Therefore, an interventional approach for treatment of TR on a compassionate use basis with or without MR treatment was suggested. Patients with poor echocardiographic visualization of the tricuspid valve on screening TOE, with any degree of mitral or tricuspid valve (TV) stenosis, with severe aortic stenosis and with tricuspid or mitral anatomy deemed unsuitable for edge-to-edge repair were excluded. Characteristics of anatomic unsuitability of the TV were not pre-specified but evolved during experience and included mainly conditions that were thought to make leaflet grasping unlikely: an effective regurgitant orifice area (EROA) of >1.5 cm2, a TV coaptation defect >15 mm, and markedly restricted leaflet mobility due to pacemaker or implantable cardioverter defibrillator leads across the TV. Advanced age, severely impaired left or right ventricular (RV) ejection fraction, and pulmonary hypertension did not serve as exclusion criteria for intervention. All patients gave written informed consent, and the analysis was approved by the local ethics committee.
All echocardiograms were performed on a GE Vivid E9 (General Electric Healthcare, Chicago, Illinois) or Epiq7 system (Philips Healthcare, Andover, Massachusetts) and analyzed from stored images by an experienced operator in the local echocardiography lab blinded to procedural details. The imaging protocol has been described previously (11) and is detailed in the Online Appendix.
Transcatheter mitral and tricuspid edge-to-edge repair
Follow-up examinations and study endpoints
All patients underwent echocardiography assessment before discharge (i.e., 2 to 5 days after procedure), and follow-up examinations were carried out 1 month and 6 months after treatment. On each visit, symptoms were recorded and a physical examination was performed. In addition, patients underwent echocardiography and a 6-min walk test. After 6 months, patients were regularly contacted by telephone if no further outpatient appointments were scheduled. Three patients who were discharged alive were lost to follow up. As such, they were excluded from the outcome analysis.
Procedural success of TTVR was defined as successful clip placement and reduction of TR ≥1 grade assessed on transthoracic echocardiography within 30 days after the procedure. Procedural success of interventional mitral valve repair was defined as a reduction of MR to grade ≤2 on echocardiography within 30 days after clip deployment.
The primary study endpoint was defined as composite endpoint including all-cause mortality and need for repeat hospitalization during follow-up. Secondary endpoints included changes in NYHA functional class and 6-min walk test distance.
A detailed description on the statistical analysis is provided in the Online Appendix.
Baseline demographic data of the 117 patients enrolled in the present analysis are shown in Table 1 and Online Table 1. The median age of the patient sample was 79.0 years ([interquartile range (IQR): 75.5 to 83.0 years) with 44% of patients being female. Patients were at increased risk for surgery (EuroSCORE II 6.3% IQR: 4.1% to 10.8%], STS Predicted Risk of Mortality score for mitral valve repair 5.3% [IQR: 2.9% to 7.1%]) and highly symptomatic with 97% of subjects presenting in NYHA functional class III or IV in both groups. Exercise capacity was markedly impaired (6-min walk distance 187 m [IQR: 120 to 309 m]). Nearly all patients were on diuretic therapy (Table 1). NT-proBNP levels were elevated in all patients, and 39 of 117 patients (33%) presented with HF with reduced left ventricular (LV) ejection fraction (LVEF), according to recent European Society of Cardiology guidelines (13). A pacemaker or defibrillator lead was present in 38 of 117 patients (33%). Nineteen patients (16%) had undergone prior coronary artery bypass grafting, 37 patients (32%) had prior percutaneous coronary interventions, and 9 patients (8%) had undergone prior aortic valve implantation.
Results of echocardiographic characterization are displayed in Table 2 and Online Table 2. Median LVEF was 50% (IQR: 35% to 61%) with LV end-diastolic diameter being within the upper normal range (51 mm [IQR: 45 to 58 mm]). Patients demonstrated dilated right-sided heart chambers (RV mid cavity diameter 42 ± 8 mm, right atrial area 34 cm2 [IQR: 29 to 44 cm2]) with enlarged tricuspid annular diameter (49 ± 7 mm). RV function was impaired in 58% of patients, as defined by tricuspid annular plane systolic excursion (TAPSE) <17 mm (Table 2). All patients displayed severe-to-torrential TR on pre-procedural echocardiography, and the etiology of TR was functional in all but 4 patients (97%).
In patients undergoing TMTVR, MR was functional in 69% of patients. Patients with TMTVR showed a more pronounced left-sided heart disease with lower LVEF (p < 0.01) and more pronounced LV dilatation (p < 0.01) when compared with patients with isolated TTVR. Although RV and right atrial dimensions were comparable between both groups, patients undergoing isolated TTVR had more frequently an impaired TAPSE (p = 0.02), slightly higher functional TR parameters, and more often a central/anteroseptal jet location (p = 0.01) (Online Table 2).
TV clip implantation failed in 5 of 117 patients (4%) due to insufficient echo view (n = 1), excessive rete chiari (n = 1), chordal clip entrapment (n = 1), or inability to reduce TR despite successful clip placement between the anterior and posterior TV leaflets (n = 2). In the remaining patients, a total of 185 clips were implanted at the anteroseptal commissure in 107 of 117 patients (92%) and a total of 34 clips at the posteroseptal commissure in 31 of 117 patients (27%) (Table 3, Online Table 3). Overall cohort procedural success of transcatheter TR repair could be achieved in 81% of patients with 25 of 117 patients (22%) demonstrating residual TR grade 3+ and 4+ (Table 3, Online Table 3). Median vena contracta (VC) of TR was reduced from 9 mm (IQR: 7 to 11 mm) to 5 mm (IQR: 3 to 7 mm) (p < 0.01) and median TR EROA from 0.5 cm2 (IQR: 0.3 to 0.7 cm2) to 0.2 cm2 (IQR: 0.1 to 0.3 cm2) (p < 0.01), whereas median TAPSE (16 mm [IQR: 13 to 20 mm] vs. 16 mm [IQR: 13 to 20 mm]; p = 0.79) and median TR jet maximal pressure gradients (39 mm Hg [IQR: 28 to 49 mm Hg] vs. 35 mm Hg [IQR: 28 to 40 mm Hg]; p = 0.63) were unchanged. Three of 74 patients (4%) showed residual MR grade 3+ despite successful mitral clip implantation before discharge. Hence, overall MR improvement was achieved in 96% of TMTVR cases (Online Table 3).
Symptoms and clinical outcomes during follow-up
During a median of 184 days of follow-up, 24 of 114 patients (21%) died, and 21 of 114 patients (18%) were readmitted to hospital for decompensated HF, whereas the combined endpoint was reached in 35 of 114 patients (31%) (Online Table 4). Cardiac death occurred in 10 of 24 patients (42%). Causes of cardiac death were progressive HF (n = 8), ST-segment elevation myocardial infarction (n = 1), and endocarditis (n = 1). A noncardiac cause of death was identified in 6 patients (sepsis in 4 patients, and stroke and gastrointestinal bleeding in 1 patient each). Cause of death remained unknown in 8 patients. Two patients died in-hospital (in-hospital mortality 1.7%) with 1 patient experiencing malignant stroke 7 days after successful isolated TTVR, and another patient experiencing progressive HF following combined TMTVR without reduction in MR and TR because of massive annular dilatation. Another 2 patients died within 30 days after hospital discharge: 1 patient died for unknown reason 15 days after successful combined TMTVR, and 1 patient with severely impaired LV function died from progressive HF 24 days after combined TMTVR with successful MR reduction from severe to mild but without TR reduction (30-day mortality 3.4%).
Patients reaching the combined clinical endpoint did not differ in baseline characteristics from patients not experiencing an event (n = 82), except for a slightly lower body mass index (p = 0.04) (Table 1). Echocardiographic parameters did not differ between patients with and without a clinical event. Patients reaching the combined clinical endpoint were less likely to experience successful transcatheter TR repair (60% vs. 89%; p < 0.01) and demonstrated more severe residual TR (p < 0.01) (Table 3). No differences were observed between the clinical endpoint rates in patients with isolated TTVR (n = 43) and TMTVR (n = 74) (Online Table 4). When compared with patients with isolated TTVR, patients with TMTVR were less likely to be female (34% vs. 61%; p = 0.01), were more likely to be in a higher NYHA functional class (p = 0.03), had more often HF with reduced ejection fraction (41% vs. 21%; p = 0.04) and displayed more severe MR (p < 0.01) (Online Table 1). Improvement of NYHA functional class was observed in 76% of patients at their last follow-up with patients experiencing a clinical event being significantly more often in NYHA functional class III to IV (57% vs. 25%; p < 0.01). Although a higher percentage of patients with TMTVR experienced an improvement in NYHA functional class (84% vs. 64%; p = 0.02), overall improvement in NYHA grades was independent from concomitant mitral valve repair (p for interaction = 0.16). In patients with 6-min walk test at baseline and at least 1 follow-up visit (n = 89), covered median distance improved significantly by 29% (from 189 m [IQR: 119 to 311 m] to 244 m [IQR: 164 to 374 m]; p < 0.01), and 72% of patients experienced an improvement of at least 25 m. No impact of concomitant mitral valve repair was observed (p for interaction = 0.52).
Predictors of clinical outcomes
Rates of the combined clinical endpoints as well as rates for mortality and readmission for HF alone were significantly higher in patients with unsuccessful transcatheter TR repair (death/HF hospitalization 64% vs. 23%; death 46% vs. 15%, and HF hospitalization 50% vs. 11%; p < 0.01 for all). Kaplan-Meier estimates demonstrated a significant longer event-free survival (p < 0.01), a longer mortality-free survival (p = 0.02) and longer freedom from HF readmission (p < 0.01) in patients with successful transcatheter TR repair (Figure 1). Successful transcatheter TR repair was the only predictor for freedom from clinical outcomes and independently predicted freedom from the combined endpoint (hazard ratio [HR]: 0.20 [95% confidence interval (CI): 0.08 to 0.48]; p < 0.01), freedom from death (HR: 0.40 [95% CI: 0.18 to 0.91]; p = 0.03), and freedom from hospitalization for HF (HR: 0.15 [95% CI: 0.06 to 0.36]; p < 0.01). Transcatheter mitral valve repair success failed to significantly predict outcomes in the regression models.
Predictors of procedural success
Five echocardiographic parameters were univariate predictors for procedural success; these included a smaller TR EROA, a smaller TR tenting area, TR VC, a smaller TV coaptation gap and a central/anteroseptal TR jet location (Table 4). In the multivariate model, a smaller TV coaptation gap and a central/anteroseptal TR jet location independently predicted transcatheter TR repair success. Receiver-operating characteristic curve analysis demonstrated a cutoff value for a coaptation gap of 7.2 mm as the best discriminator for successful transcatheter TR repair. Combining the 2 independent predictors as binary variables, patients could be further stratified according to procedural success. Notably, none of the patients with a TV coaptation gap larger than 7.2 mm and a non-central/non-anteroseptal TR jet location could be treated successfully (Figures 2 and 3⇓⇓). Treatment success declined linearly with the magnitude of TV coaptation gap, yielding a success rate of <30% with a gap of more than 10 mm. Youden index-based cutoff values for the other univariate predictors were 0.6 cm2 for TR EROA, 2.1 cm2 for TV tenting area, and 11 mm for TR VC.
The key findings of our bicentric study suggest that successful interventional TR edge-to-edge repair translates into lower mortality and reduced hospitalization for HF when performed as an isolated procedure or combined with MR treatment. Small coaptation gap size and a central/anteroseptal location of the TR jet noted on pre-procedural echocardiography are important anatomic predictors of procedural success of transcatheter tricuspid valve repair.
Prognostic value of TR treatment
A growing body of evidence indicates that patients with isolated TR or residual TR following treatment of left-sided valvular pathologies face an inferior clinical outcome (1–6,14–16). Based on data from the Framingham Study, estimates suggest that as many as 1.6 million Americans may have relevant TR (17,18), and this population is estimated to grow further (19). This high prevalence together with the low incidence of surgery for severe TR and stagnant, but relevant operative mortality (20) has created a large population of patients in need of percutaneous, innovative therapies to improve clinical outcome of TR.
However, data on the impact of TR on clinical outcome are not uniform, and some studies have even questioned the incremental prognostic value of TR after adjustment for comorbidities and RV dysfunction in patients with advanced HF, late after left-sided heart valve surgery and following transcatheter aortic valve replacement (21–23). These findings, among others, have raised concern about the pathophysiological and therapeutic relevance of TR in these situations, and there is an ongoing debate whether TR rather reflects a surrogate marker for other cardiac or systemic comorbidities, which ultimately determine clinical outcome. The debate is further complicated by the lack of adequately powered clinical trials.
Hitherto, data on transcatheter TR repair have been limited by short clinical follow-up and use of surrogate clinical endpoints to assess the procedure's efficacy (9,10). The present study is the first to our knowledge to analyze outcomes in the largest cohort of patients undergoing TTVR/TMTVR by use of hard clinical endpoints over an extended follow-up period. In keeping with a previous report on a cohort undergoing transcatheter TR repair by various devices (8), patients in the present study were at an advanced age, highly symptomatic despite optimal medical therapy and presented with many comorbidities. Despite this high rate of comorbidities, successful transcatheter TR repair emerged as the only independent predictor for death and rehospitalization for HF during follow-up. The strong association of transcatheter TR repair success with superior outcome suggests that TR is causative for an inferior outcome and that transcatheter TR reduction could indeed improve the natural history of these patients.
Outcome in TMTVR
Because of the pathophysiological link between functional TR and left-sided valvular heart disease (in particular MR), a significant proportion of patients evaluated for TTVR have multivalvular disease (7). In the present study, 63% of patients underwent TMTVR. Interestingly, clinical outcome in patients with TMTVR did not differ when compared with patients with isolated TTVR. In fact, effective TR reduction predicted survival in both high-risk groups, those with isolated severe TR and those successfully treated for combined MR and TR. In patients with TMTVR, effective TR reduction was the only predictor for survival and freedom from HF hospitalization. Together, these data support the concept that TR is not just a bystander in coexisting mitral valve disease, but is rather of prognostic importance and, above all, a valuable target to potentially change the course of the disease.
Predictors of success in TTVR
Given the various mode of action of available transcatheter devices, one might assume that predictors of success may vary depending on the transcatheter procedure performed. Severe leaflet tenting and very large tricuspid annular diameter are considered as predictors of inferior outcome in patients undergoing surgical tricuspid valve repair (24,25), and one might speculate that transcatheter tricuspid annuloplasty devices (such as Trialign [Mitralign Inc., Tewksbury, Massachusetts], Cardioband [Edwards Lifesciences, Irvine, California], or TriCinch [4TECH, Galway, Ireland]) would have the same predictors of success. By contrast, predictors of procedural success for transcatheter leaflet repair devices such as MitraClip are still lacking despite the increasing use of the technique (8). The findings of the present study suggest that 2 echocardiographically derived parameters may assist to determine suitability of TTVR, namely coaptation gap and non-central/non-anteroseptal location of the TR jet. The coaptation gap observed in patients with severe TR is likely a result of tricuspid annular dilatation and leaflet tethering. Larger coaptation gaps are associated with more severe TR and consequently increase the likelihood of residual TR. In addition, a larger coaptation gap will either prevent successful clip placement or will lead to clip placement away from the region of main TR, both resulting in inefficient TR reduction. This may provide an explanation for the predictive role of the coaptation gap. It should be mentioned that iterations of the current MitraClip device with larger clip arms or the Pascal system (Edwards Lifesciences, Irvine, California) might overcome some current technical limitations in large TV gaps. The association of a non-central/non-anteroseptal TR jet with procedural failure might be less obvious. From our experience, clip placement in a posteroseptal position and even more so in anteroposterior position is more challenging. Therefore, a non-central/non-anteroseptal TR jet might reflect a technically more challenging situation or less suitable substrate. Apart from technical considerations, recent experimental work demonstrated less favorable outcome of clip placement in the posteroseptal and in particular the anteroposterior positions (26), supporting our clinical observation.
On the basis of these findings, we propose a sequential evaluation approach, considering the TV coaptation gap followed by TR jet location (Figure 3). The varying success rate stratified according to these 2 echocardiographic parameters could aid consenting of patients and physicians at present, but certainly requires confirmation in larger cohorts before widespread use of TTVR outside of clinical trials can be recommended. Also, given the complex anatomy of the tricuspid valve apparatus, it appears likely that there are other, not-yet-identified imaging characteristics that may help to plan for type of repair and device selection.
Although the present cohort of patients undergoing TTVR or TMTVR is the largest published thus far, the number of patients included is still small with a follow-up limited to a median of 6 months. On the basis of the present data, it is tempting to speculate that TTVR or TMTVR may provide prognostic benefit over and above optimal medical therapy alone; however, the present study did not include a control group on optimal medical therapy, and therefore, no definite conclusions can be drawn. Also, the high success rate of MR correction might limit the analysis of MR reduction as a predictor for more favorable outcome in patients with TMTVR. Finally, although echocardiographic data were analyzed by experienced institutional echocardiographers, there was no echocardiographic core lab analysis performed.
Successful TR reduction by means of TTVR in patients at increased surgical risk serves as a major predictor for reduced mortality and HF hospitalization during follow-up, suggesting that TTVR provides prognostic benefit in these patients. Small TV coaptation gap size and a central/anteroseptal jet location are major anatomic determinants of procedural success and may provide a means for patient selection for TTVR in the future.
WHAT IS KNOWN? Recent evidence suggests that transcatheter TTVR is safe and feasible in patients with symptomatic TR at high surgical risk, and associated with functional improvement early after the procedure.
WHAT IS NEW? The present analysis suggests that successful TR reduction by TTVR is an independent predictor of survival and freedom from heart failure hospitalization. Moreover, the present study is the first to demonstrate that small TR coaptation gap size and a central/anteroseptal TR jet location are major predictors for TTVR success.
WHAT IS NEXT? The present findings will need confirmation in larger prospective studies to validate the impact of TTVR on clinical outcomes and the value of TR coaptation gap and jet location in decision making for TTVR.
The authors thank Martin Petzold, Andrea Englmaier, and Diana Rösler for excellent technical support in study organization.
↵∗ Drs. Besler, Orban, and Rommel contributed equally to this work and are joint first authors.
↵† Drs. Hausleiter and Lurz contributed equally to this work and are joint senior authors.
Dr. Braun has received speakers honoraria from Abbott Vascular. Dr. Hausleiter has been a consultant to and received speakers honoraria from Abbott Vascular and speakers honoraria from Edwards Lifesciences. Drs. Nabauer and Lurz have been consultants to and received speakers honoraria from Abbott Vascular. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- confidence interval
- effective regurgitant orifice area
- heart failure
- hazard ratio
- interquartile range
- left ventricle/ventricular
- left ventricular ejection fraction
- mitral regurgitation
- N-terminal pro–B-type natriuretic peptide
- New York Heart Association
- right ventricle/ventricular
- tricuspid annular plane systolic excursion
- combined transcatheter mitral and tricuspid valve edge-to-edge repair
- transesophageal echocardiography
- tricuspid regurgitation
- transcatheter tricuspid valve edge-to-edge repair
- tricuspid valve
- vena contracta
- Received February 1, 2018.
- Revision received April 23, 2018.
- Accepted May 1, 2018.
- 2018 American College of Cardiology Foundation
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