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EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED EXPERT CONSENSUS DECISION PATHWAY 2017 ACC Expert Consensus Decision Pathway on the Management of Mitral Regurgitation A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways WRITING COMMITTEE Patrick T. O'Gara, MD, MACC, Chair Paul A. Grayburn, MD, FACC, Vice-Chair Vinay Badhwar, MD, FACC, Vice-Chair Luis C. Afonso, MBBS, FACC John D. Carroll, MD, FACC Sammy Elmariah, MD, FACC Aaron P. Kithcart, MD Rick A. Nishimura, MD, MACC Thomas Ryan, MD, FACC Allan Schwartz, MD, FACC Lynne Warner Stevenson, MD, FACC TASK FORCE ON EXPERT CONSENSUS DECISION PATHWAYS James L. Januzzi Jr., MD, FACC, Chair Luis C. Afonso, MBBS, FACC Joseph E. Marine, MD, FACC Brendan Everett, MD, FACC Pamela B. Morris, MD, FACC Adrian F. Hernandez, MD, FACC Robert N. Piana, MD, FACC William Hucker, MD, PhD Karol E. Watson, MD, FACC Hani Jneid, MD, FACC Barbara S. Wiggins, PharmD, AACC Dharam J. Kumbhani, MD, SM, FACC This document was approved by the American College of Cardiology Clinical Policy Approval Committee on behalf of the Board of Trustees in [insert month] 2017. The American College of Cardiology requests that this document be cited as follows: O’Gara PT, Grayburn PA, Badhwar V, Afonso LC, Carroll JD, Elmariah S, Kithcart AP, Nishimura RA, Ryan T, Schwartz A, Stevenson LW. 2017 ACC Expert Consensus Decision Pathway on the Management of Mitral Regurgitation. J Am Coll Cardiol 2017; XX:XXX-XX. Copies: This document is available on the World Wide Web site of the American College of Cardiology (www.acc.org). For copies of this document, please contact Elsevier Inc. Reprint Department, fax (212) 633-3820, e-mail [email protected]. 1 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American College of Cardiology. Please contact Elsevier’s permission department [email protected] © 2017 by the American College of Cardiology Foundation 2 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED TABLE OF CONTENTS PREFACE ....................................................................................................................................... 5 1. ABSTRACT ............................................................................................................................... 7 2. INTRODUCTION ...................................................................................................................... 8 3. METHODS ................................................................................................................................. 9 4. ASSUMPTIONS AND DEFINITIONS ................................................................................... 10 5. CENTRAL ILLUSTRATION .................................................................................................. 11 Figure 1. Pathway for Management of MR ............................................................................... 11 6. DESCRIPTION AND RATIONALE ........................................................................................ 12 6.1. Evaluation of the Patient .................................................................................................... 13 6.2. Hemodynamic Effects of MR............................................................................................. 15 6.3. Determining Mechanism and Etiology of MR ................................................................... 16 Figure 2. Decision Tree for Distinguishing Primary from Secondary MR ........................... 16 Table 1. Suggested Qualitative and Quantitative Parameters for Standardized Echo Reporting ............................................................................................................................... 19 Figure 3. Anterior Leaflet Override in Functional MR ......................................................... 21 6.3.1. Spectrum of Functional MR ........................................................................................ 21 6.4. Assessment of MR Severity ............................................................................................... 22 6.4.1 Color Flow Doppler (CFD) Jet Size ............................................................................. 22 Figure 4. Effect of Driving Velocity on Size and Penetration of Color Doppler MR Jet ..... 23 6.4.2. Quantitative Parameters............................................................................................... 24 Figure 5. MR Limited to Late Systole in Mitral Valve Prolapse.......................................... 25 Figure 6. Example of Underestimation of EROA by 2D PISA in a Patient with Secondary MR and a Markedly Crescentic Orifice Shape ...................................................................... 26 6.4.3. Integration of Multiple Parameters .............................................................................. 27 Figure 7. Decision Tree for Assessing Severity of MR by TTE .......................................... 27 Table 2. Strengths and Limitations of Common Echocardiographic Parameters of MR Severity.................................................................................................................................. 29 Figure 8. Clinical Algorithm for the Management of MR based on TTE ............................. 32 6.4.4 Dynamic Nature of MR ................................................................................................ 33 6.4.5 Differences in Assessing MR Severity in Primary vs. Secondary MR ........................ 34 6.4.6 Prognosis in MR ........................................................................................................... 35 3 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 6.5. Treatment of Chronic Mitral Regurgitation........................................................................ 36 6.5.1. Surgical Treatment of Mitral Regurgitation ................................................................ 37 6.5.2. Feasibility of Surgical Repair ...................................................................................... 39 Figure 9. Decision Tree for Determining Surgical Mitral Valve Repair vs. Replacement in Patients with Severe MR ....................................................................................................... 39 Table 4: Pathoanatomically Directed Contemporary Surgical Techniques for Mitral Regurgitation ......................................................................................................................... 42 Table 5. Feasibility of Transcatheter Edge-to-Edge Clip Repair .......................................... 43 Figure 10. Examples of Valve Morphology that is Amenable to Surgical Repair in Patients with Primary MR ................................................................................................................... 44 6.5.3. Determination of Risk for Surgery .............................................................................. 44 6.5.4. Transcatheter Treatment of Mitral Regurgitation ........................................................ 45 6.5.5. Edge-to-Edge Leaflet Coaptation ................................................................................ 46 Figure 11. Transcatheter Edge-to-Edge Mitral Valve Clip .................................................. 47 Figure 12. Algorithm for Determining Eligibility for Transcatheter Edge-to-Edge Mitral Valve Clip.............................................................................................................................. 48 6.5.6. Feasibility of Edge-to-Edge Leaflet Coaptation .......................................................... 48 Figure 13. Transcatheter Edge-to-Edge Mitral Valve Clip .................................................. 49 7. DISCUSSION AND IMPLICATION OF PATHWAY ........................................................... 49 PRESIDENTS AND STAFF......................................................................................................... 52 APPENDIX 1: Author Relationships With Industry and Other Entities (Relevant) ..................... 53 APPENDIX 2: Peer Reviewer Relevant RWI ............................................................................... 57 APPENDIX 3: Abbreviations........................................................................................................ 58 References ..................................................................................................................................... 59 4 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 PREFACE 2 The American College of Cardiology (ACC) develops a number of clinical policy 3 documents to provide members with guidance on clinical topics. While clinical practice 4 guidelines remain the primary mechanism for offering evidence based recommendations, 5 such guidelines may contain gaps in how to make clinical decisions, particularly when 6 equipoise is present in a topic. Expert Consensus Documents are intended to provide 7 guidance for clinicians in areas where evidence may be limited, new and evolving, or 8 lack sufficient data to fully inform clinical decision making. 9 In an effort to increase the impact of ACC clinical policy on patient care, an ACC 10 Presidential Task Force was formed in 2014 to examine processes of ACC’s clinical 11 documents. The main recommendation of the Task Force was a new focus on concise 12 decision pathways and/or key points of care, instead of the traditional longer documents. 13 The Task Force also established criteria for identifying high-value clinical topics to be 14 addressed, as well as an innovative approach to collecting stakeholder input through a 15 roundtable or think tank meeting. To complement the new focus on brief decision 16 pathways and key points, Expert Consensus Documents were rebranded Expert 17 Consensus Decision Pathways (ECDPs). 18 While Decision Pathways have a new format, they maintain the same goal of 19 Expert Consensus Documents to develop clinical policy based on expert opinion in areas 20 which important clinical decisions are not adequately addressed by the available existing 21 trials. ECDPs are designed to complement the guidelines and bridge the gaps in clinical 22 guidance that remain. In some cases, topics covered by ECDPs will be addressed 23 subsequently by ACC/AHA guidelines as the evidence base evolves. The writing 5 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 committees are charged with developing algorithms that are more actionable and can be 2 implemented into tools or apps to accelerate the use of these documents at point of care. 3 Decision Pathways are not intended to provide a single correct answer, but to encourage 4 clinicians to ask certain questions and consider important factors as they come to their 5 own decision on a treatment plan for their patients. There may be multiple pathways that 6 can be taken for treatment decisions and the goal is to help clinicians make a more 7 informed decision. 8 9 10 James L. Januzzi, MD, FACC Chair, ACC Task Force on Expert Consensus Decision Pathways 11 6 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 1. ABSTRACT 2 Mitral regurgitation is a complex valve lesion that can pose significant management 3 challenges for the cardiovascular clinician. Recognition should prompt an assessment of 4 its etiology, mechanism, severity, and indications for treatment. A structured approach to 5 evaluation based on clinical findings, precise echocardiographic imaging and adjunctive 6 testing when necessary should help clarify decision making. Treatment goals include 7 timely intervention by an experienced heart team to prevent left ventricular dysfunction, 8 heart failure, reduced quality of life and premature death. 7 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 2. INTRODUCTION 2 Improvements in multi-modality imaging, surgical outcomes and the advent of 3 transcatheter techniques have transformed the approach to patients with valvular heart 4 disease. Long-term natural history studies have informed clinical decision-making 5 regarding the appropriate timing for valve intervention. Nevertheless, knowledge and 6 performance gaps remain that may adversely affect patient outcomes and for which 7 practice tools may provide a means for improvement. 8 Recent emphasis has been placed on the heart valve team approach to patients 9 with calcific aortic stenosis, in large measure due to improvements in transcatheter and 10 surgical therapies. The evaluation and management of patients with mitral regurgitation 11 (MR), a highly prevalent valve lesion among aging U.S. adults, is more complex, in part 12 related to its varying etiologies, dynamic nature and the intricate interplay among the 13 functional components of the mitral apparatus, including the left ventricle, papillary 14 muscles, chordae tendineae, leaflets and annulus. 15 This manuscript contains clinical expert consensus recommendations to guide the 16 approach to patients identified with MR with emphasis on clinical and echocardiographic 17 assessment, establishment of etiology and mechanism, consideration of associated 18 hemodynamic consequences, recognition of the triggers for surgical referral, appreciation 19 of the graded complexity of mitral valve repair as a function of pathoanatomy, and 20 understanding the limited role for transcatheter mitral valve repair in the United States at 21 the current time. Recommendations are based on the AHA/ACC 2014 Guideline for the 22 Management of Patients with Valvular Heart Disease (1), but augmented with additional 8 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 clinical context and practical tips for medical and surgical decision-making in complex 2 patient scenarios. 3 3. METHODS 4 The writing committee was assembled in September 2015. In addition to the master 5 document, figures and tables contained herein, the writing committee developed a 6 template for structured echocardiographic reporting of MR etiology, mechanism, 7 Carpentier (functional) classification, severity and associated findings, as well as a 8 checklist for use when contemplating referral of patients for advanced imaging or 9 surgical/interventional therapy. The manuscript and tools were based on the writing 10 committee’s knowledge of the evidence assembled and recommendations made in the 11 AHA/ACC 2014 Guideline for Management of Patients with Valvular Heart Disease (1), 12 additional literature review through July 2016, and expert consensus when evidence was 13 lacking or limited. The writing committee included representatives from the following 14 areas: general cardiology, heart valve disease, heart failure, imaging, 15 interventional/structural heart disease, valve surgery, fellows-in-training and early career 16 professionals. 17 The work of the writing committee was supported exclusively by the ACC 18 without commercial support. Writing committee members volunteered their time to this 19 effort. Conference calls of the writing committee were confidential and attended only by 20 committee members and ACC staff. A formal peer review process was completed 21 consistent with ACC policy and included expert reviewers nominated by the ACC (see 22 Appendix 2). A public comment period was also held to obtain further feedback. 23 Following reconciliation of all comments, this document was approved for publication by 9 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 the ACC Clinical Policy Approval Committee on behalf of the Board of Trustees and 2 endorsed by xx. 3 4. ASSUMPTIONS AND DEFINITIONS 4 This effort was neither conceived nor designed to rewrite or re-interpret the AHA/ACC 5 2014 Guidelines for the Management of Patients with Valvular Heart Disease (1).The 6 writing committee did not stipulate the means by which mitral regurgitation may first be 7 appreciated and did not focus on community efforts to increase its rate of accurate 8 detection. Evaluation and management algorithms in this document flow from an 9 echocardiographically validated diagnosis of mitral regurgitation. Primary MR is defined 10 by principal involvement of the leaflets and/or chordae tendineae in the pathologic 11 process (e.g., myxomatous disease, endocarditis); secondary (functional) MR is 12 characterized by incompetence due to adverse changes in left ventricular size, shape or 13 function with or without annular dilatation (e.g., ischemic cardiomyopathy); mixed MR is 14 due to both primary and secondary causes (e.g., mitral valve prolapse/flail with ischemic 15 cardiomyopathy). The writing committee used the American Society of 16 Echocardiography guidelines to grade mitral regurgitation severity and emphasized the 17 need for additional testing when severity could not be established with certainty (2). The 18 writing committee acknowledged previous publications regarding institutional and 19 operator requirements for programs of transcatheter heart valve intervention (3). The 20 writing committee did not define a comprehensive valve center nor stipulate the criteria 21 by which a mitral valve surgeon is considered experienced or highly experienced. These 22 latter two issues are of intense interest to the community and the focus of current 23 deliberation and multi-societal collaboration. 10 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 5. CENTRAL ILLUSTRATION 2 Figure 1. Pathway for Management of MR 3 11 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 6. DESCRIPTION AND RATIONALE 2 Mitral regurgitation (MR) is the most common type of moderate or severe heart valve 3 disease among U.S. adults older than 55 years and its prevalence increases further as a 4 function of age (4). It can result from pathological abnormalities of the mitral valve 5 leaflets or chordae (primary MR) or when leaflet coaptation is reduced by 6 dilation/dysfunction of the left ventricle (LV) or left atrium (LA) (secondary or functional 7 MR). It is now recognized that primary and secondary MR are different diseases with 8 different prognostic implications and indications for treatment. The 2014 AHA/ACC 9 Guideline for the Management of Patients with Valvular Heart Disease (1) emphasizes 10 disease staging, wherein patients are classified as being at risk for developing MR (Stage 11 A), having mild or moderate MR which may progress over time (Stage B), asymptomatic 12 severe MR (Stage C) with normal (C1) or reduced (C2) LV function or symptomatic 13 severe MR (Stage D). Indications for treatment are dependent on disease stage, 14 characterization of which relies on accurate assessment of MR severity, as well as an 15 understanding of the efficacy and safety of therapy. A recent survey commissioned by 16 the ACC identified multiple knowledge and practice gaps among respondents, including 17 failure to identify clinically significant MR on physical examination, failure to recognize 18 the difference between primary and secondary MR, poor quality and incomplete 19 echocardiographic assessment and reporting, lack of awareness of guideline-based 20 recommendations for treatment, and lack of awareness of the volume and quality of 21 surgical repair at their institution (3). This consensus document focuses on the evaluation 22 and management of patients with MR with specific emphasis on 1) clinical assessment, 2) 23 proper identification of the mechanism and etiology of MR, 3) determination of MR 12 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 severity, 4) assessment of the feasibility of surgical or transcatheter repair, and 5) 2 indications for possible referral to a regional, comprehensive valve center. Within each 3 section, clear and precise terminology is recommended for communicating the essential 4 features of MR in the medical record. Because acute MR typically presents with 5 hemodynamic compromise for which the need for urgent intervention is well recognized, 6 this document focuses on chronic MR, where the current gaps in knowledge and practice 7 are more common. 8 6.1. Evaluation of the Patient 9 10 Assessment of the patient with chronic MR begins with a careful history and physical 11 examination. Symptoms may be absent or subtle, even in patients with severe MR due to 12 flail leaflet (Stage C) (5). The lack of symptoms in the chronic phase may relate to 13 enhanced LA compliance whereby the regurgitant volume (RVol) can be accommodated 14 within an enlarging LA without an increase in pressure sufficient to cause dyspnea. 15 Patients may also reduce their activity level to avoid symptoms, often subconsciously. It 16 is helpful to ask the patient what is the most vigorous activity s/he currently undertakes 17 and compare that to what s/he was able to do previously. Family members may often 18 report symptoms and/or diminished activity about which the patient is unaware. Another 19 simple question to ask is what s/he is capable of doing on a scale of 1-10, with 1 being no 20 activity at all and 10 being any activity without limitation (6). Common symptoms in 21 addition to exertional dyspnea include fatigue and palpitations. Incorporating a 22 standardized and validated patient questionnaire on health status into the medical record, 23 specifically the Kansas City Cardiomyopathy Questionnaire, is encouraged. This tool 24 provides insight into the patient’s perception of their functional state and quality of life 13 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 and is now routinely used before and after transcatheter therapy and entered into the 2 STS/ACC Transcatheter Valve Therapy (TVT) Registry. 3 If the patient is asymptomatic, exercise testing may be performed safely and may 4 elicit symptoms or demonstrate reduced exercise capacity. If done with 5 echocardiographic imaging exercise testing may show elevated PA systolic pressures, 6 worsening MR, or failure of LV or RV systolic function to augment normally (7-9). 7 Thus, exercise testing often results in reclassification of patients from Stage C to D or 8 even from Stage B to D. The 6 minute walk test is a simple, inexpensive, and 9 reproducible submaximal exercise tool to assess functional capacity. It may reflect 10 normal daily activity level better than maximal, symptom-limited exercise tests in fragile 11 or elderly patients. 12 In patients with primary MR, the presence of a diastolic filling complex (S3 plus 13 short diastolic murmur) suggests a significant RVol and severe MR. In secondary MR, an 14 S3 gallop is harder to interpret because it may be due to the underlying LV dysfunction. 15 If the murmur of primary MR is not audible after listening in multiple positions or with 16 dynamic maneuvers, or limited in timing to late systole only, it is likely that the 17 regurgitation is not severe. One or more non-ejection clicks may be audible. Differential 18 radiation of the murmur of primary MR provides a clue as to the underlying leaflet 19 pathology. Murmurs associated with anterior leaflet flail are directed to the axilla and left 20 infrascapular area, whereas murmurs with posterior leaflet flail radiate anteriorly and can 21 be confused with systolic ejection murmurs. With functional MR, the murmur is usually 22 best heard at the apex and radiates to the axilla. Atrial fibrillation (AF) or other 14 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 arrhythmias may be present in patients with MR and can make the examination more 2 challenging, particularly when the heart rate is rapid. 3 6.2. Hemodynamic Effects of MR 4 5 The hemodynamic effects of chronic severe primary MR are well known. Chronic MR 6 imposes a pure volume overload on the LV, resulting in eccentric hypertrophy and LV 7 dilation. Increased preload combined with low to normal afterload augments LVEF, 8 which is typically supranormal. As the LV dilates, LV wall stress increases. Incipient and 9 irreversible myocardial dysfunction may occur due to the longstanding LV volume 10 overload. Because the ejection fraction is a load dependent measure of LV function, it 11 can be preserved even when myocardial contractile function becomes abnormal. Thus, 12 current practice guidelines recommend intervention in primary MR before the LVEF falls 13 to or below 60% or the end-systolic dimension reaches or exceeds 4.0 cm (1). In 14 secondary MR, the relationship between LVEF and the associated volume overload is 15 confounded by the fact that LV dilation and decreased function are the cause rather than 16 the consequence of MR. However, the presence of any degree of secondary MR is 17 associated with worsened prognosis in both ischemic and nonischemic cardiomyopathies 18 (10-17). To date, no therapy, including valve repair or replacement, has been shown to 19 improve survival in patients with severe functional MR. 20 In addition to its effects on LV size, chronic severe MR results in LA dilation, 21 increased LA pressure and pulmonary venous hypertension. Accordingly, atrial 22 fibrillation is common in chronic severe MR. Persistent or long-standing persistent AF 23 may also cause or worsen MR due to the associated dilation of the LA and mitral 24 annulus. Therefore, the assessment of MR severity must take into account the 15 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 pathoanatomy of the mitral apparatus, the size and function of the LV, LA size/volume, 2 pulmonary artery pressure and the presence of AF. 3 6.3. Determining Mechanism and Etiology of MR 4 Figure 2. Decision Tree for Distinguishing Primary from Secondary MR 5 16 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 The identification of MR mechanism and etiology is most commonly achieved by 2 transthoracic echocardiography (TTE). Mitral valve morphology should be carefully 3 assessed in multiple views. If image quality is poor with TTE, transesophageal 4 echocardiography (TEE) may often be needed to define anatomy and function more 5 precisely. TEE may identify lesions such as vegetations or flail segments not detected by 6 TTE (18-22). Careful measurement of LV and LA volumes, as well as LV dimensions, 7 should be performed according to ASE guidelines for chamber quantification (23). Mitral 8 valve morphology, LV and LA volumes, and LV size and systolic function are used 9 together to classify the mechanism and etiology of MR (Figure 2). Abnormal mitral 10 leaflet morphology includes thickening, calcification, redundancy, perforation, 11 vegetations, other masses, and clefts. Such abnormalities should be described in detail 12 (diffuse vs focal, size, leaflet location). Abnormal subvalvular morphology includes 13 chordal rupture, thickening, fusion, vegetations or masses, which should similarly be 14 described in detail by size and location. Abnormal annular morphology includes dilation 15 and calcification. Mitral annular calcification can be localized posteriorly or extend into 16 the LV outflow tract or LV myocardium. When MR is due to primary mitral valve 17 pathology, left-sided chamber dilation should be considered a clue that the MR is both 18 chronic and severe. On the other hand, primary MR with normal LV and LA size, 19 function, and volume is unlikely to be severe. If the mitral apparatus is structurally 20 normal, significant MR is likely to be secondary. In such cases, the mechanism of MR 21 still needs to be identified. For example, most patients with secondary MR have a dilated 22 LV with global or regional wall motion abnormalities with either systolic tethering of the 23 leaflets, annular dilation, or both (24-29). However, isolated regional wall motion 17 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 abnormalities, particularly in the inferobasal or posterobasal segments may cause severe 2 secondary MR despite preserved LV function and dimensions. It is also possible to have 3 MR secondary to pure annular dilation in patients with severe LA dilation (30). This has 4 been termed “atrial functional MR” and it is mostly commonly seen in persistent or long- 5 standing persistent AF or in restrictive cardiomyopathies, such as that due to amyloid. 6 Once leaflet morphology is characterized, leaflet motion should be described using 7 Carpentier’s classification system (31). Normal leaflet motion (Type I) may be seen in 8 primary MR due to endocarditis, perforation, or clefts and in primary or secondary MR 9 due to isolated annular dilation. Excessive leaflet motion (Type II) is most commonly 10 seen with mitral valve prolapse or flail leaflet. Leaflet prolapse occurs when the leaflet 11 body moves above the saddle-shaped annulus in systole; leaflet flail occurs when a focal 12 portion of the leaflet edge moves above the annulus and zone of coaptation. With flail 13 leaflets, torn chords are usually visible and are associated with adverse prognosis. 14 Restricted leaflet motion (Type III) is sub-classified into restriction during both systole 15 and diastole (IIIA) or during systole only (IIIB). The former is classic for rheumatic 16 mitral valve disease, radiation or drug-induced injury, or other inflammatory conditions. 17 The latter is typical of MR secondary to ischemic or nonischemic cardiomyopathy. It is 18 also important to note that mixed pathology can and does occur. Untreated primary MR 19 eventually results in irreversible LV dilation/dysfunction in which both leaflet prolapse 20 and tethering may coexist. Other examples include patients with long-standing secondary 21 MR due to ischemic heart disease or AF who subsequently rupture a chord, or patients 22 with mitral valve prolapse who have a myocardial infarction or develop a 23 cardiomyopathy. A common mistake in clinical practice is to misconstrue anterior leaflet 18 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 override as prolapse. In Type IIIB leaflet motion, the posterior leaflet is often severely 2 tethered and the anterior leaflet overrides it (Figure 3) but does not move above the 3 annular plane. This finding does not equate with anterior leaflet prolapse, nor mixed 4 etiology MR. MR jet direction by color flow Doppler (CFD) provides an important clue 5 to the mechanism of MR. An anteriorly directed jet is most commonly due to posterior 6 leaflet prolapse/flail or anterior leaflet restriction, whereas a posteriorly directed jet is 7 typically due to anterior leaflet prolapse/flail or posterior leaflet restriction. If the jet 8 direction is eccentric, but the mechanism uncertain, TEE is indicated to clarify leaflet 9 pathology and motion. Table 1 lists the descriptors of MR mechanism and severity that 10 should be included in standardized echocardiographic reports. 11 12 13 Table 1. Suggested Qualitative and Quantitative Parameters for Standardized Echo Reporting 19 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 2 20 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 2 3 Figure 3. Anterior Leaflet Override in Functional MR LV PML AML LA 4 5 6 7 8 9 10 11 12 Figure 3. Anterior leaflet override in secondary MR due to ischemic cardiomyopathy. Apical long-axis views showing fixed posterior mitral leaflet (PML, blue arrow) with an overriding anterior mitral leaflet (AML, yellow arrow). Coaptation is absent with a large “wrap-around” color Doppler jet directed posteriorly by the fixed PML (right panel). This is commonly misdiagnosed as mitral valve prolapse, but cannot be such because the AML never moves superiorly to the mitral annulus (dotted line). LV = left ventricle; LA = left atrium. 13 14 6.3.1. Spectrum of Functional MR Functional MR occurs along a spectrum of severity of LV dysfunction. At one end of the 15 spectrum is a severely dilated, spherical LV with markedly depressed LV systolic 16 function and functional MR. Treatment of MR may not improve symptoms, quality of 17 life, or result in reverse LV remodeling because the primary problem is severe LV 18 dysfunction. Heart transplant or destination LV assist device therapy may be more 19 effective treatment strategies than mitral valve surgery in this context. At the other end 20 of the spectrum, a patient with an isolated inferobasal myocardial infarction may develop 21 severe functional MR due to posterior leaflet tethering, despite normal LV size and 22 ejection fraction. In such patients, the severe MR is the cause of heart failure and surgery 21 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 may be indicated for symptom relief. In the middle of the spectrum, it can be very hard 2 to distinguish whether MR, LV dysfunction, or both are contributing to heart failure 3 symptoms. 4 6.4. Assessment of MR Severity 5 6 6.4.1 Color Flow Doppler (CFD) Jet Size Severity of MR is most commonly assessed using CFD during TTE or TEE. CFD is a 7 misnomer because it is not actually a flow image. It is an image of the spatial distribution 8 of velocities within the image plane, and is profoundly affected by instrument settings 9 and hemodynamic factors (2). If these are held constant, the size of a jet through a given 10 effective regurgitant orifice area (EROA) is determined by its momentum flux, ρ AV2, 11 where ρ is blood density, A is orifice area and V2 is velocity squared (32). Thus, a 6.0 12 m/s MR jet appears 44% larger than a 5.0 m/s MR jet on CFD. High velocity MR jets, 13 such as occur with hypertension, aortic stenosis or LV outflow tract obstruction, will 14 therefore make MR appear worse on CFD (Figure 4) and this should be recognized by 15 the interpreting physician. Accordingly, it is crucial to record blood pressure, estimated 16 LV systolic pressure in the presence of aortic stenosis or LV outflow obstruction, heart 17 rate, and rhythm at the time of TTE and consider them when grading MR severity (2). 18 The tendency for CFD to overestimate MR severity has recently been shown in a study 19 comparing TTE to cardiac magnetic resonance (CMR) for quantitation (33) and also 20 explains why healthy individuals with no heart murmur often have mild MR on CFD 21 (34). On the other hand, MR can be significantly underestimated when jets have a low 22 driving velocity or are markedly eccentric as momentum is transferred to the LA wall 23 (35). Low velocity jets (i.e. 4 m/s) suggest high LA pressure and low LV pressure and 22 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 therefore indicate severe MR with hemodynamic compromise (assuming proper 2 alignment of the CW Doppler beam with the MR jet). In addition to jet driving velocity 3 and eccentricity, CFD jet size is affected by multiple other technical and hemodynamic 4 factors (36). Thus, both U.S. and European guidelines recommend that MR jet size by 5 CFD not be used alone to assess MR severity (32,37). 6 7 8 Figure 4. Effect of Driving Velocity on Size and Penetration of Color Doppler MR Jet 9 10 11 12 13 14 15 16 17 18 19 Figure 4. Example of the effect of driving velocity on size and penetration of MR jets. Top panels. Large MR jet (white arrows) penetrating deep into LA in apical 4- (left) and 2- (right) chamber views. In both views, the jet origin is narrow with a tiny proximal flow convergence zone (yellow arrows). Bottom left. CW Doppler of MR jet shows a very high velocity 6.5 m/s, corresponding to a LV-LA pressure gradient 170 mmHg. In this patient, severe aortic stenosis was present, leading to a very high LV systolic pressure. Bottom right. PISA confirms mild MR with EROA 0.10 cm2 and RVol 23 ml. 23 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 2 3 6.4.2. Quantitative Parameters Calculation of EROA, a marker of lesion severity, as well as RVol and regurgitant 4 fraction (RF), is strongly recommended by ASE Guidelines for assessing MR severity 5 (2). They can be measured by several techniques including the proximal isovelocity 6 surface area (PISA) method, volumetric methods and 3D imaging. It is crucial to 7 recognize the technical limitations and imprecision of each method and the overlap of 8 values obtained. Volumetric methods (including those with CMR) suffer from 9 multiplication of the errors inherent in measurement of stroke volumes at different 10 locations, but account for the whole of MR over the duration of systole. Single frame 11 measurements, such as with PISA or vena contracta width or area, can markedly 12 overestimate MR severity when the jet is limited to early or late systole (Figure 5) (38). 13 When MR is holosystolic, properly measured values of EROA ≥ 0.4 cm2, RVol ≥ 60 ml 14 or RF ≥50% are highly specific for severe MR. Properly measured values of EROA ≤ 0.2 15 cm2, RVol ≤ 30 ml or RF < 30% are highly specific for mild MR. Intermediate values 16 can occur in severe MR, but lack specificity. An example wherein lower values of 17 EROA and RVol may represent severe MR include markedly crescentic orifice geometry 18 in secondary MR, where PISA yields a falsely low value for EROA due to its inherent 19 assumption of a round orifice (Figure 6) (39-48). Another example is when multiple MR 20 jets are present, such that a measured EROA from a single jet does not reflect the totality 21 of MR severity. Addition of multiple EROA or vena contracta areas should be accurate, 22 but has not been well validated. It is also common to find lower quantitative values in the 23 setting of flail leaflets or with relatively smaller LV volumes (i.e. women). In such cases, 24 there are usually other signs of severe MR. 24 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 2 3 4 5 6 7 8 9 10 11 Figure 5. MR Limited to Late Systole in Mitral Valve Prolapse Figure 5. Example of non-holosystolic MR in mitral valve prolapse. Top panels show no MR by color Doppler in early systole (top left) and mid-systole (top right). Late systolic MR is present by color Doppler (bottom left) and continuous wave Doppler (bottom right). EROA calculated as 0.24 cm2 with RVol 17 ml. LA volume, LV size and systolic function and pulmonary vein flow were normal in this patient with mild MR. However, relying only on the single frame EROA in this case would overestimate MR severity. 25 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 2 3 4 5 6 7 8 9 10 11 12 13 Figure 6. Example of Underestimation of EROA by 2D PISA in a Patient with Secondary MR and a Markedly Crescentic Orifice Shape Figure 6. Underestimation of EROA and RVol by 2D PISA due to markedly crescentic orifice shape. Top Panel: TEE Image with 2D PISA EROA 0.25 cm2. Bottom Panel: 3D Reconstruction of the Vena Contracta Showing Larger Orifice of 0.5 cm2. Left panels show PISA radius (top left) and CW velocity of MR (bottom left) by TEE. EROA and RVol calculate to values of 0.17 cm2 and 22 ml, respectively. Middle and Right panels show 3D reconstruction of the vena contracta (bottom middle), which is crescentic in shape with measured area (VCA) 0.52 cm2 and calculated RVol 67 ml. The PISA values (which assume circular orifice geometry) indicate mild MR; the 3D VCA severe MR. 26 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 6.4.3. Integration of Multiple Parameters 2 3 Figure 7. Decision Tree for Assessing Severity of MR by TTE 4 5 27 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 A comprehensive approach is recommended whereby multiple parameters are evaluated 2 and integrated to form a final determination of MR severity (2,37). The strengths and 3 limitations of these parameters are listed in Table 2 and have been described in detail in 4 the ASE Guidelines for Assessment of Native Valve Regurgitation (2). Evaluation of MR 5 severity requires a comprehensive TTE study that includes assessment of these 6 parameters. It is important to emphasize that no single echocardiographic parameter has 7 the measurement precision or reproducibility to serve as the sole arbiter of MR severity. 8 Moreover, MR severity is notoriously dynamic (49-51). Therefore, the effects of chronic 9 MR on LV and LA volumes and pulmonary artery pressure must be considered in an 10 integrative fashion. Nevertheless, it is recognized that most physicians interpreting an 11 echocardiogram look at CFD to identify the presence of MR and form an initial 12 impression of its severity. This type of assessment should be considered only a starting 13 point that requires further confirmation using a Bayesian approach that integrates 14 multiple factors to arrive at a final determination (Figure 7). After an initial impression 15 of MR severity is formed, one should next consider whether LA and LV sizes are normal 16 and whether the MR is holosystolic. For example, if one assesses MR as severe based on 17 a large CFD jet, but LA and LV sizes are normal and the MR is limited to late systole, the 18 initial impression is most likely an overestimate. One should consider common reasons 19 for overestimation of MR, such as high MR driving velocity (Figure 4) and MR duration 20 limited to very early or very late systole (Figure 5). When multiple specific parameters 21 for mild or severe MR align with the initial impression of MR severity, MR can be 22 correctly graded with high probability of being accurate. Fortunately, this scenario is 23 relatively common in practice, especially with the finding of mild MR and a structurally 28 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 normal mitral valve. However, when different parameters are discordant among 2 themselves or with the clinical findings, MR severity should be considered uncertain and 3 further testing pursued. In such cases, TEE may be sufficient to define leaflet pathology 4 and quantitate MR severity. CMR is generally more accurate and reproducible for 5 quantitating RVol and RF, as well as LV volumes and LVEF (52-56). 6 7 8 Table 2. Strengths and Limitations of Common Echocardiographic Parameters of MR Severity Parameter Strengths Weaknesses Valve Morphology Flail leaflets or ruptured papillary muscles are specific for severe MR Other findings are nonspecific Regurgitant Color Flow Easy to use, evaluates spatial orientation of MR jet, differentiates mild versus severe Subject to technical and hemodynamic variation; can be underestimated with wallimpinging jets (Coanda effect); image qualitydependent Vena Contracta Width Quick and easy to use; independent of hemodynamic and instrumentation factors; applies to eccentric jets; can differentiate mild versus severe MR Not applicable to multiple jets, intermediate values require confirmation; small measurement errors can lead to big changes; 2D measure of a 3D structure Proximal Isovelocity Surface Area (PISA) Can be applied to eccentric jets (when angle corrected); not affected by etiology of MR; quantitative: provides both lesion severity (EROA) and volume data (R Vol); flow convergence at Nyquist limit of 50–60 cm/s alerts reader to significant MR Not valid with multiple jets; provides peak flow and maximal EROA; interobserver variability; errors in radius measurement are squared; multiple potential sources of measurement error Flow Quantitation–PW Quantitative; valid in multiple jets and eccentric jets; Time consuming; measurement of flow at MV 29 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED provides both lesion severity (EROA, RF) and volume data (RVol) annulus less reliable with calcified MV and/or annulus; not valid with concomitant significant AR unless pulmonic site is used; requires measurement at multiple sites, which introduces errors Jet Profile–CW Simple, readily available Qualitative; complementary data; complete signal difficult to obtain in eccentric jet; gain dependent Peak Mitral E Velocity Simple, readily available, Awave dominance excludes severe MR Influenced by LA pressure, LV relaxation, MV area, and AF; complementary data only, does not quantify MR severity Pulmonary Vein Flow Simple; systolic flow reversal is specific for severe MR Influenced by LA pressure, AF; not accurate if MR jet directed into the sampled vein; absence does not rule out severe MR LA and LV Size Enlargement sensitive for chronic severe MR, important for outcomes; normal size virtually excludes severe chronic MR Enlargement seen in other conditions (non-specific); may be normal in acute severe MR 1 2 3 Abbreviations: AF = atrial fibrillation; AR = aortic regurgitation; CW = continuous wave; EROA = effective regurgitant orifice area; LA = left atrium; LV = left ventricle; MR = mitral regurgitation; MV = mitral valve; RF = regurgitant fraction; RVol = regurgitant volume 4 Right and left heart catheterization may be indicated to assess hemodynamics; 5 despite its known limitations, a high quality biplane LV angiogram can also be helpful in 6 resolving uncertainty. Invasive measurement of pressures, cardiac output and pulmonary 7 vascular resistance allows a comprehensive assessment, results of which can be 8 correlated with symptoms and response to medical therapy. Stress echocardiography can 9 also be a valuable tool to assess any discrepancies between non-invasive and clinical 10 findings and help define symptoms, exercise capacity, MR severity, pulmonary artery 30 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 systolic pressure and LV/RV responses to exercise. High quality CMR can be very 2 helpful in many patients in whom MR severity is unclear, though the technology is not 3 widely available. Consideration should be given to referring such patients to a 4 comprehensive valve center for multidisciplinary evaluation and treatment. 5 An evidence-based algorithm for the evaluation and management of patients with 6 MR is outlined in Figure 8. Based on the 2014 ACC/AHA Guidelines for the 7 Management of Patients with Valvular Heart Disease (1), this algorithm attempts to 8 mitigate any potential gaps in the clinical approach to MR (19). Decisions as to when to 9 follow and when to refer patients with MR for further assessment or valve intervention 10 can be challenging. Once the diagnosis of MR is established by TTE, the next steps are to 11 establish the clinical context and symptomatology, the etiology of MR (primary vs. 12 secondary vs. mixed), and its severity using the integrative methods previously outlined. 13 This expert consensus algorithm provides a roadmap for the clinician to navigate 14 decision-making for additional testing or referral for definitive treatment. The latter is 15 discussed further below. 16 17 31 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 Figure 8. Clinical Algorithm for the Management of MR based on TTE 2 3 4 5 Note: Please see another attachment for the high resolution image 32 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 2 6.4.4 Dynamic Nature of MR MR is a dynamic condition and its severity can change with LV load (49). Sedation and 3 reduced blood pressure during TEE may result in a significant reduction in MR severity, 4 compared to an assessment with TTE in the awake state. Patients with hypertensive 5 urgency can present with moderate or severe MR that resolves completely with control of 6 blood pressure. On the other hand, MR severity can increase with maneuvers that 7 decrease LV afterload in patients with mitral valve prolapse (57) or hypertrophic 8 obstructive cardiomyopathy. Guideline-directed medical therapy, revascularization, and 9 cardiac resynchronization may improve MR severity in functional MR, particularly if 10 such interventions result in reverse LV remodeling or improved regional wall motion. In 11 addition to changing over time, MR severity is dynamic within the cardiac cycle (50,51). 12 The classic example is late systolic MR due to prolapse. It is important to recognize this 13 phenomenon because single frame measurements on TTE or TEE may overestimate MR 14 severity. In such circumstances, EROA or RVol should be measured with volumetric 15 techniques that include all of systole (38). It is possible to correct EROA for duration of 16 systole, but this method has not been validated. In secondary MR, a biphasic pattern can 17 be seen in which MR improves during mid-systole when LV pressure (i.e. closing force) 18 is at its maximum (50). It is important for the sonographer not to “overgain” the machine 19 to make this phenomenon disappear. It is also important to measure PISA radius and MR 20 peak velocity at the same point in the cardiac cycle (2). CFD measures of MR severity 21 can vary significantly during rapid AF or with large variations in the R-R interval. 22 Likewise, caution must be used to avoid measuring MR during PVCs or post-PVC beats. 23 Early systolic or late diastolic MR can occur with conduction system abnormalities and 33 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 this should be recognized as a potential source of overestimating MR severity by single- 2 frame technique (58). 3 4 6.4.5 Differences in Assessing MR Severity in Primary vs. Secondary MR Primary MR is generally easier to evaluate because of the morphological abnormalities of 5 the mitral leaflets or chordae. Some morphological abnormalities, such as a flail leaflet 6 with torn chords, severe leaflet retraction without visible coaptation, or leaflet destruction 7 and perforation due to endocarditis, are specific markers of severe MR. LV or LA 8 dilation in chronic primary MR is most often a consequence of the MR and a strong clue 9 that the MR is severe. Exceptions could occur if a patient with long-standing mitral valve 10 prolapse and mild MR develops an ischemic or nonischemic cardiomyopathy. On the 11 other hand, when MR is primary and LV and LA size are normal, severe MR is very 12 unlikely. Secondary MR is more difficult to grade because morphological abnormalities 13 of the leaflets and chords are absent. Symptoms, pulmonary congestion on exam or chest 14 x-ray, elevated BNP or NT-pro-BNP and adjunctive findings on TTE or TEE, such as LV 15 or LA dilation and systolic blunting of the pulmonary venous flow pattern may be due to 16 the underlying cardiomyopathy and therefore are less helpful in grading MR severity. 17 Further confounding this situation is the fact that in secondary MR, the shape of the 18 regurgitant orifice is often markedly crescentic, which leads to underestimation of EROA 19 by the PISA method because the latter assumes a round orifice (39-48). This inaccuracy 20 can be ameliorated by 3D PISA measurements or direct 3D measurement of EROA by 21 TTE or TEE. Such measurements have been validated against CMR (45,47). 22 Importantly, EROA and RVol thresholds that constitute severe MR are related to LV 23 volumes (59). As an example, consider two patients with LVEF 30%, but LV end- 24 diastolic volumes of 200 mL and 400 mL, respectively. The former has a total stroke 34 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 volume of 60 mL; the latter 120 mL. In the former patient, an EROA of 0.3 cm2 with a 2 MR velocity-time integral of 150 cm yields an RVol of 45 mL. Although these values 3 are in the traditional range of moderate MR, they constitute a RF of 75% (45mL/60mL), 4 consistent with severe MR and loss of 3/4ths of forward cardiac output into the LA. In 5 the latter patient, the same values (EROA 0.3 cm2 and RVol 45 ml) would yield a RF of 6 37.5%, consistent with moderate MR. Thus, consideration of quantitative values for MR 7 severity should also account for LV volumes and ejection fraction. 8 9 6.4.6 Prognosis in MR Table 3 lists prognostic variables important in the assessment of primary MR. Some of 10 these are clinical (age, heart failure, coronary artery disease, and functional class). 11 Others relate to MR itself or the effects of MR on the LV or LA. LVEF < 60%, LV end- 12 systolic diameter > 0.4 cm, or LA systolic volume index > 60 mL/m2 have all been 13 associated with worse prognosis (60-63). Flail leaflet itself is associated with an adverse 14 prognosis and is usually a specific sign for severe MR (5,60,61), although occasionally 15 patients with flail leaflets only have moderate MR by integrative assessment. Rare 16 patients with flail leaflet may experience sudden cardiac death (64) and consideration 17 could be given to earlier treatment referral. Secondary MR has been associated with an 18 adverse prognosis in multiple studies (10-17). In ischemic cardiomyopathy, the presence 19 of MR of any grade results in worse long-term prognosis, but severe ischemic MR is also 20 an indicator of short-term mortality. An EROA ≥ 0.2 cm2 has been shown to be a 21 predictor of adverse outcomes in some but not all studies of patients with functional MR 22 (11,14,16). Importantly, it appears that secondary MR is an independent marker of 23 adverse prognosis, even when LV volumes, LVEF, renal function, and other parameters 35 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 are included in multivariable analysis (12,15). Surgical correction of secondary MR may 2 improve symptoms and quality of life, but has not been shown to improve survival (65). 3 Table 3. Factors Affecting Prognosis in Primary MR Primary MR 1. Factors related to the LV or LA 2. Clinical factors Systolic dysfunction (EF < 60%) LV enlargement (LVESD > 4cm) LA enlargement (LA systolic volume index ≥ 60 ml/m2) Age Presence/absence heart failure Functional class Presence/absence CAD 3. Hemodynamic (other) factors AF Pulmonary hypertension 4. Factors related to the MR Severity of regurgitation flail leaflet Delay in MV intervention 4 5 Abbreviations: AF = atrial fibrillation; CAD = coronary artery disease; EF = ejection fraction; LA = left atrium; LV = left ventricle; LVESD = left ventricular end-systolic diameter; MR = mitral regurgitation; MV = mitral valve 6 6.5. Treatment of Chronic Mitral Regurgitation 7 8 Deciding on the optimal treatment of chronic MR is based on multiple variables 9 including MR type and severity, hemodynamic consequences, disease stage, patient co- 10 morbidities and the experience of the managing physician/surgeon (66). Evidence-based 11 management may be aided by use of the algorithm in Figure 8. Reporting 12 echocardiographic findings using standardized nomenclature helps guide 13 surgical/interventional decision-making (31). The anterior and posterior leaflets are 14 divided into three anatomic sections from lateral to medial (A1, A2, A3, and P1, P2, P3, 15 respectively). The two leaflets meet at the lateral and medial commissures, where focal 16 pathology (e.g., calcification) may occur. The chordal structures may have excess or 36 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 restricted motion and are defined by their leaflet insertion as primary (leading edge 2 insertion), secondary (mid-scallop insertion), and tertiary (basal insertion). A well- 3 performed TTE is sufficient for treatment planning in most instances. The majority of 4 information needed to complete surgical/interventional planning can be obtained with 4 5 conventional TEE views: the mid-esophageal 4-chamber, long-axis 2-chamber, mid- 6 commissural 2-chamber and the basal short-axis view. Though focused use of CFD at a 7 Nyquist of 50-60 cm/sec may aid in mechanism confirmation, planning for intervention 8 should be based on imaging without color in each of these views. 9 The principal treatment modality for primary MR is surgery. Transcatheter mitral 10 repair using an edge-to-edge clip has a very limited role at present for the treatment of 11 patients with primary MR and severe symptoms who are felt to be poor surgical 12 candidates. Surgical treatment for secondary MR is undertaken only after appropriate 13 medical and device therapies have been instituted. Transcatheter repair systems other 14 than the edge-to-edge clip, as well as transcatheter mitral valve replacement devices, 15 currently are not approved for clinical use in the United States but remain the subject of 16 clinical trial investigation. 17 18 6.5.1. Surgical Treatment of Mitral Regurgitation Mitral valve surgery is indicated in patients with primary severe MR and EF > 30% who 19 are symptomatic (Stage D) or when asymptomatic but with LVEF 30%-60% or LV end- 20 systolic dimension > 4.0cm (Stage C2) (1). Mitral valve repair is strongly preferred over 21 replacement for primary MR whenever anatomically feasible and as dictated by the 22 experience and skill of the operating surgeon. Mitral valve repair is reasonable in patients 23 with primary MR and preserved LV size and systolic function when AF has recently (< 3 24 months) intervened or when resting PA pressures are elevated (>50 mm Hg at rest). 37 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 Mitral valve repair is also reasonable for asymptomatic patients with normal LV size and 2 function when the likelihood of a successful and durable repair without residual MR 3 exceeds 95% and operation can be performed with <1% mortality at a comprehensive 4 heart valve center. Short- and long-term outcomes of successful valve repair for primary 5 MR exceed those for valve replacement across all age ranges. Successful repair at the 6 indicated time results in long-term survival equivalent to that of the normal age-matched 7 population (67,68). Timely surgical referral for primary MR must take into account the 8 feasibility of repair and knowledge of surgeon and institutional outcomes. The latter is 9 particularly relevant when considering referral of an asymptomatic patient. 10 Indications for mitral valve surgery for moderate or severe functional MR are 11 more limited, in part related to the recognition that valve intervention in this patient 12 group may improve symptoms and quality of life, but does not currently equate with 13 improved survival. Mitral valve repair (usually with an under-sized annuloplasty ring) 14 may be considered at the time of other cardiac surgery (e.g., CABG) for patients with 15 moderate functional MR. In patients with severe functional MR, mitral valve surgery 16 (either replacement or repair) is reasonable at the time of other cardiac surgery (e.g., 17 CABG) and can be considered as an isolated procedure for patients with advanced 18 NYHA class despite guideline-directed medical therapy and cardiac resynchronization 19 when indicated. The decision to replace or repair the valve can be challenging (65) and is 20 deferred to an experienced surgeon in consultation with the heart valve team. 38 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 6.5.2. Feasibility of Surgical Repair 2 3 4 Figure 9. Decision Tree for Determining Surgical Mitral Valve Repair vs. Replacement in Patients with Severe MR 5 39 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 Mitral valve repair is a complex operation comprising a wide spectrum of available 2 techniques to achieve durable success (69). The principal goals of mitral valve repair are 3 to restore leaflet coaptation depth to greater than 5 mm, stabilize and remodel the 4 annulus, restore normal leaflet motion, and eliminate MR. The major factors determining 5 repair feasibility are pathoanatomy and surgeon experience. 6 The surgical spectrum of primary MR with Carpentier type II motion ranges from 7 focal prolapse in the setting of an otherwise anatomically normal mitral valve, known as 8 fibroelastic deficiency, to a more diffuse process with excess, redundant, billowing tissue 9 as noted in Barlow’s syndrome (70) or an intermediate between these 2 extremes referred 10 to as a forme fruste. In primary MR with Carpentier type IIIA motion, the surgical 11 spectrum includes focal or diffuse leaflet and subvalvular thickening and commissural 12 fusion due to rheumatic heart disease, prior radiation or other inflammatory conditions. 13 Both of these causes of primary MR may occur in the same patient, potentially affecting 14 repair feasibility, and highlighting the critical importance of preoperative imaging. 15 Common techniques of mitral valve repair are listed in Table 4 and include construction 16 of artificial neochordae with polytetrafluoroethylene or limited triangular resection as 17 applied in cases of focal prolapse or fibroelastic deficiency, and extensive posterior 18 leaflet resection and remodeling in cases of diffuse myxomatous degeneration and 19 echocardiographic predictors of post-operative systolic anterior motion of the anterior 20 mitral valve leaflet. A suggested approach to determine the feasibility and complexity of 21 repair is described in Table 5. Patients presenting with echocardiographic findings of 22 focal posterior prolapse or flail without annular or leaflet calcium often have a high 23 success rate for durable repair by the majority of experienced valve surgeons. However, 40 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 once additional annular, commissural or bileaflet pathoanatomic complexities arise, in 2 isolation or combination, more specific experience with mitral valve repair may often be 3 required to achieve a technically successful and durable result. Other confounding factors 4 impacting reparability that may necessitate advanced mitral surgical evaluation include 5 mitral reoperations, prior mitral endocarditis, basal septal hypertrophy with 6 echocardiographic predictors of post-operative systolic anterior motion of the anterior 7 mitral leaflet and congenital anomalies. Patients who have a single segment flail of the 8 posterior leaflet due to fibroelastic deficiency in the absence of calcification of the 9 annulus or leaflets have the highest chance of technically successful and durable valve 10 repair. These patients should not undergo valve replacement (1). Alternatively, patients 11 with severe anterior, bileaflet, Barlow’s or mixed disease that may require extensive and 12 complex reparative techniques should be preferentially referred to an experienced mitral 13 valve surgeon at a high volume institution. There is a small subgroup of patients with 14 primary MR in whom valve replacement may be preferred over valve repair, such as 15 those who have had prior cardiac operation or prior chest radiation, in whom any 16 subsequent operation for a failed repair would be undertaken at substantially increased 17 risk. Figure 9 provides a more detailed guide to decision-making for mitral repair or 18 replacement based on Carpentier’s classification. Figure 10 shows echocardiographic 19 examples of mitral valve morphologies that are likely, possible or challenging for 20 successful and durable mitral valve repair. Surgeon experience has been recognized as a 21 primary determinant of successful mitral valve repair. Registry data from 2005 to 2007 22 estimated a nearly 3-fold likelihood of repair when surgeon experience was over 100 23 cases per year compared to 5-10 per year, with a threshold for frequency of successful 41 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 repair being over 50 mitral surgical cases per year (repair or replacement) (71). However, 2 data from the last 5 years have shown a doubling of the frequency of mitral valve repair 3 over replacement, and the initial success rate for isolated mitral valve repair for primary 4 MR is now over 75% across the United States (69,72). Nevertheless, for asymptomatic 5 Stage C1 patients or for those with complex mitral pathoanatomy, or for patients who 6 desire a minimally invasive or robotic approach, consideration should be given to referral 7 to an experienced mitral surgeon at a comprehensive valve center (1). 8 9 10 Table 4: Pathoanatomically Directed Contemporary Surgical Techniques for Mitral Regurgitation Primary Mitral Regurgitation 1. Non-resection techniques using polytetrafluorethylene (PTFE) neochord reconstruction with annuloplasty ring May be used for focal leaflet flail or bileaflet prolapse May be used for forme fruste* diffuse myxomatous disease of the posterior leaflet May be used for isolated anterior leaflet prolapse 2. Focal triangular resection with annuloplasty ring May be used for focal leaflet flail of the posterior or commissural leaflet 3. Sliding leaflet valvuloplasty with annuloplasty ring May be used for forme fruste* diffuse posterior leaflet myxomatous disease May be used in the setting of bileaflet prolapse with excess posterior leaflet May be used in any of the above with significant echocardiographic predictors of systolic anterior motion of the anterior mitral valve leaflet Secondary Mitral Regurgitation 11 12 13 14 1. Restrictive remodeling rigid annuloplasty ring May be used as primary modality for annular dilatation mechanism May be used in conjunction with secondary or tertiary chordal cutting May be used with other adjunctive procedures (i.e., papillary muscle sling) Avoided as sole therapy in setting of Carpentier Type IIIB mechanism with left ventricular inferobasal aneurysm 2. Chord-sparing mitral valve replacement May be used as primary modality for annular dilatation with severe leaflet tethering (i.e., ≥ 10 mm tenting height) or presence of inferobasal aneurysm * See text. Forme fruste refers to a pathoanatomic form of primary MR intermediate between fibroelastic deficiency and Barlow’s disease. 42 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 2 Table 5. Feasibility of Transcatheter Edge-to-Edge Clip Repair 3 4 Abbreviations: BSA = body surface area; EROA = effective regurgitant orifice area; HOCM = hypertrophic obstructive cardiomyopathy; MAC = mitral annular calcification. 5 Note: Transcatheter edge-to-edge clip repair is approved for use in the United States only for patients with primary MR, severe symptoms and high or prohibitive operative risk. 6 Adapted from Hahn, R (73). 43 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Figure 10. Examples of Valve Morphology that is Amenable to Surgical Repair in Patients with Primary MR Figure 10. TEE images showing examples of primary mitral valve pathology with different likelihood of durable surgical repair. Long-axis views (left panels), bicommissural views (middle panels) and 3D en face views (right panels) are shown. At top, durable surgical repair is likely with thin, pliable leaflets (yellow arrow, left panel) with torn chords to the posterior middle scallop (P2) seen in the middle (blue arrow) and right panels (yellow arrows). Durable surgical repair is possible in the middle panel. Both anterior and posterior leaflets exhibit marked prolapse (yellow arrows, left panel) involving multiple scallops with torn chords (middle panel, blue arrow, right panel, yellow arrows). The annulus is severely dilated. The bottom panel shows a patient for whom durable repair is challenging due to severe mitral annular and leaflet calcification (yellow arrows) with restricted leaflet excursion (right panel). In addition to severe MR, this patient had a mean transmitral gradient 14 mmHg at a resting heart rate of 68 min-1. 18 19 6.5.3. Determination of Risk for Surgery When a patient is being evaluated for treatment of MR, a key component is an assessment 20 of the individual’s risk for surgical mitral valve repair or replacement. Evaluation 21 includes the use of a standardized Predicted Risk of Mortality (PROM) developed by The 44 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 Society of Thoracic Surgeons based on the outcomes of large numbers of patients who 2 have undergone surgery (72,74). There are additional factors not included in this risk 3 score that contribute to procedural and post-procedural risk including liver disease, 4 pulmonary hypertension, porcelain aorta and post-radiation scarring, as well as the 5 patient’s ability to recover from the trauma of surgery due to frailty. Measures of frailty 6 such as the 5-meter or 6-minute walk test and hand grip strength have become part of the 7 routine evaluation of elderly patients in whom recommendations must be made 8 considering surgical and transcatheter approaches incorporating the clinical judgment of 9 the heart team. The AHA/ACC 2014 Guideline for the Management of Patients with 10 Valvular Heart Disease include a risk assessment tool that incorporates these 11 considerations. 12 13 6.5.4. Transcatheter Treatment of Mitral Regurgitation The desirability of transcatheter options for the treatment of mitral regurgitation is driven 14 by the increasing prevalence of this valve lesion among an aging population with 15 significant co-morbidities that render many patients poor candidates for surgical 16 intervention. Lower risk procedures that effectively reduce the severity of mitral 17 regurgitation and provide a means to improved clinical outcomes are the goals of 18 transcatheter interventions. 19 The complex, functional anatomy of the mitral apparatus has challenged the 20 development of effective transcatheter strategies for the management of MR. There is 21 wide inter-patient variability in the individual contributions of each component (leaflets, 22 annulus, chordae, papillary muscles and subjacent myocardium) to the emergence and 23 progression of MR. Transcatheter repair techniques can be targeted to the leaflets, 45 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 annulus or chordae, either solely or in combination. Transcatheter mitral valve 2 replacement remains investigational (75-77). At present, edge-to-edge mitral leaflet 3 coaptation using a clip to approximate opposing segments of the anterior and posterior 4 leaflets is the only FDA-approved system for transcatheter repair in the United States 5 (78,79). Furthermore, its use is restricted to the management of symptomatic (NYHA 6 Class III or IV) patients with severe, primary MR, reasonable life expectancy and 7 prohibitive surgical risk due to co-morbidities (1,79). The safety and efficacy of this 8 technology for the treatment of patients with symptomatic, severe functional MR is being 9 studied in a randomized controlled trial [Cardiovascular Outcomes Assessment of the 10 MitraClip Percutaneous Therapy (COAPT) Trial (NCT 01626079)], results of which are 11 expected in 2020. Edge-to-edge leaflet repair for patients with functional MR is used 12 more frequently in centers outside the United States (80). Several other transcatheter 13 repair systems are in development (e.g., annular devices) but are not currently available 14 for clinical use (76). This area is likely to change rapidly over time. 15 16 6.5.5. Edge-to-Edge Leaflet Coaptation Transcatheter edge-to-edge leaflet coaptation using a clip is based on the surgical 17 technique described by Alfieri (81) and results in creation of a double orifice mitral valve 18 and reduction in the severity of MR (Figure 11). Successful deployment can result in 19 improved hemodynamics and patient outcomes. Appropriate patient selection is critically 20 dependent on rigorous clinical and echocardiographic assessment (Figure 12). Intra- and 21 post-procedural management algorithms facilitate best practices. Operator and 22 institutional criteria for the performance of transcatheter mitral valve repair have been 23 published in a joint, multi-societal expert consensus document (3). 24 46 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 2 Figure 11. Transcatheter Edge-to-Edge Mitral Valve Clip 3 4 5 6 7 8 9 Figure 11. Transcatheter edge-to-edge mitral valve clip. Top left. 3D en face view showing flail anterior leaflet with torn chord (arrow). Top right. Transcatheter edge-to-edge clip creates tissue bridge between anterior and posterior leaflets (arrow). Bottom left. Color flow image showing severe MR at beginning of case. Bottom right. Reduction of MR from severe to trace after transcatheter edge-to-edge clip placement. 10 47 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 2 Figure 12. Algorithm for Determining Eligibility for Transcatheter Edge-to-Edge Mitral Valve Clip 3 4 5 6.5.6. Feasibility of Edge-to-Edge Leaflet Coaptation Figure 13 and Table 1 include the key echocardiographic parameters used to assess 6 suitability for transcatheter edge-to-edge repair (73). The procedure is usually performed 7 by 1or 2 operators in a cardiac catheterization laboratory or hybrid suite. A multi- 8 disciplinary team, which includes at a minimum a clinical heart valve specialist, multi- 9 modality cardiac imaging expert, interventional cardiologist and cardiac surgeon, is 10 required for patient evaluation, selection and periprocedural management. Other 11 transcatheter mitral valve repair systems for primary MR may become available for 12 clinical use in future years and dictate new requirements for patient assessment and 13 selection. 48 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 Figure 13. Transcatheter Edge-to-Edge Mitral Valve Clip 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Figure 13. TEE images showing examples of mitral anatomy with varying degrees of difficulty for transcatheter edge-to-edge clip therapy. Top Left: 3D en face View Showing Flail Anterior Leaflet with Torn Chord (Arrow). Top Right: Transcatheter Edge-to-Edge Clip Creates Tissue Bridge between Anterior and Posterior Leaflets (Arrow). Bottom Left: Color Flow Image Showing Severe MR at Beginning of Case. Bottom Right: Reduction of MR from Severe to Trace after Transcatheter Edge-to-Edge Clip Placement. Left panels are long-axis view, middle panels bicommissural views, and right panels 3D en face views. The top panel shows anatomy for which successful repair is likely. The posterior middle scallop (P2) is flail (arrows) with normal leaflet thickness and no mitral annular calcification. The middle panel is a challenging case with no significant pathology of the middle segments (long-axis) but flail P1 and P3 2 segments (arrows). The diastolic mitral area was 4.8 cm , allowing room for clips in both commissures. The bottom panel shows a patient with severe mitral annular calcification (yellow 2 arrows) and a flail P3 segment (blue arrows). The mitral valve area was 2.8 cm , which is below 2 the threshold value (4.0 cm ) and would likely result in mitral stenosis. 7. DISCUSSION AND IMPLICATION OF PATHWAY 21 22 The last several years have witnessed important advances in the evaluation and 23 management of patients with chronic MR. Building upon the 2014 AHA/ACC Guideline 24 for the Management of Patients with Valvular Heart Disease, the material in this expert 49 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 consensus document serves to provide the clinician with additional tools to improve the 2 care of MR patients. Multidisciplinary heart teams composed of experienced surgeons, 3 interventionalists, expert imagers and others are vital to the provision of advanced care to 4 challenging patients at comprehensive valve centers. Closing the existing knowledge and 5 treatment gaps in the management of these patients, as well as the achievement of high 6 value care, requires ongoing close collaboration across primary care, cardiology and 7 cardiac surgical communities, as emerging technologies for the treatment of mitral valve 8 disease are evaluated with a dedicated focus on high quality outcomes. 9 Key Points 10 11 12 using quantitative echocardiography and other testing as indicated. 13 14 The prognostic, evaluative and management differences between primary and secondary (functional) MR should be recognized. 17 18 Standardized echocardiographic reporting is critical for informed patient management. 15 16 Once MR is recognized, its etiology, mechanism and severity should be defined A heart valve team consensus treatment recommendation should be discussed with the patient and family to enable shared decision-making. The indications for and techniques utilized in surgical treatment of primary and 19 secondary MR differ. For patients with severe primary MR, referral for repair to 20 an experienced mitral valve surgeon at a comprehensive valve center should be 21 considered when pathoanatomic findings include lesions other than isolated 22 posterior segment pathology. 50 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 Current use of the edge-to-edge clip in the United States for transcatheter mitral 2 valve repair is limited to symptomatic patients with primary, severe MR who are 3 poor operative candidates. Other transcatheter systems are under investigation. 4 5 6 7 Evidence-based medical therapy should be optimized in patients with secondary (functional) MR before decision-making for surgical intervention. Long-term follow-up of patients after surgical or transcatheter intervention is critical for assessment of durability, functional outcomes and survival. 51 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED 1 2 3 4 5 6 7 8 9 10 11 PRESIDENTS AND STAFF Richard Chazal, MD, FACC, President Shalom Jacobovitz, Chief Executive Officer William J. Oetgen, MD, MBA, FACC, Executive Vice President, Science, Education, Quality, and Publications Joseph M. Allen, MA, Team Leader, Clinical Policy and Pathways Lea G. Binder, MA, Team Leader, Physician Clinical Pathways Sahisna Bhatia, MPH, Project Manager, Clinical Policy and Pathways Amelia Scholtz, PhD, Publications Manager, Science, Education, Quality, and Publications 52 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED APPENDIX 1: Author Relationships With Industry and Other Entities (Relevant) — 2017 ACC Expert Consensus Decision Pathway on the Assessment of Mitral Regurgitation Relationships with Industry and Other Entities To avoid actual, potential, or perceived conflicts of interest that may arise as a result of industry relationships or personal interests among the writing committee, all members of the writing committee, as well as peer reviewers of the document, are asked to disclose all current healthcare-related relationships, including those existing 12 months before initiation of the writing effort. The ACC Task Force on Clinical Expert Consensus Documents reviews these disclosures to determine what companies make products (on market or in development) that pertain to the document under development. Based on this information, a writing committee is formed to include a majority of members with no relevant relationships with industry (RWI), led by a chair with no relevant RWI. RWI is reviewed on all conference calls and updated as changes occur. Author RWI pertinent to this document is disclosed in the table below and peer reviewer RWI is disclosed in Appendix B. Additionally, to ensure complete transparency, authors’ comprehensive disclosure information— including RWI not pertinent to this document—is available online (see Online Appendix). Disclosure information for the ACC Task Force on Clinical Expert Consensus Documents is also available online at http://www.acc.org/guidelines/aboutguidelines-and-clinical-documents/guidelines-and-documents-task-forces, as well as the ACC disclosure policy for document development at http://www.acc.org/guidelines/about-guidelines-and-clinical-documents/relationships-with-industry-policy. Committee Member Patrick T. O’Gara (Chair) Employment Consultant Harvard Medical School— Professor of Medicine; Brigham and Women’s Hospital—Director, Clinical Cardiology National Institutes of Health* Speakers Bureau None Ownership/ Partnership/ Principal None 53 Personal Research None Institutional, Organizational, or Other Financial Benefit None Expert Witness None EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED Committee Member Employment Paul A. Grayburn (Vice-Chair) Baylor Heart and Vascular Institute—Director, Cardiology Research Abbott Vascular* American Journal of Cardiology Bracco Tendyne None None Abbott Vascular† Edwards† Guided Delivery Systems† Medtronic† Tendyne† Valtech Cardio† Vinay Badhwar (Vice-Chair) West Virginia University— Gordon F. Murray Professor and Chair, Department of Cardiovascular & Thoracic Surgery; Executive Chair WVU Heart & Vascular Institute Wayne State University, Division of Cardiology— Professor of Medicine None None None None On-X Technologies None Edwards Lifesciences Abbott Vascular/Tendyne Inc. Zoll Medical None Corporation† None None None University of Colorado Denver—Professor of Medicine; Director, Philips Healthcare* St. Jude None Evalve/Abbott* Philips Healthcare* None Luis C. Afonso John D. Carroll Consultant Speakers Bureau None Ownership/ Partnership/ Principal 54 Personal Research Institutional, Organizational, or Other Financial Benefit Abbott Vascular* Baylor Healthcare System Foundation* Guided Delivery Systems* Medtronic* National Institutes of Health* Valtech Cardio* Expert Witness None Third Party, fatal stroke post operatively after hip replacement, 2014 None EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED Committee Member Employment Interventional Cardiology Consultant Speakers Bureau Ownership/ Partnership/ Principal Medical* Sammy Elmariah Massachusetts General Hospital—Cardiologist, Department of Medicine None None None Aaron P. Kithcart Brigham and Women’s Hospital, Division of Cardiovascular Medicine— Cardiovascular Disease Fellow None None None Rick A. Nishimura Mayo Clinic, Division of Cardiovascular Disease— Judd and Mary Morris Leighton Professor of Medicine None None Thomas John Ryan Ohio State Heart and Vascular Center None None Personal Research St. Jude Medical* Tendyne (DSMB) † Siemens Healthcare* Institutional, Organizational, or Other Financial Benefit Expert Witness None None None None None None None None None None core lab for RCTs* Edwards Lifesciences Medtronic ABIM None Ross Heart Hospital—John G. and Jeanne Bonnet McCoy Chair in 55 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED Committee Member Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Cardiovascular Medicine; Director Allan Schwartz Columbia University— Chief, Division of Cardiology None None None None None None Lynn Warner Stevenson Brigham and Women’s Hospital—Director, Cardiomyopathy and Heart Failure Program St. Jude Medical American Heart Association† None None St. Jude Medical† NHLBI INTERMACS– Co-PI† NHLBI † None None This table represents all relationships of committee members with industry and other entities that were reported by authors, including those not deemed to be relevant to this document, at the time this document was under development. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of ≥5% of the voting stock or share of the business entity, or ownership of ≥$5,000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person’s gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. Please refer to http://www.acc.org/guidelines/about-guidelines-and-clinical-documents/relationshipswith-industry-policy for definitions of disclosure categories or additional information about the ACC Disclosure Policy for Writing Committees. *Significant relationship. †No financial benefit. ACC indicates American College of Cardiology; DSMB, Data Safety Monitoring Board; INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support; NHLBI, National Heart, Lung, and Blood Institute. 56 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED APPENDIX 2: Peer Reviewer Relevant RWI [TO BE ADDED BY STAFF] 57 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED APPENDIX 3: Abbreviations ACC = American College of Cardiology AF = Atrial Fibrillation CFD = Color Flow Doppler ECDP = Expert Consensus Decision Pathways EROA = Effective Regurgitant Orifice Area LA = Left Atrial LV = Left Ventricular LVEF = Left Ventricular Ejection Fraction MR = Mitral Regurgitation RVol = Regurgitant Volume TEE = Transesophageal Echocardiography TTE = Transthoracic Echocardiography 58 EXPERT CONSENSUS DECISION PATHWAY – CONFIDENTIAL AND EMBARGOED References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 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