Canadian Journal of Cardiology 30 (2014) 1035e1045

Review

Timing of Surgery in Valvular Heart Disease: Prophylactic Surgery vs Watchful Waiting in the Asymptomatic Patient Linda D. Gillam, MD, MPH,a Leo Marcoff, MD,a and Sofia Shames, MDb a b

Morristown Medical Center, Morristown, New Jersey, USA

Columbia University Medical Center, New York, New York, USA

ABSTRACT

  RESUM E

In the absence of randomized controlled trial data, the management of patients with severe valvular heart disease without symptoms, ventricular dysfunction, or other identified triggers for surgery is controversial. In this review, we frame the debate between prophylactic surgery vs close follow-up until triggers occur (watchful waiting) for severe aortic stenosis and degenerative mitral regurgitation (MR), the 2 conditions for which the pros and cons of these approaches are best articulated. Classic high-gradient severe aortic stenosis is generally accurately diagnosed. In asymptomatic patients, stress testing can be used to confirm asymptomatic status and identify high-risk features including reduced exercise tolerance, exercise-induced symptoms, and absolute or relative hypotension. Resting echocardiographic predictors of disease progression and/or adverse events include very high gradients, rapid progression, and extensive calcification. Surgical risk calculators can help estimate perioperative morbidity/mortality with the ultimate choice of a medical vs a prophylactic surgical approach to be made after discussion with the patient. With degenerative MR, severity can be inaccurately estimated. Stress testing might clarify whether the patient is truly asymptomatic and identify features asso-

es d’essais cliniques ale atoires, la prise en En l’absence de donne charge des patients asymptomatiques souffrant de cardiopathie valvulaire grave sans symptômes, ni dysfonction ventriculaire, ni autres clenchants de la chirurgie est controverse e. Dans cette facteurs de bat entre la chirurgie prophylactique vs le revue, nous structurons le de troit jusqu’à ce que les facteurs de clenchants de la ste nose suivi e gurgitation mitrale (RM) de  ge ne rative appaaortique grave et de la re raissent (attente vigilante), 2 affections pour lesquelles les avantages nients de ces approches sont mieux de finis. La forme et les inconve nose aortique grave à gradient e leve  est habituelle de la ste  ne ralement diagnostique e avec pre cision. Chez les patients ge preuve d’effort peut être utilise e pour confirmer asymptomatiques, l’e tat asymptomatique et de terminer les caracte ristiques à risque l’e leve , soit la diminution de la tole rance à l’effort, les symptômes e induits par l’exercice, et l’hypotension absolue ou relative. Les dicteurs e chocardiographiques au repos de la progression de la pre ve nements inde sirables comprennent les gradients maladie ou des e leve s, la progression rapide et la calcification e tendue. Les caltrès e  culateurs de risques chirurgicaux peuvent aider à estimer la morbidite

The definitive therapy for patients with valvular heart disease is mechanical intervention, with surgery currently serving as the gold standard, notwithstanding advances in catheter-based approaches. Although the onset of symptoms is an accepted indication for surgery, the timing of surgery in the asymptomatic patient remains a clinical dilemma. Additional surgical triggers based on the response of the heart and/or pulmonary vascular bed to the pathologic load imposed by valve dysfunction have been identified. However, there is considerable controversy concerning the timing of surgery in the patient who is asymptomatic and without such triggers. In this article, we review the arguments for early prophylactic

surgical intervention and an approach based on close medical surveillance until either symptoms or other triggers emerge, the so-called watchful waiting strategy. The discussion is limited to the consideration of valve surgery as the primary procedure in patients with severe valvular aortic stenosis (AS) or degenerative mitral regurgitation (MR), the 2 conditions in which this debate has been clearly articulated.1-5 That controversy as to the optimal clinical approach to such patients continues is a reflection of the fact that there has been no prospective randomized clinical trial to inform decisionmaking. The following considerations will form the framework for this discussion: (1) the reliability with which the diagnosis of severe disease can be made, the assumption being that surgery is not indicated for patients with moderate or mild disease unless as an add-on to surgery for another indication; (2) the degree to which symptoms or other triggers for surgery are inevitable and predictable; and (3) the relative risks of surgery (perioperative and long-term) vs waiting. The importance of

Received for publication April 26, 2014. Accepted June 12, 2014. Corresponding author: Dr Linda D. Gillam, Department of Cardiovascular Medicine, Morristown Medical Center, 100 Madison Ave, Morristown, New Jersey 07962, USA. Tel.: þ1-973-971-4947; fax: þ1-973-290-7145. E-mail: [email protected] See page 1043 for disclosure information.

http://dx.doi.org/10.1016/j.cjca.2014.06.019 0828-282X/
2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

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ciated with worse prognosis and symptom onset. Selecting patients with high probability of repair can be challenging. Perioperative risk and postoperative risks including those of unanticipated valve replacement and recurrent MR after repair are also considerations. In aggregate, management of patients with valvular disease who are asymptomatic and who have no clear trigger for surgery is complex, requires individualization, and should be carried out by or in collaboration with a heart valve centre of excellence.

 pe riope ratoires afin de prendre la meilleure de cision et la mortalite dicale et l’approche chirurgicale prophylactique entre l’approche me  avec le patient. Quant à la RM de  ge ne rative, la après en avoir discute  peut être estime e de manière inexacte. L’e preuve d’effort gravite terminerait clarifierait si le patient est vraiment asymptomatique et de ristiques associe es au plus sombre pronostic et à l’appales caracte lection des patients ayant une forte probrition de symptômes. La se  de re paration peut s’ave rer complexe. Le risque pe riope ratoire abilite ratoires, soit ceux lie s au remplacement valvuet les risques postope  et à la re currence de la RM après la re paration sont laire non anticipe galement à prendre en conside ration. En somme, la prise en charge e des patients souffrant de valvulopathie qui sont asymptomatiques et sentent pas de facteurs de clenchants clairs de la chirurgie qui ne pre alise e par ou en est complexe, exige l’individualisation et devrait être re collaboration avec un centre d’excellence en matière de valves cardiaques.

stress testing to confirm the patient’s asymptomatic status will also be noted as patients might subconsciously scale back activities to avoid symptoms.

disease for intervention if the decision were based predominantly on valve gradient. However, the diagnosis of severe AS based on reduced calculated aortic valve area (AVA) despite low gradients asks more of the echocardiography laboratory. Patients with small AVAs can have low gradients in the presence of reduced stroke volume (SV) on the basis of reduced LVEF. In this setting, dobutamine stress echocardiography (DSE) can help separate those with true severe AS from those whose cusp opening is limited, in part, by reduced opening forces (pseudosevere AS). The guidelines recommend surgery (class IIA) for symptomatic patients with low-gradient low-flow reduced-EF AS who, with DSE, are shown to have severe rather than pseudosevere stenosis with flow reserve. Additionally, the existence of low-gradient, low-SV (< 35 mL/m2), preserved LVEF ( 50%) severe AS is generally accepted.9,10 However, this diagnosis mandates the accurate assessment of SV because it might be impossible to increase gradients to typical severe AS levels with DSE or other interventions so that the diagnosis of severe AS is based on AVA alone. SV is typically calculated echocardiographically as the product of the LV outflow tract (LVOT) cross-sectional area (CSA) and the LVOT pulsed Doppler velocity time integral. The LVOT is assumed to be circular with CSA calculated as p(d/2)2 where d is the LVOT diameter. With the recognition that the LVOT is often not circular, that image quality might limit measurement accuracy, and that small errors in LVOT diameter measurement are amplified in the calculation of CSA, SV might be underestimated and a patient with moderate or mild stenosis might be incorrectly categorized as having severe AS based on AVA calculation alone. Additionally, there is some controversy as to the validity of defining reduced SV as < 35 mL/m2, particularly in obese subjects. This adds to concerns that one can overestimate the severity of stenosis in the obese if severe AS is defined exclusively as a body surface area-corrected AVA  0.6 cm2/m2. Finally, recognizing the interplay between systemic blood pressure and AS as determinants of LV afterload, a concept captured in the calculation of valvulo-arterial impedance,11 it should be noted that hemodynamics should be assessed when the patient is normotensive. The guidelines recommend surgery (class IIA) for symptomatic patients with low-gradient low-flow preserved-LVEF AS whose symptoms are believed to be on

Severe AS “The problem whether or not to recommend operation for patients with few symptoms but with severe stenosis is unsettled.” dRoss and Braunwald6

That the onset of symptomsdangina, syncope, or heart failuredportends a poor prognosis for the patient with AS has been recognized for decades with the result that surgery for symptomatic patients with classic high-gradient severe AS carries a class I indication in the most recent American College of Cardiology (ACC)/American Heart Association (AHA)7 and European Society of Cardiology (ESC)8 guidelines. Indeed, mortality in symptomatic patients approximates 2% per month. Surgery for asymptomatic patients with reduced left ventricular (LV) ejection fraction (EF) (< 50%) also carries a class I indication for surgery.7,8 Thus, for purposes of this discussion, the asymptomatic patient who is a candidate for watchful waiting is one with severe AS and normal LVEF. Reliability of diagnosis Although cardiac catheterization and novel noninvasive imaging techniques such as planimetry using 3-D echocardiography, computed tomography, or magnetic resonance imaging (MRI) and velocity-encoded phase contrast MRI application of the continuity equation might play a role in the identification of the patient with severe AS, echocardiography is the major diagnostic tool for AS quantitation. The accurate diagnosis of classic severe AS (peak velocity  4 m/s, mean gradient  40 mm Hg and valve area < 1.0 cm2 or 0.6 cm2/m2 regardless of LVEF) should be within the skill set of most clinical echocardiography laboratories. Indeed, the Intersocietal Accreditation Commission demands proficiency in the assessment of AS for echocardiography laboratory accreditation. Where deficiencies exist, they will typically result in underestimation of transvalvular gradient and the severity of obstruction, making it unlikely that a prophylactic surgical strategy would send someone with mild or moderate

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the basis of confirmed severe AS.7,8 However, because data are mixed as to the effect of surgery in asymptomatic patients with low-gradient low-flow preserved-LVEF AS,9,12 there is no consensus as to the role, if any, of prophylactic surgery in these patients. It is notable that both the ESC and new ACC/ AHA guidelines are silent in this regard. It is the authors’ opinion that if surgery is to be entertained in low-gradient low-flow preserved-LVEF AS, the diagnosis of severe AS must be confirmed by expert clinicians/echocardiographers, knowledgeable about the interplay between systemic blood pressure and AS and the potential for underestimating true valve area. More controversial is the existence and clinical importance of low-gradient, normal SV ( 35 mL/m2), preserved-LVEF severe AS13,14 on which the guidelines are completely silent with no recommendation for intervention in even the symptomatic patient. The remainder of this discussion will therefore focus on the asymptomatic patient with high-gradient AS and preserved LVEF. Confirming the asymptomatic state: the role of stress testing Although stress testing, typically treadmill, is contraindicated in symptomatic AS, it is safe and diagnostically helpful in asymptomatic severe AS15-18 with positivity variably defined as flat or decreasing blood pressure, symptoms, reduced exercise tolerance, or, less widely accepted,  2 mm ST-depression. Because coronary artery disease (CAD) is present in as many as 50% of asymptomatic AS patients,15 dyspnea, chest pain, and ST changes reported during stress might reflect CAD rather than AS. Dizziness is more specific for AS.16 Ischemic electrocardiographic (EKG) changes are common and do not correlate well with associated CAD.15 It has been reported that stress testing in asymptomatic severe AS uncovers symptoms or an abnormal hemodynamic response in a third of patients.19 Positive stress testing predicts symptom onset within 1 year.16,19 In the current ACC/AHA guidelines, aortic valve replacement (AVR) is considered to be reasonable (class IIA) in asymptomatic patients with severe AS and decreased exercise tolerance or an exercise decrease in blood pressure, with exercise-induced symptoms effectively moving the patient to symptomatic status.7 The ESC guidelines similarly provide indications for AVR in those who develop AS-linked symptoms on exercise testing (class I) or those whose exercise blood pressure decreases to below baseline level (class IIA).8 Are symptoms or other triggers for surgery inevitable and predictable? AS is a progressive disease. In the series of Otto et al.15 that followed 123 initially asymptomatic AS patients with baseline peak aortic valve velocities  2.5 m/s for a mean of 2.5 years, peak aortic valve velocity (AV-Vel) increased an average of 0.3 m/s/y, mean gradients increased an average of 7 mm Hg/y and AVA decreased an average of 0.12 cm2/y, although it was noted that the rates of progression were highly variable. The rate of progression with bicuspid valves was similar to that of tricuspid valves in this series although the numbers were small.15 Rapid echocardiographic progression of AS is

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Figure 1. Survival free of symptoms in a cohort of 622 patients with severe aortic stenosis (initial transvalvular velocity  4 m/s) censored at time of aortic valve replacement. Reproduced with permission from Lippincott Williams and Wilkins/Wolters Kluwer Health: Circulation, Pellikka et al.21 copyright ª 2005.

associated with increased risk of death or AVR and has been defined as an increase in AV-Vel by > 0.3 m/s/y or a decrease in AVA > 0.1 cm2/y.15,20 Rate of progression might be greater in more severely calcified valves.20 It has also been shown that if severe AS is present at baseline, it is likely that the asymptomatic patient will not remain so. In the study of Pellikka et al.,21 during the follow-up of 622 initially asymptomatic patients with severe AS characterized as a peak AV-Vel of  4 m/s, 50% of patients developed classic symptoms before AVR using the Kaplan-Meier probability of remaining asymptomatic without surgery being 82% at 1 year, 67% at 2 years, and 33% at 5 years (Fig. 1). In this study, independent predictors of symptoms were EKG-defined LV hypertrophy (LVH) and AVA although EKG has limited sensitivity for detecting LVH. LVH using EKG criteria has also been found to be predictive of greater risk of heart failure and AVR, and a combined end point of myocardial infarction, heart failure, or cardiovascular death.22 Observational data suggest that echocardiographically-defined LVH and diastolic dysfunction might play an important role in the generation of symptoms in severe AS. However, firm associations are yet to be established.23-25 In an early stress echocardiographic study, additional predictors of adverse events that include symptom onset have been stress-test positivity and an exercise-induced increase in transvalvular mean gradient of  18 mm Hg.26 A more recent study of 135 asymptomatic patients with at least moderate AS and LVEF  50% who had normal stress echocardiograms identified age  65 years, diabetes, LVH, resting mean gradient > 35 mm Hg, and exercise-induced increase in mean gradient > 20 mm Hg as predictors of symptom-driven AVR or sudden cardiac death (SCD).27 Echocardiographically assessed moderate or severe valvular calcification has also been linked with worse event-free survival at 1, 2, and 4 years (60%, 47%, and 20%, respectively, vs 92%, 84%, and 75%, respectively, in those with mild calcification).20 With electron beam computed tomographic assessment of calcium, a calcium score < 500 is associated with a 92% event-free survival compared with only 40% if the

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calcium score is > 500,28 although there might be sex differences because women have been reported to have more severe AS for the same extent of calcification.29 Brain natriuretic peptide (BNP) and N-terminal BNP (NTBNP) are cardiac biomarkers with prognostic significance in asymptomatic severe AS. In 130 patients with asymptomatic severe AS, NTBNP > 80 was associated with development of symptoms during the 12-month follow-up period and was the only multivariate predictor of postoperative survival, symptoms, and LV function.30 In the same study, 90% and 100% of patients with BNP < 130 pg/mL and NTBNP < 80 pmol/L were asymptomatic after 3 and 9 months, respectively. To address the challenges of using a parameter for which the normal range is age- and sexdependent, a recent study of 1953 subjects with at least moderate AS defined BNP activation by the ratio of measured BNP to normal values according to age and sex. This ratio was predictive of survival after adjustment for other survival determinants.31 In the study of Rosenhek et al., 116 patients with very severe AS, defined as an AV-Vel > 5 m/s, had reduced eventfree survival, events being an indication for AVR (n ¼ 90) or cardiac death (n ¼ 6). Event-free survival was 64%, 36%, 25%, 12%, and 3% at 1, 2, 3, 4, and 6 years, respectively. AV-Vel but not AVA was shown to independently affect event-free survival. Patients with an AV-Vel  5.5 m/s had a reduced event-free survival compared with those with an AVVel between 5.0 and 5.5 m/s and also had a greater likelihood of severe symptom onset.32 The importance of these predictors of disease progression and adverse outcomes is reflected in the ACC/AHA guidelines which indicate that, for patients with low surgical risk, AVR is reasonable (class IIA) for asymptomatic patients with very severe AS (AV-Vel  5.0 m/s) and that AVR might be considered (class IIB) for asymptomatic patients with severe AS and rapid disease progression.7 The ESC guidelines interpret the literature slightly differently and indicate that, with low surgical risk, in asymptomatic patients with normal LVEF and no exercise test abnormalities, AVR should be considered (class IIA) with very severe AS (AV-Vel > 5.5 m/s), severe valve calcification, or if AV-Vel increases  0.3 m/s per year, and that AVR might be considered (class IIB) in the presence of reproducibly markedly elevated and otherwise unexplained natriuretic peptide levels, a > 20 mm Hg increase in mean pressure gradient with exercise, or excessive LVH.8 Relative risks of surgery vs waiting The most feared risk of waiting in the asymptomatic patient with severe AS is that of SCD which has been estimated as 1% per year.15,21,33 Of the studies that form the basis for this statistic, that of Pellikka et al.21 is particularly informative because of the size of the study group, the duration of followup (5.4  4.0 years) and the fact that the diagnosis of AS was based on velocity rather than more error-prone AVA. The authors followed 622 initially asymptomatic patients with severe AS (AV-Vel  4 m/s). Sudden death without preceding symptoms occurred in 11 (4.1%) of 270 patients who did not receive surgery, although it is noted that medical follow-up was not available for at least a year before death in 5 of

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them. Even in this study, the number of events was too small to permit the identification of high risk features for sudden death. However, as previously discussed, the study did identify predictors of symptom onset. An additional risk that is more difficult to characterize over the period of watchful waiting is that a patient might develop increased operative risk. The risk of AVR is a function of patient characteristics and the expertise of the surgical centre. There are several risk models for predicting AVR-associated perioperative morbidity and mortalitydthe Society of Thoracic Surgeons (STS) Predicted Risk of Mortality (STSPROM), the additive and logistic EuroSCOREs, EuroSCORE-II and the Ambler Risk Score. Of these, the STS-PROM (http://riskcalc.sts.org/) score appears to be the most reliable,34-36 particularly in patients for whom additional procedures such as concomitant coronary artery bypass grafting (CABG) are performed. For an asymptomatic 75year-old Caucasian woman without comorbidities, the risk of death for isolated AVR is 1.6%; whereas at age 85, the risk would be 2.9%. For the same 75-year-old woman with class III heart failure and an LVEF of 45%, the mortality risk is increased to 2.5%. For men the risk is lower. However, death is not the only potential complication of AVR. For the hypothetical otherwise well 75-year-old woman, risks of permanent stroke, prolonged ventilation, deep sternal wound infection, renal failure, and repeated surgery are 1.4%, 7.8%, 0.2%, 1.8%, and 7.7%, respectively. The presence of class III heart failure and LVEF of 45% increase the risk of prolonged ventilation and renal failure to 11.2% and 3.1%, respectively, with no significant effect on other categories of morbidity. In addition to conditions such as chronic lung disease, diabetes, and renal dysfunction captured as risks in large databases such as that of the STS, smaller studies have identified other predictors of adverse outcome in surgery for AS including LVH.37 The effect of transcatheter AVR (TAVR), now limited to symptomatic high-risk patients, on the absolute periprocedural risk of AVR and risk-predicting algorithms remains to be clarified. Because risk prediction tools that have evolved from surgical databases have suboptimal performance when applied to TAVR patients,35 it will be important to develop TAVR-specific algorithms. The expertise of a local surgical centre might be more difficult to judge, although it is noted that the STS registry, with American and Canadian participants, has developed a star rating system originally limited to isolated CABG, but now extended to isolated AVR and AVR with CABG. In addition to perioperative risk, one must also consider the risks associated with valve prostheses. Although the inevitability of disease progression and symptom onset with AS might support downplaying long-term risks of valve replacement, even short-term risks include those of endocarditis, valve dehiscence, and other modes of premature failure. In younger patients, typically those with bicuspid aortic valves, who would be candidates for mechanical AVR, the risks of anticoagulation must also be considered. A final consideration is that prophylactic surgery might mitigate the risk of myocardial fibrosis, which might be associated with persistent diastolic dysfunction and poorer symptom relief after AVR. Because cardiac MRI can quantify myocardial fibrosis using either late gadolinium enhancement

Gillam et al. Prophylactic Surgery vs Watchful Waiting

or extracellular volume techniques, this will be an important tool in future studies. Summary How can we translate this information into an informed strategy for the management of the asymptomatic patient with AS and preserved LVEF (Fig. 2)? (1) Although the identification of patients with classic severe high-gradient AS is acceptably robust, there are challenges to the reliable identification of severe disease on the basis of AVA alone in those with low gradients. All surgical decision-making concerning such patients (symptomatic or not) should be done by or in collaboration with clinician/echocardiographer experts. (2) Stress testing is important to confirm the asymptomatic state and identify high-risk features. (3) Surgical risk stratification with consideration of not only mortality but morbidity must be performed. (4) For low surgical risk patients, predictors of either rapid disease progression or adverse events including symptom onset might be taken into consideration with arguments to be made for prophylactic intervention in those with 1 or more of these risk factors. The ultimate decision as to whether to follow a watchful waiting vs a prophylactic surgical approach must be individualized and based on discussion with the patient and family. The age and overall health of the patient are particularly important considerations. Because, for many elderly patients, fear of survival after a debilitating perioperative stroke is greater than that of sudden death, it is not a foregone conclusion that even in those with predictors of rapid disease progression or symptom onset that the best choice will be prophylactic surgery. Degenerative MR Mitral valve repair (MVrepair) is the preferred surgical approach for the patient with chronic severe MR caused by prolapse or flail on the basis of underling myxomatous disease or fibroelastic deficiency (degenerative MR).7,8 In current guidelines, surgery is recommended (class I) in the presence of symptoms, typically dyspnea, fatigue, and reduced exercise tolerance as long as LV dysfunction is not too advanced (LVEF > 30%,7,8 LV end-systolic dimension8 < 55 mm). It is also recommended in the asymptomatic patient when there is LV dysfunction (LVEF 30%-60% or LV end-systolic dimension  40 mm7 or  45 mm8). Surgery should be considered (class IIA) in the asymptomatic patient with preserved LVEF with new onset atrial fibrillation7,8 or resting (systolic pulmonary artery pressure [SPAP] > 50 mm Hg) systolic pulmonary hypertension7,8 if there is a high probability of repair. For purposes of this discussion, symptoms, LV dysfunction, new onset atrial fibrillation, and resting pulmonary hypertension are all considered triggers although it is noted that the ESC guidelines extend the definition of triggers, in stating that surgery might also be considered in asymptomatic patients with preserved LV function, a high likelihood of durable repair, and low surgical risk in the presence of left atrial dilatation (volume index  60 mL/m2 body surface area) and sinus rhythm, or pulmonary

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hypertension on exercise (SPAP  60 mm Hg). The ACC/ AHA guidelines also indicate that MVrepair is reasonable (class IIA) in asymptomatic patients with preserved LV systolic function in whom the likelihood of a successful and durable repair without residual MR is > 95% and the expected mortality rate is < 1% when performed at a heart valve centre of excellence7 and the ESC guidelines state that surgery should be considered (class IIA) in asymptomatic patients with preserved LV function, high likelihood of durable repair, low surgical risk, and flail leaflet.8 However, these last recommendations of surgery without a trigger are controversial and it is in this group of patients that the debate concerning watchful waiting vs prophylactic surgery plays out. Although recognizing that triggers might be defined as “hard” or “soft” depending on whether they are linked to a class I or II indication, respectively, in this review, we use the term, trigger, as an umbrella term that includes events or pathophysiologic responses to MR that can be reliably measured or identified and for which either a class I or class II indication has been developed. Reliability of diagnosis Echocardiography is the most widely used method for assessing the etiology and severity of MR but the challenges of accurately assessing the severity of degenerative MR and the possibility of either over- and underestimating true severity are well recognized. The American Society of Echocardiography/ European Association of Echocardiography (ASE/EAE) guidelines recommend an integrated approach38 which should be viewed as the method of choice for assessing MR severity. However, in many laboratories, the determination of severity is based exclusively on jet size, which can significantly overestimate the degree of MR when jets are not holosystolic as is frequently the case in patients with mitral prolapse. Vena contracta, another static measurement can be similarly misleading as can more quantitative approaches such as the proximal isovelocity surface area method.39,40 Indeed, when site-determined assessments of MR severity were adjudicated by core laboratories for the Acorn and Everest I trials, 41% and 38%, respectively, of study subjects diagnosed at their sites as having surgical MR had less severe regurgitation.41,42 Thus, a strategy of surgery for asymptomatic patients without triggers carries a significant risk of intervention on those with only mild MR because of the limitations of the available diagnostic tools and the suboptimal way in which they are frequently used. Cardiac MRI43 and integrative 3-D echo methods for quantitating nonholosystolic MR44 have been proposed but are not widely used. At a minimum, it can be argued that prophylactic surgery be limited to those with anatomic evidence of flail segments as is captured in the ESC guideline,8 although small flail segments might not cause severe MR. When prophylactic surgery is being contemplated in patients in whom echocardiographic measures of severity are inconsistent, cardiac MRI, if available, might be helpful in confirming that the regurgitation is indeed severe. Confirming the asymptomatic state: the role of stress testing Stress echocardiography can be very helpful in patients with degenerative MR for confirming the asymptomatic state,

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Figure 2. Proposed strategy for choice of prophylactic surgery vs watchful waiting in asymptomatic patients with severe AS and preserved LVEF. * Positive ETT includes any of the following: flat or decreasing blood pressure response, symptoms consistent with AS, unexpectedly reduced exercise tolerance. The importance of ischemic changes alone ( 2 mm ST-depression) is less clearly established. ** Current standard of care is surgical aortic valve replacement. At this time transcatheter aortic valve replacement might be considered in high-risk patients. y High-risk features include severe valve calcification, rapid echocardiographic progression of AS (increase in AV Vel by > 0.3 m/s/y or a decrease in aortic valve area > 0.1 cm2/y), expected delays in surgery, markedly increased natriuretic peptide levels, exercise-induced increase in mean aortic valve gradient by > 20 mm Hg, excessive left ventricular hypertrophy. AS, aortic stenosis; AVR, aortic valve replacement; AV Vel, peak aortic valve velocity; ETT, exercise treadmill test; LVEF, left ventricular ejection fraction.

evaluating symptomatic patients who on baseline studies have less than severe MR, and for prognosis. Twenty percent of “asymptomatic” MR patients have markedly reduced exercise capacity45 and should therefore be considered symptomatic and candidates for surgery. Additionally, MR severity might worsen with exercise,46,47 and it has been reported that worsening MR might be associated with reduced symptomfree survival and the development of pulmonary hypertension.47 Impaired contractile reserve during stress testing of asymptomatic patients, identified as an LVEF increase of < 4%, has been reported to predict either poorer LV function after surgery or development of overt LV systolic dysfunction

in those treated medically.48 Global longitudinal strain might be a superior method for assessing contractile reserve in this setting.49,50 Recently, in a study of 884 patients with  IIIþ degenerative MR undergoing exercise echocardiography, Naji et al. reported that stress testing parameters (lower percentage of age/sex-predicted metabolic equivalents, and lower heart rate recovery), in addition to resting atrial fibrillation, SPAP, and lower LVEF predicted worse outcomes (death, stroke, transient ischemic attacks, myocardial infarction, and heart failure). Interestingly, patients who exercised to at least 85% of predicted metabolic equivalents, had similarly excellent outcomes regardless of whether they had surgery (Fig. 3).51

Gillam et al. Prophylactic Surgery vs Watchful Waiting

Figure 3. Kaplan-Meier curves demonstrating long-term outcomes, separated into 4 subgroups based on mitral valve surgery and achievement of 85% age/sex-predicted metabolic equivalents (METs): subgroup a, no surgery and achieved METs  85%; subgroup b, surgery and achieved METs  85%; subgroup c, surgery and achieved METs < 85%; and subgroup d, no surgery and achieved METs < 85%. Reproduced with permission from Lippincott Williams and Wilkins/ Wolters Kluwer Health: Circulation, Naji et al.51 Copyright ª 2014.

Thus, stress testing is an important tool in decision-making for patients with degenerative MR. Are symptoms or other triggers for surgery inevitable and predictable? A number of studies have demonstrated that the onset of symptoms or other triggers for surgery in patients with degenerative MR is not inevitable at least during midterm follow-up (5-8 years). In the only prospective trial in which a clearly articulated watchful waiting strategy has been evaluated

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(Fig. 4), Rosenhek et al. reported trigger-free survival to 8 years in 55% of subjects with no significant difference between patients with flail vs those with prolapse alone.52 Overall survival was similar to that of an age- and sexmatched Austrian population. In another prospective study of patients with asymptomatic severe degenerative MR, survival free of indications for surgery was 76% at 5 years and 67% at 7 years.53 Indeed, in an earlier study oft quoted as supporting prophylactic surgery, in initially asymptomatic patients with severe MR, new atrial fibrillation and congestive heart failure occurred at a rate of only 5.2% per year.54 As previously noted, the results of stress testing might predict symptom onset. Contractile reserve demonstrated according to global longitudinal strain has been independently associated with better cardiac event-free survival after adjustment for age, sex, BNP, and exercise values for regurgitant volume, pulmonary artery systolic pressure, and E/e’.50 Relative risks of surgery vs waiting The crux of the debate as to whether early surgery is the preferred strategy over watchful waiting lies in the interpretation of a series of studies in which patients with and without indicators for surgery at baseline had been followed with variable medical and surgical treatment strategies. A consistent concern is that with the exception of the study from Rosenhek et al.,52 there are no assurances that patients with medical treatment have undergone intervention when triggers develop. Thus, although the study from Enriquez-Sarano et al.54 of 456 initially asymptomatic patients with degenerative MR nicely noted the importance of MR quantitation and that patients with severe MR do worse than those with milder dysfunction, it provided inadequate data to support a prophylactic surgical approach. Although overall, patients treated medically did worse that those who underwent surgery, there was no consistent policy of follow-up or trigger-driven intervention. Indeed, a number of patients treated medically

Figure 4. (A) Kaplan-Meier event-free survival. Solid black line shows survival free of any event to indicate surgery; grey line, survival free of symptoms; dashed line, survival free of asymptomatic LV dysfunction; and dotted line, survival free of asymptomatic development of AF and/or PHT to indicate surgery. (B) Kaplan-Meier overall survival of pts with asymptomatic severe degenerative MR managed according to a watchful waiting strategy. Solid black line indicates total pt population; dotted line, pts with flail leaflet. AF, atrial fibrillation; asympt, asymptomatic; MR, mitral regurgitation; PHT, pulmonary hypertension; pt, patient. Reproduced with permission from Lippincott Williams and Wilkins/Wolters Kluwer Health: Circulation, Gillam et al.1 Copyright ª 2010.

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Figure 5. Kaplan-Meier overall survival based on initial (3- month) treatment strategy after diagnosis of mitral regurgitation due to flail leaflet in the (A) overall population and (B) propensity score-matched cohort. Reproduced from Suri et al.55 with permission from the American Medical Association.

already had triggers for surgery at baseline (5% had atrial fibrillation, and an indeterminate number had LV systolic dysfunction and/or pulmonary hypertension). Recently, Suri et al.55 reported results from the Mitral Regurgitation International Database (MIDA) registry that included data from 2097 consecutive patients with MR due to flail leaflet. Although the MR was apparently graded using an integrated approach, no data were provided as to severity. Patients were followed for a mean of 10.3 years. Of 1021 patients without ACC/AHA class I triggers, 575 patients were initially medically managed for 3 months with either medical or surgical approaches taken subsequently and 446 underwent mitral valve surgery within 3 months. There was no significant difference in early mortality (1.1% for early surgery vs 0.5% for medical management) and new-onset heart failure rates (0.9%), but new atrial fibrillation was more common in the early surgery group. Long-term survival rates were greater and prevalence of heart failure was less in patients with early surgery (86% vs 69% at 10 years and 7% vs 23% at 10 years, respectively) (Fig. 5). There was no difference in the rate of new onset atrial fibrillation and no data were provided concerning stroke, cardiac death, or prosthetic valve complications, such as bleeding or endocarditis. The authors are to be commended for this large multi-centre collaborative effort. At first glance, the results are provocative, but there are several important limitations to the study. First, even after propensity-matching and inverse probability-weighting, 19% of patients in the medical arm had class II indications for surgery at baseline and a primary end point of all-cause rather than cardiovascular mortality raises the possibility of important confounders that were not considered. More importantly, care was individualized with no clearly articulated strategy for those in the medical arm and no data provided concerning the use of stress testing. Additionally because the cutoff for categorizing patients as medically vs surgically treated was early (3 months), the study could not compare outcomes with a prolonged watchful waiting strategy vs surgery. The relatively young age (mean 55 years) of subjects in the study by Rosenhek et al.52 has been noted as a reason that the results might not be generalizable. Indeed, the mean ages in

the initial medical and early surgery arms of the recent article by Suri et al.55 were, for example, considerably older (67 and 62 years, respectively), as were those in the study by Grigioni et al.,56 also drawn from the MIDA registry (64 years) and the study from Enriquez-Sarano et al. in 200554 (63 years). However, the mean age in the series from Kang et al.53 (50 years) was similar to that of Rosenhek et al.52 Not so widely appreciated are the sex differences in the various study groupsdmen accounting for 57%, 63%, 63%, 67%, and 73% in the Kang, Rosenhek, Enriquez-Sarano, Grigioni, and Suri groups,52-56 respectively. Age and sex have the potential to be important confounding variables in the various studies. The basis for these differences in the study group baseline characteristics is uncertain although geographical differences in referral patterns might contribute. As in AS, SCD is a feared consequence of degenerative MR and, as with AS, the risk is low. In the Rosenhek series, there was no SCD in patients without surgical triggers.52 In a retrospective study of patients with flail leaflets who were initially asymptomatic, the linearized annual risk of SCD was only 1% with 53% of deaths occurring in patients who were no longer asymptomatic,57 and in the series from Kang et al.,53 the approximate risk in patients who did not reach triggers was < 0.5% per year. Other concerns about a watchful waiting strategy are that surgical outcomes will be poorer if surgery is delayed. However, although Suri et al.55 and Kang et al.53 suggest that surgical outcomes will be poorer if surgery is delayed, their results do not support this position. As in AS, the risk of mitral valve surgery depends on patient characteristics and the expertise of the surgical centre with an added variable being the likelihood of successful repair, which is preferred to mitral valve replacement.7,8 Thus, guidelines emphasize a low-risk patient profile (< 1% perioperative mortality) and 95% predictability of repair as requisites for consideration of prophylactic intervention. Although this degree of predictability might be achieved for isolated P2 scallop flail/prolapse in surgical centres of excellence, repair of valves with anterior or multiple scallops is more challenging.58 With newer surgical techniques and

Gillam et al. Prophylactic Surgery vs Watchful Waiting

single-centre reports emerging of improved results for anterior and bileaflet repair,59 it is hoped that the overall predictability of repair will increase. Three-dimensional echocardiography has emerged as the procedure of choice for delineating the location of flail/prolapsing scallops, thereby assisting in preprocedural planning. However, this technology and the expertise required to use it are not universally available. It is notable that surgical repair rates in the MIDA surgical arm were only 93%, in their medical arm only 87%, and in the series from Kang et al.,53 in which presumably surgery was limited to those thought to have reparable valves, only 94%. Moreover, 2000-2007 STS data noted that only 69% of patients with isolated MR underwent MVrepair vs replacement.60 It is, of course, hoped that expertise in MVrepair will continue to grow. Recurrence of MR after repair is also a consideration with Flameng et al. reporting an annualized linearized recurrence rate of moderate or severe regurgitation of 3.2% per year.61 In a single-surgeon series of 840 patients who underwent MVrepair for degenerative MR from 1985 to 2004, David et al. reported that 20-year freedom from moderate to severe MR was 69% and from severe MR was 90%.62 In an earlier study, the same group reported that freedom from moderate to severe MR at 12 years was 80% for posterior, 65% for anterior, and 67% for bileaflet prolapse.63 Thus, even in the best of hands, mitral repair might not be a permanent solution. Perioperative risk can be calculated using the STS scoring system. Overall mortality for isolated MVrepair per the STS database is 1.2% vs 3.8% with mitral replacement.60 The early risk of ischemic stroke has been reported at slightly > 1% even in patients who underwent MVrepair vs a 2.2% overall lifetime risk of ischemic stroke in those with degenerative mitral valve disease,64 at least partially attributable to surgery and atrial fibrillation. Overall rates of valve-related complications after mitral valve replacement are 1% to 2% per year,65 something that must be considered because, even in the best of hands, predictability of repair is imperfect. Summary Although there is considerable debate as to the best management strategy for asymptomatic patients with degenerative MR but without triggers, there is agreement on several points. (1) If prophylactic surgery is being considered, MR must unequivocally be severe. This mandates at least an integrated echocardiographic assessment that includes evidence of LV and left atrial volume overload and demonstration of an anatomic basis for severe MR (ideally a substantial flail segment). Severe MR cannot be diagnosed on the basis of jet dimensions alone. (2) Stress testing is very helpful in assessing functional status, exercise hemodynamics (MR severity and pulmonary artery systolic pressure), and LV contractile reserve and might therefore newly identify patients with triggers for intervention. (3) Management should occur in or in collaboration with a centre of excellence with expert imagers, repair surgeons, and clinical cardiologists. (4) Careful preoperative assessment of the likelihood of repair and perioperative mortality and morbidity risk must be

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performed. It should be noted that by applying guideline definitions of high probability of repair (95%) and low perioperative risk (< 1% mortality), the number of patients eligible for prophylactic intervention would be very small. Until there is a randomized trial or prospective comparative study with a consistent approach to management in its medical and surgical arms, watchful waiting might be the preferred strategy for most asymptomatic patients without triggers although those with isolated P2 flail who are at very low surgical risk and who have access to valve centres of excellence might be candidates for prophylactic surgery. However, as in the patient with AS, decision-making must be individualized and, as with AS, if a watchful waiting strategy is to be used, patients must understand the importance of regular follow-up and awareness of symptoms. Equally important will be ongoing research in valvular heart disease with expansion of registries and ideally, randomized clinical trials. Because the disease burden of disease attributable to AS7 and degenerative MR, both of these conditions are arguably prime candidates for multicentre randomized clinical trials that would guide decision-making in the asymptomatic patient. Of the 2, AS might be the easier to study because there is more equipoise related to management options for this condition and there is more widespread access to surgeons capable of successful AVR (as opposed to mitral repair). In addition, the duration of a study likely to give interpretable results would likely be shorter because of the inevitable shortand midterm progression of the disease and the advanced age of the typical AS patient. It is the authors’ hope that funding might be made available to address these and other important questions related to the management of patients with valvular heart disease. Disclosures The authors have no conflicts of interest to disclose. References 1. Gillam LD, Schwartz A. Primum non nocere: the case for watchful waiting in asymptomatic “severe” degenerative mitral regurgitation. Circulation 2010;121:813-21. 2. Enriquez-Sarano M, Sundt TM. Early surgery is recommended for mitral regurgitation. Circulation 2010;121:804-12. 3. Grayburn PA. Should we operate on asymptomatic patients with severe mitral regurgitation? JACC Cardiovasc Imaging 2008;1:142-4. 4. Shah PK. Severe aortic stenosis should not be operated on before symptom onset. Circulation 2012;126:118-25. 5. Carabello BA. Aortic valve replacement should be operated on before symptom onset. Circulation 2012;126:112-7. 6. Ross J, Braunwald E. Aortic stenosis. Circulation 1968;38(suppl 1):61-7. 7. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2438-88. 8. Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012): the Joint Task Force on the

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