Level 1 Evidence Remains Elusive in Asymptomatic Severe Organic Mitral Valve Regurgitation (2018)

A long-standing question facing cardiologists and cardiac surgeons has been the management of asymptomatic severe organic mitral valve regurgitation in the absence of left ventricular impairment. Two treatment algorithms appear valid and have historically been utilized. A “watchful waiting” approach allows patients to defer surgery until the onset of symptoms or other traditional surgical indications (atrial fibrillation, pulmonary hypertension or ventricular changes) manifest. However, others favor a more proactive approach, with early intervention once the diagnosis is made In this issue of Structural Heart, Jansen and colleagues1Jansen R, Kluin J, Ray SG, Chamuleau SAJ. Mission: impossible; the first randomized trial in asympomatic patients with severe organic mitral valve regurgitation. Struct Heart. 2018;2:this issue.Google Scholar report the challenges of the Dutch Asymptomatic Mitral Regurgitation (Dutch AMR) trial. This ambitious trial would have been the first multicenter prospective randomized controlled trial to address this clinical question. Enrollment began in 2013 with the goal to include 250 patients randomized 1:1 to either a strategy of watchful waiting or immediate surgical repair. Concurrently, the investigators designed parallel registries (surgical and conservative treatment) to monitor patients who did not provide consent for randomization. This trial would have provided the strongest evidence for the ideal treatment strategy for patients presenting with this pathology. Unfortunately, of the 175 patients screened, 47 were eligible and only 10 were ultimately randomized, forcing the steering committee to abandon the trial. The authors cite a number of factors that led to poor enrollment. Predominant among them were clinician biases and patient preferences. True equipoise was thought to exist, but its absence was only realized once put to the test. Our experience was similar at the outset of the Cardiothoracic Surgical Trials Network (CTSN), but sufficient clinical uncertainty was able to overcome prevailing dogma. In the case of the Dutch AMR trial, after initial trial referral, evaluation by the multidisciplinary heart team concluded that a significant proportion of patients were inappropriate for randomization due to the need for surgical intervention. In an era where more treatment options are available than ever, the importance of collaboration among individuals with diverse skills and expertise continues to grow in importance. Randomized controlled trials have long been the gold standard for evaluating therapeutic efficacy. Undoubtedly, conducting a multicenter randomized controlled trial in cardiac surgery is a herculean task. There are strong biases strewn throughout our field, especially in areas where the highest-level data remain unavailable. Looking back at our own history, with the development of the CTSN, the challenges we initially faced were no different from those presently reported. After the initial activation of the core sites for the moderate ischemic mitral regurgitation trial in 2009, patient accrual was significantly less than expected and it was clear that without revision the trial would ultimately fail to enroll sufficient patients.2Smith PK Michler RE Woo YJ et al.Design, rationale, and initiation of the surgical interventions for moderate ischemic mitral regurgitation trial: a report from the Cardiothoracic Surgical Trials Network.J Thorac Cardiovasc Surg. 2012; 143 (e1. doi: 10.1016/j.jtcvs.2011.05.006.): 111-117Google Scholar This prompted a comprehensive evaluation of the protocol coupled with individual site visits to assess unforeseen hurdles. The site visits were illuminating and revealed previously underestimated, and thoroughly ingrained practice patterns that were limiting patient accrual. Thoughtful revisions to inclusion and exclusion criteria, along with a reaffirmation of the commitment to appropriate referral, led to the success of these trials and the subsequent knowledge we have gained from them. The importance of which is even more pronounced when trial results may contradict long held beliefs. Understanding the hurdles faced in trials involving cardiac surgery is not enough. In the wake of a failed trial we need to re-evaluate what is known, where gaps in knowledge remain, and what information can be gleaned from the patients that did participate. The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines continue to recommend that asymptomatic repair is reasonable in the absence of ventricular dysfunction or dilation (Ejection Fraction < 60% or Left ventricular end systolic diameter > 40mm).3Nishimura RA Otto CM Bonow RO et al.2017 AHA/ACC focused update of the 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 clinical practice guidelines.Circulation. 2017; 137: e1159-e1195Google Scholar These recommendations are based on the known natural history and key pathophysiologic principles of this disease process. Importantly, over the long term, there is a high probability of disease progression in the asymptomatic patient.4Rosenhek R Rader F Klaar U et al.Outcome of watchful waiting in asymptomatic severe mitral regurgitation.Circulation. 2006; 113 (doi: 10.1161/CIRCULATIONAHA.105.599175.): 2238-2244Google Scholar,5Enriquez-Sarano M Avierinos JF Messika-Zeitoun D et al.Quantitative determinants of the outcome of asymptomatic mitral regurgitation.N Engl J Med. 2005; 352 (doi: 10.1056/NEJMoa041451.): 875-883Google Scholar This observation is likely due to the fact that even before overt ventricular impairment, myocardial remodeling and subtle dysfunction has begun.6Suri RM Schaff HV Dearani JA et al.Determinants of early decline in ejection fraction after surgical correction of mitral regurgitation.J Thorac Cardiovasc Surg. 2008; 136 (doi: 10.1016/j.jtcvs.2007.10.067.): 442-447Google Scholar,7Quintana E Suri RM Thalji NM et al.Left ventricular dysfunction after mitral valve repair – the fallacy of “normal” preoperative myocardial function.J Thorac Cardiovasc Surg. 2014; 148 (doi: 10.1016/j.jtcvs.2014.07.029.): 2752-2760Google Scholar Given this understanding, surgical repair prior to the onset of symptoms is a rational decision, and empiric evidence exists to show improved short- and long-term outcomes after repair in earlier stages of disease.8Suri RM Vanoverschelde JL Grigioni F et al.Association between early surgical intervention vs watchful waiting and outcomes for mitral regurgitation due to flail mitral valve leaflets.JAMA. 2013; 310 (doi: 10.1001/jama.2013.8643.): 609-616Google Scholar,9Enriquez-Sarano M Suri RM Clavel MA et al.Is there an outcome penalty linked to guideline-based indications for valvular surgery? Early and long-term analysis of patients with organic mitral regurgitation.J Thorac Cardiovasc Surg. 2015; 150 (doi: 10.1016/j.jtcvs.2015.04.009.): 50-58Google Scholar How then do we create guidelines, and more importantly advise our patients on treatment options when faced with difficult decisions that lack level 1 evidence? More focus on disease specific registries, such as the ones created by the Dutch AMR trial is needed. It will be interesting to see the outcomes within their registry arms, and how these new data will help to form a more complete picture of how to care for patients with this clinical dilemma. In the absence of clear data on how to proceed in individual cases, the heart team concept is particularly important in decision making. No potential conflicts of interest were reported by the authors.