Research Spotlight

Hamandi, M., Lanfear, A.T., Squiers, J.J., George, T., Harrington, K., Szerlip, M.A., DiMaio, J.M. and Smith, R.L. (2021). “Double-Valve Replacement in Patients With Mitral Annular Calcification and Aortic Stenosis.” Ann Thorac Surg 111(5): e311-e313.

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Mitral annular calcification (MAC) is a degenerative process of the fibrous structure of the mitral valve. Surgical mitral valve replacement in the presence of MAC is technically challenging because of a high calcium burden and is associated with prohibitive operative mortality. There is no standard management strategy for patients with severe aortic stenosis and severe mitral valve disease with MAC. We report a case series of 3 patients who underwent concomitant surgical, transatrial implantation of a transcatheter heart valve in the mitral position and transcatheter aortic valve replacement.

Mehra, M.R., Cleveland, J.C., Jr., Uriel, N., Cowger, J.A., Hall, S., Horstmanshof, D., Naka, Y., Salerno, C.T., Chuang, J., Williams, C. and Goldstein, D.J. (2021). “Primary results of long-term outcomes in the MOMENTUM 3 pivotal trial and continued access protocol study phase: a study of 2200 HeartMate 3 left ventricular assist device implants.” Eur J Heart Fail.

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AIM: The MOMENTUM 3 pivotal trial established superiority of the HeartMate 3 (HM3) left ventricular assist device (LVAD), a fully magnetically levitated centrifugal-flow pump, over the HeartMate II axial-flow pump. We now evaluate HM3 LVAD outcomes in a single-arm prospective continuous access protocol (CAP) post-pivotal trial study. METHODS AND RESULTS: We enrolled 2200 HM3 implanted patients (515 pivotal trial and 1685 CAP patients) and compared outcomes including survival free of disabling stroke or reoperation to replace or remove a malfunctioning device (primary composite endpoint), overall survival and major adverse events at 2 years. The 2-year primary endpoint [76.7% vs. 74.8%; adjusted hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.71-1.08, P = 0.21] and overall survival (81.2% vs. 79.0%) were similar among CAP and pivotal cohorts despite sicker patients (more intra-aortic balloon pump use and INTERMACS profile 1) in CAP who were more often intended for destination therapy. Survival was similar between the CAP and pivotal trial in transplant ineligible patients (79.1% vs. 76.7%; adjusted HR 0.89, 95% CI 0.68-1.16, P = 0.38). In a pooled analysis, the 2-year primary endpoint was similar between INTERMACS profiles 1-2 (‘unstable’ advanced heart failure), profile 3 (‘stable’ on inotropic therapy), and profiles 4-7 (‘stable’ ambulatory advanced heart failure) (75.7% vs. 77.6% vs. 72.9%, respectively). The net burden of adverse events was lower in CAP (adjusted rate ratio 0.93, 95% CI 0.88-0.98, P = 0.006), with consequent decrease in hospitalization. CONCLUSIONS: The primary results of accumulating HM3 LVAD experience suggest a lower adverse event burden and similar survival compared to the pivotal MOMENTUM 3 trial.

Halaby, R., Herrmann, H.C., Gertz, Z.M., Lim, S., Kar, S., Lindenfeld, J., Abraham, W.T., Grayburn, P.A., Naidu, S., Asch, F.M., Weissman, N.J., Zhang, Y., Mack, M.J. and Stone, G.W. (2021). “Effect of Mitral Valve Gradient After MitraClip on Outcomes in Secondary Mitral Regurgitation: Results From the COAPT Trial.” JACC Cardiovasc Interv 14(8): 879-889.

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OBJECTIVES: The authors sought to evaluate the association between mean mitral valve gradient (MVG) and clinical outcomes among patients who underwent MitraClip treatment for secondary mitral regurgitation (SMR) in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial. BACKGROUND: In the COAPT trial, patients with heart failure (HF) and severe SMR who remained symptomatic despite guideline-directed medical therapy had marked 2-year reductions in mortality and HF hospitalizations after treatment with MitraClip. METHODS: MitraClip-treated patients were divided into quartiles (Q) based on discharge echocardiographic MVG (n = 250). Endpoints including all-cause mortality, HF hospitalization, and health status measures at 2 years were compared between quartiles. RESULTS: Mean MVG after MitraClip was 2.1 ± 0.4 mm Hg, 3.0 ± 0.2 mm Hg, 4.2 ± 0.5 mm Hg, and 7.2 ± 2.0 mm Hg in Q1 (n = 63), Q2 (n = 61), Q3 (n = 62), and Q4 (n = 64), respectively. There was no difference across quartiles in the 2-year composite endpoint of all-cause mortality or HF hospitalization (43.2%, 49.2%, 40.6%, and 40.9%, respectively; p = 0.80), nor in improvements in New York Heart Association functional class, Kansas City Cardiomyopathy Questionnaire score, or 6-min walk time. Results were similar after adjustment for baseline clinical and echocardiographic characteristics, post-procedure MR grade, and number of clips (all-cause mortality or HF hospitalization Q4 [44.6%] vs. Q1 to Q3 [40.3%]; adjusted hazard ratio: 1.23, 95% confidence interval: 0.60 to 2.51; p = 0.57). CONCLUSIONS: Among HF patients with severe SMR, higher MVGs on discharge did not adversely affect clinical outcomes following MitraClip. These findings suggest that in select patients with HF and SMR otherwise meeting the COAPT inclusion criteria, the benefits of MR reduction may outweigh the effects of mild-to-moderate mitral stenosis after MitraClip.

Gammie, J.S., Grayburn, P.A., Quinn, R.W., Hung, J. and Holmes, S.D. (2021). “Quantitating Mitral Regurgitation in Clinical Trials: The Need for a Uniform Approach.” Ann Thorac Surg.

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BACKGROUND: There is an established relationship between the degree of mitral regurgitation (MR) and prognosis. Quantitation of MR severity guides therapeutic approaches. Inconsistent definitions and categorization of MR severity in clinical studies limit meaningful comparisons between trials and compromise development of an effective evidence base. The purpose of this study was to quantify heterogeneity in grading systems for MR severity in the contemporary literature. METHODS: We performed a systematic review of randomized (RCT) and propensity score (PS) adjusted clinical studies of MV interventions (surgical or percutaneous). A total of 35 articles from 2015-2020 were included (15 RCT, 20 PS). RESULTS: There were 22 studies that reported MR severity in numerical categories, either values from the historical “plus” system or numerical MR grades, while 9 studies reported MR severity using text-only descriptive categories. Among the studies that used numerical categories, 2+ MR was defined as moderate in 64% of studies, mild in 27%, and mild-moderate in 9% and 3+ MR was defined as moderate in 14%, moderate-severe in 52%, and severe in 14%. CONCLUSIONS: There was substantial variability in MR severity definition and reporting in contemporary clinical studies of MV interventions. We recommend the historical “plus” numerical grading system be abandoned and that inclusion and outcome criteria in MR clinical trials be based on American and European guideline-recommended categories as none/trace, mild, moderate, and severe. Adoption of these simple recommendations will improve the consistency and quality of MR clinical trial design and reporting.

Taylor, P.C., Adams, A.C., Hufford, M.M., de la Torre, I., Winthrop, K. and Gottlieb, R.L. (2021). “Neutralizing monoclonal antibodies for treatment of COVID-19.” Nat Rev Immunol: 1-12.

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Several neutralizing monoclonal antibodies (mAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and are now under evaluation in clinical trials. With the US Food and Drug Administration recently granting emergency use authorizations for neutralizing mAbs in non-hospitalized patients with mild-to-moderate COVID-19, there is an urgent need to discuss the broader potential of these novel therapies and to develop strategies to deploy them effectively in clinical practice, given limited initial availability. Here, we review the precedent for passive immunization and lessons learned from using antibody therapies for viral infections such as respiratory syncytial virus, Ebola virus and SARS-CoV infections. We then focus on the deployment of convalescent plasma and neutralizing mAbs for treatment of SARS-CoV-2. We review specific clinical questions, including the rationale for stratification of patients, potential biomarkers, known risk factors and temporal considerations for optimal clinical use. To answer these questions, there is a need to understand factors such as the kinetics of viral load and its correlation with clinical outcomes, endogenous antibody responses, pharmacokinetic properties of neutralizing mAbs and the potential benefit of combining antibodies to defend against emerging viral variants.