Treatment of Functional Mitral Regurgitation
2019; Lippincott Williams & Wilkins; Volume: 139; Issue: 20 Linguagem: Inglês
10.1161/circulationaha.118.038207
ISSN1524-4539
AutoresMaurice Enriquez‐Sarano, Héctor I. Michelena, Francesco Grigioni,
Tópico(s)Cardiac pacing and defibrillation studies
ResumoHomeCirculationVol. 139, No. 20Treatment of Functional Mitral Regurgitation Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBTreatment of Functional Mitral RegurgitationDoubts, Confusion, and the Way Forward After MITRA-FR and COAPT Maurice Enriquez-Sarano, MD, Hector I. Michelena, MD and Francesco Grigioni, MD, PhD Maurice Enriquez-SaranoMaurice Enriquez-Sarano Maurice Enriquez-Sarano, MD, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905. Email E-mail Address: [email protected] Department of Cardiovascular Medicine, Mayo College of Medicine, Rochester, MN (M.E.-S., H.I.M.). , Hector I. MichelenaHector I. Michelena Department of Cardiovascular Medicine, Mayo College of Medicine, Rochester, MN (M.E.-S., H.I.M.). and Francesco GrigioniFrancesco Grigioni Cardiovascular Department, University Campus Bio-Medico, Rome, Italy (F.G.). Originally published13 May 2019https://doi.org/10.1161/CIRCULATIONAHA.118.038207Circulation. 2019;139:2289–2291Functional mitral regurgitation (FMR) is a conundrum in terms of mechanism, assessment, and implications for outcome. FMR occurs on a structurally normal mitral valve as a result of annular enlargement/dysfunction and leaflet tenting/tethering caused mostly by left ventricular (LV) dysfunction (LVD).1 FMR is generally low volume, often silent, and detected only by color Doppler imaging. FMR grading is difficult because Doppler echocardiographic signs of severe mitral regurgitation (MR) are rarely present and quantification is hindered by discordant guidelines. Most observational series showed independent association between effective regurgitant orifice (ERO) ≥20 mm2 and excess mortality. However, whether FMR itself causes poor outcome or is a surrogate for advanced LVD remains uncertain. Confusion and doubts were amplified by discordant results of surgical and, more recently, percutaneous clinical trials of FMR treatment.FMR surgery remains high risk and rarely performed. Percutaneous MR treatment mimics surgery by using annuloplasty, edge-to-edge repair, or prosthesis implantation. Edge-to-edge repair by MitraClip, the leading device, grasps leaflets between its hooked fins. Tested against surgery (EVEREST II trial [Endovascular Valve Edge-to-Edge Repair Study]; URL: https://www.clinicaltrials.gov. Unique identifier: NCT00209274), MitraClip displayed better safety but lower efficacy, whereas the FMR subset trended for more MitraClip benefit.2Design and Conduct of MITRA-FR and COAPTMITRA-FR3 (Multicentre Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation) randomized patients with symptomatic FMR, ejection fraction of 15% to 40%, and ERO >20 mm2 to guideline-directed medical treatment (GDMT; n=152) or GDMT plus MitraClip (n=152); 90.7% had successful implantation with 75.6% predismissal MR grade ≤1. At 1 year, no benefit in the primary end point of all-cause death or heart failure hospitalization was noted (54.6% MitraClip, 51.3% GDMT; P=0.53). Secondary end points, including death, cardiovascular death, and hospitalization/major cardiovascular events, were all negative.COAPT4 (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) randomized 614 patients, symptomatic despite GDMT, with ejection fractions of 20% to 50%, end-systolic diameter ≤69 mm, and FMR grade 3 to 4; 95% had successful implantation with 82.3% predismissal MR grade ≤1. At 2 years, heart failure hospitalization (primary end point) was markedly lower with MitraClip (35.8 versus 67.9 per 100 patients-years; hazard ratio, 0.53 [95% CI, 0.40–0.70]; P<0.001). All secondary end points favored MitraClip: 1-year MR severity, quality of life, 6-minute walk distance, LV size change, hospitalization rate, 2-year mortality (29.1% versus 46.1%; hazard ratio, 0.62 [95% CI, 0.46–0.82]; P<0.001), and less ventricular assist device implantation/transplantation (hazard ratio, 0.37 [95% CI, 0.17–0.81]; P=0.01).Reconciling MITRA-FR and COAPTWe are troubled by profoundly divergent results, warranting scrutiny of baseline characteristics and selection/interventional processes in both trials. Key points include the following:General descriptors of enrolled participants appear mostly similar (Table, top).Smaller size yields lower power for MITRA-FR compared with COAPT. However, MITRA-FR showed no trend for better MitraClip performance and would be unlikely, if larger, to become positive.COAPT was internally consistent in all end points, including LV volume. In MITRA-FR, partial data showed no LV volume improvement with MitraClip, suggesting insufficient volume-overload correction (consistent with negative primary MITRA-FR end point).Marked FMR improvement with GDMT could explain negative MitraClip outcomes but was less often observed in MITRA-FR (1-year FMR grade ≤2 with GDMT alone: ≈30% for MITRA-FR versus ≈47% for COAPT).Operator/patient blinding is problematic because MitraClip is visible by echocardiography. This is unlikely to explain divergent outcomes, particularly the objective positive 6-minute walk test, 2-year mortality, and transplantations/ventricular assist device implantations in COAPT.Table. Comparisons Between MITRA-FR and COAPTMITRA-FRCOAPTMain similarities between trials ConditionSymptomatic FMR caused by LVDSymptomatic FMR caused by LVD DeviceStandard MitraClipStandard MitraClip Interventions/centers, n≈4≈4 Age, y≈71≈72 Male sex, %7565 Ischemic LVD, %6061 EF, %3331 GFR, mL/min5050 STS score/EuroSCORE, %6.58Primary outcomes of the trials Primary end point1-y death or hospitalization for HF2-y rate of hospitalization for HF Outcomes MitraClip54.6%35.8 per 100 patient-y GDMT51.3%67.9 per 100 patient-y Risk ratio (95% CI)1.16 (0.73–1.84), P=0.530.53(0.40–0.70), P 96 mL/m2) and lowest ERO (<0.30 cm2) shows no to little MitraClip benefit (hazard ratio, 0.90 [95% CI, 0.33–2.43]; P=0.83), similar to MITRA-FR.Second, interventional procedures differed. In COAPT, successful implantation was more frequent with more clips, fewer complications, and less residual MR predischarge and at 1 year. Insufficient MR correction in MITRA-FR is corroborated by unimproved LV volumes. Residual/recurrent MR, similar to postsurgical valve repair, is often underestimated intraprocedurally and causes frequent complications. Hence, percutaneous repair, similar to surgical repair, is destined to require perfection to succeed.Third, the medical process for enrollment differed. Both trials required maximal GDMT, by local management in MITRA-FR versus eligibility committee review followed by FMR reassessment in COAPT. Medications and resynchronization suggest similar use across trials, but the doses administered are unknown. A more intense medical treatment in COAPT is suggested by its GDMT arm, displaying more 1-year FMR improvement and slightly less heart failure/death than both MITRA-FR arms, despite higher baseline B-type natriuretic-peptide.Therefore, we believe these differences (patient selection, percutaneous procedures, and medical treatment process) explain, at least in great part, the outcome divergences between trials. These observations make MITRA-FR and COAPT complementary and reconcilable, suggesting the following main conclusions and ways forward:Causality: Positive COAPT results show that effective FMR treatment yields lower mortality/morbidity in patients with LVD. Hence, FMR is causal to poor outcome, not merely a surrogate, and is a legitimate target for treatment.Unresolved FMR issues: COAPT enrolled most severe FMR cases. Little is known about FMR (severity distribution, outcomes) in large cohorts from routine practice, contrasted with organic MR. New data are crucial to reconciling European and US guidelines and defining targets for future FMR trials.Medical treatment of LVD and FMR: Considering intense medical treatment in COAPT crucial to its positive results should lead to duplicating this exhaustive, intense medical therapeutic process before FMR intervention.Goals of interventional FMR repair: Fewer complications, more implantation success, and lesser residual MR are critical to positive COAPT results. Thus, interventional FMR treatment goals are similar to surgical repair: near perfection at minimal risk. Because imperfect FMR treatment yields no outcome improvement, monitoring MitraClip treatment quality postapproval is crucial.FMR imaging: Imaging of patients with LVD should focus on detecting and quantifying FMR to reduce FMR undertreatment.Continuing journey of FMR treatment: Residual FMR postclip is frequent, underestimated, and consequential for outcome.2 New interventions (longer clips, annuloplasty, prostheses) minimizing residual FMR warrant testing in clinical trials.Who should we consider for treatment by MitraClip now? In view of MITRA-FR and COAPT results, offering clinically MitraClip treatment to patients with ERO ≥0.30 cm2, without excess LV dilatation, after intense GDMT appears reasonable. Hence, most patients with FMR with smaller ERO would not be MitraClip candidates. For those patients, trials of devices with less residual MR may effectively reduce FMR-linked excess mortality, heart failure burden, and ultimately pervasive FMR undertreatment.5DisclosuresDr Enriquez-Sarano discloses a research grant funded by Edwards LLC. The other authors report no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circMaurice Enriquez-Sarano, MD, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905. Email sarano.[email protected]eduReferences1. Enriquez-Sarano M, Akins CW, Vahanian A. Mitral regurgitation.Lancet. 2009; 373:1382–1394. doi: 10.1016/S0140-6736(09)60692-9CrossrefMedlineGoogle Scholar2. Feldman T, Foster E, Glower DD, Kar S, Rinaldi MJ, Fail PS, Smalling RW, Siegel R, Rose GA, Engeron E, Loghin C, Trento A, Skipper ER, Fudge T, Letsou GV, Massaro JM, Mauri L. Percutaneous repair or surgery for mitral regurgitation.N Eng J Med. 2011; 364:1395–1406. doi: 10.1056/NEJMoa1009355CrossrefMedlineGoogle Scholar3. Obadia JF, Messika-Zeitoun D, Leurent G, Iung B, Bonnet G, Piriou N, Lefèvre T, Piot C, Rouleau F, Carrié D, Nejjari M, Ohlmann P, Leclercq F, Saint Etienne C, Teiger E, Leroux L, Karam N, Michel N, Gilard M, Donal E, Trochu JN, Cormier B, Armoiry X, Boutitie F, Maucort-Boulch D, Barnel C, Samson G, Guerin P, Vahanian A, Mewton N; MITRA-FR Investigators. Percutaneous repair or medical treatment for secondary mitral regurgitation.N Engl J Med. 2018; 379:2297–2306. doi: 10.1056/NEJMoa1805374CrossrefMedlineGoogle Scholar4. Stone GW, Lindenfeld J, Abraham WT, Kar S, Lim DS, Mishell JM, Whisenant B, Grayburn PA, Rinaldi M, Kapadia SR, Rajagopal V, Sarembock IJ, Brieke A, Marx SO, Cohen DJ, Weissman NJ, Mack MJ; COAPT Investigators. Transcatheter mitral-valve repair in patients with heart failure.N Engl J Med. 2018; 379:2307–2318. doi: 10.1056/NEJMoa1806640CrossrefMedlineGoogle Scholar5. Dziadzko V, Clavel MA, Dziadzko M, Medina-Inojosa JR, Michelena H, Maalouf J, Nkomo V, Thapa P, Enriquez-Sarano M. Outcome and undertreatment of mitral regurgitation: a community cohort study.Lancet. 2018; 391:960–969. doi: 10.1016/S0140-6736(18)30473-2CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Bruoha S, Assafin M, Ho E, Tang G and Latib A (2022) Transcatheter Mitral Valve Repair Interventional Cardiology, 10.1002/9781119697367.ch64.1, (645-655), Online publication date: 3-Jun-2022. Babaliaros V, Lederman R, Gleason P, Khan J, Kohli K, Sahu A, Rogers T, Bruce C, Paone G, Xie J, Kamioka N, Condado J, Byku I, Perdoncin E, Lisko J and Greenbaum A (2021) The Art of SAPIEN 3 Transcatheter Mitral Valve Replacement in Valve-in-Ring and Valve-in-Mitral-Annular-Calcification Procedures, JACC: Cardiovascular Interventions, 10.1016/j.jcin.2021.08.044, 14:20, (2195-2214), Online publication date: 1-Oct-2021. Enriquez-Sarano M (2021) Left Ventricular Angiography for Mitral Regurgitation Assessment, JACC: Cardiovascular Interventions, 10.1016/j.jcin.2021.06.002, 14:14, (1535-1537), Online publication date: 1-Jul-2021. Benfari G, Antoine C, Essayagh B, Batista R, Maalouf J, Rossi A, Grigioni F, Thapa P, Michelena H and Enriquez-Sarano M (2021) Functional Mitral Regurgitation Outcome and Grading in Heart Failure With Reduced Ejection Fraction, JACC: Cardiovascular Imaging, 10.1016/j.jcmg.2021.05.017, 14:12, (2303-2315), Online publication date: 1-Dec-2021. Lopes B, Kwon D, Shah D, Lesser J, Bapat V, Enriquez-Sarano M, Sorajja P and Cavalcante J (2021) Importance of Myocardial Fibrosis in Functional Mitral Regurgitation, JACC: Cardiovascular Imaging, 10.1016/j.jcmg.2020.10.027, 14:4, (867-878), Online publication date: 1-Apr-2021. ИМАЕВ Т, КОМЛЕВ А, КУЧИН И and АКЧУРИН Р (2020) Transcatheter methods of treatment of mitral valve pathology: current state of the problem, Kardiologicheskii vestnik, 10.36396/MS.2020.16.1.001:1(), (4-13), Online publication date: 14-Jun-2020. Iung B, Armoiry X, Vahanian A, Boutitie F, Mewton N, Trochu J, Lefèvre T, Messika‐Zeitoun D, Guerin P, Cormier B, Brochet E, Thibault H, Himbert D, Thivolet S, Leurent G, Bonnet G, Donal E, Piriou N, Piot C, Habib G, Rouleau F, Carrié D, Nejjari M, Ohlmann P, Saint Etienne C, Leroux L, Gilard M, Samson G, Rioufol G, Maucort‐Boulch D, Obadia J, Obadia J, Barthelet M, Grinberg D, Rioufol G, Thibault H, Thivolet S, Furber A, Benard T, Debrux J, Pinaud F, Rouleau F, Chocron S, Chopard R, Meneveau N, Schiele F, Gilard M, Boschat J, Castellant P, Jobic Y, Le Ven F, Romain D, Beygui F, Sabatier R, Saloux E, Motreff P, Clerfond G, Azarnoush K, Lusson J, Vorilhon C, Teiger E, Antoine C, Champagne S, Couetil J, Damy T, Dubois‐Rande J, Ernande L, Guendouz S, Lim P, Monin J, Nguyen A, Riant E, Ternacle J, Zerbib C, Bertrand B, Bouvaist H, Saunier C, Vaislic C, Khelifa R, Favereau X, Hilpert L, Maribas P, Azmoun A, Angel J, Baruteau A, Brenot P, Deleuze P, Garcon P, Raoux F, Slama M, Van Belle E, Prat A, Coisne A, Duvapentiah A, Juthier F, Modine T, Polge A, Richardson M, Rousse N, Spillemaeker H, Sudre A, Vincent F, Vincentelli A, Jeu A, Ketelers R, Bonnet J, Bonnet G, Habib G, Michel N, Pankert M, Salaun E, Collart F, Houël R, Bille J, Commeau P, Joly P, Michel N, Philip E, Collet F, Arméro S, Bayet G, Giacomoni M, Maximovitch A, Lefèvre T, Cormier B, Romano M, Leclercq F, Albat B, Cade S, Cransac F, Macia J, Piot C, Francois F, Pons M, Raczka F, Sportouch C, Juillière Y, Folliguet T, Huttin O, Popovic B, Selton‐Suty C, Venner C, Guérin P, Baron O, Letocart V, Letourneau T, Piriou N, Trochu J, Belliard O, Allouch P, Bensouda C, Janower S, Makowski S, Pasquier D, Pillière R, Rosencher J, Moceri P, Vahanian A, Brochet E, Himbert D, Iung B, Nataf P, Spaulding C, Achouh P, Berrebi A, Jouan J, Karam N, Mirabel M, Puscas T, Riant E, Suen P, Caussin C, Berrebi A, Diakov C, Philippe F, Veugeois A, Collet J, Choussat R, Isnard R, Montalescot G, Leroux L, Coste P, Dijos M, Labrousse L, Lafitte S, Picard F, Raud‐Raynier P, Degrand B, Bedossa M, Corbineau H, Donal E, Leurent G, Eltchaninoff H, Bauer F, Tron C, Nejjari M, Attias D, Gerbay A, Pierrard R, Fuzellier J, Drogoul L, Elebeze J, Lopez S, Mariottini C, Meyer P, Mihoubi A, Tapia M, Teboul J, Ohlmann P, Goette‐Dimarco P, Kretz J, Mommerot A, Morel O, Petit‐Eisenmann H, Samet A, Trinh A, Carrié D, Gautier M, Badie Y, Lhermusier T, Marcheix B, Tchétché D, Abouliatim I, Bonfils L, Dumonteil N, Farah B, Fondard O, Pathak A, Etienne C, Bernard A, Dion F, Loardi C, Quilliet L, Seemann A, Antoine C, Arnoult M, Meurisse Y, Wautot F, Champagnac D, Dementhon J, Doisy V, Frieh J, Garrier O, Jamal F, Lamartine S, Leroux P, Lienhart Y, Staat P and Zouaghi O (2019) Percutaneous repair or medical treatment for secondary mitral regurgitation: outcomes at 2 years, European Journal of Heart Failure, 10.1002/ejhf.1616, 21:12, (1619-1627), Online publication date: 1-Dec-2019. Armoiry X, Obadia J, Auguste P, Connock M and Ferket B (2020) Conflicting findings between the Mitra-Fr and the Coapt trials: Implications regarding the cost-effectiveness of percutaneous repair for heart failure patients with severe secondary mitral regurgitation, PLOS ONE, 10.1371/journal.pone.0241361, 15:11, (e0241361) Vinciguerra M, Grigioni F, Romiti S, Benfari G, Rose D, Spadaccio C, Cimino S, De Bellis A and Greco E (2021) Ischemic Mitral Regurgitation: A Multifaceted Syndrome with Evolving Therapies, Biomedicines, 10.3390/biomedicines9050447, 9:5, (447) May 14, 2019Vol 139, Issue 20 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.038207PMID: 31082291 Originally publishedMay 13, 2019 Keywordsmitral valve insufficiencyPDF download Advertisement SubjectsCardiomyopathyHeart FailureValvular Heart Disease
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