Degenerative Mitral Regurgitation Outcomes in Asian Compared With European-American Institutions

Background Clinical outcome and interventional thresholds for degenerative mitral regurgitation (DMR) were developed in studies of patients at European and American institutions (EAIs), but little is known about patients at Asian institutions (AsIs). Objectives This study sought to contrast DMR presentation/management/outcomes of AsI patients vs EAI patients. Methods Patients with DMR due to flail leaflet from Hong Kong and Singapore (AsI cohort, n = 737) were compared with EAI patients (n = 682) enrolled in the MIDA (Mitral regurgitation International Database) registry with similar eligibility criteria. Results AsI patients presented similar DMR lesion/consequences vs EAI patients, but they were younger, with fewer symptoms (74% vs 44% Class I), more sinus rhythm (83% vs 69%), and lower EuroSCORE II (European System for Cardiac Operative Risk Evaluation II) (0.9 ± 0.5 vs 1.4 ± 1.5; all P < 0.0001). Imaging showed smaller absolute left atrial/ventricular dimensions in AsI patients, belying cardiac dilatation with larger body surface area–indexed diameters (all P < 0.01). Surgical/interventional mitral repair was similarly predominant (90% vs 91%; P = 0.47), and early repair was similarly beneficial (for AsI patients, adjusted HR: 0.28; 95% CI: 0.16-0.49; for EAI patients, HR: 0.32; 95% CI: 0.20-0.49; both P < 0.0001). However, AsI patients underwent fewer interventions (55% ± 2% vs 77% ± 2% at 1 year; P < 0.0001) and incurred excess mortality (adjusted HR: 1.60 [95% CI: 1.13-2.27] vs EAI patients; P = 0.008) at long-term postdiagnosis. Propensity score matching (434 patient pairs), which balanced all clinical characteristics, confirmed that there was undertreatment and excess mortality in the long term in AsI patients with DMR (P < 0.0001). Conclusions Imaging may underestimate volume overload in AsI patients due to smaller cardiac cavities related to smaller body size compared with EAI patients with similar mitral lesions and DMR severity. AsI patients enjoy similar mitral repair predominance and early intervention benefits but undergo fewer mitral interventions than EAI patients and incur subsequent excess mortality, suggesting the need to account for imaging and cultural specificity to improve DMR outcomes worldwide.

2][3][4] Recent studies in Europe and the United States have demonstrated a disturbing trend toward undertreatment, even in symptomatic patients and in major institutions. 3,5These clinical registries of DMR outcomes in routine clinical practice have provided important support for guideline criteria/thresholds 6,7 and emphasized the profound impact of mitral repair 8 and early repair 9 approaches on clinical outcomes.
However, there are important and unresolved issues regarding DMR among patients diagnosed in Asia.Indeed, European and U.S. guidelines include left ventricular end-systolic diameter (LVESD) as a Class I criterion for surgery, but only as absolute dimension without accounting for body size, which hinders the care of women with DMR, 10 and may be relevant to our patients of generally smaller body sizes in Asia.Furthermore, for DMR management and outcome, most studies were conducted in Europe and the United States, 9,11 with little information on clinical management and outcomes of DMR in cohorts recruited from Asia.While benefits of early DMR repair in Asian observational studies for patients older than 50 years of age 12 appear similar to U.S. and European Union patients, whether these aggressive therapeutic approaches are implemented in routine practice is uncertain.[15][16] Hence, the pertinence of current guidelines to patients diagnosed in Asia remains uncertain and warrants careful assessment to ensure that clinical recommendations are applicable to worldwide populations for optimal outcomes.
To address these gaps in knowledge, we gathered from our practices 2 large populations of patients with DMR due to flail leaflet from Hong Kong and Singapore, summarily called the Asian institution (AsI) cohort.To provide a comparison for our patients, we obtained control subjects with similar DMR and similar definition of valve lesion enrolled in the largest international multicenter European and American institutions (EAIs) (ie, the MIDA [Mitral regurgitation International Database] registry).Thus, these cohorts provide similarly defined DMR patients, enrolled by similarly trained physicians, within EAI countries of similar economic status/standards of living/access to treatment akin to those in Hong Kong and Singapore.We aimed at comparing imaging features, management, and outcomes of patients in our AsIs vs those in EAIs, diagnosed with similar DMR.

Association of early mitral intervention and mortality.
Landmark analysis was performed to evaluate the effect of early intervention (<3 months) compared with initial conservative management on overall survival (Figure 3).Five years after diagnosis, survival was much higher after early intervention than with initial conservative management (96% AE 1% vs 84% AE 2%; P < 0.0001).Both in the overall cohort and in AsI patients and EAI patients separately, the beneficial effect of early intervention was maintained throughout follow-up (Figure 4).95% CI: 0.  2).
To further evaluate the impact of early intervention vs comorbidity on AsI patients excess mortality, we added early intervention to the comprehensive model for overall survival and observed that early intervention not only remained highly significant (P < 0.0001), but also reduced the HR attached to AsI after matching (Supplemental Figure 1).All clinical characteristics (even those not matched for) displayed no significant differences (Supplemental Table 1), while morphometric data showed the expected persistent body size and absolute heart size differences (Supplemental Table 1).Thus, matched for all clinical characteristics, AsI patients displayed similar morphometric differences (Table 1, Supplemental Table 1), similar undertreatment by mitral interventions (Supplemental Figure 2), and similar excess mortality (Supplemental Figure 3) as the overall cohort.While patients AsI and EAI treated by early surgery tended to be younger and lower risk (Supplemental Table 2) than those remaining under conservative management, comprehensive adjustment showed a similar benefit of early surgery in both subsets (Table 3).a Not adjusted for institutional origin.P for interaction institutional origin/time to surgery in adjusted models ¼ NS.
Abbreviations as in Table 1.The age-adjusted survival after degenerative mitral regurgitation (DMR) diagnosis is similar during the first 5 years of follow-up, but secondarily, high-mortality rates observed in As-I patients yields overall excess mortality in this cohort confirmed in multivariable analysis.
Abbreviations as in Figure 1.

Hamid et al
METHODSSTUDY DESIGN.Patients with DMR recruited in 1 center in Singapore (National Heart Centre Singapore) and 1 center in Hong Kong (Prince of Wales Hospital, the Chinese University of Hong Kong) were compared with patients with a similar definition of DMR due to flail leaflet enrolled in the MIDA registry.Both hospitals in Hong Kong and Singapore are tertiary institutions providing health care services to over 40% of the local Asian populations affected by DMR in their respective regions. 17,18The MIDA registry systematically merged the consecutive experience with patients diagnosed with DMR due to flail mitral leaflets in tertiary centers: 2 in France (university hospitals in Amiens and Marseille), 3 in Italy (university A B B R E V I A T I O N S A N D A C R O N Y M S AsI = Asian institution DMR = degenerative mitral regurgitation EAI = European and American institution LA = left atrium/atrial LV = left ventricle/ventricular LVESD = left ventricular endsystolic diameter LVEF = left ventricular ejection fraction From the a National Heart Centre Singapore, Singapore; b New York Presbyterian Hospital, Columbia University Medical Center, New York, New York; c University of Milan, Department of Health Sciences, Division of Cardiology, San Paolo Hospital, ASST Santi Paolo e Carlo, Milan, Italy; d Department of Cardiovascular Medicine, Mayo Clinic, Rochester Minnesota, USA; e University of Verona, Department of Medicine, Section of cardiology, Verona, Italy; f Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain and Divisions of Cardiology and Cardiothoracic Surgery, Cliniques Universitaires Saint-Luc, Brussels, Belgium; g Department of Cardiology, Amiens University Hospital, Amiens, France, and EA 7517 MP3CV Université de Picardie Jules Verne University Hospital, Amiens, France; h Cardiovascular Department, University Hospital S. Orsola-Malpighi, Bologna, Italy; i Cardiovascular Division, Aix-Marseille Université, INSERM MMG U1251, Marseille, France; j Divison of Cardiology, Department of Diagnostics, Clinical and Health Public, University of Modena, University of Modena and Reggio Emilia, Modena, Italy; k Shanghai Chest Hospital, Shanghai, P.R. China; l Cardiology and Arrhythmology Clinic, Marche Polytechnic University, University Hospital "Umberto I -Lancisi -Salesi", Ancona, Italy; m Cardiovascular Department, University Campus Bio-Medico, Rome, Italy; n Minneapolis Heart Institute, Minneapolis, Minnesota, USA; and the o Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong, P.R. China.*Drs Hamid and Bursi contributed equally to this work.The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate.For more information, visit the Author Center.Manuscript received October 2, 2023; revised manuscript received March 14, 2024, accepted March 16, 2024.hospitals in Bologna, Ancona, and Modena), 1 in Belgium (university hospital in Brussels), and 1 in the United States (Mayo Clinic in Rochester, Minnesota).All centers provided approval from ethics boards and Institutional Review Boards, which waived the informed consent requirement in some centers.Specifically, as prescribed by European law, no ethnic/ racial identification was abstracted.Patients were identified retrospectively, and their clinical data, stored in the clinical and echocardiographic repositories, were accessed electronically without alterations.PATIENT POPULATION.The inclusion/exclusion criteria of the AsI cohort and the MIDA registry were similar and have been previously described (Supplemental Appendix).

Figure 1
Figure1shows cumulative incidence of mitral intervention, which was lower in AsI patients than EAI patients at all times and was delayed (P < 0.0001).Throughout the entire follow-up, AsI patients had a 41% lower probability of undergoing mitral valve intervention (HR: 0.59; 95% CI: 0.52-0.67;P < 0.0001).This association persisted after multivariable adjustment (Table2), including

FIGURE 1
FIGURE 1 Cumulative Incidence of Mitral Valve Intervention

patients from 1 .
60 to 1.15, which became nonsignificant, demonstrating the strong association of low early surgery performance and excess mortality in AsI patients.PROPENSITY SCORE-MATCHED COHORTS.To examine AsI and EAI with as balanced as possible baseline characteristics, greedy propensity score matching of the AsI and EAI cohorts based on an extensive list of covariates was conducted (Methods and Supplemental Appendix).Matching was highly successful, with 434 patient pairs demonstrating near equalization of baseline variables, particularly age,

FIGURE 2
FIGURE 2 Postoperative Survival After Mitral Valve Intervention

FIGURE 3
FIGURE 3 Effect of Early Surgery and Long-Term Survival in Landmark Analysis

FIGURE 4
FIGURE 4 Survival by Early Surgery Stratified by Origin in Landmark Analysis

FIGURE 5
FIGURE 5 Age-Adjusted Survival After DMR Diagnosis in AsI Patients and EAI Patients

TABLE 1
Baseline and Echocardiographic Characteristics of the Study Population Values are mean AE SD, %, or n (%).AsI ¼ Asian institution; CAD ¼ coronary artery disease; EAI ¼ European and American institution; EuroSCORE II ¼ European System for Cardiac Operative Risk Evaluation II; LA ¼ left atrial; LV ¼ left ventricular; LVEDD ¼ left ventricular end-diastolic dimension; LVEF ¼ left ventricular ejection fraction; LVESD ¼ left ventricular end-systolic dimension; RVSP ¼ right ventricular systolic pressure.

TABLE 2
Relative Risk of Mitral Valve Intervention and Overall Death for AsI Patients vs EAI Patients

TABLE 3
Mitral Intervention Impact in Time-Dependent Analysis on Overall Survival in the Total Cohort and by Origin 21< 0.0001).However, with comprehensive adjustment (as per Table2), small body size became insignificant (P ¼ 0.16), while the association of AsI patients with undertreatment remained highly significant (adjusted HR: 0.49; 95% CI: 0.42-0.58;P<0.0001).DMR quantitation is not possible in all patients, and integrative DMR grading using all signs/ measures is recommended, particularly with all patients carrying flail mitral leaflet, a specific sign for severe DMR.21Yet, DMR quantitation, when performed, was quite similarly consistent with severe DMR, and is reassuring with regard to DMR severity in both cohorts.
29sitancy in taking the immediate risk, even small, of mitral surgery/intervention in AsI patients may be heightened without declared symptoms27and atrial fibrillation,29while benefits of early surgery may occur quite later.Hesitancy may also be emphasized by hypertension and diabetes, which create confusion STUDY STRENGTHS AND LIMITATIONS.The study is first to demonstrate differences in long-term out-However, similar postintervention survival and similar benefit of early repair strongly argues for lacking unsuspected excess noncardiac mortality among the AsI cohort.Short of studies covering entire countries, it is difficult to absolutely affirm geographical differences, but such countrywide studies have not been initiated to our knowledge.all clinical differences.Although the population may not represent the entire Asian continent, or the full spectrum of hospitals and diverse practices of a multifaceted geographical region, these differences in DMR imaging/management/outcome, analyzed for the first time in the present study, show that it is crucial to consider similar early mitral interventions