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Abstract
Background Severe mitral regurgitation (MR) with left ventricular dysfunction portends worse outcomes. Over the course of the last two decades, transcatheter repair of the mitral valve offered an alternative therapeutic modality for those deemed inoperable or high risk. Landmark studies such as the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation and Multicentre Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation trials have shown conflicting results with respect to all-cause death and heart failure rehospitalisations. The Gulf Mitral Transcatheter Edge to Edge Repair registry (Gulf MTEER registry) is a regional registry that captured outcomes in those undergoing transcatheter repair of the mitral valve. The objectives of this study were to describe the baseline characteristics of patients undergoing transcatheter mitral valve repair in the Gulf region and estimate the cardiovascular effects of the mitral transcatheter therapies in routine practice.
Methods The Gulf MTEER registry is an observational, multicentre, retrospective registry that enrolled all patients undergoing transcatheter repair of the mitral valve from four of the Gulf countries (Saudi Arabia, Kuwait, Bahrain, Oman) between 1 January 2017 and 31 December 2019. Baseline characteristics, echocardiographic parameters and immediate procedural success were reported. The primary outcome was a composite of death and rehospitalisations at 1 year. The secondary outcomes were the individual components of the composite endpoint; that is, death and rehospitalisations at 1 year as well as residual or recurrent MR or worsening New York Heart Association class and a need for repeat repair.
Results A total of 176 patients were enrolled. Men constituted 56.3% of the total. At 1 year the primary outcome occurred in 21.1% (95% CI 15.6, 27.9). The secondary outcomes of death occurred in 5.4% (CI 2.9, 10.0) and rehospitalisations occurred in 16.9% (CI 11.9, 23.3). Univariate analysis revealed that the odds of having death or re-hospitalisation was two times higher if the effective regurgitant orifice (ERO) >40 mm2 irrespective of the therapy.
Conclusions The Gulf MTEER registry is the first registry in the Gulf region defining the patient population receiving MTEER therapies and evaluating 1-year outcomes. This is a low risk cohort with a high rate of immediate procedural success and low rate of all-cause death and rehospitalisations at 1 year. The odds of an event was two times higher if the ERO ≥40 mm2 with only a signal to higher odds for low left ventricular ejection fraction and larger end systolic dimension.
- adult cardiology
- valvular heart disease
- heart failure
Data availability statement
All the data will be made available upon request from the Gulf MTEER steering committee.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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STRENGTHS AND LIMITATIONS OF THIS STUDY
The Gulf Mitral Transcatheter Edge to Edge Repair Registry is the first of its kind to shed light on the outcomes of transcatheter therapy for severe MR in the Gulf region.
The registry is retrospective and captures demographics and outcomes from 2017 to 2019 thus not permitting a more contemporary analysis of the use of mitral clip.
Although the immediate procedural success and 1 year rate of all-cause death and rehospitalisations were promising, a more comprehensive assessment of the results by country or operator volume cannot be evaluated.
The study would require a prospective arm after the establishment of standardised pathways and alignment of medical and device therapies.
Background
Mitral regurgitation (MR) is the most common cardiac valve disorder occurring in approximately 1.7% of the general population.1 Conventionally, surgical repair or replacement has been the standard of care for symptomatic patients with severe regurgitation.2 Those with a prohibitive surgical risk account for approximately 50% of those presenting with severe symptomatic MR. Factors such as advanced age, severe left ventricular systolic dysfunction or comorbidities especially advanced pulmonary disease are the predominant deterrents from surgery. In addition, those who do undergo surgical repair often have significant residual regurgitation or worsening of the regurgitation over time. In particular, published reports indicate that functional or secondary MR (FMR) has significant rates of re-hospitalisations and mortality at 2 years.3 4 As such, percutaneous transcatheter edge to edge repair of the mitral valve (MTEER) has become a viable alternative option. The most widely employed systems include the MitraClip system (Abbott Vascular, Abbott Park, IL, USA) and the Pascal (Edwards Lifesciences, USA) devices.
Results of the EVEREST (Endovascular Valve Edge-to-Edge Repair) trial established the safety and feasibility of the MitraClip device.5–7 EVEREST II trial demonstrated a higher degree of residual MR using MitraClip compared with surgical repair (20% vs 2.2%; p=0.0001).6 However, it is noteworthy that the EVEREST II trial enrolled patients with degenerative or primary MR (DMR). Most of the subsequent observational studies primarily examined the efficacy and durability in those with FMR.8 9 More robust data was generated by the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) and MITRA-FR (Multicentre Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation) trials.10 11 The results of these two randomised studies were not aligned. The COAPT trial demonstrated better outcomes and improvement in the quality of life. The differences primarily lay in the patient selection and optimisation of medical therapy prior to the procedure. The COAPT population had lower pulmonary arterial pressures and better right ventricular function and dimensions.
As such, it is imperative that we evaluate our current Gulf populations receiving transcatheter therapies and examine their baseline characteristics, medical therapy, procedural success and cardiovascular outcomes. The purpose of this registry was to capture the baseline characteristics of those undergoing MTEER, define optimal medical therapy and streamline the role of resynchronisation therapy in MR reduction in our population. Finally, this registry is an opportunity to identify areas needing improvement and further investigation in the future.
Methods
The Gulf Mitral Transcatheter Edge to Edge Repair Registry (Gulf MTEER) is an observational, multicentre, retrospective registry that enrolled all patients undergoing transcatheter repair of the mitral valve from four of the Gulf countries (Saudi Arabia, Kuwait, Bahrain, Oman) between 1 January 2017 and 31 December 2019. All patients with severe MR as defined by the 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease and assigned to transcatheter treatment by the heart team were screened.12 Primary or DMR was defined as a central jet MR >40% left atrial (LA) or holosystolic eccentric jet MR; vena contracta ≥0.7 cm; regurgitant volume ≥60 mL; regurgitant fraction ≥50%; effective regurgitant orifice (ERO) ≥40 mm2; angiographic grade 3+ to 4+. Secondary or FMR was defined as ERO ≥40 mm2; regurgitant volume ≥60 mL; regurgitant fraction ≥50% baseline characteristics including age, sex, comorbidities, New York Heart Association (NYHA) class, the Society of Thoracic Surgeons (STS score) and guideline directed medical therapy were recorded. Those not fulfilling the inclusion criteria or with incomplete data were excluded (figure 1).
Gulf MTEER registry flow chart. ERO, effective regurgitant orifice; Gulf MTEER, Gulf Mitral Transcatheter Edge to Edge Repair; MR, mitral regurgitation; LA, left atrial.
All baseline characteristics were collected from the patient records. Echocardiographic parameters included left ventricular ejection fraction (LVEF), MR grade, LA dimension and estimated pulmonary artery pressure (PAP), left ventricular ejection fraction (LVEF), left ventricular end-diastolic (LVEDD) and end-systolic dimensions (LVESD) and ERO were recorded at baseline and at 1 year per protocol.
Immediate procedural success was defined as placement of one or more clips resulting in a postinterventional MR severity of ≤2+ according to the EVEREST I protocol. Mitral Valve Academic Research Consortium immediate technical success of the procedure and 1 year outcomes, specifically cardiovascular mortality and rehospitalisations, as well as worsening NYHA class or need for surgical intervention of the valve were reported.
The primary outcome was a composite of all-cause death and rehospitalisations at 1 year. The secondary outcome was the individual components of the composite endpoint; that is, death and rehospitalisations at 1 year as well as residual or recurrent MR or worsening NYHA class and a need for repeat repair.
Statistical analysis
The reporting of this study is in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology guideline.13 All baseline characteristics were analysed using descriptive statistics summarised as count (percentage (%)) for categorical variables and mean (SD) or median (first quartile (Q1), third quartile (Q3)) for continuous variables depending on the distribution. Estimates of the outcomes were reported as estimates of the incidence of the composite outcome of death or re-hospitalisation, and individual components at 1 year as percent (95% CI).
We conducted exploratory tests of association between the composite of death or re-hospitalisation and a few factors that included ERO (<40 mm2 vs ≥40 mm2), baseline PAP (10 mm Hg increase), ejection fraction (≥35 vs <35), MR aetiology (DMR vs FMR), LVEDD (10 mm increase), LVESD (10 mm increase), beta blockers (yes vs no), ACE inhibitor (ACEi)/angiotensin receptor blocker (ARB) (yes vs no), angiotensin receptor neprilysin inhibitor (yes vs no) and mineralocorticoid antagonist (yes vs no) by using univariate logistic regression analysis. The results are reported as OR, 95% CI and p value. The p values were reported to three decimal places with those less than 0.001 reported as p<0.001. The criterion for statistical significance was set at alpha=0.05, and not adjusted for multiple testing since all the analyses were exploratory. All analyses were performed using R software.
Patient and public involvement
The development of the research question and outcome measures was defined by the key opinion leaders in the Gulf region providing structural interventions in order to capture the most appropriate patient centred experiences and outcomes. These are intertwined with patient preferences, expectations and survival. The patient records were reviewed to register the patient reported symptoms including NYHA class. Patients were not directly recruited or involved since this was a retrospective chart review. On publication in an open access journal, the results will be available to their contributing physicians and the patients.
Results
A total of 176 patients were enrolled in the Gulf MTEER registry (figure 1). Men constituted 56.3% of the total. The mean age was 69.22 years (10.63); the mean body mass index was 29.06. The risk factors and baseline characteristics are described in table 1. A large percentage of the population were hypertensive (81.8%) and diabetic (67.6%). 55.1% had advanced kidney disease beyond stage V. 59.7% had concomitant coronary artery disease (CAD) with 53.4% undergoing prior revascularisation with percutaneous coronary intervention or coronary artery bypass grafting. Only 11.4% had a prior cardiac resynchronisation therapy device implanted. The mean STS score was 4.34. Degenerative or primary MR accounted for only 23.3% of the total population with the majority having functional or secondary MR. At baseline, the mean ERO was 0.63 with a mean left ventricular end-systolic volume of 42.86 mL and a mean ejection fraction of 37.94% (online supplemental table 1). The mean PAP was 51.31 mm Hg. The baseline NYHA class noted advanced heart failure symptoms with 21% having NYHA class IV and 68.2 having NYHA class III symptoms at baseline (online supplemental figure 1). Of note, this cohort were well treated with guideline directed medical therapy; 91.4% of the patients were on beta-blockers, 70.1% were on an ACEi or ARB and 46.6% were on a mineralocorticoid antagonist and 8% were on an angiotensin receptor neprilysin inhibitor (online supplemental table 2).
Supplemental material
Supplemental material
Supplemental material
Demographic baseline characteristics, n=176
Acute procedural success was achieved and 94.3% of the patients with only 5.8% having grade 3 or 4 residual MR (online supplemental figure 2). The mean MG post percutaneous repair was 4.51 mm Hg. Only 5.2% had an iatrogenic atrial septal defect that required intervention. The mean PAP immediately postprocedure was 42.1 mm Hg. There were no periprocedural myocardial infarctions only two cerebrovascular accidents and two deaths during hospitalisation (table 2).
Procedural baseline characteristics, n=176
At 1 year the primary outcome occurred in 35 individuals (21.1%–95% CI 15.6, 27.9). The secondary outcomes of death occurred in nine individuals (5.4%, CI 2.9, 10.0) and rehospitalisations occurred in 28 individuals (16.9%, CI 11.9, 23.3). Grade 3 and 4 residual MR at 1 year occurred in 17% (25). The mean gradient at 1 year for the cohort was 4.42 mm Hg and the mean PAP was 43 mm Hg. Univariate analysis revealed that the odds of having death or re-hospitalisation is almost two times higher if the ERO >40 mm2 irrespective of the therapy. There was no increase in the odds of an event with severe pulmonary hypertension (PAP >70 mm Hg) nor based on the aetiology of MR. There was a signal to higher events with a lower EF (<35%) and larger LVEDD. Regarding the LVESD, there was an increase in the odds of 10% for every 10 mm increase (tables 3 and 4).
Outcome frequencies, n=176
Logistic regression (univariate analysis)
Discussion
The Gulf MTEER registry is the first registry in the region to assess the baseline characteristics and 1 year outcomes of MTEER in the region and is an opportunity to review patient selection, optimal medical therapy and procedural outcomes in this population. Previously, the landmark COAPT trial demonstrated a lower rate of hospitalisations and all-cause mortality for heart failure in patients undergoing MTEER with severe heart failure and moderate to severe to severe MR.10 Conversely, the MITRA-FR study failed to register a similar reduction in death or rehospitalisations.11 The most salient differences between those two cohorts were the degree of LV damage, severity of MR and severity of pulmonary hypertension.14 15 The MITRA-FR patients had larger LV end-diastolic volumes (135±35 mL/m2 MITRA-FR vs 101±34 mL/m2 COAPT) and more severe dysfunction (LVEF 20%–50% in COAPT vs 15%–40% in MITRA-FR). The COAPT investigators excluded patients with very severe LV dilation (LV end-systolic diameter <70 mm) which was not a criterion for the MITRA-FR registry. Recurrent MR and slower LV reverse remodelling has been reported in studies where high rates of persistent/recurrent MR, less reverse LV remodelling and worse outcomes after surgical correction of ischaemic MR.16 Furthermore, the MR was less severe MITRA-FR (ERO area: 31±10 mm2) compared with COAPT (41±15 mm2). The MITRA-FR investigators used the European Society of Cardiology’s guidelines of 2012 to define severity: ERO ≥20 mm2 and/or regurgitant volume ≥30 mL.15 The COAPT criteria were aligned with the American College of Cardiology guidelines of 2006 with a stricter definition of ERO ≥30 mm2 and/or regurgitant volume ≥45 mL.17 The more recent 2014 set of guidelines defined severity differently according to secondary versus primary MR. A less severe MR with an ERO of ≥20 mm2 for secondary and 40 mm2 for primary MR.18 Comparatively, 57.5% of the Gulf MTEER cohort had an ERO ≥40 mm2, mean EF of 37.9% and a mean LVESD 89.22 mm making the regional cohort more aligned with the COAPT inclusion criteria. Similarly, the mean PAP at baseline in the Gulf cohort was 51.3 mm Hg which is below the 70 mm Hg cut-off stipulated by the COAPT trialists. Unlike other registries in Europe and Asia, the Gulf cohort is younger with fewer comorbidities which could account for the overall better outcomes despite a lower overall LVEF (online supplemental table 3).
The immediate procedural success rate in the Gulf MTEER registry was 94.3% with a low rate of procedural complications which is similar to reported rates in both the MITRA-FR (95.8%) and COAPT (97%) trials confirming safe practice in the regional centres offering this therapy. This was also reflected in the prescribed medical therapy regimens which were optimal except for the angiotensin receptor neprilysin inhibitor which were only prescribed for 8% of this heart failure population (online supplemental table 2). This may partly be explained by the delayed availability of the drug in the region after the guidelines added them to the pillars of heart failure management in 2018.
The baseline characteristics in the Gulf MTEER translated into a primary outcome rate of 21.1% with all-cause death occurring at 5.4% and heart failure rehospitalisations at 16.9%. In the MITRA-FR, the primary outcome occurred in 54.6% of the cohort with a 24.3% rate of death from any cause and a rate 48.7% of unplanned hospitalisation for heart failure. The COAPT study reported a 35.8% per patient-year rate of heart failure hospitalisations and death from any cause of 29.1% within 24 months. The astonishingly lower event rate in the Gulf MTEER population is likely multifactorial. The mean age of the treated population was 69.22 (10.63) years versus 72.2 (11.2) years in COAPT and 70.1 (10.1) years in MITRA-FR. The mean STS score was 4.34 (3.32) in Gulf MTEER cohort compared with 8.2 (5.9) in the COAPT cohort (Euroscore 6.6 in MITRA-FR). The other factors such as hypertension and CAD were similar across the groups. In addition, the Gulf cohort had more preserved LVEF with a mean of 37.94% compared with 33.3% in MITRA-FR and 31.3% in COAPT. It does warrant further exploration of outcomes in early percutaneous intervention for MR. The majority of the patients in the Gulf population were considered to have a prohibitive surgical risk based on their frailty and not age. This also begs the question whether frailty indices should be standardised in different ethnicities and reported more objectively. The very low rate of heart failure readmissions of 16.9% in the Gulf registry is likely an under-representation since the recruiting centres only provide tertiary level care. The vast majority of the enrolled patients return to their primary referring centre for follow-up and heart failure management and readmission. Yet it also signals to better outcomes in early intervention for severe MR. As early as 2005, Enriquez-Sarano et al reported a 40% 5-year cardiac mortality rate and a >60% cardiac event rate in patients with asymptomatic severe MR suggesting early repair to curtail such high event rates.19–21 In fact, even the early guidelines of 2002 recommended repair for those with mild symptoms or for asymptomatic patients who develop early signs of LV dysfunction, pulmonary hypertension or atrial fibrillation.22 The mode of repair, surgical or transcatheter, remains to be determined through randomised trials.
The univariate analysis revealed that the odds of having death or re-hospitalisation is almost two times higher if the ERO ≥40 mm2 irrespective of the therapy. However, the caveat is we cannot control for confounders in a univariate analysis. The cohort also had too few events; therefore, a multivariate analysis was not permissible making these exploratory results. At least 20 events for each variable are required to detect a difference. Pulmonary hypertension was also non-discriminatory since the majority of patients had a PAP <70 mm Hg. Due to the low event rate identifying drivers of events and sex disparities is not possible.
Limitations
This is a retrospective study, which does not permit an analysis of unmeasured confounding variables. The number of missing reported outcomes at 1 year may contaminate outcome data. The results can be influenced by differences in disease assessment and documentation patterns at participating centres that have adopted different clinical pathways and procedural protocols. The overall event rates of the predetermined outcome points are small thereby underpowered to detect temporal trends or regional differences, and cause‐and‐effect suppositions.
Conclusion
The Gulf MTEER registry is a unique registry that captured baseline characteristics and outcomes in patients with severe MR and heart failure. The cohort is low risk with a high rate of immediate procedural success and low rate of all-cause death and rehospitalisations at 1 year. The odds of an event was two times higher if the ERO ≥40 mm2 with only a signal to higher odds for low LVEF and larger LVESD.
Data availability statement
All the data will be made available upon request from the Gulf MTEER steering committee.
Ethics statements
Patient consent for publication
Ethics approval
The study complies with the Declaration of Helsinki. The research protocol has been approved by the locally appointed ethics committee and informed consent has been obtained from subjects (or their guardians). Ethics committee approval NCBE-KACSTY Registration No. H-01-R-096.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Twitter @mirvatalasnag, @kfaridy
Contributors All authors have contributed to the final manuscript. MA and KA-S are responsible for the overall content as the guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.