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Prognostic Value of Pulmonary Hypertension, Right Ventricular Function and Tricuspid Regurgitation on Mortality After Transcatheter Mitral Valve Repair: A Systematic Review and Meta-Analysis
Pulmonary hypertension (PH), right ventricular (RV) dysfunction, and tricuspid regurgitation (TR) are commonly present in patients with mitral regurgitation (MR) and known to impair prognosis. This systematic review and meta-analysis aimed to determine the prognostic value of PH, RV function, and TR on mortality after transcatheter mitral valve repair (TMVR).
Methods
A systematic search was performed to identify studies investigating PH, RV function, or TR in patients who underwent TMVR. Studies were included for pooled analysis if hazard ratios (HR) for all-cause mortality were given.
Results
A total of 8,672 patients from 21 selected studies were included (PH, 11 studies; RV function, nine studies; TR, 10 studies). Mean follow-up was 2.7±1.6 years. The HRs and 95% CIs for all-cause mortality of PH (dichotomised: HR 1.70, 95% CI 1.00–2.87; per 10 mmHg increase in systolic PAP: HR 1.17, 95% CI 1.07–1.29), RV function (dichotomised: HR 1.86, 95% CI 1.45–2.38; per 5 mm decrease in TAPSE: HR 1.18, 95% CI 0.97–1.43) and TR (HR 1.51, 95% CI 1.28–1.79) indicated a significant association.
Conclusion
Prognosis after TMVR is worse in patients with significant MR when concomitant PH, RV dysfunction, or TR are present. Careful assessment of these parameters should therefore precede clinical decision-making for TMVR. The current results encourage investigation into whether (1) intervention at an earlier stage of MR reduces incidence of PH, RV dysfunction, and TR; and (2) transcatheter treatment of concomitant TR can improve clinical outcome and prognosis for these patients.
Transcatheter mitral valve repair (TMVR) is increasingly being performed to treat symptomatic mitral regurgitation (MR) in patients at high risk for surgery [
]). However, the patient population is characterised by the presence of numerous comorbidities, which are known to affect prognosis. As such, pulmonary hypertension (PH), right ventricular (RV) dysfunction, and significant tricuspid regurgitation (TR) are highly prevalent (up to 54%, 45%, and 63%, respectively); however, assessment of these parameters remains challenging [
Impact of right heart function on outcome in patients with functional mitral regurgitation and chronic heart failure undergoing percutaneous edge-to-edge-repair.
]. The protocol was registered on the international prospective register of systematic reviews (PROSPERO) on 9 August 2019 under registration number CRD42020199887.
Search Strategy
An information specialist (JL) performed a systematic search in OVID Medline and OVID EMBASE, from 2005 to 4 May 2020, using controlled terms (like MeSH-terms in MEDLINE) and free text terms. To gather more relevant studies, an updated search was performed on 4 March 2021. The whole search consisted of two parts: (1) a search of terms for TMVR, MR, and pulmonary artery pressure (PAP), RV (dys)function, TR; (2) a search for long-term follow-up or prediction studies with TMVR as a major topic to find relevant studies that only reported the desired outcomes in full text and that would otherwise be missed. Conference abstracts, reviews, editorials, and non-human studies were excluded. No language restrictions were applied. Identified records were imported in EndNote X9.3.3 and duplicate records were removed. Reference lists and citing articles of identified relevant papers were cross-checked for additional relevant studies using Web of Science.
Screening
Titles and abstracts were independently screened by two reviewers (FM and SW) using the webtool Rayyan [
]. Thereafter, full-text screening of selected studies was performed. Disagreements on eligible studies were solved by group discussions.
Eligibility Criteria (and Study Selection)
Studies that reported clinical outcome data associated with PH, RV function, or TR after TMVR were considered eligible for inclusion. Since this study aimed to determine the prognostic value of these parameters, observational cohort studies and randomised controlled trials (with clearly specified data of a TMVR treated arm) were most appropriate. Studies were excluded that: (1) involved patients treated by MV surgery; (2) had a sample size <50; (3) had not studied predictors for all-cause mortality (including hazard ratio, HR); or (4) had an overlapping cohort with other studies.
Data Extraction and Endpoints
All study characteristics, patients’ baseline demographics, clinical and echo characteristics, and duration of follow-up were extracted. The HR (of the different parameters) for all-cause mortality after TMVR was the primary endpoint of the analyses. Pulmonary hypertension as a dichotomous parameter considered patients with systolic PAP >50 mmHg versus those with systolic PAP ≤50 mmHg. If expressed as a continuous parameter, HR and 95% CI were reported per 10 mmHg increase in systolic PAP. Right ventricular function as a dichotomous parameter considered patients with tricuspid annular plane systolic excursion (TAPSE) <17 mm versus TAPSE ≥17 mm. If expressed as a continuous parameter, HR, and 95% CI were given per 5 mm decrease. Presence of TR considered moderate or severe TR versus less than moderate or severe TR. In all studies these parameters were determined according to American Society of Echocardiography/European Association for Cardiovascular Imaging standards [
Recommendations for noninvasive evaluation of native valvular regurgitation: a report from the American Society of Echocardiography developed in collaboration with the Society for Cardiovascular Magnetic Resonance.
Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging.
]. The relevant adjusted or (if unavailable) unadjusted HRs and 95% CIs were extracted for each study. If both were available, adjusted HRs were applied.
Assessment of Study Quality and Risk of Bias
All studies underwent bias assessment by two reviewers (FM and SW), using the Newcastle-Ottawa scale, which has been designed for systematic reviews of prognostic studies [
]. The domains of (1) sample selection, (2) comparability, and (3) outcomes were scored (with a maximum of eight stars).
Statistical Analysis
Adjusted or unadjusted HRs and their 95% CIs were pooled. A random-effects model was used. The individual study findings and pooled-analysis results were expressed in a forest plot. Statistical significance was established at p≤0.05. Heterogeneity was measured using the I2-test and considered as follows: 0–25% insignificant, 26–50% low, 51–75% moderate, >75% high [
]. A ‘leave-one-out’ sensitivity analysis was performed to test for the effect of individual study data. Also, this was performed after removing studies that had follow-up ≥3 years and after removal of studies reporting unadjusted estimates. Publication bias was determined using funnel plots [
]. All statistical analyses were performed using RevMan (version 5.4; Cochrane Community).
Results
Study Selection Process and Characteristics
The search identified 366 unique references, of which 144 could be excluded based on title and abstract (Figure 1). After full-text assessment, 21 studies were included for quantitative synthesis [
Impact of right heart function on outcome in patients with functional mitral regurgitation and chronic heart failure undergoing percutaneous edge-to-edge-repair.
Left ventricular end-systolic dimension and outcome in patients with heart failure undergoing percutaneous MitraClip valve repair for secondary mitral regurgitation.
Right ventricular evaluation to improve survival outcome in patients with severe functional mitral regurgitation and advanced heart failure undergoing MitraClip therapy.
Predictors of mortality in ischaemic versus non-ischaemic functional mitral regurgitation after successful transcatheter mitral valve repair using MitraClip: results from two high-volume centres.
Invasive hemodynamics and cardiac biomarkers to predict outcomes after percutaneous edge-to-edge mitral valve repair in patients with severe heart failure.
Mid-term outcomes (up to 5 years) of percutaneous edge-to-edge mitral repair in the real-world according to regurgitation mechanism: a single-center experience.
]. These studies represented 8,672 patients with a mean (±SD) length of follow-up of 2.0±1.5 years. Pulmonary hypertension was assessed in 11 studies (3,325 patients), RV function in nine studies (2,011 patients), and TR in 10 studies (6,620 patients). An overview of study characteristics is given in Table 1. Patient demographics and echo characteristics are given in Table 2. Twelve (12) studies scored 8/8, eight studies scored 7/8, and one study scored 6/8 at the NOS risk of bias assessment. Specific characteristics of the predictor variable in the included studies are given in Supplementary Table 1.
Figure 1Flow diagram of Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Mid-term outcomes (up to 5 years) of percutaneous edge-to-edge mitral repair in the real-world according to regurgitation mechanism: a single-center experience.
Left ventricular end-systolic dimension and outcome in patients with heart failure undergoing percutaneous MitraClip valve repair for secondary mitral regurgitation.
Right ventricular evaluation to improve survival outcome in patients with severe functional mitral regurgitation and advanced heart failure undergoing MitraClip therapy.
Predictors of mortality in ischaemic versus non-ischaemic functional mitral regurgitation after successful transcatheter mitral valve repair using MitraClip: results from two high-volume centres.
Invasive hemodynamics and cardiac biomarkers to predict outcomes after percutaneous edge-to-edge mitral valve repair in patients with severe heart failure.
Impact of right heart function on outcome in patients with functional mitral regurgitation and chronic heart failure undergoing percutaneous edge-to-edge-repair.
Mid-term outcomes (up to 5 years) of percutaneous edge-to-edge mitral repair in the real-world according to regurgitation mechanism: a single-center experience.
Left ventricular end-systolic dimension and outcome in patients with heart failure undergoing percutaneous MitraClip valve repair for secondary mitral regurgitation.
Right ventricular evaluation to improve survival outcome in patients with severe functional mitral regurgitation and advanced heart failure undergoing MitraClip therapy.
Predictors of mortality in ischaemic versus non-ischaemic functional mitral regurgitation after successful transcatheter mitral valve repair using MitraClip: results from two high-volume centres.
Invasive hemodynamics and cardiac biomarkers to predict outcomes after percutaneous edge-to-edge mitral valve repair in patients with severe heart failure.
Impact of right heart function on outcome in patients with functional mitral regurgitation and chronic heart failure undergoing percutaneous edge-to-edge-repair.
Pulmonary Hypertension and All-Cause Mortality (Including Heterogeneity)
When assessing PH as a dichotomous parameter, it was associated with increased incidence of all-cause mortality (HR 1.70, 95% CI 1.00–2.87), with high heterogeneity among studies (I2=77%) (Figure 2). When comparing subgroups for different cut-offs used (50 mmHg vs 60 mmHg), it was observed that the pooled estimated HR for studies using a 60 mmHg cut-off was higher and significant compared to those using a 50 mmHg cut-off (HR 3.84, 95% CI 1.81–8.11 vs HR 1.38, 95% CI 0.87–2.20). The pooled estimate of studies assessing PH as a continuous parameter indicated increased mortality when systolic PAP increased (HR [per 10 mmHg increase], 1.17, 95% CI 1.07–1.29, I2=12%) (Figure 2).
Figure 2Forest plot showing the effect of pulmonary hypertension (PH) (increase of systolic pulmonary artery pressure [PAP]) on all-cause mortality.
Right Ventricular Function and All-Cause Mortality (Including Heterogeneity)
When assessing RV function with TAPSE as a dichotomous parameter, RV dysfunction was associated with increased all-cause mortality (HR 1.86, 95% CI 1.45–2.38), with insignificant heterogeneity (I2=0%) (Figure 3). When comparing subgroups for different cut-offs used (17 mm vs 16 mm vs 15 mm), no relevant difference in HR was observed (see Supplementary Table 2). The pooled estimate of studies assessing TAPSE as a continuous parameter indicated a trend toward increased mortality when TAPSE decreased (HR [per 5 mm decrease of TAPSE], 1.18, 95% CI 0.97–1.43, I2=7%) (Figure 3).
Figure 3Forest plot showing the effect of right ventricular (RV) dysfunction (as decrease of tricuspid annular plane systolic excursion [TAPSE]) on all-cause mortality.
Tricuspid Regurgitation and All-Cause Mortality (Including Heterogeneity)
Presence of moderate/severe TR was associated with increased all-cause mortality compared with patients with less than moderate/severe TR (HR 1.51, 95% CI 1.28–1.79, p<0.001) (Figure 4). Heterogeneity analysis showed no important heterogeneity (I2=40%). When comparing studies that dichotomised between (1) severe and less than severe TR and (2) moderate-severe and less than moderate TR, no subgroup difference in HR was observed (see Supplementary Table 3).
Figure 4Forest plot showing the effect of the presence of moderate-severe tricuspid regurgitation (TR) on all-cause mortality.
The effect of PH, RV dysfunction, and TR on all-cause mortality was confirmed when all meta-analyses were performed removing one study at a time (Supplementary Table 4). For all pooled analyses PH (dichotomous), PH (continuous), RV function (dichotomous), RV function (continuous), TR, additional sensitivity analyses were performed to compare for length of follow-up of the study and use of adjusted and unadjusted HRs (Supplementary Table 5). For PH (continuous), RV function (dichotomous), RV function (continuous), and TR, the effect on all-cause mortality was consistent when leaving out studies with 3–5 years of follow-up. Hazard ratios for PH (dichotomous) increased when leaving out studies with 3–5 years of follow-up (HR 3.84, 95% CI 1.81–8.11 [1–2 years follow-up] vs HR 1.38, 95% CI 0.87–2.20 [3–5 years follow-up]). For PH (continuous), RV function (dichotomous), and TR, results were consistent when leaving out studies with unadjusted HRs. The effect on all-cause mortality increased for PH (dichotomous) and RV function (continuous) when leaving out studies with unadjusted HRs.
Publication Bias
Visual examination of the funnel plots did not indicate publication bias of the studies that were included (Supplementary Figure 1).
Discussion
In this systematic review and meta-analysis, the prognostic value of baseline PH, RV dysfunction, and TR on mortality after TMVR was investigated. A total of 21 studies enrolling 8,672 patients were included and the main findings indicated that PH, RV dysfunction, and TR are related to increased all-cause mortality after TMVR. Pulmonary hypertension, RV dysfunction, and TR are commonly present in patients referred for TMVR; however, the impact of these parameters on prognosis continues to be a matter of debate. The current results support the findings of earlier studies. In recent years, the results of worldwide TMVR registries have indicated important prognostic value of PH and RV function, and since TMVR is increasingly being performed, its relevance will also increase. A meta-analysis conducted by Pavasini et al. indicated the major importance of TR for mortality after TMVR and transcatheter aortic valve implantation [
]. It is believed that assessment of TR in these patients should always comprise the assessment of PH and RV function as well. Therefore, this clear and up-to-date systematic review and meta-analysis expands the findings of earlier work.
This analysis pooled nine studies for PH (2,011 patients), 11 studies for RV function (3,325 patients), and 10 studies for TR (6,620 patients) (Figure 5). The results suggest a significantly increased risk for mortality in four of the five analyses performed and a trend toward significance in one. Some heterogeneity was present in one analysis; however, the effect on mortality was consistent for all analyses when performing leave-one-out sensitivity analysis. The effect of PH (as a continuous parameter), RV function, and TR on mortality was comparable throughout the analyses when comparing studies with 1–2 years versus 3–5 years follow-up. The effect of PH (as a dichotomous parameter) on mortality was significantly higher in studies with 1–2 years of follow-up.
Figure 5Number of studies and patients included in the current analysis for PH, RV dysfunction, and TR, and pooled HR for mortality after TMVR (separated for studies reporting systolic PAP and TAPSE as a continuous parameter).
The relationship between PH, RV function, and TR in patients with MR is complex. While MR initially induces post-capillary PH (due to increase in left atrial filling pressure), chronically elevated pressures might ultimately lead to pre-capillary PH as well (due to structural and functional changes in pulmonary arterial vasculature). Reversibility of PH is significantly greater when pre-capillary PH is not (yet) present [
]. In the early phase, structural RV remodelling (concentric hypertrophy) causes mild dilatation and mild TR. When present for longer, maladaptive remodelling (eccentric hypertrophy) causes further dilatation and significant TR. Once significant TR is present, a vicious circle arises where volume overload leads to further RV dilatation and deterioration of TR. Right ventricular dysfunction and right atrial pressure increase cause reduced venous return (to right heart), reduced cardiac output, and further deterioration of renal and liver function, which importantly affect the prognosis [
While outcome assessment was limited to mortality in the current study, the effect of PH, RV function, and TR on clinical benefit of TMVR should also be considered. Earlier studies have indicated that improvement in New York Heart Association (NYHA) functional class and exercise capacity (6-minute walk test) was limited when significant PH, RV dysfunction, or TR were present [
Impact of right heart function on outcome in patients with functional mitral regurgitation and chronic heart failure undergoing percutaneous edge-to-edge-repair.
Association of tricuspid regurgitation with clinical and echocardiographic outcomes after percutaneous mitral valve repair with the MitraClip System: 30-day and 12-month follow-up from the GRASP Registry.
Impact of baseline tricuspid regurgitation on long-term clinical outcomes and survival after interventional edge-to-edge repair for mitral regurgitation.
]. Hence, the impact is not limited to decreased survival, but also affects clinical and functional improvement.
The current results leave the question of whether TMVR (and significant MR reduction) leads to improvement in PH, RV dysfunction, and TR. Recent studies have shown that PAP could often be reduced after TMVR, but PAP remained significantly higher in patients with baseline PH compared with those without PH at baseline [
]. Tricuspid regurgitation improved in 23–35%, and persistence of TR after TMVR was associated with impaired long-term prognosis and decreased symptomatic benefit [
Clinical outcome and prognosis of patients with significant TR might be further improved since transcatheter treatment options are now available. Results of the Triluminate trial and TriValve registry showed that a TR ≥1 grade reduction rate up to 87%, a decrease in hospitalisations for heart failure up to 40%, and a survival rate of 93% could be achieved at one year. It is important to note that significant improvements in RV function and size were also observed at one year [
]. In patients with MR and TR who underwent combined transcatheter MV and TV treatment, a clear survival benefit was observed compared to those who underwent isolated TMVR (1 year mortality 16.4% vs 34.0%) [
]. Randomised studies are needed to confirm the clinical benefit of combined TV and MV treatment in these patients.
Besides RV dysfunction and TR, LV dysfunction is also highly prevalent in TMVR patients. While RV dysfunction and TR reflect the often longstanding impact of MR, LV dysfunction can be considered both a cause and a repercussion. In five studies that were included in the current analysis, LV dysfunction and/or dilatation were also a determinant for increased mortality [
Left ventricular end-systolic dimension and outcome in patients with heart failure undergoing percutaneous MitraClip valve repair for secondary mitral regurgitation.
Invasive hemodynamics and cardiac biomarkers to predict outcomes after percutaneous edge-to-edge mitral valve repair in patients with severe heart failure.
]. It is speculated that earlier treatment of MR may result in lower prevalence of TR, RV, and LV dysfunction. This might potentially lead to improved clinical outcome and prognosis, and further studies are therefore warranted. Importantly, in daily cardiology practice, patients with significant MR should be closely monitored, including regular clinical evaluation and echocardiographic assessment. Progression in clinical state or echo parameters (MR, PAP, TR, RV, or LV function) should be an indication for heart team discussion and potential surgical or transcatheter valve treatment. When right-sided heart failure is already at an advanced stage and clinical improvement is unlikely, it could also be decided to abstain from valve intervention.
Limitations
In the current study, outcome assessment after TMVR was limited to all-cause mortality. The pooled analysis was performed using published data from the selected studies, which did not enable investigation of the impact of the relevant parameters on clinical outcome parameters (exercise capacity, quality of life, NYHA, heart failure hospitalisations). PAP was estimated with echocardiography in all studies. Whilst right heart catheterisation is more accurate, echocardiography-derived PAP strongly correlates and is standard practice for heart failure patients. Data regarding RV function were derived as TAPSE from the selected studies, which is known to be load dependent and could therefore have been underestimated. The results of the current meta-analysis should be cautiously interpreted, considering its inherent limitations (variation in sample size, analysis methodology, and availability of parameter data).
Conclusions
Prognosis after TMVR is worse in patients with significant MR when concomitant PH, RV dysfunction or TR are present. Careful assessment of these parameters should therefore precede clinical decision-making for TMVR. The current results encourage investigation into whether (1) intervention at an earlier stage of MR reduces incidence of PH, RV dysfunction, and TR and (2) if transcatheter treatment of concomitant TR can improve clinical outcome and prognosis for these patients.
Funding Sources
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Disclosures
JB receives an unrestricted research grant from Abbott Vascular. None of the remaining authors declare any conflict of interest.
Impact of right heart function on outcome in patients with functional mitral regurgitation and chronic heart failure undergoing percutaneous edge-to-edge-repair.
Recommendations for noninvasive evaluation of native valvular regurgitation: a report from the American Society of Echocardiography developed in collaboration with the Society for Cardiovascular Magnetic Resonance.
Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging.
Left ventricular end-systolic dimension and outcome in patients with heart failure undergoing percutaneous MitraClip valve repair for secondary mitral regurgitation.
Right ventricular evaluation to improve survival outcome in patients with severe functional mitral regurgitation and advanced heart failure undergoing MitraClip therapy.
Predictors of mortality in ischaemic versus non-ischaemic functional mitral regurgitation after successful transcatheter mitral valve repair using MitraClip: results from two high-volume centres.
Invasive hemodynamics and cardiac biomarkers to predict outcomes after percutaneous edge-to-edge mitral valve repair in patients with severe heart failure.
Mid-term outcomes (up to 5 years) of percutaneous edge-to-edge mitral repair in the real-world according to regurgitation mechanism: a single-center experience.
Association of tricuspid regurgitation with clinical and echocardiographic outcomes after percutaneous mitral valve repair with the MitraClip System: 30-day and 12-month follow-up from the GRASP Registry.
Impact of baseline tricuspid regurgitation on long-term clinical outcomes and survival after interventional edge-to-edge repair for mitral regurgitation.
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