Abstract
Background:
Pulmonary hypertension (pHTN) has been associated with increased morbidity and mortality after mitral Transcatheter Edge-to-Edge Repair (TEER), but the association remains uncertain. This study aims to evaluate the impact of pHTN on cardiovascular outcomes following TEER.
Methods:
We searched PubMed, Scopus, and Medline to identify studies reporting outcomes after TEER in individuals with pHTN. Utilizing a random-effects model, we ascertained a pooled odds ratio (OR) of clinical outcomes in patients with pulmonary artery systolic pressure (PASP >50 mmHg) vs. without (PASP <50 mmHg) severe pHTN.
Results:
We included seven studies with 27,965 patients. The mean age was 79.9 (±5.2) years; 53 % were male, and 75 % were New York Heart Association (NYHA) class-III/IV with a median follow-up of 360 days. Patients with severe pHTN had higher odds of in-hospital all-cause mortality (OR: 1.99, 95 % CI: 1.69–2.34, p < 0.00001) and Major adverse cardiovascular events (MACE) (OR: 1.38,95 % CI: 1.22–1.56, p < 0.00001) compared to patients without severe pHTN.
Conclusions:
Severe pHTN is associated with increased risks of all-cause mortality, MACE, and higher heart failure rehospitalizations in patients undergoing mitral TEER. Prospective trials are necessary to validate the findings and determine if early intervention improves clinical outcomes.
Keywords: Pulmonary hypertension, Mitral transcatheter edge-to-edge repair, Mortality, Hospitalizations
1. Introduction
Mitral regurgitation (MR) is one of the most common valvular abnormalities, affecting 2 % of the global population. Recent estimates suggest that a staggering 2.5 million individuals in the United States currently have moderate to severe MR. As the population ages, the number of affected individuals is expected to double by 2030 [1–4]. These statistics emphasize the importance of timely detection and appropriate management of MR and the need for extensive research and development of effective treatment options. Managing severe MR involves medical, surgical, and transcatheter approaches, depending on the underlying cause. While traditional surgical options, like mitral valve repair or replacement, have been the cornerstone of treatment for severe primary MR due to structural abnormalities, the emergence of transcatheter edge-to-edge repair (TEER) presents a vital alternative for patients deemed at high surgical risk [7].
In severe secondary or functional MR, often resulting from ventricular dysfunction, initial treatment involves guideline-directed medical therapy to manage heart failure and mitigate MR severity. However, in cases where MR remains severe despite optimal medical management, surgical mitral valve repair or replacement (SMVR) has traditionally been the standard intervention [5]. Nonetheless, for individuals presenting with significant comorbidities and elevated surgical risk, TEER represents a validated and effective therapeutic alternative [6,7]. Growing evidence has shown the efficacy of TEER in the management of functional and degenerative MR [8,9], with a significant reduction in mortality and heart failure (HF) hospitalization by 38 % and 47 %, respectively [10].
Pulmonary hypertension (pHTN) due to long-standing left heart disease such as MR represents a marker of advanced disease and poor prognosis [11]. It increases the risk of perioperative complications, with a surgical mortality rate of up to 30 % in patients undergoing SMVR [12–16]. Although TEER has been shown to decrease the severity of MR with subsequent reduction in pulmonary artery pressure and improvement of right ventricular function in some studies [17], the impact of pHTN on the short and long-term prognosis following TEER is still lacking. This study aims to evaluate short and long-term outcomes of pHTN in patients undergoing TEER.
2. Methods
2.1. Search and selection criteria
This systematic review was designed and conducted according to the Cochrane Handbook Of Systemic Reviews and following the Preferred Reporting Items for Systemic Reviews and meta-Analyses (PRISMA) [33] (Supplemental S-1), and AMSTAR-2 (Assessing the methodological quality of systematic reviews-2) guidelines checklist (Supplemental S-2). We systematically Searched PubMed and Embase databases till December 2023 using the following keywords:
“Transcatheter edge-to-edge mitral valve repair,” “Transcatheter mitral valve repair,” “Percutaneous mitral valve” OR “Transcutaneous mitral valve” combined with “pulmonary hypertension” and “pHTN.” Search results were first screened at the title and abstract levels.
Potentially relevant studies were included for full-text review. The inclusion criteria were all prospective and retrospective human studies evaluating the outcomes of pHTN in patients undergoing TEER with a sample size of ≥ 20 subjects. Exclusion criteria were studies with insufficient data, conference papers, review articles, editorials, case reports, studies with a sample size <20 subjects, animal studies, and non-English-language studies. We included the study with the largest patient size or the most completed research for duplicate studies. The articles collected from the systematic search were transferred to the Endnote library software, where duplicates were eliminated. Subsequently, two reviewers (SN and HC) independently evaluated the remaining articles, and only those that satisfied the abovementioned criteria were included. Additionally, we manually examined the reference lists of the included studies. The search strategy, research question, PICO, MeSH, Keywords, and search strategy were mentioned in Supplemental S-3.
2.2. Study subjects and comparison strategies
The following baseline characteristics were extracted from included studies: number of subjects, age, gender, and comorbidities, including diabetes mellitus, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, acute kidney injury, previous history of myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, congestive heart failure, the New York Heart Association (NYHA) functional classification, atrial fibrillation, and surgical risk scoring based on the Society of Thoracic Surgeons (STS) Predicted Risk of Mortality. Reported echocardiographic parameters were also extracted, including left ventricular (LV) ejection fraction, pulmonary artery systolic pressure (PASP), LV end-systolic diameter, and LV end-diastolic diameter. We categorized pHTN severity based on Pulmonary Artery Systolic Pressures (PASP) into two groups: patients with severe pHTN (PASP ≥ 50 mmHg) and those without severe pHTN (PASP <50 mmHg). We then subcategorized patients into PASP <35 mmHg, PASP 35–49 mmHg, and PASP ≥50 mmHg.
2.3. Study outcomes
Primary short-term outcomes included in-hospital - all-cause mortality, major adverse cardiovascular events (MACE), stroke, and vascular complications following TEER. Secondary long-term outcomes included all-cause mortality, MACE, and HF hospitalizations within the first year. The definitions of the significant outcomes were provided in Supplemental S7 (Fig. 1).
Fig. 1.
Central Illustration demonstrating the brief study, patient characteristics, and Results for patients with and without severe Pulmonary Hypertension undergoing Mitral TEER.
2.4. Statistical analysis
Continuous variables were presented as mean ± standard deviation (SD), while categorical variables were presented as counts and frequencies (%). The normality for the continuous variables was tested using the Shapiro-Wilk test. Differences in baseline characteristics were performed using a t-test for continuous variables and a Chi-square test for categorical variables. Odds ratios [OR] with their 95 % confidence intervals (CI) were calculated using multivariable logistic regression for both the primary and secondary outcomes. The confounding factors matched in regression include age, sex, and relevant comorbidities, including diabetes, hypertension, COPD, congestive heart failure, renal disease, obesity, coronary artery disease, atrial fibrillation, and others (Supplemental S8). All reported P-values are two-sided, with a value of <0.05 considered significant. To ensure the reliability of the findings, a sensitivity analysis was carried out by eliminating one study at a time. A subgroup analysis of the secondary outcome was also conducted by dividing the data based on PASP pressures. Critical appraisal of studies was performed using Joanna Briggs Institute (JBI) appraisal tool for meta-analyses of observational cohort or cross-sectional studies [34]. Publication bias was assessed through the examination of funnel plots. The study's quality was evaluated using the Newcastle-Ottawa Scale, with scores ranging from 0 to 8 [36]. Open Meta [Analyst] software was used for random effects models and I2 statistics to estimate pooled odds ratio and heterogeneity. This meta-analysis's forest and funnel plots were generated using STATA software version 18 (Stata Corporation, College Station, TX, U.S.A.).
3. Results
We identified 392 published manuscripts, and 306 records were excluded after screening titles and abstracts. Upon applying inclusion and exclusion criteria, 51 more studies were excluded.
Out of the remaining 35 studies, duplicates, animal studies, and abstracts were excluded, and seven studies with a total of 27,965 patients, were finally included in the analysis after quality assessment with a total of 27,965 patients, as mentioned in the PRISMA flowchart (Supplemental S4). Meta-analysis was performed on 27,437 patients for primary outcomes and 5423 patients for secondary outcomes. 6 studies reported in-hospital outcomes, including mortality, MACE, stroke, and vascular complications, and five studies reported long-term outcomes, including 1-year all-cause mortality, MACE, and HF hospitalizations. All the studies included in the analysis were published within the last ten years. When sensitivity analysis was performed by excluding 1 study at a time, the change in results was not significant. The central illustration in our manuscript concisely presents the study design, patient demographics, and outcomes for those undergoing mitral transcatheter edge-to-edge repair (TEER), comparing individuals with and without severe pulmonary hypertension (Fig. 1). Additionally, the symmetrical funnel plots of the primary and secondary endpoints analysis further validate the robustness of our findings (Supplemental S5).
3.1. Patients’ characteristics
A total of 27,965 patients were included in our analysis, with 8183 patients with severe pHTN and 19,782 patients without severe pHTN. The mean age of the entire cohort was 79.9 SD 5.2 years, with 53 % males. We have found no significant differences between study groups for the main baseline characteristics, as shown in Table 1. Generally, patients with severe pHTN were at higher surgical risk than patients without severe pHTN, considering the mean values of the STS-PROM at 7.8 and 5.1, respectively. Overall median follow-up was 12–14 months.
Table 1.
Baseline characteristics of included studies with and without pulmonary hypertension undergoing mitral TEER.
| Pulmonary artery pressure > 50 mmHg |
Pulmonary ARTERY PRESSURE < 50 mmHg |
|||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Author | Elke Tigges [28] |
Rasha Al-Bawardy [27] |
Hector R Caiñas [35] |
Ori Ben-Yehuda [25] |
Abdelrahman n Ahmed | Muhammad Zia Khan [31] |
Takashi Matsumoto |
Subtotal | Eike Tigges [28] |
Rasha Al-Bawardy [27] |
Hector R Ceilas [35] |
Ori Ben-Yehuda [25] |
Abdelrahman Ahmed [30] |
Muhammad Zia Khan (31.1) |
Takashi Matsumoto [28] |
Subtotal | Totals |
P Value |
|
| ||||||||||||||||||
| Year | 2018 | 2020 | 2022 | 2020 | 2019 | 2021 | 2018 | 2018 | 2020 | 2022 | 2020 | 2018 | 2021 | 2018 | 0.66 | |||
| Mean Age | 76.2 | 78 | 73 | 72.9 | 75.1 | 81 | 76.5 | 75 | 81.4 | 71 | 71.7 | 74.1 | 80 | 73.7 | 0.64 | |||
| Total Number | 216 | 558 | 58 | 184 | 339 | 6780 | 48 | 8183 | 427 | 3513 | 32 | 344 | 698 | 14,725 | 43 | 19,782 | 27,965 | 0.62 |
| Male No. (%) | 127 (59 %) |
210 (38 %) | 17 (29 %) | 128 (70 %) | 175 (52 %) | 3431 (51 %) |
31 (65 %) | 4119 (50 %) |
272 (64 %) |
1804 (51 %) |
12 (36 %) | 205 (60 %) | 409 (59 %) | 7981 (54 %) |
11 (25 %) | 10,694 (54 %) |
14,813 (53 %) |
0.54 |
| Female No. (%) | 89 (41 %) | 348 (62 %) | 41 (71 %) | 56 (30 %) | 164 (48 %) | 3349 (49 %) |
17 (35 %) | 4064 (50 %) |
155 (36 %) |
1709 (49 %) |
20 (64 %) | 139 (40 %) | 289 (41 %) | 6744 (46 %) |
32 (75 %) | 9088 (46 %) |
13,152 (47 %) |
0.71 |
| DM No. (%) | 72 (33 %) | 189 (34 %) | 24 (42 %) | 79 (43 %) | 89 (26 %) | 675 (10 %) | 17 (35 %) | 1145 (14 %) |
135 (32 %) |
909 (26 %) | 20 (63 %) | 114 (33 %) | 180 (26 %) | 1495 (10 %) |
13 (30 %) | 2866 (14 %) |
4011 (14 %) |
0.53 |
| HTN No. (%) | 175 (81 %) |
497 (89 %) | 48 (83 %) | 148 (80 %) | 254 (75 %) | 5640 (83 %) |
43 (90 %) | 6805 (83 %) |
332 (78 %) |
2974 (85 %) |
27 (84 %) | 275 (80 %) | 487 (70 %) | 11,850 (80 %) | 30 (70 %) | 15,975 (81 %) |
22,780 (81 %) |
0.71 |
| COPD No. (%) | 51 (24 %) | 111 (20 %) | 25 (44 %) | 41 (22 %) | 105 (31 %) | 3105 (46 %) |
8 (17 %) | 3446 (42 %) |
99 (23 %) | 441 (13 %) | 12 (38 %) | 85 (25 %) | 169 (24 %) | 3730 (25 %) |
9 (21 %) | 4545 (23 %) |
7991 (29 %) |
0.62 |
| AKI/Renal Disease No. (%) |
88 (41 %) | 24 (4 %) | 29 (50 %) | 82 (45 %) | 148 (44 %) | 3050 (45 %) |
4 (8 %) | 3425 (42 %) |
187 (44 %) |
138 (4 %) | 17 (53 %) | 179 (52 %) | 221 (32 %) | 5325 (36 %) |
3 (7 %) | 6070 (31 %) |
9495 (34 %) |
0.4 |
| CHF No. (%) | N/A | N/A | N/A | N/A | 268 (79 %) | 5945 (88 %) |
12 (25 %) | 6225 (76 %) |
N/A | N/A | N/A | N/A | 520 (74 %) | 11,675 (79 %) |
15 (35 %) | 12,210 (62 %) |
18,435 (66 %) |
0.7 |
| Atrial Fibrillation No. (%) |
91 (42 %) | 347 (62 %) | 25 (43 %) | 56 (56 %) | N/A | 4625 (68 %) |
29 (60 %) | 5173 (64 %) |
194 (45 %) |
2166 (62 %) |
12 (38 %) | 184 (54 %) | N/A | 8530 (58 %) |
17 (40 %) | 11,104 (56 %) |
16,276 (61 %) |
0.9 |
| CAD No. (%) | 162 (75 %) |
N/A | 34 (59 %) | N/A | N/A | 4235 (62 %) |
30 (63 %) | 4461 (55 %) |
330 (77 %) |
NA | 12 (38 %) | NA | N/A | 9050 (61 %) |
27 (63 %) | 9419 (48 %) |
13,880 (52 %) |
0.9 |
| Previous MI, No. (%) |
52 (24 %) | 146 (26 %) | 7 (13 %) |
99 (54 %) | N/A | N/A | N/A | 304 (4 %) |
118 (28 %) |
854 (24 %) | 3 (9 %) |
168 (49 %) | N/A | N/A | N/A | 1143 (6 %) |
1447 (5 %) |
0.9 |
| Prior CABG No. (%) |
51 (24 %) | 161 (29 %) | 21 (36 %) | 80 (44 %) | N/A | N/A | 22 (46 %) | 335 (4 %) |
108 (25 %) |
948 (27 %) | 7 (22 %) |
133 (39 %) | N/A | N/A | 18 (42 %) | 1214 (6 %) |
1549 (6 %) |
0.9 |
| Prior PCI No. (%) |
33 (15 %) | 169 (30 %) | N/A | 83 (45 %) | N/A | N/A | 17 (35 %) | 302 (4 %) |
78 (18 %) | 1045 (30 %) |
N/A | 160 (47 %) | N/A | N/A | 11 (26 %) | 1294 (7 %) |
1596 (6 %) |
0.8 |
| NYHA II No. (%) | N/A | 67 (12 %) | 5 (9 %) |
66 (36 %) | N/A | N/A | N/A | 138 (2 %) |
N/A | 502 (14 %) | 4 (13 %) |
129 (38 %) | N/A | N/A | N/A | 635 (3 %) |
773 (3 %) |
0.81 |
| NYHA III No. (%) |
153 (71 %) |
366 (66 %) | 26 (45 %) | 99 (54 %) | N/A | N/A | N/A | 644 (8 %) |
301 (70 %) |
2322 (66 %) |
16 (50 %) | 190 (55 %) | N/A | N/A | N/A | 2829 (14 %) |
3473 (13 %) |
0.83 |
| NYHA IV No. (%) |
39 (18 %) | 118 (21 %) | 27 (47 %) | 19 (10 %) | N/A | N/A | N/A | 203 (2 %) |
79 (19 %) | 601 (17 %) | 12 (38 %) | 24 (7 %) | N/A | N/A | N/A | 716 (4 %) |
919 (3 %) |
0.83 |
| LVEF <30 No. (%) |
71 (33 %) | 98 (18 %) | 7 (12 %) |
59 (32 %) | N/A | N/A | N/A | 235 (3 %) |
146 (34 %) |
351 (10 %) | 3 (9 %) |
131 (38 %) | N/A | N/A | N/A | 631 (3 %) |
866 (3 %) |
0.72 |
| LVEF 30– 45 No. (%) |
71 (33 %) | 129 (23 %) | 12 (21 %) | 55 (30 %) | N/A | N/A | N/A | 267 (3 %) |
160 (37 %) |
815 (23 %) | 8 (25 %) |
144 (42 %) | N/A | N/A | N/A | 1127 (6 %) |
1394 (5 %) |
0.72 |
| LVEF >45 No. (%) |
75 (35 %) | 331 (59 %) | 39 (68 %) | 70 (38 %) | N/A | N/A | N/A | 515 (6 %) |
120 (28 %) |
2347 (67 %) |
20 (63 %) | 69 (20 %) | N/A | N/A | N/A | 2556 (13 %) |
3071 (11 %) |
0.86 |
| LVESD (mm) | 44 | 37 | N/A | 52 | N/A | N/A | N/A | 46 | 36 | N/A | 53 | N/A | N/A | N/A | ||||
| LVEDD (mm) | 58 | 53 | N/A | 61 | N/A | N/A | N/A | 59 | 52 | N/A | 62 | N/A | N/A | N/A | ||||
| Average STS Score |
9.5 | 5.4 | 17.4 | 9.2 | N/A | N/A | 11.8 | 7.8 | 6.1 | 5.7 | 12.8 | 7.7 | N/A | N/A | 10.4 | 5.1 | 6.4 | |
| Study quality | 6.5/8 | 7.5/8 | 7.0/8 | 7.0/8 | 6.5/8 | 6.0/8 | 6.0/8 | 6.5/8 | 7.5/8 | 7.0/8 | 7.0/8 | 6.5/8 | 6.0/8 | 6.0/8 | ||||
3.2. Primary outcomes
In patients undergoing Mitral TEER, the presence of severe pHTN (PASP >50 mmHg) is linked to significantly increased risks of in-hospital all-cause mortality and MACE compared to those without severe pulmonary hypertension (PASP ≤50 mmHg). Notably, the odds ratio for in-hospital all-cause mortality (Fig. 2) stands at 1.99 (95 % CI: 1.69–2.34), indicating a robust correlation with no evidence of heterogeneity (I2 = 0 %). Additionally, for in-hospital MACE (Fig. 3), the odds ratio is 1.38 (95 % CI: 1.22–1.56), again demonstrating no heterogeneity (I2 = 0 %). We have found no significant difference in the incidence of stroke and vascular complications in both groups. Specifically, the odds ratio for stroke (Fig. 4) is 0.90 (95 % CI: 0.57–1.40), demonstrating no heterogeneity among studies (I2 = 0 %). However, when it comes to vascular complications (Fig. 5), the odds ratio is 1.31 (95 % CI: 0.85–2.02), which reveals a considerable level of heterogeneity (I2 = 70 %), pointing to notable variability across different studies. Similarly, leave- -one out of sensitivity for vascular complications with 0 % Khan et al. weight in analysis shows no statistical significance in the risk of vascular complication between both groups but with decreased heterogenicity (I2 = 33 %).
Fig. 2.
Forrest plot for In-hospital All-Cause Mortality. Forrest plot predicting In-hospital all-cause mortality in patients undergoing Mitral TEER with severe Pulmonary hypertension vs. without severe Pulmonary hypertension. CI: confidence interval, OR: odds ratio, PASP: Pulmonary artery systolic pressure, TEER: transcatheter edge-to-edge repair.
Fig. 3.
Forest plot for In-hospital MACE. Forest plot predicting In-hospital MACE in patients undergoing Mitral TEER with severe Pulmonary hypertension vs. without severe Pulmonary hypertension. CI: confidence interval, OR: odds ratio, PASP: pulmonary artery systolic pressure, TEER: transcatheter edge-to-edge repair, MACE: Major Adverse Cardiovascular Events.
Fig. 4.
Forest plot for Stroke. Forest plot predicting stroke in patients undergoing Mitral TEER with severe Pulmonary hypertension vs. without severe Pulmonary hypertension. CI: confidence interval, OR: odds ratio, PASP: pulmonary artery systolic pressure, TEER: transcatheter edge-to-edge repair.
Fig. 5.
Forest plot of vascular complications. This Forest plot predicts vascular complications in patients undergoing Mitral TEER with severe Pulmonary hypertension vs. those without severe Pulmonary hypertension. CI: confidence interval, OR: odds ratio, PASP: pulmonary artery systolic pressure, TEER: transcatheter edge-to-edge repair. Another forest plot that leaves one out of sensitivity with 0 % Khan et al. weight in analysis shows no statistical significance in the risk of vascular complication between both groups.
3.3. Secondary outcomes
Our meta-analysis demonstrates that patients with severe pHTN face a significantly heightened risk of adverse outcomes within one year, especially when compared to their counterparts without severe pHTN. Notably, elevated pulmonary artery systolic pressure (PASP) contributes to a striking 66 % increase in the odds of all-cause mortality (OR: 1.66, 95 % CI: 1.42–1.95, I2 = 0 %). Furthermore, these patients experience an alarming 80 % rise in the likelihood of MACE (OR 1.80, 95 % CI 1.42–2.29, I2 = 37 %). Although our analysis did not reveal a statistically significant association with hospitalization due to heart failure (OR 1.32, 95 % CI 0.85–2.05, p = 0.21, I2 = 83 %) during this timeframe, the leave-one-out sensitivity analysis excluding Tigges et al. revealed a notable increase in the risk of 1-year heart failure hospitalizations among patients with severe pHTN which is statistically significant (OR 1.67, 95 % CI 1.08–2.39, I2 = 67 %). While heterogeneity is low for all-cause mortality (I2 = 0 %) and moderate for MACE (I2 = 37 %), the marked variability regarding heart failure hospitalization (I2 = 67 %) emphasizes critical differences across studies on this outcome (Supplemental S6). Moreover, the leave-one-out sensitivity analysis for MACE, excluding Al-Bawardy et al., reveals a statistically significant heightened risk of MACE in patients with severe pHTN (OR 2.6, 95 % CI 1.60–2.67, I2 = 0 %).
Subgroup analysis was done for secondary outcomes in 4804 (17.2 %) patients from 3 studies. Patients with PASP ≥ 50 mmHg were associated with a significantly higher incidence of 1-year all-cause mortality compared to patients with PASP of 35–49 mmHg (OR: 1.4, CI: 1.13–1.69, p = 0.001) and patients with PASP of <35mmHg(OR: 1.9, CI: 1.58–2.26, p < 0.0001) at a median of 360-day follow-up. Similarly, patients with PASP ≥50 mmHg were associated with a significantly higher rate of 1-year MACE compared to patients with PASP 35–49 mmHg (OR: 1.4, CI: 1.12–1.66, p = 0.001) and patients with PASP <35 mmHg (OR: 1.8, CI: 1.49–2.13, p < 0.0001). Also, patients with PASP ≥50 mmHg were associated with a significantly higher rate of 1-year HF rehospitalization compared to patients with PASP 35–49 mmHg (OR: 1.3, CI: 1.1–1.56, p = 0.002) and patients with PASP <35 mmHg (OR: 1.9, CI: 1.65–2.27, p < 0.0001) (Table 2).
Table 2.
Subgroup analysis included studies with and without pulmonary hypertension undergoing mitral TEER.
| PASP, mmHg | 1-year mortality |
1-year MACE |
1-year HF hospitalization |
|||
|---|---|---|---|---|---|---|
| OR (95 % CI) | P-value | OR (95 % CI) | P-value | OR (95 % CI) | P-value | |
|
| ||||||
| ≥ 50 vs 35–49 | 1.4(1.13–1.69) | 0.001 | 1.4(1.12–1.66) | 0.001 | 1.3(1.1–1.56) | 0.002 |
| ≥ 50 vs <35 | 1.9(1.58–2.26) | <0.0001 | 1.8(1.49–2.13) | <0.0001 | 1.9(1.65–2.27) | <0.0001 |
CI: confidence interval; HF: heart failure; MACE: major adverse cardiovascular events; PASP: pulmonary artery systolic pressure; OR: odds ratio.
4. Discussion
Our comprehensive analysis, incorporating data from seven studies and 27,965 patients, represents a groundbreaking effort to elucidate the impact of preprocedural pulmonary hypertension on the clinical outcomes following mitral valve transcatheter edge-to-edge repair (TEER). The key findings of our study were as follows: 1) Severe preprocedural pulmonary hypertension was associated with significantly worse short-term outcomes post- TEER, including a heightened risk of in-hospital all-cause mortality and major adverse cardiovascular events (MACE). 2) Additionally, severe pulmonary hypertension was linked to an increased incidence of 1-year all-cause mortality, MACE, and hospitalizations due to heart failure compared to patients without pulmonary hypertension. 3) We found no noteworthy disparity between these patient groups in vascular complications and stroke.
Pulmonary hypertension is a common complication of left-sided heart disease, which accounts for 60–85 % of pHTN cases worldwide [18]. Mitral valve disease is more likely to result in pHTN compared to other forms of left heart disease [19,20]. This is primarily because of its effects on the left atrial structure and its hemodynamic properties, which cause pressure to flow backward into the pulmonary circulation [18,21]. Studies showed that patients with severe MR and severe pHTN had poorer long-term survival and event-free survival following successful SMVR [22,23]. A recent study has identified that patients with pre-existing severe pHTN and degenerative MR who underwent SMVR had higher risks of HF hospitalization and postsurgical reduction in LV ejection fraction [24]. Similar findings were reported in another study focused on mitral stenosis [23]. TEER is considered a less invasive, safe, and effective alternative for SMVR in high-risk populations [6,9]. TEER has been shown to decrease pulmonary artery pressure following the procedure, especially if patients undergo the procedure before pHTN becomes irreversible, leading to right HF [8,26]. However, the available evidence is inconclusive in determining TEER’s effectiveness for individuals with mitral valve disease and severe pHTN.
The COAPT (Cardiovascular Outcomes Assessment of the Mitra Clip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) study assessed the outcomes in patients with moderate to severe MR following randomization to treatment with guideline-directed medical therapy (GDMT) alone or GDMT in combination with TEER. Recent study reported that patients with severe pHTN had a higher incidence of all-cause mortality, cardiovascular death, and HF hospitalization compared to patients without severe pHTN, regardless of treatment arm (with and without GDMT) [25]. They also report that patients treated with TEER plus GDMT had a lower incidence of combined outcomes compared to GDMT alone, regardless of the presence or absence of pulmonary hypertension. Similarly, a study involving 4071 patients from the Society of Thoracic Surgery/American College of Cardiology Transcatheter Valve Therapy registry reported a similar finding, showing increased 30-day and one-year mortality rates, as well as rehospitalization rates in patients with baseline severe pHTN [27]. The researchers also observed significant improvements in functional capacity and quality of life following TEER, with heart failure symptoms declining from 86 % to 17.5 % [27]. Additionally, a recent investigation utilizing the National Inpatient Sample (NIS) database which included 21,505 hospitalizations from 2014 to 2018 further corroborated these findings. This study highlighted that pre-operative severe pHTN is associated with a heightened risk of in-hospital mortality, along with an increased length of stay and cost, when compared to patients without severe pHTN [31].
Contrary to the above findings, results from the German transcatheter mitral valve regurgitation registry, reports that patients with severe pHTN show no significant difference in 30-day mortality and HF hospitalizations but did have an increased risk of MACE and mortality at 1-year follow-up [28]. Similar contrary results have been reported by other studies, who found no significant difference in 30-day mortality for patients with or without severe pHTN who underwent TEER. However, it should be noted that these studies [28–30] were underpowered, as they were conducted on a small patient size before TEER's approval in October 2014.
According to our analysis, patients with mitral valve disease and associated severe pHTN were found to have a higher mortality rate after undergoing TEER. Additionally, we discovered that PASP following TEER not only indicates a poor prognosis but also has a direct correlation with the risk of death and hospitalizations due to heart failure. Similar findings were reported in a previous study, indicating an 18 % increase in two-year mortality for every 10-mmHg increase in baseline PASP [25]. Some studies have suggested that decreasing PASP following TEER is independently associated with reduced deaths and hospitalizations at 30-day and 1-year follow-ups [25,28]. The pathogenesis of pulmonary hypertension in individuals with valvular heart disease is typically multifactorial [37,38]. During the early stages, there is a gradual increase in left ventricular filling pressures and left atrial pressures, which leads to a passive increase in backward pressures of the pulmonary vein [38]. Patients often remain asymptomatic during this stage due to left ventricle compliance and normal pulmonary arterial pressures. However, if the pressures persistently increase, it can cause structural damage to the pulmonary vascular system, leading to irreversible damage and increased pulmonary vascular resistance mediated by an imbalance in nitric oxide and endothelin 1 [39,40].
Several studies have revealed decreased PASP pressures following surgical procedures, but long-term studies are limited [32,41,42]. In certain studies, a reduction in PASP following TEER was independently linked to reduced deaths and hospitalizations at 30-day and 1-year follow-ups [25,28]. It showed notable improvements in functional capacity and quality of life. However, long-term follow-up studies are necessary to determine whether PASP levels decrease after 3–5 years, as the surgical literature suggests that reoccurrence of severe pHTN is often detected at more extended follow-up periods, around 2–5 years [32].
Therefore, an early interventional approach, in combination with GDMT, is the best approach to reduce mortality following TEER. Furthermore, it is recommended that the positioning of the implanted Mitra Clip be analyzed postoperatively, and repositioning should be considered if an elevated pressure gradient persists following the procedure. According to the 2020 ACC/AHA guidelines [43], mitral valve repair is recommended as a class II indication with PASP <70 mmHg. However, according to our analysis, there is an increased risk of all-cause mortality, heart failure hospitalizations, MACE, and surgical complications with PASP levels >50 mmHg when compared to patients with PASP <50 mmHg. Thus, treating patients pre-operatively with medications that lower pulmonary pressures and mitral regurgitation would be a safer option.
Further studies are indicated to investigate the long-term effects of severe pHTN on outcomes following TEER, particularly in conjunction with GDMT, given the recent evidence of improved LV dynamics, as discussed previously. Additionally, limited data exist on the effectiveness of medical therapies such as endothelin receptor antagonists, phosphodiesterase inhibitors, and prostanoids in reducing pulmonary artery pressure before mitral valve interventions.
5. Limitations
The findings of this meta-analysis are subject to certain limitations. These include the potential for selection bias resulting from the inclusion of single-center studies and the absence of randomization, which may have allowed for residual confounding factors. Furthermore, several studies included in the analysis did not provide essential baseline data, including correct heart catheterization information, medication usage, and laboratory results, which could have influenced the overall study outcomes. Additionally, the limited sample sizes and relatively short follow-up periods following Transcatheter Edge-to-Edge Repair (TEER) have restricted the scope of some of the studies. It is essential to acknowledge that various confounding variables, such as other comorbidities and surgical procedures, could impact the overall outcomes of the included studies.
It is worth highlighting that a single study carries a substantial weight, amounting to almost 70–80 % of the analysis. Nevertheless, we have taken steps to address this by conducting a thorough evaluation, which included a sensitivity analysis and an assessment of funnel plots. Given the observational nature of this study, it is crucial to emphasize the need for comprehensive, randomized, prospective studies with extended follow-up periods. Although such studies are currently lacking, it is essential to note that our meta-analysis suggests a potential negative impact of baseline pulmonary hypertension on the short- and long-term outcomes post-TEER. This is a crucial finding, especially considering the lack of relevant research.
6. Conclusion
In conclusion, the findings of this meta-analysis indicate that pre-existing severe pHTN is associated with an increased risk of all-cause mortality, MACE, and HF hospitalizations following TEER. Consequently, severe pHTN should be regarded as a predictor of adverse outcomes. Most of the available data on TEER outcomes were based on short-term follow-ups. As such, caution should be exercised when evaluating the impact of severe pHTN on long-term outcomes. Future, well-designed prospective trials are necessary to assess the long-term implications of severe pHTN on MACE and mortality.
Supplementary Material
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.org/10.1016/j.carrev.2024.12.012.
Acknowledgments
This research has received no external funding.
Footnotes
CRediT authorship contribution statement
Sivaram Neppala: Writing - review & editing, Writing - original draft, Data curation. Himaja Dutt Chigurupati: Writing - review & editing, Investigation, Data curation. Ayman R. Fath: Writing - review & editing. Gowthami Sai Kogilathota Jagirdhar: Formal analysis. Harigopal Sandhyavenu: Writing - review & editing. Jeffery Bolte: Visualization. Abdullah Naveed Muhammad: Visualization. Yasar Sattar: Supervision. Rupak Desai: Validation, Supervision, Software. Ralph A. Defronzo: Writing - review & editing, Validation, Supervision. Timir K. Paul: Writing - review & editing, Supervision. Anand Prasad: Writing - review & editing, Validation, Supervision.
Declaration of competing interest
All authors have no conflict of interest to disclose that is related to this article.
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