Research Article - Interventional Cardiology (2021)

Chronic obstructive pulmonary disease is associated with increased mortality in patients undergoing MitraClip therapy: A systematic review and meta-analysis

Corresponding Author:
Chanavuth Kanitsoraphan
Department of Medicine, University of Hawaii Internal Medicine Residency Program,Honolulu, HI,USA,

Received date: April 28, 202; Accepted date: May 12, 2021;Published date: May 19, 2021


Introduction: Chronic Obstructive Pulmonary Disease (COPD) is highly prevalent in patients undergoing MitraClip with up to 39% reported. Nonetheless, whether COPD has effect on mortality in this patient population remains unclear. We conduct a systematic review and meta-analysis to evaluate the effect of COPD on the outcome in patient undergoing MitraClip therapy.

Methods: We comprehensively searched the data bases of MEDLINE and EMBASE from inception to August 2020. Published cohort and randomized controlled trials of patients undergoing MitraClip therapy which reported univariate or multivariate analyses on the effect of COPD to mortality were included. Data were integrated using the random-effects, generic inverse variance method of DerSimonian and Laird.

Results: Six studies from 2014-2018 involving 5,076 patients undergoing MitraClip therapy were included. Baseline COPD was associated with increased mortality (Risk Ratio [RR]=1.22, 95% Confidence Interval [CI]: 1.07-1.38, p=0.002, I2=0.00%).

Conclusion: COPD is associated with increased mortality in patient undergoing MitraClip therapy up to 1.22 folds. Therefore, COPD could be a predictor of outcome in patients undergoing Mitraclip therapy and could be potentially integrated in risk stratification in this patient population.


Percutaneous mitral valve repair • MitraClip • Chronic obstructive pulmonary disease • Mortality


COPD: Chronic Obstructive Pulmonary Disease; FEV: Forced Expiratory Volume; HF: Heart Failure; HR: Hazard Ratio; LVEF: Left Ventricular Ejection Fraction; MR: Mitral Regurgitation; NOS: The Newcastle-Ottawa Quality Assessment Scale; OR: Odds Ratio; PFT: Pulmonary Function Test; PMVR: Percutaneous Mitral Valve Repair; RR: Relative Risk; TAVR: Transcatheter Aortic Valve Replacement.


Secondary Mitral Regurgitation (MR) due to left ventricular dilation, or functional MR, is widely known to be associated with a worse outcome regarding rehospitalization and mortality in Heart Failure (HF) patients [1]. The geometric dislocation of the papillary muscles and chordae tendineae lead to an incomplete closure of the mitral leaflets causing MR [1]. Guideline-directed medical therapy has been the cornerstone treatment to reduce symptoms, improve Left Ventricular Ejection Function (LVEF), which then decrease the severity of MR [2]. However, in patients who failed medical treatment or with significant LV chamber distortion, surgical options are necessary [3,4]. Percutaneous Mitral Valve Repair (PMVR) with MitraClip has emerged as a relatively safe therapeutic option for patients with prohibitively high surgical risks [5-9]. The COAPT trial demonstrated that MitraClip therapy in patients with moderate-to-severe or severe functional MR secondary to heart failure who failed guideline-directed medical therapy had a lower rate of hospitalization for heart failure and lower all-cause mortality at 2 years follow-up [10]. However, despite a promising result of MitraClip, there are several factors that should be taken into consideration in selecting appropriate patients to undergo the intervention [11]. A thorough risk assessment can help physicians select patients who will likely benefit from the procedure and will help in making a shared decision with patients. This includes procedural tolerability, severity of MR, degree of LV dilatation, comorbidities and life expectancy.

Chronic Obstructive Pulmonary Disease (COPD) is long known to have a close relationship with cardiovascular disease, including HF, and is associated with worse prognosis when the two diseases combine [12,13]. Common risk factors are shared between COPD and cardiovascular diseases (i.e., smoking, elderly), and several features of COPD can predispose patients to cardiovascular diseases (i.e., abnormal gas exchange, chronic inflammation, sedentary lifestyle) [14]. There is currently limited data regarding the association between COPD and outcome in patients with severe MR undergoing MitraClip therapy. Thus, we aimed to evaluate this association via systematic review and meta-analysis.


Search strategy

Two investigators (JK and CT) independently searched for published studies indexed in MEDLINE and EMBASE databases from inception to August 2020 using a search strategy that including the terms “percutaneous mitral valve repair”, “chronic obstructive pulmonary disease” as described in Figure 1. Only full articles in English were included. A manual search for additional pertinent studies and review articles using references from retrieved articles was also completed.

Inclusion criteria

The eligibility criteria included the following:

• Cohort studies (prospective or retrospective), case-control studies, cross-sectional studies, randomized control trials reporting

• Relative Risk (RR), Odds Ratio (OR), Hazard Ratio (HR) or adjusted hazard ratio with 95% Confidence Interval (CI) or sufficient raw data for the calculation were provided. Patients without COPD were used as controls.

Two investigators (JK and CT) independently determined study eligibility and discussed to reach mutual consensus should there were discrepancies. The Newcastle-Ottawa Quality Assessment Scale (NOS) was used to assess each study’s quality in three domains, recruitment and selection of the participants, similarity and comparability between the groups, and ascertainment of the outcome of interest among cohort and case-control studies [15].

Data extraction

A standardized data collection form was used to obtain the following information from each study: name of first author, year of publication, country of origin, study design, study population, total population, type of MR, median follow-up time, surgical risk profile, participants demographic, and confounders that were adjusted in the multivariable analysis, if available.

Two investigators (JK and CT) independently performed this data extraction process to ensure accurate data extraction. Any data discrepancy was resolved by reviewing the primary data from the original articles.


Mortality defined was all-cause mortality, both short-term and long-term, following MitraClip therapy.

Statistical analysis

Randon-effects model was used to perform meta-analysis of included studies. We pooled the point estimates of risk ratio and rate ratio from each study by using the generic inverse-variance method of Der Simonian and Laird [16]. The I2 statistic, which ranges from 0% to 100% (I2<25%, low heterogeneity; I2=25%-50%, moderate heterogeneity; and I2>50%, substantial heterogeneity) was used to quantify the heterogeneity of effect size estimates across the studies [17]. A sensitivity analysis was performed to assess the influence of the individual studies on the overall results by omitting one study at a time. Publication bias was assessed using a funnel plot and the Egger’s regression test [18]. All data analyses were performed using the STATA SE version 14.2.

Sensitivity analysis

We used a sequential exclusion strategy to examine whether overall estimates were influenced by the substantial heterogeneity among studies [19]. We sequentially and cumulatively excluded studies that accounted for the largest share of heterogeneity until I2 was less than 50%. We then examined whether RR estimates were consistent.


Search results

Our search strategy yielded 58 potentially relevant articles (58 articles from EMBASE and 28 articles from MEDLINE). After the exclusion of 28 duplicated articles, 30 articles underwent title and abstract review. Four articles were excluded at this stage since they were not cohort/case control studies, randomized controlled trials or were not conducted in MitraClip population, or topics. Remaining 16 articles underwent full-length review. Ten articles were excluded at this stage as there were no comparing outcomes between the exposure group and the control group. Finally, a total of 6 studies were included in this meta-analysis. Figure 1 reveals the search and literature review process.

Description of included studies

A total of 6 studies from 2014 to 2020 were included in our meta- analysis with a total of 5,076 patients who underwent MitraClip therapy. Median follow-up duration ranged from 12 to 43 months, mean age ranged from 71.6 to 79.4 years old. Female gender represented 20.6% to 27.4% of the study participants. Table 1 demonstrates characteristics of all included studies.

First author, year Country Study design Study population Total population (n)+ Type of MR Median follow-up duration (Months) COPD (%) Mean age (years) Male (%) Mean LVEF (%) Mortality at follow-up (%) STS score Euroscore II Adjusting factors
Baldi, 2018 Italy Prospective cohort Symptomatic moderate-to-severe or severe MR 74 Functional MR 13.9 39.2 71.6 ± 8.3 78.4 33.2  ±  6.8 35.10% N/A 6.1 N/A
Bozdag-Turan, 2014 Germany Prospective cohort Severe MR (at least grade 3+) 121 Primary MR and Secondary MR 12 28.1 77  ±  7 57 42  ±  16 23.10% 10.9  ±  6.4 10.6  ±  5.6 EuroSCORE II, STS score, mTPG, mVOA, LVEF<=30, MR grade after MitraClip
Kalbacher, 2018 Germany Prospective cohort Severe MR 799 Functional MR (69.3%) 34.5 21.9 75.3  ±  8.6 60.7 N/A 45.70% 8.5  ±  7.5 Logistic EuroSCORE 23.7  ±  16.0 Gender, Prior cardiac decompensation, Previous aortic valve intervention, Renal function, Severe TR, LVEF<30%
Kreusser, 2018 Germany Prospective cohort Symptomatic moderate-to-severe or severe MR with reduced EF 174 Functional MR 12 19 75.2 69.5 25 17.80% 14.7 5.7 N/A
Kundi, 2018 United States Retrospective cohort Patients who had undergone MitraClip procedures 3782 N/A 13.6 27.1 79.4  ±  9.3 55.2 N/A 29.50% N/A N/A Age, CHF, AF, Gender, History of valvular surgery, Non-cardiac history, Presentation characteristics, Nontraditional risk factors
Orban, 2017 Germany Prospective cohort Severe symptomatic MR 126 Primary MR and Secondary MR 43 18.3 72.6  ±  10.6 62.7 48.4  ±  15.6 35.70% 14.0  ±  15.5 Logistic EuroSCORE 19.1  ±  20.0 LVEF, TR severity, Renal function, Post-procedural MR severity

Table 1: Characteristics of included studies.

Quality assessment of included studies

The NOS of included studies are described in the Table 2. The NOS uses a scoring system to evaluate qualities of studies on 3 domains, including selection, comparability, and outcomes.

First author, year Selection Comparability Outcome Total score
Represent-ativeness Selection of the non-exposed cohort Ascertainment Endpoint not present at start Comparability Assessment of outcome Follow-up duration Adequacy follow-up
Baldi, 2018 * * * * * * * * 8
Bozdag-Turan, 2014 * * * * ** * * * 9
Kalbacher, 2018 * * * * ** * * * 9
Kreusser, 2018 * * * * * * * * 8
Kundi, 2018 * * * * ** * * * 9
Orban, 2017 * * * * ** * * * 9

Table 2: Newcastle-Ottawa quality assessment scale of included studies in meta-analysis.

Meta-analysis results

We found that baseline COPD is associated with an increased risk of mortality following MitraClip therapy (pooled HR=1.22, 95%CI: 1.07-1.38, I2=0.0%, p=0.002). Forest plot is demonstrated in Figure 1.

Figure 1: Search methodology and selection process.

Sensitivity analysis

To assess the stability of the results of the meta-analysis, we conducted a sensitivity analysis for each outcome by excluding one study at a time. There were no significant alterations of results for every outcome.


Despite a lot of evidence indicating COPD as an independent predictor of mortality in patients undergoing cardiac surgeries or other transcatheter interventions i.e., transcatheter aortic valve replacement [20-24], conflicting data exist regarding its impact on outcomes of patients undergoing MitraClip. There has yet to be a dedicated study on impact of COPD on outcomes of patients undergoing MitraClip procedure. Five out of six studies included in our meta-analysis did not shown statistically significant increase in mortality in patients with COPD undergoing MitraClip therapy. Our study is the first meta-analysis to assess the relation COPD and mortality among patients undergoing MitraClip therapy (Figure 2).

Figure 2: The Forest plot showing the association between baseline COPD and risk of mortality in patients undergoing MitraClip therapy.

Mechanism to explain increased mortality rate in patient with COPD has yet to be elucidated. First, patients with COPD were more likely to have associated cardiovascular, renal, neurologic, infectious, liver, and respiratory comorbidities [25,26]. COPD patients were also more often found to have lower BMI which may be resulted from nutritional deficiency [25]. Protein malnutrition is commonly seen in patients with lower BMI and can cause more pulmonary complications, due to respiratory muscle strength impairment, reduction in diaphragmatic muscular mass, and maximum voluntary ventilation [27]. COPD patients also have gas exchange and mucociliary clearance of aspirated bacteria dysfunction, which predispose patients to postoperative pneumonia and respiratory failure [28,29]. COPD patients were also found to have increased risk of postoperative wound dehiscence [30], sepsis [25], cardiac arrhythmia and myocardial infarction [31], as well as acute kidney injuries [32].

Currently, preoperative surgical risk evaluation for patients undergoing MitraClip is based on Society of Thoracic Surgeons (STS) risk score, with predicted operative mortality of ≥ 8 percent being used as a prohibitive cut-point [6]. However, the STS does not include the presence of COPD in its risk formula. The STS score only utilizes only FEV1 from Pulmonary Function Test (PFT) to define chronic lung disease. In addition to STS score, COPD diagnosis should also be considered separately in risk stratification as well.

Obtaining accurate COPD diagnosis is thus important for pre- operative assessment for patients undergoing MitraClip. COPD many times is diagnosed in clinical practice based on symptoms of dyspnea and history of smoking without confirmation with PFTs [33]. Adabag et al. [34] had shown that preoperative PFTs done in patients undergoing cardiac surgeries in a tertiary cardiac center revealed COPD status of 30% of patients were misclassified, and half of these patients were newly diagnosed with COPD by the these pre-operative PFTs. With accurate diagnosis of COPD, appropriate medical optimization and improvement of pulmonary hygiene can subsequently be done to prevent morbidities and mortalities in these groups of patients, although there is no study of benefits of these interventions in patients undergoing MitraClip thus far.


There are a few limitations in our meta-analysis. First, there were minor differences among baseline patient, which are illustrated in Table 1. Secondly, as a nature of cohort studies which are used in the meta-analysis, causal relationship cannot be inferred. Third, all studies were conducted in European countries. Therefore, extrapolation of the results to apply in other ethnicities could be limited. Fourth, despite attempts to adjust with possible confounders in some studies, these confounders were not adjusted identically in all studies and there were potential confounders that remained unadjusted.


COPD is associated with increased mortality in patient undergoing MitraClip therapy up to 1.22 folds. Therefore, COPD could be a predictor of outcome in patients undergoing Mitraclip therapy and could be potentially integrated in risk stratification in this patient population.

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