Abstract
Small aortic prosthetic valves have been associated with suboptimal performance due to patient–prosthesis mismatch (PPM). This meta-analysis compared the outcomes of patients with a small root who received tissue versus mechanical aortic valves.
A systematic literature review identified 7 candidate studies; of these, 5 met the meta-analysis criteria. We analysed outcomes for a total of 680 patients (227 tissue valves and 453 mechanical valves) using random effects modelling. Each study was assessed for heterogeneity and quality. The primary end point was mortality at follow-up. Secondary end points included intraoperative and postoperative outcomes, the rate of PPM and left ventricle mass regression and major cardiac and prosthesis-related adverse events at follow-up.
There was no between-group difference in mortality at follow-up [incidence rate ratio 1, 95% confidence interval (CI) 0.50–2.01; P = 0.99]. The tissue group had a higher rate of PPM (odds ratio 17.19, 95% CI 8.6–25.78; P = 0.002) and significantly less reduction in ventricular mass (weighted mean difference 40.79, 95% CI 4.62–76.96; P = 0.02). There were no significant differences in the incidence of structural valve disease at follow-up compared to that in the mechanical valve group. There was also no between-group difference in aggregated adverse events at follow-up (P = 0.68).
Tissue and mechanical valves were associated with similar mortality rates; however, patients receiving tissue valves had a higher rate of PPM and significantly less left ventricle mass regression. These findings indicate that patients receiving small tissue valves may require closer clinical surveillance than those receiving mechanical valves.
INTRODUCTION
Aortic valve replacement (AVR) using small valves has been associated with the postoperative development of a high transvalvular gradient. The most common cause of an elevated gradient in a normally functioning prosthesis is patient–prosthesis mismatch (PPM) [1]. Downstream consequences of PPM include lesser regression of the left ventricular mass, minimal improvement in functional class and ultimately a reduction in life expectancy [2]. Recent reports have shown that any degree of PPM significantly decreases long-term survival and increases readmission rates for both heart failure and reoperation for AVR [3]. Although both tissue and mechanical valves can be associated with PPM, the primary trade-off is an increased risk of haemorrhage in patients receiving mechanical AVRs and an increased risk of late reoperation in all patients receiving tissue valve replacements [4].
Structural valve deterioration (SVD) is the ‘Achilles heel’ of the small valve bioprosthesis, especially in elderly patients [5]. Annulus enlargement procedures are sometimes necessary to fit larger prostheses; however, this approach can expose patients to prolonged operation times [6]. The downside of the mechanical valve is the need for lifelong anticoagulation; yet, it may offer better haemodynamic performance than the tissue valve. To date, it is not known whether mechanical valves offer superior clinical and haemodynamic performance compared to tissue valves in the presence of a small aortic annulus.
Therefore, the aim of this study was to compare the mortality rate, rate of PPM and degree of left ventricular mass regression at follow-up in patients with small tissue and mechanical valve replacements.
MATERIALS AND METHODS
Literature search
We performed a literature search of the PubMed, Ovid, Medline, Embase, Medline, Google scholar and Cochrane databases using the MeSH terms ‘aortic valve replacement’, ‘tissue’, ‘mechanical’, ‘patient prosthesis mismatch’, and ‘small root’. The search was extended to include the clinicaltirals.gov database for further rigour. The related-articles function in PubMed was also used to ensure completeness. The date for this search was inception to March 2018 (Fig. 1).
Search strategy.
Inclusion and exclusion criteria
We included all articles reporting comparative outcomes for tissue (control group) and mechanical (experimental group) valve replacements related to PPM. PPM was defined as indexed orifice area ≤0.85 cm2/m2 [7]. Studies were excluded from the review if (i) inconsistencies in the data precluded valid extraction; (ii) the data were duplicated; (iii) the experimental or control group included root and ascending aorta replacements or stentless/sutureless valves and homografts; or (iv) the study was performed in an animal model. Using these criteria, 2 researchers (M.M. and K.F.) independently selected studies for further examination by title and abstract review. All full texts of potentially eligible studies were retrieved for further evaluation. Disagreements between the reviewers were resolved by discussion with a third author (T.A.). Statistical concordance testing was performed using Cohen’s kappa coefficient as a measure of inter-rater agreement.
Data analyses
Using a predefined protocol, 2 authors (M.M. and K.F.) independently extracted the following data from each paper: first author, year of publication, study type, number of subjects and study population demographics. Specific outcome data were extracted when available as follows: (i) the primary end point mortality at follow-up (cardiac and prosthesis-related causes) and (ii) secondary end points including PPM, the left ventricle mass regression index, structural valve disease, postoperative outcomes (in-hospital mortality and stroke) and incidences of aggregated cardiac and prosthesis events, including major adverse cardiac and cerebrovascular events (MACCE) and adverse prosthesis-related events (MAPE). MACCE included cardiac death, cerebrovascular death, myocardial infarction, congestive heart failure, stroke or cardiac arrhythmia. MAPE was defined as reoperation, major bleeding, thromboembolic event or endocarditis during follow-up.
The meta-analysis was performed in accordance with the Cochrane Collaboration recommendations and in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and MOOSE (Meta-analysis Of Observational Studies in Epidemiology) guidelines [8, 9].
Extracted data were originally stored in Excel spreadsheets and uploaded onto R-project (R Core Team 2013, Vienna, Austria; http://www.R-project.org/); data modelling was carried out with the following packages: metafor, stats, meta and graphics (for data visualization). Data were analysed using a weighted DerSimonian and Laird random effects model. Continuous data are expressed as the weighted mean difference with the 95% confidence interval (CI). The point estimate of the weighted mean difference was statistically significant when P-value <0.05 if the 95% CI did not include 0. Categorical variables are expressed as odds ratios (ORs) with 95% CIs. An OR of <1 favoured the treatment group. The point estimate of the OR was statistically significant when P-value <0.05 if the 95% CI did not include 1. The incidence rate ratio (IRR) was used for long-term outcome. Relative effect estimates were calculated as log IRRs with 95% CIs (95% CIs) for long-term outcomes. Event rates were estimated from the Kaplan–Meier curves using Plot Digitizer 2.6.2. If Kaplan–Meier curves were not available, we used the reported event rates to calculate the IRR. Statistical methods for time-to-event data were used to analyse outcomes at follow-up, including the Kaplan–Meier estimator with the log-rank test for comparisons (as sensitivity analysis). Meta-regression was carried out to assess the influence of the covariates’ age and gender on the primary outcome (survival).
Heterogeneity
Interstudy heterogeneity was explored for each variable using the χ2 statistic. I2 values were calculated to quantify the degree of heterogeneity across trials that could not be attributed to chance alone. Significant heterogeneity was considered to be present when I2 >50%. Two strategies were used to assess data validity and heterogeneity: (i) funnel plots to evaluate publication bias and (ii) a subgroup analysis of higher quality studies (studies with quality scores > 10).
Quality scoring
The modified Newcastle–Ottawa scale was used to assess the quality of each study [9]. Studies attaining a score higher than the median score of 10 (maximum score: 20) were considered to have high matching quality. The modified Newcastle–Ottawa scoring criteria are summarized in Table 1, and quality scoring results are reported in Table 2.
Criteria for quality assessment
| Quality checklist |
|---|
| Selection |
| 1. Assignment for treatment—any criteria reported (if yes, 1 star)? |
| 2. How representative was the reference group (tissue valve group) in comparison to the alternative group (mechanical valve group) (if yes, 1 star; no star if the patients were selected or if group selection was not described)? |
| Comparability |
| Comparability variables: (1) age; (2) sex; (3) renal function; (4) extracardiac arteriopathy; (5) poor mobility; (6) previous cardiac surgery; (7) chronic lung disease; (8) active endocarditis; (9) critical preoperative state; (10) insulin-dependent diabetes mellitus; (11) New York Heart Association; (12) Canadian Cardiovascular Society IV; (13) left ventricular function; (14) recent myocardial infarction; (15) pulmonary hypertension; (16) urgency; (17) combined; (18) body surface area; (19) valve size; (20) surgical technique. |
| 3. Groups comparable for 1, 2, 3, 4, 5, 6, 7, 8 and 9 (if yes, 1 star for each variable). |
| 4. Groups comparable for 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 (if yes, 1 star for each variable). |
| Outcome assessment |
| 6. Clearly defined outcome of interest (if yes, 1 star). |
| 7. Follow-up (if yes, 1 star). |
| Quality checklist |
|---|
| Selection |
| 1. Assignment for treatment—any criteria reported (if yes, 1 star)? |
| 2. How representative was the reference group (tissue valve group) in comparison to the alternative group (mechanical valve group) (if yes, 1 star; no star if the patients were selected or if group selection was not described)? |
| Comparability |
| Comparability variables: (1) age; (2) sex; (3) renal function; (4) extracardiac arteriopathy; (5) poor mobility; (6) previous cardiac surgery; (7) chronic lung disease; (8) active endocarditis; (9) critical preoperative state; (10) insulin-dependent diabetes mellitus; (11) New York Heart Association; (12) Canadian Cardiovascular Society IV; (13) left ventricular function; (14) recent myocardial infarction; (15) pulmonary hypertension; (16) urgency; (17) combined; (18) body surface area; (19) valve size; (20) surgical technique. |
| 3. Groups comparable for 1, 2, 3, 4, 5, 6, 7, 8 and 9 (if yes, 1 star for each variable). |
| 4. Groups comparable for 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 (if yes, 1 star for each variable). |
| Outcome assessment |
| 6. Clearly defined outcome of interest (if yes, 1 star). |
| 7. Follow-up (if yes, 1 star). |
Comparability included all of the EuroSCORE II risk factors.
Criteria for quality assessment
| Quality checklist |
|---|
| Selection |
| 1. Assignment for treatment—any criteria reported (if yes, 1 star)? |
| 2. How representative was the reference group (tissue valve group) in comparison to the alternative group (mechanical valve group) (if yes, 1 star; no star if the patients were selected or if group selection was not described)? |
| Comparability |
| Comparability variables: (1) age; (2) sex; (3) renal function; (4) extracardiac arteriopathy; (5) poor mobility; (6) previous cardiac surgery; (7) chronic lung disease; (8) active endocarditis; (9) critical preoperative state; (10) insulin-dependent diabetes mellitus; (11) New York Heart Association; (12) Canadian Cardiovascular Society IV; (13) left ventricular function; (14) recent myocardial infarction; (15) pulmonary hypertension; (16) urgency; (17) combined; (18) body surface area; (19) valve size; (20) surgical technique. |
| 3. Groups comparable for 1, 2, 3, 4, 5, 6, 7, 8 and 9 (if yes, 1 star for each variable). |
| 4. Groups comparable for 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 (if yes, 1 star for each variable). |
| Outcome assessment |
| 6. Clearly defined outcome of interest (if yes, 1 star). |
| 7. Follow-up (if yes, 1 star). |
| Quality checklist |
|---|
| Selection |
| 1. Assignment for treatment—any criteria reported (if yes, 1 star)? |
| 2. How representative was the reference group (tissue valve group) in comparison to the alternative group (mechanical valve group) (if yes, 1 star; no star if the patients were selected or if group selection was not described)? |
| Comparability |
| Comparability variables: (1) age; (2) sex; (3) renal function; (4) extracardiac arteriopathy; (5) poor mobility; (6) previous cardiac surgery; (7) chronic lung disease; (8) active endocarditis; (9) critical preoperative state; (10) insulin-dependent diabetes mellitus; (11) New York Heart Association; (12) Canadian Cardiovascular Society IV; (13) left ventricular function; (14) recent myocardial infarction; (15) pulmonary hypertension; (16) urgency; (17) combined; (18) body surface area; (19) valve size; (20) surgical technique. |
| 3. Groups comparable for 1, 2, 3, 4, 5, 6, 7, 8 and 9 (if yes, 1 star for each variable). |
| 4. Groups comparable for 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 (if yes, 1 star for each variable). |
| Outcome assessment |
| 6. Clearly defined outcome of interest (if yes, 1 star). |
| 7. Follow-up (if yes, 1 star). |
Comparability included all of the EuroSCORE II risk factors.
Quality scoring
| Authors (number of patients) | Selection | Comparability | Outcome | Total | |||
|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | ||
| Mahon et al. [10] (n = 61) | * | * | *** | * | * | 7 | |
| Okamura et al. [11] (n = 65) | * | * | ** | ***** | * | * | 11 |
| Teshima et al. [12] (n = 127) | * | * | *** | ****** | * | * | 13 |
| Prifti et al. [13] (n = 323) | * | **** | ****** | * | * | 13 | |
| Okamoto et al. [14] (n = 104) | * | * | *** | ***** | * | * | 12 |
| Authors (number of patients) | Selection | Comparability | Outcome | Total | |||
|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | ||
| Mahon et al. [10] (n = 61) | * | * | *** | * | * | 7 | |
| Okamura et al. [11] (n = 65) | * | * | ** | ***** | * | * | 11 |
| Teshima et al. [12] (n = 127) | * | * | *** | ****** | * | * | 13 |
| Prifti et al. [13] (n = 323) | * | **** | ****** | * | * | 13 | |
| Okamoto et al. [14] (n = 104) | * | * | *** | ***** | * | * | 12 |
The quality scoring system was based on the EuroSCORE II, a modified Newcastle–Ottawa scale, also including body surface area, valve size and surgical technique (root widening).
Quality scoring
| Authors (number of patients) | Selection | Comparability | Outcome | Total | |||
|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | ||
| Mahon et al. [10] (n = 61) | * | * | *** | * | * | 7 | |
| Okamura et al. [11] (n = 65) | * | * | ** | ***** | * | * | 11 |
| Teshima et al. [12] (n = 127) | * | * | *** | ****** | * | * | 13 |
| Prifti et al. [13] (n = 323) | * | **** | ****** | * | * | 13 | |
| Okamoto et al. [14] (n = 104) | * | * | *** | ***** | * | * | 12 |
| Authors (number of patients) | Selection | Comparability | Outcome | Total | |||
|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | ||
| Mahon et al. [10] (n = 61) | * | * | *** | * | * | 7 | |
| Okamura et al. [11] (n = 65) | * | * | ** | ***** | * | * | 11 |
| Teshima et al. [12] (n = 127) | * | * | *** | ****** | * | * | 13 |
| Prifti et al. [13] (n = 323) | * | **** | ****** | * | * | 13 | |
| Okamoto et al. [14] (n = 104) | * | * | *** | ***** | * | * | 12 |
The quality scoring system was based on the EuroSCORE II, a modified Newcastle–Ottawa scale, also including body surface area, valve size and surgical technique (root widening).
Risk of bias
A domain-based evaluation of risk of bias was performed as previously described [15, 16] and in accordance with the guidelines outlined in the Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0 [17]. Three authors (M.M., K.F. and T.A.) subjectively reviewed all included studies and assigned a value of ‘yes’, ‘no’ or ‘unclear’ to the following questions: (i) Was the allocation sequence adequately generated? (ii) Was allocation adequately concealed? (iii) Was there blinding of participants, personnel and outcome assessors? (iv) Were incomplete outcome data sufficiently assessed? (v) Are reports in the study free of the suggestion of selective outcome reporting? Risk-of-bias plots were generated using Review Manager® version 5.1.7 for Windows (The Cochrane Collaboration, Oxford, UK).
RESULTS
The research output is visualized in Fig. 1, where the reasons for the inclusion/exclusion criteria are also specified (Supplementary Material 1: PRISMA check list). The literature search identified 5 studies [10–14] that met the study inclusion and exclusion criteria, yielding a pooled data set of 680 patients (227 who underwent tissue AVR and 453 who underwent mechanical AVR) (Table 3). There was 100% concordance between reviewers, which equated to a Cohen’s kappa coefficient of κ = 1. Four studies were retrospective observational studies [10–13] and 1 was a propensity matched study [14]. Three of the observational studies included 2 very homogeneous populations [11–13]. Two other studies identified during screening only reported echocardiographic results and amalgamated outcomes for valve sizes >21 mm and were therefore excluded [18, 19].
Study characteristics
| Author (total patients) Study type | T/M (N) | Age (years) | Sex (female) | BSA (m2) | Valve size (mm) | Root enlargement (n) | REDO (n) | PPM (n) | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| T | M | T | M | T | M | T | M | T | M | T | M | T | M | ||
| Mahon et al. [10] (n = 61) | 35/26 | 72.9 (6.6) | 67.9 (5.2) | NR | NR | 1.63 (0.15) | 1.63 (0.03) | 19/21 | 19 | 5 | 3 | 0 | 0 | 14 | 1 |
| Retrospective observational | |||||||||||||||
| Okamura et al. [11] (n = 65) | 15/50 | 76.9 (3.4) | 69.9 (8.6) | 27 | 13 | 1.43 (0.16) | 1.49 (0.13) | 19 | 17/19 | 0 | 0 | 0 | 0 | 11 | 13 |
| Retrospective observational | |||||||||||||||
| Teshima et al. [12] (n = 127) | 67/60 | 79.0 (5.1) | 79.1 (5.2) | 54 | 56 | 1.4 (0.11) | 1.33 (0.13) | 19 | 17 | 0 | 0 | 1 | 3 | 3 | 6 |
| Retrospective observational | |||||||||||||||
| Prifti et al. [13] (n = 323) | 58/265 | 71.0 (16) | 67.5 (12.7) | 44 | 214 | 1.69 (0.2) | 1.67 (0.1) | 19 | 19 | 4 | 36 | 4 | 31 | 24 | 110 |
| Retrospective observational | |||||||||||||||
| Okamoto et al. [14] (n = 104) | 52/52 | 79.3 (3.4) | 79.5 (3.5) | 33 | 33 | 1.44 (0.16) | 1.43 (0.18) | 21/19 | 16/21 | 3 | 5 | 0 | 1 | 21 | 14 |
| Propensity score | |||||||||||||||
| Author (total patients) Study type | T/M (N) | Age (years) | Sex (female) | BSA (m2) | Valve size (mm) | Root enlargement (n) | REDO (n) | PPM (n) | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| T | M | T | M | T | M | T | M | T | M | T | M | T | M | ||
| Mahon et al. [10] (n = 61) | 35/26 | 72.9 (6.6) | 67.9 (5.2) | NR | NR | 1.63 (0.15) | 1.63 (0.03) | 19/21 | 19 | 5 | 3 | 0 | 0 | 14 | 1 |
| Retrospective observational | |||||||||||||||
| Okamura et al. [11] (n = 65) | 15/50 | 76.9 (3.4) | 69.9 (8.6) | 27 | 13 | 1.43 (0.16) | 1.49 (0.13) | 19 | 17/19 | 0 | 0 | 0 | 0 | 11 | 13 |
| Retrospective observational | |||||||||||||||
| Teshima et al. [12] (n = 127) | 67/60 | 79.0 (5.1) | 79.1 (5.2) | 54 | 56 | 1.4 (0.11) | 1.33 (0.13) | 19 | 17 | 0 | 0 | 1 | 3 | 3 | 6 |
| Retrospective observational | |||||||||||||||
| Prifti et al. [13] (n = 323) | 58/265 | 71.0 (16) | 67.5 (12.7) | 44 | 214 | 1.69 (0.2) | 1.67 (0.1) | 19 | 19 | 4 | 36 | 4 | 31 | 24 | 110 |
| Retrospective observational | |||||||||||||||
| Okamoto et al. [14] (n = 104) | 52/52 | 79.3 (3.4) | 79.5 (3.5) | 33 | 33 | 1.44 (0.16) | 1.43 (0.18) | 21/19 | 16/21 | 3 | 5 | 0 | 1 | 21 | 14 |
| Propensity score | |||||||||||||||
Data are presented as mean ± standard deviation or number.
BSA: body surface area; M: mechanical valve group; NR: not reported; PPM: patient–prosthesis mismatch (defined as indexed orifice area ≤0.75 cm2/m2); T: tissue valve group.
Study characteristics
| Author (total patients) Study type | T/M (N) | Age (years) | Sex (female) | BSA (m2) | Valve size (mm) | Root enlargement (n) | REDO (n) | PPM (n) | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| T | M | T | M | T | M | T | M | T | M | T | M | T | M | ||
| Mahon et al. [10] (n = 61) | 35/26 | 72.9 (6.6) | 67.9 (5.2) | NR | NR | 1.63 (0.15) | 1.63 (0.03) | 19/21 | 19 | 5 | 3 | 0 | 0 | 14 | 1 |
| Retrospective observational | |||||||||||||||
| Okamura et al. [11] (n = 65) | 15/50 | 76.9 (3.4) | 69.9 (8.6) | 27 | 13 | 1.43 (0.16) | 1.49 (0.13) | 19 | 17/19 | 0 | 0 | 0 | 0 | 11 | 13 |
| Retrospective observational | |||||||||||||||
| Teshima et al. [12] (n = 127) | 67/60 | 79.0 (5.1) | 79.1 (5.2) | 54 | 56 | 1.4 (0.11) | 1.33 (0.13) | 19 | 17 | 0 | 0 | 1 | 3 | 3 | 6 |
| Retrospective observational | |||||||||||||||
| Prifti et al. [13] (n = 323) | 58/265 | 71.0 (16) | 67.5 (12.7) | 44 | 214 | 1.69 (0.2) | 1.67 (0.1) | 19 | 19 | 4 | 36 | 4 | 31 | 24 | 110 |
| Retrospective observational | |||||||||||||||
| Okamoto et al. [14] (n = 104) | 52/52 | 79.3 (3.4) | 79.5 (3.5) | 33 | 33 | 1.44 (0.16) | 1.43 (0.18) | 21/19 | 16/21 | 3 | 5 | 0 | 1 | 21 | 14 |
| Propensity score | |||||||||||||||
| Author (total patients) Study type | T/M (N) | Age (years) | Sex (female) | BSA (m2) | Valve size (mm) | Root enlargement (n) | REDO (n) | PPM (n) | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| T | M | T | M | T | M | T | M | T | M | T | M | T | M | ||
| Mahon et al. [10] (n = 61) | 35/26 | 72.9 (6.6) | 67.9 (5.2) | NR | NR | 1.63 (0.15) | 1.63 (0.03) | 19/21 | 19 | 5 | 3 | 0 | 0 | 14 | 1 |
| Retrospective observational | |||||||||||||||
| Okamura et al. [11] (n = 65) | 15/50 | 76.9 (3.4) | 69.9 (8.6) | 27 | 13 | 1.43 (0.16) | 1.49 (0.13) | 19 | 17/19 | 0 | 0 | 0 | 0 | 11 | 13 |
| Retrospective observational | |||||||||||||||
| Teshima et al. [12] (n = 127) | 67/60 | 79.0 (5.1) | 79.1 (5.2) | 54 | 56 | 1.4 (0.11) | 1.33 (0.13) | 19 | 17 | 0 | 0 | 1 | 3 | 3 | 6 |
| Retrospective observational | |||||||||||||||
| Prifti et al. [13] (n = 323) | 58/265 | 71.0 (16) | 67.5 (12.7) | 44 | 214 | 1.69 (0.2) | 1.67 (0.1) | 19 | 19 | 4 | 36 | 4 | 31 | 24 | 110 |
| Retrospective observational | |||||||||||||||
| Okamoto et al. [14] (n = 104) | 52/52 | 79.3 (3.4) | 79.5 (3.5) | 33 | 33 | 1.44 (0.16) | 1.43 (0.18) | 21/19 | 16/21 | 3 | 5 | 0 | 1 | 21 | 14 |
| Propensity score | |||||||||||||||
Data are presented as mean ± standard deviation or number.
BSA: body surface area; M: mechanical valve group; NR: not reported; PPM: patient–prosthesis mismatch (defined as indexed orifice area ≤0.75 cm2/m2); T: tissue valve group.
All studies except one [10] were classified as high-quality studies (score > 10; Table 2).
The mean age of the overall population was 74.2 years (range 67–79.5 years). There was no significant difference between the ages of the 2 populations (75.2 vs 72.6 years, tissue versus mechanical, respectively; P = 0.56).
Definition of ‘small valve’
Both tissue and mechanical valves <21 mm in diameter were considered to be small valves and were included in the analysis. All tissue valves were stented valves. Teshima et al. [12] specifically compared 17-mm mechanical valves and 19-mm tissue valves. In the Okamura series [11], 15.3% of the mechanical valves were 16 mm, 21.1% were 17 mm, 15.3% were 18 mm, 11.3% were 20 mm and 1.9% were 21 mm; this series also included 2 valves of 23 mm in the mechanical group and 6 valves >23 mm, but the results could not be separated to exclude these valves. In general, patients in the mechanical group received smaller valves due to the availability of prostheses <19 mm.
Body surface area values were available for all of the included studies (Table 3). In general, the threshold for PPM was an indexed effective orifice area ≤0.85 cm2/m2 [7]. Ring enlargement strategies were performed in a small number of patients. Studies used both interrupted and semi-continuous implantation suturing techniques. Comparability between studies was ensured with a modified Newcastle–Ottawa scale using baseline factors, valve sizes and surgical strategies (Table 1).
Primary outcome
Results for primary and secondary end points in each study are summarized in Table 4. There was no difference in mortality at follow-up between patients who received tissue and mechanical valves (IRR 1, 95% CI 0.5–2.01; P = 0.99) with no heterogeneity (Figs 2A and B and 3: merged Kaplan–Meier overall survival tissue versus mechanical, log-rank test; P = 0.33). The overall mean follow-up duration was 47.6 (15.1) months. Meta-regression did not show significant effect of the covariate age [P = 0.88 and 0.84 (beta = 0.39 and 0.31) tissue and mechanical, respectively] and gender [P = 0.36 and 0.37 (beta = 0.03 and 0.08) tissue and mechanical, respectively] on the primary outcome.
(A) Forest plot and (B) funnel plot of mortality at follow-up for groups having tissue valve replacement versus mechanical valve replacement. CI: confidence interval; df: degrees of freedom; IV: inverse variance.
Long-term survival after tissue (blue) and mechanical (red) aortic valve replacement in small annulus. Log-rank test (P = 0.33). Overall mean follow-up duration was 47.6 (15.1) months. Mech: mechanical.
Overall results of the meta-analysis
| Outcome | N | Overall effect | Heterogeneity | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Studies | T | M | Mean difference | Odds ratio/IRR | 95% CI | P-value | χ2 | P-value | I2 (%) | ||
| Primary outcome | |||||||||||
| Late deaths | 5 | 227 | 453 | 1 | 0.5–2.01 | 0.99 | 1.91 | 0.75 | 0 | ||
| Secondary outcomes | |||||||||||
| Patient–prosthesis mismatcha | 5 | 227 | 453 | 17.19 | 8.6–25.78 | 0.002 | 2.2 | 0.07 | 55.2 | ||
| LVMI regressiona | 3 | 140 | 375 | 40.79 | 4.62–76.96 | 0.02 | 25.8 | 0.01 | 89.7 | ||
| 30-Day mortality | 5 | 227 | 453 | 3.22 | −5.61 to 12.11 | 0.47 | 2 | 0.72 | 0 | ||
| Postoperative stroke | 5 | 227 | 453 | 0.91 | −8.46 to 10.35 | 0.84 | 1 | 0.99 | 0 | ||
| Late stroke | 4 | 173 | 202 | 0.6 | −1.9 to 0.58 | 0.29 | 1 | 0.88 | 0 | ||
| Structural valve degeneration | 5 | 227 | 453 | 1.03 | −0.12 to 2.18 | 0.08 | 1 | 0.93 | 0 | ||
| MACCE + MAPE at follow-up | 5 | 227 | 453 | 0.12 | −0.46 to 0.71 | 0.68 | 1.35 | 0.34 | 25.6 | ||
| Outcome | N | Overall effect | Heterogeneity | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Studies | T | M | Mean difference | Odds ratio/IRR | 95% CI | P-value | χ2 | P-value | I2 (%) | ||
| Primary outcome | |||||||||||
| Late deaths | 5 | 227 | 453 | 1 | 0.5–2.01 | 0.99 | 1.91 | 0.75 | 0 | ||
| Secondary outcomes | |||||||||||
| Patient–prosthesis mismatcha | 5 | 227 | 453 | 17.19 | 8.6–25.78 | 0.002 | 2.2 | 0.07 | 55.2 | ||
| LVMI regressiona | 3 | 140 | 375 | 40.79 | 4.62–76.96 | 0.02 | 25.8 | 0.01 | 89.7 | ||
| 30-Day mortality | 5 | 227 | 453 | 3.22 | −5.61 to 12.11 | 0.47 | 2 | 0.72 | 0 | ||
| Postoperative stroke | 5 | 227 | 453 | 0.91 | −8.46 to 10.35 | 0.84 | 1 | 0.99 | 0 | ||
| Late stroke | 4 | 173 | 202 | 0.6 | −1.9 to 0.58 | 0.29 | 1 | 0.88 | 0 | ||
| Structural valve degeneration | 5 | 227 | 453 | 1.03 | −0.12 to 2.18 | 0.08 | 1 | 0.93 | 0 | ||
| MACCE + MAPE at follow-up | 5 | 227 | 453 | 0.12 | −0.46 to 0.71 | 0.68 | 1.35 | 0.34 | 25.6 | ||
Patient–prosthesis mismatch was defined as indexed orifice area ≤0.85 cm2/m2.
Denotes significance.
CI: confidence interval; IRR: incidence rate ratio; LVMI: left ventricle mass index (g/m2); M: mechanical valve group; MACCE: major adverse cardiocerebral event; MAPE: major adverse prosthesis event; T: tissue valve group.
Overall results of the meta-analysis
| Outcome | N | Overall effect | Heterogeneity | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Studies | T | M | Mean difference | Odds ratio/IRR | 95% CI | P-value | χ2 | P-value | I2 (%) | ||
| Primary outcome | |||||||||||
| Late deaths | 5 | 227 | 453 | 1 | 0.5–2.01 | 0.99 | 1.91 | 0.75 | 0 | ||
| Secondary outcomes | |||||||||||
| Patient–prosthesis mismatcha | 5 | 227 | 453 | 17.19 | 8.6–25.78 | 0.002 | 2.2 | 0.07 | 55.2 | ||
| LVMI regressiona | 3 | 140 | 375 | 40.79 | 4.62–76.96 | 0.02 | 25.8 | 0.01 | 89.7 | ||
| 30-Day mortality | 5 | 227 | 453 | 3.22 | −5.61 to 12.11 | 0.47 | 2 | 0.72 | 0 | ||
| Postoperative stroke | 5 | 227 | 453 | 0.91 | −8.46 to 10.35 | 0.84 | 1 | 0.99 | 0 | ||
| Late stroke | 4 | 173 | 202 | 0.6 | −1.9 to 0.58 | 0.29 | 1 | 0.88 | 0 | ||
| Structural valve degeneration | 5 | 227 | 453 | 1.03 | −0.12 to 2.18 | 0.08 | 1 | 0.93 | 0 | ||
| MACCE + MAPE at follow-up | 5 | 227 | 453 | 0.12 | −0.46 to 0.71 | 0.68 | 1.35 | 0.34 | 25.6 | ||
| Outcome | N | Overall effect | Heterogeneity | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Studies | T | M | Mean difference | Odds ratio/IRR | 95% CI | P-value | χ2 | P-value | I2 (%) | ||
| Primary outcome | |||||||||||
| Late deaths | 5 | 227 | 453 | 1 | 0.5–2.01 | 0.99 | 1.91 | 0.75 | 0 | ||
| Secondary outcomes | |||||||||||
| Patient–prosthesis mismatcha | 5 | 227 | 453 | 17.19 | 8.6–25.78 | 0.002 | 2.2 | 0.07 | 55.2 | ||
| LVMI regressiona | 3 | 140 | 375 | 40.79 | 4.62–76.96 | 0.02 | 25.8 | 0.01 | 89.7 | ||
| 30-Day mortality | 5 | 227 | 453 | 3.22 | −5.61 to 12.11 | 0.47 | 2 | 0.72 | 0 | ||
| Postoperative stroke | 5 | 227 | 453 | 0.91 | −8.46 to 10.35 | 0.84 | 1 | 0.99 | 0 | ||
| Late stroke | 4 | 173 | 202 | 0.6 | −1.9 to 0.58 | 0.29 | 1 | 0.88 | 0 | ||
| Structural valve degeneration | 5 | 227 | 453 | 1.03 | −0.12 to 2.18 | 0.08 | 1 | 0.93 | 0 | ||
| MACCE + MAPE at follow-up | 5 | 227 | 453 | 0.12 | −0.46 to 0.71 | 0.68 | 1.35 | 0.34 | 25.6 | ||
Patient–prosthesis mismatch was defined as indexed orifice area ≤0.85 cm2/m2.
Denotes significance.
CI: confidence interval; IRR: incidence rate ratio; LVMI: left ventricle mass index (g/m2); M: mechanical valve group; MACCE: major adverse cardiocerebral event; MAPE: major adverse prosthesis event; T: tissue valve group.
Secondary end points
The rate of PPM was significantly higher in the tissue valve group than in the mechanical valve group (OR 17.19, 95% CI 8.6–25.78; P = 0.002). Although some heterogeneity was observed, it was not statistically significant (χ2 = 2.2, I2 = 55.2%; P = 0.07). Consistent with a higher rate of PPM in the tissue valve group, left ventricle mass index (g/m2) regression was significantly lower in the tissue valve group than in the mechanical valve group (weighted mean difference 40.79, 95% CI 4.62–76.96; P = 0.02), although significant heterogeneity was observed for this variable (χ2 = 25.8, I2 = 89.2%; P = 0.001). There was a tendency towards a higher rate for SVD in the tissue group (P = 0.08). However, there were no significant between-group differences in aggregated outcomes (MACCE + MAPE) at follow-up, and the level of heterogeneity was relatively low (IRR 0.12, 95% CI −0.46 to 0.71; P = 0.68; and χ2 = 1; I2 = 0%) (Table 4).
Heterogeneity assessment: bias exploration
A risk of bias analysis was performed for all included studies per the Cochrane guidelines [17] (Fig. 4). Overall, there was a high level of bias due to the fact that a majority of the studies were not randomized or blinded. Moreover, we assigned scores for each of the following: (i) multicentre trial, (ii) propensity matched study and (iii) confounder adjustment. No study fulfilled all 3 of these criteria (Fig. 4). One study was propensity matched [14], and 2 others were corrected for potential confounders. Funnel plots were used to assess publication bias for all primary and secondary outcomes. The funnel plot for primary outcome is shown in Fig. 2A and in Supplementary Material, Fig. S1 for the secondary outcomes.
Risk of bias assessment.
A subgroup analysis of high-quality studies did not demonstrate a significant between-group difference for the primary outcome (P = 0.72).
DISCUSSION
Mechanical valves require lifelong anticoagulation, whereas tissue valves are subjected to structural deterioration over time. Small mechanical valves generally have a larger effective orifice area than small bioprosthetic valves. There is evidence that in some cases patients with a small annulus may benefit from a mechanical valve [20]. The impact of small tissue versus mechanical valve on early and long-term outcomes has not yet been clarified. To our knowledge, this is the first pairwise meta-analysis to compare the performance of small aortic tissue valve replacement and mechanical valve replacement in patients with a small aortic annulus.
Although we did not identify significant differences in early or late mortality, tissue valve replacement was associated with a worrisome rate of PPM, less reduction of the left ventricle mass index and a high rate of SVD at follow-up compared to mechanical valve replacement. Additionally, the population included in our meta-analysis was older (range 67–79 years) with several comorbidities. Patients received tissue or mechanical valves in accordance with patient characteristics (e.g. atrial fibrillation) or surgeon preference.
Several studies have described the suboptimal performance of small bioprostheses. Senage et al. [21] reported that SVD occurred preferentially in small bioprostheses with higher postoperative gradients and in the presence of PPM. The study also described female sex as an independent risk factor for SVD. In the studies included in our meta-analysis, a majority of patients with bioprostheses and PPM were women. De Paulis et al. [5] reported a high incidence of SVD associated with 19-mm stented bioprostheses in elderly patients. Both of the foregoing studies utilized Mitroflow bioprostheses. In contrast, various types of tissue valves were used in the studies included in our meta-analysis, such as the Sorin pericardial valve [10], the Medtronic Mosaic valve [11], the Perimount Carpentier-Edwards Magna valve [12], the Perimount Carpentier-Edwards valve [11, 13] and the Perimount Carpentier-Edwards Magna Ease valve [14]. Given the limited representation of the Mitroflow valve in our meta-analysis, it can be inferred that PPM can be associated with various types of small tissue valves.
Khalpey et al. [22] reported the 10-year follow-up course of 257 patients who underwent AVR with a 19-mm bioprosthesis. Although the use of this prosthesis was safe and effective, more than 80% of the patients had PPM at long-term follow-up.
The surgical treatment of a small annulus remains an important challenge. Given previous reports of a negative association between PPM and survival [3], efforts should be made to avoid the use of small prostheses. For years, surgical aortic root widening performed with different techniques has allowed the fitting of larger valves; however, this option has limited utility in ageing populations due to prolonged surgical times and higher technical demand. Penaranda et al. [23] examined the number of deaths after AVR and root enlargement in patients >80 years of age and identified a mortality rate of 10% with complications occurring in almost 75% of patients.
It is important to interpret these findings in a modern context where transcatheter aortic valve replacement (TAVR) technologies are increasingly available. The Placement of Aortic Transcatheter Valves (PARTNER) trial demonstrated that TAVR was associated with fewer instances of PPM than surgical AVR, especially in cases of small annular size [24]. Similarly, a subgroup analysis of the CorValve US Pivotal Trial showed that TAVR yielded better haemodynamics and fewer cases of PPM for annuli <26 mm than its surgical counterpart [25]. A growing body of literature favours the use of TAVR in a small ring context [26]. PPM also affects survival following aortic valve-in-valve procedures for degenerated bioprostheses [27].
Although our results indicate that mechanical valves were associated with a lower rate of PPM than tissue valves, mechanical valves are not indicated in elderly patients according to current guidelines [28, 29]. At present, there are no specific recommendations for valve selection for patients with a small annulus.
From a surgical perspective, stentless and sutureless valves may offer equivalent haemodynamic performance and reduce the rate of PPM; however, stentless valves can be associated with prolonged cross-clamp times and therefore may also be contraindicated in elderly patients [30]. Sutureless valves require shorter operating times and may be a preferred choice for decreasing the likelihood of PPM. Indeed, some evidence indicates that sutureless valves such as the Perceval prosthesis provide excellent haemodynamic results and adequate effective orifice area, especially in patients with small roots [30].
Limitations
An important strength of this meta-analysis was the inclusion of 680 patients; obtaining a similar cohort in a prospective study would be particularly difficult for this research topic. Yet, this study also had several limitations. None of the 5 included studies were randomized controlled trials. Additionally, the analysis included relatively limited and AVR-specific long-term outcomes. We did not assess the influence of the geometric orifice area on the outcomes. Very long-term follow-up was not available. Perhaps the major limitation of this analysis is the fact that functional class was not reported in all the included studies; hence it could not be included in the meta-analysis.
CONCLUSION
In conclusion, stented bioprostheses <21 mm may have suboptimal performance in patients with a small aortic annulus. If a mechanical valve must be avoided because of advanced age or poor warfarin compliance, surgeons might offer alternative options such as a sutureless valve or TAVR. There is a clear need for further indirect or individual data meta-analyses on different types of valves (TAVR included) in patients with a small root.
ACKNOWLEDGEMENTS
The authors thank Ashley Symons (symonsediting@gmail.com) for professional scientific editing of this article.
Conflict of interest: none declared.
