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Ann Thorac Surg 2007;84:73-78
© 2007 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Meta-Analysis of Valve Hemodynamics and Left Ventricular Mass Regression for Stentless Versus Stented Aortic Valves

The James Cook University Hospital, Middlesbrough, United Kingdom

Accepted for publication February 14, 2007.

^_* Address correspondence to Dr Kunadian, c/o Mr Dunning, Department of Cardiothoracic Surgery, James Cook University Hospital, Middlesbrough TS4 3BW, UK (Email: babu.kunadian{at}stees.nhs.uk).

	Abstract

Top Abstract Introduction Material and Methods Results Comment References

 
Background: Stentless aortic bioprostheses have been advocated as being superior to conventional bioprosthetic valves, with benefits including superior left ventricular mass regression and larger effective orifice area. Several high-quality randomized studies now exist on this topic, and we sought to summarize them by meta-analysis.

Methods: The literature was searched from 1995 to 2006, in MEDLINE, EMBASE, CRISP, metaRegister of Controlled Trials, and the Cochrane database. Experts were also contacted and reference lists searched. Studies were combined using the inverse variance fixed-effects model. Heterogeneity was assessed and a sensitivity analysis performed. Publication bias was also investigated.

Results: Ten studies were identified that included 919 patients in which the Freedom (Sorin Biomedica Cardio, Via Crescentino, Italy), Freestyle (Medtronic, Minneapolis, MN), Prima Plus (Edwards Life Sciences, Irvine, CA) and the Toronto and Biocor (St Jude Medical, St. Paul, MN) valves were used. The mean aortic valve gradient was lower in the stentless groups, with a weighted mean difference (WMD) of –3.57 mm Hg (95% confidence interval [CI], –4.36 to –2.78; p < 0.01). The left ventricular mass index was significantly lower in the stentless groups at 6 months (WMD, –6.42; 95% CI, –11.63 to –1.21; p = 0.02), but this improvement disappeared after 12 months (WMD, 1.19; 95% CI, –4.15 to 6.53; p = 0.66). The weighted mean increase in cross-clamp time was 23 minutes, and the increase in bypass time was 29 minutes with a stentless valve.

Conclusions: This meta-analysis showed that stentless aortic valves provide an improved level of left ventricular mass regression at 6 months, reduced aortic gradients, and an improved effective orifice area index, at the expense of a 23-minute longer cross-clamp time and a 29-minute longer bypass time.

	Introduction

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Aortic valve replacement (AVR) with a biologic prosthesis is the treatment of choice in patients aged older than 65 years with significant aortic valve stenosis. However, despite excellent early postoperative outcome, long-term survival is not satisfactory. Survival rates are 50% to 66% after 10 years in all age groups [1, 2] and decrease to 18% in patients aged older than 75 years after 15 years of follow-up [3]. Left ventricular hypertrophy (LVH), a known complication of aortic stenosis, has been strongly correlated with increased risk of sudden death, congestive heart failure, stroke, myocardial infarction, coronary artery disease, and cardiovascular mortality. Therefore, incomplete regression of LVH after AVR has been suggested as a reason for these poor long-term results [4].

Incomplete regression of LVH after AVR may be due to the obstructive nature of the valve sewing ring and stent or to patient–prosthesis mismatch. Stentless aortic tissue valves were developed with the goal of maximizing the effective orifice area and therefore facilitating left ventricular mass regression (LVMR). Cohort studies monitoring patients for up to 10 years have shown good results and improvements in LVH with stentless valves, but randomized controlled trials have shown more equivocal results. We undertook this meta-analysis to determine whether stentless valves provide superior LVMR compared with conventional stented valves.

	Material and Methods

Top Abstract Introduction Material and Methods Results Comment References

 
Search Strategy
We searched the MEDLINE, EMBASE, CRISP, metaRegister of Controlled Trials, and Cochrane databases for English-language, randomized, clinical trials from 1995 to 2006 using the following Medical Subject Heading terms: aortic valve replacement, bioprosthetic valves, left ventricular function, left ventricular mass index, randomized controlled trials, stentless, and stented aortic valves. We also hand-searched relevant journals, corresponded with investigators and experts in the field, and used the Science Citation Index to cross-reference any articles that met our selection criteria. MEDLINE was searched in accordance with the Cochrane Collaboration recommendations.

Selection Criteria
Citations initially selected by systematic search were first retrieved as title or abstract, or both, and screened independently by two reviewers (JD, BK). Those that were potentially relevant were then retrieved as complete reports and assessed for compliance with inclusion and exclusion criteria.

Inclusion criteria for retrieved studies were (1) prospective comparison of stentless aortic valves with stented bioprosthetic aortic valves in patients undergoing isolated AVR with or without concomitant coronary artery bypass grafting, (2) randomized treatment allocation, (3) intention-to-treat analysis, and (4) trials reporting data on left ventricular mass index (LVMI).

Exclusion criteria were unretrievable or unclear data [5, 6], no data on LVMI, and trials with no clear comparison data between stented and stentless valve [7].

Data Abstraction, Validity Assessment, and Outcomes
Two nonblinded reviewers (JD, BK) independently performed data abstraction on prespecified structure collection forms and evaluated the study quality according to the Jadad score [8], allocating 1 point for the presence of each of the following: (1) study defined as randomized, (2) study defined as blinded, (3) clear description and discussion of withdrawals and dropouts. If randomization and blinding were appropriate, 1 additional point was added for each; otherwise, a point was deducted. Thus, the total score was 0 to 5. Divergences in data abstraction and quality evaluation were resolved by consensus. The primary outcome was LVMI at 6 months and 1 year (g/m²). We also assessed cross-clamp time (minutes), bypass time (minutes), the postoperative peak and mean aortic gradient (mm Hg), effective orifice area index (cm²/m²), and mortality up to the 1-year follow-up.

Statistical Analysis
Statistical analysis was performed using the Review Manager 4.2 [9]. Continuous variables are reported as mean ± standard deviation and were compared using the inverse variance fixed-effect model. Weighted mean differences (WMDs) with 95% confidence intervals (CI) were used as summary statistics for the comparison of continuous variables. Reported values were two-tailed, and results were considered statistically significant at p < 0.05. Formal Cochran Q ² tests were performed to investigate heterogeneity between trials (respective scores, degrees of freedom, and p values are reported). Statistical heterogeneity was considered substantial if the Cochran Q test yielded a value of p < 0.10. To assess the sensitivity of the results, several subgroup analyses were performed. A funnel plot of treatment effect versus study precision was created for the primary outcome, and the Egger test was computed to look for possible publication bias.

	Results

Top Abstract Introduction Material and Methods Results Comment References

 
Study Selection
A total of 262 abstracts were identified using the reported search strategies. Of these, 34 articles were reviewed in full for compliance with inclusion and exclusion criteria. Twenty studies were excluded because they were not randomized, and four randomized trials were excluded because no data on LVMI were presented. Ten published studies were finally selected (Table 1) [10–20]. In addition, we included our own Middlesbrough trial data. The median Jadad score was 2 (range, 1 to 3).

Echocardiographic Outcomes
The overall mean aortic valve gradient in the stentless group was lower compared with the stented group (WMD, –3.57 mm Hg; 95% CI, –4.36 to –2.78 mm Hg; p < 0.01). The overall peak gradient was also lower in the stentless valve group compared with the stented group (WMD, –5.80 mm Hg; 95% CI, –6.90 to –4.69 mm Hg; p < 0.01). The effective orifice index was higher in the stentless group compared with the stented group (p < 0.01).

The LVMI at 6 months was reported in six trials (n = 599). A significant reduction in LVMI was demonstrated at 6 months in the stentless valve groups compared with the stented valve groups (WMD, –6.42; 95% CI, –11.63 to –1.21; p = 0.02; Fig 1). The aggregated data by meta-analysis showed a significant heterogeneity (p < 0.01). To assess the sensitivity of these results, additional subgroup analyses were performed (Table 2). Substantial heterogeneity was present in all the subgroups.

View larger version (12K): [in this window] [in a new window]   Fig 1. Comparison between stentless and stented aortic valve protheses of left ventricular mass index at 6 months. Squares are weighted mean differences (WMD) and horizontal lines show 95% confidence intervals (CI). (ASSERT = Aortic Stentless Versus Stented Valve Assessed by Echocardiography Randomized Trial; SD = standard deviation.)

View larger version (11K): [in this window] [in a new window]   Fig 2. Comparison between stentless and stented aortic valve protheses of left ventricular mass index at 12 months or more. Squares are weighted mean differences (WMD) and horizontal lines show 95% confidence intervals (CI). (ASSERT = Aortic Stentless Versus Stented Valve Assessed by Echocardiography Randomized Trial; SD = standard deviation.)

View larger version (8K): [in this window] [in a new window]   Fig 3. Funnel plot of effect size for left ventricular mass index at 6 months between stentless and stented aortic valve protheses. (SE = standard error; WMD, weighted mean difference.)

View larger version (8K): [in this window] [in a new window]   Fig 4. Funnel plot of effect size for left ventricular mass index at 12 months or more between stentless and stented aortic valve protheses. (SE = standard error; WMD = weighted mean difference.)

View larger version (13K): [in this window] [in a new window]   Fig 5. Mortality at 1-year follow-up between stentless and stented aortic valve protheses. Squares show odds ratios (ORs) and horizontal lines show confidence intervals (CIs). (ASSERT = Aortic Stentless Versus Stented Valve Assessed by Echocardiography Randomized Trial; CI = confidence interval; OR = odds ratio.)

	Comment

Top Abstract Introduction Material and Methods Results Comment References

Stentless bioprostheses were developed to achieve superior hemodynamic performance compared with stented valves. Elimination of the sewing ring and stents was designed to result in less obstruction to blood flow and decreased transvalvular gradients. Improved hemodynamic performance may lead to increased LVMR and thereby increase survival.

Implantation of a stentless valve is more demanding than a stented valve, which is reflected by longer times for cardiopulmonary bypass and cross-clamp, but this is not associated with worse long-term outcomes. Jin and colleagues [21, 22] showed that a 20-minute-longer cross-clamp time (51 minutes versus 72 minutes) had no effect on postoperative left ventricular function, morbidity, or mortality in a cohort of patients matched for age, gender, and valve size.

The advantage of the stentless design is that it resembles the native aortic valve more closely than a stented valve by providing a greater effective orifice area index for a given valve size. In this meta-analysis, we have shown that use of a stentless valve resulted in a greater effective orifice area index and lower transvalvular gradients compared with stented valves. The lower pressure gradient seen with stentless valves has been attributed in part to a flow-related increase in effective orifice area [23, 24]. In comparison, the flow characteristics are predominantly resistive and turbulent in nature in the stented valves.

LVH develops as an adaptation to the increased pressure load in patients with aortic stenosis. LVH correlates well with mortality and morbidity in patients with aortic stenosis, increasing the risk of congestive cardiac failure, myocardial infarction, and sudden death. Furthermore, incomplete regression of LVH after aortic valve replacement is associated with an increased mortality [25].

The two recent major randomized controlled studies failed to show a significant difference in LVMR at 1 year. Ali and colleagues [10] have recently performed a multicenter randomized controlled trial comparing the Edwards Prima Plus Stentless valve with the Carpentier-Edwards Perimount (Edwards Lifesciences, Irvine, CA) stented valve. A total of 161 patients were randomized and assessed by echocardiography at 1 week, 8 weeks, and 12 months. In addition, 50 patients underwent preoperative and 1-year postoperative magnetic resonance imaging (MRI). They found no differences between groups in the aortic valve gradient, effective orifice area index, or LVMI by echocardiography or MRI.

The Aortic Stentless versus Stented valve assessed by Echocardiography Randomized Trial (ASSERT) [12] randomized 190 patients to either the Freestyle stentless valve or the Mosaic stented valve (Medtronic, Minneapolis, MN). They assessed LVMI at 6 and 12 months, and a further 38 patients were assessed by MRI. Again, they found no significant differences between the two groups in LVMI by echocardiography or MRI.

The negative results of these trials could be attributed first to the superior hemodynamic performance of the new generation of stented valves used, which produce less impedance to transvalvular flow than older designs. Second, lack of use of more sensitive measures such as detailed imaging to detect subtle changes in left ventricular remodelling, measurements of natriuretic peptides, and coronary flow dynamics to assess the difference between the modern low-profile stentless and stented valves may have masked significant but subtle differences.

The important confounding factor not considered by most of these randomized studies is the prosthesis–patient mismatch. Ali and colleges [10] have shown a trend towards improved hemodynamic performance of stentless valves in a small subgroup of patient with smaller aortic annuli and patients with preoperative ventricular impairment. However, this needs to be proved in a large-scale multicenter randomized study to determine the indicators for implantation and to optimize LVMR, thereby improving long-term survival rates.

In contrast to these two large randomized controlled trials, the third published randomized controlled trials of more than 100 patients by Walther and colleagues [18] did find a clinically significant difference. They randomized 180 patients to the Freestyle stentless valve, the Toronto stentless valve (St. Jude Medical, St. Paul, MN) or the Perimount stented valve. They found a statistically significant increased reduction in LVMI in the stentless valve groups at 6 months.

We demonstrated that across all studies, implantation of a stentless valve replacement results in a reduced aortic valve gradient and an effective orifice area index, and that there is also an increased reduction in LVMI at 6 months. The pooled data across the 10 studies demonstrate that this improvement in LVMI disappears after 1 year. We hypothesize that stentless aortic valves allow the myocardium to recover more rapidly from LVH owing to the reduced residual gradient in the aortic annulus. The myocardium of patients who receive a stented valve will eventually fully recover; however, this recovery is delayed rather than prevented by the raised aortic valve gradients found in stented valves. The other reason for similar reduction in left ventricular mass could be attributed to superior hemodynamic performance of second-generation and third-generation stented valves compared with the older stented valves.

Our meta-analysis has limitations. Not all studies reported all outcome measures at 6 and 12 months, and the study by Walther and colleagues reported two types of stentless valve compared with one stented valve, requiring the splitting of their data. In addition, significant heterogeneity was found between studies. The reasons for this difference in study outcome is likely to be multifactorial in complex randomized studies such as these, but will include the differing hemodynamic characteristics of the valves used, the differing implantation techniques, and patient demographics.

The results for other events of interest, including low cardiac output syndrome and lengths of stay could not be reported because these events have been inconsistently reported in most the trials included in the study. There is some evidence that decreased patient–prosthesis mismatch may result in less low output syndrome and death (early and late) in high-risk patients. In addition, longer cardiopulmonary bypass and cross-clamp times may be associated with longer intensive care unit and hospital stays.

Finally, we included only randomized controlled trials and excluded several cohort studies and case reports. Although their inclusion might have provided additional data, significant differences between patients having stentless or stented valves are more difficult to interpret owing to nonrandomized patient-related factors.

In our meta-analysis of 10 randomized controlled trials comparing stentless valves with conventional valves, we found that stentless aortic valves provide an improved level of LVMR at 6 months, reduced aortic gradients, and an improved effective orifice area index, at the expense of a 23-minute-longer cross-clamp time and a 29-minute-longer bypass time.

	References

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