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Ann Thorac Surg 2002;74:1443-1449
© 2002 The Society of Thoracic Surgeons
a Division of Cardiac Surgery, University of Verona, Verona, Italy
Accepted for publication June 26, 2002.
* Address reprint requests to Dr Luciani, Division of Cardiac Surgery, University of Verona, O. C. M. Piazzale Stefani 1, Verona 37126, Italy.
e-mail: gbluciani{at}yahoo.com
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Abstract |
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METHODS: Two hundred ninety-two patients had stented (group 1) and 376 stentless (group 2) xenograft aortic valve replacements. Age was older in group 1 (75 ± 4 vs 70 ± 7 years, p = 0.01), whereas male gender and aortic stenosis were equally prevalent. Advanced New York Heart Association class III-IV (85% vs 78%, p = 0.03) and associated procedures (53% vs 41%, p = 0.01) were more common in group 1. Aortic cross-clamp (80 ± 28 vs 96 ± 23 minutes, p = 0.01) and bypass (91 ± 56 vs 129 ± 34 minutes, p = 0.01) times were shorter in group 1. Logistic regression and Cox proportional hazard methods were used to define the role of demographic and operative variables on hospital and late survival, freedom from valve-related mortality, and reintervention.
RESULTS: Early mortality was higher in group 1 (6.2% vs 2.6%, p = 0.02). Smaller aortic anulus (p = 0.008), aortic cross-clamp (p = 0.03), and coronary disease requiring bypass (p = 0.03) were associated with hospital mortality. During follow-up (37 ± 30 vs 43 ± 35 months, p = NS), 66 late deaths were recorded (12% vs 9%, p = NS). At 8 years, survival (70 ± 5% vs 81 ± 3%, p = 0.01), freedom from cardiac- (85 ± 1% vs 92 ± 3%, p = 0.02), and valve-related death (79 ± 5% vs 95 ± 2%, p = 0.004) were higher in group 2. Freedom from structural deterioration was similar (92 ± 5% vs 93 ± 3%, p = NS), but freedom from reoperation was lower in group 2 (99 ± 1% vs 90 ± 4%, p = 0.009). Multivariate analysis showed female gender (p = 0.02), age (p = 0.03), and smaller valve size (p = 0.05) to be associated with late mortality; age (p = 0.06) and diagnosis of aortic stenosis (p = 0.008) with cardiac mortality; longer intensive care unit stay (p = 0.001) and stented xenografts (p = 0.05) with valve-related mortality; and younger age (p = 0.01) and stentless xenograft (p = 0.05) with reoperation.
CONCLUSIONS: Use of stentless xenografts correlates with better survival and freedom from cardiac- and valve-related mortality than stented valves. However, bias favoring stented valves in older and sicker patients exists. Selective survival advantage of stentless xenograft is confined to valve-related mortality. Stentless valves are more likely to be replaced for dysfunction.
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsCommentReferences |
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Among the methods to mitigate the bias introduced by retrospective studies, case-match analysis has recently been proposed. In a work by David and associates, stentless aortic xenografts have been associated with durability similar to stented valves, but with greater survival and freedom from adverse cardiac events [8]. To account for these observations, a correlation has been suggested between the property of stentless valves to enhance left ventricular mass regression [9] and the observed decrease in cardiac mortality [8]. In an attempt to validate these findings and to extend them to other models of stentless valves, an analysis of outcome after xenograft aortic valve replacement in 668 consecutive patients has been undertaken.
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Patients and methods |
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Operative technique
Porcine xenograft valve replacement was performed with the aid of moderately hypothermic cardiopulmonary bypass, during a period of cold myocardial ischemia. Before 1994, crystalloid cardioplegia was used for myocardial protection. Thereafter, blood cardioplegia was routinely employed. The technique of stentless valve implant was freehand, subcoronary grafting using inflow and outflow suturelines for all xenograft models, except for Cryolife-O’Brien valves. The latter were implanted in subcoronary, supraanular position with a single sutureline. Stented xenografts were anchored to the native aortic anulus by means of interrupted pledget-reinforced sutures.
Anticoagulant therapy
Oral anticoagulation was adopted for patients undergoing stented AVR during the first 3 postoperative months and discontinued thereafter. No anticoagulation was used in patients having stentless AVR. Routine oral antiplatelet therapy was adopted in patients with associated vascular (ie, coronary or carotid artery) lesions. All patients with chronic atrial fibrillation were treated with lifelong anticoagulant therapy regardless of the type of aortic valve prosthesis.
Follow-up methods
Cross-sectional patient follow-up was completed between February and April 2000 by means of in-hospital clinical assessment and telephone interview, carried out by nonblinded medical personnel. Four (0.6%) patients were lost to follow-up investigation.
Statistical analysis
Continuous variables were expressed as means ± SD. Categorical variables were expressed as percentages. Comparison of continuous variables was performed using the two-tailed Student’s t test for paired data and comparison of discrete using Pearson 
2 test or Fisher’s exact, as appropriate. Time-related events were described using the Kaplan-Meier estimate and compared with the log-rank analysis. Significance was inferred at a p <0.05. End points of the study were survival, survival free from cardiac death, valve-related death structural valve deterioration, and reoperation on the xenograft. Linearized rates were used for repeated valve-related complications and were expressed as percent per patient-years. Because the disparity in baseline demographic and operative variables between the two patient groups may reflect in clinical outcome, multivariate analysis was performed on the overall patient population using logistic regression, to identify predictors of hospital mortality, and Cox proportional hazards method, to identify risk factors for time-related occurrence of events after AVR, including: late mortality, cardiac mortality, valve-related mortality, and reoperation. The variables entered in the analysis are listed in the Appendix. Definitions of the above events were established according to previously recommended guidelines [10].
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Results |
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Structural valve failure was equally prevalent in the two groups (6 [2.2%] vs 10 [2.7%], p = 0.6), as shown by the similar actuarial freedom from valve deterioration at 8 years (92 ± 5% vs 93 ± 3%, p = 0.6). Reoperation was performed in 2 (structural deterioration, endocarditis) group 1 patients versus 17 (10 structural deterioration, five nonstructural deterioration, two endocarditis) group 2 patients (p = 0.004). Cases of nonstructural failure were due to technical cause in 4 patients (all with the Cryolife-O’Brien valve) and to pannus formation in 1. Freedom from reoperation on the xenograft was thus significantly lower in patients with stentless valves (99 ± 1% vs 90 ± 4%, p = 0.009), due to higher prevalence of nonstructural failure. Cox analysis showed younger age, stentless xenograft, and, among the latter, Cryolife-O’Brien valve, to be predictive of reoperation on the xenograft (Table 3).
There were no deaths in patients having replacement of a stented valve, and three (17.6%) among patients having replacement of a stentless valve, all operated on at nearby hospitals. Mortality for emergent reoperation was significantly higher than for elective (2/3 [66.7%] vs 1/14 [7.1%], p = 0.01).
Functional status
Follow-up clinical conditions were equally rewarding with 224 (92.6%) of group 1 and 299 (90.6%) of group 2 patients in NYHA class I or II (p = 0.2).
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Comment |
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TopAbstractIntroductionPatients and methodsResultsCommentReferences |
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Ever since it has been observed that durability of stentless valves may indeed not prove longer than stented [8], survival late after operation has become the primary focus of clinical research [3, 4, 6, 7]. A wealth of data has shown distinct hemodynamic advantages of stentless xenografts, as relates to timing and extent of regression of left ventricular hypertrophy early after AVR [9, 11, 12]. Although uncertainty remains about the possibility that such changes might be maintained over time, great effort has been devoted to the demonstration that more physiologic behavior of the valve would translate into enhanced survival [2–8]. To date, however, conclusive evidence on survival advantages of stentless xenografts over stented is not available due to absence of long-term prospective, randomized trials. Explanations for the paucity of prospective studies include the technical demands of stentless valve surgery, the restrictions imposed by pathology of the aortic root (dilatation, calcification, anomalies of coronary ostia), the concern over longer grafting time, particularly in the presence of a failing left ventricle, and the great variety of stentless valve models.
Several retrospective clinical observations comparing stentless xenografts with stented have shown superior survival and freedom from valve-related adverse events with the former [2–4, 6, 7]. The results in the present work are therefore in line with previous studies. Similar to prior work [2], however, bias in the selection of patients assigned to the two valve substitutes is evident in the different profile of the two populations. Patients receiving stented xenografts are generally older and more commonly affected by advanced cardiac failure and associated disease than those having stentless valves. To reduce the impact of such disparities on survival, David and associates have proposed a case-match study, where homogeneous patient pairs have been identified based on age, NYHA class, left ventricular ejection fraction, and presence of coronary artery disease [8]. These variables have all been recognized to affect long-term survival after AVR with stented bioprostheses [13]. In the work by David and colleagues, superior overall survival, freedom from cardiac death, and valve-related morbidity have been shown in operative survivors with the Toronto SPV stentless valve compared with the Hancock II stented valve [8]. A Cox proportional hazard model has confirmed the latter two results.
Because case-match analysis is theoretically exposed to the same bias influencing simple retrospective comparison, in the current study, a choice was made to apply multivariate analysis to the entire xenograft AVR population instead. The findings herein partly agree with the observations by David, as overall survival and survival free from cardiac- and from valve-related death are greater in recipients of stentless valves, but Cox analysis suggests the benefits of stentless valves to be limited to valve-related mortality. Reasons that may account for this difference comprise the older average age (62 vs 72 years), the higher prevalence of female patients (29% vs 49% of patients) and of associated cardiac disease (32% vs 45% of patients), and the inclusion of patients with associated mitral, aortic, and carotid artery disease, in the present series. Accordingly, demographic (advanced age, female gender, aortic stenosis, smaller aortic anulus, associated disease) and operative variables (size of prosthesis, aortic cross-clamp time) emerge as predictors of hospital, overall, and cardiac-related mortality, in the current analysis. The disparity in patient age has relevant implications, as Del Rizzo and coworkers have shown that survival advantage of stentless bioprostheses is most prominent in younger patients (less than 60 years of age) and diminishes with advancing age [4].
The present concurrent, control trial corroborates the observations by David and associates on superior freedom from valve-related mortality in patients having the Toronto SPV stentless xenografts [8] and extends the same findings to older patients and to other models of stentless valves (Biocor PSB, Cryolife-O’Brien). Prior work by Del Rizzo and colleagues has shown the unique hemodynamic advantages of the Toronto SPV valve [9]. Similar behavior has been documented after AVR using the Biocor PSB [6] and the Cryolife-O’Brien valves [14]. Common to most stentless xenograft models is the property to enhance regression of left ventricular hypertrophy to a greater extent than stented bioprostheses, as two recent prospective, randomized trials have proved [11, 12]. It has been demonstrated that the larger effective orifice area of stentless valves, when compared with stented of the same external diameter (ie, lower incidence of prosthesis patient mismatch) [15], may account for the more thorough regression of left ventricular hypertrophy after operation [16]. As ventricular hypertrophy has since been associated with increased cardiac mortality [17], the most credited hypothesis is that the unique hemodynamic properties of stentless xenografts are responsible for the observed greater survival free from cardiac death. Additional reasons, however, explain the selective survival advantage of stentless valves in the current study. In fact, a sizable proportion of late casualties has been caused by valve-related events. In particular, rate of embolic complications, including lethal, has proved higher among recipients of stented xenografts, as previously found by others [6, 7]. Whether lower thrombogenicity of stentless valves or, simply, unsatisfactory control of blood anticoagulation in patients with stented valves is responsible for this result awaits verification. Based on the current findings, the survival advantage conferred by stentless xenograft may be due not so much to the more favorable impact of the valve on left ventricular function and remodeling, as much to the lower morbidity related to the prosthetic device per se.
Contrary to the hypothesis on selective survival benefits of stentless valves, the expectation of longer durability than stented bioprostheses thus far has been unsatisfied. Similar to the observations by David and associates [8], the present control trial confirms that structural deterioration affects all xenografts, whether stentless or stented, at the same rate, albeit still low 8 years after implant. A series of explanations exists that can account for this finding, including: an incorrect hypothesis underlying the causes of degeneration of bioprostheses; the instability of the anatomic substrate, where stentless valves are grafted; the detrimental impact of technical factors connected with stentless valve surgery; and the substantial improvement in durability of second-generation stented bioprostheses. The original observation that freehand-sewn aortic homografts have proved less prone to structural deterioration than stent-mounted has led to the anticipation that freehand stentless xenografts would outlast stented bioprostheses [1]. The hypothesis entertained was that greater resemblance to the native aortic valve anatomy and physiology would minimize shear stress on the leaflets, a factor recognized among the primary causes of tissue valve degeneration [18]. It is possible that this hypothesis may not be correct and that other factors, such as immune response to the xenograft (therefore irrespective of valve design), play a predominant role. Moreover, the functional properties of stentless valves are strictly dependent on the integrity of the aortic valve-root complex, as the prostheses are anchored to the native aortic root. Jin and Westaby have shown how progressive dilatation of the sinotubular junction, which frequently occurs with aging, causes progressive prosthetic valve insufficiency due to reduced leaflet coaptation [19]. Dysfunction of the stentless valve may, in turn, be associated with increased shear stress and premature xenograft deterioration. Prior work from our institution has shown that, contrary to stented bioprostheses, deterioration of stentless valves manifests with progressive stiffening and rupture, often abrupt, of the leaflets at the commissures, in the absence of calcification [20]. In addition, mode and rate of degeneration are identical with the three different valve models: Toronto SPV, Biocor PSB, and Cryolife-O’Brien [20]. Therefore, a unique way of failure exists, common to most stentless xenografts, that reflects prosthetic valve design, as demonstrated by the morphologic findings of degenerated xenografts. As a corollary, it follows that even minor mishaps with the implant technique, often undetected at the time of operation, may translate into relevant valve dysfunction with time [21]. This finding is again specific of stentless xenografts and will obviously not affect stent-mounted bioprostheses. Lastly, a growing body of evidence has shown that durability of second-generation stented xenografts has dramatically improved, possibly due to low-pressure fixation and antimineralization treatment of the leaflets [13, 22]. When considered as a whole and added to the observation that nonstructural deterioration may be more common due to greater complexity of operation, as seen in the present and in prior series [23, 24], it is not surprising that freedom from valve failure with stentless xenografts has not proved more gratifying than with stented.
Survival free from reoperation on the valve is not a valid end point to compare the durability of stentless and stented xenografts. Given the slowly progressing nature of transprosthetic obstruction in deteriorated stented bioprostheses, the decision to intervene may often be deferred, particularly in the very elderly patient. On the contrary, degeneration of stentless valves is less predictable, and the volume overload consequent to prosthetic valve regurgitation is poorly tolerated by a noncompliant left ventricle, such as the one in senile aortic stenosis. Therefore, replacement of a failing stentless valve must be scheduled promptly at the time of diagnosis. Accordingly, multivariate analysis has confirmed older age to be inversely and stentless valve to be directly related with the replacement of a dysfunctional xenograft, in the present experience. The importance of elective planning is evident from the current and prior work [25], showing significantly higher mortality for emergent procedures. The influence of clinical experience is also apparent, as operative risk may be greatly contained at centers with longstanding acquaintance with aortic root surgery.
Similar to the findings on freedom from structural valve failure and reoperation, functional status late after implant does not allow to distinguish between stentless and stented xenografts. Both types of prostheses are associated with satisfactory clinical conditions, even in an elderly population commonly affected by associated cardiac disease, such as the one herein. This result agrees with previous studies on stentless and stented valves [2, 3, 6, 7, 13, 22]. However, it seems at odds with the superior hemodynamic behavior demonstrated for stentless xenografts [11, 12, 15], which could in theory be associated with improved clinical status. Restrictions inherent with the NYHA classification, particularly its subjective nature, and the advanced patient age may conceivably account for this divergence.
Limitations
The present study presents the limitations of any retrospective analysis, primarily bias in the selection of patients. Contrary to prior works, however, it reports on a numerous and mostly older population, undergoing concurrent, rather than consecutive, surgical treatment using either stentless or stented bioprostheses. A second limitation is that three stentless valve models are simultaneously compared with one stented valve model, possibly weakening the conclusions of the study due to small sample size. However, the ability to extend the observations on the Toronto SPV valve to other prostheses may at the same time represent the original aspect of the current analysis. Based on the premise that functional behavior is similar with different stentless valve models, the present work confirms that clinical outcome may also be equally favorable. Lastly, and most notably, the study herein only partly overcomes the limitations inherent with simple retrospective comparison by using multivariate analysis methodology. In theory, only prospective, randomized long-term trials will provide rigorous information on comparative clinical outcome.
In conclusion, this concurrent, control trial demonstrates that stentless aortic xenografts may confer selective advantages in terms of survival free from valve-related mortality when compared with stented. Because freedom from valve deterioration is similar, extension of stentless AVR to any patient without anatomic contraindication deserves further consideration.
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Appendix |
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References |
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TopAbstractIntroductionPatients and methodsResultsCommentReferences |
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