Ann Thorac Surg 2001;71:S344-S348
© 2001 The Society of Thoracic Surgeons
Autografts, allografts, and biological valves in children
Estimated event-free life expectancy after autograft aortic root replacement in adults
Johanna J.M. Takkenberg, MDa,
Marinus J.C. Eijkemans, MScb,
Lex A. van Herwerden, MD, PhDa,
Ewout W. Steyerberg, PhDb,
Gary L. Grunkemeier, PhDa,
J. Dik F. Habbema, PhDb,
Ad J.J.C. Bogers, MD, PhDa
a Department of Cardiothoracic Surgery, and the Center for Clinical Decision Sciences, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
b Department of Public Health, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands
Address reprint requests to Dr Takkenberg, Department of Cardiothoracic Surgery, Erasmus Medical Center Rotterdam, Bd162, PO Box 2040, 3000CA Rotterdam, The Netherlands
e-mail: takkenberg{at}thch.azr.nl
Presented at the VIII International Symposium on Cardiac Bioprostheses, Cancun, Mexico, Nov 3–5, 2000.
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Abstract
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Background. Autograft aortic root replacement is an established therapeutic option for young adults with aortic valve disease. Unfortunately, most series are small with a limited follow-up. Meta-analysis and microsimulation modeling were used to predict long-term outcome based on currently available midterm data.
Methods. We combined our center’s experience with autograft aortic root replacement in 85 adult patients in a meta-analysis with reported results of three other hospitals. The outcomes of this meta-analysis were entered in a microsimulation model, calculating (event-free) life expectancy after autograft aortic root replacement.
Results. The pooled results comprised 380 patients with a total follow-up of 1,077 patient-years. Mean age was 37 years (range 16 to 68 years). Male/female ratio was 2.7. Operative mortality was 2.6% (n = 10); during follow-up 6 more patients died. Linearized annual risk estimates were 0.5% for thromboembolism, 0.3% for endocarditis, and 0.4% for nonstructural valve failure. Structural autograft failure requiring reoperation occurred in 5 patients, and a Weibull function was constructed accordingly. Using this information, the microsimulation model predicted age- and gender-specific mean, reoperation-free, and event-free life expectancy.
Conclusions. Based on current evidence the calculated average autograft-related reoperation-free life expectancy is 16 years. The combination of meta-analysis and microsimulation provides a promising and powerful tool for estimating long-term outcome after aortic valve replacement.
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Introduction
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In 1967 Ross was the first to describe the use of the pulmonary autograft in aortic valve replacement. Autograft aortic root replacement, also known as the modified Ross procedure, was introduced in 1986 [1] and has become an established therapeutic option for young adults with aortic valve disease. There is concern, however, about the long-term durability of the autograft root [2]. Based on current evidence from the relatively small reported series with a limited follow-up, it is difficult to draw conclusions on longer-term outcome. In this study we combined meta-analysis and Monte Carlo type microsimulation as a method to predict life expectancy and event-free life expectancy after autograft aortic root replacement.
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Material and methods
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Meta-analysis
Rotterdam experience
Data were analyzed from all 85 adult patients (16 years of age or older at time of operation) who underwent autograft aortic root replacement and replacement of the pulmonary valve with a cryopreserved allograft between November 1988 and February 2000. Mean follow-up was 4.2 years (SD 2.6; total follow-up 358 patient-years) and 99% complete at the closing date of the study (June 1, 2000). Cumulative survival was calculated using the Kaplan–Meier method.
Literature search
We performed a literature search of the PUBMED and MEDLINE databases for the period starting from January 1996 until September 1999. This search was conducted to obtain the most recent reports with the longest follow-up. Terms used for the search were both MeSH terms and the text words "autograft," "root," "aortic valve," and "Ross." All titles and abstracts were screened for study design (reports of clinical experience with autograft aortic root replacement), completeness of follow-up (more than 90%), surgical technique (modified Ross or autograft procedure), study size (N > 40; reflecting the experience at that particular center), etiology of valve disease similar to our patient population (not with predominant rheumatic valve disease), and patient age (16 years and older). The references in the remaining studies were cross-checked for other potentially relevant studies.
Data extraction and analysis
The selected published studies were reviewed and patient characteristics and results were tabulated in a spreadsheet. The authors of the selected published studies were contacted for clarification and additional information, if necessary. Events and outcomes in all studies including our own were defined according to the guidelines of Edmunds and coworkers [3]. Heterogeneity between the different studies was investigated by means of a sensitivity analysis. A combined estimate of outcome was obtained by means of direct pooling, because the studies were small and had only few events. For valvular thrombosis, thromboembolism, bleeding, endocarditis, and nonstructural valve failure, linearized annual event rates were calculated. The risk of structural valvular failure requiring replacement of the valve was described by a Weibull curve, which is a generalization of the exponential distribution that accommodates a changing risk over time. The limits of the Weibull model were estimated using the pooled structural valve failure data from the meta-analysis.
Microsimulation model
The basic assumption of the simulation model is that a disease follows a course in time that can be adequately characterized by a number of discrete health states. A schematic representation of these health states and events after aortic valve replacement is given in Figure 1. In microsimulation or Monte Carlo-type simulation, one calculates random life histories of the course of disease for individual patients with predefined characteristics. These calculations are repeated many times, producing a simulated or "virtual" population of patients.
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Fig 1. Schematic representation of different health states of a patient after autograft aortic root replacement as implemented in the microsimulation model. (AVR = aortic valve replacement.)
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The information on outcome after autograft aortic root replacement from the meta-analysis was entered into the microsimulation model. Ten thousand virtual life histories were calculated for men and women at different ages (25, 35, 45, 55, and 65 years). The age of death from nonvalve-related causes was randomly drawn from the Dutch general population life table. However, there is an excess mortality in patients after aortic valve replacement compared with the general population that cannot be explained solely by postoperative valve-related events. This difference is caused by, for example, sudden unexpected unexplained death and cardiac death related to valve disease, cardiomyopathy, and factors introduced by valve replacement devices [4]. We therefore multiplied the age- and gender-specific mortality hazard of the general population with an age- and gender-related hazard ratio for excess mortality, based on previous work [5]. Other assumptions made were that operative mortality increases with age (odds ratio [OR] = 1.022 per year) and with each reoperation (OR = 1.7 with each reoperation).
Life expectancy, reoperation-free life expectancy, actual lifetime reoperation risk, event-free life expectancy, and actual lifetime event risk were calculated. In addition, cumulative survival, reoperation-free survival, and event-free survival were generated.
Validation of the model was attempted by comparing its outcome with long-term outcome of aortic valve replacement patients in a large dataset from Portland, Oregon [6]. A Gompertz model was constructed for late survival for aortic valve replacement patients operated since 1975 in this dataset. The Gompertz distribution was obtained by modifying a previously reported Gompertz model for late survival after valve replacement [7]. Variables in the model were age, age2, gender, coronary artery bypass grafting, and valve type (tissue versus mechanical).
In addition, outcome as predicted with the microsimulation model was compared with outcome after autograft aortic root replacement according to a recently published study from a large center in Oklahoma [8].
To investigate the effect of uncertainty in the parameter estimates on life-expectancy one-way sensitivity analyses were performed. This was done by ranging the estimates for valve-related events from half to double the base line parameter values.
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Results
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Meta-analysis
Rotterdam experience
Preoperative patient characteristics and outcome are displayed in Table 1. Operative mortality was 3.5% (n = 3, all nonvalve-related). During follow-up no more patients died. Cumulative survival was 97% at 7 years (SE 2%). Replacement of the autograft was necessary in 3 patients. One patient developed recurrent rheumatic fever requiring replacement of the autograft with a mechanical prosthesis 1.8 years after the initial operation. Two other patients developed progressive dilatation of the autograft root requiring replacement with a cryopreserved aortic allograft and a mechanical prosthesis at 4.0 and 6.5 years, respectively, after the autograft procedure. Autograft reoperation-free survival was 86% (SE 7%) at 7 years. Stenosis of the pulmonary allograft required replacement in 1 patient and balloon dilatation in another patient, 2.1 and 0.7 years after operation, respectively. No valvular thrombosis, thromboembolism, or bleeding events were observed. One patient developed endocarditis of the pulmonary allograft and was treated with antibiotic therapy.
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Table 1. Overview of Patient Characteristics and Outcome After Autograft Aortic Valve Replacement From the Four Studies Selected for the Meta-Analysis
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Literature search, data-extraction, and pooling
The literature search yielded 42 papers of which only three satisfied our inclusion criteria [9–11]. Two authors were contacted for clarification and additional information, and one responded. An overview of the patient characteristics and outcome from these three studies is displayed in Table 1. No heterogeneity was detected between the four studies. Pooled mean age was 37 years (range 16 to 68 years). Male/female ratio was 2.7. Pooled operative mortality was 2.6%. The pooled hazard for the different types of valve-related events is shown in Table 2.
Because none of the valve-related events in the meta-analysis resulted in death (a probable underestimation of their true lethality), lethality was estimated using recent literature on this subject (Table 2).
Microsimulation
Average life expectancy, reoperation-free life expectancy, actual lifetime reoperation risk, event-free life expectancy, and actual lifetime event risk for men in different age groups are displayed in Figure 2. For example, for a 37-year-old male patient average life expectancy was 21.0 years, reoperation-free life expectancy 16.3 years, actual lifetime reoperation risk 46%, event-free life expectancy 15.6 years, and actual lifetime event risk 52%. Corresponding cumulative survival was 57%, reoperation-free survival 35%, and event-free survival 32% at 20 years.
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Fig 2. Average life expectancy, reoperation-free life expectancy, event-free life expectancy (left y-axis), actual lifetime reoperation risk, and actual lifetime event risk (right y-axis) for men in different age groups.
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We observed an adequate similarity between the survival as calculated with the microsimulation method or with the Gompertz model (Fig 3). Also, a good agreement at midterm follow-up was seen by comparing outcome produced by the microsimulation model with recently reported results from Oklahoma [8].
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Fig 3. Comparison of survival of 35-year old men after autograft aortic root replacement as calculated using the microsimulation model with survival of 35-year old men after aortic valve replacement derived from the Portland dataset using the Gompertz model.
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One-way sensitivity analyses showed that varying the individual parameters had little effect on the mean life expectancy in all age groups. The most pronounced effect was seen in the youngest age group. By ranging the estimates of valve-related events from half to double the base line parameter values, for structural valve failure the maximum change in life expectancy was 0.6 year, for thromboembolism 0.4 year, for endocarditis 0.4 year, and for nonstructural valve failure 0.1 year.
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Comment
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We demonstrated that the combined use of meta-analysis and microsimulation allows one to estimate long-term outcome after autograft aortic root replacement based on current midterm results. Comparison with published data indicates that the microsimulation model is capable of producing a reliable estimate of long-term prognosis after autograft aortic root replacement [6, 8].
Microsimulation allows detailed insight into the occurrence of events that affect patient survival. This insight cannot be achieved with standard statistical methods. According to the model, life expectancy for patients who undergo autograft aortic root replacement is much shorter than for the healthy age-matched population. For instance, life expectancy of a healthy 37-year-old man is 40 additional years, whereas after autograft root replacement the life expectancy is only 21 years, a loss of 19 years. Of these 19 years, 16.4 years can be explained by excess mortality because of the heart valve disease of the patient (for instance, sudden unexpected unexplained death and cardiac death) and only 2.6 years by the occurrence of autograft valve-related events. Autograft valve-related events therefore seem to have little impact on survival. However, they do have a major impact on reoperation-free survival and event-free survival, evidenced by a actual lifetime reoperation risk of 46% and a actual lifetime event risk of 52%.
Choosing a particular aortic valve prosthesis for the individual patient is complex, influenced by patient factors, physician factors, and the center’s surgical experience with different types of aortic valve replacement or repair. With the increasing number of valve replacement or reconstruction options, it becomes even more difficult to make a rational choice. For the younger patient it would be ideal to choose a durable valve (mechanical prosthesis) that will last a lifetime, but avoiding lifelong anticoagulation is preferred, so a human tissue valve may be chosen. The durability of mechanical prostheses is well recognized since long-term follow-up data have been available. However, long-term data on durability of autograft roots are not available yet. In this respect, the microsimulation model is an important tool to accurately predict (reoperation-free) life expectancy for individual patients by taking into account patient age and gender. Of course, the choice of an aortic valve prosthesis is a complex one that cannot be solved by solely taking into account age and gender. The model should be expanded by adding other valve-type options and factors that may influence the choice of prosthesis. Eventually, the model could be used as an objective decision support system to help the physician and the patient in making an adequate choice.
The current version of the microsimulation model still has several other limitations. It is based on pooled midterm clinical results from different centers, surgeons, and patients. Furthermore, we assumed that the pooled hazard of valve-related events for thromboembolism, endocarditis, and nonstructural valve failure is linear. Because the autograft is used mainly in younger patients we did not add age-adjusted hazards for thromboembolism. Also, we constructed the Weibull model for the occurrence of structural valve failure requiring reoperation based on a small number of events. In addition, reoperation for structural valvular failure of the pulmonary allograft was not included. However, because outcome as calculated using microsimulation was similar to recently reported long-term clinical results we are confident that it represents an accurate estimate of long-term outcome in patients after autograft aortic root replacement. A final limitation is the fact that the excess mortality in the microsimulation model due to heart valve disease is based on data from mechanical and bioprosthetic valve studies, and therefore represents a "worst-case scenario."
The clinical application of a model such as we have described is feasible only if the input of the model is being provided regularly with new information that arises from the growing worldwide clinical experience with implantation of aortic valve substitutes. This requires a continuous effort to ascertain precision and validity of the predictions made by the model. Also, new surgical strategies such as aortic valve repair, and new types of prostheses such as the stentless bioprosthesis, should be considered in the future.
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Acknowledgments
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We thank Alain Prat for providing us with additional information on his study [10], and Ada Matser-van den Berg and Marijke Rozema for their secretarial assistance.
This study was in part supported by grant 99141 from the Board of Health Care Insurance, College voor Zorgverzekering, The Netherlands.
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References
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Abstract
Introduction
