Data Analysis
Data analysis was performed with Microsoft Excel (Microsoft Office 2010, Microsoft, Redmond, WA, USA) and IBM SPSS version 21.0 (IBM, Somers, NY, USA) and in the R statistical software (version 3.1.0. R Development Core Team, R Foundation for Statistical Computing, Vienna, Austria) using the metaphor package. Pooled baseline patient characteristics were calculated with the use of sample-size weighting. Early mortality and linearized occurrence rates (LOR) of late valve-related complications were pooled on a logarithmic scale with the use of inverse variance weighting in a random-effects model. Reported study characteristics and pre- and peri-operative patient characteristics are presented as mean ± standard deviation for continuous variables and percentages for discrete variables. For outcome variables, individual and pooled statistics are presented as LOR and 95% confidence interval (CI). In studies where median and ranges instead of mean and variance were reported, the method described by Hozo et al. (10) was used to calculate the mean. In case of absence of total number of patient-years, this was calculated by multiplying the number of patients with the mean follow-up duration in years. In case a certain event did not occur in an individual study, we assumed that 0.5 events occurred for that particular outcome for the purpose of inverse variance weighting. When an event was not reported, this study was excluded from the analysis of that event. For late mortality and reintervention, subgroup analyses were performed stratifying the root replacement by prosthesis type (stented vs. stentless), follow-up duration (individual study mean follow-up less than pooled mean follow-up versus individual study mean follow-up more than pooled mean follow-up), and age at surgery. To assess the association of these variables with late mortality and reintervention rates, linear regression analyses were performed with weighting the studies according to the inverse variance of the occurrence rate. Heterogeneity between the studies was assessed using the I2 test. Funnels plots were used to investigate publication bias. To investigate the potential influence of publication bias on pooled outcome, sensitivity analyses were conducted by temporarily excluding the smallest quartile (by sample size) of included studies. This systematic review and meta-analysis was conducted according to the PRISMA guidelines (11).
Microsimulation model: the concept
The microsimulation model is a computer application that simulates the life of a patient after aortic valve replacement, considering the morbidity and mortality events that the patient could experience. The calculated mortality of a patient is composed of the background mortality of the general population, operative mortality, mortality due to valve-related events and an additional “excess mortality”. This so-called excess mortality in the patient compared to a matched person in the general population reflects mortality associated with the underlying left ventricular function, valve pathology, and the root replacement procedure. All pooled and weighted occurrence rates of (operative) mortality risk, the occurrence rate of valve-related events together with the risk of mortality and reintervention directly due to valve-related events were obtained from the meta-analysis. The occurrence rates of all events were assumed to be linear and non-age dependent.
For patients aged 61-70 and > 70 years, these “excess mortality“ hazard ratios were 1.2 and 0.8 for males, and 2.2 and 1.3 for females, respectively. The background mortality of the general population was obtained from the 2004 United States Life Tables, as 2004 was the pooled median year of intervention, assuming a constant incidence rate over time in each study (12).
To obtain age-specific estimates of life expectancy and lifetime risk of valve-related morbidity, the microsimulation model was run for the ages of 60, 65 and 70 years for 10,000 iterations each and separately for males and females. The age-specific outcomes of both genders were then pooled at the male/female ratio obtained from our meta-analysis. For the internal validation of the model, we performed an additional run for 10,000 iterations at the pooled mean age (65.5 years) and male/female ratio (70%) of the meta-analysis. The actuarial survival obtained from the microsimulation model for these data was then plotted against the pooled (overall) mortality observed in the meta-analysis. A more detailed account of the microsimulation and the methodology has been supplied previously (13).
ResultsStudy and baseline patient characteristicsThe initial literature search exposed 2,106 publications. The selection procedure is illustrated in Figure 1. Cross-referencing did not result in additional papers. Thirty-one studies were finally included in this systematic review with a total number of 5,227 patients, mean follow-up of 4.1 years (range 1-10 years), and total follow-up of 22,706 patient-years. Root replacements was performed with a stented prosthesis in 26% of patients and 74% were stentless valve prostheses. In one study the implantation period was missing, which was provided by the authors (14). Supplementary file 3 shows an overview of the included publications and study characteristics. Pooled pre- and peri-operative characteristics are presented in Table 1.