The analysis of this study was conducted with an exploratory intent.

All analysis variables were tabulated with summary statistics, and graphical representations were used as appropriate. Statistical tests were used to highlight interesting aspects of the data, such as differences between the groups in the analyzed endpoints. The tests were conducted with a two-sided alternative and the p-values will be reported. Statistical significance is declared for p-values below 5%. If appropriate, 95% confidence intervals for point estimates based on suitable distributions were additionally provided. No correction of the significance level for multiple comparisons was performed.

In general the analysis variables were compared by means of statistical tests between the EPS group and the two Control groups taken separately.

All data analyses were performed using the statistical package R 2.0.1 (The R Foundation for Statistical Computing), for Windows XP. Statistical support was provided by Corrado Bernasconi, M.D. Ph.D.

Based on the definition of the ESP and the 2 Control groups (see 2.1 and 2.2) Eurotransplant provided data on a total of 3456 patients transplanted between 4 January 1999 and 4 January 2004. 7 patients from non-heart beating donors and 18 ESP patients for whom either the donor or the recipient was less than 65 years of age at time of transplant were excluded from all analyses, leaving a total number of 3431 patients for the analysis. Due to the definition of the two Control groups there is an overlap of 109 patients between Control 1 and 2(Table 5; see also 3.2.).

N

%

Total number of patients
(excluded patients: see below)

3431

100.00

ESP

1406

40.98

Control 1
(ETKAS, donor ≥ 65 y)

446

13.00

Control 2
(ETKAS, recipient ≥ 60 and

1687

49.17

Overlap between Control 1 and 2

109

3.18

Table 5: Overview analysis populations

Figure 7 shows the number of patients in each of the groups by year of transplantation. The number of patients transplanted in the ESP increased from 227 in 1999 to 382 in 2003.

Figure 7: Number of patients transplanted by year

“Updated patient group”: Out of 64 centres that were contacted and asked to provide missing information, 50 centres (79%) completed and returned data on a total of 2903 patients (85% of all patients, ESP Group n=1294; Control 1 n=355, and Control 2 n=1346 – considering also the overlaps)

The analysis for all evaluations concerning rejections was performed with the “updated patient population” only. In the data collection tool "no information” concerning rejection events and "no rejection" were not distinguished. Since detailed rejection data are available only for the "updated patient group", it was decided to restrict the analysis to this population.

The time of documented follow up was comparable in all groups indicating that there is no systematic error in the data capture (data not shown).

The majority of patients in all groups were transplanted in Germany (71.8%), followed by Austria (10.3%), Holland (9.1%) and Belgium (8%)(Figure 8). 83.8% of all ESP patients were transplanted in Germany.

Figure 8: Patients (all groups) per country

No imputation of missing data was done. This implies that some of the analyses could in effect be performed only on a subset of the entire analysis population.

In particular for the analysis of patient and graft survival, several patients had to be excluded due to the fact that an event or censoring time could not be determined. Reasons were that such times were missing, negative (death, graft loss or loss to follow up reported as having occurred before transplantation) or events occurred after database closure (the maximum accepted event date was 06 June 2005). A maximum of 15.5% of the patients was excluded from such analyses.

As far as the analysis of rejection is concerned, it should be mentioned that the outcome “no rejection” could not be distinguished form the absence of rejection information. For analysis purposes, both cases were considered as no rejection, but the analysis population was restricted to the 2877 patients for which rejection information was collected.

With regard to SCr values it was agreed to exclude outliers (value < 10 or > 1000 μmol/l). Waiting times < 4 weeks and > 15 years were excluded from the waiting time analysis. However, values incorrectly expressed in mg/dl were kept if the value with supposedly correct unit fell between the 100-300 μmol/l limits.

Demographic and background data are summarized for the ESP and the 2 Control groups.

The subdivision into categories of certain variables is only used in the presentation of summary statistics to but not in the statistical models except for the grouping of the reason for end-stage renal disease (ESRD), cause of graft loss and death, and the preservation solution.

Descriptive statistics were provided according to the nature of variables: number of observations, mean, standard deviation, minimum and maximum and quartiles for continuous variables, and frequency counts and percentages for categorical variables. Summary statistics were presented by group and in addition in selected cases broken down by other categorical variables, such as the transplantation year.

Continuous variables were compared by means of the Wilcoxon rank-sum test. Categorical variables, including proportions were analyzed with the chi-square test or in selected cases with Fisher’s exact test. Survival times were analyzed using the Kaplan-Meier method. A plot of the estimated probabilities of survival was created and log-rank tests of the difference between groups in survival probabilities were carried out.

Cox regression analysis was used to additionally evaluate the impact of baseline and treatment characteristics (including HLA matches and selected IS regimens) on:

• Patient survival

• Graft survival

• Time to AR

Cox regression models were also used to evaluate early graft function and the occurrence of AR as predictors for patient and graft survival.