Statistical analysis
All patients participating in this study belong to one of the following
two groups for analysis: the group with antihypertensive treatment
(β-blockers or ACEI) and the group without such treatment. The analyses
concerning the outcome “systemic adverse event” are based on the
patients who completed the up-dosing phase of immunotherapy, while
analyses concerning the outcome “systemic sting reaction” are based on
all patients included in the study.
The primary outcome and secondary outcomes were analyzed using logistic
linear mixed models with a random intercept. This model type takes into
account the clustered structure of the data, i.e., observations
clustered in the different participating centers. Parameters, having a
p-value <0.15 in the univariable model analysis were kept for
further analysis with multivariable models. For further parameter
reduction, the Bayesian information criterion (BIC) was calculated as a
measure of the relative quality of the models. However, age and taking
antihypertensive treatment were always kept in the multivariable models
for the outcome “systemic adverse event” as well as for the outcome
“systemic sting reaction.” For these outcomes, complete case model
analyses were performed, if missing data in parameters of interest were
rare (<1%). Otherwise, missing at random was assumed, and
multiple imputations were conducted with 50 imputations taking into
account the cluster design. The level of significance was set at 0.05.
All analyses were performed using the statistical software R (version
3.6.3) with the lme4 package (version 1.1-23) to carry out multilevel
modeling and the MICE package for the multiple imputation analysis
(version 3.8.0).21,22