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Hydroxyurea in polycythemia vera
about confounders were imputed to the sample size-weighted mean of the other studies. For reasons of interpretability and estimability of the model, predictor variables were all centered on their weighted mean. Intraclass Correlation Coefficients (ICC) were calculated conditional on fixed effects = 0 (i.e. the mean) and reported as heterogeneity measure.
To evaluate whether results could depend on model choice, a sensitivity analysis was conducted by fitting a negative-binomial regression on events count, with persons/year as exposure vari- able. As opposed to the GLMM, such a model assigns the same weight to each study regardless of sample size and assumes a con- stant yearly event rate with no upper boundary.
Results
Literature search and study characteristics
The study selection process is detailed in Figure 1.
The search on Medline and EMBASE retrieved a total 420 results; nine additional results were retrieved from dif- ferent sources (clinicaltrials.gov, Cochrane Central Register of Controlled Trials, WHO International Clinical Trials Registry, references from relevant articles) for a total 429 results, which were reduced to 340 after removing duplicates. Abstract and full-text screening allowed for the exclusion of 291 articles, as they fell into the following cat- egories: reviews, case reports, animal studies, patients aged <18 years or pregnant. Other studies were not con- sidered as they had a total sample size < 20 patients,
and/or they did not report incidence data or follow-up duration.
Consequently, a total 49 studies were selected for methodological evaluation. Thirty-three were excluded. Eleven had unclear reporting of data (e.g. it was impossi- ble to distinguish data due to HU-treated patients from those due to other cytoreductive treatments, or PV from other myeloproliferative neoplasms). Seven did not meet the number of 20 HU-treated patients as required by our study protocol. Seven studies referred to cases diagnosed outside the time window (2008-2018) and not with WHO 2008-2016 criteria. In one, follow-up data were missing. One was specifically aimed at HU-resistant patients. In case of multiple studies from the same author(s), we inquired whether they referred to overlapping popula- tions, by questioning authors when necessary, and exclud- ed duplicates (6 studies) from review. The final selection comprised 14 full text articles and two conference abstracts to be included in the meta-analysis.
Table 1 summarizes the main characteristics of the 16 eligible articles and abstracts. The selection included three reports on two RCT4,17,18 (one comparing HU and IFN ther- apy, and one comparing HU to ruxolitinib), one RCT in which HU was not a comparator,19 and 12 observational retrospective cohort studies.7,20-33 The great majority of the studies were conducted in Europe and some involved mul- tiple countries; only one study in our selection32 was con- ducted in the US.
Number of HU-treated patients ranged from 25 to 890
Figure 1. Study flowchart.
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