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An analysis of bleeding complications by sequence of enrollment in ADDRESS also indicated that sites enrolled patients at lower risk of bleeding in both the DrotAA and placebo groups.
In certain cases, students may be permitted to vary the sequence of enrollment described above.
Subgroup analyses suggested heterogeneity in the observed treatment effect for some subgroups, including those defined by baseline Acute Physiology and Chronic Health Evaluation (APACHE) II score, by protocol violation status, and by the sequence of enrollment at a study site [ 2, 3].
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Based on a prospectively defined analysis, there was a significant treatment-by-sequence of enrollment interaction for the first patient enrolled at each site compared with all subsequently enrolled patients at that site (P = 0.04).
A treatment-by-sequence of enrollment interaction was present in the ADDRESS (P = 0.006) but not in the PROWESS MOD subpopulations.
As statistically significant treatment-by-sequence of enrollment interactions were present in both ADDRESS and PROWESS, selected subgroups from both studies were also examined.
For single-organ dysfunction surgical patients, no treatment-by-sequence of enrollment interaction was present in either the ADDRESS or the PROWESS study.
A treatment-by-sequence of enrollment interaction was present in ADDRESS (P = 0.04) and only a trend in PROWESS (P = 0.11).
As with the MOD subgroup in PROWESS, no treatment-by-sequence of enrollment interaction was present in PROWESS patients with APACHE II scores ≥25.
As the above results suggested that any treatment-by-sequence of enrollment interaction might be most apparent in lower-risk patients, the entire ADDRESS population was compared with the lower-risk population in PROWESS as defined by an APACHE II score of less than 25.
To explore interactions between mortality and the sequence of patient enrollment, ADDRESS patients were divided into subgroups comprising the first two enrolled patients at each site (≤2 subgroup, n = 904) and those comprising the third and subsequently enrolled patients (≥3 subgroup, n = 1,709).
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