Objective: Medications are frequently prescribed outside their approved indications (off-label), particularly when appropriate therapies are not available. However, the risk/benefit ratio of drugs in off-label use needs to be critically appraised because it may differ substantially from approved on-label usage. Therefore, an extensive exploration of current evidence is well-advised. The objective of this study was to develop two search strategies that facilitate detection of off-label drug use documents in MEDLINE and EMBASE via OvidSP.
Study Design and Setting: We compiled a gold standard reference set of reports classified as "relevant" or "not relevant" to off-label drug use. Search queries, including search words and strings, were conceived based on a definition of off-label use of medications as well as text analysis of 500 randomly selected relevant documents. The selected terms were searched in MEDLINE (from 1948 to 2011) and EMBASE (from 1988 to 2011). In comparison with the gold standard, we determined sensitivity and precision of search queries and their combinations. We developed a sensitivity-maximizing, and a sensitivity- and precision-maximizing search strategy for each bibliographic database.
Results: Our gold standard set contained 4,067 relevant documents overall out of 6,785 records. The most sensitive single term was "off label*.af." in both MEDLINE (sensitivity 40.9%, precision 84.4%) and EMBASE (sensitivity: 77.5%, precision 88.1%). The highest sensitive search strategy in MEDLINE was achieved by combining 31 search queries (sensitivity 53.3%, precision 60.3%) and 36 search queries in EMBASE (sensitivity 94.0%, precision 69.5%). Two optimal sensitive and precise search strategies yielded a precision of 84.0% in MEDLINE and 87.4% in EMBASE at the expense of decreasing sensitivity to 49.0% and 89.4%, respectively.
Conclusions: We empirically developed two versions of optimized sensitive search strategies which can achieve reasonable performance for retrieving off-label drug use documents in OvidSP MEDLINE and OvidSP EMBASE.
Background: Erythropoiesis stimulating agents (ESAs) are prescribed in critically ill patients to treat anaemia. This indication is off-label, because it is not licensed by regulatory authorities.
Recently ESAs were suspected to cause harm in case of critical illness.
Objectives: Our objective was to assess whether ESAs are safe and reduce overall mortality in critical illness.
Search methods: In April 2012, we conducted a systematic search on EMBASE, MEDLINE, all EBM reviews, IPA, PASCAL and PsycINFO via OvidSP as well as SCI-Expanded, Conference Proceedings Citation Index- Science, CINAHL, BIOSIS Previews and TOXLINE. We also searched trials registeries, checked reference lists of relevant studies and tracked their citations by using SciVerse Scopus.
Selection criteria: We considered randomized controlled trials (RCT) and controlled observational studies in any language that compared scheduled systemic administration of ESAs with other effective interventions, placebo or no treatment in critically ill patients.
Data collection and analysis: Two authors independently screened and evaluated the eligibility of retrieved records, extracted data and assessed risk of bias (ROB) and quality of included studies. Differences in opinion were settled by consensus or involving a third author. We used fixed or random effects models depending on heterogeneity between studies.
Results: We screened 12,888 citations and included 48 studies (34 RCTs and 14 observational studies), involving a total of 944,856 participants (6,332 in RCTs and 938,524 in observational studies) from 21 countries.
Overall, 95 adverse events were identified in 37 studies and mortality was reported in 38 studies. We classified 27 RCTs and 10 observational studies as being at low to medium risk of bias for safety outcome. Harm assessment and reporting in the included studies was of medium to low quality.
In summary, ESA treatment did not significantly increase the risk of frequently reported adverse events and mortality but decreased the risk of central and peripheral nervous system disorders (RR= 0.37, 95% CI:
0.15- 0.91).
Conclusions: Our findings indicate that ESAs treatment in critically ill patients was not associated with a significant increase in most frequently reported adverse events and had no effect on mortality.