The fragility index in 2010-2021 chronic lymphocytic leukemia randomized controlled trials.
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ABSTRACT:
SUBMITTER: Bagacean C
PROVIDER: S-EPMC8753221 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundAs a metric to determine the robustness of trial results, the fragility index (FI) is the number indicating how many patients would be required to reverse the significant results. This study aimed to calculate the FI in randomized controlled trials (RCTs) involving premature.MethodsTrials were included if they had a 1:1 study design, reported statistically significant dichotomous outcomes, and had an explicitly stated sample size or power calculation. The FI was calculated for binary outcomes using Fisher's exact test, and the FIs of subgroups were compared. Spearman's correlation was applied to determine correlations between the FI and study characteristics.ResultsFinally, 66 RCTs were included in the analyses. The median FI for these trials was 3.00 (interquartile range [IQR]: 1.00-5.00), with a median fragility quotient of 0.014 (IQR: 0.008-0.028). FI was ≤ 3 in 42 of these 66 RCTs (63.6%), and in 42.4% (28/66) of the studies, the number of patients lost to follow-up was greater than that of the FI. Significant differences were found in the FI among journals (p = 0.011). We observed that FI was associated with the sample size, total number of events, and reported p-values (r s = 0.437, 0.495, and -0.857, respectively; all p < 0.001).ConclusionFor RCTs in the premature population, a median of only three events was needed to change from a "non-event" to "event" to render a significant result non-significant, indicating that the significance may hinge on a small number of events.
| S-EPMC9124941 | biostudies-literature
Project description:HIV/AIDS is associated with significant morbidity, mortality, and financial burden. For these reasons, robust clinical evidence is critical. We aim to investigate the fragility index, fragility quotient, and risk of bias of clinical trial endpoints in HIV medicine. The fragility index represents the minimum amount of trial endpoint "nonevents" changed to "events" in one trial arm required to nullify statistical significance. The fragility quotient contextualized the fragility index by dividing the index by the total trial sample size. We selected eligible trials from the Department of Health and Human Services guideline for the use of antiretroviral agents in HIV-1-infected adults and adolescents. We calculated the fragility index and fragility quotient for all included trials. The Cochrane "risk of bias" Tool 2.0 was used to evaluate the likelihood and sources of bias in the included trials. Thirty-nine RCTs were included for our analysis of fragility. Thirty-six were included for our analysis of the risk of bias. The median fragility index was 5. Three RCTs were at high risk of bias, all due to the selection of the endpoint or statistical test. Twenty had some concerns for risk of bias. The analyzed HIV medicine RCT endpoints were fragile, overall. This indicates that a median of 5 patients across all included studies would nullify the statistical significance of the endpoints. Furthermore, we found evidence that concerns for bias are present at a high rate.
| S-EPMC6614212 | biostudies-literature
Project description:Acalabrutinib, a second-generation and more selective Bruton's tyrosine kinase inhibitor, was developed to potentiate efficacy while minimizing ibrutinib-associated side effects. We undertook a systematic review and meta-analysis of randomized clinical trials to determine the risks of acalabrutinib-related cardiac toxicities in patients with chronic lymphocytic leukemia. Patients on acalabrutinib experienced higher risk of any-grade cardiac events (risk ratio, 1.75; p = 0.01) while there was a considerable trend toward statistical significance in the risk of any-grade atrial fibrillation (risk ratio, 2.56; p = 0.05). There was no significant increase in the risk of hypertension or high-grade cardiac events or atrial fibrillation in the acalabrutinib group.
| S-EPMC9153250 | biostudies-literature
Project description:The effectiveness of corticosteroids in acute respiratory distress syndrome (ARDS) and COVID-19 still remains uncertain. Since ARDS is due to a hyperinflammatory response to a direct injury, we decided to perform a meta-analysis and an evaluation of robustness of randomised clinical trials (RCTs) investigating the impact of corticosteroids on mortality in ARDS in both COVID-19 and non-COVID-19 patients. We conducted a systematic search of the literature from inception up to 30 October 2020, using the MEDLINE database and the PubMed interface. We evaluated the fragility index (FI) of the included RCTs using a two-by-two contingency table and the p-value produced by the Fisher exact test; the fragility quotient (FQ) was calculated by dividing the FI score by the total sample size of the trial. Thirteen RCTs were included in the analysis; five of them were conducted in COVID-19 ARDS, including 7692 patients, while 8 RCTS were performed in non-COVID ARDS with 1091 patients evaluated. Three out of eight RCTs in ARDS had a FI > 0 while 2 RCTs out of five in COVID-19 had FI > 0. The median of FI for ARDS was 0.625 (0.47) while the median of FQ was 0.03 (0.014). The median of FI for COVID-19 was 6 (2) while the median of FQ was 0.059 (0.055). In this systematic review, we found that FI and FQ of RCTs evaluating the use of corticosteroids in ARDS and COVID-19 were low.
| S-EPMC8624335 | biostudies-literature
Project description:BackgroundThe fragility index (FI) of trial results can provide a measure of confidence in the positive effects reported in randomized controlled trials (RCTs). The aim of this study was to calculate the FI of RCTs supporting HCC treatments.MethodsA methodological systematic review of RCTs in HCC treatments was conducted. Two-arm studies with randomized and positive results for a time-to-event outcome were eligible for the FI calculation.ResultsA total of 6 trails were included in this analysis. The median FI was 0.5 (IQR 0-10). FI was ≤7 in 4 (66.7%) of 6 trials; in those trials the fragility quotient was ≤1%.ConclusionMany phase 3 RCTs supporting HCC treatments have a low FI, which challenges the confidence in concluding the superiority of these drugs over control treatments.
| S-EPMC8034173 | biostudies-literature
Project description:This study investigated the impact of comorbidity in 555 patients with chronic lymphocytic leukemia enrolled in two trials of the German Chronic Lymphocytic Leukemia Study Group on first-line treatment with fludarabine plus cyclophosphamide, fludarabine, or chlorambucil. Patients with two or more comorbidities and patients with less than two comorbidities differed in overall survival (71.7 versus 90.2 months; P<0.001) and progression-free survival (21.0 versus 31.5 months; P<0.01). After adjustment for other prognostic factors and treatment, comorbidity maintained its independent prognostic value in a multivariate Cox regression analysis. Chronic lymphocytic leukemia was the major cause of death in patients with two or more comorbidities. Disease control in patients with two or more comorbidities was better with fludarabine plus cyclophosphamide than with fludarabine treatment, but not with fludarabine compared to chlorambucil treatment. These results give insight into interactions between comorbidity and therapy of chronic lymphocytic leukemia and suggest that durable control of the hematologic disease is most critical to improve overall outcome of patients with increased comorbidity. The registration numbers of the trials reported are NCT00276848 and NCT00262795.
| S-EPMC4040914 | biostudies-literature
Project description:BackgroundEvidence-based care relies on robust research. The fragility index (FI) is used to assess the robustness of statistically significant findings in randomized controlled trials (RCTs). While the traditional FI is limited to dichotomous outcomes, a novel tool, the continuous fragility index (CFI), allows for the assessment of the robustness of continuous outcomes.PurposeTo calculate the CFI of statistically significant continuous outcomes in RCTs evaluating interventions for managing anterior shoulder instability (ASI).Study designMeta-analysis; Level of evidence, 2.MethodsA search was conducted across the MEDLINE, Embase, and CENTRAL databases for RCTs assessing management strategies for ASI from inception to October 6, 2022. Studies that reported a statistically significant difference between study groups in ≥1 continuous outcome were included. The CFI was calculated and applied to all available RCTs reporting interventions for ASI. Multivariable linear regression was performed between the CFI and various study characteristics as predictors.ResultsThere were 27 RCTs, with a total of 1846 shoulders, included. The median sample size was 61 shoulders (IQR, 43). The median CFI across 27 RCTs was 8.2 (IQR, 17.2; 95% CI, 3.6-15.4). The median CFI was 7.9 (IQR, 21; 95% CI, 1-22) for 11 studies comparing surgical methods, 22.6 (IQR, 16; 95% CI, 8.2-30.4) for 6 studies comparing nonsurgical reduction interventions, 2.8 for 3 studies comparing immobilization methods, and 2.4 for 3 studies comparing surgical versus nonsurgical interventions. Significantly, 22 of 57 included outcomes (38.6%) from studies with completed follow-up data had a loss to follow-up exceeding their CFI. Multivariable regression demonstrated that there was a statistically significant positive correlation between a trial's sample size and the CFI of its outcomes (r = 0.23 [95% CI, 0.13-0.33]; P < .001).ConclusionMore than a third of continuous outcomes in ASI trials had a CFI less than the reported loss to follow-up. This carries the significant risk of reversing trial findings and should be considered when evaluating available RCT data. We recommend including the FI, CFI, and loss to follow-up in the abstracts of future RCTs.
| S-EPMC11344964 | biostudies-literature
Project description:In addition to clinical staging, a number of biomarkers predicting overall survival (OS) have been identified in chronic lymphocytic leukemia (CLL). The multiplicity of markers, limited information on their independent prognostic value, and a lack of understanding of how to interpret discordant markers are major barriers to use in routine clinical practice. We therefore performed an analysis of 23 prognostic markers based on prospectively collected data from 1948 CLL patients participating in phase 3 trials of the German CLL Study Group to develop a comprehensive prognostic index. A multivariable Cox regression model identified 8 independent predictors of OS: sex, age, ECOG status, del(17p), del(11q), IGHV mutation status, serum ?2-microglobulin, and serum thymidine kinase. Using a weighted grading system, a prognostic index was derived that separated 4 risk categories with 5-year OS ranging from 18.7% to 95.2% and having a C-statistic of 0.75. The index stratified OS within all analyzed subgroups, including all Rai/Binet stages. The validity of the index was externally confirmed in a series of 676 newly diagnosed CLL patients from Mayo Clinic. Using this multistep process including external validation, we developed a comprehensive prognostic index with high discriminatory power and prognostic significance on the individual patient level. The studies were registered as follows: CLL1 trial (NCT00262782, http://clinicaltrials.gov), CLL4 trial (ISRCTN 75653261, http://www.controlled-trials.com), and CLL8 trial (NCT00281918, http://clinicaltrials.gov).
| S-EPMC4260976 | biostudies-literature
Project description:BackgroundThe clinical course of chronic lymphocytic leukemia (CLL) is highly variable. A prognostic index based on widely available clinical and laboratory features was recently developed to predict survival among patients with previously untreated CLL. This index requires validation in an independent series of patients before widespread use can be recommended.MethodsThe Mayo Clinic CLL database was used to evaluate the validity and reproducibility of the new prognostic index.ResultsA total of 440 patients with newly diagnosed CLL who were seen at the Mayo Clinic within 12 months of diagnosis and for whom data were available with which to calculate index score were identified. Patients were classified as low, intermediate, or high risk using the prognostic index. The estimated median survival times were: not reached for low risk, 10.1 years for intermediate risk, and 7.2 years for high risk. The estimated median and 5-year survival by prognostic index risk category were similar to those originally reported. The prognostic index risk category added predictive value beyond that of Rai risk alone (P=.004). The prognostic index risk category remained a predictor of survival when analysis was limited to Rai stage 0 (P=.03) and nonreferred patients (P<.0001) and also predicted time to treatment (P<.0001).ConclusionsThe results of the current study confirm the ability of a newly developed prognostic index to predict survival among patients with previously untreated CLL. The study also extended the utility of the index by demonstrating that it is useful at diagnosis, retains prognostic value when applied exclusively to Rai stage 0 patients, is effective in nonreferred patients, and predicts time to treatment.
| S-EPMC2629134 | biostudies-literature
Project description:BackgroundThe established clinical staging systems (Rai/Binet) of chronic lymphocytic leukemia (CLL) cannot accurately predict the appropriate treatment of patients in the earlier stages. In the past two decades, several prognostic factors have been identified to predict the outcome of patients with CLL, but only a few studies investigated more markers together. To predict the time to first treatment (TTFT) in patients of early stages, we evaluated the prognostic role of conventional markers as well as cytogenetic abnormalities and combined them together in a new prognostic scoring system, the CLL prognostic index (CLL-PI).MethodsTaking advantage of a population of 406 untreated Chinese patients with CLL at early and advanced stage of disease, we identified the strongest prognostic markers of TTFT and, subsequently, in a cohort of 173 patients who had complete data for all 3 variables, we integrated the data of traditional staging system, cytogenetic aberrations, and mutational status of immunoglobulin heavy chain variable region (IGHV) in CLL-PI. The median follow-up time was 45 months and the end point was TTFT.ResultsThe median TTFT was 38 months and the 5-year overall survival was 80%. According to univariate analysis, patients of advanced Rai stages (P < 0.001) or with 11q- (P = 0.002), 17p- (P < 0.001), unmutated IGHV (P < 0.001), negative 13q- (P = 0.007) and elevated lactate dehydrogenase levels (P = 0.001) tended to have a significantly shorter TTFT. And subsequently, based on multivariate Cox regression analysis, three independent factors for TTFT were identified: advanced clinical stage (P = 0.002), 17p- (P = 0.050) and unmutated IGHV (P = 0.049). Applying weighted grading of these independent factors, a CLL-PI was constructed based on regression parameters, which could categorize four different risk groups (low risk [score 0], intermediate low [score 1], intermediate high [score 2] and high risk [score 3-6]) with significantly different TTFT (median TTFT of not reached (NR), 65.0 months, 36.0 months and 19.0 months, respectively, P < 0.001).ConclusionsThis study developed a weighted, integrated CLL-PI prognostic system of CLL patients which combines the critical genetic prognostic markers with traditional clinical stage. This novel modified PI system could be used to discriminate among groups and may help predict the TTFT and prognosis of patients with CLL.
| S-EPMC5282668 | biostudies-literature