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 | 2022 Jan
REPOSITORIES: biostudies-literature
Publications
The fragility index in 2010-2021 chronic lymphocytic leukemia randomized controlled trials.
Bagacean Cristina C Ianotto Jean-Christophe JC Sritharan Nanthara N Cymbalista Florence F Berthou Christian C Lévy Vincent V
Blood advances 20220101 1
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Project description:BackgroundEfficacy of an intervention is commonly evaluated using P values, in addition to effect size measures such as absolute risk reduction, relative risk reduction, and numbers needed to treat. However, these measures are not always intuitive to clinicians. The fragility index (FI) is a more intuitive number that can facilitate interpretation but can only be used with binary outcomes. FI is the minimum number of patients who must be moved from the nonevent group to the event group to turn a significant result nonsignificant. In this retrospective analysis, we assessed the robustness of cardiovascular randomized controlled trials (RCTs), which report a positive (statistically significant) primary outcome by using the FI.Methods and resultsWe searched Medline from 2007 to 2017 to identify cardiovascular RCTs published in 6 high impact journals (The Lancet, New England Journal of Medicine, Journal of the American Medical Association, Circulation, Journal of the American College of Cardiology and European Heart Journal). Only RCTs with sample sizes >500 and a 2-by-2 factorial design or dichotomous primary outcomes were selected. FI was calculated using a defined approach. Among the cohort of 123 RCTs that met inclusion criteria, median FI was 13 (interquartile range, 5-26). In 28 trials (22.8%), FI ranged between 1 and 4. In 37 trials (30.1%), number of patients lost to follow-up was higher than the FI. Pharmaceutical interventions had higher FI compared with other interventions, FI=19 (7-52; P=0.002). Median FI varied according to subspecialty (electrophysiology=2; heart failure=11; interventional cardiology=8; P=0.020) and multiregional RCTs had higher FI=22 (12-53.25; P=0.023). FI did not differ based on risk of bias indicators, funding, or publication year.ConclusionsConsiderable variations in FI were observed among cardiovascular trials, suggesting the need for careful interpretation of results, particularly when number of patients lost to follow-up exceeds FI.
| S-EPMC7962007 | biostudies-literature
Project description:BackgroundThe reverse fragility index (RFI) is a measure used to evaluate the neutrality of statistically nonsignificant findings in randomized controlled trials (RCTs). The RFI represents the minimum number of events needed to reverse a statistically nonsignificant result into a significant one. This study applied the RFI to examine the robustness of statistically nonsignificant RCTs in plastic surgery.MethodsA systematic literature search of the 10 highest impact journals covering plastic and reconstructive surgery topics was conducted to identify RCTs published between January 2000 and March 2023. The Fisher exact test was used to calculate the RFI for each primary outcome. Bivariate analysis was performed to investigate the association of trial characteristics with the RFI.ResultsForty RCTs that yielded 65 primary outcomes were included in the analysis with a median sample size of 76 participants (interquartile range [IQR], 49-129) and a median of 10 events (IQR, 3-22). The median RFI was 4 (IQR, 3-5), indicating that statistical significance would have been achieved if 4 participants had a change in event status. The median RFQ was 0.053 (IQR, 0.038-0.08). Most studies (21 of 40) did not perform statistical power analysis. Twelve of 40 RCTs did not report or clearly indicate loss to follow-up.ConclusionsThe findings of RCTs in the plastic surgery literature demonstrate fragility as the preservation of nonsignificant results rested on a small number of events. The RFI is a useful measure to complement the P value and examine the neutrality of null clinical trials.
| S-EPMC11756890 | biostudies-literature
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:IntroductionThe Fragility Index (FI) and the FI family are statistical tools that measure the robustness of randomized controlled trials (RCT) by examining how many patients would need a different outcome to change the statistical significance of the main results of a trial. These tools have recently gained popularity in assessing the robustness or fragility of clinical trials in many clinical areas and analyzing the strength of the trial outcomes underpinning guideline recommendations. However, it has not been applied to perioperative care Clinical Practice Guidelines (CPG).ObjectivesThis study aims to survey clinical practice guidelines in anesthesiology to determine the Fragility Index of RCTs supporting the recommendations, and to explore trial characteristics associated with fragility.Methods and analysisA methodological survey will be conducted using the targeted population of RCT referenced in the recommendations of the CPG of the North American and European societies from 2012 to 2022. FI will be assessed for statistically significant and non-significant trial results. A Poisson regression analysis will be used to explore factors associated with fragility.DiscussionThis methodological survey aims to estimate the Fragility Index of RCTs supporting perioperative care guidelines published by North American and European societies of anesthesiology between 2012 and 2022. The results of this study will inform the methodological quality of RCTs included in perioperative care guidelines and identify areas for improvement.
| S-EPMC11392262 | 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: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:Inhibition of the renin-angiotensin-aldosterone system (RAAS) is broadly recommended in many nephrological guidelines to prevent chronic kidney disease (CKD) progression. This work aimed to analyze the robustness of randomized controlled trials (RCTs) investigating the renal and cardiovascular outcomes in CKD stages 3-5 patients treated with RAAS inhibitors (RAASi). We searched for RCTs in MEDLINE (PubMed), EMBASE databases, and the Cochrane register. Fragility indexes (FIs) for every primary and secondary outcome were calculated according to Walsh et al., who first described this novel metric, suggesting 8 as the cut-off to consider a study robust. Spearman coefficient was calculated to correlate FI to p value and sample size of statistically significant primary and secondary outcomes. Twenty-two studies met the inclusion criteria, including 80,455 patients. Sample size considerably varied among the studies (median: 1693.5, range: 73-17,276). The median follow-up was 38 months (range 24-58). The overall median of both primary and secondary outcomes was 0 (range 0-117 and range 0-55, respectively). The median of FI for primary and secondary outcomes with a p value lower than 0.05 was 6 (range: 1-117) and 7.5 (range: 1-55), respectively. The medians of the FI for primary outcomes with a p value lower than 0.05 in CKD and no CKD patients were 5.5 (range 1-117) and 22 (range 1-80), respectively. Only a few RCTs have been shown to be robust. Our analysis underlined the need for further research with appropriate sample sizes and study design to explore the real potentialities of RAASi in the progression of CKD.
| S-EPMC9605379 | biostudies-literature
Project description:BackgroundAlthough chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are the same biologic disease entity and warrant identical treatment approaches, patients with SLL have frequently been excluded from clinical trials in CLL.MethodsThis study assessed the representation of patients with SLL among Phase II or III clinical trials cited in the 2024 National Comprehensive Cancer Network (NCCN) treatment guidelines.ResultsPatients with SLL were explicitly eligible for only 21 (38%) of the 56 clinical trials for CLL, comprising 222 (6%) of the 3440 enrolled patients. Notably, 380 patients with SLL were enrolled in 16 separate non-CLL clinical trials alongside patients with indolent B-cell lymphomas such as follicular lymphoma. In CLL trials, patients with SLL were included in a greater proportion of studies evaluating BTK inhibitors (67%) or BTK/BCL2 inhibitor combinations (67%) compared to BCL2 inhibitors (0%) or chemoimmunotherapy (0%).ConclusionsAlthough recent and upcoming trials show a promising trend toward the inclusion of patients with SLL, further advocacy is needed to raise awareness of the biological similarities between CLL and SLL and to promote the representation of patients with SLL in CLL/SLL clinical research.
| S-EPMC11880966 | biostudies-literature