Analysis of robustness of the landmark Cardiovascular outcome trials of antidiabetic drugs – A systematic review

2021 ◽  
Vol 17 ◽  
Author(s):  
Debdipta Bose ◽  
Mahanjit Konwar
Keyword(s):  
Statistical Significance ◽  
Rank Correlation ◽  
Primary Objective ◽  
Antidiabetic Drugs ◽  
Cardiovascular Outcome ◽  
P Value ◽  
Fragility Index ◽  
Cardiovascular Outcome Trials ◽  
Lost To Follow Up

Background: It is essential for Randomized controlled trials [RCTs] to report its results in a comprehensive manner. Hence, it is necessary to assess the robustness of the trials with statistically significant and as well as non-significant results. Robustness can be evaluated using fragility index (FI) and reverse fragility index [RFI] is for trials with statistically significant and as well as non-significant results. The primary aim of this study was to calculate FI and RFI for cardiovascular outcome trials [CVOT]. Materials & Methods: PubMed/MEDLINE was searched to identify all RCTs of antidiabetic drugs where the primary objective was to evaluate the cardiovascular outcomes. We recorded the trial characteristics of each CVOT trial. The FI, RFI, Fragility quotient [FQ] and reverse fragility quotient [FQ] was calculated to evaluate the robustness of the trials. Spearman rank correlation test was used for correlation. Findings: A total of 889 studies were identified and 24 RCTs was included. Among the 24 trials, 12 [50%] trials achieved statistical significance. The median FI and RFI were 29 [4-12] and 22.5 [1-37] for trials with statistically significant and non-significant results. The median FQ and RFQ were 0.0075 [0.002-0.013] and 0.0003 [0.0001-0.004] for trials with statistically significant and non-significant results. The hazard ratio, p value and NNT-B had strong negative relation with FI. Interpretation: Our study showed that half of the trials showing superiority of cardioprotective benefits have favourable FI. The trials failed to show superiority also have a reasonable RFI indicating the robustness of these trials. But the results pf the trials where patients lost to follow-up exceed the FI of that trial demands caution during interpretation.

Fragility index of trials supporting approval of anti-cancer drugs in common solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2055-2055
Author(s):  
Alexandra Desnoyers ◽  
Michelle Nadler ◽  
Ramy Saleh ◽  
Eitan Amir
Keyword(s):  
Solid Tumors ◽  
Randomized Trials ◽  
Statistical Significance ◽  
P Value ◽  
Inverse Association ◽  
Fragility Index ◽  
Real World Data ◽  
Number Of Patients ◽  
Lost To Follow Up

2055 Background: The Fragility Index (FI) quantifies the reliability of positive trials by estimating the number of events which would change statistically significant results to non-significant results. Here, we calculate the FI of trials supporting approval of drugs for common solid tumors. Methods: We searched Drugs@FDA to identify randomized trials (RCT) supporting drug approvals by the US Food and Drug Administration between January 2009 and December 2019 in lung, breast, prostate, gastric and colon cancers. We adapted the FI framework (Walsh et al. J Clin Epidemiol 2014) to allow use of time to event data. First, we reconstructed survival tables from reported data using the Parmar Toolkit (Parmar et al. Stat Med 1998) and then calculated the number of events which would result in a non-significant effect for the primary endpoint of each trial. The FI was then compared quantitatively to the number of patients in each trial who withdrew consent or were lost to follow-up. Multivariable linear regression was used to explore association between RCT characteristics and the FI. Results: We identified 69 RCT with a median of 669 patients (range 123-4804) and 358 primary outcome events (range 56-884). The median FI was 26 (range 1-322). The FI was ≤10 in 21 trials (30%) and ≤20 in 31 trials (45%). Among the 69 RCT, the median number of patients who withdrew consent or were lost to follow up was 27 (range, 6-317). The number of patients who withdrew consent or were lost to follow-up was equal or greater than the FI in 42 trials (61%). There was statistically significant inverse association between FI and trial hazard ratio (p0,001) and a positive association with number of patients who were lost to follow-up or withdrew consent (p0,001). There was no association between trial sample size, year of approval or reported p-value and the FI. Conclusions: Statistical significance of trials supporting drug approval in common solid tumors relies often on a small number of events. In most trials the FI was lower than the number of patients lost to follow up or withdrawing consent. Post-approval randomized trials or real-world data analyses should be performed to ensure that effects observed in registration trials are robust.

scholarly journals On clinical trial fragility due to patients lost to follow up

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Benjamin R. Baer ◽  
Stephen E. Fremes ◽  
Mario Gaudino ◽  
Mary Charlson ◽  
Martin T. Wells
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Intermediate State ◽  
Statistical Tests ◽  
Statistical Significance ◽  
Artery Bypass ◽  
Fragility Index ◽  
Lost To Follow Up ◽  
Statistical Results

Abstract Background Clinical trials routinely have patients lost to follow up. We propose a methodology to understand their possible effect on the results of statistical tests by altering the concept of the fragility index to treat the outcomes of observed patients as fixed but incorporate the potential outcomes of patients lost to follow up as random and subject to modification. Methods We reanalyse the statistical results of three clinical trials on coronary artery bypass grafting (CABG) to study the possible effect of patients lost to follow up on the treatment effect statistical significance. To do so, we introduce the LTFU-aware fragility indices as a measure of the robustness of a clinical trial’s statistical results with respect to patients lost to follow up. Results The analyses illustrate that clinical trials can either be completely robust to the outcomes of patients lost to follow up, extremely sensitive to the outcomes of patients lost to follow up, or in an intermediate state. When a clinical trial is in an intermediate state, the LTFU-aware fragility indices provide an interpretable measure to quantify the degree of fragility or robustness. Conclusions The LTFU-aware fragility indices allow researchers to rigorously explore the outcomes of patients who are lost to follow up, when their data is the appropriate kind. The LTFU-aware fragility indices are sensitivity measures in a way that the original fragility index is not.

Role of ctDNA to predict risk of recurrence following potentially curative resection of biliary tract and pancreatic malignancies.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 336-336
Author(s):  
Angela Lamarca ◽  
Mairead Geraldine McNamara ◽  
Richard Hubner ◽  
Juan W. Valle
Keyword(s):  
Relapse Rate ◽  
Curative Resection ◽  
Cox Regression ◽  
Statistical Significance ◽  
Molecular Profiling ◽  
P Value ◽  
Relapse Risk ◽  
Baseline Characteristics

336 Background: The potential role of ctDNA to identify residual disease after potentially curative resection has been suggested in some malignancies; its role in resected pancreatico(P)-biliary(B) malignancies is unknown. Methods: Patients diagnosed with PB malignancies underwent molecular profiling (ctDNA) using FoundationMedicine Liquid (72 cancer-related genes) following potentially curative resection. Baseline patient characteristics and molecular profiling outcomes, including mutant allele frequency (MAF) for pathological alterations were extracted. Primary objective: prevalence of ctDNA identification and its correlation with recurrence (relapse-free survival (RFS) and relapse rate). Results: Total of 11 individuals had ctDNA analysed following potentially curative resection for PB malignancies: 8 B (4 extra-hepatic cholangiocarcinoma (eCCA), 2 ampulla, 1 intrahepatic cholangiocarcinoma (iCCA), 1 gallbladder cancer (GBC)) and 3 P. Baseline characteristics: 6 female (54.55%), median age 71.59 years (range 39.98-81.19). Most were pT2 (45.45%), pN0 (54.55%) and R0 (63.64%). Following surgery, 6 patients were started on adjuvant chemotherapy; at the end of follow-up (data cut-off 25/6/2020; median follow-up 11.15 months (range 5.45-13.52); 5 relapsed (45.45%) and 2 died (18.18%). Estimated median RFS was 11.43 months (95% CI 2.28-not reached); median overall survival was not reached. No sample failed ctDNA analysis; presence of ctDNA was identified in 3/11 (27.27%) of the samples; 2 and 1 samples had 2 and 1 pathological alterations identified, respectively: ALK fusion (1 sample; GBC), TP53 mutation (2 samples; eCCA and GBC), CHEK2 mutation (1 sample; pancreas), IDH2 mutation (1 sample; eCCA). Mean maximum MAF was 1.47 (2 in biliary; 0.43 in pancreas). Variants of unknown significance were identified in 72.73% of the samples (87.5% in B; 33.33% in P; p-value 0.152). None of the baseline characteristics explored correlated with presence of ctDNA. There was a trend towards increased relapse risk in the patients with ctDNA present following potentially curative surgery; Cox regression for RFS [HR 2.64 (95% CI 0.36-19.31); median RFS 11.44 months (95% CI 2.28-not reached) vs 10.87 (95% CI 2.21-not reached)]; relapse rate 37.5% (ctDNA absent) vs 66.67% (ctDNA present); statistical significance was not reached (p-value 0.340 and p-value 0.545, respectively). Conclusions: This pilot study demonstrates the feasibility of testing for ctDNA following potentially curative resection in PB malignancies. Presence of ctDNA may be associated with increased relapse risk; further studies are required to increase sample size and assess clinical implications.

Treatment Outcomes of Childhood Tuberculosis in Three Districts of Balochistan, Pakistan: Findings from a Retrospective Cohort Study

2020 ◽  
Author(s):  
Abid Abdullah ◽  
Nafees Ahmad ◽  
Muhammad Atif ◽  
Shereen Khan ◽  
Abdul Wahid ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cohort Study ◽  
Treatment Outcomes ◽  
Retrospective Cohort Study ◽  
Retrospective Cohort ◽  
P Value ◽  
Childhood Tb ◽  
Study Sites ◽  
Lost To Follow Up

Abstract Background This study aimed to evaluate treatment outcomes and factors associated unsuccessful outcomes among pediatric tuberculosis (TB) patients (age ≤14 years). Methods This was a retrospective cohort study conducted at three districts (Quetta, Zhob and Killa Abdullah) of Balochistan, Pakistan. All childhood TB patients enrolled for treatment at Bolan Medical Complex Hospital (BMCH) Quetta and District Headquarter Hospitals of Zhob and Killa Abdullah from 1 January 2016 to 31 December 2018 were included in the study and followed until their treatment outcomes were reported. Data were collected through a purpose developed standardized data collection form and analyzed by using SPSS 20. A p-value <0.05 was considered statistically significant. Results Out of 5152 TB patients enrolled at the study sites, 2184 (42.4%) were children. Among them, 1941 childhood TB patients had complete medical record were included in the study. Majority of the study participants were <5 years old (66.6%) and had pulmonary TB (PTB; 65%). A total of 45 (2.3%) patients were cured, 1680 (86.6%) completed treatment, 195 (10%) lost to follow-up, 15 (0.8%) died, 5 (0.3%) failed treatment and 1 (0.1%) was not evaluated for outcomes. In multivariate binary logistic regression analysis, treatment at BMCH Quetta (OR = 25.671, p-value < 0.001), rural residence (OR = 3.126, p-value < 0.001) and extra-PTB (OR = 1.619, p-value = 0.004) emerged as risk factors for unsuccessful outcomes. Conclusion The study sites collectively reached the World Health Organization’s target of treatment success (>85%). Lost to follow-up was the major reason for unsuccessful outcomes. Special attention to patients with identified risk factors for unsuccessful outcomes may improve outcomes further.

scholarly journals Long-Term Postoperative Total Knee Arthroplasty Flexion Scores in Relation to Body Mass Index

2020 ◽  
Author(s):  
Matthew A. Siegel ◽  
Michael J. Patetta ◽  
Angie M. Fuentes ◽  
Armaan S. Haleem ◽  
Craig W. Forsthoefel ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Total Knee Arthroplasty ◽  
Body Mass ◽  
Knee Arthroplasty ◽  
Statistical Significance ◽  
P Value ◽  
Preoperative Body Mass Index ◽  
Total Knee

AbstractKnee range of motion (ROM) is an important postoperative measure of total knee arthroplasty (TKA). There is conflicting literature whether patients who are obese have worse absolute ROM outcomes than patients who are not obese. This study analyzed whether preoperative body mass index (BMI) influences knee ROM after patients' primary TKA. A retrospective investigation was performed on patients, who underwent primary TKA at an academic institution, by one of three fellowship-trained adult reconstruction surgeons. Patients were stratified according to their preoperative BMI into nonobese (BMI < 30.0 kg/m2) and obese (BMI ≥ 30.0 kg/m2) classifications. Passive ROM was assessed preoperatively as well as postoperatively at patients' most recent follow-up visit that was greater than 2 years. Mann–Whitney U tests were performed to determine statistical significance at p-value <0.05 for ROM outcomes. No statistically significant differences were observed when ROM in the nonobese group was compared with ROM in the obese group both preoperatively (105.73 ± 11.58 vs. 104.14 ± 13.58 degrees, p-value = 0.417) and postoperatively (105.83 ± 14.19 vs. 104.49 ± 13.52 degrees, p-value = 0.777). Mean follow-up time for all patients was 4.49 ± 1.92 years. In conclusion, long-term postoperative ROM outcomes were similar between patients who were nonobese and patients who were obese.

scholarly journals Primary intra-articular osteotomy for varus malunion of the medial condyle of the tibial plateau

2020 ◽  
Vol 6 (2) ◽  
pp. 360
Author(s):  
Jeremy Bliss ◽  
Dan Barnabas Inja ◽  
Manasseh Nithyananth ◽  
Vinoo Mathew Cherian
Keyword(s):  
Functional Outcome ◽  
Tibial Plateau ◽  
Statistical Significance ◽  
P Value ◽  
Medial Condyle ◽  
Medial Condyle Fracture ◽  
Excellent Functional Outcome ◽  
Male Patients ◽  
Condyle Fracture

<p class="abstract"><strong>Background:</strong> Reconstructive operative procedures for post-traumatic deformities of the tibial plateau have been described in literature, though rarely. We report short term follow-up of eleven such cases of primary intra-articular osteotomy.</p><p class="abstract"><strong>Methods:</strong> From 2005 through 2011, a primary intra-articular osteotomy for varus malunion of the medial condyle of the tibial plateau was performed in eleven consecutive cases. The patients were assessed clinically and radiologically at a minimum of 28 months post-operatively. The functional outcome was assessed using Rasmussen score.  Paired ‘t’ test was used to determine the statistical significance.<strong></strong></p><p class="abstract"><strong>Results:</strong> There were eleven male patients. Average follow up was 59 months (range 28 to 159). Articular congruity was restored to acceptable in all patients and varus malalignment was corrected from a mean of 1.5 degrees varus to 5.7 degrees of valgus (statistically significant, two-tailed P value of 0.0056) to an extent comparable to the normal side (mean 5.8 degrees). There were no infections. All patients had good to excellent functional outcome.</p><p class="abstract"><strong>Conclusions:</strong> A primary intra-articular osteotomy and osteosynthesis for malunited medial condyle fracture of the tibial plateau would help to restore mechanical alignment and improve functional outcome.</p>

scholarly journals Milk-free diet followed by breastfeeding women

2020 ◽  
pp. 181-189
Keyword(s):  
Fast Food ◽  
Statistical Significance ◽  
Rank Correlation ◽  
Food Products ◽  
Elimination Diet ◽  
P Value ◽  
Computer Assisted ◽  
Significance Level ◽  
Spearman’S Rank Correlation ◽  
Low Calcium Diet

Background. Breastfeeding is the most common way of feeding infants. Human milk contains nutrients which are necessary to provide proper growth of a child. Nowadays there aren't any recommendations to follow elimination diet in order to decrease the risk of allergy or baby colic. Only the occurrence of health problems such as lactose intolerance or cow's milk protein allergy in breastfeeding mother or infant should be a reason for eliminating dairy products from diet. It seems to be important to explore the reasons and the frequency of following milk-free diet by breastfeeding women. Objectives. The main purpose of the study was to find the reasons for following milk-free diet by breastfeeding women and making an assessment of their nutrition knowledge and food habits. Material and methods. Thirty-three breastfeeding women following milk-free diet took part in the project. The women were interviewed by the Computer Assisted Web Interview (CAWI) method with an original questionnaire. The results were developed with Spearman's rank correlation, Chi2 test and the gamma coefficient. The statistical significance level for the p-value was <0.05. Results. The main reason for following milk-free diet by the breastfeeding women was the occurrence of hypersensitivity reactions of the children's gastrointestinal system after consuming milk by mother (72% responses). After excluding milk from diet only 42% respondents declared consuming new food products or dietary supplements in order to refill the potential deficiency of nutrients. The majority of respondents also eliminated from diet highly processed food products, fast-food and the carbonated drinks. The most often declared source of information about lactation was Internet (85%). Only 12% respondents asked a nutritionist in order to get the information about breastfeeding. Conclusions. It's necessary to promote a specific nutritional advice about following milk-free diet in breastfeeding women group in order to decrease the health risk connected with low calcium diet.

scholarly journals Adherence patterns among patients receiving  healthcare services in the Muhimbili Sickle Cell Cohort, Tanzania

2020 ◽  
Author(s):  
Upendo Masamu ◽  
Raphael Zozimus Sangeda ◽  
Daniel Kandoga ◽  
Jesca Ondego ◽  
Florah Ndobho ◽  
...  
Keyword(s):  
Survival Analysis ◽  
Sickle Cell ◽  
Parametric Method ◽  
Healthcare Services ◽  
Rank Test ◽  
P Value ◽  
Mean Cell Volume ◽  
Loss To Follow Up ◽  
Lost To Follow Up

Abstract Background: Monitoring of patient’s clinical attendance is one of the crucial means that is used to improve adherence to care and treatment among the Sickle Cell Disease (SCD) patients. Adherence to care has been shown to improve health outcomes in SCD patients. However, these benefits cannot be achieved when patients are lost to follow-up to care. Method : We analyzed data on loss to follow up to determine the patterns among sickle cell patients registered at Muhimbili Sickle Cell Cohort (MSC), in Dar es Salaam, Tanzania. Data was aggregated and analysed using R software and Microsoft Excel Spreadsheet. Survival analysis techniques, both non-parametric methods (Kaplan-Meier estimator and Log-rank test) and semi-parametric method (Cox’s proportional hazard model), were used. A p-value of 0.05 was considered significant to make a strong inference of the analysis. Results: 5476 SCD patients were registered at MSC from 2004 to 2016, 3350 (58.13%) were actively participating in clinics while, 2126 (41.87%) were inactive, out of which 35.19% were lost to follow-up. From the survival analysis results, patients who were between 5 to 17 years were more likely to be lost to follow-up than the rest with a hazard ratio of 2.65 times more than those who were above 18 years. Patients with mean cell volume above 77.73 fL and white blood cell above 15.73(10ˆ3/uL) were more likely to be loss to follow-up than those below average. Conclusion: Loss to follow-up is evident in a cohort of patients in long term comprehensive care follow-up. It is, therefore, necessary to design interventions that minimize its impacts. Suggested solutions might include training of the health care workers, more emphasis on newborn screening and advocacy to patients regarding the effect of loss to follow-up.

Sign in / Sign up

Export Citation Format

Share Document