The challenges of determining noninferiority margins: a case study of noninferiority randomized controlled trials of novel oral anticoagulants.
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ABSTRACT:
SUBMITTER: Wangge G
PROVIDER: S-EPMC3576440 | biostudies-literature | 2013 Feb
REPOSITORIES: biostudies-literature
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The challenges of determining noninferiority margins: a case study of noninferiority randomized controlled trials of novel oral anticoagulants.
Wangge Grace G Roes Kit C B KC de Boer Anthonius A Hoes Arno W AW Knol Mirjam J MJ
CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 20120820 3
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Project description:BackgroundNoninferiority trials are increasingly common in cardiovascular medicine, but their reporting and interpretation are challenging, particularly when an absolute risk difference is used as noninferiority margin.ObjectivesThis study aimed to investigate the effect of using absolute rather than relative noninferiority margins in cardiovascular trials.MethodsWe reviewed noninferiority trials presented at major cardiovascular conferences from 2015 to 2022 and published within the same period. Based on the actual versus anticipated event rates in the control group, we recalculated the absolute noninferiority margin and re-assessed the trial results. The primary outcome of interest was the proportion of trials with a different interpretation after recalculation. Additionally, we analyzed the conclusion statements of these trials to determine if cautionary notes for the interpretation of study results were included.ResultsWe analyzed a total of 768 trials, of which 88 had a noninferiority design and 66 used an absolute noninferiority margin. Of 48 comparisons from 45 trials qualifying for the analysis, 11 (22.9%) had divergent results after recalculation of the absolute noninferiority margin based on the observed rather than anticipated event rate. Ten trials originally claiming noninferiority, did not meet it after the margin recalculation. All of them did not include statements suggesting cautionary interpretation of the study results in the conclusion section. Compared with the other trials, these displayed a larger median difference between anticipated and recalculated noninferiority margins (44.7% [IQR: 38.6%-56.7%] vs 15.3% [IQR: -1.5% to 28.9%]; P < 0.001).ConclusionsRecalculating noninferiority margins based on actual event rates, rather than anticipated ones, led to different outcomes in approximately 1 out of 4 cardiovascular trials, with most divergent trials lacking cautionary interpretation. These findings emphasize the importance of using or supplementing the relative noninferiority margin, particularly in studies with significant deviations between observed and expected event rates. This underscores the critical need for enhanced methodological and reporting standards in noninferiority trials, especially those employing absolute margins.
| S-EPMC11312784 | biostudies-literature
Project description:BackgroundAcute venous thromboembolism (VTE) in children presents unique challenges due to the limitations of standard anticoagulation therapies. Herein, we aimed to systematically review randomized controlled trials (RCTs) evaluating the efficacy and safety of direct oral anticoagulants (DOACs) in pediatric patients with acute VTE.MethodsPubMed and Embase databases were searched for RCTs comparing DOACs to standard anticoagulation in pediatric VTE patients. Efficacy outcomes included VTE recurrence and all-cause mortality, while safety outcomes comprised major bleeding and other adverse events.ResultsThree RCTs with 790 participants were included. When compared with standard anticoagulation, DOACs demonstrated a reduced risk of VTE recurrence (risk difference[RD] = -3%, 95% confidence interval[CI]: -6% to 0%, P = 0.04) and an increased risk of any adverse event (RD = 8%, 95% CI: 1% to 14%, P = 0.02). No significant differences were found in all-cause mortality, major bleeding, clinically relevant non-major bleeding, or total bleeding between the DOAC and control groups.ConclusionDOACs, primarily dabigatran and rivaroxaban, are non-inferior to standard anticoagulants in reducing VTE recurrence in pediatric patients, with comparable safety profiles. Further research is essential to confirm these findings.
| S-EPMC11307352 | biostudies-literature
Project description:Background: There is no direct comparison from clinical trials amongst the direct oral anticoagulants (DOACs) in patients with acute venous thromboembolism (VTE), leaving an evidence gap in decision-making regarding the choice of a DOAC. Methods: We performed a systematic review for an indirect comparison from randomized controlled trials (RCTs) for comparative effects amongst DOACs in the patients with acute VTE. Results: A total of 16 RCTs were included for analyses, among which three for dabigatran (n = 7,963 patients), six rivaroxaban (n = 17,935), five apixaban (n = 12,823), and two edoxaban (n = 9,286). There was no significant difference in risk of recurrent VTE (evidence quality: low) and major bleeding (evidence quality: very low) for treatment effects between the four DOACs. Albeit non-significantly, apixaban seemed to have a lowest risk of major bleeding while rivaroxaban had a smallest risk of VTE. Although in general all the included trials were comparable, data from the included trials indicated that the assumption of transitivity may be challenged. Further methodological research including simulation studies, using a net-benefit or benefit-harm approach, running ranking probability analysis, and developing decision aids with machine-learning may be a worthwhile endeavor to help with the choice of DOACs in patients with acute VTE. Conclusions: To conclude, based on results from the indirect comparison no significant difference in the efficacy and safety was found among the DOACs in patients with acute VTE. More evidence from direct comparative trials is needed to further inform the choice of DOACs in patients with acute VTE.
| S-EPMC7316891 | biostudies-literature
Project description:The remarkable global development of disease-modifying therapies (DMTs) specific for multiple sclerosis (MS) has significantly reduced the frequency of relapse, slowed the progression of disability, and improved the quality of life in patients with MS. With increasing numbers of approved DMTs, neurologists in North America and Europe are able to present multiple treatment options to their patients to achieve a better therapeutic outcome, and in many cases, no evidence of disease activity. MS patients have improved accessibility to various DMTs at no or minimal out-of-pocket cost. The ethical guidelines defined by the Edinburgh revision of the Declaration of Helsinki strongly discourage the use of placebo control groups in modern MS clinical trials. The use of an active comparator control group increases the number of participants in each group that is essential to achieve statistical significance, thus further increasing the difficulty of completing randomized controlled trials (RCTs) for the development of new MS therapies. There is evidence of a high prevalence of MS and a large number of patients in Asia. The belief of the existence of Asian types of MS that are distinct from Western types, and regulatory policies are among the reasons why DMTs are limited in most Asian countries. Lack of access to approved DMTs provides a good opportunity for clinical trials that are designed for the development of new MS therapies. Recently, data from RCTs have demonstrated excellent recruitment of participants and the completion of multi-nation and single-nation MS trials within this region. Recent studies using the McDonald MS diagnostic criteria carefully excluded patients with neuromyelitis optica (NMO) and NMO spectrum disorder, and demonstrated that patients with MS in Asia have clinical characteristics and treatment responses similar to those in Western countries.
| S-EPMC5563727 | biostudies-other
Project description:Randomized controlled trials (RCTs) are subject to bias if they lack methodological quality. Furthermore, optimal and transparent reporting of RCT findings aids their critical appraisal and interpretation. This study aimed to comprehensively evaluate the report quality of RCTs of non-vitamin K oral anticoagulants (NOACs) for the treatment of atrial fibrillation (AF) and to analyze the factors influencing the quality. By searching PubMed, Embase, Web of Science, and Cochrane Library databases RCTs published from inception to 2022 evaluating the efficacy of NOACs on AF were collected. By using the 2010 Consolidated Standards for Reporting Tests (CONSORT) statement, the overall quality of each report was assessed. Sixty-two RCTs were retrieved in this study. The median of overall quality score in 2010 was 14 (range: 8.5-20). The extent of compliance with the Consolidated Standards of Reporting Trials reporting guideline differed substantially across items: 9 items were reported adequately (more than 90%), and 3 were reported adequately in less than 10% of trials. Multivariate linear regression analysis showed that the higher reporting scores were associated with higher journal impact factor (P = 0.01), international collaboration (P < 0.01), and Sources of trial funding (P = 0.02). Although a large number of randomized controlled trials of NOACs for the treatment of AF were published after the CONSORT statement in 2010, the overall quality is still not satisfactory, thus weakening their potential utility and may mislead clinical decisions. This survey provides the first hint for researchers conducting trials of NOACs for AF to improve the quality of reports and to actively apply the CONSORT statement.
| S-EPMC10155658 | biostudies-literature
Project description:BackgroundEmulating randomized controlled trials (RCTs) by real-world evidence (RWE) studies would benefit future clinical and regulatory decision-making by balancing the limitations of RCT. We aimed to evaluate whether the findings from RWE studies can support regulatory decisions derived from RCTs of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with venous thromboembolism (VTE).MethodsFive landmark trials (AMPLIFY, RE-COVER II, Hokusai-VTE, EINSTEIN-DVT, and EINSTEIN-PE) of NOACs were emulated using the South Korean nationwide claims database (January 2012 to August 2020). We applied an active comparator and new-user design to include patients who initiated oral anticoagulants within 28 days from their VTE diagnoses. The prespecified eligibility criteria, exposure (each NOAC, such as apixaban, rivaroxaban, dabigatran, and edoxaban), comparator (conventional therapy, defined as subcutaneous heparin followed by warfarin), and the definition of outcomes from RCTs were emulated as closely as possible in each separate emulation cohort. The primary outcome was identical to each trial, which was defined as recurrent VTE or VTE-related death. The safety outcome was major bleeding. Propensity score matching was conducted to balance 69 covariates between the exposure groups. Effect estimates for outcomes were estimated using the Mantel-Haenszel method and Cox proportional hazards model and subsequently compared with the corresponding RCT estimates.ResultsCompared to trial populations, real-world study populations were older (range: 63-69 years [RWE] vs. 54-59 years [RCT]), with more females (55-60.5% vs. 39-48.3%) and had a higher prevalence of active cancer (4.2-15.4% vs. 2.5-9.5%). The emulated estimates for effectiveness outcomes showed superior effectiveness of NOAC (AMPLIFY: relative risk 0.81, 95% confidence interval 0.70-0.94; RE-COVER II: hazard ratio [HR] 0.60, 0.37-0.96; Hokusai-VTE: 0.49, 0.31-0.78; EINSTEIN-DVT: 0.54, 0.33-0.89; EINSTEIN-PE: 0.50, 0.34-0.74), when contrasted with trials that showed non-inferiority. For safety outcomes, all emulations except for AMPLIFY and EINSTEIN-DVT yielded results consistent with their corresponding RCTs.ConclusionsThis study revealed the feasibility of complementing RCTs with RWE studies by using claims data in patients with VTE. Future studies to consider the different demographic characteristics between RCT and RWE populations are needed.
| S-EPMC10542685 | biostudies-literature
Project description:BackgroundThe aim of the study was to compare clinical characteristics of real-life atrial fibrillation (AF) patients with populations included in randomized clinical trials (ROCKET AF and RE-LY).MethodsThe analysis included 3528 patients who are participants of the ongoing, multicentre, retrospective CRAFT study. The study is registered in ClinicalTrials.gov: NCT02987062. The study is based on a retrospective analysis of hospital records of AF patients treated with vitamin K antagonists (VKAs) (acenocoumarol, warfarin) and non-vitamin K oral anticoagulants (NOACs) (dabigatran, rivaroxaban). CHADS2 score was used for risk of stroke stratification.ResultsVKA was prescribed in 1973 (56.0%), while NOAC in 1549 (44.0%), including dabigatran - 504 (14.3%) and rivaroxaban - 1051 (29.8%), of the 3528 patients. VKA patients in the CRAFT study were at significantly lower risk of stroke (CHADS2 1.9 ± 1.3), compared with the VKA population from the RE-LY (2.1 ± 1.1) and the ROCKET-AF (3.5 ± 1.0). Patients in the CRAFT study treated with NOAC (CHADS2 for patients on dabigatran 150 mg - 1.3 ± 1.2 and on rivaroxaban - 2.2 ± 1.4) had lower risk than patients from the RE-LY (2.2 ± 1.2) and the ROCKET AF (3.5 ± 0.9).ConclusionsReal-world patients had a lower risk of stroke than patients included in the RE-LY and ROCKET AF trials.
| S-EPMC8078963 | biostudies-literature
Project description:BackgroundDirect oral anticoagulants (DOACs) have been widely applied in adults for thrombosis prophylaxis. However, the effect of DOACs in pediatric patients with congenital or acquired heart diseases who need anticoagulation therapy remains unclear.MethodsWe systematically searched the databases of PubMed, Embase, and the Cochrane Library, as well as the ClinicalTrials.gov registry and the World Health Organization's International Clinical Trials Registry Platform until June 2024 to identify relevant randomized clinical trials (RCTs). If the number of included studies was less than 5, we performed a narrative review to assess the effect of DOACs in pediatric patients.ResultsFour studies were included. In the UNIVERSE study, thrombotic events occurred in 2% of the rivaroxaban group and 9% of the aspirin group, with bleeding events in 36% and 41%, respectively. The ENNOBLE-ATE study showed no thromboembolic events in the edoxaban group and 1.7% in the SOC group (rate difference: -0.07%, 95% CI: -0.22 to 0.07%). Major bleeding rates were similar (rate difference: -0.03%, 95% CI: -0.18 to 0.12%). The SAXOPHONE trial showed no thromboembolic events in either group and similar major bleeding rates (-0.8%, 95% CI: -8.1 to 3.3%). In the DIVERSITY trial, 81% of dabigatran patients achieved the primary outcome versus 59.3% in the SOC group (Odds ratio: 0.342, 95% CI: 0.081-1.229). No major bleeding occurred in either group.ConclusionExisting studies suggest that the use of DOACs hold promise as an effective and safe alternative for preventing and treating thromboembolism in pediatric patients with heart conditions.
| S-EPMC11301724 | biostudies-literature
Project description:ObjectiveOur objective was to evaluate the impact of early oral feeding (EOF) on postoperative cardiac, respiratory, and gastrointestinal (CRG) complications after McKeown minimally invasive esophagectomy for esophageal cancer.Summary background dataNil-by-mouth with enteral tube feeding is routinely practiced after esophagectomy.MethodsPatients were randomly allocated to receive oral feeding on the first postoperative day (EOF group) or late oral feeding (LOF group) 7 days after surgery. The primary endpoint was the occurrence of postoperative CRG complications, and the secondary outcomes included bowel function recovery and short-term quality of life (QOL).ResultsBetween February 2014 and October 2015, 280 patients were enrolled in this study. There were 140 patients in the EOF group and 140 patients in the LOF group. EOF was noninferior to LOF for CRG complications (30.0% in the EOF group vs. 32.9% in the LOF group; 95% confidence interval of the difference: -13.8% to 8.0%). Compared with the LOF group, the EOF group showed significantly shorter time to first flatus (median of 2 days vs. 3 days, P = 0.001) and bowel movement (median of 3 vs. 4 days, P < 0.001). Two weeks after the operation, patients in the EOF group reported higher global QOL and function scores and lower symptom scores than patients in the LOF group.ConclusionsIn patients after McKeown minimally invasive esophagectomy is noninferior to the standard of care with regard to postoperative CRG complications. In addition, patients in the EOF group had a quicker recovery of bowel function and improved short-term QOL.
| S-EPMC5937132 | biostudies-literature
Project description:Warfarin is a traditional oral anticoagulant for preventing thrombotic events in patients with atrial fibrillation (AF) and venous thromboembolism. Along with the widespread clinical use, the potential association between warfarin use and fracture risk have been addressed gradually. Non-vitamin K antagonist oral anticoagulants (NOACs), targeting thrombin or Xa factor, have been recommended as an optimal alternative due to their favorable property of thromboembolism prophylaxis and reduced bleeding risk. However, evidence of the fracture risk with NOACs use is limited. Therefore, the present study investigated this issue by a meta-analysis. Medline, Embase, Cochrane Library and the ClinicalTrials.gov Website were searched for randomized controlled trials (RCTs) that reported the fracture data of NOACs and warfarin. The primacy outcome was a composite of any fracture. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random- or fixed-effects models according to between-study heterogeneity. Heterogeneity was assessed through I2 test and Q statistic, and the number of patients needed to treat (NNT) was calculated based on fracture incidence. Subgroup analyses were conducted according to individual NOACs, indications, and duration of follow up. Finally, 12 RCTs involving 89,549 patients were included, among which 44,816 (50%) receiving NOACs and 44,733 (50%) receiving warfarin. Overall, 1,139 (1.3%) patients including 515 NOACs users (1.1%) and 624 warfarin users (1.4%) developed fracture. Risk of fracture was significantly lower in NOACs compared to warfarin (RR: 0.82, 95%CI: 0.73-0.93, P = 0.001), with a NNT of 333. No significantly decreased risk was detected according to fracture sites. Subgroup analysis confirmed that the estimate of decreased fracture risk was derived mainly from AF patients receiving long-term anticoagulation treatment. The meta-regression did not detect any potential confounding on fracture risk. No heterogeneity between the studies (I2 = 15.0%) and no publication bias was identified. In conclusion, the use of NOACs was associated with a lower risk of fracture compared to warfarin, but with a relatively low absolute risk reduction. Therefore, screening for the fracture risk should be considered before initiating anticoagulation treatment. For patients who are at high risk of fracture or expected long-term treatment of anticoagulation, NOACs may represent a preferable alternative to warfarin.
| S-EPMC5903161 | biostudies-literature