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Annual Bleeding Rates: Pitfalls of Clinical Trial Outcomes in Hemophilia Patients.

ABSTRACT: Emerging treatment options for hemophilia, including gene therapy, modified factor products, antibody-based products, and other nonreplacement therapies, are in development or on their way to marketing authorization. For proof of efficacy, annual bleeding rates (ABRs) have become an increasingly important endpoint in hemophilia trials. We hypothesized that ABR analyses differ substantially between and within medicinal product classes and that the ABR observation period constitutes a major bias. For ABR characterization, an internal factor VIII (FVIII) treatment database has been built based on confidential clinical trial data submitted to the Paul-Ehrlich-Institut (PEI). Furthermore, anonymized data from 46 trial protocols submitted for review to the PEI were analyzed (FVIII replacement, n = 27; antibody-based, n = 12; and gene therapy, n = 7) for methodology. Definitions of bleeding episodes and ABR observational periods differed substantially in clinical trials. In the initial observation phase, individual ABRs of patients, treated prophylactically for 1 year, vary by about 40% (P < 0.001), which finally led to a significant reduction of the ABR group mean by 20% (P < 0.05). Furthermore, the high variance in ABRs constitutes a major challenge in statistical analyses. In conclusion, considerable heterogeneity and bias in the ABR estimation in clinical trials was identified, which makes it substantially more difficult to compare the efficacy of different treatment regimens and products. Thus, awareness of the important pitfalls when using ABR as a clinical outcome is needed in the evaluation of hemophilia therapies for patients, physicians, regulators, and health technology assessment agencies.

SUBMITTER: Keipert C

PROVIDER: S-EPMC7719362 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Annual Bleeding Rates: Pitfalls of Clinical Trial Outcomes in Hemophilia Patients.

Keipert Christine C Müller-Olling Mirco M Gauly Franca F Arras-Reiter Cornelia C Hilger Anneliese A

Clinical and translational science 20200530 6

Emerging treatment options for hemophilia, including gene therapy, modified factor products, antibody-based products, and other nonreplacement therapies, are in development or on their way to marketing authorization. For proof of efficacy, annual bleeding rates (ABRs) have become an increasingly important endpoint in hemophilia trials. We hypothesized that ABR analyses differ substantially between and within medicinal product classes and that the ABR observation period constitutes a major bias. ...[more]

PMID: 32472976

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Project description:Background and aimsOver 404 million people worldwide have been infected with coronavirus disease-2019 (COVID-19), 145 million in the United States (77 million) and Europe (151 million) alone (as of February 10, 2022). This paper aims to analyze data from studies reporting gastrointestinal bleeding (GIB) and/or endoscopic findings in COVID-19 patients in Western countries.MethodsWe conducted a systematic review of articles on confirmed COVID-19 cases with GIB in Western countries published in PubMed and Google Scholar databases from June 20, 2020, to July 10, 2021.ResultsA total of 12 studies reporting GIB and/or endoscopic findings in 808 COVID-19 patients in Western countries were collected and analyzed. Outcomes and comorbidities were compared with 18,179 non-GIB COVID-19 patients from Italy and the United States. As per our study findings, the overall incidence of GIB in COVID-19 patients was found to be 0.06%. When compared to the non-GIB cohort, the death rate was significantly high in COVID-19 patients with GIB (16.4% vs 25.4%, P < .001, respectively). Endoscopic treatment was rarely necessary, and blood transfusion was the most common GIB treatment. The most common presentation in GIB patients is melena (n = 117, 47.5%). Peptic, esophageal, and rectal ulcers were the most common endoscopic findings in upper (48.4%) and lower (36.4%) endoscopies. The GIB cohort had worse outcomes and higher incidence of hypertension (61.1%), liver disease (11.2%), and cancer (13.6%) than the non-GIB cohort. Death was strongly associated with hypertension (P < .001, r = 0.814), hematochezia (P < .001, r = 0.646), and esophagogastroduodenoscopy (P < .001, r = 0.591) in COVID-19 patients with GIB.ConclusionsOverall, the incidence of GIB in COVID-19 patients is similar to that estimated in the overall population, with melena being the most common presentation. The common endoscopic findings in GIB COVID-19 patients were ulcers, esophagitis, gastritis, and colitis. Patients with GIB were more prone to death than non-GIB COVID-19 patients.

Project description:BackgroundBleeding is the most dreaded complication of anticoagulant therapy for acute venous thromboembolism (VTE). Limited data exist about patient characteristics, time course and outcomes of major bleeding, according to the bleeding site.MethodsWe used the data from the Registro Informatizado Enfermedad TromboEmbólica (RIETE) registry (03/2001-07/2018) and identified patients who suffered from major bleeding during anticoagulation. We assessed patient characteristics, time course, and 30-day outcomes including mortality, re-bleeding, and VTE recurrences, according to bleeding site.ResultsAmong 78,136 patients with VTE receiving anticoagulation, 2244 (2.9%) suffered from major bleeding (gastrointestinal in 800, intracranial in 417, hematoma in 410, genitourinary in 222, retroperitoneal in 145; other sites in 250). There were variations in baseline characteristics, including older age (P < 0.001) and predominance of women (70.2% [95% confidence interval [CI]]: 65.6-74.6% versus 50.5%, 95% CI: 48.2-52.9, P < 0.001) in patients with hematoma, compared with other patients. Overall, 82.7% of hematomas and 81.4% of retroperitoneal bleeds occurred in the first 90 days after the diagnosis of the VTE event, compared with only 50.6% of intracranial bleeds. Across the bleeding subgroups, 30-day all-cause mortality rates were highest in patients who suffered from intracranial bleeding (41.0%; 99% confidence interval [CI]: 34.8-47.4%), and lowest in patients who suffered from hematoma (17.8%; 99% CI: 13.2-23.2%). Patients who suffered from a major bleeding event in the first 30 days after VTE had significantly higher odds at 90-day follow-up to develop mortality (including from bleeding), recurrent VTE, and recurrent major bleeding (all Ps < 0.001). Variations were observed in the results according to the bleeding site.ConclusionsMajor bleeding is a serious complication in VTE patients. Patient characteristics, time course and outcomes varied substantially according to the bleeding site. Additional studies are needed to tease out the impact of patient risk factors, treatment regimens, and a potential distinct effect from the site of bleeding.Trial registrationhttps://clinicaltrials.gov/ct2/show/NCT02832245 (RIETE registry).

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Annual Bleeding Rates: Pitfalls of Clinical Trial Outcomes in Hemophilia Patients.

Publications

Annual Bleeding Rates: Pitfalls of Clinical Trial Outcomes in Hemophilia Patients.

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