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Lung Feb 2020Until recently, many clinical trials in patients with pulmonary arterial hypertension (PAH) evaluated exercise capacity with 6-minute walk distance (6MWD) as the primary... (Review)
Review
BACKGROUND
Until recently, many clinical trials in patients with pulmonary arterial hypertension (PAH) evaluated exercise capacity with 6-minute walk distance (6MWD) as the primary endpoint. Common secondary endpoints include PAH functional class (FC), which assesses symptoms, and either brain natriuretic peptide (BNP) or the inactive N-terminal cleavage product of its prohormone (NT-proBNP), which assesses cardiac function.
OBJECTIVE
Examine the relationships among 6MWD, FC, and BNP/NT-proBNP measured at baseline or follow-up with long-term outcomes in PAH studies.
METHODS
Relevant literature from January 1990 to April 2018 were obtained by searching PubMed, Embase, and Cochrane. Articles in English reporting on associations between 6MWD, FC, or BNP/NT-proBNP and outcomes in PAH were identified. Each endpoint was evaluated individually. Prespecified inclusion and exclusion criteria were applied at level 1 (titles/abstracts) and level 2 (full-text review).
RESULTS
The database search yielded 836 unique records; 65 full-text articles were reviewed. Twenty-five studies were eligible for inclusion. Findings supported the importance of measuring PAH noninvasive endpoints in predicting long-term outcomes. Patients with shorter or decreased 6MWD, poor (III/IV) or declining FC (e.g., from II to III), or elevated or increasing BNP/NT-proBNP had a higher risk of death and costly events (e.g., hospitalization, lung transplant). FC also predicted health care resource utilization and costs. Collectively, these endpoints establish risk groups that predict likelihood of complications from PAH or death.
CONCLUSION
Assessment of 6MWD, FC, and BNP/NT-proBNP provides low-cost, efficient, and noninvasive means of predicting long-term health and economic outcomes in patients with PAH.
Topics: Biomarkers; Disease Progression; Functional Status; Hospitalization; Humans; Lung Transplantation; Mortality; Natriuretic Peptide, Brain; Outcome Assessment, Health Care; Peptide Fragments; Prognosis; Pulmonary Arterial Hypertension; Severity of Illness Index; Walk Test
PubMed: 31722043
DOI: 10.1007/s00408-019-00289-2 -
Transplant International : Official... 2022Clinical study endpoints that assess the efficacy of interventions in patients with chronic renal insufficiency can be adopted for use in kidney transplantation trials,...
Clinical study endpoints that assess the efficacy of interventions in patients with chronic renal insufficiency can be adopted for use in kidney transplantation trials, given the pathophysiological similarities between both conditions. Kidney dysfunction is reflected in the glomerular filtration rate (GFR), and although a predefined (e.g., 50%) reduction in GFR was recommended as an endpoint by the European Medicines Agency (EMA) in 2016, many other endpoints are also included in clinical trials. End-stage renal disease is strongly associated with a change in estimated (e)GFR, and eGFR trajectories or slopes are increasingly used as endpoints in clinical intervention trials in chronic kidney disease (CKD). Similar approaches could be considered for clinical trials in kidney transplantation, although several factors should be taken into account. The present Consensus Report was developed from documentation produced by the European Society for Organ Transplantation (ESOT) as part of a Broad Scientific Advice request that ESOT submitted to the EMA in 2020. This paper provides a contemporary discussion of primary endpoints used in clinical trials involving CKD, including proteinuria and albuminuria, and evaluates the validity of these concepts as endpoints for clinical trials in kidney transplantation.
Topics: Albuminuria; Allografts; Disease Progression; Glomerular Filtration Rate; Humans; Kidney Transplantation; Renal Insufficiency, Chronic
PubMed: 35669976
DOI: 10.3389/ti.2022.10139 -
Annals of Oncology : Official Journal... Apr 2017The consensus statements regarding first-line therapies in women with ovarian cancer, reached at the Fifth Ovarian Cancer Consensus Conference held in Tokyo, Japan, in...
The consensus statements regarding first-line therapies in women with ovarian cancer, reached at the Fifth Ovarian Cancer Consensus Conference held in Tokyo, Japan, in November 2015 are reported. Three topics were reviewed and the following statements are recommended: (i) Surgery: the subgroups that should be considered in first-line ovarian cancer clinical trials should be (a) patients undergoing primary debulking surgery and (b) patients receiving neo-adjuvant chemotherapy. The amount of residual disease following surgery should further stratify patients into those with absent gross residual disease and others. (ii) Control arms for chemotherapy: for advanced stage ovarian cancer the standard is intravenous 3-weekly carboplatin and paclitaxel. Acceptable alternatives, which should be stratified variables in trials when more than one regimen is offered, include weekly paclitaxel plus 3-weekly carboplatin, the addition of bevacizumab to 3-weekly carboplatin and paclitaxel, and intraperitoneal therapy. (iii) Trial Endpoints: overall survival is the preferred primary endpoint for first-line clinical trials with or without a maintenance component. Progression-free survival (PFS) is an alternative primary endpoint, but if PFS is chosen overall survival must be measured as a secondary endpoint and PFS must be supported by additional endpoints, including predefined patient reported outcomes and time to first or second subsequent therapy. For neoadjuvant therapy, additional 'window of opportunity' endpoints should be included.
Topics: Carcinoma, Ovarian Epithelial; Female; Humans; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Research Design
PubMed: 28327917
DOI: 10.1093/annonc/mdx011 -
Clinical Cancer Research : An Official... May 2013Progression-free survival (PFS) is increasingly used as an important and even a primary endpoint in randomized cancer clinical trials in the evaluation of patients with... (Review)
Review
Progression-free survival (PFS) is increasingly used as an important and even a primary endpoint in randomized cancer clinical trials in the evaluation of patients with solid tumors for both practical and clinical considerations. Although in its simplest form, PFS is the time from randomization to a predefined endpoint, there are many factors that can influence the exact moment of when disease progression is recorded. In this overview, we review the circumstances that can devalue the use of PFS as a primary endpoint and attempt to provide a pathway for a future desired state when PFS will become not just a secondary alternative to overall survival but rather an endpoint of choice.
Topics: Disease Progression; Disease-Free Survival; Endpoint Determination; Humans; Neoplasms; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic
PubMed: 23669420
DOI: 10.1158/1078-0432.CCR-12-2934 -
ESC Heart Failure Aug 2023We sought to investigate the relationship between circulating tissue plasminogen activator (t-PA) level and long-term outcomes in stable coronary artery disease patients...
AIMS
We sought to investigate the relationship between circulating tissue plasminogen activator (t-PA) level and long-term outcomes in stable coronary artery disease patients with or without aortic valve sclerosis (AVSc).
METHODS AND RESULTS
Serum levels of t-PA were determined in 347 consecutive stable angina patients with (n = 183) or without (n = 164) AVSc. Outcomes were prospectively recorded as planned clinic evaluations every 6 months up to 7 years. The primary endpoint was a composite of cardiovascular death and rehospitalization due to heart failure. The secondary endpoint included all-cause mortality, cardiovascular death, and rehospitalization due to heart failure. Serum t-PA was significantly higher in AVSc than in non-AVSc patients (2131.22 pg/mL vs. 1495.85 pg/mL, P < 0.001). For patients with AVSc, those with t-PA level above the median (>1840.68 pg/mL) were more likely to meet the primary and secondary endpoints (all P < 0.001). After adjusting for potential confounding factors, serum t-PA level remained significantly predictive for each endpoint in the Cox proportional hazard models. The prognostic value of t-PA was good, with an AUC-ROC of 0.753 (P < 0.001). The combination of t-PA with traditional risk factors improved the risk reclassification of AVSc patients, with a net reclassification index of 0.857 and an integrated discrimination improvement of 0.217 (all P < 0.001). However, for patients without AVSc, both primary and secondary endpoints were similar, irrespective of t-PA levels.
CONCLUSIONS
Elevated circulating t-PA confers an increased risk for poor long-term clinical outcomes in stable coronary artery disease patients with AVSc.
Topics: Humans; Coronary Artery Disease; Tissue Plasminogen Activator; Prognosis; Aortic Valve; Sclerosis; Heart Failure
PubMed: 37308095
DOI: 10.1002/ehf2.14420 -
Frontiers in Endocrinology 2022The ongoing COVID-19 pandemic calls for extensive research on various medical topics. Since the beginning of the pandemic, multiple studies investigated the impact of...
The ongoing COVID-19 pandemic calls for extensive research on various medical topics. Since the beginning of the pandemic, multiple studies investigated the impact of SARS CoV-2 on thyroid function. However, crucial data, such as trend progression over time or influence of commonly used drugs, might still be missing. We checked the thyroid function in 174 patients with PCR-confirmed COVID-19. Our research covered three separate time points of hospitalization (days 1, 4, and 10). We did not exclude patients treated with glucocorticoids but, instead, compared them with patients not treated with steroids. We correlated the results of thyroid function tests with markers of systemic inflammation. We checked if abnormal thyroid function can predict unfavorable outcomes defined as combined primary endpoint and/or secondary endpoints; the combined primary endpoint was the occurrence of death, mechanical ventilation, non-invasive ventilation, vasopressor infusion, or prolonged hospital stay, and the secondary endpoint was any of the listed events. In general, 80.46% of evaluated patients displayed abnormalities in thyroid function tests over at least one time point throughout the observation. We noticed a high prevalence of features typical for thyroid dysfunction in non-thyroidal illness (NTI). Free triiodothyronine (fT3) concentration was significantly lower in the group requiring glucocorticoids. Patients displaying abnormal thyroid function were statistically more likely to meet the predefined combined primary endpoint. We found that fT3 measured at admission could be perceived as an independent predictor of endpoint completion for all analyzed groups. Thyroid involvement is common in COVID-19. Our study supports the idea of thyroid function abnormalities being important clinical tools and allowing early recognition of possible detrimental outcomes of the disease.
Topics: COVID-19; Glucocorticoids; Humans; Pandemics; Thyroid Diseases; Thyroid Dysgenesis; Thyroid Function Tests; COVID-19 Drug Treatment
PubMed: 35966079
DOI: 10.3389/fendo.2022.939842 -
The Journal of Antimicrobial... Dec 1995In 1994, an international group of interested clinicians and biostatisticians met to discuss the design of clinical trials in herpes zoster. They agreed that trials in... (Review)
Review
In 1994, an international group of interested clinicians and biostatisticians met to discuss the design of clinical trials in herpes zoster. They agreed that trials in herpes zoster should have prospectively agreed definitions of all outcome measures and plans for data analysis. In immunocompetent individuals, in whom pain is the major outcome measure, trials should only include patients over the age of 50 years, and for those recruited within 72 h of rash onset, should be designed to demonstrate superiority of any new therapy over existing antivirals. The primary endpoint should be time to cessation of pain for at least 4 weeks and, for the purposes of statistical analysis of its duration, the pain associated with herpes zoster ought to be considered as a continuum. All other variables, including the incidence of post-herpetic neuralgia and effects upon quality of life should be considered as secondary end-points. Evaluation of treatment effects on primary endpoints should be based upon an intent-to-treat (ITT) analysis and subgroup analysis should be used only to support the findings of the ITT analysis. These elements of good study design should be borne in mind in the evaluation of current and future trails of antiviral drugs in herpes zoster.
Topics: Clinical Trials as Topic; Herpes Zoster; Humans; Research Design; Treatment Outcome
PubMed: 8821612
DOI: 10.1093/jac/36.6.1089 -
Allergo Journal International 2018Allergen immunotherapy has proven to be efficacious in allergic rhinitis and asthma. However, results from randomised clinical trials may vary substantially. Clinical... (Review)
Review
BACKGROUND
Allergen immunotherapy has proven to be efficacious in allergic rhinitis and asthma. However, results from randomised clinical trials may vary substantially. Clinical trials may unexpectedly fail. The purpose of this review is to discuss the possible factors that may contribute to a successful or unsuccessful study.
METHODS
Descriptive review exploring the possible causes of negative outcomes in allergen immunotherapy trials.
RESULTS
A series of factors may lead to negative results. Among of these are underpowering of the study, low allergen content in tested extracts, insufficient allergen exposure during monitoring and recruitment of inappropriate patients. In addition, the choice of the primary endpoint may be critical.
DISCUSSION
A clinical trial aims to evaluate the efficacy of an agent. However, studies with potential effective compounds may fail because of methodical issues. Sometimes, they are the cause of discrepancies between successful phase II and unsuccessful phase III trials. To understand more about failure of studies, investigators and editors should be encouraged to publish negative trials.
PubMed: 30221124
DOI: 10.1007/s40629-018-0058-y -
EClinicalMedicine Apr 2023Moderate-intensity statin role with ezetimibe combination therapy following percutaneous coronary intervention (PCI) has not been thoroughly investigated, particularly...
Efficacy and safety of moderate-intensity statin with ezetimibe combination therapy in patients after percutaneous coronary intervention: a post-hoc analysis of the RACING trial.
BACKGROUND
Moderate-intensity statin role with ezetimibe combination therapy following percutaneous coronary intervention (PCI) has not been thoroughly investigated, particularly compared to high-intensity statin monotherapy. We aimed to investigate the effect of ezetimibe combination with moderate-intensity statin in patients with atherosclerotic cardiovascular disease following PCI.
METHODS
This was a post-hoc analysis of a subset of patients who underwent PCI in the RACING trial. At 26 centres in South Korea, patients with atherosclerotic cardiovascular disease (ASCVD) were randomly assigned to receive either moderate-intensity statin with ezetimibe combination therapy (rosuvastatin 10 mg with ezetimibe 10 mg) or high-intensity statin monotherapy (rosuvastatin 20 mg). The prespecified endpoints of the RACING trial were used. The primary endpoint was the 3-year composite of cardiovascular death, major cardiovascular events, and nonfatal stroke. Event rates between the two groups were compared using log-rank tests, and hazard ratios (HR) with 95% confidence intervals (CI) were estimated using Cox regression analysis. Consistent with the RACING trial, the primary and secondary efficacy endpoints were evaluated using an intention-to-treatment approach, and the safety endpoints were assessed in the safety population. The RACING trial was registered at ClinicalTrials.gov (NCT03044665).
FINDINGS
Between Feb 14, 2017, and Dec 18, 2018, 3780 participants were enrolled in the RACING trial. Prior history of PCI was found in 2497 patients (67%, median 64 years, 79% male), and was associated with higher rates of the primary endpoint (hazard ratio [HR], 1.34; 95% confidence interval [CI], 1.06-1.69; p = 0.014). Among patients with prior PCI, moderate-intensity statin therapy with ezetimibe combination versus high-intensity statin therapy did not increase the risk of the primary endpoint (HR, 0.95; 95% CI, 0.74-1.24; p = 0.781). The proportion of patients with low-density lipoprotein cholesterol (LDL-C) <70 mg/dL at 1, 2, and 3 years was 74%, 76%, and 73%, respectively, in the combination therapy group, and was significantly higher than that in the high-intensity statin monotherapy group (57%, 62%, and 59%, respectively, all p < 0.001). Discontinuation of lipid-lowering drugs occurred less frequently in the combination group (4.2% vs. 7.6%, p = 0.001).
INTERPRETATION
The effects of ezetimibe combination therapy observed in the RACING trial were consistently preserved among patients with ASCVD following PCI. Ezetimibe combination could be considered as a suitable therapeutic strategy to achieve strict control of LDL-C and reduce drug intolerance in patients who underwent PCI.
FUNDING
Hanmi Pharmaceutical, Seoul, South Korea.
PubMed: 37090440
DOI: 10.1016/j.eclinm.2023.101933 -
Insights Into Imaging Aug 2023Entropy is a new late gadolinium enhanced (LGE) cardiac magnetic resonance (CMR)-derived parameter that is independent of signal intensity thresholds. Entropy can be...
Late gadolinium enhancement entropy as a new measure of myocardial tissue heterogeneity for prediction of adverse cardiac events in patients with hypertrophic cardiomyopathy.
OBJECTIVES
Entropy is a new late gadolinium enhanced (LGE) cardiac magnetic resonance (CMR)-derived parameter that is independent of signal intensity thresholds. Entropy can be used to measure myocardial tissue heterogeneity by comparing full pixel points of tissue images. This study investigated the incremental prognostic value of left ventricular (LV) entropy in patients with hypertrophic cardiomyopathy (HCM).
METHODS
This study enrolled 337 participants with HCM who underwent 3.0-T CMR. The LV entropy was obtained by calculating the probability distribution of the LV myocardial pixel signal intensities of the LGE sequence. Patients who underwent CMR imaging were followed up for endpoints. The primary endpoint was defined as readmission to the hospital owing to heart failure. The secondary endpoint was the composite of the primary endpoint, sudden cardiac death and non-cardiovascular death.
RESULTS
During the median follow-up of 24 months ± 13 (standard deviation), 43 patients who reached the primary and secondary endpoints had a higher entropy (6.20 ± 0.45, p < 0.001). The patients with increased entropy (≥ 5.587) had a higher risk of the primary and secondary endpoints, compared with HCM patients with low entropy (p < 0.001 for both). In addition, Cox analysis showed that LV entropy provided significant prognostic value for predicting both primary and secondary endpoints (HR: 1.291 and 1.273, all p < 0.001). Addition of LV entropy to the multivariable model improved model performance and risk reclassification (p < 0.05).
CONCLUSION
LV entropy assessed by CMR was an independent predictor of primary and secondary endpoints. LV entropy assessment contributes to improved risk stratification in patients with HCM.
CRITICAL RELEVANCE STATEMENT
Myocardial heterogeneity reflected by entropy the derived parameter of LGE has prognostic value for adverse events in HCM. The measurement of LV entropy helped to identify patients with HCM who were at risk for heart failure and sudden cardiac death.
KEY POINTS
• Left ventricular entropy can reflect myocardial heterogeneity in HCM patients. • Left ventricular entropy was significantly higher in HCM patients who reached endpoint events. • Left ventricular entropy helps to predict the occurrence of heart failure and death in HCM patients.
PubMed: 37603140
DOI: 10.1186/s13244-023-01479-6