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Clinical Epidemiology 2024In response to the COVID-19 pandemic, the World Health Organization (WHO) developed a set of outcome measures for trials primarily aimed at hospitalised patients.... (Review)
Review
PURPOSE
In response to the COVID-19 pandemic, the World Health Organization (WHO) developed a set of outcome measures for trials primarily aimed at hospitalised patients. However, a gap exists in defining outcome standards for non-hospitalised patients. Therefore, this study aims to discuss hospitalisation as a primary outcome in outpatient trials and its potential pitfalls, specifically focusing on trials related to anti-SARS-COV-2 therapy.
METHODS
In this narrative review, researchers thoroughly searched MEDLINE and ClinicalTrials.gov from January 2020 to December 2022, targeting Phase III randomized controlled trials involving outpatients with mild-to-moderate COVID-19. The trials were specifically related to anti-SARS-COV-2 monoclonal antibodies or antiviral agents. The study collected essential data, including the type of intervention, comparator, primary objective, primary endpoint, and the use of estimands in the trial.
RESULTS
The search identified 12 trials that evaluated the efficacy of anti-SARS COV-2 therapies in a predefined population. Three studies used hospitalisation and death as primary endpoints in high-risk patients receiving monoclonal antibodies. Nine studies assessed the efficacy of several antiviral agents: four trials used hospitalisation and death as the main endpoints, while others used different measures such as virologic measures using the Reverse Transcription-Polymerase Chain Reaction test (RT-PCR), the eight-point WHO ordinal scale, symptom alleviation by Day 7 and time to clinical response.
CONCLUSION
Choosing hospitalization as an endpoint may provide meaningful data such as the cost-effectiveness ratio of a drug. However, different hospital utilisation patterns and investigator decisions could bias clinical outcomes if no specific criteria are considered. Therefore, investigators should have clear criteria for determining variables that influence this measure.
PubMed: 38803423
DOI: 10.2147/CLEP.S464310 -
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 -
Journal of Cachexia, Sarcopenia and... Jun 2024Regulatory agencies require evidence that endpoints correlate with clinical benefit before they can be used to approve drugs. Biomarkers are often considered surrogate... (Review)
Review
Regulatory agencies require evidence that endpoints correlate with clinical benefit before they can be used to approve drugs. Biomarkers are often considered surrogate endpoints. In cancer cachexia trials, the measurement of biomarkers features frequently. The aim of this systematic review was to assess the frequency and diversity of biomarker endpoints in cancer cachexia trials. A comprehensive electronic literature search of MEDLINE, Embase and Cochrane (1990-2023) was completed. Eligible trials met the following criteria: adults (≥18 years), prospective design, more than 40 participants, use of a cachexia intervention for more than 14 days and use of a biomarker(s) as an endpoint. Biomarkers were defined as any objective measure that was assayed from a body fluid, including scoring systems based on these assays. Routine haematology and biochemistry to monitor intervention toxicity were not considered. Data extraction was performed using Covidence, and reporting followed PRISMA guidance (PROSPERO: CRD42022276710). A total of 5975 studies were assessed, of which 52 trials (total participants = 6522) included biomarkers as endpoints. Most studies (n = 29, 55.7%) included a variety of cancer types. Pharmacological interventions (n = 27, 51.9%) were most evaluated, followed by nutritional interventions (n = 20, 38.4%). Ninety-nine different biomarkers were used across the trials, and of these, 96 were assayed from blood. Albumin (n = 29, 55.8%) was assessed most often, followed by C-reactive protein (n = 22, 42.3%), interleukin-6 (n = 16, 30.8%) and tumour necrosis factor-α (n = 14, 26.9%), the latter being the only biomarker that was used to guide sample size calculations. Biomarkers were explicitly listed as a primary outcome in six trials. In total, 12 biomarkers (12.1% of 99) were used in six trials or more. Insulin-like growth factor binding protein 3 (IGFBP-3) and insulin-like growth factor 1 (IGF-1) levels both increased significantly in all three trials in which they were both used. This corresponded with a primary outcome, lean body mass, and was related to the pharmacological mechanism. Biomarkers were predominately used as exploratory rather than primary endpoints. The most commonly used biomarker, albumin, was limited by its lack of responsiveness to nutritional intervention. For a biomarker to be responsive to change, it must be related to the mechanism of action of the intervention and/or the underlying cachexia process that is modified by the intervention, as seen with IGFBP-3, IGF-1 and anamorelin. To reach regulatory approval as an endpoint, the relationship between the biomarker and clinical benefit must be clarified.
Topics: Cachexia; Humans; Neoplasms; Biomarkers; Clinical Trials as Topic
PubMed: 38783477
DOI: 10.1002/jcsm.13491 -
Bratislavske Lekarske Listy 2020Recent breakthrough recognition of metastasis-free survival as a clinically relevant endpoint has opened a new era in the management of advanced prostate cancer. The... (Review)
Review
INTRODUCTION
Recent breakthrough recognition of metastasis-free survival as a clinically relevant endpoint has opened a new era in the management of advanced prostate cancer. The need for new, intermediate endpoints is the logical consequence of scientific advances in prostate carcinoma. The treatment algorithms for non-metastatic castration-resistant prostate cancer (M0 CRPC) have recently been updated by adding novel anti-androgen apalutamide, and also enzalutamide for high-risk patients.
OBJECTIVE
To review clinical evidence of metastasis-free survival as an efficacy endpoint used in prostate cancer studies, especially those in an advanced stage of the disease and identify its clinical benefit and correlation with overall survival.
METHODS
Literature search up to October 2019 was conducted, including clinical trials and clinical practice guidelines.
EVIDENCE SYNTHESIS
Metastasis-free survival (MFS) was used as the primary endpoint in the registration of clinical trials of second-generation anti-androgens. The study results have demonstrated the beneficial effect of these anti-androgens on delaying the development of metastases or death (MFS), with median MFSextended by 22‒24 months. The correlation tests have shown a positive correlation of MFS and overall survival.
CONCLUSION
The metastasis-free survival can be considered a clinically significant and reliable efficacy endpoint in both localized prostate cancer patients and M0 CRPC patients being at high-risk of disease progression (Ref. 15).
Topics: Androgen Antagonists; Castration; Disease Progression; Endpoint Determination; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant
PubMed: 32484704
DOI: 10.4149/BLL_2020_066 -
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 -
Acta Neurologica Scandinavica May 2021Mechanical thrombectomy (MT) is effective in treating ischemic strokes due to large vessel occlusion. However, the risk-benefit ratio of intravenous thrombolysis (IVT)... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Mechanical thrombectomy (MT) is effective in treating ischemic strokes due to large vessel occlusion. However, the risk-benefit ratio of intravenous thrombolysis (IVT) prior to MT is still unclear. Aim of the study was to provide a pooled analysis of only randomized controlled trials (RCTs) comparing direct MT (dMT) vs bridging treatment (IVT+MT).
METHODS
PubMed, EMBASE and Cochrane Central were searched only for RCTs comparing IVT+MT vs dMT in ischemic stroke patients. Primary endpoint was functional independence at 90 days (mRS<3), while secondary endpoints were represented by successful recanalization (TICI>2a), mortality at 90 days and symptomatic intracranial hemorrhage (sICH). Odds ratios for endpoints were pooled with meta-analysis and compared between reperfusion strategies.
RESULTS
The pooled analysis comprised 5 studies (n. patients = 1657). The rates for the primary endpoint were 39% and 34.5% for dMT and IVT+MT, respectively (OR 1.06; 95%CI 0.80-1.40). For the secondary endpoints, we did not observe significant differences between groups, even if the rate of successful recanalization was higher in IVT+MT treated patients (OR: 0.58; 95%CI 0.26-1.30;p = 0.002), without a significant increase in sICH rates (4.3% vs 5.5%; OR: 0.96; 95%CI 0.43-2.13;p = 0.26). Finally, mortality rates were 19.8% and 15.9% for dMT and IVT+MT, respectively.
CONCLUSIONS
In this meta-analysis including only RCTs, dMT and bridging treatment were substantially equivalent for good functional outcome. IVT+MT was associated to higher rates of successful recanalization, even if not significant. Therefore, further adequately powered RCTs comparing dMT vs IVT+MT are warranted.
Topics: Combined Modality Therapy; Female; Fibrinolytic Agents; Humans; Male; Randomized Controlled Trials as Topic; Stroke; Thrombectomy; Thrombolytic Therapy; Treatment Outcome
PubMed: 33523458
DOI: 10.1111/ane.13390 -
Obstetrics and Gynecology Jun 2022To compare the safety and effectiveness of transvaginal mesh repair and native tissue repair, in response to a U.S. Food and Drug Administration (FDA) 522 study order to...
OBJECTIVE
To compare the safety and effectiveness of transvaginal mesh repair and native tissue repair, in response to a U.S. Food and Drug Administration (FDA) 522 study order to assess co-primary endpoints of superiority and noninferiority.
METHODS
This was a prospective, nonrandomized, parallel cohort, multi-center trial comparing transvaginal mesh with native tissue repair for the treatment of pelvic organ prolapse. The primary endpoints were composite treatment success at 36 months comprised of anatomical success (defined as pelvic organ prolapse quantification [POP-Q] point Ba≤0 and/or C≤0), subjective success (vaginal bulging per the PFDI-20 [Pelvic Floor Distress Inventory]), and retreatment measures, as well as rates of serious device-related or serious procedure-related adverse events. Secondary endpoints included a composite outcome similar to the primary composite outcome but with anatomical success defined as POP-Q point Ba<0 and/or C<0, quality-of-life measures, mesh exposure and mesh- and procedure-related complications. Propensity score stratification was applied.
RESULTS
Primary endpoint composite success at 36 months was 89.3% (201/225) for transvaginal mesh and 80.2% (389/485) for native tissue repair, demonstrating noninferiority at the preset margin of 12% (propensity score-adjusted treatment difference 6.5%, 90% CI -0.2% to 13.2%). Using the primary composite endpoint, transvaginal mesh was not superior to native tissue repair (P=.056). Using the secondary composite endpoint, superiority of transvaginal mesh over native tissue repair was noted (P=.009), with a propensity score-adjusted difference of 10.6% (90% CI 3.3-17.9%) in favor of transvaginal mesh. Subjective success for both the primary and secondary endpoint was 92.4% for transvaginal mesh, 92.8% for native tissue repair, a propensity score-adjusted difference of -4.3% (CI -12.3% to 3.8%). For the primary safety endpoint, 3.1% (7/225) of patients in the transvaginal mesh (TVM) group and 2.7% (13/485) of patients in the native tissue repair (NTR) group developed serious adverse events, demonstrating that transvaginal mesh was noninferior to native tissue repair (-0.4%, 90% CI -2.7% to 1.9%). Overall device-related and/or procedure-related adverse event rates were 35.1% (79/225) in the TVM group and 46.4% (225/485) in the NTR group (-15.7%, 95% CI -24.0% to -7.5%).
CONCLUSION
Transvaginal mesh repair for the treatment of anterior and/or apical vaginal prolapse was not superior to native tissue repair at 36 months. Subjective success, an important consideration from the patient-experience perspective, was high and not statistically different between groups. Transvaginal mesh repair was as safe as native tissue repair with respect to serious device-related and/or serious procedure-related adverse events.
FUNDING SOURCE
This study was sponsored by Boston Scientific and developed in collaboration with FDA personnel from the Office of Surveillance and Biometrics, Division of Epidemiology.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, NCT01917968.
Topics: Female; Humans; Pelvic Floor; Pelvic Organ Prolapse; Prospective Studies; Surgical Mesh; Treatment Outcome; Uterine Prolapse; Vagina
PubMed: 35675593
DOI: 10.1097/AOG.0000000000004794 -
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 -
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 -
Journal of the National Cancer Institute Sep 2021Screening mammography was assessed in 9 randomized trials initiated between 1963 and 1990, with breast cancer-specific mortality as the primary endpoint. In contrast,...
Screening mammography was assessed in 9 randomized trials initiated between 1963 and 1990, with breast cancer-specific mortality as the primary endpoint. In contrast, breast cancer detection has been the primary endpoint in most screening trials initiated during the past decade. These trials have evaluated digital breast tomosynthesis, magnetic resonance imaging, and ultrasound, and novel screening strategies have been recommended solely on the basis of improvements in breast cancer detection rates. Yet, the assumption that increases in tumor detection produce reductions in cancer mortality has not been validated, and tumor-detection endpoints may exacerbate the problem of overdiagnosis. Indeed, the detection of greater numbers of early stage breast cancers in the absence of a subsequent decline in rates of metastatic cancers and cancer-related mortality is the hallmark of overdiagnosis. There is now evidence to suggest that both ductal carcinoma in situ and invasive cancers are overdiagnosed as a consequence of screening. For each patient who is overdiagnosed with breast cancer, the adverse consequences include unnecessary anxiety, financial hardships, and a small risk of morbidity and mortality from unnecessary treatments. Moreover, the overtreatment of breast cancer, as a consequence of overdiagnosis, is costly and contributes to waste in health-care spending. In this article, we argue that there is a need to establish better endpoints in breast cancer screening trials, including quality of life and composite endpoints. Tumor-detection endpoints should be abandoned, because they may lead to the implementation of screening strategies that increase the risk of overdiagnosis.
Topics: Breast Neoplasms; Early Detection of Cancer; Female; Humans; Mammography; Mass Screening; Overdiagnosis; Quality of Life
PubMed: 32898241
DOI: 10.1093/jnci/djaa140