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The prognostic role of anticoagulants in COVID-19 patients: national COVID-19 cohort in South Korea.Annals of Palliative Medicine Apr 2022There currently exists a paucity of data on whether pre-admission anticoagulants use may have benefits among COVID-19 patients by preventing COVID-19 associated...
BACKGROUND
There currently exists a paucity of data on whether pre-admission anticoagulants use may have benefits among COVID-19 patients by preventing COVID-19 associated thromboembolism. The aim of this study was to assess the association between pre-admission anticoagulants use and COVID-19 adverse outcomes.
METHODS
We conducted a population-based cohort studying using the Health Insurance Review and Assessment Service (HIRA) claims data released by the South Korean government. Our study population consisted of South Koreans who were aged 40 years or older and hospitalized with COVID-19 between 1 January 2020 through 15 May 2020. We defined anticoagulants users as individuals with inpatient and outpatient prescription records in 120 days before cohort entry. Our primary endpoint was a composite of all-cause death, intensive care unit (ICU) admission, and mechanical ventilation use. Individual components of the primary endpoint were secondary endpoints. We compared the risk of endpoints between the anticoagulants users and non-users by logistic regression models, with the standardized mortality ratio weighting (SMRW) adjustment.
RESULTS
In our cohort of 4,349 patients, for the primary endpoint of mortality, mechanical ventilation and ICU admission, no difference was noted between anticoagulants users and non-users (SMRW OR 1.11, 95% CI: 0.60-2.05). No differences were noted, among individual components. No effect modification was observed by age, sex, history of atrial fibrillation and thromboembolism, and history of cardiovascular disease. When applying the inverse probability of treatment weighting (IPTW) and SMRW with doubly robust methods in sensitivity analysis, anticoagulants use was associated with increased odds of the primary endpoint.
CONCLUSIONS
Pre-admission anticoagulants were not determined to have a protective role against severe COVID-19 outcomes.
Topics: Anticoagulants; COVID-19; Humans; Prognosis; SARS-CoV-2; Thromboembolism
PubMed: 35400157
DOI: 10.21037/apm-21-3466 -
Journal of Cardiovascular Development... Sep 2022It remains unclear whether the acute-phase ambulation program (AAP) improves the prognosis of heart failure (HF) patients. We examined the association between the...
It remains unclear whether the acute-phase ambulation program (AAP) improves the prognosis of heart failure (HF) patients. We examined the association between the initiation of AAP and the prognosis of patients with worsening HF. We enrolled 560 consecutive patients admitted due to worsening HF from March 2019 to April 2021. Our hospital introduced AAP in May 2020, but we did not perform AAP until April 2020. We retrospectively compared cardiac events within 180 days after discharge between patients admitted before April 2020 (conventional group) and after May 2020 (AAP group). Primary endpoints were all-cause mortality and readmission for worsening HF. The Kaplan-Meier survival curves showed a significantly lower event rate in the AAP group in HF readmission or the primary endpoint ( = 0.020 and = 0.014). The occurrence of the primary endpoint was associated with age, history of HF, systolic blood pressure, medications including renin-angiotensin system inhibitors or angiotensin receptor blocker, hemoglobin, NT-proBNP, and AAP participation. After adjusting for these parameters and sex, participation in AAP was an independent factor associated with a reduced risk of primary endpoint occurrence (hazard ratio of 0.62 (0.41-0.95), = 0.028). The AAP for patients with acute HF might lead to improved short-term prognosis and should be considered for implementation.
PubMed: 36286266
DOI: 10.3390/jcdd9100314 -
Journal of Clinical Medicine Apr 2023Salvage re-irradiation (rRT) for patients with locoregionally recurrent head and neck cancer (rHNC) remains challenging. A retrospective analysis was performed on 49...
Salvage re-irradiation (rRT) for patients with locoregionally recurrent head and neck cancer (rHNC) remains challenging. A retrospective analysis was performed on 49 patients who received rRT between 2011 and 2018. The co-primary endpoint of the study was 2-year freedom from cancer recurrence rate (FCRR) and overall survival (OS), and secondary endpoints were 2-year disease-free survival (DFS), local failure (LF), regional failure (RF), distant metastases (DM), and RTOG grade 3 ≥ late toxicities. Adjuvant and definitive rRT were delivered to 22 and 27 patients, respectively. A total of 91% of patients were managed with conventional re-RT and 71% of patients received concurrent chemotherapy. The median follow-up after rRT was 30 months. The 2-year FCRR, OS, DFS, LF, RF, and DM were 64%, 51%, 28%, 32%, 9%, and 39% respectively. MVA showed that poor performance status (PS: 1-2 vs. 0) and age > 52 years were predictive of worse OS. In comparison, poor PS (1-2 vs. 0) and total dose of rRT < 60 Gy were predictive of worse DFS. Late RTOG toxicity of grade 3 ≥ was reported in nine (18.3%) patients. FCRR at 2 years after salvage rRT for rHNC was higher than other traditional endpoints and could be an important endpoint to be included in future rRT studies. rRT for rHNC at our cohort was relatively successful, with a manageable level of late severe toxicity. Replacing this approach in other developing countries is a viable option.
PubMed: 37109315
DOI: 10.3390/jcm12082979 -
Journal of Cachexia, Sarcopenia and... Jun 2024The use of patient-reported outcomes (PROMs) of quality of life (QOL) is common in cachexia trials. Patients' self-report on health, functioning, wellbeing, and... (Review)
Review
The use of patient-reported outcomes (PROMs) of quality of life (QOL) is common in cachexia trials. Patients' self-report on health, functioning, wellbeing, and perceptions of care, represent important measures of efficacy. This review describes the frequency, variety, and reporting of QOL endpoints used in cancer cachexia clinical trials. Electronic literature searches were performed in Medline, Embase, and Cochrane (1990-2023). Seven thousand four hundred thirty-five papers were retained for evaluation. Eligibility criteria included QOL as a study endpoint using validated measures, controlled design, adults (>18 years), ≥40 participants randomized, and intervention exceeding 2 weeks. The Covidence software was used for review procedures and data extractions. Four independent authors screened all records for consensus. Papers were screened by titles and abstracts, prior to full-text reading. PRISMA guidance for systematic reviews was followed. The protocol was prospectively registered via PROSPERO (CRD42022276710). Fifty papers focused on QOL. Twenty-four (48%) were double-blind randomized controlled trials. Sample sizes varied considerably (n = 42 to 469). Thirty-nine trials (78%) included multiple cancer types. Twenty-seven trials (54%) featured multimodal interventions with various drugs and dietary supplements, 11 (22%) used nutritional interventions alone and 12 (24%) used a single pharmacological intervention only. The median duration of the interventions was 12 weeks (4-96). The most frequent QOL measure was the EORTC QLQ-C30 (60%), followed by different FACIT questionnaires (34%). QOL was a primary, secondary, or exploratory endpoint in 15, 31 and 4 trials respectively, being the single primary in six. Statistically significant results on one or more QOL items favouring the intervention group were found in 18 trials. Eleven of these used a complete multidimensional measure. Adjustments for multiple testing when using multicomponent QOL measures were not reported. Nine trials (18%) defined a statistically or clinically significant difference for QOL, five with QOL as a primary outcome, and four with QOL as a secondary outcome. Correlation statistics with other study outcomes were rarely performed. PROMs including QOL are important endpoints in cachexia trials. We recommend using well-validated QOL measures, including cachexia-specific items such as weight history, appetite loss, and nutritional intake. Appropriate statistical methods with definitions of clinical significance, adjustment for multiple testing and few co-primary endpoints are encouraged, as is an understanding of how interventions may relate to changes in QOL endpoints. A strategic and scientific-based approach to PROM research in cachexia trials is warranted, to improve the research base in this field and avoid the use of QOL as supplementary measures.
Topics: Humans; Cachexia; Quality of Life; Neoplasms; Clinical Trials as Topic; Patient Reported Outcome Measures
PubMed: 38553255
DOI: 10.1002/jcsm.13453 -
Journal of Atherosclerosis and... Mar 2023To examine the efficacy and safety of prasugrel vs clopidogrel in thrombotic stroke patients at risk of ischemic stroke. (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and Safety of Prasugrel vs Clopidogrel in Thrombotic Stroke Patients With Risk Factors for Ischemic Stroke Recurrence: A Double-blind, Phase III Study (PRASTRO-III).
AIM
To examine the efficacy and safety of prasugrel vs clopidogrel in thrombotic stroke patients at risk of ischemic stroke.
METHODS
This multicenter, active-controlled, randomized, double-blind, double-dummy, parallel group study enrolled thrombotic stroke patients aged ≥ 50 years at risk of ischemic stroke. Patients received prasugrel (3.75 mg/day) or clopidogrel (75 or 50 mg/day) for 24-48 weeks; other antiplatelet drugs were prohibited. The primary efficacy endpoint was the composite incidence of ischemic stroke, myocardial infarction (MI), and death from other vascular causes from the start to 1 day after treatment completion or discontinuation. Secondary efficacy endpoints included the incidences of ischemic stroke, MI, death from other vascular causes, ischemic stroke and transient ischemic attack, and stroke. Safety endpoints included bleeding events and adverse events (AEs).
RESULTS
In the prasugrel (N=118) and clopidogrel (N=112; all received 75 mg) groups, the primary efficacy endpoint composite incidence (95% confidence interval) was 6.8% (3.0%-12.9%) and 7.1% (3.1%-13.6%), respectively. The risk ratio (prasugrel/clopidogrel) was 0.949 (0.369-2.443). Secondary efficacy endpoints followed a similar trend. The combined incidences of life-threatening, major, and clinically relevant bleeding were 5.0% and 3.5% in the prasugrel and clopidogrel groups, respectively. The incidences of all bleeding events and AEs were 19.2% and 24.6% and 76.7% and 82.5% in the prasugrel and clopidogrel groups, respectively. No serious AEs were causally related to prasugrel.
CONCLUSIONS
We observed a risk reduction of 5% with prasugrel vs clopidogrel, indicating comparable efficacy. There were no major safety issues for prasugrel.
Topics: Humans; Prasugrel Hydrochloride; Clopidogrel; Ischemic Stroke; Platelet Aggregation Inhibitors; Stroke; Myocardial Infarction; Hemorrhage; Risk Factors; Thrombotic Stroke; Treatment Outcome; Acute Coronary Syndrome
PubMed: 35599000
DOI: 10.5551/jat.63473 -
Lung Cancer (Amsterdam, Netherlands) Mar 2023While the discovery of oncogenic driver mutations has personalized the metastatic non-small cell lung cancer (NSCLC) treatment landscape with effective targeted... (Review)
Review
Primary endpoints to assess the efficacy of novel therapeutic approaches in epidermal growth factor receptor-mutated, surgically resectable non-small cell lung cancer: A review.
While the discovery of oncogenic driver mutations has personalized the metastatic non-small cell lung cancer (NSCLC) treatment landscape with effective targeted therapies, implementation of new treatments in resectable NSCLC has been limited due to the long follow-up needed for overall survival (OS). Until recently, treatment for patients with early-stage resectable NSCLC has been limited to perioperative chemotherapy, which provides modest benefits. However, the regulatory acceptance of two surrogate endpoints for OS has allowed recent approval of both adjuvant osimertinib and atezolizumab, providing patients with new treatment options to improve outcomes. In phase 3 oncology trials, OS has historically been viewed as the gold-standard efficacy measure, but disease-free survival and event-free survival (EFS) are now validated surrogate endpoints for OS in clinical trials and should be considered when mature OS data is unavailable. Another potential surrogate endpoint in the adjuvant NSCLC setting is circulating tumor DNA (ctDNA)-based minimal residual disease (MRD), although prospective validation is needed. For neoadjuvant targeted therapies, EFS, major pathologic response and ctDNA-based MRD are potential surrogate endpoints. To fully translate the success of the personalized treatment advances in the metastatic setting to earlier-stage disease, prospective validation studies of these potential surrogate endpoints that can accelerate the evaluation of drug efficacy are needed. A collaborative effort is also needed from all clinical and regulatory parties to collate surrogate endpoint data for large-scale validation. In this review we discuss the trends in surrogate endpoints used in oncology trials, with a focus on considerations for selecting appropriate primary endpoints in early-stage resectable EGFR-mutant NSCLC, an area of unmet need for novel treatment options.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Disease-Free Survival; Small Cell Lung Carcinoma; Biomarkers; ErbB Receptors
PubMed: 36736076
DOI: 10.1016/j.lungcan.2023.01.002 -
Journal of Thoracic Disease Nov 2023Pulmonary resection can present technical challenges for surgeons due to the dissection and closure of tissues, which vary in thickness and elastic properties,...
BACKGROUND
Pulmonary resection can present technical challenges for surgeons due to the dissection and closure of tissues, which vary in thickness and elastic properties, occasionally leading to prolonged air leaks. Staple line reinforcements (SLRs) are widely utilized tools for fortifying the stability and integrity of closures in thoracic surgery, however, materials available and ease of use for both surgeon and scrub nurse have been suboptimal. A novel "click-and-go" device pre-loaded with bioabsorbable buttress material was recently developed, the Echelon Endopath SLR (ESLR, Ethicon, Inc., Cincinnati, OH, USA). This prospective study examines the safety and efficacy of this novel device in lung resections.
METHODS
Adult surgical candidates undergoing primary pulmonary resection (both open and thoracoscopic) where the ESLR would be used were enrolled. Exclusion included reoperation/revision in same anatomical location, hypersensitivity to polyglactin or related products, and body mass index (BMI) ≥46.0 kg/m. The primary endpoint assessed the incidence of specific device-related adverse events (AEs): prolonged air leak and empyema. Additional endpoints included number of devices replaced during surgery due to slippage or bunching, and surgeon-reported usability responses. Data was summarized for AEs deemed device-related and usability questionnaire responses.
RESULTS
A total of 131 subjects were included in the primary endpoint analysis data set with 120 subjects completing the study (91.6%). The mean age at consent was 62.8±12.0 years and 55.7% were female. The most common primary indication for the procedure was malignancy 61.1%, and primary non-malignant lung disease (non-chronic obstructive pulmonary disease) 12.2%. Common procedures performed were wedge resection (58.0%) and lobectomy (34.4%). There were zero reported device-specific/-related AEs which counted toward the primary endpoint. Responses from a usability questionnaire found all surgeons (100.0%) reported the ease of setup was superior to previous devices utilized. Surgeons expressed greater confidence in the buttress material of the ESLR than that of previous SLR devices (strongly agree 88.9%; slightly agree 11.1%). Most also felt that there was less wastage with the click-and-go ESLR (strongly agree 77.8%, slightly agree 11.1%, neutral 11.1%).
CONCLUSIONS
The ESLR device demonstrates safe and effective performance in this post-market study of specific thoracic procedures. Furthermore, surgeons found this was easier to use.
PubMed: 38090287
DOI: 10.21037/jtd-23-1019 -
World Journal of Hepatology Sep 2023Surrogate endpoints are needed to estimate clinical outcomes in primary sclerosing cholangitis (PSC). Serum alkaline phosphatase was among the first markers studied, but... (Review)
Review
Surrogate endpoints are needed to estimate clinical outcomes in primary sclerosing cholangitis (PSC). Serum alkaline phosphatase was among the first markers studied, but there is substantial variability in alkaline phosphatase levels during the natural history of PSC without intervention. The Mayo risk score incorporates noninvasive variables and has served as a surrogate endpoint for survival for more than two decades. Newer models have better test performance than the Mayo risk score, including the primary sclerosing risk estimate tool (PREsTo) model and UK-PSC score that estimate hepatic decompensation and transplant free survival, respectively. The c-statistics for transplant-free survival for the Mayo risk model and the long-term UK-PSC model are 0.68 and 0.85, respectively. The c-statistics for hepatic decompensation for the Mayo risk model and PREsTo model are 0.85 and 0.90, respectively. The Amsterdam-Oxford model included patients with large duct and small duct PSC and patients with PSC-autoimmune hepatitis overlap and had a c-statistic of 0.68 for transplant-free survival. Other noninvasive tests that warrant further validation include magnetic resonance imaging, elastography and the enhanced liver fibrosis score. Prognostic models, noninvasive tests or a combination of these surrogate endpoints may not only serve to be useful in clinical trials of investigational agents, but also serve to inform our patients about their prognosis.
PubMed: 37900215
DOI: 10.4254/wjh.v15.i9.1013 -
Statistics in Medicine Jun 2022Mixed outcome endpoints that combine multiple continuous and discrete components are often employed as primary outcome measures in clinical trials. These may be in the...
Mixed outcome endpoints that combine multiple continuous and discrete components are often employed as primary outcome measures in clinical trials. These may be in the form of co-primary endpoints, which conclude effectiveness overall if an effect occurs in all of the components, or multiple primary endpoints, which require an effect in at least one of the components. Alternatively, they may be combined to form composite endpoints, which reduce the outcomes to a one-dimensional endpoint. There are many advantages to joint modeling the individual outcomes, however in order to do this in practice we require techniques for sample size estimation. In this article we show how the latent variable model can be used to estimate the joint endpoints and propose hypotheses, power calculations and sample size estimation methods for each. We illustrate the techniques using a numerical example based on a four-dimensional endpoint and find that the sample size required for the co-primary endpoint is larger than that required for the individual endpoint with the smallest effect size. Conversely, the sample size required in the multiple primary case is similar to that needed for the outcome with the largest effect size. We show that the empirical power is achieved for each endpoint and that the FWER can be sufficiently controlled using a Bonferroni correction if the correlations between endpoints are less than 0.5. Otherwise, less conservative adjustments may be needed. We further illustrate empirically the efficiency gains that may be achieved in the composite endpoint setting.
Topics: Endpoint Determination; Humans; Models, Statistical; Neoplasms, Multiple Primary; Sample Size
PubMed: 35199380
DOI: 10.1002/sim.9356 -
Journal of Pain Research 2023The monoclonal antibody fremanezumab has been shown effective and well tolerated in numerous Phase 2 and Phase 3 trials. This subgroup analysis of the international HALO...
PURPOSE
The monoclonal antibody fremanezumab has been shown effective and well tolerated in numerous Phase 2 and Phase 3 trials. This subgroup analysis of the international HALO episodic migraine (EM; [NCT02629861]) trial and a similarly designed phase 2b/3 trial in Japanese and Korean patients (NCT03303092) sought to evaluate the efficacy and safety of fremanezumab in Japanese patients with EM.
PATIENTS AND METHODS
In both trials, eligible patients were randomly assigned at baseline to receive subcutaneous monthly fremanezumab, quarterly fremanezumab, or placebo in a 1:1:1 ratio. The primary endpoint was the mean change from baseline in the monthly (28-day) average number of migraine days during the 12-week period after the first dose of fremanezumab or placebo. Secondary endpoints assessed other aspects of efficacy, including disability and medication use.
RESULTS
A total of 301 patients in the Japanese and Korean phase 2b/3 trial and 75 patients in the HALO EM trial were Japanese with baseline and treatment characteristics similar between treatment groups. According to ANCOVA analysis of the primary endpoint, both fremanezumab quarterly and monthly led to greater reductions in the monthly (28-day) average number of migraine days than placebo. This was supported by MMRM analysis of the primary endpoint over the initial 4 weeks, highlighting the rapid onset of action of fremanezumab. Results of secondary endpoint analysis supported the primary endpoint analyses. Fremanezumab was well tolerated with no new safety signals seen in this population of Japanese patients.
CONCLUSION
Fremanezumab appears to be an effective and well-tolerated preventive medication for Japanese patients with EM.
PubMed: 37223438
DOI: 10.2147/JPR.S393896