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JAMA May 2024Surrogate markers are increasingly used as primary end points in clinical trials supporting drug approvals.
IMPORTANCE
Surrogate markers are increasingly used as primary end points in clinical trials supporting drug approvals.
OBJECTIVE
To systematically summarize the evidence from meta-analyses, systematic reviews and meta-analyses, and pooled analyses (hereafter, meta-analyses) of clinical trials examining the strength of association between treatment effects measured using surrogate markers and clinical outcomes in nononcologic chronic diseases.
DATA SOURCES
The Food and Drug Administration (FDA) Adult Surrogate Endpoint Table and MEDLINE from inception to March 19, 2023.
STUDY SELECTION
Three reviewers selected meta-analyses of clinical trials; meta-analyses of observational studies were excluded.
DATA EXTRACTION AND SYNTHESIS
Two reviewers extracted correlation coefficients, coefficients of determination, slopes, effect estimates, or results from meta-regression analyses between surrogate markers and clinical outcomes.
MAIN OUTCOMES AND MEASURES
Correlation coefficient or coefficient of determination, when reported, was classified as high strength (r ≥ 0.85 or R2 ≥ 0.72); primary findings were otherwise summarized.
RESULTS
Thirty-seven surrogate markers listed in FDA's table and used as primary end points in clinical trials across 32 unique nononcologic chronic diseases were included. For 22 (59%) surrogate markers (21 chronic diseases), no eligible meta-analysis was identified. For 15 (41%) surrogate markers (14 chronic diseases), at least 1 meta-analysis was identified, 54 in total (median per surrogate marker, 2.5; IQR, 1.3-6.0); among these, median number of trials and patients meta-analyzed was 18.5 (IQR, 12.0-43.0) and 90 056 (IQR, 20 109-170 014), respectively. The 54 meta-analyses reported 109 unique surrogate marker-clinical outcome pairs: 59 (54%) reported at least 1 r or R2, 10 (17%) of which reported at least 1 classified as high strength, whereas 50 (46%) reported slopes, effect estimates, or results of meta-regression analyses only, 26 (52%) of which reported at least 1 statistically significant result.
CONCLUSIONS AND RELEVANCE
Most surrogate markers used as primary end points in clinical trials to support FDA approval of drugs treating nononcologic chronic diseases lacked high-strength evidence of associations with clinical outcomes from published meta-analyses.
Topics: Humans; Biomarkers; Chronic Disease; Clinical Trials as Topic; Meta-Analysis as Topic; Treatment Outcome; United States; Drug Approval
PubMed: 38648042
DOI: 10.1001/jama.2024.4175 -
Frontiers in Artificial Intelligence 2024Machine learning (ML) techniques have gained increasing attention in the field of healthcare, including predicting outcomes in patients with lung cancer. ML has the...
INTRODUCTION
Machine learning (ML) techniques have gained increasing attention in the field of healthcare, including predicting outcomes in patients with lung cancer. ML has the potential to enhance prognostication in lung cancer patients and improve clinical decision-making. In this systematic review and meta-analysis, we aimed to evaluate the performance of ML models compared to logistic regression (LR) models in predicting overall survival in patients with lung cancer.
METHODS
We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. A comprehensive search was conducted in Medline, Embase, and Cochrane databases using a predefined search query. Two independent reviewers screened abstracts and conflicts were resolved by a third reviewer. Inclusion and exclusion criteria were applied to select eligible studies. Risk of bias assessment was performed using predefined criteria. Data extraction was conducted using the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies (CHARMS) checklist. Meta-analytic analysis was performed to compare the discriminative ability of ML and LR models.
RESULTS
The literature search resulted in 3,635 studies, and 12 studies with a total of 211,068 patients were included in the analysis. Six studies reported confidence intervals and were included in the meta-analysis. The performance of ML models varied across studies, with C-statistics ranging from 0.60 to 0.85. The pooled analysis showed that ML models had higher discriminative ability compared to LR models, with a weighted average C-statistic of 0.78 for ML models compared to 0.70 for LR models.
CONCLUSION
Machine learning models show promise in predicting overall survival in patients with lung cancer, with superior discriminative ability compared to logistic regression models. However, further validation and standardization of ML models are needed before their widespread implementation in clinical practice. Future research should focus on addressing the limitations of the current literature, such as potential bias and heterogeneity among studies, to improve the accuracy and generalizability of ML models for predicting outcomes in patients with lung cancer. Further research and development of ML models in this field may lead to improved patient outcomes and personalized treatment strategies.
PubMed: 38646415
DOI: 10.3389/frai.2024.1365777 -
Frontiers in Microbiology 2024Hemorrhagic fever with renal syndrome (HFRS) is an acute infectious disease comprising five stages: fever, hypotension, oliguria, diuresis (polyuria), and convalescence....
INTRODUCTION
Hemorrhagic fever with renal syndrome (HFRS) is an acute infectious disease comprising five stages: fever, hypotension, oliguria, diuresis (polyuria), and convalescence. Increased vascular permeability, coagulopathy, and renal injury are typical clinical features of HFRS, which has a case fatality rate of 1-15%. Despite this, a comprehensive meta-analyses of the clinical characteristics of patients who died from HFRS is lacking.
METHODS
Eleven Chinese- and English-language research databases were searched, including the China National Knowledge Infrastructure Database, Wanfang Database, SinoMed, VIP Database, PubMed, Embase, Scopus, Cochrane Library, Web of Science, Proquest, and Ovid, up to October 5, 2023. The search focused on clinical features of patients who died from HFRS. The extracted data were analyzed using STATA 14.0.
RESULTS
A total of 37 articles on 140,295 patients with laboratory-confirmed HFRS were included. Categorizing patients into those who died and those who survived, it was found that patients who died were older and more likely to smoke, have hypertension, and have diabetes. Significant differences were also observed in the clinical manifestations of multiple organ dysfunction syndrome, shock, occurrence of overlapping disease courses, cerebral edema, cerebral hemorrhage, toxic encephalopathy, convulsions, arrhythmias, heart failure, dyspnea, acute respiratory distress syndrome, pulmonary infection, liver damage, gastrointestinal bleeding, acute kidney injury, and urine protein levels. Compared to patients who survived, those who died were more likely to demonstrate elevated leukocyte count; decreased platelet count; increased lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase levels; prolonged activated partial thromboplastin time and prothrombin time; and low albumin and chloride levels and were more likely to use continuous renal therapy. Interestingly, patients who died received less dialysis and had shorter average length of hospital stay than those who survived.
CONCLUSION
Older patients and those with histories of smoking, hypertension, diabetes, central nervous system damage, heart damage, liver damage, kidney damage, or multiorgan dysfunction were at a high risk of death. The results can be used to assess patients' clinical presentations and assist with prognostication.https://www.crd.york.ac.uk/prospero/, (CRD42023454553).
PubMed: 38638893
DOI: 10.3389/fmicb.2024.1329683 -
JAMA Surgery Apr 2024Unlike medications, procedural interventions are rarely trialed against placebo prior to becoming accepted in clinical practice. When placebo-controlled trials are...
IMPORTANCE
Unlike medications, procedural interventions are rarely trialed against placebo prior to becoming accepted in clinical practice. When placebo-controlled trials are eventually conducted, procedural interventions may be less effective than previously believed.
OBJECTIVE
To investigate the importance of including a placebo arm in trials of surgical and interventional procedures by comparing effect sizes from trials of the same procedure that do and do not include a placebo arm.
DATA SOURCES
Searches of MEDLINE and Embase identified all placebo-controlled trials for procedural interventions in any specialty of medicine and surgery from inception to March 31, 2019. A secondary search identified randomized clinical trials assessing the same intervention, condition, and end point but without a placebo arm for paired comparison.
STUDY SELECTION
Placebo-controlled trials of anatomically site-specific procedures requiring skin incision or endoscopic techniques were eligible for inclusion; these were then matched to trials without placebo control that fell within prespecified limits of heterogeneity.
DATA EXTRACTION AND SYNTHESIS
Random-effects meta-regression, with placebo and blinding as a fixed effect and intervention and end point grouping as random effects, was used to calculate the impact of placebo control for each end point. Data were analyzed from March 2019 to March 2020.
MAIN OUTCOMES AND MEASURES
End points were examined in prespecified subgroups: patient-reported or health care professional-assessed outcomes, quality of life, pain, blood pressure, exercise-related outcomes, recurrent bleeding, and all-cause mortality.
RESULTS
Ninety-seven end points were matched from 72 blinded, placebo-controlled trials (hereafter, blinded) and 55 unblinded trials without placebo control (hereafter, unblinded), including 111 500 individual patient end points. Unblinded trials had larger standardized effect sizes than blinded trials for exercise-related outcomes (standardized mean difference [SMD], 0.59; 95% CI, 0.29 to 0.89; P < .001) and quality-of-life (SMD, 0.32; 95% CI, 0.11 to 0.53; P = .003) and health care professional-assessed end points (SMD, 0.40; 95% CI, 0.18 to 0.61; P < .001). The placebo effect accounted for 88.1%, 55.2%, and 61.3% of the observed unblinded effect size for these end points, respectively. There was no significant difference between unblinded and blinded trials for patient-reported end points (SMD, 0.31; 95% CI, -0.02 to 0.64; P = .07), blood pressure (SMD, 0.26; 95% CI, -0.10 to 0.62; P = .15), all-cause mortality (odds ratio [OR], 0.23; 95% CI, -0.26 to 0.72; P = .36), pain (SMD, 0.03; 95% CI, -0.52 to 0.57; P = .91), or recurrent bleeding events (OR, -0.12; 95% CI, -1.11 to 0.88; P = .88).
CONCLUSIONS AND RELEVANCE
The magnitude of the placebo effect found in this systematic review and meta-regression was dependent on the end point. Placebo control in trials of procedural interventions had the greatest impact on exercise-related, quality-of-life, and health care professional-assessed end points. Randomized clinical trials of procedural interventions may consider placebo control accordingly.
PubMed: 38630462
DOI: 10.1001/jamasurg.2024.0718 -
International Angiology : a Journal of... Apr 2024Inferior vena cava (IVC) filters act in preventing pulmonary embolisms (PE). Various complications have been reported with their use. However, a credible urological...
INTRODUCTION
Inferior vena cava (IVC) filters act in preventing pulmonary embolisms (PE). Various complications have been reported with their use. However, a credible urological complication rate, filter characteristics, and clinical presentation has yet to be summarized. Thus, we reported these complications in the form of a systematic review.
EVIDENCE ACQUISITION
A search strategy was designed using PubMed, MEDLINE, and EMBASE on February 10, 2022. The design of this search strategy did not include any language restrictions. The key words (and wildcard terms) used in the search strategy were urolog*, ureter*, bladder, kidney coupled with filter, inferior vena cava, and cava*. Inclusion criteria were: patients older than 18, with previous IVC filter placement, and urologic complication reported. Exclusion criteria were: patients younger than 18, no IVC filter placement, and no urologic complication reported. Other case series and reviews were excluded to avoid patient duplication.
EVIDENCE SYNTHESIS
Thirty-five articles were selected for full-text screening. Thirty-seven patient cases were reviewed, and the median age was 53 (range: 21-92 years old). Abdominal and or flank pain was reported in 16 (43%) patients, hematuria was seen in eight (22%) and two (5%) patients died due to acute renal failure resulting from the urologic complications of the IVC filter. Indications for IVC filter placement were recurrent pulmonary embolism (PE), contraindication to or noncompliance with anticoagulant therapy. The IVC filters were infrarenal in 29 (78.4%) patients, suprarenal in five (13.5%) patients, not reported in two patients, and misplaced into the right ovarian vein in one patient. Three or more imaging modalities were obtained in 19 patients (51%) for planning. IVC filter removal was not performed in 17 (45.9%) patients, endovascular retrieval occurred in nine (24.3%) patients, and open removal was performed in seven (18.9%) patients, and tissue interposition was performed in two (5.4%) patients. One patient did not have the management reported.
CONCLUSIONS
Urological complications caused by IVC filters although rare, are likely underreported, require extensive workup, and pose surgical challenges. Due to their complex management, filter retrieval should be planned for as soon as feasible, and plans should be made as early as during the IVC filter implant. For those that do develop complications, clinical judgement must be exercised in management, and open surgical, endovascular or even conservative management strategies can be viable options and should be discussed in a multidisciplinary setting.
Topics: Vena Cava Filters; Humans; Aged; Female; Pulmonary Embolism; Middle Aged; Adult; Aged, 80 and over; Male; Hematuria; Young Adult; Device Removal; Risk Factors; Vena Cava, Inferior; Urologic Diseases
PubMed: 38619204
DOI: 10.23736/S0392-9590.24.05041-7 -
Environmental Research Jul 2024Polychlorinated biphenyls (PCBs), extensively used in various products, prompt ongoing concern despite reduced exposure since the 1970s. This systematic review explores... (Review)
Review
BACKGROUND
Polychlorinated biphenyls (PCBs), extensively used in various products, prompt ongoing concern despite reduced exposure since the 1970s. This systematic review explores prenatal PCB and hydroxylated metabolites (OH-PCBs) exposure's association with child neurodevelopment. Encompassing cognitive, motor development, behavior, attention, ADHD, and ASD risks, it also evaluates diverse methodological approaches in studies.
METHODS
PubMed, Embase, PsycINFO, and Web of Science databases were searched through August 23, 2023, by predefined search strings. Peer-reviewed studies published in English were included. The inclusion criteria were: (i) PCBs/OH-PCBs measured directly in maternal and cord blood, placenta or breast milk collected in the perinatal period; (ii) outcomes of cognitive development, motor development, attention, behavior, attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD) among children≤18 years old. Quality assessment followed the National Heart, Lung, and Blood Institute's tool.
RESULTS
Overall, 87 studies were included in this review. We found evidence for the association between perinatal PCB exposure and adverse cognitive development and attention issues in middle childhood. There appeared to be no or negligible link between perinatal PCB exposure and early childhood motor development or the risk of ADHD/ASD. There was an indication of a sex-specific association with worse cognition and attention scores among boys. Some individual studies suggested a possible association between prenatal exposure to OH-PCBs and neurodevelopmental outcomes. There was significant heterogeneity between the studies in exposure markers, exposure assessment timing, outcome assessment, and statistical analysis.
CONCLUSIONS
Significant methodological, clinical and statistical heterogeneity existed in the included studies. Adverse effects on cognitive development and attention were observed in middle childhood. Little or no apparent link on both motor development and risk of ADHD/ASD was observed in early childhood. Inconclusive evidence prevailed regarding other neurodevelopmental aspects due to limited studies. Future research could further explore sex-specific associations and evaluate associations at lower exposure levels post-PCB ban in the US. It should also consider OH-PCB metabolites, co-pollutants, mixtures, and their potential interactions.
Topics: Humans; Polychlorinated Biphenyls; Female; Pregnancy; Environmental Pollutants; Prenatal Exposure Delayed Effects; Child; Child Development; Child, Preschool; Attention Deficit Disorder with Hyperactivity; Neurodevelopmental Disorders; Maternal Exposure; Male; Cognition; Infant
PubMed: 38615789
DOI: 10.1016/j.envres.2024.118912 -
Annals of Cardiac Anaesthesia Apr 2024The potential benefits of epidural anesthesia on mortality, atrial fibrillation, and pulmonary complications must be weighed against the risk of epidural hematoma...
The potential benefits of epidural anesthesia on mortality, atrial fibrillation, and pulmonary complications must be weighed against the risk of epidural hematoma associated with intraoperative heparinization. This study aims to provide an updated assessment of the clinical risks of epidural anesthesia in cardiac surgery, focusing on the occurrence of epidural hematomas and subsequent paralysis. A systematic search of Embase, Medline, Ovid Central, Web of Science, and PubMed was conducted to identify relevant publications between 1966 and 2022. Two independent reviewers assessed the eligibility of the retrieved manuscripts. Studies reporting adult patients undergoing cardiac surgery with epidural catheterization were included. The incidence of hematomas was calculated by dividing the number of hematomas by the total number of patients in the included studies. Risk calculations utilized various denominators based on the rigor of trial designs, and the risks of hematoma and paralysis were compared to other commonly encountered risks. The analysis included a total of 33,089 patients who underwent cardiac surgery with epidural catheterization. No epidural hematomas were reported across all published RCTs, prospective, and retrospective trials. Four case reports associated epidural hematoma with epidural catheterization and perioperative heparinization. The risks of epidural hematoma and subsequent paralysis were estimated at 1:7643 (95% CI 1:3860 to 380,916) and 1:10,190 (95% CI 1:4781 to 0:1), respectively. The risk of hematoma is similar to the non-obstetric population (1:5405; 95% CI 1:4784 to 6134). The risk of hematoma in cardiac surgery patients receiving epidural anesthesia is therefore similar to that observed in some other surgical non-obstetric populations commonly exposed to epidural catheterization.
Topics: Adult; Humans; Prospective Studies; Retrospective Studies; Cardiac Surgical Procedures; Hematoma; Risk Assessment; Paralysis
PubMed: 38607874
DOI: 10.4103/aca.aca_160_23 -
Journal of Evidence-based Medicine Jun 2024The efficacy and prognostic value of circulating tumor cells (CTCs) in nonsmall cell lung cancer (NSCLC) are controversial based on the existing research. This... (Meta-Analysis)
Meta-Analysis
The detection of circulating tumor cells indicates poor therapeutic efficacy and prognosis in patients with nonsmall cell lung cancer: A systematic review and meta-analysis.
OBJECTIVE
The efficacy and prognostic value of circulating tumor cells (CTCs) in nonsmall cell lung cancer (NSCLC) are controversial based on the existing research. This systematic review and meta-analysis evaluated the significance of CTCs in NSCLC therapy monitoring and prognosis prediction, supporting their potential as clinical biomarkers.
METHODS
We conducted a comprehensive search of PubMed, Embase, Web of Science, The Cochrane Library, WanFang Data, CNKI, and VIP through September 20, 2023. Inclusion criteria were cohort studies involving NSCLC patients, focusing on peripheral blood CTCs, and assessing outcomes such as pre- and posttreatment CTC rates or levels, progression-free survival (PFS), and overall survival (OS). Two reviewers independently extracted the data and assessed risk of bias using the Newcastle-Ottawa Scale. We utilized Review Manager 5.4.1 for meta-analysis, calculating pooled odds ratios (ORs) for dichotomous outcomes, mean differences for continuous variables and hazard ratios (HRs) for survival data, applying fixed- or random-effects models based on heterogeneity assessed by the I statistic. This study was registered in PROSPERO (No. CRD42023450035).
RESULTS
Twenty-two eligible studies with a total of 1674 NSCLC patients were included. Meta-analysis results showed that the CTCs-positive rate (OR = 0.59, 95% CI 0.45 to 0.77, p = 0.0001) and CTCs count (mean difference = -3.10, 95% CI -5.52 to -0.69, p = 0.01) were significantly decreased after antitumor treatment. Compared with the CTCs nonreduced group, the CTC-reduced group showed better PFS (HR = 1.71, 95% CI 1.35 to 2.17, p < 0.00001) and OS (HR = 1.50, 95% CI 1.21 to 1.86, p = 0.0003) after treatment. PFS and OS in CTC-positive groups were lower than those in the CTCs-negative group pretreatment (HR = 2.49, 95% CI 1.78 to 3.47, p < 0.00001; HR = 1.80, 95% CI 1.29 to 2.52, p = 0.0006) and posttreatment (HR = 3.36, 95% CI 2.12 to 5.33, p < 0.00001; HR = 3.31, 95% CI 1.75 to 6.27, p = 0.0002).
CONCLUSIONS
CTCs can be used as a biomarker to monitor NSCLC efficacy, predict prognosis and guide follow-up treatment.
Topics: Neoplastic Cells, Circulating; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Prognosis; Biomarkers, Tumor; Treatment Outcome; Progression-Free Survival
PubMed: 38600712
DOI: 10.1111/jebm.12606 -
Allergy, Asthma, and Clinical... Apr 2024Immunoglobulin replacement therapy is a standard treatment for patients with antibody production deficiencies, which is of interest in patients with chronic obstructive...
PURPOSE
Immunoglobulin replacement therapy is a standard treatment for patients with antibody production deficiencies, which is of interest in patients with chronic obstructive pulmonary disease (COPD). This systematic review, registered with PROSPERO (CRD42021281118), assessed the current literature regarding immunoglobulin replacement therapy on COPD clinical outcomes in patients with low immunoglobulin G (IgG) serum concentrations.
METHODS
Literature searches conducted from inception to August 23, 2021, in databases including MEDLINE, EMBASE, and CINAHL. Population (sex, age, comorbidities), baseline clinical characteristics (pulmonary function testing results, IgG levels), and outcome (hospitalizations, emergency department visits) were extracted after title/abstract and full text screening. The Cochrane risk of bias assessment form was used for risk of bias assessment of randomized controlled trials and the National Heart, Lung, and Blood Institute (NHLBI) assessment was used for pre and post studies.
RESULTS
A total of 1381 studies were identified in the preliminary search, and 874 records were screened after duplicates were removed. Screening 77 full texts yielded four studies that were included in the review.
CONCLUSION
It is unclear whether immune globulin replacement therapy reduces acute exacerbation frequency and severity in COPD. Current evidence suggests that it is worth considering, but better developed protocols for administration of immune globulin supplementation is required for future randomized controlled trials.
PubMed: 38600554
DOI: 10.1186/s13223-024-00886-8 -
International Journal of Stroke :... Apr 2024Venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), are frequent complications in patients with intracerebral hemorrhage... (Review)
Review
BACKGROUND
Venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), are frequent complications in patients with intracerebral hemorrhage (ICH). Various prophylactic strategies have been employed to mitigate this risk, such as heparin, intermittent pneumatic compression (IPC), and graduated compression stockings (GCS). The optimal thromboembolic prophylaxis approach remains uncertain due to the lack of randomized controlled trials (RCTs) comparing all interventions.
AIMS
We conducted a network meta-analysis and meta-analysis to systematically review and synthesize evidence from RCTs and non-randomized studies on the efficacy and safety of thromboembolic prophylaxis strategies in hospitalized ICH patients.
SUMMARY OF FINDINGS
Our study followed a registered protocol (PROSPERO CRD42023489217) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines incorporating the extension for network meta-analyses. Search for eligible studies was performed up to December 2023. We considered the occurrence of DVT, PE, hematoma expansion (HE), and all-cause mortality as outcome measures. A total of 16 studies, including 7 RCTs and 9 non-randomized studies, were included in the analysis. Network meta-analysis revealed that IPC demonstrated the highest efficacy in reducing DVT incidence (odds ratios (OR) 0.30, 95% confidence interval (CI) 0.08-1.16), particularly considering only RCTs (OR 0.33, 95% CI 0.16-0.67). GCS showed the highest safety profile for HE (OR 0.67, 95% CI 0.14-3.13), but without efficacy. Chemoprophylaxis did not reduce the risk of PE events (OR 1.10, 95% CI 0.17-7.19) with a higher occurrence of HE (OR 1.33, 95% CI 0.60-2.96), but the differences were not significant.
CONCLUSION
Our study supports the use of IPC as the primary thromboembolic prophylaxis measure in ICH patients. Further research, including head-to-head RCTs, is needed to strengthen the evidence base and optimize clinical decision-making for thromboembolic prophylaxis in this vulnerable patient population.
PubMed: 38591740
DOI: 10.1177/17474930241248542